Impact of high glucose and AGEs on cultured kidney-derived cells. Effects on cell viability, lysosomal enzymes and effectors of cell signaling pathways

Publication date: Available online 14 February 2017
Source:Biochimie
Author(s): Giovani B. Peres, Nestor Schor, Yara M. Michelacci
We have previously reported decreased expression and activities of lysosomal cathepsins B and L in diabetic kidney. Relevant morphological changes were observed in proximal tubules, suggesting that these cells are implicated in the early stages of the disease. The aim of the present study was to investigate the mechanisms that lead to these changes. The effects of high glucose (HG) and advanced glycation end products (AGEs) on cell viability, lysosomal enzymes and other effectors of cell signaling of cultured kidney cells were studied. HG increased viable mesangial cells (ihMC) in 48 h, while epithelial tubular cells were not affected (LLC-PK1 and MDCK). In contrast, the number of viable cells was markedly decreased, for all cell lines, by AGE-BSA. Concerning lysosomal enzymes, the main cysteine-protease expressed by these cells was cathepsin B, and its concentration was much higher in epithelial than in mesangial cells. Exposure to HG had no effect on the cathepsin B activity, but AGE-BSA caused a marked decrease in LLC-PK1, and increased the enzyme activities in the other cell lines. The levels of nitric oxide (NO) was increased by AGE-BSA in all cell lines, suggesting oxidative stress, and Western blotting has shown that, among the investigated proteins, cathepsin B, mTOR and transcription factor EB (TFEB) were the most significantly affected by exposure to AGE-BSA. As mTOR induces anabolism and inhibits autophagy, and TFEB is a master transcription factor for lysosomal enzymes, it is possible that this pathway plays a role in the inhibition of lysosomal enzymes in proximal tubule cells.

Graphical abstract

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Lipomatous/Extensively Vacuolated Ependymoma with Signet-Ring Cell-Like Appearance: Analysis of a Case with Extensive Literature Review

“Lipomatous” and “extensively vacuolated” are descriptive captions that have been used to portray a curious subset of ependymomas distinctively bearing cells with a large vacuole pushing the nucleus to the periphery and, thus, simulating a signet-ring cell appearance. Here, we would like to report the first ependymoma of this kind in a Latin American institution. A 16-year-old boy experienced cephalea during three months. Magnetic resonance imaging scans showed a left paraventricular tumour which corresponded to anaplastic ependymoma. Intriguingly, it was also composed of cells with single or multiple hollow cytoplasmic vacuoles sometimes giving a signet-ring cell-like configuration. Immunolabeling of these showed membrane positivity for GFAP, PS100, and CD99, while Ki-67 expression was null. Ultrastructural examination of retrieved paraffin-embedded tissue showed the presence of scarce microlumina filled with microvilli but failed to demonstrate any content in such optically empty vacuoles as only scant granulofibrillary debris was observed. A schism prevails at present regarding these unusual morphological variants, being either “lipomatous” or “vacuolated” based mainly on the EMA immunoprofile. This, however, is a misappropriate approaching. Could it be that perhaps we are dealing with the same histopathological entity or it may simply happen that fixation and artefacts cannot allow for their proper identification?

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The Efficacy of Acupuncture for Treating Depression-Related Insomnia Compared with a Control Group: A Systematic Review and Meta-Analysis

Objective. To evaluate the effectiveness of acupuncture as monotherapy and as an alternative therapy in treating depression-related insomnia. Data Source. Seven databases were searched starting from 1946 to March 30, 2016. Study Eligibility Criteria. Randomized-controlled trials of adult subjects (18–75 y) who had depression-related insomnia and had received acupuncture. Results. 18 randomized-controlled clinical trials (RCTs) were introduced in this meta-analysis. The findings determined that the acupuncture treatment made significant improvements in PSQI score (MD = −2.37, 95% CI −3.52 to −1.21) compared with Western medicine. Acupuncture combined with Western medicine had a better effect on improving sleep quality (MD = −2.63, 95% CI −4.40 to −0.86) compared with the treatment of Western medicine alone. There was no statistical difference (MD = −2.76, 95% CI −7.65 to 2.12) between acupuncture treatment and Western medicine towards improving the HAMD score. Acupuncture combined with Western medicine (MD = −5.46, CI −8.55 to −2.38) had more effect on improving depression degree compared with the Western medicine alone. Conclusion. This systematic review indicates that acupuncture could be an alternative therapy to medication for treating depression-related insomnia.

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Mechanical Stress Regulates Osteogenesis and Adipogenesis of Rat Mesenchymal Stem Cells through PI3K/Akt/GSK-3β/β-Catenin Signaling Pathway

Osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs) are regarded as being of great importance in the regulation of bone remodeling. In this study, rat BMSCs were exposed to different levels of cyclic mechanical stress generated by liquid drops and cultured in general medium or adipogenic medium. Markers of osteogenic (Runx2 and Collagen I) and adipogenic (C/EBPα, PPARγ, and lipid droplets) differentiation were detected using Western blot and histological staining. The protein levels of members of the phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase 3β (GSK-3β)/β-catenin signaling pathway were also examined. Results showed that small-magnitude stress significantly upregulated Runx2 and Collagen I and downregulated PPARγ and C/EBPα expression in BMSCs cultured in adipogenic medium, while large-magnitude stress reversed the effect when compared with unloading groups. The PI3K/Akt signaling pathway could be strongly activated by mechanical stimulation; however, large-magnitude stress led to decreased activation of the signaling pathway when compared with small-magnitude stress. Activation of β-catenin with LiCl led to increased expression of Runx2 and Collagen I and reduction of C/EBPα and PPARγ expression in BMSCs. Inhibition of PI3K/Akt signaling partially blocked the expression of β-catenin. Taken together, our results indicate that mechanical stress-regulated osteogenesis and adipogenesis of rat BMSCs are mediated, at least in part, by the PI3K/Akt/GSK-3β/β-catenin signaling pathway.

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The Strategy to Prevent and Regress the Vascular Calcification in Dialysis Patients

The high prevalence of arterial calcification in end-stage renal disease (ESRD) is far beyond the explanation by common cardiovascular risk factors such as aging, diabetes, hypertension, and dyslipidemia. The finding relies on the fact that vascular and valvular calcifications are predictors of cardiovascular diseases and mortality in persons with chronic renal failure. In addition to traditional cardiovascular risk factors such as diabetes mellitus and blood pressure control, other ESRD-related risks such as phosphate retention, excess calcium, and prolonged dialysis time also contribute to the development of vascular calcification. The strategies are to reverse “calcium paradox” and lower vascular calcification by decreasing procalcific factors including minimization of inflammation (through adequate dialysis and by avoiding malnutrition, intravenous labile iron, and positive calcium and phosphate balance), correction of high and low bone turnover, and restoration of anticalcification factor balance such as correction of vitamin D and K deficiency; parathyroid intervention is reserved for severe hyperparathyroidism. The role of bone antiresorption therapy such as bisphosphonates and denosumab in vascular calcification in high-bone-turnover disease remains unclear. The limited data on sodium thiosulfate are promising. However, if calcification is to be targeted, ensure that bone health is not compromised by the treatments.

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X-Linked Retinoschisis in Juveniles: Follow-Up by Optical Coherence Tomography

Purpose. To explore the structural progression of X-linked retinoschisis (XLRS) in patients by using spectral-domain optical coherence tomography (SD-OCT). Design. Retrospective, observational study. Methods. Patients who were diagnosed with XLRS by genetic testing underwent comprehensive ophthalmological examinations from December 2014 to October 2016. Each eye was measured by SD-OCT using the same clinical protocol. A correlation between best-corrected visual acuity (VA) and SD-OCT measurements was observed. Results. Six patients demonstrated retinoschisis (12 eyes) and typical foveal cyst-like cavities (10 eyes) on SD-OCT images with a mean logMAR VA of 0.48. The median age was 7.5 years at the initial visit. Their foveal retinal thickness (516.9 μm) and choroid thickness (351.4 μm) decreased at a rate of 38.1 and 7.5 μm, respectively, at the 10.5-month follow-up visit; however, there were no significant differences ( and , resp.). There was no significant correlation between VA, the foveal retinal thickness, and subfoveal choroid thickness. Conclusions. SD-OCT images for XLRS patients during the juvenile period revealed no significant changes in the fundus structure, including the foveal retinal thickness and choroid thickness within one-year follow-up. There was a lack of correlation between VA, foveal retinal thickness, and subfoveal choroid thickness.

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Prokaryotic Expression of α-13 Giardin Gene and Its Intracellular Localization in Giardia lamblia

To study prokaryotic expression and subcellular localization of α-13 giardin in Giardia lamblia trophozoites, α-13 giardin gene was amplified and cloned into prokaryotic expression vector pET-28a(+). The positive recombinant plasmid was transformed into E. coli BL21(DE3) for expression by using IPTG and autoinduction expression system (ZYM-5052). The target protein was validated by SDS-PAGE and Western blotting and purified by Ni-NTA Resin. Rabbits were immunized with purified fusion proteins for preparation of polyclonal antibody; then the intracellular location of α-13 giardin was determined by fluorescence immunoassay. The results showed that the length of α-13 giardin gene was 1038 bp, encoding a polypeptide of 345 amino acids. The expressed product was a fusion protein with about 40 kDa largely present in soluble form. The target protein accounted for 21.0% of total proteins after being induced with IPTG, while it accounted for 28.8% with ZYM-5052. The anti-α13-giardin polyclonal antibody possessed good antigenic specificity as well as excellent binding activity with recombinant α-13 giardin. Immunofluorescence assays revealed that α-13 giardin was localized in the cytoplasm of G. lamblia trophozoite, suggesting that it is a cytoplasm-associated protein. The present study may lay a foundation for further functional research on α-13 giardin of G. lamblia.

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The Effect of Different Attentional Focus Instructions during Finger Movement Tasks in Healthy Subjects: An Exploratory Study

External focus of attention (EFA) and internal focus of attention (IFA) represent commonly used strategies to instruct subjects during exercise. Several studies showed EFA to be more effective than IFA to improve motor performance and learning. To date the role of these strategies on motor performance during finger movement was less studied. The objective of the study was to investigate motor performance, patient’s preference induced by IFA and EFA, and the focus during control condition. Ten healthy right-handed participants performed a finger movement task in control, EFA, and IFA conditions (counterbalanced). Errors, patient’s preference, and type of attentional focus spontaneously adopted during the control condition were recorded. EFA determined less error () compared to control and IFA. Participants preferred EFA against IFA and control condition. In the control group 10% of subjects adopted a purely EFA, 70% of subjects adopted a purely IFA, and 20% of subjects adopted a mixture of the two foci. Our results confirm that EFA is more effective than IFA and control in finger movement task. Due its clinical relevance, the interaction between attention and finger movement should be further investigated.

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Developing an App by Exploiting Web-Based Mobile Technology to Inspect Controlled Substances in Patient Care Units

We selected iOS in this study as the App operation system, Objective-C as the programming language, and Oracle as the database to develop an App to inspect controlled substances in patient care units. Using a web-enabled smartphone, pharmacist inspection can be performed on site and the inspection result can be directly recorded into HIS through the Internet, so human error of data translation can be minimized and the work efficiency and data processing can be improved. This system not only is fast and convenient compared to the conventional paperwork, but also provides data security and accuracy. In addition, there are several features to increase inspecting quality: (1) accuracy of drug appearance, (2) foolproof mechanism to avoid input errors or miss, (3) automatic data conversion without human judgments, (4) online alarm of expiry date, and (5) instant inspection result to show not meted items. This study has successfully turned paper-based medication inspection into inspection using a web-based mobile device.

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Comparison and Validation of Putative Pathogenicity-Related Genes Identified by T-DNA Insertional Mutagenesis and Microarray Expression Profiling in Magnaporthe oryzae

High-throughput technologies of functional genomics such as T-DNA insertional mutagenesis and microarray expression profiling have been employed to identify genes related to pathogenicity in Magnaporthe oryzae. However, validation of the functions of individual genes identified by these high-throughput approaches is laborious. In this study, we compared two published lists of genes putatively related to pathogenicity in M. oryzae identified by T-DNA insertional mutagenesis (comprising 1024 genes) and microarray expression profiling (comprising 236 genes), respectively, and then validated the functions of some overlapped genes between the two lists by knocking them out using the method of target gene replacement. Surprisingly, only 13 genes were overlapped between the two lists, and none of the four genes selected from the overlapped genes exhibited visible phenotypic changes on vegetative growth, asexual reproduction, and infection ability in their knockout mutants. Our results suggest that both of the lists might contain large proportions of unrelated genes to pathogenicity and therefore comparing the two gene lists is hardly helpful for the identification of genes that are more likely to be involved in pathogenicity as we initially expected.

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Nicotine

Nicotine: An alkaloid (a nitrogen-containing chemical) made by the tobacco plant or produced synthetically. Nicotine has powerful pharmacologic effects (including increased heart rate, heart stroke volume, and oxygen consumption by the heart muscle), as well as powerful psychodynamic effects (such as euphoria, increased alertness, and a sense of relaxation). Nicotine is also powerfully addictive.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Edoxaban in Atrial Fibrillation and Venous Thromboembolism—Ten Key Questions and Answers: A Practical Guide

Abstract

Edoxaban is the fourth non-vitamin K antagonist oral anticoagulant now available for clinical use in the prevention of stroke/systemic embolism in atrial fibrillation (AF) and in the treatment of venous thromboembolism (VTE), after the completion of large-scale randomized comparative clinical trials with the vitamin K antagonist warfarin. Edoxaban has some peculiar pharmacological properties and outcome data. Here a group of experts in AF and VTE answers a set of questions on its practical use, trying to define the profile of patients that would be most appropriate for its use.

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Viruses, Vol. 9, Pages 30: Microscopic Characterization of the Brazilian Giant Samba Virus

Prior to the discovery of the mimivirus in 2003, viruses were thought to be physically small and genetically simple. Mimivirus, with its ~750-nm particle size and its ~1.2-Mbp genome, shattered these notions and changed what it meant to be a virus. Since this discovery, the isolation and characterization of giant viruses has exploded. One of the more recently discovered giant viruses, Samba virus, is a Mimivirus that was isolated from the Rio Negro in the Brazilian Amazon. Initial characterization of Samba has revealed some structural information, although the preparation techniques used are prone to the generation of structural artifacts. To generate more native-like structural information for Samba, we analyzed the virus through cryo-electron microscopy, cryo-electron tomography, scanning electron microscopy, and fluorescence microscopy. These microscopy techniques demonstrated that Samba particles have a capsid diameter of ~527 nm and a fiber length of ~155 nm, making Samba the largest Mimivirus yet characterized. We also compared Samba to a fiberless mimivirus variant. Samba particles, unlike those of mimivirus, do not appear to be rigid, and quasi-icosahedral, although the two viruses share many common features, including a multi-layered capsid and an asymmetric nucleocapsid, which may be common amongst the Mimiviruses.

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Erratum

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Issue Information - Table of Contents

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Quantitative characterization of the carbon/carbon composites components based on video of polarized light microscope

Abstract

The components of carbon/carbon (C/C) composites have significant influence on the thermal and mechanical properties, so a quantitative characterization of component is necessary to study the microstructure of C/C composites, and further to improve the macroscopic properties of C/C composites. Considering the extinction crosses of the pyrocarbon matrix have significant moving features, the polarized light microscope (PLM) video is used to characterize C/C composites quantitatively because it contains sufficiently dynamic and structure information. Then the optical flow method is introduced to compute the optical flow field between the adjacent frames, and segment the components of C/C composites from PLM image by image processing. Meanwhile the matrix with different textures is re-segmented by the length difference of motion vectors, and then the component fraction of each component and extinction angle of pyrocarbon matrix are calculated directly. Finally, the C/C composites are successfully characterized from three aspects of carbon fiber, pyrocarbon, and pores by a series of image processing operators based on PLM video, and the errors of component fractions are less than 15%.

The Graphical Abstract shows the framework of C/C composites quantitative characterization. In this figure, quantitative characterization was carried out from three aspects according to the component in horizontal, and the important steps were shown in vertical.

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Heterogeneous expression of DnaK gene from Alicyclobacillus acidoterrestris improves the resistance of Escherichia coli against heat and acid stress

Alicyclobacillus acidoterrestris, an acidophilic and thermophilic bacteria, is an important microbial resource for stress resistance genes screening. In this study, DnaK gene from A. acid...

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Comparison of microbial communities from different Jinhua ham factories

Microbes in different aged workshops play important roles in the flavor formation of Jinhua ham. However, microbial diversity, community structure and age related changes in workshops are poorly understood. Th...

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Heme Assimilation in Schizosaccharomyces pombe Requires Cell Surface-anchored Protein Shu1 and Vacuolar Transporter Abc3 [Cell Biology]

The Schizosaccharomyces pombe shu1+ gene encodes a cell-surface protein required for assimilation of exogenous heme. In this study, shaving experiments showed that Shu1 is released from membrane preparations when spheroplast lysates are incubated with phosphoinositide-specific phospholipase C (PI-PLC). Shu1 cleavability by PI-PLC and its predicted hydropathy profile strongly suggested that Shu1 is a glycosylphosphatidyl inositol-anchored protein. When heme biosynthesis is selectively blocked in hem1Δ mutant cells, the heme analog zinc mesoporphyrin IX (ZnMP) first accumulates into vacuoles and then subsequently, within the cytoplasm in a rapid and Shu1-dependent manner. An HA4-tagged shu1+ allele that retained wild-type function localizes to the cell surface in response to low hemin concentrations, but under high hemin concentrations, Shu1-HA4 re-localizes to the vacuolar membrane. Inactivation of abc3+, encoding a vacuolar membrane transporter, results in hem1Δ abc3Δ mutant cells being unable to grow in the presence of hemin as the sole iron source. In hem1Δ abc3Δ cells, ZnMP accumulates primarily in vacuoles and does not sequentially accumulate in the cytosol. Consistent with a role for Abc3 as vacuolar hemin exporter, results with hemin-agarose pull-down assays showed that Abc3 binds to hemin. In contrast, an Abc3 mutant in which an inverted CysPro motif had been replaced with Ala residues fails to bind hemin with high affinity. Taken together, these results show that Shu1 undergoes rapid hemin-induced internalization from the cell surface to the vacuolar membrane and that the transporter Abc3 participates in the mobilization of stored heme from the vacuole to the cytosol.

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Bound Substrate in the Structure of Cyanobacterial Branching Enzyme Supports a New Mechanistic Model [Enzymology]

Branching enzyme (BE) catalyzes the formation of α-1,6-glucosidic linkages in amylopectin and glycogen. The reaction products are variable depending on the organism sources, and the mechanistic basis for these different outcomes is unclear. Although most cyanobacteria have only one BE isoform belonging to glycoside hydrolase (GH) family 13, Cyanothece sp. ATCC 51142 has three isoforms (BE1, BE2, and BE3) with distinct enzymatic properties, suggesting that investigations of these enzymes might provide unique insights into this system. Here, we report the crystal structure of ligand-free wild-type BE1 (residues 5−759 of 1−773) at 1.85 Å resolution. The enzyme consists of four domains, including domain N, carbohydrate-binding module family 48 (CBM48), domain A containing the catalytic site, and domain C. The central domain A displays a (β/α)8-barrel fold, whereas the other domains adopted β-sandwich folds. Domain N was found in a new location at the back of the protein, forming hydrogen bonds and hydrophobic interactions with CBM48 and domain A. Site-directed mutational analysis identified a mutant (W610N) that bound maltoheptaose with sufficient affinity to enable structure determination at 2.30 Å resolution. In this structure, maltoheptaose was bound in the active site cleft, allowing us to assign subsites -7 to -1. Moreover, seven oligosaccharide-binding sites were identified on the protein surface, and we postulated that two of these in domain A served as the entrance and exit of the donor/acceptor glucan chains, respectively. Based on these structures, we propose a substrate binding model explaining the mechanism of glycosylation/deglycosylation reactions catalyzed by BE.

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Experimental Arthritis is Dependent on Mouse Mast Cell Protease 5 [Immunology]

The constitutive heparin+ (HP) mast cells (MCs) in mice express mouse MC protease (mMCP)-5 and carboxypeptidase A (mMC CPA). The amino acid sequence of mMCP-5 is most similar to that of human chymase-1, as is the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP 2+ MCs in the jejunal mucosa of Trichinella spiralis-infected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP 5 protein is therefore needed to target translated mMC CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell granules. Fibronectin was identified as a target of mMCP 5, and the exocytosis of mMCP 5 from the MCs in the mouse peritoneal cavity resulted in the expression of metalloproteinase protease 9 which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wild type mice in two disease models.

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Metformin Promotes AMP-activated Protein Kinase-independent Suppression of {Delta}Np63{alpha} and Inhibits Cancer Cell Viability [Signal Transduction]

The blood-glucose modifier metformin is used to treat type II diabetes and has also been shown to possess anti-cancer activities. Recent studies indicate that glucose deprivation can greatly enhance metformin-mediated inhibition of cell viability, but the molecular mechanism involved in this inhibition is unclear. In this study, we report that under glucose deprivation metformin inhibited expression of ΔNp63α, a p53 family member involved in cell adhesion pathways, resulting in disruption of cell-matrix adhesion and in subsequent apoptosis in human squamous carcinoma cells. We further show that metformin promoted ΔNp63α protein instability independent of AMP-activated protein kinase and that WWP1, an E3 ligase of ΔNp63α, was involved in metformin-mediated down-regulation of ΔNp63α levels. In addition, we demonstrate that a combination of metformin and the glycolysis inhibitor 2-DG significantly inhibited ΔNp63α expression and also suppressed xenographic tumor growth in vivo. In summary, this study reveals a new mechanism for metformin-mediated anticancer activity and suggests a new strategy in treating human squamous cell carcinoma.

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Selenocysteine insertion at a predefined UAG codon in a release factor 1 (RF1) depleted Escherichia coli host strain bypasses species barriers in recombinant selenoprotein translation [Protein Synthesis and Degradation]

Selenoproteins contain the amino acid selenocysteine (Sec), co-translationally inserted at a predefined UGA opal codon by means of Sec-specific translation machineries. This process is in E. coli dependent upon binding of the Sec-dedicated elongation factor SelB to a SECIS element in the selenoprotein-encoding mRNA and competes with UGA-directed translational termination. Here we found that Sec can also be efficiently incorporated at a predefined UAG amber codon, thereby competing with RF1 rather than RF2. Subsequently utilizing the RF1 depleted E. coli strain C321.∆A we could produce mammalian selenoprotein thioredoxin reductases (TrxR) with unsurpassed purity and yield. We also found that a SECIS element was no longer absolutely required in such system. Human glutathione peroxidase 1 (GPx1) could thereby also be produced, and we could confirm a previously proposed catalytic tetrad in this selenoprotein. We believe that the versatility of this new UAG-directed production methodology should enable many further studies of diverse selenoproteins.

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Co-chaperone Hsp70/Hsp90 organizing protein (Hop) is Required for Transposon Silencing and piRNA Biogenesis [Gene Regulation]

piRNAs are 26-30nt germ-line specific small non-coding RNAs that have evolutionarily conserved function in mobile genetic element (transposons) silencing and maintenance of genome integrity. Drosophila Hsp70/90 Organizing Protein Homolog (Hop), a co-chaperone, interacts with piRNA binding protein Piwi and mediates silencing of phenotypic variations. However, it is not known if Hop has a direct role in piRNA biogenesis and transposon silencing. Here, we show that knockdown of Hop in the germ-line nurse cells (GLKD) of Drosophila ovaries leads to activation of transposons. Hop GLKD females can lay eggs at the same rate as wild type counterparts but the eggs do not hatch into larvae. Hop GLKD leads to the accumulation of γ-H2Av foci in the germline indicating increased DNA damage in the ovary. We also show that Hop GLKD induced transposon up-regulation is due to inefficient piRNA biogenesis. Based on these results, we conclude that Hop is a critical component of piRNA pathway and it maintains genome integrity by silencing transposons.

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Dual roles of Akirin2 during Xenopus neural development [Neurobiology]

To ensure correct spatial and temporal patterning, embryos must maintain pluripotent cell populations and control when cells undergo commitment. The newly identified nucleoprotein Akirin has been shown to modulate the innate immune response through epigenetic regulation and to play important roles in other physiological processes, but its role in neural development remains unknown. Here, we show that Akirin2 is required for neural development in Xenopus and knockdown of Akirin2 expands the expression of the neural progenitor marker Sox2 and inhibits expression of the differentiated neuronal marker N-tubulin. Akirin2 acts antagonistically to Geminin, thus regulating Sox2 expression, and maintains the neural precursor state by participating in Brg1/Brm-associated factor (BAF) complex mediated by BAF53a. Additionally, Akirin2 also modulates N-tubulin expression by acting upstream of NeuroD and in parallel with Ngnr1 during terminal neuronal differentiation. Thus, our results reveal a novel model in which Akirin2 precisely coordinates and temporally controls Xenopus neural development.

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Individual patient data meta-analysis of combined treatments versus psychotherapy (with or without pill placebo), pharmacotherapy or pill placebo for adult depression: a protocol

Introduction

There are many proven treatments (psychotherapy, pharmacotherapy or their combination) for the treatment of depression. Although there is growing evidence for the effectiveness of combination treatment (psychotherapy + pharmacotherapy) over pharmacotherapy alone, psychotherapy alone or psychotherapy plus pill placebo, for depression, little is known about which specific groups of patients may respond best to combined treatment versus monotherapy. Conventional meta-analyses techniques have limitations when tasked with examining whether specific individual characteristics moderate the effect of treatment on depression. Therefore, this protocol outlines an individual patient data (IPD) meta-analysis to explore which patients, with which clinical characteristics, have better outcomes in combined treatment compared with psychotherapy (alone or with pill placebo), pharmacotherapy and pill placebo.

Methods and Analysis

Study searches are completed using an established database of randomised controlled trials (RCTs) on the psychological treatment of adult depression that has previously been reported. Searches were conducted in PubMed, PsycInfo, Embase and the Cochrane Central Register of Controlled Trials. RCTs comparing combination treatment (psychotherapy + pharmacotherapy) with psychotherapy (with or without pill placebo), pharmacotherapy or pill placebo for the treatment of adult depression will be included. Study authors of eligible trials will be contacted and asked to contribute IPD. Conventional meta-analysis techniques will be used to examine differences between studies that have contributed data and those that did not. Then, IPD will be harmonised and analysis using multilevel regression will be conducted to examine effect moderators of treatment outcomes.

Dissemination

Study results outlined above will be published in peer-reviewed journals. Study results will contribute to better understanding whether certain patients respond best to combined treatment or other depression treatments and provide new information on moderators of treatment outcome that can be used by patients, clinicians and researchers.

Trial registration number

CRD42016039028.

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Toxoplasma gondii exposure and Parkinson's disease: a case-control study

Objectives

To determine the association between Toxoplasma gondii infection and Parkinson's disease and to investigate whether T. gondii seropositivity is associated with the general characteristics of patients with Parkinson's disease.

Design

Case–control study.

Setting

Cases and controls were enrolled in Durango City, Mexico.

Participants

65 patients with Parkinson's disease and 195 age- and gender-matched control subjects without Parkinson's disease.

Primary and secondary outcome measures

Serum samples of participants were analysed for anti-T. gondii IgG and IgM antibodies by commercially available enzyme-linked immunoassays. Prevalence of T. gondii DNA was determined in seropositive subjects using PCR. The association between clinical data and infection was examined by bivariate analysis.

Results

Anti-T. gondii IgG antibodies were found in 6/65 cases (9.2%) and in 21/195 controls (10.8%) (OR 0.84; 95% CI 0.32 to 2.18; p=0.81). The frequency of high (>150 IU/mL) antibody levels was similar among cases and controls (p=0.34). None of the anti-T. gondii IgG positive cases and four of the anti-T. gondii IgG positive controls had anti-T. gondii IgM antibodies (p=0.54). The prevalence of T. gondii DNA was comparable in seropositive cases and controls (16.7% and 25%, respectively; p=1.0). Seroprevalence of T. gondii infection was associated with a young age onset of disease (p=0.03), high Unified Parkinson Disease Rating Scale scores (p=0.04) and depression (p=0.02). Seropositivity to T. gondii infection was lower in patients treated with pramipexole than in patients without this treatment (p=0.01). However, none of the associations remained significant after Bonferroni correction.

Conclusions

The results do not support an association between T. gondii infection and Parkinson's disease. However, T. gondii infection might have an influence on certain symptoms of Parkinson's disease. Further research to elucidate the role of T. gondii exposure on Parkinson's disease is warranted.

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Retrospective observational study of trends in hospital admissions for idiopathic pulmonary fibrosis in Spain (2004-2013) using administrative data

Objective

To assess changes in incidence, diagnostic procedures, comorbidity profiles, length of hospital stay (LOHS), economic costs and in-hospital mortality (IHM) associated with idiopathic pulmonary fibrosis (IPF).

Methods

We identified patients hospitalised with IPF in Spain from 2004 to 2013. Data were collected from the National Hospital Discharge Database.

Results

The study population comprised 22 214 patients. Overall crude incidence increased from 3.82 to 6.98 admissions per 100 000 inhabitants from 2004 to 2013 (p<0.05). The percentage of lung biopsies decreased significantly from 10.68% in 2004 to 9.04% in 2013 (p<0.05). The percentage of patients with a Charlson comorbidity index ≥2 was 15.14% in 2004, increasing to 26.95% in 2013 (p<0.05). IHM decreased from 14.77% in 2004 to 13.72% in 2013 (adjusted OR 0.98; 95% CI 0.97 to 0.99). Mean LOHS was 11.87±11.18 days in 2004, decreasing to 10.20±11.12 days in 2013 (p<0.05). The mean cost per patient increased from 4838.51 in 2004 to 5410.90 in 2013 (p<0.05).

Conclusions

The frequency of hospital admissions for IPF increased during the study period, as did healthcare costs. However, IHM and LOHS decreased.

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Correction

Conget I, Mauricio D, Ortega R on behalf of the CHADIG Study investigators, et al. Characteristics of patients with type 2 diabetes mellitus newly treated with GLP-1 receptor agonists (CHADIG Study): a cross-sectional multicentre study in Spain. BMJ Open 2016;6:e010197. doi: 10.1136/bmjopen-2015-010197

Four of the Collaborator names were written incorrectly. ‘Francisco Merino Torres’ should have been written ‘Juan Francisco Merino-Torres’, ‘Fernando Gómez Peralta’ as ‘Fernando Gomez-Peralta’, ‘Diego Bellido Guerrero’ as ‘Diego Bellido’ and ‘Miguel Ángel Mangas’ as ‘Miguel Angel Mangas-Cruz’.

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Measurement properties of self-report physical activity assessment tools in stroke: a protocol for a systematic review

Introduction

Self-report physical activity assessment tools are commonly used for the evaluation of physical activity levels in individuals with stroke. A great variety of these tools have been developed and widely used in recent years, which justify the need to examine their measurement properties and clinical utility. Therefore, the main objectives of this systematic review are to examine the measurement properties and clinical utility of self-report measures of physical activity and discuss the strengths and limitations of the identified tools.

Methods and analysis

A systematic review of studies that investigated the measurement properties and/or clinical utility of self-report physical activity assessment tools in stroke will be conducted. Electronic searches will be performed in five databases: Medical Literature Analysis and Retrieval System Online (MEDLINE) (PubMed), Excerpta Medica Database (EMBASE), Physiotherapy Evidence Database (PEDro), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Electronic Library Online (SciELO), followed by hand searches of the reference lists of the included studies. Two independent reviewers will screen all retrieve titles, abstracts, and full texts, according to the inclusion criteria and will also extract the data. A third reviewer will be referred to solve any disagreement. A descriptive summary of the included studies will contain the design, participants, as well as the characteristics, measurement properties, and clinical utility of the self-report tools. The methodological quality of the studies will be evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and the clinical utility of the identified tools will be assessed considering predefined criteria. This systematic review will follow the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement.

Discussion

This systematic review will provide an extensive review of the measurement properties and clinical utility of self-report physical activity assessment tools used in individuals with stroke, which would benefit clinicians and researchers.

Trial registration number

PROSPERO CRD42016037146.

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The Effectiveness of Various Salacca Vinegars as Therapeutic Agent for Management of Hyperglycemia and Dyslipidemia on Diabetic Rats

The aim of this study was to explore the potency of salacca vinegar made from various Indonesian salacca fruit extracts as therapeutic agent for hyperglycemia and dyslipidemia for STZ-induced diabetic rats. The rats were grouped into untreated rats, STZ-induced diabetic rats without treatment, and STZ-induced diabetic rats treated with Pondoh salacca vinegar, Swaru salacca vinegar, Gula Pasir salacca vinegar, Madu salacca vinegar, or Madura salacca vinegar. Parameter observed included blood glucose, total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglyceride (TG), malondialdehyde (MDA), superoxide dismutase (SOD), and pancreas histopathology of the samples. The results demonstrated that all salacca vinegars were capable of reducing blood sugar (from 25.1 to 62%) and reducing LDL (from 9.5 to 14.8 mg/dL), TG (from 58.3 to 69.5 mg/dL), MDA (from 1.1 to 2.2 mg/dL), and TC (from 56.3 to 70.5 mg/dL) as well as increasing HDL blood sugar of STZ-induced diabetic Wistar rats (from 52.3 to 60 mg/dL). Various salacca vinegars were also capable of regenerating pancreatic cells. Nevertheless, the ability of Swaru salacca vinegar to manage hyperglycemia and dyslipidemia appeared to be superior to other salacca vinegars. Swaru salacca vinegar is a potential therapeutic agent to manage hyperglycemia and dyslipidemia of STZ-induced diabetic rats.

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Near-Infrared Spectroscopy Reveals Abnormal Hemodynamics in the Left Dorsolateral Prefrontal Cortex of Menopausal Depression Patients

Background/Objective. Menopausal depression (MD) is characterized by depressive symptoms along with hormonal fluctuations. We investigate brain function alteration between major depressive disorder (MDD) and MD. Methods. The difference in oxygenated hemoglobin (Oxy-Hb) for the prefrontal cortex (PFC) was compared retrospectively among 90 females presented with 30 MDD, 30 MD, and 30 healthy controls (HCs) using verbal fluency task (VFT) with near-infrared spectroscopy (NIRS). Results. We observed a significant difference in Oxy-Hb alteration in the left dorsolateral PFC (DLPFC) using VFT with NIRS (channel 18, ) between the MD and MDD groups. A significant difference in Oxy-Hb levels was observed among the three groups in the bilateral DLPFC (channels 18, 27, 33, 39, 41, and 45; ). Compared to the HCs, the MD group presented lower Oxy-Hb activation in the right DLPFC (channel 41; ) and the left DLPFC (channels 18, 39, and 45; ), and the MDD group presented lower Oxy-Hb activation in the right DLPFC (channels 27, 33, and 41; ) and the left DLPFC (channels 39 and 45; ). Conclusion. Abnormal hemodynamics of the left DLPFC can differentiate MD from MDD by NIRS.

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Influence of Gliricidia sepium Biochar on Attenuate Perchlorate-Induced Heavy Metal Release in Serpentine Soil

Perchlorate () is a strong oxidizer, capable of accelerating heavy metal release into regolith/soil. Here, we assessed interactions between and serpentine soil to simulate and understand the fate of Ni and Mn and their immobilization with the presence of biochar (BC). A soil incubation study (6 months) was performed using serpentine soil in combination with different concentrations (0.25, 0.5, 0.75, and 1 wt.%) and three different amendment rates (1, 2.5, and 5 wt.%) of Gliricidia sepium BC. Bioavailable fraction of Ni and Mn was analyzed using CaCl2 extraction method. An increase of concentrations enhanced bioavailability fraction of Ni and Mn. However, BC amendments reduced the bioavailability of Ni and Mn. In comparison, 5% BC amendment significantly immobilized the bioavailability of Ni (68–92%) and Mn (76–93%) compared to other BC amendment rates. Electrostatic attractions and surface diffusion could be postulated for Ni and Mn immobilization by BC. In addition, may have adsorbed to BC via hydrogen bonding which may reduce the influence of on Ni and Mn mobility. Overall, it is obvious that BC could be utilized as an effective amendment to immobilize Ni and Mn in heavy metal and contaminated soil.

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Complete Obstruction of Endotracheal Tube in an Infant with a Retropharyngeal and Anterior Mediastinal Abscess

Intraoperative ventilatory failure is not an uncommon complication; however, acute endotracheal obstruction by a foreign body or blood clot can be difficult to quickly discriminate from other causes. Once the diagnosis is made, quick action is needed to restore ventilation. The ultimate solution is to exchange the endotracheal tube; however, there can be other ways of resolving this in situations where reintubation would be difficult or unsafe. This case report discusses such an event in an infant with multiple airway challenges including a retropharyngeal and anterior mediastinal abscess. We have also formulated a pathway based on various case reports involving complete ETT obstruction.

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Dynamic Route Choice Prediction Model Based on Connected Vehicle Guidance Characteristics

A route choice prediction model is proposed considering the connected vehicle guidance characteristics. This model is proposed to prevent the delay in the release of guidance information and route planning due to inaccurate timing predictions of the traditional guidance systems. Based on the analysis of the impact of different connected vehicle (CV) guidance strategies on traffic flow, an indexes system for CV guidance characteristics is presented. Selecting five characteristic indexes, a route choice prediction model is designed using the logistic model. A simulation scenario is established by programming different agents for controlling the flow of vehicles and for information acquisition and transmission. The prediction model is validated using the simulation scenario, and the simulation results indicate that the characteristic indexes have a significant influence on the probability of choosing a particular route. The average root mean square error (RMSE) of the prediction model is 3.19%, which indicates that the calibration model shows a good prediction performance. In the implementation of CV guidance, the penetration rate can be considered an optional index in the adjustment of the guidance effect.

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Basic Sets of Special Monogenic Polynomials in Fréchet Modules

This article is concerned with the study of the theory of basic sets in Fréchet modules in Clifford analysis. The main aim of this account, which is based on functional analysis consideration, is to formulate criteria of general type for the effectiveness (convergence properties) of basic sets either in the space itself or in a subspace of finer topology. By attributing particular forms for the Fréchet module of different classes of functions, conditions are derived from the general criteria for the convergence properties in open and closed balls. Our results improve and generalize some known results in complex and Clifford setting concerning the effectiveness of basic sets.

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Research on Suspension with Novel Dampers Based on Developed FOA-LQG Control Algorithm

To enhance working-performance robustness of suspension, a vehicle suspension with permanent-magnet magnetic-valve magnetorheological damper (PMMVMD) was studied. Firstly, mechanical structure of traditional magnetorheological damper (MD) used in vehicle suspensions was redesigned through introducing a permanent magnet and a magnetic valve. Based on theories of electromagnetics and Bingham model, prediction model of damping force was built. On this basis, two-degree-of-freedom vehicle suspension model was established. In addition, fruit fly optimization algorithm- (FOA-) line quadratic Gaussian (LQG) control algorithm suitable for PMMVMD suspensions was designed on the basis of developing normal FOA. Finally, comparison simulation experiments and bench tests were conducted by taking white noise and a sine wave as the road surface input and the results indicated that working performance of PMMVMD suspension based on FOA-LQG control algorithm was good.

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Effects of Different Treatments on the Quality and Safety of Crayfish (Astacus leptodactylus)

This study was aimed to determine the effect of different killing methods (frozen, mechanical, and traditional) on the quality, safety, and shelf life of crayfish that are aerobically stored under chilled conditions. The population of microorganisms (i.e., total mesophilic aerobic bacteria (TMAB), total psychrophilic aerobic bacteria (TPAB), and Enterobacteriaceae) was increased regarding to storage time (). Significant differences () were not observed in pH values during storage time. In contrast to this, total volatile basic nitrogen (TVB-N) values of the samples were increased significantly () during storage. Sensory results were highly correlated with the microbiological counts ( for TMAB odour; for TPAB odour; and for Enterobacteriaceae odour). Fifteen different fatty acids and 5 biogenic amines were detected for the determination of initial quality and safety of crayfish. In conclusion, frozen killed samples were found to be effective and laborsaving method as an alternative to traditional killing methods by maintaining the quality and safety of crayfish at the beginning and during storage under chilled conditions.

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Prenatal and Peripartum Management of Patients with Hypofibrinogenemia Resulted in Two Successful Deliveries

Fibrinogen is an essential agent involved in maintaining pregnancy and coagulation. Since inherited fibrinogen disorders introduce greater risks for conditions such as placental abruption and postpartum hemorrhage, careful prenatal and perinatal management is essential for this patient population. We report two cases of successful deliveries in patients with hypofibrinogenemia. Case 1 is of a 26-year-old (gravida 1, para 1) woman. The patient’s fibrinogen level increased spontaneously to higher than 300 mg/dL during pregnancy, without treatment. She delivered at week 38 of gestation, with no complications. Case 2 is of a 30-year-old (gravida 3, para 1) woman. We performed repeated infusions of fibrinogen to maintain the level higher than 100 mg/dL during pregnancy and at least 200 mg/dL in the perioperative period; the patient delivered a healthy infant. We identified a new mutation, Hiroshima I (γ278Tyr→His). It is important to maintain appropriate fibrinogen levels in cases of inherited fibrinogen disorders for successful prenatal and peripartum management.

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Efficient Techniques for Solving the Periodic Projected Lyapunov Equations and Model Reduction of Periodic Systems

We have presented the efficient techniques for the solutions of large-scale sparse projected periodic discrete-time Lyapunov equations in lifted form. These types of problems arise in model reduction and state feedback problems of periodic descriptor systems. Two most popular techniques to solve such Lyapunov equations iteratively are the low-rank alternating direction implicit (LR-ADI) method and the low-rank Smith method. The main contribution of this paper is to update the LR-ADI method by exploiting the ideas of the adaptive shift parameters computation and the efficient handling of complex shift parameters. These approaches efficiently reduce the computational cost with respect to time and memory. We also apply these iterative Lyapunov solvers in balanced truncation model reduction of periodic discrete-time descriptor systems. We illustrate numerical results to show the performance and accuracy of the proposed methods.

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Exhaled Nitric Oxide in Systemic Sclerosis Lung Disease

Background. Exhaled nitric oxide (eNO) is a potential biomarker to distinguish systemic sclerosis (SSc) associated pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). We evaluated the discriminative validity, feasibility, methods of eNO measurement, and magnitude of differences across lung diseases, disease-subsets (SSc, systemic lupus erythematosus), and healthy-controls. Methods. Consecutive subjects in the UHN Pulmonary Hypertension Programme were recruited. Exhaled nitric oxide was measured at 50 mL/s intervals using chemiluminescent detection. Alveolar and conducting airway NO were partitioned using a two-compartment model of axial diffusion (CMAD) and the trumpet model of axial diffusion (TMAD). Results. Sixty subjects were evaluated. Using the CMAD model, control subjects had lower median (IQR) alveolar NO than all PAH subjects (2.0 (1.5, 2.5) versus 3.14 ppb (2.3, 4.0), ). SSc-ILD had significantly lower median conducting airway NO compared to controls (1009.5 versus 1342.1 mlppb/s, ). SSc-PAH had increased median (IQR) alveolar NO compared to controls (3.3 (3.0, 5.7) versus 2.0 ppb (1.5, 2.5), ). SSc-PAH conducting airway NO inversely correlated with DLCO (r −0.88 (95% CI −0.99, −0.26)). Conclusion. We have demonstrated feasibility, identified that CMAD modeling is preferred in SSc, and reported the magnitude of differences across cases and controls. Our data supports discriminative validity of eNO in SSc lung disease.

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Development of a Motion Sensing and Automatic Positioning Universal Planisphere Using Augmented Reality Technology

This study combines the augmented reality technology and the sensor functions of GPS, electronic compass, and 3-axis accelerometer on mobile devices to develop a motion sensing and automatic positioning universal planisphere. It can create local star charts according to the current date, time, and position and help users locate constellations on the planisphere easily through motion sensing operation. By holding the mobile device towards the target constellation in the sky, the azimuth and elevation angles are obtained automatically for mapping to its correct position on the star chart. The proposed system combines observational activities with physical operation and spatial cognition for developing correct astronomical concepts, thus making learning more effective. It contains a built-in 3D virtual starry sky to enable observation in classroom for supporting teaching applications. The learning process can be shortened by setting varying observation date, time, and latitude. Therefore, it is a useful tool for astronomy education.

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Evaluation of a Pilot Project to Introduce Simulation-Based Team Training to Pediatric Surgery Trauma Room Care

Introduction. Several studies in pediatric trauma care have demonstrated substantial deficits in both prehospital and emergency department management. Methods. In February 2015 the PAEDSIM collaborative conducted a one and a half day interdisciplinary, simulation based team-training course in a simulated pediatric emergency department. 14 physicians from the medical fields of pediatric surgery, pediatric intensive care and emergency medicine, and anesthesia participated, as well as four pediatric nurses. After a theoretical introduction and familiarization with the simulator, course attendees alternately participated in six simulation scenarios and debriefings. Each scenario incorporated elements of pediatric trauma management as well as Crew Resource Management (CRM) educational objectives. Participants completed anonymous pre- and postcourse questionnaires and rated the course itself as well as their own medical qualification and knowledge of CRM. Results. Participants found the course very realistic and selected scenarios highly relevant to their daily work. They reported a feeling of improved medical and nontechnical skills as well as no uncomfortable feeling during scenarios or debriefings. Conclusion. To our knowledge this pilot-project represents the first successful implementation of a simulation-based team-training course focused on pediatric trauma care in German-speaking countries with good acceptance.

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Determination of Ten Corticosteroids in Illegal Cosmetic Products by a Simple, Rapid, and High-Performance LC-MS/MS Method

The aim of our present work was the development of a rapid high-performance liquid chromatography method with electrospray ionization and tandem mass spectrometry detection (LC-ESI-MS/MS) for the determination of several corticosteroids in cosmetic products. Corticosteroids are suspected to be illegally added in cosmetic preparations in order to enhance the curative effect against some skin diseases. Sample preparation step consists in a single extraction with acetonitrile followed by centrifugation and filtration. The compounds were separated by reversed-phase chromatography with water and acetonitrile (both with 0.1% formic acid) gradient elution and detected by ESI-MS positive and negative ionization mode. The method was validated at the validation level of 0.1 mg kg−1. Linearity was studied in the 5–250 μg L−1 range and linear coefficients () were all over 0.99. The accuracy and precision of the method were satisfactory. The LOD ranged from 0.085 to 0.109 mg kg−1 and the LOQ from 0.102 to 0.121 mg kg−1. Mean recoveries for all the analytes were within the range 91.9–99.2%. The developed method is sensitive and useful for detection, quantification, and confirmation of these corticosteroids in cosmetic preparations and can be applied in the analysis of the suspected samples under investigation.

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Polyhedral Star-Shaped Distributions

A new method of probabilistic modelling of polyhedrally contoured sample clouds is presented and applied to statistical reasoning for a real dataset. Various representations of the new class of polyhedral star-shaped distributions are derived and basic properties of the moments as well as characteristic and moment generating functions of these distributions are studied. Along with location-scale transformations, estimating and hypothesis testing are dealt with.

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Generation of Monoclonal Antibodies against Immunoglobulin Proteins of the Domestic Ferret (Mustela putorius furo)

The domestic ferret (Mustela putorius furo) serves as an animal model for the study of several viruses that cause human disease, most notably influenza. Despite the importance of this animal model, characterization of the immune response by flow cytometry (FCM) is severely hampered due to the limited number of commercially available reagents. To begin to address this unmet need and to facilitate more in-depth study of ferret B cells including the identification of antibody-secreting cells, eight unique murine monoclonal antibodies (mAb) with specificity for ferret immunoglobulin (Ig) were generated using conventional B cell hybridoma technology. These mAb were screened for reactivity against ferret peripheral blood mononuclear cells by FCM and demonstrate specificity for CD79β+ B cells. Several of these mAb are specific for the light chain of surface B cell receptor (BCR) and enable segregation of kappa and lambda B cells. Additionally, a mAb that yielded surface staining of nearly all surface BCR positive cells (i.e., pan ferret Ig) was generated. Collectively, these MαF-Ig mAb offer advancement compared to the existing portfolio of polyclonal anti-ferret Ig detection reagents and should be applicable to a wide array of immunologic assays including the identification of antibody-secreting cells by FCM.

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SiC Conversion Coating Prepared from Silica-Graphite Reaction

The β-SiC conversion coatings were successfully synthesized by the SiO(v)-graphite(s) reaction between silica powder and graphite specimen. This paper is to describe the effects on the characteristics of the SiC conversion coatings, fabricated according to two different reaction conditions. FE-SEM, FE-TEM microstructural morphologies, XRD patterns, pore size distribution, and oxidation behavior of the SiC-coated graphite were investigated. In the XRD pattern and SAD pattern, the coating layers showed cubic SiC peak as well as hexagonal SiC peak. The SiC coatings showed somewhat different characteristics with the reaction conditions according to the position arrangement of the graphite samples. The SiC coating on graphite, prepared in reaction zone (2), shows higher intensity of beta-SiC main peak (111) in XRD pattern as well as rather lower porosity and smaller main pore size peak under 1 μm.

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Ductal Breast Carcinoma In Situ: Mammographic Features and Its Relation to Prognosis and Tumour Biology in a Population Based Cohort

Casting-type calcifications and a histopathological picture with cancer-filled duct-like structures have been presented as breast cancer with neoductgenesis. We correlated mammographic features and histopathological neoductgenesis with prognosis in a DCIS cohort with long follow-up. Mammographic features were classified into seven groups according to Tabár. Histopathological neoductgenesis was defined by concentration of ducts, lymphocyte infiltration, and periductal fibrosis. Endpoints were ipsilateral (IBE) in situ and invasive events. Casting-type calcifications and neoductgenesis were both related to high nuclear grade, ER- and PR-negativity, and HER2 overexpression but not to each other. Casting-type calcifications and neoductgenesis were both related to a nonsignificant lower risk of invasive IBE, HR 0.38 (0.13–1.08) and 0.82 (0.29–2.27), respectively, and the HR of an in situ IBE was 0.90 (0.41–1.95) and 1.60 (0.75–3.39), respectively. Casting-type calcifications could not be related to a worse prognosis in DCIS. We cannot explain why a more aggressive phenotype of DCIS did not correspond to a worse prognosis. Further studies on how the progression from in situ to invasive carcinoma is driven are needed.

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Chinese Herbal Medicine Baoyuan Jiedu Decoction Inhibited Muscle Atrophy of Cancer Cachexia through Atrogin-l and MuRF-1

The aim of this study is to investigate the mechanisms of Chinese herbal medicine called “Baoyuan Jiedu” (BYJD for short) decoction, improving life quality and preventing muscle atrophy of cancer cachexia model mice. We showed that the effect of BYJD decoction increased body weights of mice and reduced tumor volume and tumor mass. Furthermore, BYJD decoction increased the gastrocnemii mass and the transverse diameter of muscle fiber morphology. Moreover, BYJD reduced the expression of Atrogin-1 and MuRF-1 protein. Collectively, our results show that BYJD decoction improves the life quality of cancer cachexia mice and prevents muscle atrophy by downregulating expression of Atrogin-1 and MuRF-1.

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Beneficial Effects on Pregnancy Outcomes of Thyroid Hormone Replacement for Subclinical Hypothyroidism

Background. Hypothyroidism and raised thyroid antibody levels have been associated with adverse obstetrical outcomes. Several studies have investigated causal associations, but results have been inconsistent and few studies have reported the effects of thyroxine replacement therapy on pregnancy outcomes in hypothyroid patients. Objective. The primary study objective was to determine the outcome of pregnancies in women diagnosed with overt and subclinical hypothyroidism (SCH) (serum TSH > 2.5 mIU/L) and those with elevated circulating thyroid autoantibody levels in the first trimester of pregnancy and after the institution of appropriate thyroxine replacement therapy to maintain the serum TSH ≤ 2.5 mIU/L. Study Design. This prospective observational study was undertaken between 2013 and 2016. Blood samples were taken from 1025 women at presentation for thyroid stimulating hormone (TSH), anti-thyroglobulin antibodies (TGAb), and thyroid peroxidase antibodies (TPOAb). Those with a TSH > 2.5 mIU/L were treated with thyroxine and managed appropriately to ensure that the TSH was maintained ≤2.5 mIU/L. Outcomes in these patients were compared to those in euthyroid patients. Maternal antenatal complications and perinatal outcomes were recorded. Results. There were a total of 1025 patients of whom 382 (37.5%) were nulliparous. 10.1% had a TSH level > 2.5 mIU/L and 18.2% had at least one raised thyroid antibody level. No differences in adverse outcomes of pregnancy were evident in women treated for SCH or overt hypothyroidism compared to the euthyroid group. There was also no association between raised thyroid antibodies and adverse pregnancy outcomes in either group. Conclusion. There were no adverse outcomes of pregnancy found in pregnant women who had been diagnosed and treated with thyroxine for SCH at the time of presentation when compared to euthyroid patients. There was also no relationship with thyroid antibodies and adverse pregnancy outcomes in the two groups. It is not possible to unequivocally advocate for thyroxine replacement in pregnant women with subclinical and overt hypothyroidism until large scale randomized controlled trials are performed.

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Medical students unique experience of army leadership training: a qualitative study

Objectives

To assess the interactive experience of first year medical students attending the leadership and management course hosted by a British Army Reserve Field Hospital developed in partnership with Liverpool University.

Methods

244 students submitted a 1000-word structured reflective learning assignment about their reaction to, learning from and any behaviour and attitude changes as a result of, the training. The assignments were thematically analysed to identify how aspects of the training had impacted upon the students' understanding of leadership and teamwork. Their comments relating to the army were analysed to gain insight into their views and experience of the training.

Results

Students were surprised at how enjoyable and useful they found the course. Initially they expressed scepticism about what they could learn in an army-based environment. However, the training, particularly command and planning tasks, helped them appreciate and understand the different skills individuals can bring to a team environment, and the importance of everyone contributing. While some students were challenged by aspects of the course, with support and encouragement from team-mates and the army personnel, they learned they could achieve more together.

Conclusions

Teaching leadership and management skills to medical students is a challenge which can be effectively addressed by adapting and developing army training resources. Students overcame initial scepticism about participating, and learned a lot about themselves and each other. In addition, the army developed a better understanding of the doctors of the future. The expertise of the army in delivering this training was crucial to its success as the medical school could not have provided this experience unsupported.

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Novel porcine model of cutaneous myiasis: a training tool for healthcare workers

Cutaneous myiasis is a well-described problem in travellers to endemic regions including military personnel. Realistic training is important to ensure that healthcare workers have the confidence and expertise to recognise cutaneous myiasis and safely remove larvae if required. A model is described here that is simple, reproducible and realistic, and will allow for training of military healthcare workers in safe surgical removal of larvae when required.

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Ovarian tumor domain-containing protein 1 deubiquitinates and stabilizes p53

Publication date: Available online 13 February 2017
Source:Cellular Signalling
Author(s): Shudong Piao, Han Zhong Pei, Bin Huang, Suk-Hwan Baek
Ubiquitination and deubiquitination pathways play important roles in the regulation of p53 stability and activity. p53 is ubiquitinated and destabilized by E3 ubiquitin ligases and is deubiquitinated and stabilized by deubiquitinases (DUBs). We screened ovarian tumor (OTU) subfamily proteins to identify novel DUBs that stabilized p53. OTU domain-containing protein 1 (OTUD1) is a DUB belonging to the OTU family; however, its substrates and its role in cells are unknown. Here, we used an overexpression and knockdown system to show that OTUD1 is a novel regulator of p53 stability. OTUD1 overexpression increased p53 stability, whereas OTUD1 knockdown decreased p53 stability. Moreover, we observed that OTUD1 directly interacted with p53. Our results showed that OTUD1 deubiquitinated p53 and that functional OTUD1 was required for p53 stabilization. The deubiquitination activity of OTUD1 was necessary for p53 stabilization, as confirmed using an inactive OTUD1 mutant (C320S OTUD1 mutant). We also found that wild-type OTUD1 upregulated p21 and Mdm2 expression but inactive OTUD1 mutant did not. Furthermore, OTUD1 significantly suppressed colony formation. Next, we confirmed that OTUD1 overexpression increased the cleavage of caspase-3 and PARP and subsequently increased apoptosis. Together, these results suggest that OTUD1 is a novel regulator of p53 stability and activity.



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Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study

Planta Med
DOI: 10.1055/s-0043-101915

Natural products are generally ingested as part of traditional herbal decoctions or in the current diet. However, in natural product research, the bioavailability of secondary metabolites is often poorly investigated. In this work, a systematic study was carried out in order to highlight the physicochemical parameters that mainly influence the passive intestinal absorption of natural products. For this, a representative set of natural products including alkaloids, coumarins, flavonoid aglycones and glycosides, and carboxylic acids was selected and their physicochemical properties were predicted using relevant Volsurf+ descriptors. The chemical space obtained with this unbiased method was then correlated with experimental passive intestinal permeability data, which highlighted the main influence of lipophilicity, global hydrophilicity, size, and the ionisation state on passive intestinal absorption of natural products. Since the pH range encountered in the intestine is wide, the influence of the ionisation was investigated deeper experimentally. The ionisation state of weakly ionisable natural products, such as flavonoid aglycones, alkaloids, and carboxylic acids, was found to prevent the passive intestinal absorption of such natural products completely. In addition, the impact of solubility issues on passive permeability results was evaluated in cases of poorly water-soluble natural products, such as flavonoid aglycones and coumarins. The biomimetic fasted state simulated fluid-version 2 was found to improve the apparent solubility of such poorly soluble natural products without influencing their permeability behaviours. The use of such a solubilising buffer was found to be well adapted to the hexadecane membrane-parallel artificial membrane permeability assay and can circumvent the solubility issues encountered with poorly soluble natural products in such an assay.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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In Situ Patterning of Ultrasharp Dopant Profiles in Silicon

ACS Nano

DOI: 10.1021/acsnano.6b07359

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Bandgap Extraction and Device Analysis of Ionic Liquid Gated WSe2 Schottky Barrier Transistors

ACS Nano

DOI: 10.1021/acsnano.6b07360

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Optomagnetic Detection of MicroRNA Based on Duplex-Specific Nuclease-Assisted Target Recycling and Multilayer Core-Satellite Magnetic Superstructures

ACS Nano

DOI: 10.1021/acsnano.6b07763

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Effect of Vitamin D Deficiency on the laryngo-pharyngeal Tract

To investigate the effect of vitamin D deficiency on the laryngopharyngeal tract.

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Bilateral Sinonasal Extramedulary Plasmacytoma treated with radiotherapy and a Medial Maxillectomy with a Denker's procedure

Extramedullary plasmacytoma (EMP), multiple myeloma (MM), and solitary plasmacytoma of the bone (SPB) are each classified as distinct manifestations of a disease continuum with varying symptoms, treatment regimens, and prognostic implications. While the etiology for each of these neoplastic entities is due to a derangement of plasma cells, these B-cell neoplasms are indistinguishable histologically [1] [1]. EMP, a rare neoplasm, accounts for approximately 2–3% of all plasma cell tumors, SPB accounts for up to 4–6% of cases, and multiple myeloma for 91–94% [1] [2] [3].

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Lobular capillary hemangiomas: Case report and review of literature of vascular lesions of the nasal cavity

Vascular tumors of the nasal cavity can represent a variety of pathologies. In this case report, we discuss two patients presenting with a large vascular lesion occupying the nasal cavity. Significant bleeding was encountered during the initial attempts for endoscopic surgical resection. One lesion was successfully excised following preoperative embolization while a second following sphenopalatine artery ligation vascular ligation. In both cases, final pathology showed lobular capillary hemangioma (LCH).

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Is histopathological diagnosis useful in choosing treatments for tumors of the temporal bone?

We were pleased to read the article by Olcott C. andStrasnick B. titled “A blue middle ear mass: Cholesterol granuloma mimicking a glomus tumor and endolymphatic sac tumor”. Am J Otolaryngol.2017;38(1):100-102 [1], which presents very important clinical observations. Based on our experience and the literature review, we would like to present some comments on this problem. The benign tumors of the temporal bone (TB) have been divided into three groups: cholesterol granuloma (CG), glomus tumor (GT) and endolymphatic sac tumor (ELST) [1].

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More people now believe human-made climate change is happening

The proportion of people in the UK who accept climate change is happening and is largely human-made has risen from 57 per cent three years ago to 64 per cent now

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More people now believe human-made climate change is happening

The proportion of people in the UK who accept climate change is happening and is largely human-made has risen from 57 per cent three years ago to 64 per cent now

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Potential probiotic properties of lactic acid bacteria isolated from the intestinal mucosa of healthy piglets

Abstract

In the present study, the probiotic properties of 52 lactic acid bacteria strains, isolated from the intestinal mucosa of 60-day-old healthy piglets, were evaluated in vitro in order to acquire probiotics of potential application. Based on acidic and bile salt resistance, 11 lactic acid bacteria strains were selected, among which 1 was identified as Pediococcus acidilactici, 3 as Enterococcus faecium, 3 as Lactobacillus rhamnosus, 2 as Lactobacillus brevis, and 2 as Lactobacillus plantarum by 16S rRNA gene sequencing. All selected strains were further investigated for transit tolerance in simulated upper gastrointestinal tract, for adhesion capacity to swine intestinal epithelial cells J2 (IPEC-J2), for cell surface characteristics including hydrophobicity, co-aggregation and auto-aggregation, and for antimicrobial activities. Moreover, hemolytic, bile salt hydrolase and biogenic amine-producing abilities were investigated for safety assessment. Two E. faecium (WEI-9 and WEI-10) and one L. plantarum (WEI-51) exhibited good simulated upper gastrointestinal tract tolerance, and showed high auto-aggregation and co-aggregation with Escherichia coli 1570. The strains WEI-9 and WEI-10 demonstrated the highest adherence capacity. The 11 selected strains mentioned above exhibited strong antimicrobial activity against E. coli CVCC1570, Staphylococcus aureus CVCC1882 and Salmonella pullorum AS1.1859. None of the 11 selected strains, except WEI-9 and WEI-33, exhibited bile salt hydrolase, hemolytic or biogenic amine-producing abilities. This work showed that the E. faecium WEI-10 and L. plantarum WEI-51were found to have the probiotic properties required for use as potential probiotics in animal feed supplements.

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The Accuracy of Preoperative Rigid Stroboscopy in the Evaluation of Voice Disorders in Children

Stroboscopy is considered the most appropriate tool for evaluating the function of the vocal folds but may harbor significant limitations in children. Still, direct laryngoscopy (DL), under general anesthesia, is regarded the “gold standard” for establishing a diagnosis of vocal fold pathology. The aim of the study is to examine the accuracy of preoperative rigid stroboscopy in children with voice disorders.

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Determining the best recipient vessel site for autologous microsurgical breast reconstruction with DIEP flaps: an anatomical study

The deep inferior epigastric perforators (DIEP) flap is a reliable and reproducible technique for autologous microsurgical breast reconstruction. Several recipient vessels sites for microvascular anastomosis have been described: the internal thoracic vessels, the thoracodorsal vessels and the circumflex scapular vessels. Nonetheless, the choice of the recipient site depends mainly on individual operator’s experience and preferences, and currently the best recipient vessel site is still debated. The aim of this anatomical observational study was to determine whether anatomy could address this dilemma by determining the best vessel diameter to match the donor with these 3 recipient sites.

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Plasmonic Nanolenses: Electrostatic Self-Assembly of Hierarchical Nanoparticle Trimers and Their Response to Optical and Electron Beam Stimuli

ACS Nano

DOI: 10.1021/acsnano.6b07336

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DXA-Based Measurements in Diabetes: Can They Predict Fracture Risk?

Abstract

In the absence of a fragility fracture, osteoporosis is usually diagnosed from bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). Osteoporosis is an increasingly prevalent disease, as is diabetes [in particular type 2 diabetes (T2D)], in part due to aging populations worldwide. It has been suggested that an increased risk of fracture may be another complication ensuing from longstanding diabetes. The purpose of this review is to concentrate on skeletal parameters and techniques readily available from DXA scanning, and their utility in routine clinical practice for predicting fracture risk. In addition to BMD, other applications and measures from DXA include trabecular bone score (TBS), skeletal geometry and DXA-based finite-element analysis, vertebral fracture assessment, and body composition. In type 1 diabetes (T1D), BMD and FRAX^R (when secondary osteoporosis is included without BMD) only partially account for the excess risk of fracture in T1D. Consistent data exist to show that BMD and FRAX^R can be used to stratify fracture risk in T2D, but do not account for the increased risk of fracture. However, several adjustments to the FRAX score can be made as proxies for T2D to inform the use of FRAX by primary care practitioners. Examples include using the rheumatoid arthritis input (as a proxy for T2D), lumbar spine TBS (to adjust FRAX probability) or an altered hip T-score (lowered by 0.5 units). These adjustments can improve fracture risk prediction in T2D and help to avoid systematically underestimating the risk of osteoporosis-related fractures in those with diabetes.

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Efficacy of Osteoporosis Therapies in Diabetic Patients

Abstract

Diabetes is characterized by increased fracture risk and by reduced bone strength for a given density. Contributing factors may include lower bone turnover and accumulation of advanced glycation endproducts. There are concerns that the pharmacological therapies for osteoporosis, particularly anti-resorptive therapies that suppress bone turnover, may not be as effective in the setting of diabetes. This review considers clinical trials and observational studies that have assessed the efficacy of anti-resorptive and anabolic therapies in diabetic patients. Post hoc analyses of randomized trials indicate that raloxifene has similar efficacy for prevention of vertebral fractures in diabetic compared with non-diabetic patients. Evidence from randomized clinical trials is lacking for anti-fracture efficacy of other osteoporosis therapies in diabetes. However, observational studies suggest that bisphosphonates are effective in preventing fractures in diabetic patients. The great majority of diabetic patients in studies to date have been type 2, and efficacy of osteoporosis therapies in type 1 diabetic patients remains to be addressed. Further evaluation of the efficacy of osteoporosis therapies in the setting of diabetes is needed to provide optimal fracture prevention for this population.

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Risk factors for hospitalization of children with congenital adrenal hyperplasia

Abstract

Background and Objectives

Patients with congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency are prone to potentially life-threatening adrenal crises. We tried to identify risk factors for post-diagnosis hospitalization for children with the salt wasting form of CAH.

Methods

We reviewed medical records of all children who presented to Children's Medical Center Dallas from 1999 to 2013 with congenital adrenal hyperplasia (ICD-9 code 255.2).

Results

522 unique patients were coded for ICD-9 code of 255.2 (CAH) from 1999-2013; 155 patients had salt- wasting disease. 55 patients were hospitalized a total of 105 times. Patients who were hospitalized were more likely to have non-commercial insurance (RR=1.8; 95% CI [1.1-2.8]; p=0.02); this included 5 patients hospitalized a total of 37 times. Children younger than 2 years (RR=3.3 [2.2-4.8]; p<0.0001) were more likely to be hospitalized. In a nested case control analysis, the risk of hospitalization was correlated with daily fludrocortisone dose (p≤0.0001) but not hydrocortisone dose; no outpatient laboratory test predicted hospitalization. Gastroenteritis was the most frequent admitting diagnosis.

Conclusions

Younger children may be at greater risk of hospitalization owing to increased susceptibility to viral infections and decreased ability to withstand stress and dehydration. A minority of patients with non-commercial insurance may have higher risk owing to social barriers that interfere with treatment compliance. Those requiring higher daily fludrocortisone dosages likely have inherently more severe disease leading to higher rates of hospitalization.

This article is protected by copyright. All rights reserved.

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[ 68 Ga]NOTA-Galactosyl Human Serum Albumin: a Tracer for Liver Function Imaging with Improved Stability

Abstract

Purpose

Non-invasive techniques allowing quantitative determination of the functional liver mass are of great interest for patient management in a variety of clinical settings. Recently, we presented [⁶⁸Ga]DTPA-GSA to target the hepatic asialoglycoprotein receptor for this purpose. Here, we introduce [⁶⁸Ga]NOTA-GSA to improve metabolic stability of the radiopharmaceutical and compare the imaging properties with [⁶⁸Ga]DTPA-GSA.

Procedures

Labeling of the compounds was carried out at room temperature using 1.9 M sodium acetate as buffer. For quality control, thin-layer, high-performance liquid, and size exclusion chromatographies were used. Metabolic stability was studied in rat and human serums. For in vivo evaluation, Fischer rats were scanned by positron emission tomography and magnetic resonance imaging and subsequently sacrificed for biodistribution studies. Time activity curves (TACs) for heart and liver were generated and corresponding parameters (T₅₀, T₉₀, LHL15, HH15) were calculated.

Results

[⁶⁸Ga]NOTA-GSA can be produced in high radiochemical yield and purity (>95 %) within 15 min. Stability studies revealed almost no metabolite formation over the 2-h observation period. Analysis of the TACs showed comparable results for most of the investigated parameters. The only significant difference was found in the T₉₀ value, where [⁶⁸Ga]NOTA-GSA showed slower uptake in comparison with ⁶⁸Ga-DTPA-GSA (123 ± 10 vs. 89 ± 3 s, p < 0.01).

Conclusions

[⁶⁸Ga]NOTA-GSA showed a significant increase of the metabolic stability and in most organs lower background activity. However, comparison of LHL15 and HH15 indicates that the increased stability did not further improve the diagnostic value. Thus, [⁶⁸Ga]NOTA-GSA and [⁶⁸Ga]DTPA-GSA can be used equivalent for imaging hepatic function with positron emission tomography.

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Characterization of an Orthotopic Colorectal Cancer Mouse Model and Its Feasibility for Accurate Quantification in Positron Emission Tomography

Abstract

Purpose

Quantification in positron emission tomography (PET) imaging of an orthotopic mouse model of colorectal cancer (CRC) is challenging due to difficult tumor delineation. We aimed to establish a reproducible delineation approach, evaluate its feasibility for reliable PET quantification and compare its added translational value with its subcutaneous counterpart.

Procedures

A subcutaneous Colo205-luc2 tumor fragment harvested from a donor mouse was transplanted onto the caecum of nude mice, with (n = 10) or without (n = 10) the addition of an X-ray detectable thread. Animals underwent 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) PET imaging, complemented with X-ray computed tomography (CT) and magnetic resonance imaging (MRI, 7T). Animals without a thread underwent additional contrast enhanced (Exitron) CT imaging. Tumors were delineated on the MRI, μPET image or contrast enhanced μCT images and correlations between in vivo and ex vivo [¹⁸F]FDG tumor uptake as well as between image-derived and caliper-measured tumor volume were evaluated. Finally, cancer hallmarks were assessed immunohistochemically for the characterization of both models.

Results

Our results showed the strongest correlation between both in vivo and ex vivo uptake (r = 0.84, p < 0.0001) and image-derived and caliper-measured tumor volume (r = 0.96, p < 0.0001) when the tumor was delineated on the MR image. Orthotopic tumors displayed an abundance of stroma, higher levels of proliferation (p = 0.0007), apoptosis (p = 0.02), and necrosis (p < 0.0001), a higher number of blood vessels (p < 0.0001); yet lower tumor hypoxia (p < 0.0001) as compared with subcutaneous tumors.

Conclusions

This orthotopic mouse model proved to be a promising tool for the investigation of CRC through preclinical imaging studies provided the availability of anatomical MR images for accurate tumor delineation. Furthermore, the tumor microenvironment of the orthotopic tumor resembled more that of human CRC, increasing its likelihood to advance translational nuclear imaging studies of CRC.

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ESPMIS: Helping Young Scientists Navigate the Molecular Imaging Landscape

Abstract

The core mission of the Early Stage Professionals in Molecular Imaging Sciences (ESPMIS) Interest Group is to help young scientists navigate the professional landscape of molecular imaging. Since its formation in early 2015, ESPMIS has used the annual World Molecular Imaging Congress (WMIC) as a platform to provide education and guidance on three areas that are particularly critical to young scientists: networking, career development, and funding. In the coming years, ESPMIS plans to continue its focus on these topics, work with the WMIS on the creation of new digital tools for young scientists, and introduce two new areas of emphasis: the importance of mentoring and international career opportunities. We at ESPMIS sincerely believe that the future is bright for young scientists in molecular imaging, and we are here to help.

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Source-Based Morphometry Multivariate Approach to Analyze [ 123 I]FP-CIT SPECT Imaging

Abstract

Purpose

[¹²³I]FP-CIT (DaTSCAN®) single-photon emission computed tomography (SPECT) imaging is widely used to study neurodegenerative parkinsonism, by measuring presynaptic dopamine transporter (DAT) in striatal regions. Beyond DAT, [¹²³I]FP-CIT may be considered for other monoaminergic systems, in particular the serotonin transporter (SERT). Independent component analysis (ICA) implemented in source-based morphometry (SBM) could represent an alternative method to explore monoaminergic pathways, studying the relationship among voxels and grouping them into “neurotransmission” networks.

Procedures

One hundred forty-three subjects [84 with Parkinson’s disease (PD) and 59 control individuals (CG)] underwent DATSCAN® imaging. The [¹²³I]FP-CIT binding was evaluated by multivariate SBM approach, as well as by a whole-brain voxel-wise univariate (statistical parametric mapping, SPM) approach.

Results

As compared to the univariate whole-brain approach (SPM) (only demonstrating striatal [¹²³I]FP-CIT binding reduction in PD group), SBM identified six sources of non-artefactual origin, including basal ganglia and cortical regions as well as brainstem. Among them, three sources (basal ganglia and cortical regions) presented loading scores (as index of [¹²³I]FP-CIT binding) significantly different between PD and CG. Notably, even if not significantly different between PD and CG, the remaining three non-artefactual sources were characterized by a predominant frontal, brainstem, and occipito-temporal involvement.

Conclusion

The concept of source blind separation by the application of ICA (as implemented in SBM) represents a feasible approach to be considered in [¹²³I]FP-CIT (DaTSCAN^®) SPECT imaging. Taking advantage of this multivariate analysis, specific patterns of variance can be identified (involving either striatal than extrastriatal regions) that could be useful in differentiating neurodegenerative parkinsonisms.

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Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

Abstract

Purpose

The folate receptor (FR) has emerged as an interesting diagnostic and therapeutic drug target with many potential applications in oncologic and inflammatory disorders. It was therefore the aim of this study to develop a folate-derived Ga-68-based positron emission tomography (PET) imaging tracer that is straightforward to radiolabel and could be broadly used in clinical studies. We validated its target binding affinity and specificity and compared it to [^99mTc]EC20, the folate single-photon emission computed tomography (SPECT) imaging tracer that has been most extensively studied clinically so far.

Procedures

The new folic acid-derived PET imaging agent is linked via a polyethyleneglycol linker to the chelator 1,4,7-triazacyclononane-1,4,7-trisacetic acid (NOTA). This new compound, NOTA-folate, was labeled with gallium-68. We tested the probe’s stability in human plasma and its selectivity in vitro, using the FR-positive KB cell line as well as the FR-negative A549 cell line. The pharmacokinetic profile of [⁶⁸Ga]NOTA-folate was evaluated in FR-positive KB mouse xenografts. Following intravenous injection of [⁶⁸Ga]NOTA-folate (383 ± 53 μCi), PET/computed tomography (CT) imaging studies as well as biodistribution studies were performed using KB tumor-bearing mice (n = 3). In vitro as well as in vivo studies were performed in parallel with the SPECT imaging tracer [^99mTc]EC20.

Results

In comparison to [^99mTc]EC20 (radiochemical yield (RCY) = 82.0 ± 2.9 %, 91.8 ± 2.0 % purity), similar radiochemical yield (87.2 ± 6.9 %) and radiochemical purity (95.6 ± 1.8 %) could be achieved for [⁶⁸Ga]NOTA-folate. For both tracers, we observed high affinity for FR-positive cells in vitro and high plasma stability. In PET/CT and biodistribution studies, [⁶⁸Ga]NOTA-folate appeared to display slightly superior in vivo performance in comparison to [^99mTc]EC20. In detail, ⁶⁸Ga-NOTA-folate showed very good tumor uptake and retention (6.6 ± 1.1 %ID/g), relatively low kidney uptake (21.7 ± 1.1 %ID/g), and very low liver uptake (0.38 ± 0.08 %ID/g). In vivo blocking studies using a fivefold excess of EC20 reduced the tumor uptake to 2.5 ± 0.7 %ID/g, confirming receptor specific binding of [⁶⁸Ga]NOTA-folate in vivo.

Conclusion

We validated a new Ga-68 folate-based PET imaging agent with excellent pharmacokinetics and tumor uptake. Based on a head-to-head comparison between both tracers, [⁶⁸Ga]NOTA-folate is a suitable imaging probe for the delineation of FR-positive tumors and a promising candidate for clinical translation.

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Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway [Research]

Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3a^f/f mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL⁺ cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.—Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

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