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Sample records for lesanded hes sellega

  1. Hypereosinophilic Syndrome (HES)

    MedlinePlus

    ... and is part of the larger group of Myeloproliferative Neoplasms. Closely related disease to HES is chronic eosinophilic ... long-term therapy. Overall experience with IFNa in myeloproliferative neoplasms is that about 25-30% of patients require ...

  2. HES6 enhances the motility of alveolar rhabdomyosarcoma cells

    SciTech Connect

    Wickramasinghe, Caroline M; Domaschenz, Renae; Amagase, Yoko; Williamson, Daniel; Missiaglia, Edoardo; Shipley, Janet; Murai, Kasumi; Jones, Philip H

    2013-01-01

    Absract: HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.

  3. HES6 promotes prostate cancer aggressiveness independently of Notch signalling.

    PubMed

    Carvalho, Filipe L F; Marchionni, Luigi; Gupta, Anuj; Kummangal, Basheer A; Schaeffer, Edward M; Ross, Ashley E; Berman, David M

    2015-07-01

    Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high-grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer-specific up-regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up- and down-regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor-independent manner. Using a Notch-sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell-autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression.

  4. Enzymatically catalyzed HES conjugation using microbial transglutaminase: Proof of feasibility.

    PubMed

    Besheer, Ahmed; Hertel, Thomas C; Kressler, Jörg; Mäder, Karsten; Pietzsch, Markus

    2009-11-01

    Polymer-drug and polymer-protein conjugates are promising candidates for the delivery of therapeutic agents. PEGylation, using poly(ethylene glycol) for the conjugation, is now the gold standard in this field, and some PEGylated proteins have successfully reached the market. Hydroxyethyl starch (HES) is a water-soluble, biodegradable derivative of starch that is currently being investigated as a substitute for PEG. So far, only chemical methods have been suggested for HES conjugation; however, these may have detrimental effects on proteins. Here, we report an enzymatic method for HES conjugation using a recombinant microbial transglutaminase (rMTG). The latter catalyzes the acyl transfer between the gamma-carboxamide group of a glutaminyl residue (acyl donors) and a variety of primary amines (acyl acceptors), including the amino group of lysine. HES was modified with N-carbobenzyloxy glutaminyl glycine (Z-QG) and hexamethylene diamine (HMDA) to act as acyl donor and acyl acceptor, respectively. Using (1)H NMR, the degree of modification with Z-QG and HMDA was found to be 4.6 and 3.9 mol%, respectively. Using SDS-PAGE, it was possible to show that the modified HES successfully coupled to test compounds, proving that it is accepted as a substrate by rMTG. Finally, the process described in this study is a simple, mild approach to produce fully biodegradable polymer-drug and polymer-protein conjugates. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

  5. [Abnormal Notch-Hes Signaling Pathways and Acute Leukemia -Review].

    PubMed

    Gu, Zhen-Yang; Wang, Li; Gao, Chun-Ji

    2017-02-01

    The abnormal activation of Notch signaling is closely related to the development of acute leukemia (AL). The core elements of the Notch signaling system include Notch receptors, Notch ligands, CSL DNA-binding proteins, and effectors like target genes. Any factors, which affect ligands, receptors, signal transducers and effectors, can influence the signal transduction of Notch signaling greatly. Based on the role of Notch signaling in AL, several targeted drugs against Notch upstream signaling have been developed. However, due to the complexity and pleiotropic effects of Notch upstream signaling, these targeted drugs display strong side effects. Thus, Hes (Hairy Enhancer of Split) factors as a primary Notch effector, also play an important role in the pathogenesis of AL. This review summarizes recent progresses on Notch-Hes signaling in AL, hopping to provide references for further excavation of the Notch-Hes signaling, and lay foundations for developing the next generation of targeted drugs.

  6. Results of NASA/NOAA HES Trade Studies

    NASA Technical Reports Server (NTRS)

    Susskind, Joel

    2011-01-01

    This slide presentation reviews the trade studies that were done for the Hyperspectral Environmental Suite (HES). The goal of the trade studies was to minimize instrument cost and risk while producing scientifically useful products. Three vendors were selected to perform the trade study, and were to conduct 11 studies, with the first study a complete wish list of things that scientists would like from GEO orbit to the 11th study which was for a Reduced Accommodation Sounder (RAS) which would still result in useful scientific products, within constrains compatible with flight on GEOS-R. The RAS's from each vendor and one other HES sounders designs are reviewed.

  7. Expression dynamics and functions of Hes factors in development and diseases.

    PubMed

    Kobayashi, Taeko; Kageyama, Ryoichiro

    2014-01-01

    Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1-7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences, while the HLH region forms homo- and heterodimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits corepressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate-determination steps of embryonic stem cells and neural progenitor cells. Here, we discuss some key features of Hes factors in development and diseases.

  8. The Hospice Environmental Survey (HES): Pilot Test of a New Measurement Instrument.

    ERIC Educational Resources Information Center

    Taylor, Jean H.; Perrill, Norman K.

    1988-01-01

    Describes development of the Hospice Environmental Survey (HES) to measure user's perception of the homelike atmosphere provided by a hospital inpatient unit called Hospice House. Presents the HES instrument, methodology, and pilot study data. (Author/NB)

  9. Identification of small molecule Hes1 modulators as potential anticancer chemotherapeutics.

    PubMed

    Sail, Vibhavari; Hadden, M Kyle

    2013-03-01

    Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.

  10. Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling

    PubMed Central

    Guiu, Jordi; Shimizu, Ritsuko; D’Altri, Teresa; Fraser, Stuart T.; Hatakeyama, Jun; Bresnick, Emery H.; Kageyama, Ryoichiro; Dzierzak, Elaine; Yamamoto, Masayuki; Espinosa, Lluis

    2013-01-01

    Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs. PMID:23267012

  11. Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development.

    PubMed

    Tateya, Tomoko; Imayoshi, Itaru; Tateya, Ichiro; Ito, Juichi; Kageyama, Ryoichiro

    2011-04-15

    Notch-mediated lateral inhibition has been reported to regulate auditory hair cell and supporting cell development from common precursors. While the Notch effector genes Hes1, Hes5 and Hey1 are expressed in the developing cochlea, inactivation of either of them causes only mild abnormality, suggesting their functional redundancy. To explore the roles of Hes/Hey genes in cochlear development, we examined compound heterozygous or homozygous mutant mice that lacked Hes1, Hes5 and Hey1 alleles. We found that a reduction in Hes/Hey gene dosage led to graded increase of hair cell formation. However, if at least one allele of Hes1, Hes5 or Hey1 was intact, excessive hair cells were accompanied by overproduction of supporting cells, suggesting that the hair cell increase does not occur at the expense of supporting cells, and that each Hes/Hey gene functions to induce supporting cells. By contrast, when all alleles of Hes1, Hes5 and Hey1 were inactivated, the number of hair cells increased more drastically, whereas that of supporting cells was unchanged compared with control, suggesting that supporting cell formation was balanced by their overproduction and fate conversion into hair cells. The increase of the cell numbers seemed to occur after the prosensory domain formation in the mutants because the proliferation state and the size of the prosensory domain were not affected. Thus, Hes1, Hes5 and Hey1 cooperatively inhibit hair cell formation, and one allele of Hes1, Hes5 or Hey1 is sufficient for supporting cell production probably by lateral inhibition in the sensory epithelium. Strikingly, Hes/Hey mutations lead to disorganized cell alignment and polarity and to hearing loss despite hair cell overproduction. These results suggest that Hes/Hey gene dosage is essential not only for generation of appropriate numbers of hair cells and supporting cells by controlling cell proliferation and lateral inhibition but also for the hearing ability by regulating the cell alignment

  12. History of a prolific family: the Hes/Hey-related genes of the annelid Platynereis

    PubMed Central

    2014-01-01

    Background The Hes superfamily or Hes/Hey-related genes encompass a variety of metazoan-specific bHLH genes, with somewhat fuzzy phylogenetic relationships. Hes superfamily members are involved in a variety of major developmental mechanisms in metazoans, notably in neurogenesis and segmentation processes, in which they often act as direct effector genes of the Notch signaling pathway. Results We have investigated the molecular and functional evolution of the Hes superfamily in metazoans using the lophotrochozoan Platynereis dumerilii as model. Our phylogenetic analyses of more than 200 Metazoan Hes/Hey-related genes revealed the presence of five families, three of them (Hes, Hey and Helt) being pan-metazoan. Those families were likely composed of a unique representative in the last common metazoan ancestor. The evolution of the Hes family was shaped by many independent lineage specific tandem duplication events. The expression patterns of 13 of the 15 Hes/Hey-related genes in Platynereis indicate a broad functional diversification. Nevertheless, a majority of these genes are involved in two crucial developmental processes in annelids: neurogenesis and segmentation, resembling functions highlighted in other animal models. Conclusions Combining phylogenetic and expression data, our study suggests an unusual evolutionary history for the Hes superfamily. An ancestral multifunctional annelid Hes gene may have undergone multiples rounds of duplication-degeneration-complementation processes in the lineage leading to Platynereis, each gene copies ensuring their maintenance in the genome by subfunctionalisation. Similar but independent waves of duplications are at the origin of the multiplicity of Hes genes in other metazoan lineages. PMID:25250171

  13. Differential regulation of Hes/Hey genes during inner ear development.

    PubMed

    Petrovic, Jelena; Gálvez, Hector; Neves, Joana; Abelló, Gina; Giraldez, Fernando

    2015-07-01

    Notch signaling plays a crucial role during inner ear development and regeneration. Hes/Hey genes encode for bHLH transcription factors identified as Notch targets. We have studied the expression and regulation of Hes/Hey genes during inner ear development in the chicken embryo. Among several Hes/Hey genes examined, only Hey1 and Hes5 map to the sensory regions, although with salient differences. Hey1 expression follows Jag1 expression except at early prosensory stages while Hes5 expression corresponds well to Dl1 expression throughout otic development. Although Hey1 and Hes5 are direct Notch downstream targets, they differ in the level of Notch required for activation. Moreover, they also differ in mRNA stability, showing different temporal decays after Notch blockade. In addition, Bmp, Wnt and Fgf pathways also modify Hey1 and Hes5 expression in the inner ear. Particularly, the Wnt pathway modulates Hey1 and Jag1 expression. Finally, gain of function experiments show that Hey1 and Hes5 cross-regulate each other in a complex manner. Both Hey1 and Hes5 repress Dl1 and Hes5 expression, suggesting that they prevent the transition to differentiation stages, probably by preventing Atoh1 expression. In spite of its association with Jag1, Hey1 does not seem to be instrumental for lateral induction as it does not promote Jag1 expression. We suggest that, besides being both targets of Notch, Hey1 and Hes5 are subject to a rather complex regulation that includes the stability of their transcripts, cross regulation and other signaling pathways.

  14. The transcriptional repressor Hes1 attenuates inflammation via regulating transcriptional elongation

    PubMed Central

    Shang, Yingli; Coppo, Maddalena; He, Teng; Ning, Fei; Yu, Li; Kang, Lan; Zhang, Bin; Ju, Chanyang; Qiao, Yu; Zhao, Baohong; Gessler, Manfred; Rogatsky, Inez; Hu, Xiaoyu

    2016-01-01

    Most of the known regulatory mechanisms that curb inflammatory gene expression target pre-transcription initiation steps and evidence for regulation of inflammatory gene expression post initiation remains scarce. Here we show that transcription repressor hairy and enhancer of split 1 (Hes1) suppresses production of CXCL1, a chemokine crucial for recruiting neutrophils. Hes1 negatively regulates neutrophil recruitment in vivo in a manner that is dependent on macrophage-produced CXCL1 and attenuates severity of inflammatory arthritis. Mechanistically, inhibition of Cxcl1 expression by Hes1 does not involve modification of transcription initiation. Instead, Hes1 inhibits signal-induced recruitment of positive transcription elongation complex P-TEFb, thereby preventing phosphorylation of RNA polymerase II on serine-2 and productive elongation. Thus, our results identify Hes1 as a homeostatic suppressor of inflammatory responses which exerts its suppressive function by regulating transcription elongation. PMID:27322654

  15. Hes1: a key role in stemness, metastasis and multidrug resistance

    PubMed Central

    Liu, Zi-Hao; Dai, Xiao-Meng; Du, Bin

    2015-01-01

    Hes1 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability. Recent studies have shown that Hes1 functions in the maintenance of cancer stem cells (CSCs), metastasis and antagonizing drug-induced apoptosis. Pathways that are involved in the up-regulation of Hes1 level canonically or non-canonically, such as the Hedgehog, Wnt and hypoxia pathways are frequently aberrant in cancer cells. Here, we summarize the recent data supporting the idea that Hes1 may have an important function in the maintenance of cancer stem cells self-renewal, cancer metastasis, and epithelial–mesenchymal transition (EMT) process induction, as well as chemotherapy resistance, and conclude with the possible mechanisms by which Hes1 functions have their effect, as well as their crosstalk with other carcinogenic signaling pathways. PMID:25781910

  16. Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

    PubMed Central

    Markenstein, Lisa; Appelt-Menzel, Antje; Metzger, Marco

    2014-01-01

    Summary The mono-6-deoxy-6-azides of 2,6-di-O-methyl-β-cyclodextrin (DIMEB) and randomly methylated-β-cyclodextrin (RAMEB) were conjugated to propargylated hydroxyethyl starch (HES) by Cu+-catalysed [2 + 3] cycloaddition. The resulting water soluble polymers showed lower critical solution temperatures (LCST) at 52.5 °C (DIMEB-HES) and 84.5 °C (RAMEB-HES), respectively. LCST phase separations could be completely avoided by the introduction of a small amount of carboxylate groups at the HES backbone. The methylated CDs conjugated to the HES backbone exhibited significantly lower cytotoxicities than the corresponding monomeric CD derivatives. Since the binding potentials of these CD conjugates were very high, they are promising candidates for new oral dosage forms of anaesthetic actives. PMID:25670977

  17. Hes1 Is Expressed in the Second Heart Field and Is Required for Outflow Tract Development

    PubMed Central

    Mesbah, Karim; Jarry, Thérèse; Mattei, Marie-Geneviève; Kelly, Robert G.

    2009-01-01

    Background Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation of this process leads to congenital heart defects. In order to provide further insight into second heart field development we characterized the insertion site of a transgene expressed in the second heart field and outflow tract as the result of an integration site position effect. Results Here we show that the integration site of the A17-Myf5-nlacZ-T55 transgene lies upstream of Hes1, encoding a basic helix-loop-helix containing transcriptional repressor required for the maintenance of diverse progenitor cell populations during embryonic development. Transgene expression in a subset of Hes1 expression sites, including the CNS, pharyngeal epithelia, pericardium, limb bud and lung endoderm suggests that Hes1 is the endogenous target of regulatory elements trapped by the transgene. Hes1 is expressed in pharyngeal endoderm and mesoderm including the second heart field. Analysis of Hes1 mutant hearts at embryonic day 15.5 reveals outflow tract alignment defects including ventricular septal defects and overriding aorta. At earlier developmental stages, Hes1 mutant embryos display defects in second heart field proliferation, a reduction in cardiac neural crest cells and failure to completely extend the outflow tract. Conclusions Hes1 is expressed in cardiac progenitor cells in the early embryo and is required for development of the arterial pole of the heart. PMID:19609448

  18. HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression

    PubMed Central

    Revollo, Javier R.; Oakley, Robert H.; Lu, Nick Z.; Kadmiel, Mahita; Gandhavadi, Maheer; Cidlowski, John A.

    2014-01-01

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the genome. We now establish a genome wide molecular link between HES1 and glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This glucocorticoid-dependent repression of HES1 was necessary for the glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper glucocorticoid signaling. PMID:24300895

  19. HES5 silencing is an early and recurrent change in prostate tumourigenesis

    PubMed Central

    Massie, Charles E; Spiteri, Inmaculada; Ross-Adams, Helen; Luxton, Hayley; Kay, Jonathan; Whitaker, Hayley C; Dunning, Mark J; Lamb, Alastair D; Ramos-Montoya, Antonio; Brewer, Daniel S; Cooper, Colin S; Eeles, Rosalind; Warren, Anne Y; Tavaré, Simon; Neal, David E; Lynch, Andy G

    2015-01-01

    Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86–97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour–normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2′-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies. PMID:25560400

  20. Dynamic expression and essential functions of Hes7 in somite segmentation.

    PubMed

    Bessho, Y; Sakata, R; Komatsu, S; Shiota, K; Yamada, S; Kageyama, R

    2001-10-15

    The basic helix-loop-helix (bHLH) gene Hes7, a putative Notch effector, encodes a transcriptional repressor. Here, we found that Hes7 expression oscillates in 2-h cycles in the presomitic mesoderm (PSM). In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. As a result, the somite derivatives such as vertebrae and ribs are severely disorganized. Although expression of Notch and its ligands is not affected significantly, the oscillator and Notch modulator lunatic fringe is expressed continuously throughout the mutant PSM. These results indicate that Hes7 controls the cyclic expression of lunatic fringe and is essential for coordinated somite segmentation.

  1. The viscous characterization of hydroxyethyl starch (HES) plasma volume expanders in a non-Newtonian blood analog.

    PubMed

    Walker, Andrew M; Xiao, Yao; Johnston, Clifton R; Rival, David E

    2013-01-01

    Although information pertaining to the viscous characterization of HES 130/0.4 Voluven® and HES 260/0.45 Pentaspan® is available, quantification is limited to 100% concentrations. We focus here on the quantification of their viscous behavior along with HES 130/0.4 Volulyte® in a shear thinning non-Newtonian blood analog of aqueous xanthan gum and glycerol. Dynamic viscosities of multiple batches of HES fluids were measured through capillary viscometry. The viscous behavior of 100%, 25% and 12.5% concentrations were then measured through a closed flow loop across physiologically relevant flow rates. Measured viscosities were 2.57 millipascal second (mPa·s) 6.52 mPa·s and 2.48 mPa·s for HES 130/0.4 Voluven®, HES 260/0.45 and HES 130/0.4 Volulyte®, respectively. Pipe flow analysis found that all HES fluids displayed Newtonian behavior at 100% concentrations. 25% concentrations of both HES 130/0.4 fluids decreased analog viscosity 23%-29% at a flow rate of 1.0 ml/s and 16%-21% at a flow rate of 22.5 ml/s. At a flow rate of 22.5 ml/s, 25% and 12.5% concentrations of HES 260/0.45 resulted in analog viscosity changes of 3.9%-4.5%. Capillary viscosity reductions of approximately 7% and 14.5% in HES 130/0.4 Voluven® and HES 260/0.45 suggest changes in molecular composition to batches previously measured. Maintenance of analog viscosity suggests that HES 260/0.45 would be suitable as a high viscosity plasma expander in extreme hemodilution through preservation of microcirculatory function and wall shear stress (WSS).

  2. Hes4 controls proliferative properties of neural stem cells during retinal ontogenesis.

    PubMed

    El Yakoubi, Warif; Borday, Caroline; Hamdache, Johanna; Parain, Karine; Tran, Hong Thi; Vleminckx, Kris; Perron, Muriel; Locker, Morgane

    2012-12-01

    The retina of fish and amphibian contains genuine neural stem cells located at the most peripheral edge of the ciliary marginal zone (CMZ). However, their cell-of-origin as well as the mechanisms that sustain their maintenance during development are presently unknown. We identified Hes4 (previously named XHairy2), a gene encoding a bHLH-O transcriptional repressor, as a stem cell-specific marker of the Xenopus CMZ that is positively regulated by the canonical Wnt pathway and negatively by Hedgehog signaling. We found that during retinogenesis, Hes4 labels a small territory, located first at the pigmented epithelium (RPE)/neural retina (NR) border and later in the retinal margin, that likely gives rise to adult retinal stem cells. We next addressed whether Hes4 might impart this cell subpopulation with retinal stem cell features: inhibited RPE or NR differentiation programs, continuous proliferation, and slow cell cycle speed. We could indeed show that Hes4 overexpression cell autonomously prevents retinal precursor cells from commitment toward retinal fates and maintains them in a proliferative state. Besides, our data highlight for the first time that Hes4 may also constitute a crucial regulator of cell cycle kinetics. Hes4 gain of function indeed significantly slows down cell division, mainly through the lengthening of G1 phase. As a whole, we propose that Hes4 maintains particular stemness features in a cellular cohort dedicated to constitute the adult retinal stem cell pool, by keeping it in an undifferentiated and slowly proliferative state along embryonic retinogenesis.

  3. HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion

    SciTech Connect

    Ball, Andrew J.; Abrahamsson, Annelie E.; Tyrberg, Bjoern; Itkin-Ansari, Pamela; Levine, Fred; E-mail: flevine@ucsd.edu

    2007-04-06

    To examine the mechanism by which growth-stimulated pancreatic {beta}-cells dedifferentiate, somatic cell fusions were performed between MIN6, a highly differentiated mouse insulinoma, and {beta}lox5, a cell line derived from human {beta}-cells which progressively dedifferentiated in culture. MIN6/{beta}lox5 somatic cells hybrids underwent silencing of insulin expression and a marked decline in PDX1, NeuroD, and MafA, indicating that {beta}lox5 expresses a dominant transacting factor(s) that represses {beta}-cell differentiation. Expression of Hes1, which inhibits endocrine differentiation was higher in hybrid cells than in parental MIN6 cells. Hes6, a repressor of Hes1, was highly expressed in primary {beta}-cells as well as MIN6, but was repressed in hybrids. Hes6 overexpression using a retroviral vector led to a decrease in Hes1 levels, an increase in {beta}-cell transcription factors and partial restoration of insulin expression. We conclude that the balance of Notch activators and inhibitors may play an important role in maintaining the {beta}-cell differentiated state.

  4. Hes1 Desynchronizes Differentiation of Pluripotent Cells by Modulating STAT3 Activity

    PubMed Central

    Zhou, Xinzhi; Smith, Andrew JH; Waterhouse, Anna; Blin, Guillaume; Malaguti, Mattias; Lin, Chia-Yi; Osorno, Rodrigo; Chambers, Ian; Lowell, Sally

    2013-01-01

    Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously. Stem Cells 2013;31:1511–1522 PMID:23649667

  5. Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity.

    PubMed

    Zhou, Xinzhi; Smith, Andrew J H; Waterhouse, Anna; Blin, Guillaume; Malaguti, Mattias; Lin, Chia-Yi; Osorno, Rodrigo; Chambers, Ian; Lowell, Sally

    2013-08-01

    Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously.

  6. Hes1 is involved in the self-renewal and tumourigenicity of stem-like cancer cells in colon cancer.

    PubMed

    Gao, Fei; Zhang, YuQin; Wang, ShengChun; Liu, YuanQiang; Zheng, Lin; Yang, JianQuan; Huang, Wei; Ye, YanFen; Luo, WeiRen; Xiao, Dong

    2014-02-04

    A small subpopulation of cancer cells with stem cell-like features might be responsible for tumour generation, progression, and chemoresistance. Hes1 influences the maintenance of certain stem cells and progenitor cells and the digestive systems. We found upregulated Hes1 in poorly differentiated cancer samples compared with well-differentiated tumour samples, and most of the adenocarcinomas exhibited significantly higher levels of Hes1 mRNA compared with that observed in matched normal colon samples. Moreover, Hes1 expression was found to be correlated with the expression of stem cell markers in colon cancer samples, and Hes1 upregulates the expression of stemness-related genes in colon cancer cells. In addition, Hes1 enhances the self-renewal properties of the stem-like cells by increasing the sizes of CD133+ cells and SP cells and the ability of tumour sphere formation. Additionally, the Hes1-overexpressing cells formed significantly larger and higher number of colonies, as determined through the colony and the soft agar assays. More importantly, Hes1 enhances the tumourigenicity of colon cancer cell lines in nude mice and exhibits a strong tumour-formation ability at a cell density of 1 × 10(3). Taken together, our data indicate that Hes1 induces stem-like cell self-renewal and increases the number of tumour-initiating cells in colon cancer.

  7. Geostationary Operational Environmental Satellites (GOES): R series hyperspectral environmental suite (HES) overview

    NASA Astrophysics Data System (ADS)

    Martin, Gene; Criscione, Joseph C.; Cauffman, Sandra A.; Davis, Martin A.

    2004-11-01

    The Hyperspectral Environmental Suite (HES) instrument is currently under development by the NASA GOES-R Project team within the framework of the GOES Program to fulfill the future needs and requirements of the National Environmental Satellite, Data, and Information Service (NESDIS) Office. As part of the GOES-R instrument complement, HES will provide measurements of the traditional temperature and water vapor vertical profiles with higher accuracy and vertical resolution than obtained through current sounder technologies. HES will provide measurements of the properties of the shelf and coastal waters and back up imaging (at in-situ resolution) for the GOES-R Advanced Baseline Imager (ABI). The HES team is forging the future of remote environmental monitoring with the development of an operational instrument with high temporal, spatial and spectral-resolution and broad hemispheric coverage. The HES development vision includes threshold and goal requirements that encompass potential system solutions. The HES team has defined tasks for the instrument(s) that include a threshold functional complement of Disk Sounding (DS), Severe Weather/Mesoscale Sounding (SW/M), and Shelf and Coastal Waters imaging (CW) and a goal functional complement of Open Ocean (OO) imaging, and back up imaging (at in-situ resolution) for the GOES-R Advanced Baseline Imager (ABI). To achieve the best-value procurement, the GOES-R Project has base-lined a two-phase procurement approach to the HES design and development; a Formulation/study phase and an instrument Implementation phase. During Formulation, currently slated for the FY04-05 timeframe, the developing team(s) will perform Systems Requirements Analysis and evaluation, System Trade and Requirements Baseline Studies, Risk Assessment and Mitigation Strategy and complete a Preliminary Conceptual Design of the HES instrument. The results of the formulation phase will be leveraged to achieve an effective and efficient system solution during

  8. hESCCO: development of good practice models for hES cell derivation.

    PubMed

    Franklin, Sarah B; Hunt, Charles; Cornwell, Glenda; Peddie, Valerie; Desousa, Paul; Livie, Morag; Stephenson, Emma L; Braude, Peter R

    2008-01-01

    One response of the UK research community to the public sensitivity and logistical complexity of embryo donation to stem cell research has been the formation of a national network of 'human embryonic stem cell coordinators' (hESCCO). The aim of hESCCO is to contribute to the formation and implementation of national standards for hES cell derivation and banking, in particular the ethical protocols for patient information and informed consent. The hESCCO project is an innovative practical intervention within the broader attempt to establish greater transparency, consistency, efficiency and standardization of hES derivation in the UK. A major outcome of the hESCCO initiative has been the drafting and implementation of a national consent form. The lessons learned in this context may be relevant to other practitioners and regulators as a model of best practice in hES cell derivation.

  9. Using ABI to help HES for cloud property and atmospheric sounding retrieval

    NASA Astrophysics Data System (ADS)

    Li, Jun; Liu, Chian-Yi; Schmit, Timothy J.; Gurka, James J.; Menzel, W. P.

    2005-08-01

    The Advanced Baseline Imager (ABI) and the Hyperspectral Environmental Suite (HES) on GOES-R and beyond will enable improved monitoring of the distribution and evolution of atmospheric thermodynamics and clouds. The HES will be able to provide hourly atmospheric soundings with spatial resolution of 4 ~ 10 km with high accuracy using its high spectral resolution measurements. However, presence of clouds affects the sounding retrieval and needs to be dealt with properly. The ABI is able to provide at high spatial resolution (0.5 ~ 2km) a cloud mask, surface and cloud types, cloud phase mask, cloud top pressure (CTP), cloud particle size (CPS), and cloud optical thickness (COT), etc. The combined ABI/HES system offers the opportunity for atmospheric and cloud products improved over those possible from either system alone. The key step for synergistic use of ABI/HES radiance measurements is the collocation in space and time. Collocated ABI can (1) provide HES sub-pixel cloud characterization (mask, amount, phase, layer information, etc.) within the HES footprint; (2) be used for HES cloudclearing for partly cloudy HES footprints; (3) provide background information in variational retrieval of cloud properties with HES cloudy radiances. The Moderate-Resolution Imaging Spectroradiometer (MODIS) and the Atmospheric Infrared Sounder (AIRS) measurements from the Earth Observing System's (EOS) Aqua satellite provide the opportunity to study the synergistic use of advanced imager and sounder measurements. The combined MODIS and AIRS data for various scenes are analyzed to study the utility of synergistic use of ABI products and HES radiances for better retrieving atmospheric soundings and cloud properties. In order to derive sounding from combined ABI and HES radiances under HES partly cloudy footprint where no microwave sounding unit is available, an optimal cloud-removal or cloud-clearing algorithm is developed. MODIS and AIRS are used to verify the algorithm. AIRS clear

  10. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5.

    PubMed

    Langeron, O; Doelberg, M; Ang, E T; Bonnet, F; Capdevila, X; Coriat, P

    2001-04-01

    Hydroxyethyl starch (HES) solutions are effective plasma volume expanders. Impairment of coagulation occurs with large HES volumes infused perioperatively. Therefore, a lower substituted novel HES (Voluven; Fresenius Kabi, Bad Homburg, Germany) was developed to minimize hemostatic interactions, and was compared with HAES-steril (Fresenius Kabi) (pentastarch) regarding safety and efficacy. We performed a prospective, randomized, double-blinded study in 100 major orthopedic surgery patients. Because the 95% confidence interval (-330 mL; +284 mL) for the treatment contrast Voluven-HAES-steril was entirely included in the predefined equivalence range (+/- 500 mL), comparable efficacy was established. Voluven interfered significantly less than HAES-steril with coagulation factor VIII levels and partial thromboplastin time postoperatively. Total amounts of red blood cells transfused were comparable between the Voluven and HAES-steril groups, but a significantly reduced need for homologous red blood cells was observed in the Voluven group. We conclude that in large-blood-loss surgery, Voluven has a comparable efficacy with HAES-steril and may reduce coagulation impairment, possibly leading to a smaller number of allogeneic blood transfusions. Hydroxyethyl starches are common plasma volume expanders, but may interfere with coagulation at large doses. We tested a novel hydroxyethyl starch specification (Voluven; Fresenius Kabi, Bad Homburg, Germany) which was developed to reduce hemostatic interactions while preserving its efficacy in restoring plasma volume in comparison to HAES-steril (pentastarch; Fresenius Kabi) in major orthopedic surgery.

  11. Vertical resolution study on the GOES-R Hyperspectral Environmental Suite (HES)

    NASA Astrophysics Data System (ADS)

    Li, Jun; Wang, Fang; Schmit, Timothy J.; Menzel, W. Paul; Gurka, James J.

    2005-01-01

    High spectral resolution infrared radiances from the Hyperspectral Environmental Suite (HES) on Geostationary Operational Environmental Satellite (GOES-R and beyond) will allow for monitoring the evolution of atmospheric temperature and moisture vertical distributions. HES, together with the Advanced Baseline Imager (ABI), will operationally provide enhanced spatial, temporal and vertical information for radiances and atmospheric soundings that are desired by numerical weather forecast models. An algorithm has been developed to analyze the retrieval error and the vertical resolution of soundings from HES radiances. Trade-off studies have been done to balance the spectral coverage, spectral resolution, and signal-to-noise ratio in order to achieve the GOES users' requirement of 1 K accuracy with 1km vertical resolution for temperature and 10% accuracy with 2km vertical resolution for relative humidity. The vertical resolution capability of HES is also compared with that of the current GOES Sounder which has 18 infrared spectral channels and the Advanced Microwave Sounding Unit (AMSU) on the NOAA polar orbiting satellites that has good temperature sensitivity in the lower stratosphere and upper troposphere. The advantage of combination of GOES sounder and AMSU is also investigated.

  12. Delta-1 Activation of Notch-1 Signaling Results in HES-1 Transactivation

    PubMed Central

    Jarriault, Sophie; Le Bail, Odile; Hirsinger, Estelle; Pourquié, Olivier; Logeat, Frédérique; Strong, Clare F.; Brou, Christel; Seidah, Nabil G.; Israël, Alain

    1998-01-01

    The Notch receptor is involved in many cell fate determination events in vertebrates and invertebrates. It has been shown in Drosophila melanogaster that Delta-dependent Notch signaling activates the transcription factor Suppressor of Hairless, leading to an increased expression of the Enhancer of Split genes. Genetic evidence has also implicated the kuzbanian gene, which encodes a disintegrin metalloprotease, in the Notch signaling pathway. By using a two-cell coculture assay, we show here that vertebrate Dl-1 activates the Notch-1 cascade. Consistent with previous data obtained with active forms of Notch-1 a HES-1-derived promoter construct is transactivated in cells expressing Notch-1 in response to Dl-1 stimulation. Impairing the proteolytic maturation of the full-length receptor leads to a decrease in HES-1 transactivation, further supporting the hypothesis that only mature processed Notch is expressed at the cell surface and activated by its ligand. Furthermore, we observed that Dl-1-induced HES-1 transactivation was dependent both on Kuzbanian and RBP-J activities, consistent with the involvement of these two proteins in Notch signaling in Drosophila. We also observed that exposure of Notch-1-expressing cells to Dl-1 results in an increased level of endogenous HES-1 mRNA. Finally, coculture of Dl-1-expressing cells with myogenic C2 cells suppresses differentiation of C2 cells into myotubes, as previously demonstrated for Jagged-1 and Jagged-2, and also leads to an increased level of endogenous HES-1 mRNA. Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do. PMID:9819428

  13. A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed.

    PubMed

    Hartog, Christiane S; Kohl, Matthias; Reinhart, Konrad

    2011-03-01

    Hydroxyethyl starches (HES) are widely used for intravascular volume therapy in surgical, emergency, and intensive care patients. There are safety concerns with regard to coagulopathy, renal failure, pruritus, tissue storage, and mortality. Third-generation HES 130/0.4 is considered to have an improved risk profile. A common rationale for the use of HES is the belief that 3 to 4 times more crystalloid than colloid volume is needed to achieve similar hemodynamic end points. Our goal was to assess whether published studies on HES 130/0.4 resuscitation are sufficiently well designed to draw conclusions about the safety of this compound. In addition, we wanted to assess crystalloid-to-colloid fluid ratios in studies with goal-directed fluid regimen. Systematic review of randomized controlled trials in which HES 130/0.4 is used for resuscitation. We identified 56 randomized controlled trials (RCTs) with HES 130/0.4 in. acute hypovolemia, mainly from the elective surgical setting (n = 45). Surgical studies were small-sized (median 25 patients in the HES groups, range 10 to 90) and of short duration (median 12 hours, range 0.5 to 144 hours). The median cumulative HES dose was 2465 mL (range 328 to 6229 mL), corresponding to 35 mL/kg in a 70-kg patient, the daily dose limit being 50 mL/kg. End points mostly addressed variable surrogate outcomes. Sixty percent of control fluids were other HES solutions, gelatins, or dextran, which have a similar risk profile. Without exception, these studies were not designed for clinically important safety outcomes, primarily because they were too small, used mostly inadequate control fluids, and had inappropriately short observation periods. Therefore, and also because of heterogeneity of patient groups and outcome definitions, results from these studies cannot be pooled. These studies do not allow any conclusion about the safety of HES 130/0.4. There is a common belief that 3 to 4 times more crystalloid than colloid volume is necessary

  14. Molecular weight and molar substitution are more important in HES-induced renal impairment than concentration after hemorrhagic and septic shock.

    PubMed

    Simon, T P; Thiele, C; Schuerholz, T; Fries, M; Stadermann, F; Haase, G; Amann, K U; Marx, G

    2015-06-01

    Clinical studies have raised concerns about the safety of 6% hydroxyethylstarch (HES) 130/0.42, but the pathomechanisms of this renal impairment remain unknown. To evaluate the effects of different HES concentrations, molar substitutions and molecular weights in HES-induced renal impairment, we used a porcine two-hit model that combined haemorrhagic and septic shock. We conducted a prospective, randomised, double-blinded, controlled study in a university animal laboratory. Thirty anaesthetised and ventilated pigs were randomised to receive volume replacement therapy using 6% HES130/0.42, 6% HES200/0.5, 10% HES130/0.42 or 10% HES200/0.5, all dissolved in 0.9% NaCl rather than 0.9% NaCl alone. First, we bled the animals until they reached half of their baseline mean arterial pressure (MAP) for 45 minutes followed by fluid resuscitation. As a second hit, sepsis was induced using an Escherichia coli-laden clot 6 hours after haemorrhagic shock. Volume resuscitation started with a delay of two hours and a central venous pressure goal of 12 mmHg. At the end of the study, the groups showed no difference in cardiac output or MAP, but the volume balance (mL/kg BW) was significantly higher in the 0.9% NaCl group (346±90; P≤0.05) than in the other groups (6% HES130, 125±26; 6% HES200, 105±15; 10% HES130, 114±17; 10% HES200, 96±23). Creatinine clearance (mL/min) was significantly lower in the 6% HES200 (26±33) and 10% HES200 (15±18) groups compared to the 0.9% NaCl group (104±46; P≤0.05) but not in the HES 130 formulations (6% HES130: 64±51; 10% HES130: 58±38) at the end of the study. In this porcine two-hit shock model, treatment with 0.9% NaCl, HES 130/0.42 or HES 200/0.5 led to a similar maintenance of haemodynamic values. Despite this similar maintenance of the haemodynamic values, volume replacement with 6% and 10% HES 200/0.5 led to an accumulation of HES, higher colloid osmotic pressure and significantly reduced renal function after haemorrhagic and septic

  15. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness.

    PubMed

    Zhang, P; Yang, Y; Nolo, R; Zweidler-McKay, P A; Hughes, D P M

    2010-05-20

    The highly conserved NOTCH signaling pathway has many essential functions in the development of diverse cells, tissues and organs from Drosophila to humans, and dysregulated NOTCH signaling contributes to several disorders, including vascular and bone defects, as well as several cancers. Here we describe a novel mechanism of NOTCH regulation by reciprocal inhibition of two NOTCH downstream effectors: Deltex1 and HES1. This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH/HES1 signaling. The inhibitory effect of endogenous Deltex1 on NOTCH signaling is mediated through binding with the intracellular domain of NOTCH and ubiquitination and degradation of NOTCH receptors. Conversely, we show that the NOTCH target gene HES1 causes transcriptional inhibition of Deltex1 by directly binding to the promoter of Deltex1. An HES1 binding site is identified 400 bp upstream of the transcription start site of Deltex1. HES1-mediated repression of Deltex1 requires the C-terminal H3/H4 and WRPW domains of HES1, which associate with the TLE/Groucho corepressors. Taken together, we define a molecular mechanism regulating NOTCH signaling by reciprocal inhibition of the NOTCH target genes HES1 and Deltex1 in mammalian cells. This mechanism may have important clinical implications for targeting NOTCH signaling in osteosarcoma and other cancers.

  16. Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity

    PubMed Central

    Wall, Dana S.; Mears, Alan J.; McNeill, Brian; Mazerolle, Chantal; Thurig, Sherry; Wang, Yaping; Kageyama, Ryoichiro; Wallace, Valerie A.

    2009-01-01

    Sonic hedgehog (Shh) is an indispensable, extrinsic cue that regulates progenitor and stem cell behavior in the developing and adult mammalian central nervous system. Here, we investigate the link between the Shh signaling pathway and Hes1, a classical Notch target. We show that Shh-driven stabilization of Hes1 is independent of Notch signaling and requires the Shh effector Gli2. We identify Gli2 as a primary mediator of this response by showing that Gli2 is required for Hh (Hedgehog)-dependent up-regulation of Hes1. We also show using chromatin immunoprecipitation that Gli2 binds to the Hes1 promoter, which suggests that Hes1 is a Hh-dependent direct target of Gli2 signaling. Finally, we show that Shh stimulation of progenitor proliferation and cell diversification requires Gli2 and Hes1 activity. This paper is the first demonstration of the mechanistic and functional link between Shh, Gli, and Hes1 in the regulation of progenitor cell behavior. PMID:19124651

  17. Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells

    SciTech Connect

    Murano, Tatsuro; Okamoto, Ryuichi; Ito, Go; Nakata, Toru; Hibiya, Shuji; Shimizu, Hiromichi; Fujii, Satoru; Kano, Yoshihito; Mizutani, Tomohiro; Yui, Shiro; Akiyama-Morio, Junko; Nemoto, Yasuhiro; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Watanabe, Mamoru

    2014-01-17

    Highlights: •Hes1 enhances IL-22-STAT3 signaling in human intestinal epithelial cells. •Hes1 enhances REG family gene induction by IL-22-STAT3 signaling. •Protein level of Hes1 restricts the response to IL-22. •Present regulation of a cytokine signal represents a new mode of Hes1 function. -- Abstract: Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a γ-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs.

  18. Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review.

    PubMed

    Hartog, Christiane S; Reuter, Dorit; Loesche, Wolfgang; Hofmann, Michael; Reinhart, Konrad

    2011-11-01

    Hydroxyethyl starch solutions (HES) are plasma volume expanders which affect hemostasis. Newer HES 130/0.4 is said to be safer. Reevaluation of published evidence is necessary after the recent retraction of studies. Systematic review of studies assessing HES 130/0.4 effects on hemostasis by thrombelastography (TEG, ROTEM) or Sonoclot (SCR) in comparison with crystalloid or albumin control fluids was performed. Only studies which provided statistical comparisons between study fluids were analyzed. Studies were divided into in vitro or in vivo hemodilution studies. We assessed study quality, HES effects which differed significantly from controls, values outside normal range, degree of hemodilution, and cumulative HES dose. Seventeen in vitro and seven in vivo hemodilution studies were analyzed. Four studies reported quality control measures. Nineteen studies (all 15 ROTEM studies, 3 of 5 in vitro TEG, and 1 of 2 SCR studies) showed a significant hypocoagulatory effect of HES 130/0.4 on clot formation, while clotting time was not uniformly affected. Three in vivo TEG studies with low HES doses or cancer patients found mixed or nonsignificant results. In studies which provided normal ranges (n = 9), more values were outside normal ranges in the HES than in the control groups (87/122 vs. 58/122, p < 0.001). Dose effects were apparent in the in vitro studies, which investigated higher dilutions up to 80%. In vivo studies were fewer and did not investigate doses >40 ml/kg. HES 130/0.4 administration results in a weaker and smaller clot. Until results from well-designed clinical trials are available, safer fluids should be chosen for patients with impaired coagulation.

  19. Effects of different types of hydroxyethyl starch (HES) on microcirculation perfusion and tissue oxygenation in patients undergoing liver surgery.

    PubMed

    Cui, Yinghua; Sun, Bo; Wang, Changsong; Liu, Shujuan; Li, Peng; Shi, Jinghui; Li, Enyou

    2014-01-01

    To compare the effects of hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5, which have different molecular weights and degrees of substitution, on microcirculation perfusion and tissue oxygenation in patients undergoing liver surgery. Thirty patients with an American Society of Anesthesiologists status I/II who were scheduled for liver surgery were randomly divided into two groups: one received an intraoperative HES 130/0.4 infusion equal to the amount of blood loss (HES 130/0.4 group, n=15), and the other received HES 200/0.5 equal to the amount of blood loss (HES 200/0.5 group, n=15). Gastric mucosal perfusion and tissue oxygenation were monitored by measuring the gastric mucosal pH (pHi), which was determined using a carbon dioxide tonometer inserted through a nasogastric tube. Gastric mucosal pHi , hemodynamic parameters, body temperature, and blood gas parameters were recorded upon entering the operating room, before skin incision, one hour and two hours after skin incision, and at the end of surgery. The intraoperative pHi decreased in both groups of patients, but the decline in the HES 130/0.4 group was smaller than that of the HES 200/0.5 group. The pHi of the HES 130/0.4 group was significantly higher than that of the HES 200/0.5 group two hours after skin incision and at the end of surgery (P<0.05). A multivariate analysis showed that the type of colloid used intraoperatively was the only variant that affected pHi (F=0.626, P<0.05). Moreover, there were good correlation between pHi at the end of surgery and the length of postoperative hospital stay (r=-0.536, P<0.05) and the time intervals from surgery to the passage of flatus (r=-0.547, P<0.05). Compared with HES 200/0.5, the use of HES 130/0.4 (with a relatively lower molecular weight and lower degree of substitution) could significantly improve internal organ perfusion and tissue oxygenation in patients undergoing liver surgery with a relatively large amount of blood loss.

  20. Re: Coagulation and Fluid Resuscitation by HyperHES in Severe Hemorrhage

    DTIC Science & Technology

    2013-08-01

    administration of 4% gelatin or 6% hydroxyethyl starch solution. Anesth Analg. 2008;106:1078Y1086, table of contents. 5. Kramer GC. Hypertonic resuscitation...impair- ment of clot formation when compared with administration of 6% HES or 4% gelatine .4 Contrary to isotonic crystalloids and colloids, which play...pigs after resuscitation from hem- orrhagic shock using the small-volume con- cept with hypertonic saline/hydroxyethyl starch as compared to

  1. Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development.

    PubMed

    Ichi, Shunsuke; Costa, Fabricio F; Bischof, Jared M; Nakazaki, Hiromichi; Shen, Yueh-Wei; Boshnjaku, Vanda; Sharma, Saurabh; Mania-Farnell, Barbara; McLone, David G; Tomita, Tadanori; Soares, Marcelo B; Mayanil, Chandra S K

    2010-11-19

    The mechanism(s) behind folate rescue of neural tube closure are not well understood. In this study we show that maternal intake of folate prior to conception reverses the proliferation potential of neural crest stem cells in homozygous Splotch embryos (Sp(-/-)) via epigenetic mechanisms. It is also shown that the pattern of differentiation seen in these cells is similar to wild-type (WT). Cells from open caudal neural tubes of Sp(-/-) embryos exhibit increased H3K27 methylation and decreased expression of KDM6B possibly due to up-regulation of KDM6B targeting micro-RNAs such as miR-138, miR-148a, miR-185, and miR-339-5p. In our model, folate reversed these epigenetic marks in folate-rescued Sp(-/-) embryos. Using tissue from caudal neural tubes of murine embryos we also examined H3K27me2 and KDM6B association with Hes1 and Neurog2 promoters at embryonic day E10.5, the proliferative stage, and E12.5, when neural differentiation begins. In Sp(-/-) embryos compared with WT, levels of H3K27me2 associated with the Hes1 promoter were increased at E10.5, and levels associated with the Neurog2 promoter were increased at E12.5. KDM6B association with Hes1 and Neurog2 promoters was inversely related to H3K27me2 levels. These epigenetic changes were reversed in folate-rescued Sp(-/-) embryos. Thus, one of the mechanisms by which folate may rescue the Sp(-/-) phenotype is by increasing the expression of KDM6B, which in turn decreases H3K27 methylation marks on Hes1 and Neurog2 promoters thereby affecting gene transcription.

  2. Leak testing of IR sensor dewars to 1E-15 std He/s

    NASA Astrophysics Data System (ADS)

    Sasaki, Y. Tito; Bergquist, Lyle E.

    1990-09-01

    The results of tests for leakage performed on ten IR sensor dewars are presented, and the design principles of the new testing devices are discussed. The ultrasensitive leak detector used for testing is compared to conventional detectors. The superfine leak calibrator consisting of a tracer gas supply, an aliquot volume, a pressure transducer, temperature gage, and valves was used to measure leak rates in the E-4 to E-12 std cc He/s range. The testing method is explained, including the gases used, the quadrupole mass analyzer, the reference leak calibration, and the temperature coefficient of the reference leak. The test results of the IR sensor dewars are shown: seven showed leak rates in the E-15 std cc He/s range, two had no detectable leaks, and one had a mid-range E-14 leak. The shelf lives of the dewars are calculated based on the results. The vacuum integrity of small IR sensor dewars can be reliably tested to the range of 1E-15 std cc He/s using the ultrasensitive leak detector and the superfine leak calibrator.

  3. Qingyihuaji Formula Inhibits Pancreatic Cancer and Prolongs Survival by Downregulating Hes-1 and Hey-1.

    PubMed

    Xu, Yanli; Xu, Shan; Cai, Yueqin; Liu, Luming

    2015-01-01

    The dire prognosis of pancreatic cancer has not markedly improved during past decades. The present study was carried out to explore the effect of Qingyihuaji formula (QYHJ) on inhibiting pancreatic cancer and prolonging survival in related Notch signaling pathway. Proliferation of pancreatic cancer cells (SW1990 and PANC-1) was detected by MTT assay at 24, 48, and 72 h with exposure to various concentrations (0.08-50 mg/mL) of QYHJ water extract. Pancreatic tumor models of nude mice were divided into three groups randomly (control, QYHJ, and gemcitabine). mRNA and protein expression of Notch target genes (Hes-1, Hey-1, Hey-2, and Hey-L) in dissected tumor tissue were detected. Results showed that proliferation of SW1990 cells and PANC-1 cells was inhibited by QYHJ water extract in a dose-dependent and time-dependent manner. QYHJ effectively inhibited tumor growth and prolonged survival time in nude mice. Expression of both Hes-1 and Hey-1 was decreased significantly in QYHJ group, suggesting that Hes-1 and Hey-1 in Notch signaling pathway might be potential targets for QYHJ treatment. This research could help explain the clinical effectiveness of QYHJ and may provide advanced pancreatic cancer patients with a new therapeutic option.

  4. Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains

    PubMed Central

    Bai, Guang; Cheung, Iris; Shulha, Hennady P.; Coelho, Joana E.; Li, Ping; Dong, Xianjun; Jakovcevski, Mira; Wang, Yumei; Grigorenko, Anastasia; Jiang, Yan; Hoss, Andrew; Patel, Krupal; Zheng, Ming; Rogaev, Evgeny; Myers, Richard H.; Weng, Zhiping; Akbarian, Schahram; Chen, Jiang-Fan

    2015-01-01

    To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing. Neuron-specific mapping of the genome-wide distribution of H3K4me3 revealed 136 differentially enriched loci associated with genes implicated in neuronal development and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 at CpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteins to the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striatal development. Moreover, hypermethylation of HES4 promoter sequences was strikingly correlated with measures of striatal degeneration and age-of-onset in a cohort of 25 HD brains (r = 0.56, P = 0.006). Lastly, shRNA knockdown of HES4 in human neuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates and cell death. These findings, taken together, suggest that epigenetic dysregulation of HES4 could play a critical role in modifying HD disease pathogenesis and severity. PMID:25480889

  5. T cell development requires constraint of the myeloid regulator C/EBPa by the Notch target and transcriptional repressor Hes1

    PubMed Central

    De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin; Harly, Christelle; Yashiro-Ohtani, Yumi; DeLong, Jonathan H; Zlotoff, Daniel A; Sultana, Dil Afroz; Pear, Warren S; Bhandoola, Avinash

    2014-01-01

    Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBPa restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development. PMID:24185616

  6. Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses.

    PubMed

    Hartog, Christiane S; Skupin, Helga; Natanson, Charles; Sun, Junfeng; Reinhart, Konrad

    2012-08-01

    Hydroxyethyl starch (HES) is a synthetic colloid used widely for resuscitation despite the availability of safer, less costly fluids. Numerous HES reviews have been published that may have influenced clinicians' practice. We have therefore examined the relationship between the methodological quality of published HES reviews, authors' potential conflicts of interest (pCOI) and the recommendations made. Systematic analysis of reviews on HES use. Between 1975 and 2010, 165 reviews were published containing recommendations for or against HES use. From the 1990s onwards, favorable reviews increased from two to eight per year and HES's share of the artificial colloid market tripled from 20 to 60 %. Only 7 % (12/165) of these reviews of HES use contained meta-analyses; these 7 % had higher Overview Quality Assessment Questionnaire (OQAQ) scores [median (range) 6.5 (3-7)] than reviews without meta-analysis [2 (1-4); p < 0.001]. The rates of recommending against HES use are 83 % (10/12) in meta-analyses and 20 % (31/153) in reviews without meta-analysis (p < 0.0001). Fourteen authors published the majority (70/124) of positive reviews, and ten of these 14 had or have since developed a pCOI with various manufacturers of HES. Low-quality HES reviews reached different conclusions than high-quality meta-analyses from independent entities, such as Cochrane Reviews. The majority of these low-quality positive HES reviews were written by a small group of authors, most of whom had or have since established ties to industry. The proliferation of positive HES reviews has been associated with increased utilization of an expensive therapy despite the lack of evidence for meaningful clinical benefit and increased risks. Clinicians need to be more informed that marketing efforts are potentially influencing scientific literature.

  7. Hes1 triggers epithelial-mesenchymal transition (EMT)-like cellular marker alterations and promotes invasion and metastasis of nasopharyngeal carcinoma by activating the PTEN/AKT pathway.

    PubMed

    Wang, Sheng-Chun; Lin, Xiao-Lin; Wang, Hui-Yan; Qin, Yu-Juan; Chen, Lin; Li, Jing; Jia, Jun-Shuang; Shen, Hong-Fen; Yang, Sheng; Xie, Rao-Ying; Wei, Fang; Gao, Fei; Rong, Xiao-Xiang; Yang, Jie; Zhao, Wen-Tao; Zhang, Ting-Ting; Shi, Jun-Wen; Yao, Kai-Tai; Luo, Wei-Ren; Sun, Yan; Xiao, Dong

    2015-11-03

    Overexpression of the transcriptional factor Hes1 (hairy and enhancer of split-1) has been observed in numerous cancers, but the precise roles of Hes1 in epithelial-mesenchymal transition (EMT), cancer invasion and metastasis remain unknown. Our current study firstly revealed that Hes1 upregulation in a cohort of human nasopharyngeal carcinoma (NPC) biopsies is significantly associated with the EMT, invasive and metastatic phenotypes of cancer. In the present study, we found that Hes1 overexpression triggered EMT-like cellular marker alterations of NPC cells, whereas knockdown of Hes1 through shRNA reversed the EMT-like phenotypes, as strongly supported by Hes1-mediated EMT in NPC clinical specimens described above. Gain-of-function and loss-of-function experiments demonstrated that Hes1 promoted the migration and invasion of NPC cells in vitro. In addition, exogenous expression of Hes1 significantly enhanced the metastatic ability of NPC cells in vivo. Chromatin immunoprecipitation (ChIP) assays showed that Hes1 inhibited PTEN expression in NPC cells through binding to PTEN promoter region. Increased Hes1 expression and decreased PTEN expression were also observed in a cohort of NPC biopsies. Additional studies demonstrated that Hes1-induced EMT-like molecular changes and increased motility and invasion of NPC cells were mediated by PTEN. Taken together, our results suggest, for what we believe is the first time, that Hes1 plays an important role in the invasion and metastasis of NPC through inhibiting PTEN expression to trigger EMT-like phenotypes.

  8. A calcium-containing electrolyte-balanced hydroxyethyl starch (HES) solution is associated with higher factor VIII activity than is a non-balanced HES solution, but does not affect von Willebrand factor function or thromboelastometric measurements - results of a model of in vitro haemodilution

    PubMed Central

    Rau, Juliane; Rosenthal, Christoph; Langer, Elisabeth; Sander, Michael; Schulte, Erika; Schuster, Michael; von Heymann, Christian

    2014-01-01

    Background Hydroxyethyl starch (HES) is known to impair blood coagulation. The impact of calcium-containing, balanced carrier solutions of HES on coagulation is controversial. We investigated the effects of increasing degrees of haemodilution with modern 6%, electrolyte-balanced HES vs non-balanced HES on coagulation in vitro, and compared the balanced HES to a balanced crystalloid solution for an internal control. Materials and methods Blood samples from ten healthy volunteers were diluted in vitro by 20%, 40% and 60% with either calcium-containing balanced 130/0.42 HES, non-balanced 130/0.4 HES or balanced crystalloid. In all samples, blood counts, prothrombin time ratio, activated partial thromboplastin time, ionized calcium, factor VIII activity, von Willebrand factor antigen, von Willebrand factor collagen binding activity, and von Willebrand factor activity were determined, and activated rotational thromboelastometry (EXTEM and FIBTEM assays) was performed. Results Haemodilution impaired coagulation in a dilution-dependent manner as determined by both conventional laboratory assays and thromboelastometry. Ionized calcium increased with balanced HES (p≤0.004), but decreased with non-balanced HES (p≤0.004). Prothrombin time ratio (p≤0.002) and factor VIII levels (p=0.001) were better preserved with balanced HES than with non-balanced HES in dilutions ≥40%. Thromboelastometry showed no differences between values in blood diluted with the balanced or non-balanced HES. Discussion In vitro, a balanced calcium-containing carrier solution of 6% HES 130/0.42 preserved coagulation better than did non-balanced HES 130/0.4 as quantified by conventional coagulation assays, but not in activated thromboelastometry. One explanation could be the increased ionized calcium levels after dilution with calcium-containing carrier solutions. PMID:24333074

  9. The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

    PubMed Central

    Harrington, Heather A.; Dale, Trevor; Gavaghan, David J.

    2017-01-01

    The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch’s interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain

  10. The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt.

    PubMed

    Kay, Sophie K; Harrington, Heather A; Shepherd, Sarah; Brennan, Keith; Dale, Trevor; Osborne, James M; Gavaghan, David J; Byrne, Helen M

    2017-02-28

    The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its

  11. Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses

    PubMed Central

    Hartog, Christiane S.; Skupin, Helga; Natanson, Charles; Sun, Junfeng; Reinhart, Konrad

    2013-01-01

    Purpose Hydroxyethyl starch (HES) is a synthetic colloid used widely for resuscitation despite the availability of safer, less costly fluids. Numerous HES reviews have been published that may have influenced clinicians’ practice. We have therefore examined the relationship between the methodological quality of published HES reviews, authors’ potential conflicts of interest (pCOI) and the recommendations made. Methods Systematic analysis of reviews on HES use. Results Between 1975 and 2010, 165 reviews were published containing recommendations for or against HES use. From the 1990s onwards, favorable reviews increased from two to eight per year and HES’s share of the artificial colloid market tripled from 20 to 60 %. Only 7 % (12/165) of these reviews of HES use contained meta-analyses; these 7 % had higher Overview Quality Assessment Questionnaire (OQAQ) scores [median (range) 6.5 (3–7)] than reviews without meta-analysis [2 (1–4); p < 0.001]. The rates of recommending against HES use are 83 % (10/12) in meta-analyses and 20 % (31/153) in reviews without meta-analysis (p < 0.0001). Fourteen authors published the majority (70/124) of positive reviews, and ten of these 14 had or have since developed a pCOI with various manufacturers of HES. Conclusions Low-quality HES reviews reached different conclusions than high-quality meta-analyses from independent entities, such as Cochrane Reviews. The majority of these low-quality positive HES reviews were written by a small group of authors, most of whom had or have since established ties to industry. The proliferation of positive HES reviews has been associated with increased utilization of an expensive therapy despite the lack of evidence for meaningful clinical benefit and increased risks. Clinicians need to be more informed that marketing efforts are potentially influencing scientific literature. PMID:22790311

  12. Inflammatory Kidney and Liver Tissue Response to Different Hydroxyethylstarch (HES) Preparations in a Rat Model of Early Sepsis

    PubMed Central

    Schimmer, Ralph C.; Urner, Martin; Voigtsberger, Stefanie; Booy, Christa; Roth Z’Graggen, Birgit; Beck-Schimmer, Beatrice; Schläpfer, Martin

    2016-01-01

    Background Tissue hypoperfusion and inflammation in sepsis can lead to organ failure including kidney and liver. In sepsis, mortality of acute kidney injury increases by more than 50%. Which type of volume replacement should be used is still an ongoing debate. We investigated the effect of different volume strategies on inflammatory mediators in kidney and liver in an early sepsis model. Material and Methods Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) and assigned to three fluid replenishment groups. Animals received 30mL/kg of Ringer’s lactate (RL) for 2h, thereafter RL (75mL/kg), hydroxyethyl starch (HES) balanced (25mL/kg), containing malate and acetate, or HES saline (25mL/kg) for another 2h. Kidney and liver tissue was assessed for inflammation. In vitro rat endothelial cells were exposed to RL, HES balanced or HES saline for 2h, followed by stimulation with tumor necrosis factor-α (TNF-α) for another 4h. Alternatively, cells were exposed to malate, acetate or a mixture of malate and acetate, reflecting the according concentration of these substances in HES balanced. Pro-inflammatory cytokines were determined in cell supernatants. Results Cytokine mRNA in kidney and liver was increased in CLP animals treated with HES balanced compared to RL, but not after application of HES saline. MCP-1 was 3.5fold (95% CI: 1.3, 5.6) (p<0.01) and TNF-α 2.3fold (95% CI: 1.2, 3.3) (p<0.001) upregulated in the kidney. Corresponding results were seen in liver tissue. TNF-α-stimulated endothelial cells co-exposed to RL expressed 3529±1040pg/mL MCP-1 and 59±23pg/mL CINC-1 protein. These cytokines increased by 2358pg/mL (95% CI: 1511, 3204) (p<0.001) and 29pg/ml (95% CI: 14, 45) (p<0.01) respectively when exposed to HES balanced instead. However, no further upregulation was observed with HES saline. PBS supplemented with acetate increased MCP-1 by 1325pg/mL (95% CI: 741, 1909) (p<0.001) and CINC-1 by 24pg/mL (95% CI: 9, 38) (p<0

  13. TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells.

    PubMed

    Lee, Sung Hee; Hong, Hannah S; Liu, Zi Xiao; Kim, Reuben H; Kang, Mo K; Park, No-Hee; Shin, Ki-Hyuk

    2012-07-20

    Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.

  14. Hes1 is required for the development of the superior cervical ganglion of sympathetic trunk and the carotid body.

    PubMed

    Kameda, Yoko; Saitoh, Takayoshi; Nemoto, Noriko; Katoh, Tokio; Iseki, Sachiko

    2012-08-01

    Hes1 gene represses the expression of proneural basic helix-loop-helix (bHLH) factor Mash1, which is essential for the differentiation of the sympathetic ganglia and carotid body glomus cells. The sympathetic ganglia, carotid body, and common carotid artery in Wnt1-Cre/R26R double transgenic mice were intensely labeled by X-gal staining, i.e., the neural crest origin. The deficiency of Hes1 caused severe hypoplasia of the superior cervical ganglion (SCG). At embryonic day (E) 17.5-E18.5, the volume of the SCG in Hes1 null mutants was reduced to 26.4% of the value in wild-type mice. In 4 of 30 cases (13.3%), the common carotid artery derived from the third arch artery was absent in the null mutants, and the carotid body was not formed. When the common carotid artery was retained, the organ grew in the wall of the third arch artery and glomus cell precursors were provided from the SCG in the null mutants as well as in wild-types. However, the volume of carotid body in the null mutants was only 52.5% of the value in wild-types at E17.5-E18.5. These results suggest that Hes1 plays a critical role in regulating the development of neural crest derivatives in the mouse cervical region.

  15. Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice

    PubMed Central

    Hosokawa, Shinichi; Furuyama, Kenichiro; Horiguchi, Masashi; Aoyama, Yoshiki; Tsuboi, Kunihiko; Sakikubo, Morito; Goto, Toshihiko; Hirata, Koji; Tanabe, Wataru; Nakano, Yasuhiro; Akiyama, Haruhiko; Kageyama, Ryoichiro; Uemoto, Shinji; Kawaguchi, Yoshiya

    2015-01-01

    In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions. PMID:25687338

  16. The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia.

    PubMed

    Espinosa, Lluis; Cathelin, Severine; D'Altri, Teresa; Trimarchi, Thomas; Statnikov, Alexander; Guiu, Jordi; Rodilla, Veronica; Inglés-Esteve, Julia; Nomdedeu, Josep; Bellosillo, Beatriz; Besses, Carles; Abdel-Wahab, Omar; Kucine, Nicole; Sun, Shao-Cong; Song, Guangchan; Mullighan, Charles C; Levine, Ross L; Rajewsky, Klaus; Aifantis, Iannis; Bigas, Anna

    2010-09-14

    It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.

  17. The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

    PubMed Central

    Espinosa, Lluis; Cathelin, Severine; D’Altri, Teresa; Trimarchi, Thomas; Statnikov, Alexander; Guiu, Jordi; Rodilla, Veronica; Inglés-Esteve, Julia; Nomdedeu, Josep; Bellosillo, Beatriz; Besses, Carles; Abdel-Wahab, Omar; Kucine, Nicole; Sun, Shao-Cong; Song, Guangchan; Mullighan, Charles C.; Levine, Ross L.; Rajewsky, Klaus; Aifantis, Iannis; Bigas, Anna

    2010-01-01

    SUMMARY It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo. PMID:20832754

  18. Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells.

    PubMed

    Lee, Jung Bok; Werbowetski-Ogilvie, Tamra E; Lee, Jong-Hee; McIntyre, Brendan A S; Schnerch, Angelique; Hong, Seok-Ho; Park, In-Hyun; Daley, George Q; Bernstein, Irwin D; Bhatia, Mickie

    2013-08-15

    Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and small interfering RNA to Notch receptors we have demonstrated that Notch1, but not Notch2, activation induced hairy and enhancer of split 1 (HES1) expression and generation of committed hematopoietic progenitors. Using gain- and loss-of-function approaches, this was shown to be attributed to Notch-signaling regulation through HES1, which dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs endothelial fate specification.

  19. Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats.

    PubMed

    Xu, Xiao; Sun, Xin; Hu, Xue-Song; Zhuang, Yan; Liu, Yue-Chen; Meng, Hao; Miao, Lin; Yu, He; Luo, Shu-Jin

    2016-08-25

    Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits.

  20. Delta–Notch—and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors

    PubMed Central

    Fischer, Andreas; Gessler, Manfred

    2007-01-01

    Hes and Hey genes are the mammalian counterparts of the Hairy and Enhancer-of-split type of genes in Drosophila and they represent the primary targets of the Delta–Notch signaling pathway. Hairy-related factors control multiple steps of embryonic development and misregulation is associated with various defects. Hes and Hey genes (also called Hesr, Chf, Hrt, Herp or gridlock) encode transcriptional regulators of the basic helix-loop-helix class that mainly act as repressors. The molecular details of how Hes and Hey proteins control transcription are still poorly understood, however. Proposed modes of action include direct binding to N- or E-box DNA sequences of target promoters as well as indirect binding through other sequence-specific transcription factors or sequestration of transcriptional activators. Repression may rely on recruitment of corepressors and induction of histone modifications, or even interference with the general transcriptional machinery. All of these models require extensive protein–protein interactions. Here we review data published on protein–protein and protein–DNA interactions of Hairy-related factors and discuss their implications for transcriptional regulation. In addition, we summarize recent progress on the identification of potential target genes and the analysis of mouse models. PMID:17586813

  1. Astragaloside IV protects cardiomyocytes from anoxia/reoxygenation injury by upregulating the expression of Hes1 protein.

    PubMed

    Huang, Huang; Lai, Songqing; Wan, Qing; Qi, Wanghong; Liu, Jichun

    2016-05-01

    Astragaloside IV (ASI), a traditional Chinese medicine, is a main active ingredient of Astragalus membranaceus. Many clinical studies have found that ASI protects cardiomyocytes in cardiovascular diseases, but the underlying mechanisms remain obscure. The aim of this study was to investigate the molecular mechanisms responsible for the protective effects of ASI in cardiomyocytes from anoxia/reoxygenation (A/R) injury. According to the previous studies, we hypothesized that the cardioprotective effects of ASI against A/R injury might be associated with Notch1/Hes1 signaling pathway. In this study, neonatal rat primary cardiomyocytes were preconditioned with ASI prior to A/R injury. Our results showed that ASI effectively increased the cell viability, decreased the content of MDA, decreased the activities of CPK and LDH, increased the activities of GSH-Px and SOD, and reduced the reactive oxygen species (ROS) generation and the loss of mitochondrial membrane potential (Δψm). ASI inhibited the mitochondrial permeability transition pore (mPTP) opening and activation of caspase-3, and finally decreased the cell apoptosis in cardiomyocytes. Furthermore, ASI upregulated Hes1 protein expression. However, pretreatment with DAPT, a Notch1 inhibitor, effectively attenuated the cardioprotective effects of ASI against A/R injury, except MDA, SOD, GSH-Px, and the ROS generation. Taken together, we demonstrated that ASI could protect against A/R injury via the Notch1/Hes1 signaling pathway.

  2. Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats

    PubMed Central

    Xu, Xiao; Sun, Xin; Hu, Xue-Song; Zhuang, Yan; Liu, Yue-Chen; Meng, Hao; Miao, Lin; Yu, He; Luo, Shu-Jin

    2016-01-01

    Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits. PMID:27560986

  3. Discovery of HeLa Cell Contamination in HES Cells: Call for Cell Line Authentication in Reproductive Biology Research.

    PubMed

    Kniss, Douglas A; Summerfield, Taryn L

    2014-08-01

    Continuous cell lines are used frequently in reproductive biology research to study problems in early pregnancy events and parturition. It has been recognized for 50 years that many mammalian cell lines contain inter- or intraspecies contaminations with other cells. However, most investigators do not routinely test their culture systems for cross-contamination. The most frequent contributor to cross-contamination of cell lines is the HeLa cell isolated from an aggressive cervical adenocarcinoma. We report on the discovery of HeLa cell contamination of the human endometrial epithelial cell line HES isolated in our laboratory. Short tandem repeat analysis of 9 unique genetic loci demonstrated molecular identity between HES and HeLa cells. In addition, we verified that WISH cells, isolated originally from human amnion epithelium, were also contaminated with HeLa cells. Inasmuch as our laboratory did not culture HeLa cells at the time of HES cell derivations, the source of contamination was the WISH cell line. These data highlight the need for continued diligence in authenticating cell lines used in reproductive biology research. © The Author(s) 2014.

  4. Regulation of the Notch target gene Hes-1 by TGF{alpha} induced Ras/MAPK signaling in human neuroblastoma cells

    SciTech Connect

    Stockhausen, Marie-Therese; Sjoelund, Jonas; Axelson, Hakan . E-mail: hakan.axelson@molmed.mas.lu.se

    2005-10-15

    Ras and Notch signaling have recently been shown to cooperate in the maintenance of neoplastic transformation. Here, we show that TGF{alpha}, a known activator of Ras signaling, can drive cell proliferation and at the same time induce the expression of the Notch target Hes-1 in the neuroblastoma cell line SK-N-BE(2)c. The up-regulation of Hes-1 occurred both at the transcriptional and protein levels and by use of EGFR and MEK inhibitors we could show that the Hes-1 response was dependent on activation of the MAP kinase ERK. Blocking Notch activation by {gamma}-secretase inhibition did not profoundly affect the Hes-1 levels, neither in untreated nor in TGF{alpha} treated cells. The up-regulation of Hes-1 was associated with down-regulation of its pro-neuronal target gene Hash-1. Taken together, these results show that TGF{alpha} is a potent mitogen of neuroblastoma cells and suggest a connection between activation of ERK and Hes-1, thus providing a link between the Ras and Notch signaling pathways.

  5. Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis.

    PubMed

    Lin, Neng-Yu; Distler, Alfiya; Beyer, Christian; Philipi-Schöbinger, Ariella; Breda, Silvia; Dees, Clara; Stock, Michael; Tomcik, Michal; Niemeier, Andreas; Dell'Accio, Francesco; Gelse, Kolja; Mattson, Mark P; Schett, Georg; Distler, Jörg Hw

    2016-11-01

    Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  6. The Evaluation of Hydroxyethyl Starch (6% HES 130/0.4) Solution’s Potential Preventive Effects on Coagulation Status in Women with Gynecologic Malignancies Using Rotation Thromboelastography

    PubMed Central

    Akay, Meltem Olga; Bilir, Ayten; Öge, Tufan; Kuş, Gökhan; Mutlu, Fezan Şahin

    2014-01-01

    Objective: The aim of this study was to determine the effects of in vitro hemodilution with 6% hydroxyethyl starch (HES) 130/0.4 solution on the coagulation status of women with gynecologic malignancies by using rotation thromboelastogram (ROTEM®). Materials and Methods: Twenty-two patients with gynecological tumors scheduled for anesthesia were enrolled. Blood samples were diluted by 20% with 6% HES (130/0.4) solution. Results: In the INTEM assay, clotting time (CT) (p<0.01) and clot formation time (CFT) (p<0.001) were significantly increased and maximum maximum clot formation (MCF) (p< 0.001) was significantly decreased in HES hemodilution compared with the undiluted control samples. In the EXTEM assay, there was a similar significant increase in increase in CFT (p<0.01) and a decrease in maximum a decrease in MCF (p<0.01) in HES hemodilution when compared with control samples. Conclusion: HES 130/0.4 solution causes significant hypocoagulable changes in the thromboelastographic profile of gynecologic cancer patients in vitro. PMID:25330518

  7. RNAi for contactin 2 inhibits proliferation of U87-glioma stem cells by downregulating AICD, EGFR, and HES1

    PubMed Central

    Guo, Yang; Zhang, Peidong; Zhang, Hongtian; Zhang, Peng; Xu, Ruxiang

    2017-01-01

    Glioblastoma is the most common form of malignant brain tumors and has a poor prognosis. Glioma stem cells (GSCs) are thought to be responsible for the aberrant proliferation and invasion. Targeting the signaling pathways that promote proliferation in GSCs is one of the strategies for glioma treatment. In this study, we found increased expression of contactin 2 (CNTN2) and amyloid β precursor protein (APP) in U87-derived GSCs (U87-GSCs). RNA interference (RNAi) for CNTN2 downregulated the expression of APP intracellular domain (AICD), which is the proteolytic product of APP. Treatment with CNTN2 RNAi inhibited the proliferation of U87-GSCs. CNTN2 RNAi decreased the expression of epidermal growth factor receptor and HES1, which are potential targets of AICD. In summary, inhibition of the CNTN2/APP signaling pathway may repress the proliferation in U87-GSCs via downregulating the expression of HES1 and epidermal growth factor receptor. CNTN2/APP/AICD signaling pathway plays an important role in U87 glial tumorigenesis. Further studies are warranted to elucidate the role of these signaling pathways in other sources of GSCs. Depending on their role in proliferation in other sources of GSCs, members of the CNTN2/APP/AICD signaling pathway may provide novel targets for the development of therapy for glioblastomas. PMID:28243115

  8. Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1.

    PubMed

    Keohane, Aoife; Ryan, Sinead; Maloney, Eimer; Sullivan, Aideen M; Nolan, Yvonne M

    2010-01-01

    Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1.

  9. The interference of Notch1 target Hes1 affects cell growth, differentiation and invasiveness of glioblastoma stem cells through modulation of multiple oncogenic targets.

    PubMed

    Cenciarelli, Carlo; Marei, Hany E; Zonfrillo, Manuela; Casalbore, Patrizia; Felsani, Armando; Giannetti, Stefano; Trevisi, Gianluca; Althani, Asma; Mangiola, Annunziato

    2017-02-02

    The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.

  10. The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease.

    PubMed

    Yamada, Yoshiyuki; Rothenberg, Marc E; Lee, Andrew W; Akei, Hiroko Saito; Brandt, Eric B; Williams, David A; Cancelas, Jose A

    2006-05-15

    Dysregulated tyrosine kinase activity by the Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRA) (F/P) fusion gene has been identified as a cause of clonal hypereosinophilic syndrome (HES), called F/P-positive chronic eosinophilic leukemia (CEL) in humans. However, transplantation of F/P-transduced hematopoietic stem cells/progenitors (F/P(+) HSCs/Ps) into mice results in a chronic myelogenous leukemia-like disease, which does not resemble HES. Because a subgroup of patients with HES show T-cell-dependent interleukin-5 (IL-5) overexpression, we determined if expression of the F/P fusion gene in the presence of transgenic T-cell IL-5 overexpression in mice induces HES-like disease. Mice that received a transplant of CD2-IL-5-transgenic F/P(+) HSC/Ps (IL-5Tg-F/P) developed intense leukocytosis, strikingly high eosinophilia, and eosinophilic infiltration of nonhematopoietic as well as hematopoietic tissues, a phenotype resembling human HES. The disease phenotype was transferable to secondary transplant recipients of a high cell dose, suggesting involvement of a short-term repopulating stem cell or an early myeloid progenitor. Induction of significant eosinophilia was specific for F/P since expression of another fusion oncogene, p210-BCR/ABL, in the presence of IL-5 overexpression was characterized by a significantly lower eosinophilia than IL-5Tg-F/P recipients. These results suggest that F/P is not sufficient to induce a HES/CEL-like disease but requires a second event associated with IL-5 overexpression.

  11. Effects of 10% hydroxyethyl starch (HES 200/0.5) solution in intraoperative fluid therapy management of horses undergoing elective surgical procedures.

    PubMed

    Brünisholz, H P; Schwarzwald, C C; Bettschart-Wolfensberger, R; Ringer, S K

    2015-12-01

    The aim of the present study was to investigate the effect of pentastarch on colloid osmotic pressure (COP) and cardiopulmonary function during and up to 24 h after anaesthesia in horses. Twenty-five systemically healthy horses were anaesthetised using isoflurane-medetomidine balanced anaesthesia. Twelve were assigned to treatment with hydroxyethyl starch (HES) (H group) and 13 to no HES (NH group). In the H group, 6 mL/kg of pentastarch 10% HES (200/0.5) was infused over 1 h starting 30 min after induction of anaesthesia. Horses of the NH group received an equal amount of lactated Ringer's solution (LRS). COP and blood biochemical, cardiopulmonary and anaesthesia-related variables were measured at different time points before and after treatment. Pentastarch was effective in correcting the decrease in COP observed with LRS administration. No differences between treatments were detected for blood glucose, lactate, total proteins and electrolytes. Packed cell volume was lower with the H group immediately after finishing HES-administration and for an additional 30 min. In all horses, all blood biochemical variables other than lactate returned to normal after 12 h. No clinically relevant differences between treatments were detected for cardiopulmonary variables, although 23.1% of the NH-horses needed rescue-HES to maintain cardiovascular function, while none of the H-horses needed additional colloids. Overall, 6 mL/kg HES (200/0.5) was found to be effective in maintaining COP during anaesthesia in systemically healthy horses. Intermediate and long-term effects were below the limit of detection. The potentially beneficial effects on cardiovascular function need further investigation, especially in critically ill horses. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. CDKN1C/P57 is regulated by the Notch target gene Hes1 and induces senescence in human hepatocellular carcinoma.

    PubMed

    Giovannini, Catia; Gramantieri, Laura; Minguzzi, Manuela; Fornari, Francesca; Chieco, Pasquale; Grazi, Gian Luca; Bolondi, Luigi

    2012-08-01

    CDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers, including hepatocellular carcinoma (HCC); however, little is known regarding the role of CDKN1C/P57 and its regulation in HCC. In this study, we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation, CDKN1C/P57 up-regulation, and reduced cell growth. In line with these data, we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector, Hes1. We found that the up-regulation of CDKN1C/P57 by cDNA transfection decreased tumor growth, as determined by growth curve, flow cytometry analysis, and cyclin D1 down-regulation, without affecting the apoptosis machinery. Indeed, the expression of Bax, Noxa, PUMA, BNIP(3), and cleaved caspase-3 was not affected by CDKN1C/P57 induction. Morphologically CDKN1C/p57-induced HCC cells became flat and lengthened in shape, accumulated the senescence-associated β-galactosidase marker, and increased P16 protein expression. Evaluation of senescence in cells depleted both for Hes1 and CDKN1C/P57 revealed that the senescent state really depends on the accumulation of CDKN1C/p57. Finally, we validated our in vitro results in primary HCCs, showing that Hes1 protein expression inversely correlates with CDKN1C/P57 mRNA levels. In addition, reduced Hes1 protein expression is accompanied by a shorter time to recurrence after curative resection, suggesting that Hes1 may represent a biomarker for prediction of patients with poor prognosis.

  13. Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression.

    PubMed

    Takata, Takehiko; Ishikawa, Fuyuki

    2003-01-31

    The Hairy-related bHLH proteins function as transcriptional repressors in most cases and play important roles in diverse aspects of metazoan development. Recently, it was shown that the Drosophila bHLH repressor proteins, Hairy and Deadpan, bind to and function with the NAD(+)-dependent histone deacetylase, Sir2. Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo. Moreover, using the reporter assay, we show that both SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions mediated by these bHLH repressors. These results indicate that the molecular association between bHLH proteins and Sir2-related proteins is conserved among metazoans, from Drosophila to human, and suggest that the Sir2-bHLH interaction also plays important roles in human cells.

  14. The increasing number of surgical procedures for female genital fistula in England: analysis of Hospital Episode Statistics (HES) data.

    PubMed

    Ismail, S I M F

    2015-01-01

    The aim of this study was to describe the number and trend of surgical procedures for female genital fistula in England. An online search of Hospital Episode Statistics (HES) data was carried out. Data were available for the 4-year period from 2002-03 until 2005-06. The total number of surgical procedures carried out for female genital fistula steadily increased by 28.7% from 616 in 2002-03 to 793 in 2005-06. The number of surgical procedures performed for rectovaginal fistula exceeded the total number of surgical procedures carried out for vesicovaginal and urethrovaginal fistula in each year of the study period. This pattern needs to be monitored and investigated further.

  15. Effect of rapid set binder on early strength and permeability of HES latex modified road repair pre-packed concrete

    NASA Astrophysics Data System (ADS)

    Han, J. W.; Lee, S. K.; Yu, C.; Park, C. G.

    2015-12-01

    The early strength development characteristics and permeability resistance of high early strength (HES) pre-packed road repair concrete incorporating a rapid-set binder material were evaluated for emergency repairs to road pavement. The rapid-set binder is a mixture of rapid-set cement and silica sands whose fluidity improves with the addition of styrene butadiene latex (latex). The resulting mixture has a compressive strength of 21 MPa or higher and a flexural strength of greater than 3.5 MPa after 4 hours, the maximum curing age allowed for emergency repair materials. This study examines the strength development properties and permeability resistance of HES latex-modified pre-packed road repair concrete using a rapid- set binder as a function of the latex-to-binder mixing ratio at values of 0.40, 0.33, 0.29 and 0.25. Both early strength development properties and permeability resistance increased as the ratio of latex to rapid-set binder decreased. The mixture showed a compressive strength of 21 MPa or higher after 4 hours, which is the design standard of emergency repair concrete, only when this ratio was 0.29 or lower. A flexural strength of 3.5 MPa or greater was observed after hours only when this ratio was 0.33 or lower. The standard for permeability resistance, less than 2,000 C of chloride after 7 days of curing, was satisfied by all ratios. The ratio of latex to rapid-set binder satisfying all of the conditions for an emergency road repair material was 0.29 or less.

  16. The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance

    PubMed Central

    Schreck, Karisa C.; Taylor, Pete; Marchionni, Luigi; Gopalakrishnan, Vidya; Bar, Eli E.; Gaiano, Nicholas; Eberhart, Charles G.

    2010-01-01

    Purpose Multiple developmental pathways including Notch, Hedgehog, and Wnt are active in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating a different one. We investigated whether brain tumors show resistance to therapies against Notch, and whether targeting multiple pathways simultaneously would kill brain tumor cells more effectively than monotherapy. Experimental Design We used GBM neurosphere lines to investigate the effects of a gamma-secretase inhibitor (MRK-003) on tumor growth, and chromatin immunoprecipitation (ChIP) to study the regulation of other genes by Notch targets. We also evaluated the effect of combined therapy with a Hedgehog inhibitor (cyclopamine) in GBM and medulloblastoma lines, and primary human GBM cultures. Results GBM cells are at least partially resistant to long-term MRK-003 treatment, despite ongoing Notch pathway suppression, and show concomitant upregulation of Wnt and Hedgehog activity. The Notch target Hes1, a repressive transcription factor, bound the Gli1 first intron, and may inhibit its expression. Similar results were observed in a melanoma-derived cell line. Targeting Notch and Hedgehog simultaneously induced apoptosis, decreased cell growth, and inhibited colony-forming ability more dramatically than monotherapy. Low-passage neurospheres isolated from freshly resected human GBMs were also highly susceptible to co-inhibition of the two pathways, indicating that targeting multiple developmental pathways can be more effective than monotherapy at eliminating glioblastoma-derived cells. Conclusion Notch may directly suppress Hedgehog via Hes1 mediated inhibition of Gli1 transcription, and targeting both pathways simultaneously may be more effective at eliminating GBMs cells. PMID:21169257

  17. Aberrant expression of Notch1, HES1, and DTX1 genes in glioblastoma formalin-fixed paraffin-embedded tissues.

    PubMed

    Narayanappa, Rajeswari; Rout, Pritilata; Aithal, Madhuri G S; Chand, Ashis Kumar

    2016-05-01

    Glioblastoma is the most common malignant brain tumor accounting for more than 54 % of all gliomas. Despite aggressive treatments, median survival remains less than 1 year. This might be due to the unavailability of effective molecular diagnostic markers and targeted therapy. Thus, it is essential to discover molecular mechanisms underlying disease by identifying dysregulated pathways involved in tumorigenesis. Notch signaling is one such pathway which plays an important role in determining cell fates. Since it is found to play a critical role in many cancers, we investigated the role of Notch genes in glioblastoma with an aim to identify biomarkers that can improve diagnosis. Using real-time PCR, we assessed the expression of Notch genes including receptors (Notch1, Notch2, Notch3, and Notch4), ligands (JAG1, JAG2, and DLL3), downstream targets (HES1 and HEY2), regulator Deltex1 (DTX1), inhibitor NUMB along with transcriptional co-activator MAML1, and a component of gamma-secretase complex APH1A in 15 formalin-fixed paraffin-embedded (FFPE) patient samples. Relative quantification was done by the 2(-ΔΔCt) method; the data are presented as fold change in gene expression normalized to an internal control gene and relative to the calibrator. The data revealed aberrant expression of Notch genes in glioblastoma compared to normal brain. More than 85 % of samples showed high Notch1 (P = 0.0397) gene expression and low HES1 (P = 0.011) and DTX1 (P = 0.0001) gene expression. Our results clearly show aberrant expression of Notch genes in glioblastoma which can be used as putative biomarkers together with histopathological observation to improve diagnosis, therapeutic strategies, and patient prognosis.

  18. Effect of the colloids gelatin and HES 130/0.4 on blood coagulation in cardiac surgery patients: a randomized controlled trial.

    PubMed

    Kimenai, D M; Bastianen, G W; Daane, C R; Megens-Bastiaanse, C M; van der Meer, N J M; Scohy, T V; Gerritse, B M

    2013-11-01

    The choice of the prime solution for cardiopulmonary bypass can play an important role in limiting the effect on blood coagulation, but it is still unclear what the effect of colloids on blood coagulation is. The aim of this study was to investigate the effect of synthetic colloids on blood loss and blood coagulation in patients after on-pump coronary artery bypass graft (CABG) procedures. Sixty elective, on-pump CABG patients were randomly assigned to receive the prime solutions lactated Ringer's solution combined with hydroxyethyl starch 130/0.4 (HES, 6% Volulyte, Fresenius Kabi Nederland BV, Zeist, the Netherlands) (HES group) or gelatin (Gelofusin(®), B Braun Melsung AG, Melsungen, Germany) (Gelo group). Blood loss was assessed using post-operative chest tube output; secondary endpoints were number of blood component transfusions, routine coagulation test values and rotation thromboelastometry values (Rotem(®) delta, Pentapharm GmbH, Munich, Germany). Total post-operative chest tube output was 500 ± 420 ml in the HES group versus 465 ± 390 ml in the Gelo group (p = 0.48). No significant differences were observed in any of the routine coagulation tests values, thromboelastometry parameters or number of blood component transfusions between the groups. In this randomized, controlled trial of adults after on-pump CABG procedures, there was no significant difference in blood loss or blood coagulation between the HES group and the Gelo group.

  19. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

    PubMed Central

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-01-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies. PMID:24737870

  20. Minor physical anomalies in bipolar I and bipolar II disorders - Results with the Méhes Scale.

    PubMed

    Berecz, Hajnalka; Csábi, Györgyi; Jeges, Sára; Herold, Róbert; Simon, Maria; Halmai, Tamás; Trixler, Dániel; Hajnal, András; Tóth, Ákos Levente; Tényi, Tamás

    2017-03-01

    Minor physical anomalies (MPAs) are external markers of abnormal brain development, so the more common appearence of these signs among bipolar I and bipolar II patients can confirm the possibility of a neurodevelopmental deficit in these illnesses. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in patients with bipolar I and - first in literature - with bipolar II disorders compared to matched healthy control subjects. Using a list of 57 minor physical anomalies (the Méhes Scale), 30 bipolar I and 30 bipolar II patients, while as a comparison 30 matched healthy control subjects were examined. Significant differences were detected between the three groups comparing the total number of minor physical anomalies, minor malformations and phenogenetic variants and in the cases of the ear and the mouth regions. The individual analyses of the 57 minor physical anomalies by simultaneous comparison of the three groups showed, that in the cases of furrowed tongue and high arched palate were significant differences between the three groups. The results can promote the concept, that a neurodevelopmental deficit may play a role in the etiology of both bipolar I and bipolar II disorders. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  1. Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation.

    PubMed

    Phillips, Nick E; Manning, Cerys S; Pettini, Tom; Biga, Veronica; Marinopoulou, Elli; Stanley, Peter; Boyd, James; Bagnall, James; Paszek, Pawel; Spiller, David G; White, Michael Rh; Goodfellow, Marc; Galla, Tobias; Rattray, Magnus; Papalopulu, Nancy

    2016-10-04

    Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted.

  2. Murine leukemia provirus-mediated activation of the Notch1 gene leads to induction of HES-1 in a mouse T lymphoma cell line, DL-3.

    PubMed

    Lee, J S; Ishimoto, A; Honjo, T; Yanagawa, S

    1999-07-23

    Constitutive activation of Notch signaling is known to be associated with tumorigenesis. In a mouse T lymphoma cell line, DL-3, we found that a murine leukemia provirus was inserted in the Notch1 locus, which led to marked expression of a virus-Notch1 fusion mRNA encoding an intracellular portion of the Notch1 protein. Furthermore, expression and nuclear localization of this constitutively active form of Notch1 protein were confirmed. Corresponding to this finding, the transcription of the hairy/enhancer of split (HES-1) gene, a known target of Notch1 signaling, was elevated in this cell line. A potential role for overexpressed HES-1 in the development of the lymphoma was discussed.

  3. NF-κB-inducing kinase (NIK) prevents the development of hypereosinophilic syndrome (HES)-like disease in mice independent of IKKα activation

    PubMed Central

    Häcker, Hans; Chi, Liying; Rehg, Jerold E.; Redecke, Vanessa

    2012-01-01

    Immune cell-mediated tissue injury is the common feature of different inflammatory diseases, yet the pathogenetic mechanisms and cell types involved vary significantly. Hypereosinophilic Syndrome (HES) represents a group of inflammatory diseases that are characterized by increased numbers of pathogenic eosinophilic granulocytes in the peripheral blood and diverse organs. Based on clinical and laboratory findings, various forms of HES have been defined, yet the molecular mechanism and potential signaling pathways that drive eosinophil expansion remain largely unknown. Here we show that mice deficient of the serine/ threonine-specific protein kinase NF-κB inducing kinase (NIK) develop a HES-like disease, reflected by progressive blood and tissue eosinophilia, tissue injury and premature death at around 25–30 weeks of age. Similar to the lymphocytic form of HES, CD4+ T-cells from NIK-deficient mice express increased levels of T-helper 2 (Th2)-associated cytokines, and eosinophilia and survival of NIK deficient mice could completely be prevented by genetic ablation of CD4+ T-cells. Experiments based on bone marrow chimeric mice, however, demonstrated that inflammation in NIK-deficient mice depended on radiation-resistant tissues, implicating that NIK-deficient immune cells mediate inflammation in a non-autonomous manner. Surprisingly, disease development was independent of NIKs known function as IkappaB kinase (IKK)-α kinase, as mice carrying a mutation in the activation loop of IKKα, which is phosphorylated by NIK, did not develop inflammatory disease. Our data show that NIK activity in non-hematopoietic cells controls Th2-cell development and prevents eosinophil-driven inflammatory disease, most likely using a signaling pathway that operates independent of the known NIK substrate IKKα. PMID:22474019

  4. Notch-Hes-1 axis controls TLR7-mediated autophagic death of macrophage via induction of P62 in mice with lupus

    PubMed Central

    Li, Xiaojing; Liu, Fei; Zhang, Xuefang; Shi, Guoping; Ren, Jing; Ji, Jianjian; Ding, Liang; Fan, Hongye; Dou, Huan; Hou, Yayi

    2016-01-01

    The increased death of macrophages has been considered as a pathogenic factor for systemic lupus erythematosus (SLE), and dysfunction of autophagy may contribute to improper cell death. However, the effect of autophagy on macrophage during the pathogenesis of SLE is still unclear. Here we found that the death rate and autophagy level of macrophages significantly increased in MRL/lpr lupus-prone mice. Activation of toll-like receptor 7 (TLR7) triggered macrophage death in an autophagy-dependent but caspase-independent way in vitro. Moreover, P62/SQSTM1 is thought to have an essential role in selective autophagy. We also demonstrated that P62/SQSTM1 was required for TLR7-induced autophagy, and knockdown of P62 suppressed R848-induced cell death and LC3II protein accumulation. As an important mediator for cell–cell communication, Notch signaling is responsible for cell-fate decisions. Our results showed that activation of TLR7 also upregulated the expression of Notch1, especially its downstream target gene Hairy and enhancer of split 1 (Hes-1) in macrophages. Of note, we found that Hes-1, as a transcriptional factor, controlled TLR7-induced autophagy by regulating P62 expression. Furthermore, to confirm the above results in vivo, TLR7 agonist imiquimod (IMQ)-induced lupus mouse model was prepared. Splenic macrophages from IMQ-treated mice exhibited increased autophagy and cell death as well as enhanced expressions of Notch1 and Hes-1. Our results indicate that Notch1-Hes-1 signaling controls TLR7-induced autophagic death of macrophage via regulation of P62 in mice with lupus. PMID:27537524

  5. Data compression studies for NOAA Hyperspectral Environmental Suite (HES) using 3D integer wavelet transforms with 3D set partitioning in hierarchical trees

    NASA Astrophysics Data System (ADS)

    Huang, Bormin; Huang, Hung-Lung; Chen, Hao; Ahuja, Alok; Baggett, Kevin; Schmit, Timothy J.; Heymann, Roger W.

    2004-02-01

    The next-generation NOAA/NESDIS GOES-R hyperspectral sounder, now referred to as the HES (Hyperspectral Environmental Suite), will have hyperspectral resolution (over one thousand channels with spectral widths on the order of 0.5 wavenumber) and high spatial resolution (less than 10 km). Hyperspectral sounder data is a particular class of data requiring high accuracy for useful retrieval of atmospheric temperature and moisture profiles, surface characteristics, cloud properties, and trace gas information. Hence compression of these data sets is better to be lossless or near lossless. Given the large volume of three-dimensional hyperspectral sounder data that will be generated by the HES instrument, the use of robust data compression techniques will be beneficial to data transfer and archive. In this paper, we study lossless data compression for the HES using 3D integer wavelet transforms via the lifting schemes. The wavelet coefficients are processed with the 3D set partitioning in hierarchical trees (SPIHT) scheme followed by context-based arithmetic coding. SPIHT provides better coding efficiency than Shapiro's original embedded zerotree wavelet (EZW) algorithm. We extend the 3D SPIHT scheme to take on any size of 3D satellite data, each of whose dimensions need not be divisible by 2N, where N is the levels of the wavelet decomposition being performed. The compression ratios of various kinds of wavelet transforms are presented along with a comparison with the JPEG2000 codec.

  6. Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer.

    PubMed

    Moon, Chang Mo; Kwon, Ji-Hee; Kim, Ji Suk; Oh, Sun-Hee; Jin Lee, Kyoung; Park, Jae Jun; Pil Hong, Sung; Cheon, Jae Hee; Kim, Tae Il; Kim, Won Ho

    2014-02-01

    Cancer stem cells (CSCs) play a pivotal role in cancer relapse or metastasis. We investigated the CSC-suppressing effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and the relevant mechanisms in colorectal cancer. We measured the effect of NSAIDs on CSC populations in Caco-2 or SW620 cells using colosphere formation and flow cytometric analysis of PROM1 (CD133)(+) CD44(+) cells after indomethacin treatment with/without prostaglandin E2 (PGE2) or peroxisome proliferator-activated receptor γ (PPARG) antagonist, and examined the effect of indomethacin on transcriptional activity and protein expression of NOTCH/HES1 and PPARG. These effects of indomethacin were also evaluated in a xenograft mouse model. NSAIDs (indomethacin, sulindac and aspirin), celecoxib, γ-secretase inhibitor and PPARG agonist significantly decreased the number of colospheres formation compared to controls. In Caco-2 and SW620 cells, compared to controls, PROM1 (CD133)(+) CD44(+) cells were significantly decreased by indomethacin treatment, and increased by 5-fluorouracil (5-FU) treatment. This 5-FU-induced increase of PROM1 (CD133)(+) CD44(+) cells was significantly attenuated by combination with indomethacin. This CSC-inhibitory effect of indomethacin was reversed by addition of PGE2 and PPARG antagonist. Indomethacin significantly decreased CBFRE and increased PPRE transcriptional activity and their relative protein expressions. In xenograft mouse experiments using 5-FU-resistant SW620 cells, the 5-FU treatment combined with indomethacin significantly reduced tumor growth, compared to 5-FU alone. In addition, treatment of indomethacin alone or combination of 5-FU and indomethacin decreased the expressions of PROM1 (CD133), CD44, PTGS2 (cyclooxygenase 2) and HES1, and increased PPARG expression. NSAIDs could selectively reduce the colon CSCs and suppress 5-FU-induced increase of CSCs via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1, and activating PPARG.

  7. Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation

    PubMed Central

    Phillips, Nick E; Manning, Cerys S; Pettini, Tom; Biga, Veronica; Marinopoulou, Elli; Stanley, Peter; Boyd, James; Bagnall, James; Paszek, Pawel; Spiller, David G; White, Michael RH; Goodfellow, Marc; Galla, Tobias; Rattray, Magnus; Papalopulu, Nancy

    2016-01-01

    Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted. DOI: http://dx.doi.org/10.7554/eLife.16118.001 PMID:27700985

  8. Notch 1 Receptor, Delta 1 Ligand and HES 1 Transcription Factor are Expressed in the Lining Epithelium of Periapical Cysts (Preliminary Study)

    PubMed Central

    Meliou, E; Kerezoudis, NP; Tosios, KI; Kiaris, H

    2010-01-01

    Periapical cyst is a chronic inflammatory disorder of periradicular tissues. The precise pathological mechanisms involved in periapical cyst enlargement remain unclear. Notch signaling is an evolutionarily conserved pathway with a regulatory role in cell fate decisions during development and in carcinogenesis. To date, there are no published data available on the expression of Notch signaling components in periapical cysts or any other jaw cyst. In this immunohistochemical study we have examined the expression of the receptor Notch 1, the ligand Delta 1 and the transcription factor HES 1 in the epithelium of well defined periapical cysts. Immunostaining reaction of Notch 1, Delta 1 and HES 1 was observed in the cytoplasm and/or the cytoplasmic membrane and occasionally in the nucleus in the majority of epithelial cells of all periapical cysts. The present observations indicate that Notch pathway is active in the epithelium of periapical cysts. It can be speculated that activation of epithelial cells of periapical cysts is associated with activation of Notch pathway and imply involvement of this pathway in periapical cyst growth and expansion. PMID:21116324

  9. Notch 1 Receptor, Delta 1 Ligand and HES 1 Transcription Factor are Expressed in the Lining Epithelium of Periapical Cysts (Preliminary Study).

    PubMed

    Meliou, E; Kerezoudis, Np; Tosios, Ki; Kiaris, H

    2010-07-27

    Periapical cyst is a chronic inflammatory disorder of periradicular tissues. The precise pathological mechanisms involved in periapical cyst enlargement remain unclear. Notch signaling is an evolutionarily conserved pathway with a regulatory role in cell fate decisions during development and in carcinogenesis. To date, there are no published data available on the expression of Notch signaling components in periapical cysts or any other jaw cyst. In this immunohistochemical study we have examined the expression of the receptor Notch 1, the ligand Delta 1 and the transcription factor HES 1 in the epithelium of well defined periapical cysts. Immunostaining reaction of Notch 1, Delta 1 and HES 1 was observed in the cytoplasm and/or the cytoplasmic membrane and occasionally in the nucleus in the majority of epithelial cells of all periapical cysts. The present observations indicate that Notch pathway is active in the epithelium of periapical cysts. It can be speculated that activation of epithelial cells of periapical cysts is associated with activation of Notch pathway and imply involvement of this pathway in periapical cyst growth and expansion.

  10. Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest.

    PubMed

    Zalc, Antoine; Hayashi, Shinichiro; Auradé, Frédéric; Bröhl, Dominique; Chang, Ted; Mademtzoglou, Despoina; Mourikis, Philippos; Yao, Zizhen; Cao, Yi; Birchmeier, Carmen; Relaix, Frédéric

    2014-07-01

    A central question in development is to define how the equilibrium between cell proliferation and differentiation is temporally and spatially regulated during tissue formation. Here, we address how interactions between cyclin-dependent kinase inhibitors essential for myogenic growth arrest (p21(cip1) and p57(kip2)), the Notch pathway and myogenic regulatory factors (MRFs) orchestrate the proliferation, specification and differentiation of muscle progenitor cells. We first show that cell cycle exit and myogenic differentiation can be uncoupled. In addition, we establish that skeletal muscle progenitor cells require Notch signaling to maintain their cycling status. Using several mouse models combined with ex vivo studies, we demonstrate that Notch signaling is required to repress p21(cip1) and p57(kip2) expression in muscle progenitor cells. Finally, we identify a muscle-specific regulatory element of p57(kip2) directly activated by MRFs in myoblasts but repressed by the Notch targets Hes1/Hey1 in progenitor cells. We propose a molecular mechanism whereby information provided by Hes/Hey downstream of Notch as well as MRF activities are integrated at the level of the p57(kip2) enhancer to regulate the decision between progenitor cell maintenance and muscle differentiation. © 2014. Published by The Company of Biologists Ltd.

  11. Identification of a new clock-related element EL-box involved in circadian regulation by BMAL1/CLOCK and HES1.

    PubMed

    Ueshima, Taichi; Kawamoto, Takeshi; Honda, Kiyomasa K; Noshiro, Mitsuhide; Fujimoto, Katsumi; Nakao, Sanae; Ichinose, Natsuhiro; Hashimoto, Seiichi; Gotoh, Osamu; Kato, Yukio

    2012-12-01

    Several cis-acting elements play critical roles in maintaining circadian expression of clock and clock-controlled genes. Using in silico analysis, we identified 10 sequence motifs that are correlated with the circadian phases of gene expression in the cartilage. One of these motifs, an E-box-like clock-related element (EL-box; GGCACGAGGC), can mediate BMAL1/CLOCK-induced transcription, which is typically regulated through an E-box or E'-box. Expression of EL-box-containing genes, including Ank, Dbp, and Nr1d1 (Rev-erbα), was induced by BMAL1/CLOCK or BMAL1/NPAS2. Compared with the E-box, the EL-box elements had distinct responsiveness to DEC1, DEC2, and HES1: suppressive actions of DEC1 and DEC2 on the EL-box were less potent than those on the E-box. HES1, which is known to bind to the N-box (CACNAG), suppressed enhancer activity of the EL-box, but not the E-box. In the Dbp promoter, an EL-box worked cooperatively with a noncanonical (NC) E-box to mediate BMAL1/CLOCK actions. These findings suggest that in addition to known clock elements, the EL-box element may contribute to circadian regulation of clock and clock-controlled genes.

  12. Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression

    PubMed Central

    2014-01-01

    Background PTOV1 is an adaptor protein with functions in diverse processes, including gene transcription and protein translation, whose overexpression is associated with a higher proliferation index and tumor grade in prostate cancer (PC) and other neoplasms. Here we report its interaction with the Notch pathway and its involvement in PC progression. Methods Stable PTOV1 knockdown or overexpression were performed by lentiviral transduction. Protein interactions were analyzed by co-immunoprecipitation, pull-down and/or immunofluorescence. Endogenous gene expression was analyzed by real time RT-PCR and/or Western blotting. Exogenous promoter activities were studied by luciferase assays. Gene promoter interactions were analyzed by chromatin immunoprecipitation assays (ChIP). In vivo studies were performed in the Drosophila melanogaster wing, the SCID-Beige mouse model, and human prostate cancer tissues and metastasis. The Excel package was used for statistical analysis. Results Knockdown of PTOV1 in prostate epithelial cells and HaCaT skin keratinocytes caused the upregulation, and overexpression of PTOV1 the downregulation, of the Notch target genes HEY1 and HES1, suggesting that PTOV1 counteracts Notch signaling. Under conditions of inactive Notch signaling, endogenous PTOV1 associated with the HEY1 and HES1 promoters, together with components of the Notch repressor complex. Conversely, expression of active Notch1 provoked the dismissal of PTOV1 from these promoters. The antagonist role of PTOV1 on Notch activity was corroborated in the Drosophila melanogaster wing, where human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed the effects of constitutively active Notch. PTOV1 was required for optimal in vitro invasiveness and anchorage-independent growth of PC-3 cells, activities counteracted by Notch, and for their efficient growth and metastatic spread in vivo. In prostate tumors, the overexpression of PTOV1 was associated with decreased expression

  13. Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter.

    PubMed

    Abdolazimi, Yassan; Stojanova, Zlatka; Segil, Neil

    2016-03-01

    Determination of cell fate within the prosensory domain of the developing cochlear duct relies on the temporal and spatial regulation of the bHLH transcription factor Atoh1. Auditory hair cells and supporting cells arise in a wave of differentiation that patterns them into discrete rows mediated by Notch-dependent lateral inhibition. However, the mechanism responsible for selecting sensory cells from within the prosensory competence domain remains poorly understood. We show in mice that rather than being upregulated in rows of cells, Atoh1 is subject to transcriptional activation in groups of prosensory cells, and that highly conserved sites for Hes/Hey repressor binding in the Atoh1 promoter are needed to select the hair cell and supporting cell fate. During perinatal supporting cell transdifferentiation, which is a model of hair cell regeneration, we show that derepression is sufficient to induce Atoh1 expression, suggesting a mechanism for priming the 3' Atoh1 autoregulatory enhancer needed for hair cell expression.

  14. Acid-Base and Electrolyte Status during Normovolemic Hemodilution with Succinylated Gelatin or HES-Containing Volume Replacement Solutions in Rats

    PubMed Central

    Teloh, Johanna K.; Ferenz, Katja B.; Petrat, Frank; Mayer, Christian; de Groot, Herbert

    2013-01-01

    Background In the past, several studies have compared different colloidal replacement solutions, whereby the focus was usually on the respective colloid. We therefore systematically studied the influence of the carrier solution’s composition of five approved colloidal volume replacement solutions (Gelafundin, Gelafusal, Geloplasma, Voluven and Volulyte) on acid-base as well as electrolyte status during and following acute severe normovolemic hemodilution. The solutions differed in the colloid used (succinylated gelatin vs. HES) and in the presence and concentration of metabolizable anions as well as in their electrolyte composition. Methods Anesthetized Wistar rats were subjected to a stepwise normovolemic hemodilution with one of the solutions until a final hematocrit of 10%. Subsequent to dilution (162 min), animals were observed for an additional period (150 min). During dilution and observation time blood gas analyses were performed eight times in total. Additionally, in the Voluven and Volulyte groups as well as in 6 Gelafundin animals, electrolyte concentrations, glucose, pH and succinylated gelatin were measured in urine and histopathological evaluation of the kidney was performed. Results All animals survived without any indications of injury. Although the employed solutions differed in their respective composition, comparable results in all plasma acid-base and electrolyte parameters studied were obtained. Plasma pH increased from approximately 7.28 to 7.39, the plasma K+ concentration decreased from circa 5.20 mM to 4.80-3.90 mM and the plasma Cl− concentration rose from approximately 105 mM to 111–120 mM. Urinary analysis revealed increased excretion of K+, H+ and Cl−. Conclusions The present data suggest that the carrier solution’s composition with regard to metabolizable anions as well as K+, Ca2+ only has a minor impact on acid-base and electrolyte status after application of succinylated gelatin or HES-containing colloidal volume

  15. Transcriptional Dynamics Elicited by a Short Pulse of Notch Activation Involves Feed-Forward Regulation by E(spl)/Hes Genes

    PubMed Central

    Housden, Ben E.; Fu, Audrey Q.; Krejci, Alena; Bernard, Fred; Fischer, Bettina; Tavaré, Simon; Russell, Steven; Bray, Sarah J.

    2013-01-01

    Dynamic activity of signaling pathways, such as Notch, is vital to achieve correct development and homeostasis. However, most studies assess output many hours or days after initiation of signaling, once the outcome has been consolidated. Here we analyze genome-wide changes in transcript levels, binding of the Notch pathway transcription factor, CSL [Suppressor of Hairless, Su(H), in Drosophila], and RNA Polymerase II (Pol II) immediately following a short pulse of Notch stimulation. A total of 154 genes showed significant differential expression (DE) over time, and their expression profiles stratified into 14 clusters based on the timing, magnitude, and direction of DE. E(spl) genes were the most rapidly upregulated, with Su(H), Pol II, and transcript levels increasing within 5–10 minutes. Other genes had a more delayed response, the timing of which was largely unaffected by more prolonged Notch activation. Neither Su(H) binding nor poised Pol II could fully explain the differences between profiles. Instead, our data indicate that regulatory interactions, driven by the early-responding E(spl)bHLH genes, are required. Proposed cross-regulatory relationships were validated in vivo and in cell culture, supporting the view that feed-forward repression by E(spl)bHLH/Hes shapes the response of late-responding genes. Based on these data, we propose a model in which Hes genes are responsible for co-ordinating the Notch response of a wide spectrum of other targets, explaining the critical functions these key regulators play in many developmental and disease contexts. PMID:23300480

  16. Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aβ metabolism.

    PubMed

    Leal, María C; Surace, Ezequiel I; Holgado, María P; Ferrari, Carina C; Tarelli, Rodolfo; Pitossi, Fernando; Wisniewski, Thomas; Castaño, Eduardo M; Morelli, Laura

    2012-02-01

    Cerebral amyloid β (Aβ) accumulation is pathogenically associated with sporadic Alzheimer's disease (SAD). BACE-1 is involved in Aβ generation while insulin-degrading enzyme (IDE) partakes in Aβ proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular Aβ accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at -379/-372 and -310-303 from the first translation start site in the -575/-19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on Aβ metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD.

  17. Cdc42-mTOR signaling pathway controls Hes5 and Pax6 expression in retinoic acid-dependent neural differentiation.

    PubMed

    Endo, Makoto; Antonyak, Marc A; Cerione, Richard A

    2009-02-20

    The conditional knockout of the small GTPase Cdc42 from neuroepithelial (NE) and radial glial (RG) cells in the mouse telencephalon has been shown to have a significant impact on brain development by causing these neural progenitor cells to detach from the apical/ventricular surface and to lose their cell identity. This has been attributed to the requirement for Cdc42 in establishing proper apical/basal cell polarity and cell-cell adhesions. In the present study, we provide new insights into the role played by Cdc42 in the maintenance of neural progenitor cells, using the mouse embryonal carcinoma P19 cell line as a model system. We show that the ability of P19 cells to undergo the transition from an Oct3/4-positive, undifferentiated status to microtubule-associated protein 2-positive neurons and glial fibrillary acidic protein-positive astrocytes, upon treatment with retinoic acid (RA), requires RA-induced activation of Cdc42 during the neural cell lineage specification phase. Experiments using chemical inhibitors and RNA interference suggest that the actions of Cdc42 are mediated through signaling pathways that start with fibroblast growth factors and Delta/Notch proteins and lead to Cdc42-dependent mTOR activation, culminating in the up-regulation of Hes5 and Pax6, two transcription factors that are essential for the maintenance of NE and RG cells. The constitutively active Cdc42(F28L) mutant was sufficient to up-regulate Hes5 and Pax6 in P19 cells, even in the absence of RA treatment, ultimately promoting their transition to neural progenitor cells. The ectopic Cdc42 expression also significantly augmented the RA-dependent up-regulation of these transcription factors, resulting in P19 cells maintaining their neural progenitor status but being unable to undergo terminal differentiation. These findings shed new light on how Cdc42 influences neural progenitor cell fate by regulating gene expression.

  18. Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner.

    PubMed

    Yu, Liming; Fan, Chongxi; Li, Zhi; Zhang, Jian; Xue, Xiaodong; Xu, Yinli; Zhao, Guolong; Yang, Yang; Wang, Huishan

    2017-01-01

    Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague Dawley rats were subjected to MI/R surgery and high-glucose (HG, 500 g/L) infusion (4 mL/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33 mmol/L)-incubated H9c2 cardiomyoblasts were treated in the presence or absence of luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor), or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis, and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by upregulating Notch1, N1ICD, Hes1, and p-Akt expressions, increasing Trx activity, and downregulating Txnip expression. However, these effects were blunted by luzindole, DAPT, or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study. © 2016 John Wiley & Sons A/S. Published by John Wiley

  19. Minor physical anomalies are more common among the first-degree unaffected relatives of schizophrenia patients - Results with the Méhes Scale.

    PubMed

    Hajnal, András; Csábi, Györgyi; Herold, Róbert; Jeges, Sára; Halmai, Tamás; Trixler, Dániel; Simon, Maria; Tóth, Ákos Levente; Tényi, Tamás

    2016-03-30

    Minor physical anomalies are external markers of abnormal brain development,so the more common appearance of these signs among the relatives of schizophrenia patients can confirm minor physical anomalies as intermediate phenotypes. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in the first-degree unaffected relatives of patients with schizophrenia compared to matched normal control subjects. Using a list of 57 minor physical anomalies (the Méhes Scale), 20 relatives of patients with the diagnosis of schizophrenia and as a comparison 20 matched normal control subjects were examined. Minor physical anomalies were more common in the head and mouth regions among the relatives of schizophrenia patients compared to normal controls. By the differentiation of minor malformations and phenogenetic variants, we have found that only phenogenetic variants were more common in the relatives of schizophrenia patients compared to the control group, however individual analyses showed, that one minor malformation (flat forehead) was more prevalent in the relative group. The results can promote the concept, that minor physical anomalies can be endophenotypic markers of the illness. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. An essential role for RAX homeoprotein and NOTCH-HES signaling in Otx2 expression in embryonic retinal photoreceptor cell fate determination.

    PubMed

    Muranishi, Yuki; Terada, Koji; Inoue, Tatsuya; Katoh, Kimiko; Tsujii, Toshinori; Sanuki, Rikako; Kurokawa, Daisuke; Aizawa, Shinichi; Tamaki, Yasuhiro; Furukawa, Takahisa

    2011-11-16

    The molecular mechanisms underlying cell fate determination from common progenitors in the vertebrate CNS remain elusive. We previously reported that the OTX2 homeoprotein regulates retinal photoreceptor cell fate determination. While Otx2 transactivation is a pivotal process for photoreceptor cell fate determination, its transactivation mechanism in the retina is unknown. Here, we identified an evolutionarily conserved Otx2 enhancer of ∼500 bp, named embryonic enhancer locus for photoreceptor Otx2 transcription (EELPOT), which can recapitulate initial Otx2 expression in the embryonic mouse retina. We found that the RAX homeoprotein interacts with EELPOT to transactivate Otx2, mainly in the final cell cycle of retinal progenitors. Conditional inactivation of Rax results in downregulation of Otx2 expression in vivo. We also showed that NOTCH-HES signaling negatively regulates EELPOT to suppress Otx2 expression. These results suggest that the integrated activity of cell-intrinsic and -extrinsic factors on EELPOT underlies the molecular basis of photoreceptor cell fate determination in the embryonic retina.

  1. Quality of water used during cage cultivation of rainbow trout (Oncorhynchus mykiss) in Bereket HES IV Dam Lake (Muğla, Turkey).

    PubMed

    Ozdemir, Nedim; Demirak, Ahmet; Keskin, Feyyaz

    2014-12-01

    A thorough investigation of the impact of rainbow trout (Oncorhynchus mykiss) cultivation on surface water quality in the area known as Bereket HES IV Dam Lake was conducted. Water samples were collected from October 2009 to June 2010 from four stations in the Dam Lake and analyzed for water temperature, pH, dissolved oxygen, electrical conductivity, nitrite nitrogen, nitrate nitrogen, and orthophosphate. Surface water quality was then evaluated based on the comparison of samples collected from three stations located near fish cages to those collected from a reference station outside the cultivation area as well as by the comparison with standards specified in the Water Pollution Registration Act. According to the Water Pollution Registration Act, the surface water quality of the Dam Lake was class I. Additionally, there were no significant differences in water quality within the Dam Lake among any of the sampling stations, including the reference station. Overall, these findings indicate that cage cultivation of rainbow trout may have a negative impact on the entire Dam Lake.

  2. HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44(+)/CD24(-/low) tumor-initiating subpopulation in basal-like breast cancer.

    PubMed

    So, Jae Young; Wahler, Joseph; Das Gupta, Soumyasri; Salerno, David M; Maehr, Hubert; Uskokovic, Milan; Suh, Nanjoo

    2015-04-01

    Tumor-initiating cells (also known as cancer stem cells) are the subpopulation of cells shown to be responsible for tumor initiation, maintenance and recurrence. In breast cancer, CD44(+)/CD24(-/low) cells were identified as tumor-initiating cells. We previously reported that a Gemini vitamin D analog, 1,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), reduced CD44(+)/CD24(-/low) cells in MCF10DCIS basal-like breast cancer cells. Since Notch has been identified as one of the key signaling pathways involved in breast cancer stem cells, the effect of BXL0124 on the Notch signaling pathway was investigated in breast cancer. The CD44(+)/CD24(-/low) subpopulation of MCF10DCIS cells showed elevated Notch1 signaling and increased cell proliferation compared to the CD44(+)/CD24(high) subpopulation. Treatment with the Gemini vitamin D analog BXL0124 decreased the level of activated Notch1 receptor. In addition, mRNA and protein levels of the Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly reduced by treatment with BXL0124, which was followed by repression of c-Myc, a key downstream target of Notch signaling. Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by treatment with BXL0124. The inhibitory effect of BXL0124 on Notch signaling was reversed by knockdown of HES1. Overexpression of HES1 inhibited Notch1 signaling and reduced the CD44(+)/CD24(-/low) subpopulation, confirming a role of HES1 in Notch1 signaling. In conclusion, the Gemini vitamin D analog, BXL0124, represses the tumor-initiating subpopulation by HES1-mediated inhibition of Notch1 signaling. The present study demonstrates BXL0124 as a potent inhibitor of Notch signaling to target tumor-initiating cells in basal-like breast cancer. This article is part of a Special Issue entitled "17th Vitamin D Workshop". Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids

    PubMed Central

    Farioli-Vecchioli, Stefano; Ceccarelli, Manuela; Saraulli, Daniele; Micheli, Laura; Cannas, Sara; D’Alessandro, Francesca; Scardigli, Raffaella; Leonardi, Luca; Cinà, Irene; Costanzi, Marco; Mattera, Andrea; Cestari, Vincenzo; Tirone, Felice

    2014-01-01

    Bone morphogenic proteins (BMPs) and the Notch pathway regulate quiescence and self-renewal of stem cells of the subventricular zone (SVZ), an adult neurogenic niche. Here we analyze the role at the intersection of these pathways of Tis21 (Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. In Tis21-null SVZ and cultured neurospheres, we observed a strong decrease in the expression of BMP4 and its effectors Smad1/8, while the Notch anti-neural mediators Hes1/5 and the basic helix-loop-helix (bHLH) inhibitors Id1-3 increased. Consistently, expression of the proneural bHLH gene NeuroD1 decreased. Moreover, cyclins D1/2, A2, and E were strongly up-regulated. Thus, in the SVZ Tis21 activates the BMP pathway and inhibits the Notch pathway and the cell cycle. Correspondingly, the Tis21-null SVZ stem cells greatly increased; nonetheless, the proliferating neuroblasts diminished, whereas the post-mitotic neuroblasts paradoxically accumulated in SVZ, failing to migrate along the rostral migratory stream to the olfactory bulb. The ability, however, of neuroblasts to migrate from SVZ explants was not affected, suggesting that Tis21-null neuroblasts do not migrate to the olfactory bulb because of a defect in terminal differentiation. Notably, BMP4 addition or Id3 silencing rescued the defective differentiation observed in Tis21-null neurospheres, indicating that they mediate the Tis21 pro-differentiative action. The reduced number of granule neurons in the Tis21-null olfactory bulb led to a defect in olfactory detection threshold, without effect on olfactory memory, also suggesting that within olfactory circuits new granule neurons play a primary role in odor sensitivity rather than in memory. PMID:24744701

  4. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress

    PubMed Central

    Zhang, Meng; Yu, Li-ming; Zhao, Hang; Zhou, Xuan-xuan; Yang, Qian; Song, Fan; Yan, Li; Zhai, Meng-en; Li, Bu-ying; Zhang, Bin; Jin, Zhen-xiao; Duan, Wei-xun; Wang, Si-wang

    2017-01-01

    2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg−1·d−1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1–1000 μmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis. PMID:28112174

  5. Methylprednisolone inhibits the proliferation and affects the differentiation of rat spinal cord-derived neural progenitor cells cultured in low oxygen conditions by inhibiting HIF-1α and Hes1 in vitro.

    PubMed

    Wang, Wenhao; Wang, Peng; Li, Shiyuan; Yang, Jiewen; Liang, Xinjun; Tang, Yong; Li, Yuxi; Yang, Rui; Wu, Yanfeng; Shen, Huiyong

    2014-09-01

    Although there is much controversy over the use of methylprednisolone (MP), it is one of the main drugs used in the treatment of acute spinal cord injury (SCI). The induction of the proliferation and differentiation of endogenous neural progenitor cells (NPCs) is considered a promising mode of treatment for SCI. However, the effects of MP on spinal cord-derived endogenous NPCs in a low oxygen enviroment remain to be delineated. Thus, the aim of this study was to investigate the potential effects of MP on NPCs cultured under low oxygen conditions in vitro and to elucidate the molecular mechanisms involved. Fetal rat spinal cord-derived NPCs were harvested and divided into 4 groups: 2 groups of cells cultured under normal oxygen conditions and treated with or without MP, and 2 groups incubated in 3% O2 (low oxygen) treated in a similar manner. We found that MP induced suppressive effects on NPC proliferation even under low oxygen conditions (3% O2). The proportion of nestin-positive NPCs decreased from 51.8±2.46% to 36.17±3.55% following the addition of MP and decreased more significantly to 27.20±2.68% in the cells cultured in 3% O2. In addition, a smaller number of glial fibrillary acidic protein (GFAP)-positive cells and a greater number of microtubule-associated protein 2 (MAP2)-positive cells was observed following the addition of MP under both normal (normoxic) and low oxygen (hypoxic) conditions. In response to MP treatment, hypoxia-inducible factor-1α (HIF-1α) and the Notch signaling pathway downstream protein, Hes1, but not the upstream Notch-1 intracelluar domain (NICD), were inhibited. After blocking NICD with a γ-secretase inhibitor (DAPT) MP still inhibited the expression of Hes1. Our results provide insight into the molecular mechanisms responsible for the MP-induced inhibition of proliferation and its effects on differentiation and suggest that HIF-1α and Hes1 play an important role in this effect.

  6. The incidence and healthcare costs of persistent postoperative pain following lumbar spine surgery in the UK: a cohort study using the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES).

    PubMed

    Weir, Sharada; Samnaliev, Mihail; Kuo, Tzu-Chun; Ni Choitir, Caitriona; Tierney, Travis S; Cumming, David; Bruce, Julie; Manca, Andrea; Taylor, Rod S; Eldabe, Sam

    2017-09-11

    To characterise incidence and healthcare costs associated with persistent postoperative pain (PPP) following lumbar surgery. Retrospective, population-based cohort study. Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) databases. Population-based cohort of 10 216 adults who underwent lumbar surgery in England from 1997/1998 through 2011/2012 and had at least 1 year of presurgery data and 2 years of postoperative follow-up data in the linked CPRD-HES. Incidence and total healthcare costs over 2, 5 and 10 years attributable to persistent PPP following initial lumbar surgery. The rate of individuals undergoing lumbar surgery in the CPRD-HES linked data doubled over the 15-year study period, fiscal years 1997/1998 to 2011/2012, from 2.5 to 4.9 per 10 000 adults. Over the most recent 5-year period (2007/2008 to 2011/2012), on average 20.8% (95% CI 19.7% to 21.9%) of lumbar surgery patients met criteria for PPP. Rates of healthcare usage were significantly higher for patients with PPP across all types of care. Over 2 years following initial spine surgery, the mean cost difference between patients with and without PPP was £5383 (95% CI £4872 to £5916). Over 5 and 10 years following initial spine surgery, the mean cost difference between patients with and without PPP increased to £10 195 (95% CI £8726 to £11 669) and £14 318 (95% CI £8386 to £19 771), respectively. Extrapolated to the UK population, we estimate that nearly 5000 adults experience PPP after spine surgery annually, with each new cohort costing the UK National Health Service in excess of £70 million over the first 10 years alone. Persistent pain affects more than one-in-five lumbar surgery patients and accounts for substantial long-term healthcare costs. There is a need for formal, evidence-based guidelines for a coherent, coordinated management strategy for patients with continuing pain after lumbar surgery. © Article author(s) (or their employer

  7. Genistein alleviates testicular ischemia and reperfusion injury-induced spermatogenic damage and oxidative stress by suppressing abnormal testicular matrix metalloproteinase system via the Notch 2/Jagged 1/Hes-1 and caspase-8 pathways.

    PubMed

    Al-Maghrebi, M; Renno, W M

    2016-02-01

    The aim of the study is to examine the role of matrix metalloproteinases (MMPs) and their inhibitors (TIMP) during testicular ischemia/reperfusion (t I/R). The involvement of the Notch pathway, and their modulation by the antioxidant genistein is also studied. Three groups of male Sprague-Dawley rats were used: sham rats, t I/R rats, and genistein-treated rats (10 mg/kg). The t I/R rat model underwent testicular artery occlusion of the left testis and was subjected to 60 min ischemia followed by 4 h reperfusion. Protein expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured in testicular tissue. Histological examination was performed to assess spermatogenesis. Protein levels of Notch 2, Jagged 1, and hairy/enhancer of split 1 (hes-1) was quantified. The degree of testicular oxidative stress, DNA damage and germ cell apoptosis were also evaluated. T I/R induced severe tubular damage, a significant increase in MMP- 2 and MMP-9 expression and decreased expression TIMP-1 and TIMP-2. Genistein treatment normalized the MMP-TIMP imbalance. Rats subjected to t I/R had low total antioxidant capacity of the testis, decreased superoxide dismutase activity, and increased oxidative DNA damage. Enhanced activities of caspase 8, caspase 3 and PARP were also observed during t I/R. Genistein reversed the t I/R-induced suppression of the Notch 2/Jagged 1/hes-1 pathway. Genistein was also able to salvage the testicular structure and function through restoring the MMP-TIMP anti-proteolytic balance, suppressing spermatogenic damage, alleviating oxidative stress and apoptosis. The Notch pathway is partly involved in inhibiting the t I/R-induced testicular impairment.

  8. Hematology Expert System (HES) For Tonsillectomy/Adenoidectomy Patients

    NASA Astrophysics Data System (ADS)

    Pizzi, Nicolino J.; Kapoor, Sandhya; Gerrard, Jon M.

    1989-03-01

    The purpose of this expert system is to assess a predisposition to bleeding in a patient undergoing a tonsillectomy and/or adenoidectomy as may occur with patients who have certain blood conditions such as hemophilia and von Willebrand's disease. This goal is achieved by establishing a correlation between the patients' responses to a medical questionnaire and the relative quantities of blood lost during the operation.

  9. Technical Education in 2-Year Colleges. HES Survey Number 17.

    ERIC Educational Resources Information Center

    Burton, Lawrence; Celebuski, Carin A.

    Based on a January 1993 survey of 347 two-year colleges nationwide, this report describes aspects of engineering technology and science technology education and training in the nation's two-year colleges. Following introductory materials, the first chapter estimates the number of colleges offering engineering and science programs, reviews types of…

  10. Hydrogen Energy Storage (HES) Activities at NREL; NREL (National Renewable Energy Laboratory)

    SciTech Connect

    Eichman, J.

    2015-04-21

    This presentation provides an overview of hydrogen and energy storage, including hydrogen storage pathways and international power-to-gas activities, and summarizes the National Renewable Energy Laboratory's hydrogen energy storage activities and results.

  11. Hydrogen Energy Storage (HES) and Power-to-Gas Economic Analysis; NREL (National Renewable Energy Laboratory)

    SciTech Connect

    Eichman, Joshua

    2015-07-30

    This presentation summarizes opportunities for hydrogen energy storage and power-to-gas and presents the results of a market analysis performed by the National Renewable Energy Laboratory to quantify the value of energy storage. Hydrogen energy storage and power-to-gas systems have the ability to integrate multiple energy sectors including electricity, transportation, and industrial. On account of the flexibility of hydrogen systems, there are a variety of potential system configurations. Each configuration will provide different value to the owner, customers and grid system operator. This presentation provides an economic comparison of hydrogen storage, power-to-gas and conventional storage systems. The total cost is compared to the revenue with participation in a variety of markets to assess the economic competitiveness. It is found that the sale of hydrogen for transportation or industrial use greatly increases competitiveness. Electrolyzers operating as demand response devices (i.e., selling hydrogen and grid services) are economically competitive, while hydrogen storage that inputs electricity and outputs only electricity have an unfavorable business case. Additionally, tighter integration with the grid provides greater revenue (e.g., energy, ancillary service and capacity markets are explored). Lastly, additional hours of storage capacity is not necessarily more competitive in current energy and ancillary service markets and electricity markets will require new mechanisms to appropriately compensate long duration storage devices.

  12. Pu-nvt-tv E-ten-hes-se (Animal Friends).

    ERIC Educational Resources Information Center

    Dissemination and Assessment Center for Bilingual Education, Austin, TX.

    This reader in Maskoke (Muskokee) is developed to help elementary school children begin simple reading. Black-and-white drawings personifying animals illustrate the text. An English translation is included. (NCR)

  13. Transition metal HE`s - VII ACP. Progress report, August 1971--October 1971

    SciTech Connect

    Clink, G.L.

    1998-12-31

    Physical and physicochemical properties of hexaamminechromium III perchlorate (ACP) were investigated to determine its potentiality for HE and/or HE component application. Physicochemical properties obtained through investigation of isothermally aged ACP under conditions of various system and boundary restrictions (open and closed; 50 and 80 C; 0.65 and 0.85 g/cc) show the material to be substantially stable under these simulated isothermal storage conditions from a standpoint of infrared and DTA thermal pattern behavior and chemical analysis of aged residues. Spark sensitivity was 0.25 joules at 5 kv (by LASL type test) and impact sensitivity was about 23 and 14 cm on sandpaper (12A) and steel (12B), respectively.

  14. Pu-nvt-tv E-ten-hes-se (Animal Friends).

    ERIC Educational Resources Information Center

    Dissemination and Assessment Center for Bilingual Education, Austin, TX.

    This reader in Maskoke (Muskokee) is developed to help elementary school children begin simple reading. Black-and-white drawings personifying animals illustrate the text. An English translation is included. (NCR)

  15. Plasma volume replacement with HES 130/0.42 obviates negative side effects of pneumoperitoneum in piglets.

    PubMed

    Osthaus, Wilhelm Alexander; Huber, Dirk; Bäumker, Christoph; Witt, Lars; Metzelder, Martin; Kuebler, Jochen; Sümpelmann, Robert

    2008-10-01

    Evidence-based guidelines on optimal perioperative fluid management in infants have not been established. Recent randomized trials in major abdominal surgery in adults suggest that large volumes of fluid may increase morbidity and hospital stay. Our own clinical experience in infants undergoing laparoscopic surgery is different. So the aim of this study was to compare a crystalloid vs a plasma volume stabilizing fluid management regime during prolonged pneumoperitoneum (PP) in an experimental setting. Fifteen German landrace piglets were randomized to one of the following treatment groups: control (no PP, 5 ml x kg(-1) x h(-1) electrolyte solution); crystalloid (180 min of PP, 5 ml x kg(-1) x h(-1) electrolyte solution); colloid (180 min of PP, single bolus of 5 ml x kg(-1) followed by 5 ml x kg(-1) x h(-1) hydroxyethyl starch 130/0.42/6:2). After decompression, monitoring was continued for a further 120 min. During the investigation, the hemodynamic situation including transpulmonary thermodilution and blood gases was monitored periodically. During the study, mean arterial pressure remained within the normal range in colloid-treated animals and controls, but was significantly lower in crystalloid-treated animals after decompression of PP. Cardiac output remained within the normal range in the colloid and control groups, but decreased in the crystalloid-treated animals. In the crystalloid group, the lactate concentrations were higher and base excess was lower than in the colloid and control groups at 240 and 300 min (study end). This study shows that the negative effects of prolonged PP on hemodynamics and acid-base balance can be obviated by a liberal plasma volume stabilization regimen with colloids.

  16. "HES Presidential Address": Confessions of a Positivist--How Foucault Led Me to a Meta-Narrative about School Desegregation

    ERIC Educational Resources Information Center

    Hutcheson, Philo

    2012-01-01

    This address derives from the intellectual contributions of young scholars and doctoral students, in faded memory of the author's life as a doctoral student and young scholar. This address has three purposes: (1) to define school desegregation; (2) to place--albeit briefly--that definition within the larger context of the literature on school…

  17. Low-energy R -matrix fits for the 6Li(d ,α ) 4HeS factor

    NASA Astrophysics Data System (ADS)

    Grineviciute, J.; Lamia, L.; Mukhamedzhanov, A. M.; Spitaleri, C.; La Cognata, M.

    2015-01-01

    Background: Information about the 6Li(d ,α ) 4He reaction rates of astrophysical interest can be obtained by extrapolating direct data to lower energies, or by indirect methods. The indirect Trojan horse method, as well as various R -matrix and polynomial fits to direct data, estimate electron screening energies much larger than the adiabatic limit. Calculations that include the subthreshold resonance estimate smaller screening energies. Purpose: Obtain the 6Li(d,α ) 4He reaction R -matrix parameters and the bare astrophysical S factor for energies relevant to the stellar plasmas by fitting R -matrix formulas for the subthreshold resonances to the S -factor data above 60 keV. Methods: The bare S factor is calculated using the single- and the two-level R -matrix formulas for the closest to the threshold 0+ and 2+ subthreshold states at 22.2 ,20.2 , and 20.1 MeV. The electron screening potential U e is then obtained by fitting it as a single parameter to the low-energy data. The calculations are also done by fitting U e simultaneously with other parameters. Results: The low-energy S factor is dominated by the 2+ subthreshold resonance at 22.2 MeV. The influence of the other two subthreshold states is small. The resultant electron screening is smaller than the adiabatic value. The fits that neglect the electron screening above 60 keV produce a significantly smaller electron screening potential. The calculations show a large ambiguity associated with a choice of the initial channel radius. Conclusions: The R -matrix fits do not show a significantly larger Ue than predicted by the atomic physics models. The R -matrix best fit provides U e=149.5 eV and Sb(0 ) =21.7 MeV b.

  18. Cardiac deatH prevention by aUtomated defibrillatoRs in ChurcHes: rationale and design of the CHURCH trial.

    PubMed

    Ferratini, Maurizio; Moraschi, Andrea; Ripamonti, Vittorino; Giannuzzi, Pantaleo; Lorito, Francesco; De Luca, Gianni; Grieco, Niccolò; Sesana, Giovanni; De Maria, Renata

    2010-02-01

    Early defibrillation programs by the use of automated external defibrillators (AEDs) located in high-attendance public places may improve survival and neurologic outcome of patients undergoing sudden cardiac arrest (SCA). We planned a prospective cohort study to assess the effectiveness of a public-access defibrillation program based on positioning of AEDs in churches and training of lay volunteers in Basic Life Support Defibrillation during a single-day 5-hour training session. The CHURCH project aims to promote a widespread diffusion of AEDs, to train a large number of lay volunteers in Basic Life Support Defibrillation, and to increase population awareness on the opportunities for sudden death prevention. The rationale of the study rests on a survey commissioned by the Diocese of Milan that found a high prevalence of elderly subjects (44.5% were >60 years old) attending holy services in the morning hours, when sudden death incidence peaks. The catchment areas of the 12 parishes included in the trial as of June 2008 include a population of 140,000. The projected incidence of AED-treatable SCA, based on the presence of trained volunteers in the churches during day hours, at the CHURCH participating sites was estimated at 8 episodes per year. To estimate an overall 30% mortality reduction from SCA after AED placement at the study sites with respect to conventional SCA management by the Emergency Medical Service, 25 SCA episodes will have to be treated during the 4-year study period. The CHURCH project might be of interest and applicable in every country where high-attendance worship places are present. Copyright (c) 2009 Mosby, Inc. All rights reserved.

  19. Drosophila CK2 phosphorylates Deadpan, a member of the HES family of basic-helix-loop-helix (bHLH) repressors.

    PubMed

    Karandikar, Umesh C; Shaffer, Jonathan; Bishop, Clifton P; Bidwai, Ashok P

    2005-06-01

    In Drosophila, protein kinase CK2 regulates a diverse array of developmental processes. One of these is cell-fate specification (neurogenesis) wherein CK2 regulates basic-helix-loop-helix (bHLH) repressors encoded by the Enhancer of Split Complex (E(spl)C). Specifically, CK2 phosphorylates and activates repressor functions of E(spl)M8 during eye development. In this study we describe the interaction of CK2 with an E(spl)-related bHLH repressor, Deadpan (Dpn). Unlike E(spl)-repressors which are expressed in cells destined for a non-neural cell fate, Dpn is expressed in the neuronal cells and is thought to control the activity of proneural genes. Dpn also regulates sex-determination by repressing sxl, the primary gene involved in sex differentiation. We demonstrate that Dpn is weakly phosphorylated by monomeric CK2alpha, whereas it is robustly phosphorylated by the embryo-holoenzyme, suggesting a positive role for CK2beta. The weak phosphorylation by CK2alpha is markedly stimulated by the activator polylysine to levels comparable to those with the holoenzyme. In addition, pull down assays indicate a direct interaction between Dpn and CK2. This is the first demonstration that Dpn is a partner and target of CK2, and raises the possibility that its repressor functions might also be regulated by phosphorylation.

  20. A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells

    PubMed Central

    Kjartansdóttir, Kristín Rós; Reda, Ahmed; Panula, Sarita; Day, Kelly; Hultenby, Kjell; Söder, Olle; Hovatta, Outi; Stukenborg, Jan-Bernd

    2015-01-01

    Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro. PMID:26630562

  1. A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells.

    PubMed

    Kjartansdóttir, Kristín Rós; Reda, Ahmed; Panula, Sarita; Day, Kelly; Hultenby, Kjell; Söder, Olle; Hovatta, Outi; Stukenborg, Jan-Bernd

    2015-01-01

    Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro.

  2. Physical plugging does not account for attenuation of capillary leakage by hydroxyethyl starch 130/0.4: a synthetic gel layer model.

    PubMed

    Tatara, Tsuneo; Itani, Motoi; Sugi, Takashi; Fujita, Kimihiko

    2013-01-01

    Hydroxyethyl starch (HES) solutions, widely used plasma substitutes, reportedly attenuate capillary leakage via physical plugging of capillary defects. We investigated how 2% HES solutions of different molecular weights (HES(70): 70 kDa, HES(130): 130 kDa, HES(200): 200 kDa, and HES(670): 670 kDa) affect dye release from polyacrylamide gels (PAGs) as a model of endothelial glycocalyx. We assessed dye release from 4% PAG with varying concentrations of albumin [0, 1, 2, 4, and 8% (w/v)] by measuring the change in dye absorbance (ΔAbs) at 5 h for each HES solution. For PAG containing no albumin, ΔAbs for HES(130) was 30% lower than that for HES(70) and HES(200), and 50% lower than that for HES(670). At concentrations of 1-8% albumin, ΔAbs at 5 h with HES(70), HES(130), and HES(200) solutions were almost half that with the HES(670) solution, but no significant differences were noted in ΔAbs at 5 h among HES(70), HES(130), and HES(200) solutions. The inhibition of dye release by HES(670) is likely due to the hindering effect of HES molecules partitioned into gel pores. However, a unique property of HES(130) , including the heavy hydroxyethylation at the C(2) position, may promote specific interactions with PAG and thereby inhibit solute release.

  3. Effect of 6% Hydroxyethyl Starch 130/0.4 as a Priming Solution on Coagulation and Inflammation Following Complex Heart Surgery

    PubMed Central

    Cho, Jang-Eun; Shim, Jae-Kwang; Song, Jong-Won; Lee, Hye-Won; Kim, Dong-Hwan

    2014-01-01

    Purpose Prolonged duration of cardiopulmonary bypass aggravates the degree of inflammation and coagulopathy. We investigated the influence of 6% hydroxyethyl starch (HES) 130/0.4 on coagulation and inflammation compared with albumin when used for both cardiopulmonary bypass priming and perioperative fluid therapy in patients undergoing complex valvular heart surgery. Materials and Methods Fifty four patients were randomly allocated into albumin-HES, albumin-nonHES, and HES-HES groups. The cardiopulmonary bypass circuit was primed with 5% albumin in the albumin-HES and albumin-nonHES group, and with HES in the HES-HES group. As perioperative fluid, only plasmalyte was used in the albumin-nonHES group whereas HES was used up to 20 mL/kg in the albumin-HES and albumin-HES group. Serial assessments of coagulation profiles using the rotational thromboelastometry and inflammatory markers (tissue necrosis factor-α, interleukin-6, and interleukin-8) were performed. Results Patients' characteristics and the duration of cardiopulmonary bypass (albumin-HES; 137±34 min, HES-HES; 136±47 min, albumin-nonHES; 132±39 min) were all similar among the groups. Postoperative coagulation profiles demonstrated sporadic increases in clot formation time and coagulation time, without any differences in the actual amount of perioperative bleeding and transfusion requirements among the groups. Also, inflammatory markers showed significant activation after cardiopulmonary bypass without any differences among the groups. Conclusion Even in the presence of prolonged duration of cardiopulmonary bypass, HES seemed to yield similar influence on the ensuing coagulopathy and inflammatory response when used for priming and perioperative fluid therapy following complex valvular heart surgery compared with conventional fluid regimen including albumin and plasmalyte. PMID:24719128

  4. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies.

    PubMed

    Bellmann, Romuald; Feistritzer, Clemens; Wiedermann, Christian J

    2012-04-01

    Intravenously infused hydroxyethyl starch (HES) can be found in urine, plasma and tissues. HES remaining in plasma and tissues is thought to increase the risk of clinical complications. HES solutions of lower molecular weight and substitution have been developed to increase urinary excretion and reduce plasma persistence. However, their effect on tissue uptake of HES has not been investigated in human subjects. Our objective was to test the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. Computer searches were performed of MEDLINE; EMBASE; the Cochrane Library; meeting abstract databases in surgery, anaesthesiology and intensive care; ClinicalTrials.gov; and Google. Supplementary sources were reference lists and electronic tables of journal contents. No time period or language restrictions were imposed. Clinical studies were eligible for inclusion in the meta-analysis, if data were reported both for cumulative urinary excretion of HES over 24 hours after infusion and for plasma HES concentration at 24 hours. Data were extracted on 24-hour urinary excretion of HES, 24-hour HES plasma concentration, plasma volume, HES molecular weight and substitution, study design, type and demographics of subjects, indication for fluid infusion, and HES infusion regimen. Tissue uptake of HES was computed as the difference between the infused dose and the sum of urinary excretion and residual plasma HES at 24 hours. Twenty-five clinical studies totalling 287 subjects were included. Tissue uptake of low-molecular-weight HES (≤200 kD) was 42.3% (95% confidence interval [CI] 39.6, 45.0) compared with 24.6% (CI 17.8, 31.4) for high-molecular-weight HES (p < 0.001). Similarly, tissue uptake of lower-substitution HES (≤0.5) was 42.4% (CI 39.5, 45.3) versus 26.6% (CI 19.6, 33.6) for higher-substitution HES (p < 0.001). Among the three most often investigated single HES solutions, tissue uptake of 130/0.4 (42.6%; CI 35.0, 50.2) and HES

  5. Gastrointestinal and Hepatic Involvement in Hypereosinophilic Syndrome

    PubMed Central

    Hurairah, Abu

    2016-01-01

    The objective of this investigation was to study the gastrointestinal and hepatic involvement in hypereosinophilic syndrome (HES). Gastrointestinal or hepatic involvement is estimated to affect up to one-third of patients with HES, although most of the clinical evidence has been derived from case reports. In literature, HES presenting with hepatitis and jaundice with subsequent development of colitis is a rare clinicopathologic entity. Given the clinical implications, physicians should include HES among differentials in these types of presentations. PMID:27733964

  6. Higher Education for Sustainability: Developing a Comprehensive Research Agenda

    ERIC Educational Resources Information Center

    Wright, Tarah

    2007-01-01

    From 27 to 29 October 2005, 35 experts in higher education for sustainability (HES) representing 17 countries, gathered in Halifax, Nova Scotia. This consultation represents the first gathering of HES researchers in Canada, and brought Canadian and international researchers together to further intellectual understanding of HES research and to…

  7. Higher Education for Sustainability: Developing a Comprehensive Research Agenda

    ERIC Educational Resources Information Center

    Wright, Tarah

    2007-01-01

    From 27 to 29 October 2005, 35 experts in higher education for sustainability (HES) representing 17 countries, gathered in Halifax, Nova Scotia. This consultation represents the first gathering of HES researchers in Canada, and brought Canadian and international researchers together to further intellectual understanding of HES research and to…

  8. Role of ICT in Shaping the Future of Pakistani Higher Education System

    ERIC Educational Resources Information Center

    Shaikh, Zaffar Ahmed; Khoja, Shakeel Ahmed

    2011-01-01

    This study examined the challenges faced by the Pakistani higher education system (HES) in integrating information and communication technology (ICT); it aimed at understanding ICT needs, measuring the increase in ICT demand, determining the relationship between ICT and HES performance, and understanding how the HES copes with the challenges of…

  9. Impact of the C2/C6 ratio of high-molecular-weight hydroxyethyl starch on pharmacokinetics and blood coagulation in pigs.

    PubMed

    Schramm, Sebastian; Thyes, Caroline; Frascarolo, Philippe; Buclin, Thierry; Burki, Marco; Fisch, Andreas; Burmeister, Marc-Alexander; Asmis, Lars; Spahn, Donat R

    2007-09-01

    High-molecular-weight, low-substituted hydroxyethyl starch (HES) may not affect blood coagulation more than low-molecular-weight, low-substituted HES. The authors assessed in vivo the effect of a lowered C2/C6 ratio on pharmacokinetic characteristics and the impact on blood coagulation of high-molecular-weight, low-substituted HES. A prospective, randomized, parallel study in 30 pigs compared HES 650/0.42/2.8 with HES 650/0.42/5.6. Before, during, and after infusion of 30 ml/kg body weight HES, blood samples were collected over 630 min to measure HES concentrations and plasmatic coagulation and to assess blood coagulation in whole blood by Thrombelastography (TEG; Haemoscope Corporation, Niles, IL). Pharmacokinetic parameters were estimated using a two-compartment model. The elimination constant was 0.009 +/- 0.001 min(-1) for HES 650/0.42/2.8 and 0.007 +/- 0.001 min(-1) for HES 650/0.42/5.6 (P < 0.001); the area under the plasma concentration-time curve was 1,374 +/- 340 min x g/l for HES 650/0.42/2.8 and 1,697 +/- 411 min x g/l for HES 650/0.42/5.6 (P = 0.026). The measured plasma HES concentrations were not different between HES 650/0.42/2.8 and HES 650/0.42/5.6. Both HES solutions equally affected blood coagulation: Thrombelastographic coagulation index decreased similarly at the end of infusion of HES 650/0.42/2.8 and at the end of infusion of HES 650/0.42/5.6 (P = 0.293). Also, activated partial thromboplastin and prothrombin times increased similarly for HES 650/0.42/2.8 and HES 650/0.42/5.6 (P = 0.831). Reducing the C2/C6 ratio in high-molecular, low-substituted HES solutions results in a slightly faster HES elimination. However, the blood coagulation compromising effect was unaffected.

  10. [Volume replacement with hydroxyethyl starch: is there an influence on kidney function?].

    PubMed

    Suttner, S; Boldt, J

    2004-02-01

    Hydroxyethyl starch (HES) solutions are synthetic colloids with the pharmacological properties that are closest to natural colloids. In Germany, numerous types of HES preparations with different combinations of concentration, weight-averaged mean molecular weight (Mw), and hydroxyethylation pattern are available. They differ with regard to their volume-supporting capacity, intravascular half-life, and side effect profile. The elimination of HES molecules varies with the Mw and degree of substitution (DS). Large HES molecules undergo hydrolytic cleavage by alpha-amylase and are excreted in the urine, or they are phagocytosed by the reticuloendothelial system. The smaller HES molecules are eliminated by glomerular filtration. The higher the DS, the slower the metabolism and elimination of the molecule. Although HES can be used safely even in large doses in patients without altered kidney function, renal dysfunction and acute renal failure after HES infusion have been reported in patients who share several risk factors, such as preexisting renal disease, advanced age in combination with dehydration, or treatment with high doses of slow degradable HES solutions. Since there is no direct chemical toxicity of HES, the most likely mechanism for HES-induced renal dysfunction may be swelling and vacuolization of tubular cells ("osmotic nephrosis-like lesions") and tubular obstruction due to the production of hyperviscous urine. Considering this pathogenesis, it can be hypothesized that all hyperoncotic colloid solutions can induce renal impairment. In the case of HES, the risk of high plasma colloid osmotic pressure and thus the risk of acute renal failure are probably increased by high concentrations of the colloid or repeated administration of slowly degradable HES with a high Mw and DS. With adequate hydration, using sufficient amounts of crystalloids, HES has little if any adverse effects on renal function. Furthermore, modern -rapidly degradable HES solutions with a

  11. Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients

    NASA Astrophysics Data System (ADS)

    Vuiblet, Vincent; Fere, Michael; Bankole, Ezechiel; Wynckel, Alain; Gobinet, Cyril; Birembaut, Philippe; Piot, Olivier; Rieu, Philippe

    2016-09-01

    In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival.

  12. Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients

    PubMed Central

    Vuiblet, Vincent; Fere, Michael; Bankole, Ezechiel; Wynckel, Alain; Gobinet, Cyril; Birembaut, Philippe; Piot, Olivier; Rieu, Philippe

    2016-01-01

    In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival. PMID:27608775

  13. Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients.

    PubMed

    Vuiblet, Vincent; Fere, Michael; Bankole, Ezechiel; Wynckel, Alain; Gobinet, Cyril; Birembaut, Philippe; Piot, Olivier; Rieu, Philippe

    2016-09-09

    In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival.

  14. Are renal adverse effects of hydroxyethyl starches merely a consequence of their incorrect use?

    PubMed

    Hartog, Christiane S; Brunkhorst, Frank M; Engel, Christoph; Meier-Hellmann, Andreas; Ragaller, Maximilian; Welte, Tobias; Kuhnt, Evelyn; Reinhart, Konrad

    2011-03-01

    Clinical studies such as VISEP-study, which show a negative outcome after the administration of hydroxyethyl starch (HES), are often criticized for an "incorrect" use of HES. It is argued that HES used in these studies differed from usual practice and that recommendations for maximal dosage, duration, and creatinine values were ignored, not enough "free water" was provided and more modern HES solutions should have been used. These comments imply that renal adverse events in clinical studies are the consequence of an inappropriate use of HES. We therefore searched for evidence whether these suggested measures are beneficial. Narrative review; post hoc statistical analysis of epidemiologic data from a representative nationwide survey. It is evident from published clinical studies that the renal risk of HES increases with cumulative dose and rising serum creatinine values, but no safe upper dose limit or creatinine threshold is known. Suggested safety measures were not able to prevent HES-induced renal failure in clinical studies. Published clinical trials with modern HES solutions are not suited to prove its assumed increased safety because of small sample sizes, low cumulative doses, short observation periods, and inadequate control fluids. Use of HES in a clinical study with negative outcomes conformed to clinical practice, indicating the generalizability of study results. There is no evidence for the assumption that HES-associated renal impairment may be avoided by accompanying measures. Because HES use does not improve clinical outcome, the question arises whether it should be used at all in patients at risk.

  15. Effect of high- and low-molecular-weight low-substituted hydroxyethyl starch on blood coagulation during acute normovolemic hemodilution in pigs.

    PubMed

    Thyes, Caroline; Madjdpour, Caveh; Frascarolo, Philippe; Buclin, Thierry; Bürki, Marco; Fisch, Andreas; Burmeister, Marc-Alexander; Asmis, Lars; Spahn, Donat R

    2006-12-01

    Hydroxyethyl starches (HES) with lower impact on blood coagulation but longer intravascular persistence are of clinical interest. The current study aimed to investigate in vivo the isolated effect of molecular weight on blood coagulation during progressive acute normovolemic hemodilution. Twenty-four pigs were normovolemically hemodiluted up to a total exchange of 50 ml . kg . body weight of HES 650/0.42 or HES 130/0.42. Serial blood sampling was performed to measure HES plasma concentration and to assess blood coagulation. Concentration-effect relations were analyzed by linear regression, followed by the Student t test on regression parameters. Blood coagulation was increasingly compromised toward hypocoagulability by acute normovolemic hemodilution with both treatments (P < 0.01). Significantly greater impact on activated partial thromboplastin time (P = 0.04) and significantly stronger decrease of maximal amplitude (P = 0.04), angle alpha (P = 0.02), and coagulation index (P = 0.02) was seen after acute normovolemic hemodilution with HES 650/0.42 as compared with HES 130/0.42. Except for factor VIII (P = 0.04), no significant differences between both treatments were observed when relating antihemostatic effects to HES plasma concentrations (P > 0.05). A significantly lesser decrease of hemoglobin concentration has been found with HES 650/0.42 as compared with HES 130/0.42 (P < 0.01) in relation to HES plasma concentrations. High-molecular-weight HES (650/0.42) shows a moderately greater antihemostatic effect than low-molecular-weight HES (130/0.42) during acute normovolemic hemodilution. However, similar effects on hemostasis were observed with both treatments when observed antihemostatic effects were related to measured HES plasma concentrations. In addition, HES 650/0.42 may have a lower efficacy in immediately restoring plasma volume.

  16. Hemato-endothelial differentiation from lentiviral-transduced human embryonic stem cells retains durable reporter gene expression under the control of ubiquitin promoter.

    PubMed

    Jiang, Hua; Lin, Xiaolong; Feng, Youji; Xie, Yi; Han, Jinlan; Zhang, Yueping; Wang, Zack Z; Chen, Tong

    2010-01-01

    Human embryonic stem (hES) cells are able to give rise to a variety of cell lineages under specific culture condition. An effective strategy for stable genetic modification in hES cells may provide a powerful tool for study of human embryogenesis and cell-based therapies. However, gene silences are documented in hES cells. In current study, we investigated whether genes controlled under ubiquitin promoter are expressed during hematopoietic-endothelial differentiation in hES cells. Undifferentiated hES cells (H1) were transduced by lentivirus encoding green fluorescent protein (GFP) gene under ubiquitin promoter. GFP-expressing hES cells (GFP-H1) were established after several rounds of mechanical selection under fluorescence microscope. GFP gene was stably expressed in hES cells throughout prolonged (> 50 passages) cultivation, and in differentiated embryo body (EB) and teratoma. Hematopoietic and endothelial markers, including KDR (VEGFR2), CD34, CD31, Tie-2, GATA-1 and GATA-2, were expressed at similar levels during hES cell differentiation in parent hES cells and GFP-H1 hES cells. CD34(+) cells isolated from GFP-H1 hES cells were capable to generate hematopoietic colony-forming cells and tubular structure-forming cells. Differentiated GFP-EB formed vasculature structures in a semi-solid sprouting EB model. These results indicated that a transgene under ubiquitin promoter in lentiviral transduced hES cells retained its expression in undifferentiated hES cells and in hES-derived hematopoietic and endothelial cells. With the view of embryonic mesodermal developing events in humans, genetic modification of hES cells by lentiviral vectors provides a powerful tool for study of hematopoiesis and vasculogenesis.

  17. Comparison of 7.2% hypertonic saline - 6% hydroxyethyl starch solution and 6% hydroxyethyl starch solution after the induction of anesthesia in patients undergoing elective neurosurgical procedures

    PubMed Central

    Shao, Liujiazi; Wang, Baoguo; Wang, Shuangyan; Mu, Feng; Gu, Ke

    2013-01-01

    OBJECTIVE: The ideal solution for fluid management during neurosurgical procedures remains controversial. The aim of this study was to compare the effects of a 7.2% hypertonic saline - 6% hydroxyethyl starch (HS-HES) solution and a 6% hydroxyethyl starch (HES) solution on clinical, hemodynamic and laboratory variables during elective neurosurgical procedures. METHODS: Forty patients scheduled for elective neurosurgical procedures were randomly assigned to the HS-HES group or the HES group. After the induction of anesthesia, patients in the HS-HES group received 250 mL of HS-HES (500 mL/h), whereas the patients in the HES group received 1,000 mL of HES (1000 mL/h). The monitored variables included clinical, hemodynamic and laboratory parameters. Chictr.org: ChiCTR-TRC-12002357 RESULTS: The patients who received the HS-HES solution had a significant decrease in the intraoperative total fluid input (p<0.01), the volume of Ringer's solution required (p<0.05), the fluid balance (p<0.01) and their dural tension scores (p<0.05). The total urine output, blood loss, bleeding severity scores, operation duration and hemodynamic variables were similar in both groups (p>0.05). Moreover, compared with the HES group, the HS-HES group had significantly higher plasma concentrations of sodium and chloride, increasing the osmolality (p<0.01). CONCLUSION: Our results suggest that HS-HES reduced the volume of intraoperative fluid required to maintain the patients undergoing surgery and led to a decrease in the intraoperative fluid balance. Moreover, HS-HES improved the dural tension scores and provided satisfactory brain relaxation. Our results indicate that HS-HES may represent a new avenue for volume therapy during elective neurosurgical procedures. PMID:23644851

  18. Comparison of 7.2% hypertonic saline - 6% hydroxyethyl starch solution and 6% hydroxyethyl starch solution after the induction of anesthesia in patients undergoing elective neurosurgical procedures.

    PubMed

    Shao, Liujiazi; Wang, Baoguo; Wang, Shuangyan; Mu, Feng; Gu, Ke

    2013-01-01

    The ideal solution for fluid management during neurosurgical procedures remains controversial. The aim of this study was to compare the effects of a 7.2% hypertonic saline - 6% hydroxyethyl starch (HS-HES) solution and a 6% hydroxyethyl starch (HES) solution on clinical, hemodynamic and laboratory variables during elective neurosurgical procedures. Forty patients scheduled for elective neurosurgical procedures were randomly assigned to the HS-HES group orthe HES group. Afterthe induction of anesthesia, patients in the HS-HES group received 250 mL of HS-HES (500 mL/h), whereas the patients in the HES group received 1,000 mL of HES (1000 mL/h). The monitored variables included clinical, hemodynamic and laboratory parameters. Chictr.org: ChiCTR-TRC-12002357 The patients who received the HS-HES solution had a significant decrease in the intraoperative total fluid input (p<0.01), the volume of Ringer's solution required (p<0.05), the fluid balance (p<0.01) and their dural tension scores (p<0.05). The total urine output, blood loss, bleeding severity scores, operation duration and hemodynamic variables were similar in both groups (p>0.05). Moreover, compared with the HES group, the HS-HES group had significantly higher plasma concentrations of sodium and chloride, increasing the osmolality (p<0.01). Our results suggest that HS-HES reduced the volume of intraoperative fluid required to maintain the patients undergoing surgery and led to a decrease in the intraoperative fluid balance. Moreover, HS-HES improved the dural tension scores and provided satisfactory brain relaxation. Our results indicate that HS-HES may represent a new avenue for volume therapy during elective neurosurgical procedures.

  19. Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model

    PubMed Central

    Hüter, Lars; Simon, Tim-Philipp; Weinmann, Lenard; Schuerholz, Tobias; Reinhart, Konrad; Wolf, Gunter; Amann, Kerstin Ute; Marx, Gernot

    2009-01-01

    Introduction The aim of the study was to evaluate some of the underlying pathomechanisms of hydroxyethylstarch (HES) induced adverse effects on renal function using 24 porcine kidneys in an isolated perfusion model over six hours. Methods Infusion of either 10% HES 200/0.5, 6% HES 130/0.42 or Ringer's lactate (RL) was performed to achieve an haematocrit of 20% in eight kidneys from four animals per group. Physiological and pathophysiological parameters were determined (including N-acetyl-beta-aminoglucosidase as a marker for lysosomal tubular damage). Histological investigations and immunohistological stainings of the kidneys were performed. Results Initially after haemodilution, HES 130/0.42 and HES 200/0.5 reduced urine output compared with RL (P < 0.01). After six hours, N-acetyl-beta-aminoglucosidase was significantly higher in HES 200/0.5 (81 ± 23 U/L) compared with HES 130/0.42 (38 ± 12 U/L) and RL (21 ± 13 U/L; P < 0.001). Osmotic nephrosis-like lesions (OL) of the tubuli were present in all groups showing a significantly lower number of OL in RL (1.1 ± 0.4; P = 0.002) compared with both HES groups (HES 200/0.5 = 2.1 ± 0.6; HES 130/0.42 = 2.0 ± 0.5). Macrophage infiltration was significantly higher in HES 200/0.5 compared with HES 130/0.42 (1.3 ± 1.0 vs. 0.2 ± 0.04; P = 0.044). There was a significant increase in interstitial cell proliferation in the HES 200/0.5 group vs. HES 130/0.42 (18.0 ± 6.9 vs. 6.5 ± 1.6; P = 0.006) with no significant difference in RL (13.5 ± 4.0). Conclusions We observed impaired diuresis and sodium excretion by HES and identified renal interstitial proliferation, macrophage infiltration and tubular damage as potential pathological mechanisms of HES-induced adverse effects on renal function using an isolated porcine renal perfusion model. Furthermore, we demonstrated that 10% HES 200/0.5 had more of a pro-inflammatory effect compared with 6% HES 130/0.42 and caused more pronounced tubular damage than 6% HES 130/0.42 and

  20. A Comparative Coagulopathic Study for Treatment of Vasospasm by Using Low- and High-molecular Weight Hydroxyethyl Starches.

    PubMed

    Hwang, Sung Ho; Won, Yu Sam; Yu, Jang Sun; Yang, Jae Young; Choi, Chun Sik

    2007-11-01

    High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than does low-molecular-weight HES. We compared the effects of low- and high-molecular-weight HES for the treatment of vasospasm and investigated the dose relationship with each other. Retrospectively, in a series of consecutive 102 patients with subarachnoid hemorrhage (SAH), 35 patients developed clinical symptoms of vasospasm of these fourteen patients were treated with low-molecular-weight HES for volume expansion while the other 21 received high-molecular-weight HES as continuous intravenous infusion. Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level, and platelet count were all measured prior to initiation, during treatment and after termination of therapy for symptomatic vasospasm. The total dose of HES ranged from 5 L to 14 L and median infusion duration was 10 days. A more pronounced PTT prolongation was observed in high-molecular-weight HES group compared with low-molecular-weight HES group. No other coagulation parameters were altered. Dosage (=duration) shows a positive correlation with PTT. Clinically, significant bleeding episodes were noted in four patients who received high-molecular-weight HES. Coagulopathy was developed in direct proportion to molecular weight of starch and dosages. We propose the extreme caution in the administration of HES solution for the vasospasm treatment.

  1. Effects on coagulation of balanced (130/0.42) and non-balanced (130/0.4) hydroxyethyl starch or gelatin compared with balanced Ringer's solution: an in vitro study using two different viscoelastic coagulation tests ROTEMTM and SONOCLOTTM.

    PubMed

    Casutt, M; Kristoffy, A; Schuepfer, G; Spahn, D R; Konrad, C

    2010-09-01

    Hydroxyethyl starch (HES) solutions compromise blood coagulation. Low molecular weight, low-substituted HES products, and electrolyte-balanced solutions might reduce this effect. We compared the effects of in vitro haemodilution on blood coagulation with a balanced 6% HES 130/0.42 solution (HES(BAL)), a saline-based 6% HES 130/0.4 solution (HES(SAL)), a balanced lactated Ringer's solution (RL) and a saline-based 4% gelatin solution (GEL). Blood was obtained from 10 healthy male volunteers and diluted with the test solutions by 33% and 66%. Quality of clot formation was measured using two viscoelastic coagulation tests: SONOCLOT and activated rotation thromboelastometry ROTEM. Of 16 parameters measured by the viscoelastic devices, we found three statistically significant differences compared with baseline for RL, but 11 for GEL, 10 for HES(SAL), and 11 for HES(BAL) in the 33% haemodilution group (P=0.01). Comparing the different solutions, we observed a significant difference between crystalloids and colloids but none between GEL and HES. In the 66% dilution group, effects on blood coagulation were increased when compared with the 33% dilution group. We found no differences in coagulation impairment between balanced and non-balanced HES products and no differences in the detection of impaired blood coagulation due to haemodilution between the two viscoelastic coagulation tests. Both ROTEM and SONOCLOT are sensitive tests for the detection of impaired blood coagulation due to haemodilution. There are fewer effects on blood coagulation using crystalloids compared with colloids. The effects of GEL and HES are similar. There is no difference between balanced HES 130/0.42 and non-balanced HES 130/0.4.

  2. Genetic engineering of human embryonic stem cells with lentiviral vectors.

    PubMed

    Xiong, Chen; Tang, Dong-Qi; Xie, Chang-Qing; Zhang, Li; Xu, Ke-Feng; Thompson, Winston E; Chou, Wayne; Gibbons, Gary H; Chang, Lung-Ji; Yang, Li-Jun; Chen, Yuqing E

    2005-08-01

    Human embryonic stem (hES) cells present a valuable source of cells with a vast therapeutic potential. However, the low efficiency of directed differentiation of hES cells remains a major obstacle in their uses for regenerative medicine. While differentiation may be controlled by the genetic manipulation, effective and efficient gene transfer into hES cells has been an elusive goal. Here, we show stable and efficient genetic manipulations of hES cells using lentiviral vectors. This method resulted in the establishment of stable gene expression without loss of pluripotency in hES cells. In addition, lentiviral vectors were effective in conveying the expression of an U6 promoter-driven small interfering RNA (siRNA), which was effective in silencing its specific target. Taken together, our results suggest that lentiviral gene delivery holds great promise for hES cell research and application.

  3. Campaign Assessment in Counterinsurgency: Reinventing the Wheel

    DTIC Science & Technology

    2015-04-22

    MACV achieved in Vietnam through use of the Hamlet Evaluation System (HES). Although the HES was criticized during the Vietnam War, the iterative...model to inform progress. The improved model, the Hamlet Evaluation System, analyzed a host of variables across South Vietnam to assess progress...Afghanistan HES Hamlet Evaluation System ICAF Interagency Conflict Assessment Framework IJC ISAF Joint Command ISAF-A International Security Assistance

  4. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use.

    PubMed

    Glover, Polly A; Rudloff, Elke; Kirby, Rebecca

    2014-01-01

    To review and summarize the pharmacokinetics and pharmacodynamics of hydroxyethyl starch (HES), as well as reported risks and benefits of HES infusion, and to provide administration and monitoring recommendations for HES use in dogs and cats. Veterinary and human peer-reviewed medical literature, including scientific reviews, clinical and laboratory research articles, and authors' clinical experience. HES solutions are the most frequently used synthetic colloid plasma volume expanders in human and veterinary medicine. The majority of research in human medicine has focused on the adverse effects of HES infusion, with emphasis on acute kidney injury and coagulation derangements. The studies often differ in or fail to report factors, such as the type, amount, interval, and concentration of HES administered; the patient population studied; or concurrent fluids administered. Currently, there is no definitive clinical evidence that the reported adverse effects of HES use in human medicine occur in veterinary species. There is little information available on HES administration techniques or simultaneous administration of additional fluids in human and veterinary medicine. The rationale for HES use in small animals has been largely extrapolated from human medical studies and guidelines. A controlled approach to intravenous fluid resuscitation using crystalloid and HES volumes titrated to reach desired resuscitation end point parameters is outlined for small animal practitioners. The extrapolation of data from human studies directly to small animals should be done with the knowledge that there may be species variations and different pharmacokinetics with different HES solutions. Veterinary reports indicate that bolus and continuous rate infusions of 6% hetastarch solutions at moderate doses are well tolerated in feline and canine subjects. Further research in domesticated species is necessary to better define and expand the knowledge regarding use of HES solutions in small

  5. Hall effect, edge states, and Haldane exclusion statistics in two-dimensional space

    NASA Astrophysics Data System (ADS)

    Ye, F.; Marchetti, P. A.; Su, Z. B.; Yu, L.

    2015-12-01

    We clarify the relation between two kinds of statistics for particle excitations in planar systems: the braid statistics of anyons and the Haldane exclusion statistics (HES). It is shown nonperturbatively that the HES exists for incompressible anyon liquid in the presence of a Hall response. We also study the statistical properties of a specific quantum anomalous Hall model with Chern-Simons term by perturbation in both compressible and incompressible regimes, where the crucial role of edge states to the HES is shown.

  6. Comparative characteristics of three human embryonic stem cell lines.

    PubMed

    Lee, Jung Bok; Kim, Jin Mee; Kim, Sung Jong; Park, Jong Hyuk; Hong, Seok Ho; Roh, Sung Il; Kim, Moon Kyoo; Yoon, Hyun Soo

    2005-02-28

    Human embryonic stem (hES) cells have unique features including unlimited growth capacity, expression of specific markers, normal karyotypes and an ability to differentiate. Many investigators have tried to use hES cells for cell-based therapy, but there is little information about the properties of available hES cell lines. We compared the characteristics of three hES cell lines. The expression of SSEA-1, -3, -4, and APase, was examined by immunocytochemistry, and Oct-4 expression was analyzed by RT-PCR. Differentiation of the hES cells in vitro and in vivo led to the formation of embryoid bodies (EBs) or teratomas. We examined the expression of tissue-specific markers in the differentiated cells by semiquantitative RT-PCR, and the ability of each hES cell line to proliferate was measured by flow cytometry of DNA content and ELISA. The three hES cell lines were similar in morphology, marker expression, and teratoma formation. However there were significant differences (P < 0.05) between the differentiated cells formed by the different cell lines in levels of expression of tissue-specific markers such as renin, kallikrein, Glut-2, beta- and delta-globin, albumin, and alpha1-antitrypsin (alpha1-AT). The hES cell lines also differed in proliferative activity. Our observations should be useful in basic and clinical hES cell research.

  7. Distinct profiles of human embryonic stem cell metabolism and mitochondria identified by oxygen.

    PubMed

    Lees, Jarmon G; Rathjen, Joy; Sheedy, John R; Gardner, David K; Harvey, Alexandra J

    2015-10-01

    Oxygen is a powerful regulator of cell function and embryonic development. It has previously been determined that oxygen regulates human embryonic stem (hES) cell glycolytic and amino acid metabolism, but the effects on mitochondria are as yet unknown. Two hES cell lines (MEL1, MEL2) were analyzed to determine the role of 5% (physiological) and 20% (atmospheric) oxygen in regulating mitochondrial activity. In response to extended physiological oxygen culture, MEL2 hES cells displayed reduced mtDNA content, mitochondrial mass and expression of metabolic genes TFAM, NRF1, PPARa and MT-ND4. Furthermore, MEL2 hES cell glucose consumption, lactate production and amino acid turnover were elevated under physiological oxygen. In stark contrast, MEL1 hES cell amino acid and carbohydrate use and mitochondrial function were relatively unaltered in response to oxygen. Furthermore, differentiation kinetics were delayed in the MEL1 hES cell line following BMP4 treatment. Here we report the first incidence of metabolic dysfunction in a hES cell population, defined as a failure to respond to oxygen concentration through the modulation of metabolism, demonstrating that hES cells can be perturbed during culture despite exhibiting the defining characteristics of pluripotent cells. Collectively, these data reveal a central role for oxygen in the regulation of hES cell metabolism and mitochondrial function, whereby physiological oxygen promotes glucose flux and suppresses mitochondrial biogenesis and gene expression.

  8. Human embryonic stem cells: culture, differentiation, and genetic modification for regenerative medicine applications.

    PubMed

    Lebkowski, J S; Gold, J; Xu, C; Funk, W; Chiu, C P; Carpenter, M K

    2001-01-01

    Human embryonic stem (hES) cells can proliferate extensively in culture and can differentiate into representatives of all three embryonic germ layers in vitro and in vivo. The undifferentiated hES cells have now been cultured for more than 50 passages in vitro, yet maintain a normal karyotype. The hES cells express a series of specific surface antigens, as well as OCT-4 and human telomerase, proteins associated with a pluripotent and immortal phenotype. On differentiation, OCT-4 and human telomerase expression decreases with the emergence of a maturing population of cells. During hES cell differentiation, modulation of the expression of many genes has been evaluated using microarray analysis. To improve the ease, reproducibility, and scalability of hES culture, methods have been developed to propagate the cells in the absence of mouse embryonic cell feeders. hES cells maintained in culture using extracellular matrix factors together with mouse embryonic cell conditioned medium proliferate indefinitely while maintaining a normal karyotype, proliferation rate, and complement of undifferentiated cell markers. hES cells cultured without feeder layers retain their capacity to differentiate into cells of all three germ layers in vitro and in teratomas. The hES cells can also be genetically modified transiently or stably using both plasmid and viral gene transfer agents. These analyses and technological developments will aid in the realization of the full potential of hES cells for both research and therapeutic applications.

  9. Reduced mitotic activity at the periphery of human embryonic stem cell colonies cultured in vitro with mitotically-inactivated murine embryonic fibroblast feeder cells.

    PubMed

    Heng, Boon Chin; Cao, Tong; Liu, Hua; Rufaihah, Abdul Jalil

    2005-01-01

    This study attempted to investigate whether different levels of mitotic activity exist within different physical regions of a human embryonic stem (hES) cell colony. Incorporation of 5-bromo-2-deoxyuridine (BrdU) within newly-synthesized DNA, followed by immunocytochemical staining was used as a means of detecting mitotically-active cells within hES colonies. The results showed rather surprisingly that the highest levels of mitotic activity are primarily concentrated within the central regions of hES colonies, whereas the peripheral regions exhibited reduced levels of cellular proliferation. Two hypothetical mechanisms are therefore proposed for hES colony growth and expansion. Firstly, it is envisaged that the less mitotically-active hES cells at the periphery of the colony are continually migrating outwards, thereby providing space for newly-divided daughter cells within the more mitotically-active central region of the hES colony. Secondly, it is proposed that the newly-divided hES cells within the central region of the colony somehow migrate to the outer periphery. This could possibly explain why the periphery of hES colonies are less mitotically-active, since there would obviously be an extended time-lag before newly-divided daughter cells are ready again for the next cell division. Further investigations need to be carried out to characterize the atypical mechanisms by which hES colonies grow and expand in size.

  10. Osmotic virial coefficients of hydroxyethyl starch from aqueous hydroxyethyl starch-sodium chloride vapor pressure osmometry.

    PubMed

    Cheng, Jingjiang; Gier, Martin; Ross-Rodriguez, Lisa U; Prasad, Vinay; Elliott, Janet A W; Sputtek, Andreas

    2013-09-05

    Hydroxyethyl starch (HES) is an important industrial additive in the paper, textile, food, and cosmetic industries and has been shown to be an effective cryoprotectant for red blood cells; however, little is known about its thermodynamic solution properties. In many applications, in particular those in biology, HES is used in an aqueous solution with sodium chloride (NaCl). The osmotic virial solution thermodynamics approach accurately captures the dependence of osmolality on molality for many types of solutes in aqueous systems, including electrolytes, sugars, alcohols, proteins, and starches. Elliott et al. proposed mixing rules for the osmotic virial equation to be used for osmolality of multisolute aqueous solutions [Elliott, J. A. W.; et al. J. Phys. Chem. B 2007, 111, 1775-1785] and recently applied this approach to the fitting of one set of aqueous HES-NaCl solution data reported by Jochem and Körber [Cryobiology 1987, 24, 513-536], indicating that the HES osmotic virial coefficients are dependent on HES-to-NaCl mass ratios. The current study reports new aqueous HES-NaCl vapor pressure osmometry data which are analyzed using the osmotic virial equation. HES modifications were measured after dialysis (membrane cut off: 10,000 g/mol) and freeze-drying using vapor pressure osmometry at different mass ratios of HES to NaCl for HES up to 50% and NaCl up to 25% with three different HES modifications (weight average molecular weights [g/mol]/degree of substitution: 40,000/0.5; 200,000/0.5; 450,000/0.7). Equations were then fit to the data to provide a model for HES osmotic virial coefficient dependence on mass ratio of HES to NaCl. The osmolality data of the three HES modifications were accurately described over a broad range of HES-to-NaCl mass ratios using only four parameters, illustrating the power of the osmotic virial approach in analyzing complex data sets. As expected, the second osmotic virial coefficients increase with molecular weight of the HES and

  11. Hypereosinophilic syndrome and proliferative diseases.

    PubMed

    Ionescu, Marius A; Wang, Li; Janin, Anne

    2009-01-01

    Therapy principles of the last decade and recent advances in the research of polynuclear eosinophil have led to a new approach in the hypereosinophilic syndrome (HES), with important consequences on the development of new and effective therapies. HES is defined by persistent and marked eosinophilia and eosinophil-related organ damage in the absence of any evident cause of hypereosinophilia. Two variants of HES have been characterized, with different prognosis and possible associations with malignant diseases such as myeloid leukemia or T-cell lymphomas. The lymphocytic variant of HES (L-HES) is characterized by the presence of T cell clones, IL-5 expression and possible progression to T-cell lymphoma. Besides steroid therapy, the anti-IL-5 monoclonal antibody mepolizumab is considered as a target therapy for L-HES. The myeloproliferative variant of HES (M-HES) is associated with an increased risk of myeloid leukemia and good response to anti-tyrosine-kinase therapy. The imatinib target is a kinase resulting from an 800-kb deletion on chromosome 4. The fusion gene Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) has been validated as a marker of response to anti-tyrosine-kinase therapy. Early identification of HES variants is crucial for the rapid introduction of early and appropriately adjusted therapy.

  12. Atypical Presentation of Intracardiac Floating Thrombi in Hypereosinophilic Syndrome Complicated With Stroke and Systemic Embolization

    PubMed Central

    Lai, Chih-Hung; Chang, Szu-Ling; Lin, Wei-Wen; Hsiung, Ming-Chon; Juan, Yu-Hsiang; Wang, Tzu-Lin

    2015-01-01

    Abstract Hypereosinophilic syndrome (HES) describes a disorder characterized by persistent peripheral blood eosinophilia with evidence of multiple target organs damage caused by eosinophilia. HES most commonly involves the heart, and cardiac involvement typically presents in the form of endomyocarditis or myocarditis with apical mural thrombus formation. We present a case with atypical cardiac presentation with massive intracardiac fragile thrombi, causing peripheral emboli and strokes. HES can present as floating thrombi with thin attachment to the left ventricle, and clinicians should also be vigilant of thromboembolic complications and initiate early therapy to prevent or reduce the potential complications of HES. PMID:26512591

  13. Reversible Severe Eosinophilic Endomyocardial Fibrosis During Pregnancy: A Case Report.

    PubMed

    Pineton de Chambrun, Marc; Charron, Philippe; Vauthier-Brouzes, Danièle; Cluzel, Philippe; Haroche, Julien; Kahn, Jean-Emmanuel; Amoura, Zahir; Aubart, Fleur Cohen

    2015-08-01

    Idiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and have rarely been reported, particularly in the setting of heart failure.We here report on the case of a 29-year-old woman with HES who developed severe endomyocardial fibrosis with heart failure during pregnancy. Outcome was favorable under treatment with prednisone and azathioprine.This case illustrates a favorable outcome of endomyocardial fibrosis during pregnancy.

  14. Reversible Severe Eosinophilic Endomyocardial Fibrosis During Pregnancy

    PubMed Central

    Pineton de Chambrun, Marc; Charron, Philippe; Vauthier-Brouzes, Danièle; Cluzel, Philippe; Haroche, Julien; Kahn, Jean-Emmanuel; Amoura, Zahir; Aubart, Fleur Cohen

    2015-01-01

    Abstract Idiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and have rarely been reported, particularly in the setting of heart failure. We here report on the case of a 29-year-old woman with HES who developed severe endomyocardial fibrosis with heart failure during pregnancy. Outcome was favorable under treatment with prednisone and azathioprine. This case illustrates a favorable outcome of endomyocardial fibrosis during pregnancy. PMID:26266372

  15. Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery : a randomised, double-blind study.

    PubMed

    Jungheinrich, Cornelius; Sauermann, Wilhelm; Bepperling, Frank; Vogt, Norbert H

    2004-01-01

    Different types of hydroxyethyl starch (HES) affect blood coagulation differently. We studied the effects of HES 130/0.4 on coagulation in major orthopaedic surgery in relation to the pharmacological parameter in vivo molecular weight. 52 patients were randomly allocated to either HES 130/0.4 (6%, mean molecular weight 130 kDa, molar substitution 0.4) or HES 200/0.5 (6%, control) in a double-blind fashion. Colloidal volume requirements for intra- and postoperative haemodynamic stabilisation were compared. Safety analyses of this pharmacological study included a comparison of coagulation factor tests, in vivo molecular weight, and HES plasma concentrations. The colloidal volumes given were similar at the end of surgery (1602 +/- 569 for HES 130/0.4 vs 1635 +/- 567mL for HES 200/0.5), 5h later (1958 +/- 467 vs 1962 +/- 398mL), and up to the first postoperative day (2035 +/- 446 vs 2000 +/- 424mL). HES in vivo molecular weight at the end of surgery was 88,707 +/- 13,938 versus 158,374 +/- 33,933Da (p < 0.001) and 5h later was 86,663 +/- 16,126 versus 136,299 +/- 26,208Da (p < 0.001). In parallel to the lower in vivo molecular weight, factor VIII and von Willebrand factor returned to almost normal in the HES 130/0.4 group up to 5h postoperatively, but not in the control group (p < 0.05). Residual HES plasma concentrations after 24h were low in the HES 130/0.4 group (1.0 mg/mL), but higher in the control group (2.6 mg/mL). HES 130/0.4 and HES 200/0.5 were found to be similar with regard to volume efficacy. Sensitive coagulation parameters returned more rapidly to normal in the HES 130/0.4 group. Lower in vivo molecular weight and more rapid excretion of HES 130/0.4 are the likely explanations for the smaller influence on coagulation in this group.

  16. Coagulation and biochemical effects of balanced salt-based high molecular weight vs saline-based low molecular weight hydroxyethyl starch solutions during the anhepatic period of liver transplantation.

    PubMed

    Ahn, H J; Yang, M; Gwak, M S; Koo, M S; Bang, S R; Kim, G S; Lee, S K

    2008-03-01

    The anhepatic period of liver transplantation is generally marked by a decrease in preload, and the infusion of hydroxyethyl starch (HES) solution is often an effective way to restore volume deficits in non-anaemic patients. However, the infusion of even limited amounts of HES solution during the anhepatic period may result in a worsening coagulopathy. Moreover, lactate-containing HES solution may cause some degree of biochemical derangements in compromised recipients. Therefore, we compared two different types of HES solutions: a balanced salt-based high molecular weight HES solution (670/0.75; high MW group) and a saline-based low molecular weight HES solution (130/0.4; low MW group) with respect to coagulation and biochemical profiles. First, in an in vitro study (n = 48), thromboelastography was performed to determine the effects of two HES solutions on coagulation after diluting (11%) the recipient's blood sample with each HES solution. Second, in an in vivo study, 500 ml of one of the two 6% HES solution was administered to 74 recipients (n = 37, each group) for 30 min after starting the anhepatic period. The coagulation profiles, including thromboelastography, and biochemical profiles were measured before and 30 min after the end of infusion. Less impairment in the thromboelastography profiles and aPTT was observed in the high MW group. A higher calcium concentration and less reduction in platelet count were noted in the high MW group, but lactate accumulation was greater. In conclusion, a balanced salt-based high molecular weight HES solution is a more effective volume replacement during the anhepatic period of liver transplantation with respect to coagulation than a saline-based low molecular weight HES solution, although lactate accumulation is a possible concern.

  17. Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England

    PubMed Central

    2012-01-01

    Background Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources. Methods Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman’s general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record. Results Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete. Conclusion Hospital admission data in England provide

  18. Heavy eye syndrome versus sagging eye syndrome in high myopia

    PubMed Central

    Tan, Roland Joseph D.; Demer, Joseph L.

    2015-01-01

    Background Heavy eye syndrome (HES) presents with esotropia and limited abduction due to superotemporal globe shift relative to the extraocular muscles. Sagging eye syndrome (SES) was originally described in nonmyopic patients exhibiting distance esotropia and cyclovertical strabismus with limited supraduction due to lateral rectus muscle inferodisplacement caused by degeneration of the lateral rectus–superior rectus (LR-SR) band. We hypothesized that SES might also cause strabismus in high myopia. Methods Eleven strabismic subjects with high myopia underwent ophthalmological examination and orbital magnetic resonance imaging (MRI) to assess quantitative orbital anatomy. Results Of 11 subjects, 5 had HES; 6, SES. Mean axial length in subjects with HES was 32 ± 5 mm; in subjects with SES, 32 ± 6 mm. Average distance esotropia in subjects with HES was 61Δ ± 39Δ; hypotropia was 26Δ ± 21Δ. Average distance esotropia in subjects with SES was 23Δ ± 57Δ; hypertropia was 2Δ ± 2Δ. All 5 subjects with HES had superotemporal globe prolapse; the LR-SR band was thinned in 6 orbits and ruptured in 2. The mean angle between the lateral rectus and superior rectus muscles in HES was 121° ± 7°. In SES the LR-SR band was thinned in 7 orbits and ruptured in 5, with superotemporal soft tissue prolapse. The mean angle between the lateral rectus and superior rectus muscles was 104° ± 11°, significantly less than in HES (P < 0.001). Conclusions SES occurs in highly myopic patients who also exhibit less relative globe dislocation than in HES. Unlike HES, SES exhibits superotemporal soft tissue prolapse that may limit superotemporal globe shift. The distinction is important because surgery for HES uniquely requires creation of a surgical connection between the superior rectus and lateral rectus muscles, whereas SES may be treated with conventional surgery. SES can cause strabismus in high axial myopia. Orbital MRI is useful in differentiating SES from HES. PMID

  19. Fluid replacement with hydroxyethyl starch in critical care--a reassessment.

    PubMed

    Hartog, Christiane S; Welte, Tobias; Schlattmann, Peter; Reinhart, Konrad

    2013-06-01

    Hydroxyethyl starch (HES) is used for fluid replacement in millions of patients around the world every year, yet it has been found to have adverse effects that have a negative impact on patient survival. Recent clinical trials with a modern HES solution (HES 130) and meta-analyses now enable a reassessment of its risks and benefits. On the basis of a selective literature search focusing on reports of the use of HES 130/0.4 and HES 130/0.42 in sepsis, trauma, and intensive care medicine, data from randomized controlled trials (RCTs) are presented, and up-to-date meta-analyses and reviews are discussed. Moreover, the authors conducted an independent meta-analysis of HES 130 in comparison to crystalloids or albumin in intensive care medicine, sepsis, and trauma. Seven RCTs were evaluated, involving a total of 7838 patients treated for sepsis or trauma, or in intensive care. HES 130 was associated with a higher cumulative risk of death (relative risk [RR] 1.10, 95% confidence interval [CI] 1.01-1.20), more frequent need for a renal replacement procedure (RR 1.26, 95% CI 1.08-1.46), and more frequent need for blood transfusion (RR 1.22, 95% CI 1.08-1.37). There was no patient-relevant benefit. Four recent meta-analyses of data from a total of more than 10 000 patients confirmed these concerns about the safety of HES in general and, in particular, of low-molecular-weight HES 130 for patients in intensive care. The safety of 6% HES 130 in the immediate perioperative period has not been adequately demonstrated. Because of safety concerns, fluid replacement with HES in critically ill patients cannot be recommended. Evidence for its superior efficacy, safety and cost effectiveness in preoperative use is also lacking.

  20. Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England.

    PubMed

    Wright, F Lucy; Green, Jane; Canoy, Dexter; Cairns, Benjamin J; Balkwill, Angela; Beral, Valerie

    2012-10-23

    Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources. Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman's general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record. Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete. Hospital admission data in England provide diagnostic information for vascular disease

  1. ROCK inhibitor improves survival of cryopreserved serum/feeder-free single human embryonic stem cells.

    PubMed

    Li, Xiangyun; Krawetz, Roman; Liu, Shiying; Meng, Guoliang; Rancourt, Derrick E

    2009-03-01

    Efficient slow freezing protocols within serum-free and feeder-free culture systems are crucial for the clinical application of human embryonic stem (hES) cells. Frequently, however, hES cells must be cryopreserved as clumps when using conventional slow freezing protocols, leading to lower survival rates during freeze-thaw and limiting their recovery and growth efficiency after thawing, as well as limiting downstream applications that require single cell suspensions. We describe a novel method to increase freeze-thaw survival and proliferation rate of single hES cells in serum-free and feeder-free culture conditions. hES cells maintained on Matrigel-coated dishes were dissociated into single cells with Accutase and slow freezing. After thawing at 37 degrees C, cells were cultured in mTeSR medium supplemented with 10 microM of Rho-associated kinase inhibitor Y-27632 for 1 day. The use of Y-27632 and Accutase significantly increases the survival of single hES cells after thawing compared with a control group (P < 0.01). Furthermore, by treatment of hES cell aggregates with EGTA to disrupt cell-cell interaction, we show that Y-27632 treatment does not directly affect hES cell apoptosis. Even in the presence of Y-27632, hES cells deficient in cell-cell interaction undergo apoptosis. Y-27632-treated freeze-thawed hES cells retain typical morphology, stable karyotype, expression of pluripotency markers and the potential to differentiate into derivatives of all three germ layers after long-term culture. The method described here allows for cryopreservation of single hES cells in serum-free and feeder-free conditions and therefore we believe this method will be ideal for current and future hES cell applications that are targeted towards a therapeutic end-point.

  2. Advances in diagnosis and treatment of eosinophilia

    PubMed Central

    Sheikh, Javed; Weller, Peter F.

    2013-01-01

    Purpose of review Hypereosinophilic syndromes (HESs) are disorders characterized by sustained blood or tissue hypereosinophilia or both with subsequent damage to various organs due to eosinophilic infiltration and release of mediators. HES are now recognized to include varied eosinophilic disorders for some of which there are recent insights into their pathogenesis and targeted treatment. Recent findings Studies have helped delineate two subtypes of HES: the myeloproliferative variants of HES and the lymphocytic variants of HES. Many, but not all, myeloproliferative-HES patients have interstitial deletions on chromosome 4q12 that lead to fusion of the FIP1-like 1 and platelet-derived growth factor receptor α genes, with the fusion product encoding a protein that has constitutive tyrosine kinase activity. Lymphocytic-HES is a primary lymphoid disorder characterized by nonmalignant expansion of a T-cell population able to produce eosinophilopoietic cytokines, with the T-cell population being identified by flow cytometry or reverse transcriptase-PCR for T-cell receptor usage or both. Other HES subtypes are of uncertain causes and are included in recent diagnostic algorithms for the spectrum of HES. Summary The contemporary definition of the hypereosinophilic syndromes encompasses a range of eosinophilic disorders characterized by chronic blood hypereosinophilia often with eosinophil-mediated damage to various organs. PMID:19057198

  3. Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism

    PubMed Central

    Ahnfelt-Rønne, Jonas; Jørgensen, Mette C.; Klinck, Rasmus; Jensen, Jan N.; Füchtbauer, Ernst-Martin; Deering, Tye; MacDonald, Raymond J.; Wright, Chris V. E.; Madsen, Ole D.; Serup, Palle

    2012-01-01

    Neurog3-induced Dll1 expression in pancreatic endocrine progenitors ostensibly activates Hes1 expression via Notch and thereby represses Neurog3 and endocrine differentiation in neighboring cells by lateral inhibition. Here we show in mouse that Dll1 and Hes1 expression deviate during regionalization of early endoderm, and later during early pancreas morphogenesis. At that time, Ptf1a activates Dll1 in multipotent pancreatic progenitor cells (MPCs), and Hes1 expression becomes Dll1 dependent over a brief time window. Moreover, Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge during organ regionalization, become congruent at early bud stages, and then diverge again at late bud stages. Persistent pancreatic hypoplasia in Dll1 mutants after eliminating Neurog3 expression and endocrine development, together with reduced proliferation of MPCs in both Dll1 and Hes1 mutants, reveals that the hypoplasia is caused by a growth defect rather than by progenitor depletion. Unexpectedly, we find that Hes1 is required to sustain Ptf1a expression, and in turn Dll1 expression in early MPCs. Our results show that Ptf1a-induced Dll1 expression stimulates MPC proliferation and pancreatic growth by maintaining Hes1 expression and Ptf1a protein levels. PMID:22096075

  4. The Word from a Walrus: Five Decades of the History of Education Society

    ERIC Educational Resources Information Center

    Urban, Wayne J.

    2010-01-01

    This essay is an attempt at an institutional history of the History of Education Society (HES), from its inception in 1960 to the present day. Many of the intellectual currents and cross-currents, as well as the "History of Education Quarterly" (HEQ), the journal of the HES in which these intellectual movements were featured, are slighted in this…

  5. The Word from a Walrus: Five Decades of the History of Education Society

    ERIC Educational Resources Information Center

    Urban, Wayne J.

    2010-01-01

    This essay is an attempt at an institutional history of the History of Education Society (HES), from its inception in 1960 to the present day. Many of the intellectual currents and cross-currents, as well as the "History of Education Quarterly" (HEQ), the journal of the HES in which these intellectual movements were featured, are slighted in this…

  6. [Variability in Spanish National Health System hospital emergency services utilization].

    PubMed

    Peiró, Salvador; Librero, Julián; Ridao, Manuel; Bernal-Delgado, Enrique

    2010-01-01

    The aims of this study were to estimate the rate of hospital emergency services (HES) visits per health area, the associated percentage of admissions and the standardized HES utilization ratio, and to analyze their relationship with hospital resources. We performed an ecological study that combined information from distinct sources (Survey of Health Care Hospitalization Establishments 2006 and Minimum Data Set 2006) to estimate the rate of HES visits and the percentage of associated emergency admissions in 164 health areas in 14 autonomous communities (AC). Among 35.3 million inhabitants in the 164 areas examined, there were 16.2 million visits to the HES (45.75 per 100 inhabitants); more than 2 million (12.6%) were hospitalized. Excluding 5% of extreme areas, rates oscillated between 31.60 and 78.69 HES visits/100 inhabitants, and the percentage of admissions was between 7.6% and 27.9%. These differences were not attenuated after standardization. The AC factor explained 29% of variance in HES visits and 82% of variance in admissions. The rate of visits was not associated with the number of beds or staff physicians but did correlate with the number HES doctors, and smaller and non-teaching hospitals. There is wide variability in the rates of HES visits and emergency admissions in the different areas of the Spanish National Health System. This variability seems to be associated with a differential use for minor problems. Copyright 2009 SESPAS. Published by Elsevier Espana. All rights reserved.

  7. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    EPA Science Inventory

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultur...

  8. National Innovation and Knowledge Performance: The Role of Higher Education Teaching and Training

    ERIC Educational Resources Information Center

    Saad, Mohammed; Guermat, Cherif; Brodie, Lisa

    2015-01-01

    This paper investigates the role of the higher education system (HES) in the production of national innovation. We focus on the issue of institutional diversity of HESs and its impact on national innovation systems. We identify four key HES characteristics and hypothesize their influence on the production of national innovation. The empirical…

  9. Chemical Reactivity Test (CRT)

    SciTech Connect

    Zaka, F.

    2016-12-13

    The Chemical Reactivity Test (CRT) is used to determine the thermal stability of High Explosives (HEs) and chemical compatibility between (HEs) and alien materials. The CRT is one of the small-scale safety tests performed on HE at the High Explosives Applications Facility (HEAF).

  10. National Innovation and Knowledge Performance: The Role of Higher Education Teaching and Training

    ERIC Educational Resources Information Center

    Saad, Mohammed; Guermat, Cherif; Brodie, Lisa

    2015-01-01

    This paper investigates the role of the higher education system (HES) in the production of national innovation. We focus on the issue of institutional diversity of HESs and its impact on national innovation systems. We identify four key HES characteristics and hypothesize their influence on the production of national innovation. The empirical…

  11. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue

    PubMed Central

    Rezaeyan, Abolhasan; Haddadi, Gholam Hassan; Hosseinzadeh, Massood; Moradi, Maryam; Najafi, Masoud

    2016-01-01

    This study was carried out to evaluate radioprotective effects of hesperidin (HES) administration before the irradiation on the cardiac oxidative stress and histopathological changes in an experimental rat model. The cardiovascular complications of radiation exposure cause morbidity and mortality in patients who received radiotherapy. HES, an antioxidant flavonoid found in citrus fruits, suggests the protection against the tissue damage. Fifty-eight rats were divided into four groups: Group 1 received phosphate buffered saline (PBS) and sham radiation; Group 2, HES and sham radiation; Group 3, PBS and radiation; and Group 4, HES and radiation. The rats were exposed to single dose of 18 Gy of 6 MV X-ray. One hundred milligrams per kilogram doses of HES was administered for 7 days before irradiation. The estimation of superoxide dismutase (SOD), malondialdehyde (MDA), and histopathological analyses was performed at 24 h and 8 weeks after radiation exposure. The irradiation of chest area resulted in an elevated MDA level and decreased SOD activity. Moreover, long-term pathological lesions of radiation were inflammation, fibrosis, the increased number of mast cells and macrophages, and development of plaque, vascular leakage, myocardial degeneration, and myocyte necrosis. Although the administration of HES decreases inflammation, fibrosis, mast cell and macrophage numbers, and myocyte necrosis, it did not result in reduced thrombus, myocardium degeneration, and vascular leakage. In conclusion, these results suggest that HES can perform a radioprotection action. The protective effect of HES may be attributable to its immunomodulatory effects and free radical-scavenging properties. PMID:27651565

  12. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    EPA Science Inventory

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultur...

  13. Renal thrombotic microangiopathy and FIP1L1/PDGFRα-associated myeloproliferative variant of hypereosinophilic syndrome

    PubMed Central

    Langlois, Anne Lyse; Shehwaro, Nathalie; Rondet, Claire; Benbrik, Youssef; Maloum, Karim; Gueutin, Victor; Rouvier, Philippe; Izzedine, Hassane

    2013-01-01

    We report a case of renal thrombotic microangiopathy (TMA) in a myeloproliferative variant of hypereosinophilic syndrome (HES) in a 24-year-old man which resolved with imatinib therapy. This is one of a few cases in the literature to date describing TMA in HES, suggesting that the pathogenesis of thrombosis is at least in part related to damage from activated eosinophils. PMID:27293571

  14. Renal thrombotic microangiopathy and FIP1L1/PDGFRα-associated myeloproliferative variant of hypereosinophilic syndrome.

    PubMed

    Langlois, Anne Lyse; Shehwaro, Nathalie; Rondet, Claire; Benbrik, Youssef; Maloum, Karim; Gueutin, Victor; Rouvier, Philippe; Izzedine, Hassane

    2013-08-01

    We report a case of renal thrombotic microangiopathy (TMA) in a myeloproliferative variant of hypereosinophilic syndrome (HES) in a 24-year-old man which resolved with imatinib therapy. This is one of a few cases in the literature to date describing TMA in HES, suggesting that the pathogenesis of thrombosis is at least in part related to damage from activated eosinophils.

  15. Contribution of Raman spectroscopy in nephrology: a candidate technique to detect hydroxyethyl starch of third generation in osmotic renal lesions.

    PubMed

    Vuiblet, V; Nguyen, T T; Wynckel, A; Fere, M; Van-Gulick, L; Untereiner, V; Birembaut, P; Rieu, P; Piot, O

    2015-11-07

    HydroxyEthyl Starch (HES) has been one of the most commonly used colloid volume expanders in intensive care units for over 50 years. The first and second generation HES, with a high molecular weight (≥200 kD) and a high degree of substitution (≥0.5), has been associated with both renal dysfunction and osmotic nephrosis-like lesions in histological studies. Recently, third generation HES (130 kD/<0.5) has also been shown to impair renal function in critically ill adult patients although tubular accumulation of HES has never been proven in the human kidney. Our objective was to demonstrate the potential of Raman micro-imaging to bring out the presence of third generation-HES in the kidney of patients having received the volume expander. Four biopsies presenting osmotic nephrosis-like lesions originated from HES-administrated patients with impaired renal function were compared with HES-negative biopsies (n = 10) by Raman microspectroscopy. The first step was dedicated to the identification of a specific vibration of HES permitting the detection of the cellular and tissue accumulation of the product. This specific vibration at 480 cm(-1) is assigned to a collective mode of the macromolecule; it is located in a spectral region with a limited contribution from biological materials. Based on this finding, HES distribution within tissue sections was investigated using Raman micro-imaging. Determination of HES positive pixels permitted us to clearly distinguish positive cases from HES-free biopsies (proportions of positive pixels from the total number of pixels: 23.48% ± 28 vs. 0.87% ± 1.2; p = 0.004). This study shows that Raman spectroscopy is a candidate technique to detect HES in kidney tissue samples currently manipulated in nephrology departments. In addition, on the clinical aspect, our approach suggests that renal impairment related to third generation HES administration is associated with osmotic nephrosis-like lesions and HES accumulation in the kidney.

  16. An in vitro comparison of the effects of voluven (6% hydroxyethyl starch 130/0.4) and hespan (6% hydroxyethyl starch 670/0.75) on measures of blood coagulation in canine blood.

    PubMed

    Griego-Valles, Michelle; Buriko, Yekaterina; Prittie, Jennifer E; Fox, Philip R

    2017-01-01

    To assess primary and secondary hemostasis following in vitro dilution of canine whole blood (WB) with hydroxyethyl starch (HES) 130/0.4 and HES 670/0.75. In vitro experimental study. Private practice, teaching hospital. Twenty-five healthy dogs. Each dog underwent venipuncture and 18 mL of venous blood was sampled once. Collected blood was separated in 4 aliquots. Aliquot A served as baseline sample. The remaining tubes of WB were diluted with 0.9% saline, HES 670/0.75 and HES 130/0.4 at a ratio of 1:5.5. Dilutional effects were evaluated using prothrombin time (PT), activated partial thromboplastin time (aPTT), packed cell volume (PCV), thromboelastography (TEG), and platelet closure time (Ct), which was measured using a platelet function analyzer (PFA). Clot strength (ie, G value) was calculated from measured TEG values. Significant increases in PT (P < 0.05) and aPTT (P < 0.05) were documented following WB dilution with saline. Dilution of WB with HES 670/0.75 and HES 130/0.4 resulted in significant hypocoagulable changes in K, MA and G (P < 0.05) compared to baseline and saline. When comparing saline to HES 670/0.75, both R and K values were significantly increased (P < 0.05). K value was significantly increased (P < 0.05) when comparing baseline to HES 130/0.4 and HES 670/0.75. Ct (P < 0.05) was significantly prolonged after WB dilution with HES solutions but not after saline. Dilution of WB with HES 670/0.75 and HES 130/0.4 resulted in changes in primary and secondary hemostasis. Although there were small differences between saline and HES 670/0.75, no differences between HES solutions were evident in this small study. This may suggest there would be minimal increases in bleeding risk when either solution is administered to dogs at low doses. Clinical relevance of our findings requires further investigation. © Veterinary Emergency and Critical Care Society 2016.

  17. [Properties and clinical implications of middle molecular weight low substitution hydroxyethyl starch solution].

    PubMed

    Kotake, Yoshifumi

    2014-02-01

    In this review article, the properties and clinical implications of middle molecular weight low substitution hydroxyethyl starch (HES) solution are summarized. This preparation shows larger volume effect and longer duration compared to the currently available low-molecular weight HES solution and will be available in the near future in Japan. Effects on renal function and coagulation system are supposedly dependent on the persistence of larger HES molecule in the body and this middle molecular weight low substitution HES preparation may be advantageous to the older HES preparation due to its rapid metabolism. This preparation has been successfully used in the goal-directed fluid management in the early recovery program after surgery and will offer several advantages in fluid management when introduced in Japan.

  18. A hyperbolic-equation system approach for magnetized electron fluids in quasi-neutral plasmas

    SciTech Connect

    Kawashima, Rei; Komurasaki, Kimiya; Schönherr, Tony

    2015-03-01

    A new approach using a hyperbolic-equation system (HES) is proposed to solve for the electron fluids in quasi-neutral plasmas. The HES approach avoids treatments of cross-diffusion terms which cause numerical instabilities in conventional approaches using an elliptic equation (EE). A test calculation reveals that the HES approach can robustly solve problems of strong magnetic confinement by using an upwind method. The computation time of the HES approach is compared with that of the EE approach in terms of the size of the problem and the strength of magnetic confinement. The results indicate that the HES approach can be used to solve problems in a simple structured mesh without increasing computational time compared to the EE approach and that it features fast convergence in conditions of strong magnetic confinement.

  19. Hydroxyethyl starches: different products--different effects.

    PubMed

    Westphal, Martin; James, Michael F M; Kozek-Langenecker, Sibylle; Stocker, Reto; Guidet, Bertrand; Van Aken, Hugo

    2009-07-01

    With the development of a new generation of hydroxyethyl starches (HES), there has been renewed interest in their clinical potential. High doses of first- and second-generation HES were associated with adverse effects on renal function, coagulation, and tissue storage, thereby limiting their clinical applicability. Newer HES products have lower molar substitution and in vivo molecular weight, resulting in more rapid metabolism and clearance. In this review article, the differences between HES generations are highlighted, with particular emphasis on the improved safety profile of the third generation products. These improvements have been achieved with no loss of efficacy, and they contradict the assumption that efficacy of HES solutions is directly linked to plasma concentration. The impact of source material on structure and pharmacokinetics is highlighted, and the role of the carrier solution is critically assessed.

  20. Mixed-layer deepening during Heinrich events: a multi-planktonic foraminiferal delta18O approach.

    PubMed

    Rashid, Harunur; Boyle, Edward A

    2007-10-19

    Proxies from Greenland ice cores and North Atlantic marine sediment cores document repeated extreme climate swings of a few decades to millennia during the last glacial cycle, including periods of intense ice rafting called Heinrich events (HEs). We have found similar oxygen isotope variations recorded in mixed-layer-and thermocline-dwelling planktonic foraminifera during HEs 0, 1, and 4, suggesting that three foraminiferal taxa calcified their shells at similar temperatures in a homogenized upperwater column. This implies that the surface mixed layer was deeper during HEs. Similar deepening occurred on the northern margin of the ice-rafted-debris belt, implying that these deep mixed layers during HEs were widespread in the region. We suggest that an increase in storminess during HEs intensified the vertical mixing of meltwater from ice rafting in the upper ocean.

  1. Effect of perioperative crystalloid or colloid fluid therapy on hemorrhage, coagulation competence, and outcome: A systematic review and stratified meta-analysis.

    PubMed

    Rasmussen, Kirsten C; Secher, Niels H; Pedersen, Tom

    2016-08-01

    A meta-analysis concerning perioperative coagulation competence, hemorrhage, and outcome was conducted including the use of hydroxyethyl starches (HESs), dextran, or albumin versus administration of a crystalloid as control to assess the efficacy and safety of colloids and crystalloids for fluid administration during major elective surgery. Surgery was restricted to cardiovascular and noncardiovascular surgery, and HESs were stratified to HES 130/0.4 and HES 200/0.5. We searched Cochrane Central Register of Controlled Trials, MEDLINE, ISI Web of Science, EMBASE, conference proceedings, reference lists, and databases of ongoing trials. Thirty one primary clinical randomized controlled trials included 2287 patients undergoing major surgery from January 2000 to August 2015. The perioperative changes in coagulation competence were measured by thromboelastography (TEG) maximum amplitude (MA) in 9 studies administering crystalloids versus HES and in 4 studies administering albumin versus HES. All studies but 1 disclosed increased reduction in TEG-MA following HES administration (P = 0.0001 and 0.0002). The total loss of blood was reported in 17 studies in which crystalloids were compared to HES and 12 studies reported increased blood loss after administration of HES (P < 0.003). When administering albumin versus HES, 6 studies reported reduced hemorrhage associated with albumin administration (P = 0.005). Reoperation was not significantly reduced by the use of crystalloids, but may be more frequent after HESs compared to albumin (P < 0.03). In this analysis, more patients admitted to administration of HESs were exposed to decrease coagulation competence, compared to perioperative crystalloids and albumin administration. This stratified meta-analysis showed that increased blood loss was found in noncardiovascular surgery among patients receiving HES compared with crystalloids, followed by a marked reduction in TEG-MA, and infusion of 3rd-generation HES

  2. Effect of perioperative crystalloid or colloid fluid therapy on hemorrhage, coagulation competence, and outcome

    PubMed Central

    Rasmussen, Kirsten C.; Secher, Niels H.; Pedersen, Tom

    2016-01-01

    Abstract Background: A meta-analysis concerning perioperative coagulation competence, hemorrhage, and outcome was conducted including the use of hydroxyethyl starches (HESs), dextran, or albumin versus administration of a crystalloid as control to assess the efficacy and safety of colloids and crystalloids for fluid administration during major elective surgery. Surgery was restricted to cardiovascular and noncardiovascular surgery, and HESs were stratified to HES 130/0.4 and HES 200/0.5. Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, ISI Web of Science, EMBASE, conference proceedings, reference lists, and databases of ongoing trials. Results: Thirty one primary clinical randomized controlled trials included 2287 patients undergoing major surgery from January 2000 to August 2015. The perioperative changes in coagulation competence were measured by thromboelastography (TEG) maximum amplitude (MA) in 9 studies administering crystalloids versus HES and in 4 studies administering albumin versus HES. All studies but 1 disclosed increased reduction in TEG-MA following HES administration (P = 0.0001 and 0.0002). The total loss of blood was reported in 17 studies in which crystalloids were compared to HES and 12 studies reported increased blood loss after administration of HES (P < 0.003). When administering albumin versus HES, 6 studies reported reduced hemorrhage associated with albumin administration (P = 0.005). Reoperation was not significantly reduced by the use of crystalloids, but may be more frequent after HESs compared to albumin (P < 0.03). In this analysis, more patients admitted to administration of HESs were exposed to decrease coagulation competence, compared to perioperative crystalloids and albumin administration. Conclusion: This stratified meta-analysis showed that increased blood loss was found in noncardiovascular surgery among patients receiving HES compared with crystalloids, followed by a marked

  3. High molecular weight hydroxyethyl starch solutions are not more effective than a low wmolecular weight hydroxyethyl starch solution in a porcine model of septic shock.

    PubMed

    Simon, T-P; Schuerholz, T; Haugvik, S P; Forberger, C; Burmeister, M-A; Marx, G

    2013-01-01

    There is evidence that suggests that early fluid resuscitation is beneficial in the treatment of sepsis. We previously demonstrated that hydroxyethyl starch (HES) 130/0.42 attenuated capillary leakage better than HES 200/0.5. Using a similar porcine fecal sepsis model, we tested the effects of two new synthetic high molecular weight (700 kDa) hydroxyethyl starches with the same molar substitution of 0.42 but with a different C2/C6 ratio compared to 6% HES 130/0.42 on plasma volume (PV), systemic and tissue oxygenation. This was a prospective, randomized, controlled animal study. Twenty-five anesthetized and mechanically ventilated pigs (28.4±2.3 kg) were observed over 8 h. Septic shock was induced with fecal peritonitis. Animals were randomized for volume-replacement therapy with HES 700/0.42 C2/C6/2.5:1 (N.=5), HES 700/0.42 C2/C6/6:1 (N.=5), HES 130/0.42 C2/C6/5:1 (N.=5) or Ringer’s Solution (RS, N.=5), and compared to non-septic controls receiving RS (N.=5). The albumin escape rate (AER) was calculated and plasma volume was determined at the end of the study. Tissue Oxygen Saturation was measured with the InSpectra™ Device (InSpectra Tissue Spectrometer, Hutchinson Technology Inc., Hutchinson, MN, USA). The AER increased in all groups compared to control. All colloids (HES 700/6:1 68±15; HES 130 67±4; HES 700/2.5:1 71±12; P<0.05) but not RS (44±7) stabilized PV (mL/kg BW) after eight hours of sepsis. Systemic oxygenation was significantly lower in the RS group (44±17%; P<0.05) compared to all other groups at study end (P<0.05). In this porcine fecal peritonitis model, the high molecular weight artificial colloids HES 700/2.5:1 and HES 700/6:1 were not more effective in maintaining plasma volume and systemic and tissue oxygenation than HES 130. In comparison to crystalloid RS, all HES solutions were more effective at maintaining plasma volume, mean arterial pressure (MAP), and systemic and tissue oxygenation.

  4. Effects of in vitro hemodilution with crystalloids, colloids, and plasma on canine whole blood coagulation as determined by kaolin-activated thromboelastography.

    PubMed

    Morris, Bari R; deLaforcade, Armelle; Lee, Joyce; Palmisano, Joseph; Meola, Dawn; Rozanski, Elizabeth

    2016-01-01

    To investigate the effects of in vitro hemodilution with lactated Ringers solution (LRS), hetastarch (HES), and fresh frozen plasma (FFP) on whole blood coagulation in dogs as assessed by kaolin-activated thromboelastography. In vitro experimental study. University teaching hospital. Six healthy client-owned dogs. Whole blood was collected and diluted in vitro at a 33% and 67% dilution with either LRS, HES, or FFP. Kaolin-activated thromboelastography was performed on each sample as well as a control. Thromboelastographic parameters R (min), alpha (deg), K (min), and MA (mm) were measured and compared to the sample control for each dilution using mixed model methodology. Prolongation in coagulation times were seen at both dilutions with LRS and HES. There was no significant difference in R times at the 33% dilution, but R time was significantly prolonged at the 67% dilution with HES (P = 0.004). MA was significantly decreased for LRS at both dilutions (P = 0.013, P < 0.001) and more profoundly decreased for HES (P < 0.001, P = 0.006). No significant difference in any parameter was found for FFP. In vitro hemodilution of whole blood with both LRS and HES but not FFP resulted in significant effects on coagulation with HES having a more profound effect. In vivo evaluation of changes in coagulation with various resuscitation fluids is warranted and may be clinically relevant. © Veterinary Emergency and Critical Care Society 2015.

  5. Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina.

    PubMed

    Hara, Akira; Taguchi, Ayako; Aoki, Hitomi; Hatano, Yuichiro; Niwa, Masayuki; Yamada, Yasuhiro; Kunisada, Takahiro

    2010-06-25

    Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuroretinal cells. However, the transplanted ES cells also have a tumorigenic activity as they have the ability for multipotent differentiation to various types of tissues. In the present study, human ES (hES) cells were transplanted into adult nude mouse retinas by intravitreal injections 20 h after intravitreal N-methyl-D-aspartate (NMDA) administration. After the transplantation of hES cells, the folate antagonist, methotrexate (MTX) was administrated in order to control the differentiation of the transplanted hES cells. Neuronal differentiation and teratogenic potential of hES cells were examined immunohistochemically 5 weeks after transplantation. The proliferative activity of transplanted cells was determined by both the mitotic index and the Ki-67 proliferative index. Disappearance of Oct-4-positive hES cells showing undifferentiated morphology was observed after intraperitoneal MTX treatment daily, for 15 days. Decreased mitotic and Ki-67 proliferative indices, and increased neuronal differentiation were detected in the surviving hES cells after the MTX treatment. These results suggest two important effects of intraperitoneal MTX treatment for hES cells transplanted into nude mouse retina: (1) MTX treatment following transplantation induces neuronal differentiation, and (2) MTX decreases proliferative activity and tumorigenic potential.

  6. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy.

    PubMed

    McSorley, H J; Blair, N F; Smith, K A; McKenzie, A N J; Maizels, R M

    2014-09-01

    Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1-48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.

  7. Hemodynamic effects of 6% hydroxyethyl starch infusion in sevoflurane-anesthetized thoroughbred horses.

    PubMed

    Ohta, Minoru; Kurimoto, Shinjiro; Tokushige, Hirotaka; Kuroda, Taisuke; Ishikawa, Yuhiro

    2013-07-31

    To determine hemodynamic effects of hydroxyethyl starch (HES) infusion during anesthesia in horses, incremental doses of 6% HES were administered to 6 healthy Thoroughbred horses. Anesthesia was induced with xylazine, guaifenesin and thiopental and maintained with sevoflurane at 2.8% of end-tidal concentration in all horses. The horses were positioned in right lateral recumbency and administered 3 intravenous dose of 6% HES (5 ml/kg) over 15 min with 15-min intervals in addition to constant infusion of lactated Ringer's solution at 10 ml/kg/hr. Hemodynamic parameters were measured before and every 15 min until 90 min after the administration of 6% HES. There was no significant change in heart rate and arterial blood pressures throughout the experiment. The HES administration produced significant increases in mean right atrial pressure, stroke volume, cardiac output (CO) and decrease in systemic vascular resistance (SVR) in a dose-dependent manner. There was no significant change in electrolytes (Na(+), K(+), Cl(-)) throughout the experiment, however, packed cell volume, hemoglobin concentration, and total protein and albumin concentrations decreased in a dose-dependent manner following the HES administration. In conclusion, the HES administration provides a dose-dependent increase in CO, but has no impact upon arterial blood pressures due to a simultaneous decrease in SVR.

  8. Modulation of basic helix-loop-helix transcription complex formation by Id proteins during neuronal differentiation.

    PubMed

    Jögi, Annika; Persson, Paula; Grynfeld, Anna; Påhlman, Sven; Axelson, Håkan

    2002-03-15

    It is assumed that the Id helix-loop-helix (HLH) proteins act by associating with ubiquitously expressed basic HLH (bHLH) transcription factors, such as E47 and E2-2, which prevents these factors from forming functional hetero- or homodimeric DNA binding complexes. Several tissue-specific bHLH proteins, including HASH-1, dHAND, and HES-1, are important for development of the nervous system. Neuroblastoma tumors are derived from the sympathetic nervous system and exhibit neural crest features. In differentiating neuroblastoma cells, HASH-1 is down-regulated, and there is coincident up-regulation of the transcriptional repressor HES-1, which is known to bind the HASH-1 promoter. We found that the three Id proteins expressed in neuroblastoma cells (Id1, Id2, and Id3) were down-regulated during induced differentiation, indicating that Id proteins help keep the tumor cells in an undifferentiated state. Studying interactions, we noted that all four Id proteins could dimerize with E47 or E2-2, but not with HASH-1 or dHAND. However, the Id proteins did complex with HES-1, and increased levels of Id2 reduced the DNA binding activity of HES-1. Furthermore, HES-1 interfered with Id2/E2-2 complex formation. The ability of Id proteins to affect HES-1 activity is of particular interest in neuronal cells, where regulation of HES-1 is essential for the timing of neuronal differentiation.

  9. Omega-3 Polyunsaturated Fatty Acids Enhance Neuronal Differentiation in Cultured Rat Neural Stem Cells

    PubMed Central

    Katakura, Masanori; Hashimoto, Michio; Okui, Toshiyuki; Shahdat, Hossain Md; Matsuzaki, Kentaro; Shido, Osamu

    2013-01-01

    Polyunsaturated fatty acids (PUFAs) can induce neurogenesis and recovery from brain diseases. However, the exact mechanisms of the beneficial effects of PUFAs have not been conclusively described. We recently reported that docosahexaenoic acid (DHA) induced neuronal differentiation by decreasing Hes1 expression and increasing p27kip1 expression, which causes cell cycle arrest in neural stem cells (NSCs). In the present study, we examined the effect of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on differentiation, expression of basic helix-loop-helix transcription factors (Hes1, Hes6, and NeuroD), and the cell cycle of cultured NSCs. EPA also increased mRNA levels of Hes1, an inhibitor of neuronal differentiation, Hes6, an inhibitor of Hes1, NeuroD, and Map2 mRNA and Tuj-1-positive cells (a neuronal marker), indicating that EPA induced neuronal differentiation. EPA increased the mRNA levels of p21cip1 and p27kip1, a cyclin-dependent kinase inhibitor, which indicated that EPA induced cell cycle arrest. Treatment with AA decreased Hes1 mRNA but did not affect NeuroD and Map2 mRNA levels. Furthermore, AA did not affect the number of Tuj-1-positive cells or cell cycle progression. These results indicated that EPA could be involved in neuronal differentiation by mechanisms alternative to those of DHA, whereas AA did not affect neuronal differentiation in NSCs. PMID:23365582

  10. Stable genetic modification of human embryonic stem cells by lentiviral vectors.

    PubMed

    Gropp, Michal; Itsykson, Pavel; Singer, Orna; Ben-Hur, Tamir; Reinhartz, Etti; Galun, Eithan; Reubinoff, Benjamin E

    2003-02-01

    Human embryonic stem (hES) cells are pluripotent cells derived from the inner cell mass of the early preimplantation embryo. An efficient strategy for stable genetic modification of hES cells may be highly valuable for manipulating the cells in vitro and may promote the study of hES cell biology, human embryogenesis, and the development of cell-based therapies. Here, we demonstrate that vectors derived from self-inactivating (SIN) human immunodeficiency virus type 1 (HIV-1) are efficient tools for stable genetic modification of hES cells. Transduction of hES cells by a modified vector derived from SIN HIV-1 and containing the woodchuck hepatitis regulatory element (WPRE) and the central polypurine tract (cPPT) sequence facilitated stable transgene expression during prolonged (38 weeks) undifferentiated proliferation in vitro. Southern blot analysis revealed that the viral vector had integrated into the host cells' DNA. Transgene expression was maintained throughout differentiation into progeny of all three germ layers both in vitro and in vivo in teratomas. Thus, the transduced hES cells retained the capability for self-renewal and their pluripotent potential. Genetic modification of hES cells by lentiviral vectors provides a powerful tool for basic and applied research in the area of human ES cells.

  11. Baculoviral vector-mediated transient and stable transgene expression in human embryonic stem cells.

    PubMed

    Zeng, Jieming; Du, Juan; Zhao, Ying; Palanisamy, Nallasivam; Wang, Shu

    2007-04-01

    Human embryonic stem (hES) cells as a renewable cell source have great prospective applications in both developmental biology research and regenerative medicine. To realize these potentials, the development of effective and safe genetic manipulation methods in hES cells is an obvious demand. We report here that baculoviral vectors were able to transduce hES cells efficiently. In transient transduction experiments, a recombinant baculoviral vector equipped with a human elongation factor 1-alpha promoter and a woodchuck hepatitis post-transcriptional regulatory element transduced up to 80% of cells in hES cell clumps and embryoid bodies. For prolonged transgene expression, hybrid baculoviral vectors that have incorporated a rep gene and inverted terminal repeat sequences from adeno-associated virus were produced. These hybrid vectors yielded stable transgene expression during the prolonged undifferentiated proliferation of hES cells and after differentiation. Baculoviral transduction did not affect the normal growth, phenotype, and pluripotency of hES cells. Thus, baculoviral vectors suitable for both transient overexpression and long-term stable expression are an attractive option for genetic manipulation of hES cells.

  12. Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure.

    PubMed

    Aujla, Paven K; Bogdanovic, Vedran; Naratadam, George T; Raetzman, Lori T

    2015-08-01

    As the pituitary gland develops, signals from the hypothalamus are necessary for pituitary induction and expansion. Little is known about the control of cues that regulate early signaling between the two structures. Ligands and receptors of the Notch signaling pathway are found in both the hypothalamus and Rathke's pouch. The downstream Notch effector gene Hes1 is required for proper pituitary formation; however, these effects could be due to the action of Hes1 in the hypothalamus, Rathke's pouch, or both. To determine the contribution of hypothalamic Notch signaling to pituitary organogenesis, we used mice with loss and gain of Notch function within the developing hypothalamus. We demonstrate that loss of Notch signaling by conditional deletion of Rbpj in the hypothalamus does not affect expression of Hes1 within the posterior hypothalamus or expression of Hes5. In contrast, expression of activated Notch within the hypothalamus results in ectopic Hes5 expression and increased Hes1 expression, which is sufficient to disrupt pituitary development and postnatal expansion. Taken together, our results indicate that Rbpj-dependent Notch signaling within the developing hypothalamus is not necessary for pituitary development, but persistent Notch signaling and ectopic Hes5 expression in hypothalamic progenitors affects pituitary induction and expansion. © 2015 Wiley Periodicals, Inc.

  13. Persistent expression of activated Notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure

    PubMed Central

    Aujla, Paven K.; Bogdanovic, Vedran; Naratadam, George T.; Raetzman, Lori T.

    2015-01-01

    Background As the pituitary gland develops, signals from the hypothalamus are necessary for pituitary induction and expansion. Little is known about the control of cues that regulate early signaling between the two structures. Ligands and receptors of the Notch signaling pathway are found in both the hypothalamus and Rathke’s pouch. The downstream Notch effector gene Hes1 is required for proper pituitary formation, however these effects could be due to the action of Hes1 in the hypothalamus, Rathke’s pouch or both. To determine the contribution of hypothalamic Notch signaling to pituitary organogenesis, we used mice with loss and gain of Notch function within the developing hypothalamus. Results We demonstrate that loss of Notch signaling by conditional deletion of Rbpj in the hypothalamus does not affect expression of Hes1 within the posterior hypothalamus or expression of Hes5. In contrast, expression of activated Notch within the hypothalamus results in ectopic Hes5 expression and increased Hes1 expression, which is sufficient to disrupt pituitary development and postnatal expansion. Conclusions Taken together, our results indicate that Rbpjdependent Notch signaling within the developing hypothalamus is not necessary for pituitary development, but persistent Notch signaling and ectopic Hes5 expression in hypothalamic progenitors affects pituitary induction and expansion. PMID:25907274

  14. Influence of low-molecular-weight hydroxyethyl starch on microvascular permeability in patients undergoing abdominal surgery: comparison with crystalloid.

    PubMed

    Ando, Yuko; Terao, Yoshiaki; Fukusaki, Makoto; Yamashita, Kazunori; Takada, Masafumi; Tanabe, Takahiro; Sumikawa, Koji

    2008-01-01

    Adequate volume therapy is essential for stable hemodynamics and sufficient urinary output perioperatively. Hydroxyethyl starch (HES) has been reported to attenuate the microvascular hyperpermeability which occasionally occurs in surgical patients. This study was carried out to evaluate the effect of low-molecular-weight HES on the urinary microalbumin/creatinine ratio (MACR), a marker of microvascular permeability, in surgical patients. In a prospective, controlled, and randomized clinical trial, 21 patients undergoing abdominal surgery were divided into two groups. Group HES (n = 10) received HES at 2 ml x kg(-1) x h(-1) during surgery and at 1 ml x kg(-1) x h(-1) after surgery, and additionally they received acetated Ringer's solution (AR) at a rate to keep central venous pressure (CVP) 5 mm Hg. Group AR (n = 11) received AR at a rate to keep CVP at 3-5 mmHg. MACR, soluble intercellular adhesion molecule-1 (sICAM-1), and urinary output were measured intermittently in the perioperative period. MACR was significantly increased during surgery in both groups. There was no significant difference in MACR between the two groups throughout the study period. The serum concentration of sICAM-1 decreased during surgery in both groups, and that in group HES was significantly lower than that in group AR at the end of surgery. Postoperative urinary output in group HES was greater than that in group AR. The intensive care unit (ICU) stay in group HES was shorter than that in group AR. Although low-molecular-weight HES does not improve microvascular hyperpermeability, the expansion of the intravascular volume by HES results in higher urinary output in the postoperative period than that seen with crystalloid solution. The lower concentration of sICAM-1 after surgery may be due to hemodilution.

  15. A change of colloid from hydroxyethyl starch to gelatin does not reduce rate of renal failure or mortality in surgical critical care patients: Results of a retrospective cohort study.

    PubMed

    Albrecht, Frederic W; Glas, Michael; Rensing, Hauke; Kindgen-Milles, Detlef; Volk, Thomas; Mathes, Alexander M

    2016-12-01

    Hydroxyethyl starch (HES) may compromise renal function in critically ill patients. As an alternative, gelatin (GEL) was suggested. This study investigated whether GEL (4%) may have advantages over HES (6%, 130/0.4) with respect to acute renal failure (ARF), length of intensive care unit /hospital stay, and 30-day mortality and evaluated dose-dependent effects. We performed a retrospective cohort analysis of 1522 surgical intensive care patients in a single university hospital where HES was changed to GEL in June 2006. The year before, 515 patients received HES; the year after, 540 patients received GEL. Within both years, 497 patients received crystalloids (CRY) only. Fluid therapy was performed upon clinical judgment and did not follow a study protocol. There was no difference in ARF between HES and GEL (P=.292), but ARF was more frequent in both colloid cohorts compared with CRY (HES/GEL vs CRY, P<.05). Mortality and maximum daily dose of both HES (r=0.93) and GEL (r=0.93) were significantly correlated, but mortality and total amount of CRY or total fluid intake were not significantly correlated. Cumulative amounts of fluids given were significantly higher in both colloid groups compared with CRY only, and GEL was given in higher doses than HES. In both colloid cohorts, the need for renal replacement therapy and 30-day mortality were significantly higher, and intensive care unit and hospital stay was longer, compared with CRY. A change of colloid from HES to GEL did not reduce the rate of ARF or mortality in surgical critical care patients. Both colloids appear to have dose-dependent effects on renal function. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin.

    PubMed

    Khedr, Naglaa F; Khalil, Rania M

    2015-12-01

    Doxorubicin (DOX) is widely used in cancer therapy of many carcinomas types. Unfortunately, DOX is not sufficiently effective in many cases, and increasing the dosage of it is limited due to its systemic toxicity. A citrus flavonoid hesperidin (HES) is proved to be potent antioxidant and protective agent against many diseases including cancer. In this context, the objective of this study was to examine effect of HES along with DOX on solid Ehrlich carcinoma (SEC) in mice. Forty male mice were divided into four equal groups (n = 10): control SEC, DOX, HES, and DOX + HES. HES (50 mg/kg body weight orally) was given day after day for 16 days along with DOX (4 mg/kg body weight i.p. injection) for 5 cycles every 4 days in ESC-inoculated mice. After 20 days, tumor volume, tumor weight, survival rate, tumor glutathione, nitric oxide content, and serum glutathione were determined. Tumor tissue was examined for histopathological and immunohistochemical study for p53 and VEGF. Tumor resistance for mdr1a gene was assessed in tumor tissue by RT-PCR. HES induced significant increase in tissue and serum glutathione with significant decrease in tumor volume and tumor weight. A possible role of HES to modulate gene expression of mdr1a in tumor tissue was established. In addition, HES alleviated the histopathological changes with significant decrease in p53 and VEGF expression. The use of HES as adjuvant therapy with DOX would enhance the therapeutic efficacy and alleviate the resistance to DOX in treatment of solid tumors.

  17. Effects of hydroxyethyl starch 130/0.4 on pulmonary capillary leakage and cytokines production and NF-kappaB activation in CLP-induced sepsis in rats.

    PubMed

    Feng, Xiaomei; Yan, Wei; Liu, Xiaoming; Duan, Manlin; Zhang, Xinhua; Xu, Jianguo

    2006-09-01

    Sepsis and resulting multiple system organ failure are the leading causes of mortality in intensive care units. Hydroxyethyl starch (HES) 130/0.4 was a novel preparation, developed to improve the pharmacokinetics of current medium molecular weight HES solutions. This study was designed to explore the effects of HES 130/0.4 on pulmonary capillary permeability (PCP), production of cytokines, and activation of transcription factor in septic rats induced by cecal ligation and puncture (CLP). Adult male Sprague Dawley rats were randomly divided into six groups (six rats/group): saline controls (30 ml/kg); CLP plus saline (30 ml/kg); CLP plus HES (7.5, 15, or 30 ml/kg, respectively), and HES alone (30 ml/kg). Mean arterial blood pressure and heart rate were monitored during the experiment process. Myeloperoxidase (MPO) activity, wet/dry weight ratio, PCP, tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-10, and nuclear factor-kappa B (NF-kappaB) were investigated at 6 h. We demonstrated that CLP could provoke significant injury in lung, characterized by increase in PCP, wet/dry weight ratio, MPO activity, TNF-alpha, IL-6, and IL-10 level, and NF-kappaB activation. Without obvious influence on systemic macro-hemodynamics, HES 15 ml/kg and 30 ml/kg significantly reduced CLP-induced elevation of pulmonary capillary permeability, wet/dry weight ratio, and production of IL-6. Meanwhile, HES 15 ml/kg increased IL-10 level and HES 7.5, 15, and 30 ml/kg suppressed MPO activity, TNF-alpha level, and NF-kappaB activation. HES 130/0.4 can inhibit CLP-induced PCP by attenuating pulmonary inflammation and NF-kappaB activation in vivo.

  18. Comparison of the effects of glycerol, dimethyl sulfoxide, and hydroxyethyl starch solutions for cryopreservation of avian red blood cells.

    PubMed

    Graham, Jennifer E; Meola, Dawn M; Kini, Nisha R; Hoffman, Andrew M

    2015-06-01

    To compare effectiveness of glycerol, dimethyl sulfoxide (DMSO), and hydroxyethyl starch (HES) solutions for cryopreservation of avian RBCs. RBCs from 12 healthy Ameraucana hens (Gallus gallus domesticus). RBCs were stored in 20% (wt/vol) glycerol, 10% (wt/vol) DMSO freezing medium, or various concentrations of HES solution (7.5%, 11.5%, and 20% [wt/vol]) and frozen for 2 months in liquid nitrogen. Cells were then thawed and evaluated by use of cell recovery and saline stability tests, cell staining (7-aminoactinomycin D and annexin V) and flow cytometry, and scanning electron microscopy. Percentage of RBCs recovered was highest for 20% glycerol solution (mean ± SE, 99.71 ± 0.04%) and did not differ significantly from the value for 7.5% HES solution (99.57 ± 0.04%). Mean saline stability of RBCs was highest for 10% DMSO (96.11 ± 0.25%) and did not differ significantly from the value for 20% HES solution (95.74 ± 0.25%). Percentages of cells with 7-aminoactinomycin D staining but without annexin V staining (indicating necrosis or late apoptosis) were lowest for 10% DMSO freezing medium (3%) and 20% glycerol solution (1%) and highest for all HES concentrations (60% to 80%). Scanning electron microscopy revealed severe membrane changes in RBCs cryopreserved in 20% HES solution, compared with membrane appearance in freshly harvested RBCs and RBCs cryopreserved in 10% DMSO freezing medium. Cryopreservation of avian RBCs with HES solution, regardless of HES concentration, resulted in greater degrees of apoptosis and cell death than did cryopreservation with other media. Transfusion with RBCs cryopreserved in HES solution may result in posttransfusion hemolysis in birds.

  19. Fluid therapy in critical illness: a special focus on indication, the use of hydroxyethyl starch and its different raw materials.

    PubMed

    Ertmer, Christian; Kampmeier, Tim; Van Aken, Hugo

    2013-06-01

    Fluid therapy is a complex intervention with insufficient resuscitation, as well as overinfusion and fluid accumulation being associated with adverse outcomes. Early goal-directed therapy with later conservative fluid management (i.e. prevention of positive fluid balance and weight gain) appears to markedly improve the survival of patients with severe sepsis. The impact of colloids in resuscitation of patients with sepsis has been the topic of several recently published studies. The purpose of the present review is to outline the indication of fluid administration in critically ill patients, discuss the recent findings of trials involving hydroxyethyl starch (HES) solutions and highlight the impact of different raw materials for HES synthesis. Pragmatic trials of modern HES solutions versus crystalloids in critically ill patients show either no difference or adverse outcomes associated with HES infusion. However, fluid therapy was not protocolized in most of these studies and probably associated with overinfusion and hemodilution. Data on the use of waxy maize-derived 6% HES 130/0.4 during early goal-directed therapy show no evidence for harm and an improvement in microvascular blood flow. In addition, experimental data suggest that waxy maize-derived 6% HES 130/0.4 may have different biological effects compared to potato-derived 6% HES 130/0.42 with potentially reduced pulmonary inflammation. Adverse effects of fluid resuscitation in critically ill patients appear to be a consequence of dose and timing rather than the type of fluid itself. Modern waxy maize-derived 6% HES 130/0.4 may have advantages over crystalloids in the very early course of the disease. Clinical trials of early, goal-directed and protocolized therapy with innovative endpoints of resuscitation comparing balanced crystalloids and balanced, waxy maize-derived 6% HES 130/0.4 as the initial resuscitation fluid are warranted.

  20. Detection and analysis of hard exudates by polarization-sensitive optical coherence tomography in patients with diabetic maculopathy.

    PubMed

    Lammer, Jan; Bolz, Matthias; Baumann, Bernhard; Pircher, Michael; Gerendas, Bianca; Schlanitz, Ferdinand; Hitzenberger, Christoph K; Schmidt-Erfurth, Ursula

    2014-03-13

    To image and analyze hard exudates (HEs) and their precursors in patients with diabetic macular edema (DME) by using polarization-sensitive optical coherence tomography (PS-OCT). Twenty-two eyes of 16 patients with DME were imaged by using color fundus photography (CF) and PS-OCT. In PS-OCT, HEs were automatically detected by their distinct polarization-scrambling qualities. Color fundus images were manually graded for the presence of HEs by two masked graders and correlated with the corresponding PS-OCT HE maps: corresponding images were overlaid and an identical grid of 128 × 128 fields was used for correlation of detected HEs. In all eyes, HEs were present owing to DME. Agreement of a pixel-to-pixel analysis of HEs in CF images was 0.72 (Cohen's κ) between graders and 0.44 between graders and automated detection by PS-OCT. Mean ± SD detection of HEs was significantly higher in PS-OCT than in manual grading (1180.5 ± 1009.8 fields versus 828.8 ± 695.0 fields; P = 0.02). The higher detection rate of PS-OCT was confirmed by a linear regression analysis with a slope of β = 1.18 (r = 0.81). PS-OCT enables not only two-dimensional imaging of the extent of HEs, as in CF, but also allows tissue-specific, three-dimensional imaging of HEs throughout retinal layers, based on their distinct polarization-scrambling characteristics. The higher detection rate in PS-OCT images indicates an increased sensitivity of PS-OCT imaging over conventional CF.

  1. Cryopreservation of dermal fibroblasts and keratinocytes in hydroxyethyl starch-based cryoprotectants.

    PubMed

    Naaldijk, Yahaira; Johnson, Adiv A; Friedrich-Stöckigt, Annett; Stolzing, Alexandra

    2016-12-01

    Preservation of human skin fibroblasts and keratinocytes is essential for the creation of skin tissue banks. For successful cryopreservation of cells, selection of an appropriate cryoprotectant agent (CPA) is imperative. The aim of this study was to identify CPAs that minimize toxic effects and allow for the preservation of human fibroblasts and keratinocytes in suspension and in monolayers. We cryopreserved human fibroblasts and keratinocytes with different CPAs and compared them to fresh, unfrozen cells. Cells were frozen in the presence and absence of hydroxyethyl starch (HES) or dimethyl sulfoxide (DMSO), the latter of which is a commonly used CPA known to exert toxic effects on cells. Cell numbers were counted immediately post-thaw as well as three days after thawing. Cellular structures were analyzed and counted by labeling nuclei, mitochondria, and actin filaments. We found that successful cryopreservation of suspended or adherent keratinocytes can be accomplished with a 10% HES or a 5% HES, 5% DMSO solution. Cell viability of fibroblasts cryopreserved in suspension was maintained with 10% HES or 5% HES, 5% DMSO solutions. Adherent, cryopreserved fibroblasts were successfully maintained with a 5% HES, 5% DMSO solution. We conclude that skin tissue cells can be effectively cryopreserved by substituting all or a portion of DMSO with HES. Given that DMSO is the most commonly used CPA and is believed to be more toxic than HES, these findings are of clinical significance for tissue-based replacement therapies. Therapies that require the use of keratinocyte and fibroblast cells, such as those aimed at treating skin wounds or skin burns, may be optimized by substituting a portion or all of DMSO with HES during cryopreservation protocols.

  2. Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care.

    PubMed

    Adamik, Katja N; Yozova, Ivayla D; Regenscheit, Nadine

    2015-01-01

    To (1) review the development and medical applications of hydroxyethyl starch (HES) solutions with particular emphasis on its physiochemical properties; (2) critically appraise the available evidence in human and veterinary medicine, and (3) evaluate the potential risks and benefits associated with their use in critically ill small animals. Human and veterinary original research articles, scientific reviews, and textbook sources from 1950 to the present. HES solutions have been used extensively in people for over 30 years and ever since its introduction there has been a great deal of debate over its safety and efficacy. Recently, results of seminal trials and meta-analyses showing increased risks related to kidney dysfunction and mortality in septic and critically ill patients, have led to the restriction of HES use in these patient populations by European regulatory authorities. Although the initial ban on the use of HES in Europe has been eased, proof regarding the benefits and safety profile of HES in trauma and surgical patient populations has been requested by these same European regulatory authorities. The veterinary literature is limited mostly to experimental studies and clinical investigations with small populations of patients with short-term end points and there is insufficient evidence to generate recommendations. Currently, there are no consensus recommendations regarding the use of HES in veterinary medicine. Veterinarians and institutions affected by the HES restrictions have had to critically reassess the risks and benefits related to HES usage based on the available information and sometimes adapt their procedures and policies based on their reassessment. Meanwhile, large, prospective, randomized veterinary studies evaluating HES use are needed to achieve relevant levels of evidence to enable formulation of specific veterinary guidelines. © Veterinary Emergency and Critical Care Society 2015.

  3. National hospital data for intussusception: Data linkage and retrospective analysis to assess quality and use in vaccine safety surveillance.

    PubMed

    Samad, Lamiya; Cortina-Borja, Mario; Sutcliffe, Alastair G; Marven, Sean; Cameron, J Claire; El Bashir, Haitham; Lynn, Richard; Taylor, Brent

    2016-01-12

    To assess the quality of national Hospital Episode Statistics (HES) data for intussusception, and evaluate this routinely collected database for rotavirus vaccine safety surveillance by estimating pre-vaccination trends in intussusception hospitalisation. Data linkage was performed between HES and prospective intussusception data from the British Paediatric Surveillance Unit (BPSU), followed by capture-recapture analysis to verify HES data quality. Inclusion criteria were infants aged less than 12 months and admitted for intussusception to National Health Service (NHS) hospitals in England from March 2008 to March 2009. To estimate pre-vaccination incidence rates of intussusception, we performed a retrospective analysis of HES data. Infants aged less than 12 months and admitted for intussusception to NHS hospitals in England between 1995 and 2009 were included. Data linkage between 254 cases of intussusception identified in HES data and 190 cases reported via the BPSU resulted in 163 cases common to both data sources. Of remaining 91 cases in HES, 37 had confirmed intussusception. HES data accuracy was 78.7% (200 confirmed/254 cases) and completeness for intussusception was 86% (163 matched/190 BPSU cases) compared to 81.5% (163 matched/200 HES cases) for BPSU. A total of 233 (95% CI: 227.4 to 238.8) intussusception cases were estimated for the infant population (2008 to 2009). For retrospective analysis, of 6462 intussusception admissions in HES data (1995 to 2009), 1594 (24.7%) were duplicate admissions. A declining trend in intussusception incidence was observed in the infant population, from 86/100,000 in 1997 to 34/100,000 in 2009 (60% reduction, P<0.001). Cosinor modelling showed an excess of cases among infants in winter and spring (P<0.001, n=4957, 1995 to 2009). National hospital data capture the majority of admissions for intussusception and should be considered for the post-implementation surveillance of rotavirus vaccine safety in England. Copyright

  4. Single cell enzymatic dissociation of human embryonic stem cells: a straightforward, robust, and standardized culture method.

    PubMed

    Ellerström, Catharina; Hyllner, Johan; Strehl, Raimund

    2010-01-01

    The routine culture and expansion of human embryonic stem (hES) cells has been and is still posing a challenge to researchers wishing to take advantage of the cells' unique potential. In contrast to mouse embryonic stem cells, hES cells usually have to be expanded by tedious mechanical microdissection or by enzymatic dissociation to cell clusters of a very narrow size range.It is essential to use a culture system that allows the robust and reproducible enzymatic dissociation of viable hES cell cultures to single cells to allow the scale-up of hES cell cultures as well as the application of hES cells in various experiments, such as FACS, electroporation, and clonal selection.By the development of enzyme-based protocols, which are less labor intensive and less time consuming, much progress has been made over the recent years with regard to improved culture systems for hES cell. We have developed a culture system that is based on single cell enzymatic dissociation (SCED) in combination with a highly supportive feeder cell layer of human foreskin fibroblasts (hFFs). The culture system allows defined enzymatic propagation while maintaining the hES cell lines in an undifferentiated, pluripotent, and normal state.In this chapter, we will show how hES cells, which have been derived and passaged by traditional mechanical dissection, can be rapidly adjusted to propagation by enzymatic dissociation to single cells. The protocols we describe are widely applicable and should therefore be of general use for the reliable mass cultivation of hES cells for various experiments.

  5. [Effect of hydroxyethyl starch and Ringer's solution on splanchnic perfusion in dogs with septic shock].

    PubMed

    Yang, Yi; Qiu, Hai-bo; Liu, Song-qiao; Chen, Yong-ming; Li, Na; Shen, Ju-fang; Li, Jia-qiong

    2005-12-01

    To investigate the effect of 6% hydroxyethyl starch (HES) and Ringer's solution (RS) on splanchnic perfusion in dogs with septic shock. Twenty-four mongrel dogs with septic shock induced by lipopolysaccharides (LPS) were randomly divided into two groups: HES group and RS group. Dogs of each group received an intravenous infusion of HES or RS (1 mlxkg(-1)xmin(-1)) for 60 minutes, followed by normal saline for 180 minutes with same infusion speed. Parameters of hemodynamics, oxygen dynamic, and splanchnic perfusion were monitored at 0, 30, 60, 120, 180, 240 minutes after basic measurements (pre-LPS). (1) After LPS infusion, mean arterial pressure (MAP) and cardiac index (CI) lowered significantly (P<0.05). Compared to that of 0 minutes, MAP and CI were elevated by fluid therapy in both groups, but there was no difference between HES and RS group. (2) Compared with pre-LPS, oxygen delivery (DO(2)) was reduced, arterial blood pH lowered and arterial lactate level increased markedly at 0 minutes (P<0.05). DO(2) increased by fluid therapy in both groups, but DO(2) was higher in HES group at the same time points (P<0.05). Compared to 0 minutes, arterial lactate levels were lowered at 180 minutes in both groups. (3) Mesenteric blood flow decreased after LPS infusion in all animals (P<0.05). Mesenteric blood flow increased after HES infusion, at the same time intramucosal pH (pHi) was elevated and Pg-aCO(2) decreased significantly (all P<0.05), but they showed no difference in RS group. At the same time, mesenteric blood flow and pHi was higher in HES group than that in RS group. Both HES and RS could improve MAP and DO(2) in dogs with septic shock, but the effect of HES was better than RS on splanchnic perfusion.

  6. Do we still need human embryonic stem cells for stem cell-based therapies? Epistemic and ethical aspects.

    PubMed

    Hug, Kristina; Hermerén, Göran

    2011-11-01

    While scientific community disagrees about similarities and differences between human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells, some politicians embrace translational hiPS cell research as a replacement for translational hES cell research. We examine the ethical relevance of the main differences between hES and hiPS cell-based therapies and discuss whether, given the current state of knowledge, certain differences are essential. We discuss whether well-founded preferences can be made in hypothetical scenarios with varying levels of patient safety, treatment efficacy, treatment accessibility and ethical controversy.

  7. Idiopathic Hypereosinophilic Syndrome With Cutaneous Manifestations and Flame Figures: A Spectrum of Eosinophilic Dermatoses Whose Features Overlap With Wells' Syndrome

    PubMed Central

    Kiracofe, Elizabeth A.; Clark, Lindsey N.; Gru, Alejandro A.

    2015-01-01

    Importance: Wells syndrome (WS) (eosinophilic cellulitis) is an uncommon eosinophilic dermatitis that has been rarely described in association with, but distinct from, hypereosinophilic syndrome (HES). Observations: We report a case of an eosinophilic dermatosis with flame figures in association with idiopathic HES, manifested by inflammatory myocarditis, asthma, and peripheral blood eosinophilia. Conclusions and Relevance: The diagnoses of WS and HES, rather than being distinct findings, may represent 2 entities on a spectrum of hypereosinophilic diseases. The diagnosis of WS should be made with caution and should prompt a thorough investigation that includes a work-up for a systemic eosinophilic disorder. PMID:25839890

  8. Cardiac manifestation of the hypereosinophilic syndrome: new insights.

    PubMed

    Kleinfeldt, T; Nienaber, C A; Kische, S; Akin, I; Turan, R G; Körber, T; Schneider, H; Ince, H

    2010-07-01

    Cardiac manifestation is the major cause of morbidity in patients with hypereosinophilic syndrome (HES). Clinical features range from heart failure to arterial embolism, which are caused by thickening of the endocardium and mural left ventricular thrombosis. Modern magnetic resonance imaging and echocardiography are able to detect fibrosis, eosinophilic infiltrate and thrombi to stage the fibrotic evolution of the disease. Treatment of HES involves standard medication for heart failure, anticoagulant therapy, immunosuppressive therapy and potentially surgical resection. The outcome of HES depends on both the progression of endocardial fibrosis and associated complications and the 5-year mortality is estimated at 30%.

  9. Semi-automated quantification of hard exudates in colour fundus photographs diagnosed with diabetic retinopathy.

    PubMed

    Marupally, Abhilash Goud; Vupparaboina, Kiran Kumar; Peguda, Hari Kumar; Richhariya, Ashutosh; Jana, Soumya; Chhablani, Jay

    2017-09-20

    Hard exudates (HEs) are the classical sign of diabetic retinopathy (DR) which is one of the leading causes of blindness, especially in developing countries. Accordingly, disease screening involves examining HEs qualitatively using fundus camera. However, for monitoring the treatment response, quantification of HEs becomes crucial and hence clinicians now seek to measure the area of HEs in the digital colour fundus (CF) photographs. Against this backdrop, we proposed an algorithm to quantify HEs using CF images and compare with previously reported technique using ImageJ. CF photographs of 30 eyes (20 patients) with diabetic macular edema were obtained. A robust semi-automated algorithm was developed to quantify area covered by HEs. In particular, the proposed algorithm, a two pronged methodology, involved performing top-hat filtering, second order statistical filtering, and thresholding of the colour fundus images. Subsequently, two masked observers performed HEs measurements using previously reported ImageJ-based protocol and compared with those obtained through proposed method. Intra and inter-observer grading was performed for determining percentage area of HEs identified by the individual algorithm. Of the 30 subjects, 21 were males and 9 were females with a mean age of the 50.25 ± 7.80 years (range 33-66 years). The correlation between the two measurements of semi-automated and ImageJ were 0.99 and 0.99 respectively. Previously reported method detected only 0-30% of the HEs area in 9 images, 30-60% in 12 images and 60-90% in remaining images, and more than 90% in none. In contrast, proposed method, detected 60-90% of the HEs area in 13 images and 90-100% in remaining 17 images. Proposed method semi-automated algorithm achieved acceptable accuracy, qualitatively and quantitatively, on a heterogeneous dataset. Further, quantitative analysis performed based on intra- and inter-observer grading showed that proposed methodology detects HEs more accurately than

  10. Refining the definition of hypereosinophilic syndrome

    PubMed Central

    Simon, Hans-Uwe; Rothenberg, Marc E.; Bochner, Bruce S.; Weller, Peter F.; Wardlaw, Andrew J.; Wechsler, Michael E.; Rosenwasser, Lanny J.; Roufosse, Florence; Gleich, Gerald J.; Klion, Amy D.

    2012-01-01

    Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition. PMID:20639008

  11. A Hypereosinophilic Syndrome with Cardiac Involvement from Thrombotic Stage to Fibrotic Stage

    PubMed Central

    Kim, Nam Kyun; Kim, Chang-Yeon; Kim, Jae Hee; Jang, Se Yong; Bae, Myung Hwan; Lee, Jang Hoon; Yang, Dong Heon; Park, Hun Sik; Cho, Yongkeun

    2015-01-01

    Cardiac involvement is a major cause of morbidity and mortality in hypereosinophilic syndrome (HES). It is classified into 3 stages by the degree of eosinophils-mediated heart injury; acute necrotic stage, thrombotic stage, and fibrotic stage. Nonetheless, definitive evidence that each patient passes sequentially through these stages is lacking. We present a case of 48-year-old male patient with dyspnea and peripheral edema who underwent valve replacement surgery due to severe mitral regurgitation. After the valve replacement, HES with cardiac involvement in the thrombotic stage was diagnosed. In the follow-up study, the patient progressed into fibrotic stage of HES. PMID:26140152

  12. Hydroxyethyl starch increases patency and reduces thrombus formation following arteriotomy/intimectomy in small arteries: An experimental study in the rabbit

    SciTech Connect

    Wieslander, J.B.; Salemark, L.; Dougan, P. )

    1990-10-01

    Twenty-four arteries of rabbit ears, divided into two groups of 12 vessels each, were prepared and {sup 32}P-labelled platelets were infused. Arteriotomy/intimectomy was performed after 1 hr and in vivo platelet accumulation recorded for 2 hr. Group A comprised untreated control animals and group B was treated with 1 g hydroxyethyl starch (HES), MW 450,000 in 17 ml saline/kg b.w. (Plasma-steril). Vessel bleeding-times were normal, patency was improved, and intraluminal thrombotic material was reduced after HES treatment. Initial in vivo platelet accumulation was rapid and reached similar levels in both groups. However, the platelet accumulation curves decreased more frequently following HES than in the control group. HES does not prevent platelet accumulation at trauma sites, but reduces the sizes of the thrombi formed and may enhance disaggregation/fibrinolysis.

  13. Hydrogen Energy Storage: Grid and Transportation Services (Technical Report)

    SciTech Connect

    Melaina, M.; Eichman, J.

    2015-02-01

    Proceedings of an expert workshop convened by the U.S. Department of Energy and Industry Canada, and hosted by the National Renewable Energy Laboratory and the California Air Resources Board, May 14-15, 2014, in Sacramento, California, to address the topic of hydrogen energy storage (HES). HES systems provide multiple opportunities to increase the resilience and improve the economics of energy sup supply systems underlying the electric grid, gas pipeline systems, and transportation fuels. This is especially the case when considering particular social goals and market drivers, such as reducing carbon emissions, increasing reliability of supply, and reducing consumption of conventional petroleum fuels. This report compiles feedback collected during the workshop, which focused on policy and regulatory issues related to HES systems. Report sections include an introduction to HES pathways, market demand, and the "smart gas" concept; an overview of the workshop structure; and summary results from panel presentations and breakout groups.

  14. Health Education Careers in a Post-Health Reform Era.

    PubMed

    Auld, M Elaine

    2017-09-01

    Since enactment of the Patient Protection and Affordable Care Act in 2010, health education specialists (HES) have made important contributions in implementing the law's provisions at the individual, family, and population levels. Using their health education competencies and subcompetencies, HES are improving public understanding of health insurance literacy and enrollment options, conducting community health needs assessments required of nonprofit hospitals, modifying policies or systems to improve access to health screenings and preventive health services, strengthening clinical and community linkages, and working with employee benefit plans. In addition to educating stakeholders about their complementary training and roles with respect to clinical providers, HES must keep abreast of rapid changes catalyzed by the Affordable Care Act in terms of health standards, payment models, government regulations, statistics, and business practices. For continued career growth, HES must continually acquire new knowledge and skills, access and analyze data, and develop interprofessional partnerships that meet the evolving needs of employers as the nation pursues health for all.

  15. Hybrid Energy System Modeling in Modelica

    SciTech Connect

    William R. Binder; Christiaan J. J. Paredis; Humberto E. Garcia

    2014-03-01

    In this paper, a Hybrid Energy System (HES) configuration is modeled in Modelica. Hybrid Energy Systems (HES) have as their defining characteristic the use of one or more energy inputs, combined with the potential for multiple energy outputs. Compared to traditional energy systems, HES provide additional operational flexibility so that high variability in both energy production and consumption levels can be absorbed more effectively. This is particularly important when including renewable energy sources, whose output levels are inherently variable, determined by nature. The specific HES configuration modeled in this paper include two energy inputs: a nuclear plant, and a series of wind turbines. In addition, the system produces two energy outputs: electricity and synthetic fuel. The models are verified through simulations of the individual components, and the system as a whole. The simulations are performed for a range of component sizes, operating conditions, and control schemes.

  16. Nucleofection of human embryonic stem cells.

    PubMed

    Siemen, Henrike; Nix, Michael; Endl, Elmar; Koch, Philipp; Itskovitz-Eldor, Joseph; Brüstle, Oliver

    2005-08-01

    Human embryonic stem (hES) cells provide an important tool for the study of human development, disease, and tissue regeneration. Technologies for efficient genetic modification are required to exploit hES cells fully for these applications. Here we present a customized protocol for the transfection of hES cells with the Nucleofector technology and compare its efficiency with conventional electroporation and lipofection. Cell survival and transfection efficiency were quantified using an enhanced green fluorescent protein (EGFP) reporter construct. Our optimized nucleofection parameters yielded survival rates >70%. Under these conditions, 66% of the surviving cells showed transgene expression 24 h after nucleofection. Transfected cells maintained expression of the pluripotency- associated markers Tra-1-60, Tra-1-81, and Oct4 and could be expanded to stably transgene-expressing clones. The low quantities of hES cells and DNA required for nucleofection could make this method an attractive tool for miniaturized high throughput screening (HTS) applications.

  17. VizieR Online Data Catalog: M5 RR Lyrae times of maxima (Arellano Ferro+, 2016)

    NASA Astrophysics Data System (ADS)

    Arellano Ferro, A.; Ahumada, J. A.; Kains, N.; Luna, A.

    2016-11-01

    Secular period changes in RR Lyrae M5 stars are analysed by means of two approac hes, taking advantage of the data long time-base of about 118 years. Few authentically evolved stars are identified. (3 data files).

  18. Three new active members of the I-OnuI family of homing endonucleases.

    PubMed

    Bilto, Iman M; Guha, Tuhin K; Wai, Alvan; Hausner, Georg

    2017-08-01

    In vitro characterization of 3 LAGLIDADG-type homing endonucleases (HEs) (I-CcaI, I-CcaII, and I-AstI) that belong to the I-OnuI family showed that they are functional HEs that cleave their respective cognate target sites. These endonucleases are encoded within group ID introns and appear to be orthologues that have inserted into 3 different mitochondrial genes: rns, rnl, and cox3. The endonuclease activity of I-CcaI was tested using various substrates, and its minimum DNA recognition sequence was estimated to be 26 nt. This set of HEs may provide some insight into how these types of mobile elements can migrate into new locations. This study provides additional endonucleases that can be added to the catalog of currently available HEs that may have various biotechnology applications.

  19. The Biomechanical Effects of Resuscitation Colloids on the Compromised Lung Endothelial Glycocalyx.

    PubMed

    Job, Kathleen M; O'Callaghan, Ryan; Hlady, Vladimir; Barabanova, Alexandra; Dull, Randal O

    2016-08-01

    The endothelial glycocalyx is an important component of the vascular permeability barrier, forming a scaffold that allows serum proteins to create a gel-like layer on the endothelial surface and transmitting mechanosensing and mechanotransduction information that influences permeability. During acute inflammation, the glycocalyx is degraded, changing how it interacts with serum proteins and colloids used during resuscitation and altering its barrier properties and biomechanical characteristics. We quantified changes in the biomechanical properties of lung endothelial glycocalyx during control conditions and after degradation by hyaluronidase using biophysical techniques that can probe mechanics at (1) the aqueous/glycocalyx interface and (2) inside the glycocalyx. Our goal was to discern the location-specific effects of albumin and hydroxyethyl starch (HES) on glycocalyx function. The effects of albumin and HES on the mechanical properties of bovine lung endothelial glycocalyx were studied using a combination of atomic force microscopy and reflectance interference contrast microscopy. Logistic regression was used to determine the odds ratios for comparing the effects of varying concentrations of albumin and HES on the glycocalyx with and without hyaluronidase. Atomic force microscopy measurements demonstrated that both 0.1% and 4% albumin increased the thickness and reduced the stiffness of glycocalyx when compared with 1% albumin. The effect of HES on glycocalyx thickness was similar to albumin, with thickness increasing significantly between 0.1% and 1% HES and a trend toward a softer glycocalyx at 4% HES. Reflectance interference contrast microscopy revealed a concentration-dependent softening of the glycocalyx in the presence of albumin, but a concentration-dependent increase in stiffness with HES. After glycocalyx degradation with hyaluronidase, stiffness was increased only at 4% albumin and 1% HES. Albumin and HES induced markedly different effects on

  20. Biomechanical Effects of Resuscitation Colloids on the Compromised Lung Endothelial Glycocalyx

    PubMed Central

    Job, Kathleen M.; O’Callaghan, Ryan; Hlady, Vladimir; Barabanova, Alexandra; Dull, Randal O.

    2016-01-01

    Background The endothelial glycocalyx is an important component of the vascular permeability barrier, forming a scaffold that allows serum proteins to create a gel-like layer on the endothelial surface, and transmitting mechanosensing and mechanotransduction information that influences permeability. During acute inflammation the glycocalyx is degraded, changing how it interacts with serum proteins and colloids used during resuscitation and altering its barrier properties and biomechanical characteristics. We quantified changes in the biomechanical properties of lung endothelial glycocalyx during control conditions and after degradation by hyaluronidase using biophysical techniques that can probe mechanics at: 1) the aqueous/glycocalyx interface and 2) inside the glycocalyx. Our goal was to discern the location-specific effects of albumin and hydroxyethyl starch (HES) on glycocalyx function. Methods The effects of albumin and HES on the mechanical properties of bovine lung endothelial glycocalyx were studied using a combination of atomic force microscopy (AFM) and reflectance interference contrast microscopy (RICM). Logistic regression was used to determine the odds ratios for comparing the effects of varying concentrations of albumin and HES on the glycocalyx with and without hyaluronidase (HA’ase). Results AFM measurements demonstrated that both 0.1 % and 4% albumin increased the thickness and reduced the stiffness of glycocalyx when compared with 1% albumin. The effect of HES on glycocalyx thickness was similar to albumin, with thickness increasing significantly between 0.1% and 1% HES and a trend towards a softer glycocalyx at 4% HES. RICM revealed a concentration-dependent softening of the glycocalyx in the presence of albumin but a concentration dependent increase in stiffness with HES. After glycocalyx degradation with HA’ase, stiffness was increased only at 4% albumin and 1% HES. Conclusions Albumin and HES induced markedly different effects on

  1. Characterization of integrin engagement during defined human embryonic stem cell culture

    PubMed Central

    Meng, Ying; Eshghi, Shawdee; Li, Ying J.; Schmidt, Ray; Schaffer, David V.; Healy, Kevin E.

    2010-01-01

    Human embryonic stem (hES) cells are pluripotent, capable of differentiating into any cell type of the body, and therefore have the ability to provide insights into mechanisms of human development and disease, as well as to provide a potentially unlimited supply of cells for cell-based therapy and diagnostics. Knowledge of the adhesion receptors that hES cells employ to engage extracellular matrix (ECM) proteins is of basic biological interest and can enhance the design of cell culture and implantation systems to enable these biomedical applications. Although hES cells express a variety of cell surface receptors, little is known about which integrins are involved during subculture and passage. Matrigel is broadly used as a cell adhesive matrix for hES cell culture. Here, we sought to identify which integrins hES cells exploit for adhesion to Matrigel-coated surfaces in defined medium conditions. Using RT-PCR, flow cytometry, and fluorescence immunochemistry, we found that numerous integrins were expressed by H1 hES cells; however, antibody blocking assays indicated that only αvβ3, α6, β1, and α2β1 played a significant role in the initial adhesion of the hES cells to Matrigel in defined medium conditions. We subsequently identified a cohort of synthetic peptides that, when adsorbed to the culture surface, promoted H1 hES cell attachment and proliferation, as well as maintained a pluripotent phenotype. Peptides designed to engage with αvβ3, α6, β1, and α2β1 integrins and syndecan-1 were tested both individually and in various combinations. A combination of two integrin-engaging peptides (AG-10, C-16) and one syndecan-engaging peptide (AG-73) was sufficient to promote hES cell adhesion, maintenance, and proliferation. We propose that a specific integrin “fingerprint” is necessary for maintenance of hES cell self-renewal, and synthetic culture systems must capture this engagement profile for hES cells to remain undifferentiated.—Meng, Y., Eshghi, S

  2. Comparison of the in vitro effects of saline, hypertonic hydroxyethyl starch, hypertonic saline, and two forms of hydroxyethyl starch on whole blood coagulation and platelet function in dogs.

    PubMed

    Wurlod, Virginie A; Howard, Judith; Francey, Thierry; Schweighauser, Ariane; Adamik, Katja N

    2015-01-01

    To compare the in vitro effects of hypertonic solutions and colloids to saline on coagulation in dogs. In vitro experimental study. Veterinary teaching hospital. Twenty-one adult dogs. Blood samples were diluted with saline, 7.2% hypertonic saline solution with 6% hydroxyethylstarch with an average molecular weight of 200 kDa and a molar substitution of 0.4 (HH), 7.2% hypertonic saline (HTS), hydroxyethyl starch (HES) 130/0.4 or hydroxyethyl starch 600/0.75 at ratios of 1:22 and 1:9, and with saline and HES at a ratio of 1:3. Whole blood coagulation was analyzed using rotational thromboelastometry (extrinsic thromboelastometry-cloting time (ExTEM-CT), maximal clot firmness (MCF) and clot formation time (CFT) and fibrinogen function TEM-CT (FibTEM-CT) and MCF) and platelet function was analyzed using a platelet function analyzer (closure time, CTPFA ). All parameters measured were impaired by saline dilution. The CTPFA was prolonged by 7.2% hypertonic saline solution with 6% hydroxyethylstarch with an average molecular weight of 200 kDa and a molar substitution of 0.4 (HH) and HTS but not by HES solutions. At clinical dilutions equivalent to those generally administered for shock (saline 1:3, HES 1:9, and hypertonic solutions 1:22), CTPFA was more prolonged by HH and HTS than other solutions but more by saline than HES. No difference was found between the HES solutions or the hypertonic solutions. ExTEM-CFT and MCF were impaired by HH and HTS but only mildly by HES solutions. At clinically relevant dilutions, no difference was found in ExTEM-CFT between HTS and saline or in ExTEM-MCF between HH and saline. No consistent difference was found between the 2 HES solutions but HH impaired ExTEM-CFT and MCF more than HTS. At high dilutions, FibTEM-CT and -MCF and ExTEM-CT were impaired by HES. Hypertonic solutions affect platelet function and whole blood coagulation to a greater extent than saline and HES. At clinically relevant dilutions, only CTPFA was markedly more

  3. Comparison of the effects of a balanced crystalloid-based and a saline-based tetrastarch solution on canine whole blood coagulation and platelet function.

    PubMed

    Reuteler, Annina; Axiak-Flammer, Shannon; Howard, Judith; Adamik, Katja-Nicole

    2017-01-01

    To evaluate the effects of a 6% hydroxyethyl starch (130/0.42) solution in either a buffered, electrolyte-balanced (HES-BAL), or a saline (HES-SAL) carrier solution on canine platelet function and whole blood coagulation. Prospective, randomized study. University teaching hospital. Thirty-seven client-owned dogs undergoing general anesthesia for arthroscopy or imaging studies. Dogs received a 15 mL/kg intravenous bolus of HES-SAL (n = 13), HES-BAL (n = 14), or a modified Ringer's solution (n = 10) over 30-40 minutes. Coagulation was analyzed using a Platelet Function Analyzer-100 (closure time [CtPFA ]), and whole blood thromboelastometry (ROTEM) with extrinsically (ex-tem and fib-tem) and intrinsically (in-tem) activated assays, which assessed clotting time (CT), clot formation time (CFT), maximal clot firmness (MCF), and lysis index (LI). Coagulation samples were assayed prior to fluid administration (T0), and 5 minutes (T1), and 3 hours (T2) following fluid bolus administration, respectively. Both HES solutions resulted in impaired platelet function as indicated by a significant prolongation of CtPFA at T1 as compared to T0, but which resolved by T2. An IV bolus of Ringer's solution did not alter platelet function. In both HES groups, whole blood coagulation was significantly impaired at T1 as indicated by a significant increase in in-tem CFT, and a significant decrease in ex-tem, in-tem, and fib-tem MCF compared to T0. Furthermore, a significant increase in ex-tem CFT at T1 compared to T0 was found in the HES-SAL group. With the exception of in-tem MCF after HES-BAL, these effects were not present at T2. No significant differences were found in CtPFA or any ROTEM variable at any time point between HES-SAL and HES-BAL. Administration of a single bolus of 15 mL/kg 6% HES 130/0.42 results in significant but short-lived impairment of canine platelet function and whole blood coagulation, regardless of carrier solution. © Veterinary Emergency and Critical Care

  4. Hydroxyethyl starches in the perioperative period. A review on the efficacy and safety of starch solutions.

    PubMed

    Ghijselings, I; Rex, S

    2014-01-01

    Several randomized controlled trials have raised alarming concerns about the safety of hydroxyethyl starches (HES) for the hemodynamic stabilization of critically ill patients. It has been repeatedly demonstrated that the use of HES in patients treated in an intensive care unit was associated with an increased occurrence of serious adverse events, including a higher incidence of renal injury or failure, a higher need for renal replacement therapy (RRT), and (in one study) increased mortality. HES solutions are also widely used in the perioperative period, although high-level evidence on both the efficacy and safety of HES in patients undergoing surgery is sparse. It is unknown to which extent the concerning findings in critically ill patients can be extrapolated to the perioperative setting, where a variety of distinct patient populations is encountered. However, caution and an increased awareness for possible adverse effects of HES solutions in the perioperative setting are warranted. In 2013, the European Medicines Agency (EMA) concluded that the benefits of HES solutions no longer outweigh their risks, and therefore recommended that the marketing authorizations for these medicines be suspended (1). Upon request of some of the marketing-authorization holders (MAH), the EMA re-analyzed its recommendation. After a thorough review of the available data, the Pharmacovigilance Risk Assessment Committee (PRAC) concluded, on November 11th, that the increased risk of mortality and RRT or renal failure associated with the use of hydroxyethyl starch containing medicinal products outweighs their limited clinical benefits in the approved indications, and in any patient population. In June 2013, the U.S. Food and Drug Administration also communicated a serious warning with respect to the use of HES (2). The present (non-systematic) review summarizes the evidence upon which these remarkable recommendations are based. Moreover, current guidelines on the use of HES are quoted.

  5. Quantitative evaluation of hard exudates in diabetic macular edema after short-term intravitreal triamcinolone, dexamethasone implant or bevacizumab injections.

    PubMed

    Shin, Yong Un; Hong, Eun Hee; Lim, Han Woong; Kang, Min Ho; Seong, Mincheol; Cho, Heeyoon

    2017-10-03

    To quantitatively compare short-term hard exudates (HEs) alteration in patients with diabetic macular edema (DME) after intravitreal triamcinolone, dexamethasone implant or bevacizumab injections. This retrospective study enrolled DME eyes with HEs that underwent a single-dose intravitreal injection of triamcinolone (25 eyes), dexamethasone implant (20 eyes), or three monthly injections of bevacizumab (25 eyes) and completed at least three months of follow-up. All patients were examined before and after 1, 2 and 3 months of injections. Using color fundus photographs, the amount of HEs was quantified by two masked graders. The difference in HEs area between baseline and each follow-up visit was compared among the three groups. After three months, HEs area was reduced to 52.9 ± 4.21% (P < 0.001) in the triamcinolone group, 63.6 ± 6.08% (P = 0.002) in the dexamethasone implant group, and 85.2 ± 5.07% (P = 0.198) in the bevacizumab group. A significant reduction in HEs appeared at one month in the triamcinolone group (53.5 ± 4.91%, P < 0.001) and at two months in the dexamethasone implant group (70.1 ± 5.21%, P = 0.039). Our study suggests intravitreal steroids (triamcinolone, dexamethasone implants) significantly reduce HEs in DME patients on short-term follow-up, whereas intravitreal bevacizumab does not. Therefore, intravitreal steroids may be useful in DME with HEs in the fovea.

  6. Hydroxyethylstarch supplementation in burn resuscitation--a prospective randomised controlled trial.

    PubMed

    Vlachou, E; Gosling, P; Moiemen, N S

    2010-11-01

    Hydroxyethylstarches (HES) are thought to be beneficial in trauma and major surgery management, due to their volume expansion and anti-inflammatory properties. This study examined the use of 6% (HES) in burn resuscitation. 26 adult patients with burns exceeding 15% total body surface area (TBSA) were randomised to either crystalloid (Hartmann's solution) or a colloid-supplemented resuscitation regime, where 1/3 of the crystalloid-predicted requirement was replaced by 6% HES. There was no difference in age, gender or TBSA between the two groups. The median (95% CI) fluid volume/%TBSA received in the first 24 h was 307 ml and 263 ml for the crystalloid only and HES-supplemented group respectively (p=0.0234, Mann-Whitney). Body weight gain within the first 24 h after injury was significantly lower in the HES-supplemented group 2.5 kg versus 1.4 kg respectively (p=0.0039). The median (95% CI) serum C-reactive protein at 48 h after injury was 210 (167-257) and 128 (74-145) mg/L for the crystalloid only and HES-supplemented group respectively (p=0.0001). Albumin-creatinine ratio per % burn (ACR, a marker of capillary leak) was lower in the HES-supplemented group at 12h after burn (p=0.0310). Patients treated with HES-supplemented resuscitation required less fluid, showed less interstitial oedema and a dampened inflammatory response compared to patients receiving isotonic crystalloid alone. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

  7. Validation of the Hospital Episode Statistics Outpatient Dataset in England.

    PubMed

    Thorn, Joanna C; Turner, Emma; Hounsome, Luke; Walsh, Eleanor; Donovan, Jenny L; Verne, Julia; Neal, David E; Hamdy, Freddie C; Martin, Richard M; Noble, Sian M

    2016-02-01

    The Hospital Episode Statistics (HES) dataset is a source of administrative 'big data' with potential for costing purposes in economic evaluations alongside clinical trials. This study assesses the validity of coverage in the HES outpatient dataset. Men who died of, or with, prostate cancer were selected from a prostate-cancer screening trial (CAP, Cluster randomised triAl of PSA testing for Prostate cancer). Details of visits that took place after 1/4/2003 to hospital outpatient departments for conditions related to prostate cancer were extracted from medical records (MR); these appointments were sought in the HES outpatient dataset based on date. The matching procedure was repeated for periods before and after 1/4/2008, when the HES outpatient dataset was accredited as a national statistic. 4922 outpatient appointments were extracted from MR for 370 men. 4088 appointments recorded in MR were identified in the HES outpatient dataset (83.1%; 95% confidence interval [CI] 82.0-84.1). For appointments occurring prior to 1/4/2008, 2195/2755 (79.7%; 95% CI 78.2-81.2) matches were observed, while 1893/2167 (87.4%; 95% CI 86.0-88.9) appointments occurring after 1/4/2008 were identified (p for difference <0.001). 215/370 men (58.1%) had at least one appointment in the MR review that was unmatched in HES, 155 men (41.9%) had all their appointments identified, and 20 men (5.4%) had no appointments identified in HES. The HES outpatient dataset appears reasonably valid for research, particularly following accreditation. The dataset may be a suitable alternative to collecting MR data from hospital notes within a trial, although caution should be exercised with data collected prior to accreditation.

  8. [Prophylaxis for hypotension during cesarean section under spinal anesthesia: a randomized trial comparing hydroxyethyl starch 130/0.4 to ephedrine].

    PubMed

    Osseyran Samper, F; Errando, C L; Plaza Lloret, M; Díaz Cambronero, O; García Gregorio, N; de Andrés Ibáñez, J

    2011-01-01

    Spinal anesthesia is the technique of choice for scheduled or emergency cesarean section, but the prevalence of hypotension is high in this setting. Our aim was to compare the efficacy of a colloid (6% hydroxyethyl starch [HES] 130/0.4) to ephedrine for preventing hypotension. Patients undergoing elective or emergency cesarean section (in non-life-threatening situations) were enrolled. Patients were randomized to 3 groups for prophylaxis. The first ephedrine group received 5 mg of ephedrine intravenously (EPHE-5); the second ephedrine group received 10 mg of the drug intravenously (EPHE-10); and the HES group received 500 mL of HES 130/0.4 in rapid infusion n 15 minutes. We recorded systolic and diastolic blood pressures and heart rate after 10 minutes in the operating room and 2, 5, 10, 15, 20, and 30 minutes after injection of the anesthetic. We also assessed the sensory and motor blockades on both sides 2, 5, 10, 15, 20, and 30 minutes after injection. Neonatal status was assessed by Apgar score and umbilical cord blood gas analysis. Ninety-six patients, 33 in each ephedrine group and 30 in the HES group, were enrolled. Blood pressure decreased similarly in all 3 groups (36% EPHE-5 group, 36% EPHE-10 group and 40% HES group); no significant between-group differences were observed. Nor were there significant differences in the percentages of patients requiring bolus doses of ephedrine to treat hypotension (23% in the HES group vs 33% in the EPHE-5 group and 27% in the EPHE-10 group) or in the cumulative doses of ephedrine. Neonatal status was also similarly satisfactory in all 3 groups. HES 130/0.4 is as useful for hypotension prophylaxis as 5-mg or 10-mg intravenous doses of ephedrine. HES 130/0.4 might be a substitute for sympathomimetic agents if adverse effects are predicted or contraindications to the use of such drugs are present.

  9. Operations Optimization of Hybrid Energy Systems under Variable Markets

    SciTech Connect

    Chen, Jun; Garcia, Humberto E.

    2016-07-01

    Hybrid energy systems (HES) have been proposed to be an important element to enable increasing penetration of clean energy. This paper investigates the operations flexibility of HES, and develops a methodology for operations optimization to maximize its economic value based on predicted renewable generation and market information. The proposed operations optimizer allows systematic control of energy conversion for maximal economic value, and is illustrated by numerical results.

  10. Spatial planning for a green economy: National-level hydrologic ecosystem services priority areas for Gabon

    PubMed Central

    Tallis, Heather; Cole, Aaron; Schill, Steven; Martin, Erik; Heiner, Michael; Paiz, Marie-Claire; Aldous, Allison; Apse, Colin; Nickel, Barry

    2017-01-01

    Rapidly developing countries contain both the bulk of intact natural areas and biodiversity, and the greatest untapped natural resource stocks, placing them at the forefront of “green” economic development opportunities. However, most lack scientific tools to create development plans that account for biodiversity and ecosystem services, diminishing the real potential to be sustainable. Existing methods focus on biodiversity and carbon priority areas across large geographies (e.g., countries, states/provinces), leaving out essential services associated with water supplies, among others. These hydrologic ecosystem services (HES) are especially absent from methods applied at large geographies and in data-limited contexts. Here, we present a novel, spatially explicit, and relatively simple methodology to identify countrywide HES priority areas. We applied our methodology to the Gabonese Republic, a country undergoing a major economic transformation under a governmental commitment to balance conservation and development goals. We present the first national-scale maps of HES priority areas across Gabon for erosion control, nutrient retention, and groundwater recharge. Priority sub-watersheds covered 44% of the country’s extent. Only 3% of the country was identified as a priority area for all HES simultaneously, highlighting the need to conserve different areas for each different hydrologic service. While spatial tradeoffs occur amongst HES, we identified synergies with two other conservation values, given that 66% of HES priority areas intersect regions of above average area-weighted (by sub-watersheds) total forest carbon stocks and 38% intersect with terrestrial national parks. Considering implications for development, we identified HES priority areas overlapping current or proposed major roads, forestry concessions, and active mining concessions, highlighting the need for proactive planning for avoidance areas and compensatory offsets to mitigate potential

  11. Pharmacodynamics and tolerability of acetyl starch as a new plasma volume expander in patients undergoing elective surgery.

    PubMed

    Bremerich, D H; Lischke, V; Asskali, F; Förster, H; Behne, M

    2000-08-01

    Acetyl starch (ACS) is a new synthetic colloid solution for plasma volume expansion and is now undergoing phase II clinical trials. We compared the pharmacodynamics and tolerability of ACS with those ofhydroxyethyl starch (HES) in 32 patients (American Society of Anesthesiologists physical status I and II) undergoing elective surgery. In this prospective, randomized, double-blind trial patients received either 15 ml/kg ACS 6% (average molecular weight (Mw) 200,000/molar substitution (MS) 0.5) or HES 6% (Mw 200,000/MS 0.5) i.v. up to a maximum dose of 1000 ml. Hemodynamic parameters, rheologic parameters, volume effect, acid-base status as well as effects on hemostasis were studied. After infusion of ACS and HES there was a similar increase in central venous pressure and mean arterial pressure in both groups. Acid-base status was not significantly altered after the end of the colloid infusions. After ACS infusion, plasma acetate concentration increased from 0.13+/-0.16 mg/dl to 2.87+/-1.13 mg/dl, however, after 24 h there was no significant difference in plasma acetate concentration compared to HES. The volume effect ranged from 104-116%(ACS) and from 88-118% (HES) of the colloid dose administered. These differences were not statistically significant. Partial thromboplastin time (aPTT) was only slightly increased after ACS infusion (from 38.6+/-5.7 sec to 41.4+/-5.1 sec), but was significantly increased after HES infusion (from 38.7+/-5.7 sec to 46.1+/-7.0 sec). ACS and HES are equally effective plasma volume expanders; ACS might be a new, alternative colloid solution with fewer coagulation side-effects than HES.

  12. Hesperidin as Radioprotector against Radiation-induced Lung Damage in Rat: A Histopathological Study

    PubMed Central

    Haddadi, Gholam Hassan; Rezaeyan, Abolhasan; Mosleh-Shirazi, Mohammad Amin; Hosseinzadeh, Massood; Fardid, Reza; Najafi, Masoud; Salajegheh, Ashkan

    2017-01-01

    Reactive oxygen species (ROS) are generated by ionizing radiation, and one of the organs commonly affected by ROS is the lung. Radiation-induced lung injury including pneumonia and lung fibrosis is a dose-limiting factor in radiotherapy (RT) of patients with thorax irradiation. Administration of antioxidants has been proved to protect against ROS. The present study was aimed to assess the protective effect of hesperidin (HES) against radiation-induced lung injury of male rats. Fifty rats were divided into three groups. G1: Received no HES and radiation (sham). G2: Underwent γ-irradiation to the thorax. G3: Received HES and underwent γ-irradiation. The rats were exposed to a single dose of 18 Gy using cobalt-60 unit and were administered HES (100 mg/kg) for 7 days before irradiation. Histopathological analysis was performed 24 h and 8 weeks after RT. Histopathological results in 24 h showed radiation-induced inflammation and presence of more inflammatory cells as compared to G1 (P < 0.05). Administration of HES significantly decreased such an effect when compared to G2 (P < 0.05). Histopathological evaluation in 8 weeks showed a significant increase in mast cells, inflammation, inflammatory cells, alveolar thickness, vascular thickness, pulmonary edema, and fibrosis in G2 when compared to G1 (P < 0.05). HES significantly decreased inflammatory response, fibrosis, and mast cells when compared to G2 (P < 0.05). Administration of HES resulted in decreased radiation pneumonitis and radiation fibrosis in the lung tissue. Thus, the present study showed HES to be an efficient radioprotector against radiation-induced damage in the lung of tissue rats. PMID:28405105

  13. Human embryonic stem cells reveal recurrent genomic instability at 20q11.21.

    PubMed

    Lefort, Nathalie; Feyeux, Maxime; Bas, Cécile; Féraud, Olivier; Bennaceur-Griscelli, Annelise; Tachdjian, Gerard; Peschanski, Marc; Perrier, Anselme L

    2008-12-01

    By analyzing five human embryonic stem (hES) cell lines over long-term culture, we identified a recurrent genomic instability in the human genome. An amplification of 2.5-4.6 Mb at 20q11.21, encompassing approximately 23 genes in common, was detected in four cell lines of different origins. This amplification, which has been associated with oncogenic transformation, may provide a selective advantage to hES cells in culture.

  14. A novel method for generating xeno-free human feeder cells for human embryonic stem cell culture.

    PubMed

    Meng, Guoliang; Liu, Shiying; Krawetz, Roman; Chan, Michael; Chernos, Judy; Rancourt, Derrick E

    2008-06-01

    Long-term cultures of human embryonic stem (hES) cells require a feeder layer for maintaining cells in an undifferentiated state and increasing karyotype stability. In routine hES cell culture, mouse embryonic fibroblast (MEF) feeders and animal component-containing media (FBS or serum replacement) are commonly used. However, the use of animal materials increases the risk of transmitting pathogens to hES cells and therefore is not optimal for use in cultures intended for human transplantation. There are other limitations with conventional feeder cells, such as MEFs, which have a short lifespan and can only be propagated five to six passages before senescing. Several groups have investigated maintaining existing hES cell lines and deriving new hES cell lines on human feeder layers. However, almost all of these human source feeder cells employed in previous studies were derived and cultured in animal component conditions. Even though one group previously reported the derivation and culture of human foreskin fibroblasts (HFFs) in human serum-containing medium, this medium is not optimal because HFFs routinely undergo senescence after 10 passages when cultured in human serum. In this study we have developed a completely animal-free method to derive HFFs from primary tissues. We demonstrate that animal-free (AF) HFFs do not enter senescence within 55 passages when cultured in animal-free conditions. This methodology offers alternative and completely animal-free conditions for hES cell culture, thus maintaining hES cell morphology, pluripotency, karyotype stability, and expression of pluripotency markers. Moreover, no difference in hES cell maintenance was observed when they were cultured on AF-HFFs of different passage number or independent derivations.

  15. Hydroxyethyl starch as a substitute for dextran 40 for thawing peripheral blood progenitor cell products.

    PubMed

    Zhu, Fenlu; Heditke, Sarah; Kurtzberg, Joanne; Waters-Pick, Barbara; Hari, Parameswaran; Margolis, David A; Keever-Taylor, Carolyn A

    2015-12-01

    Removing DMSO post-thaw results in: reduced infusion reactions, improved recovery and stability of viable CD34+ cells. Validated methods use 5%-8.3% Dextran 40 with 2.5%-4.2% HSA for this purpose. Recent shortages of clinical grade Dextran require identification of suitable alternatives. PBPC were used to compare a standard 2X wash medium of 5 parts 10% Dextran 40 in saline (DEX) with 1 part 25% HSA (8.3% DEX/ 4.2% HSA) with Hydroxyethyl Starch (HES)-based solutions. Cells in replicate bags were diluted with an equal volume of wash solution, equilibrated 5 minutes, the bag filled with wash medium, pelleted and the supernatant expressed. Bags were restored to the frozen volume in wash medium and tested by single platform flow cytometry and CFU. Total viability, viable TNC, MNC, and CD34+ cell recovery, and CD34+ cell viability were compared immediately post-thaw and after 90 minutes. 5.2% HES/4.2% HSA did not differ from our standard in CD34 recovery or viability. Due to concerns that high concentrations of HES could affect renal function we tested 0.6% HES/2.5% HSA resulting in significantly poorer CD34 recovery and viability. Results improved using 2.4% HES/4.2% HSA and when 0.6% HES/4.2%HSA was used no significant differences were seen. CFU assays confirmed no differences between the standard dextran arm and HES at 2.4% or 0.6% so long as HSA was at 4.2%. We conclude that HES from 0.6% to 5.2% with 4.2% HSA is a suitable substitute for Dextran 40 as a reconstitution/washing medium for PBPC products. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  16. Effect of Perfusion Fluids on Recovery of Inflammatory Mediators in Microdialysis.

    PubMed

    Khan, F; Pharo, A; Lindstad, J K; Mollnes, T E; Tønnessen, T I; Pischke, S E

    2015-11-01

    Microdialysis is an excellent tool to assess tissue inflammation in patients, but in vitro systems to evaluate recovery of inflammatory mediators have not been standardized. We aimed to develop a reference plasma preparation and evaluate different perfusion fluids with respect to recovery of metabolic and inflammatory markers. The reference preparation was produced by incubation of human blood with lipopolysaccharide and cobra venom factor to generate cytokines and activate complement, respectively. Microdialysis with 100 kDa catheters was performed using different colloid and crystalloid perfusion fluids (hydroxyethyl starch (HES) 130/0.4, HES 200/0.5, hyperosmolar HES 200/0.5, albumin 200 g/l, T1 perfusion fluid and Ringer's acetate) compared to today's recommended dextran 60 solution. Recovery of glucose, glycerol and pyruvate was not significantly different between the perfusion fluids, whereas lactate had lower recovery in HES 200/0.5 and albumin perfusion fluids. Recovery rates for the inflammatory proteins in comparison with the concentration in the reference preparation differed substantially: IL-6 = 9%, IL-1β = 18%, TNF = 0.3%, MCP-1 = 45%, IL-8 = 48%, MIG = 48%, IP-10 = 25%, C3a = 53% and C5a = 12%. IL-10 was not detectable in microdialysis dialysate. HES 130/0.4 and HES 200/0.5 yielded a recovery not significantly different from dextran 60. Hyperosmolar HES 200/0.5 and albumin showed significantly different pattern of recovery with increased concentration of MIG, IP-10, C3a and C5a and decreased concentration of IL-1β, TNF, MCP-1 and IL-8 in comparison with dextran 60. In conclusion, microdialysis perfusion fluid dextran 60 can be replaced by the commonly used HES 130/0.4, whereas albumin might be used if specific immunological variables are in focus. The present reference plasma preparation is suitable for in vitro evaluation of microdialysis systems. © 2015 The Foundation for the Scandinavian Journal of Immunology.

  17. Investigation of urinary excretion of hydroxyethyl starch and dextran by uhplc-hrms in different acquisition modes.

    PubMed

    Esposito, S; Deventer, K; Giron, A J; Roels, K; Herregods, L; Verstraete, A; Van Eenoo, P

    2014-06-01

    Plasma volume expanders (PVEs) such as hydroxyethyl starch (HES) and dextran are misused in sports because they can prevent dehydration and reduce haematocrit values to mask erythropoietin abuse. Endogenous hydrolysis generates multiple HES and dextran oligosaccharides which are excreted in urine. Composition of the urinary metabolic profiles of PVEs varies depending on post-administration time and can have an impact on their detectability. In this work, different mass spectrometry data acquisition modes (full scan with and without in-source collision-induced dissociation) were used to study urinary excretion profiles of HES and dextran, particularly by investigating time-dependent detectability of HES and dextran urinary oligosaccharide metabolites in post-administration samples. In-source fragmentation yielded the best results in terms of limit of detection (LOD) and detection times, whereas detection of HES and dextran metabolites in full scan mode with no in-source fragmentation is related to recent administration (< 24 hours). Urinary excretion studies showed detection windows for HES and dextran respectively of 72 and 48 hours after administration. Dextran concentrations were above the previously proposed threshold of 500 µg · mL(-1) for 12 hours. A "dilute-and-shoot" method for the detection of HES and dextran in human urine by ultra-high-pressure liquid chromatography-electrospray ionization-high resolution Orbitrap™ mass spectrometry was developed for this study. Validation of the method showed an LOD in the range of 10-500 µg · mL(-1) for the most significant HES and dextran metabolites in the different modes. The method allows retrospective data analysis and can be implemented in existing high-resolution mass spectrometry-based doping control screening analysis.

  18. INVESTIGATION OF URINARY EXCRETION OF HYDROXYETHYL STARCH AND DEXTRAN BY UHPLC-HRMS IN DIFFERENT ACQUISITION MODES

    PubMed Central

    Deventer, K.; Giron, A.J.; Roels, K.; Herregods, L.; Verstraete, A.; Van Eenoo, P.

    2014-01-01

    Plasma volume expanders (PVEs) such as hydroxyethyl starch (HES) and dextran are misused in sports because they can prevent dehydration and reduce haematocrit values to mask erythropoietin abuse. Endogenous hydrolysis generates multiple HES and dextran oligosaccharides which are excreted in urine. Composition of the urinary metabolic profiles of PVEs varies depending on post-administration time and can have an impact on their detectability. In this work, different mass spectrometry data acquisition modes (full scan with and without in-source collision-induced dissociation) were used to study urinary excretion profiles of HES and dextran, particularly by investigating time-dependent detectability of HES and dextran urinary oligosaccharide metabolites in post-administration samples. In-source fragmentation yielded the best results in terms of limit of detection (LOD) and detection times, whereas detection of HES and dextran metabolites in full scan mode with no in-source fragmentation is related to recent administration (< 24 hours). Urinary excretion studies showed detection windows for HES and dextran respectively of 72 and 48 hours after administration. Dextran concentrations were above the previously proposed threshold of 500 µg · mL−1 for 12 hours. A “dilute-and-shoot” method for the detection of HES and dextran in human urine by ultra-high-pressure liquid chromatography-electrospray ionization-high resolution Orbitrap™ mass spectrometry was developed for this study. Validation of the method showed an LOD in the range of 10-500 µg · mL−1 for the most significant HES and dextran metabolites in the different modes. The method allows retrospective data analysis and can be implemented in existing high-resolution mass spectrometry-based doping control screening analysis. PMID:24899772

  19. Hydroxyethyl starch reduces coagulation competence and increases blood loss during major surgery: results from a randomized controlled trial.

    PubMed

    Rasmussen, Kirsten C; Johansson, Pär I; Højskov, Michael; Kridina, Irina; Kistorp, Thomas; Thind, Peter; Nielsen, Henning B; Ruhnau, Birgitte; Pedersen, Tom; Secher, Niels H

    2014-02-01

    This study evaluated whether administration of hydroxyethyl starch (HES) 130/0.4 affects coagulation competence and influences the perioperative blood loss. Artificial colloids substitute blood volume during surgery; with the administration of HES 130/0.4 (Voluven, Fresenius Kabi, Uppsala, Sweden) only a minor effect on coagulation competence is expected. Eighty patients were scanned for enrollment in the study, and 40 patients fulfilled the inclusion criteria. Two patients withdrew their consent to participate in the study, and 5 patients were excluded. Thus, 16 patients were randomized to receive lactated Ringer's solution and 17 to receive HES 130/0.4. Among the patients receiving HES 130/0.4, thrombelastography indicated reduced clot strength (P < 0.001) and blinded evaluation of the perioperative blood loss was 2.2 (range 0.5 to 5.0) versus 1.4 (range 0.5 to 2.4) L in the patients who received HES 130/0.4 or lactated Ringer, respectively (P < 0.038). The patients in the lactated Ringer's group, however, received more fluid (P < 0.0001) than those in the HES 130/0.4 group. There was no significant difference between the 2 groups with regard to frequency of reoperations or the length of hospital stay, but use of HES 130/0.4 was both more expensive and less efficacious than the use of lactated Ringer. Administration of HES 130/0.4 reduced clot strength and perioperative hemorrhage increased by more than 50%, while administration of lactated Ringer's solution provoked an approximately 2.5 times greater positive volume balance at the end of surgery.

  20. Evaluation and differential diagnosis of marked, persistent eosinophilia

    PubMed Central

    Nutman, Thomas B.

    2007-01-01

    Synopsis: Hyperosinophilic syndromes (HES) are a group of heterogeneous disorders many of which remain ill-defined. By definition, the HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, the diagnostic approach must include non-infectious (non-parasitic) causes of marked eosinophilia as well. PMID:17868863

  1. Evaluation and differential diagnosis of marked, persistent eosinophilia

    PubMed Central

    Mejia, Rojelio; Nutman, Thomas B.

    2012-01-01

    High grade eosinophilia in patients can be a diagnostic dilemma, as the etiologies are extensive and varied. Hypereosinophilic syndromes (HES) are a group of heterogeneous disorders, many of which remain ill-defined. By definition, HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, non-infectious causes must be sought including drug reactions, malignancies, and immunologic, inflammatory and allergic diseases. PMID:22449625

  2. Influence of volume reduction and cryopreservation methodologies on quality of thawed umbilical cord blood units for transplantation.

    PubMed

    Solves, Pilar; Mirabet, Vicente; Planelles, Dolores; Carbonell-Uberos, Francisco; Roig, Roberto

    2008-04-01

    Although there is considerable variability in methodology among umbilical cord blood banks, their common goal is to achieve optimal product quality for transplantation. Cryopreservation is a critical issue for a long-term maintenance of cord blood viability and colony-forming capacities. We designed a prospective study to compare controlled (CRF) vs. non-controlled freezing (URF) of volume-reduced cord blood units. In addition, the influence of hydroxy ethyl starch (HES) on cryopreservation was also assayed. To assess the efficiency of protocols used, cell recoveries were measured and the presence of hematopoietic colony-forming units was quantified. In the study phase, we observed similar CB haematopoietc recoveries for CRF and URF strategies, except for TNC recovery that was better for HES volume reduced CB units in the URF group. When we analysed the data of routine processed CB units in samples from satellite cryovials, we found better BFU-E, CFU-GM, CFU-GEMM and CFU recoveries for those units processed with HES than without HES, in an URF manner. URF of CB units is a cryopreservation procedure that allows similar hematopoietic progenitor recoveries than CRF with programmed devices. However, our study suggests that those banks that cryopreserve CB units in a URF manner should use HES for volume reduction. On the other hand, for CRF cryopreservation methodology volume reduction with and without HES are equally useful.

  3. Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511.

    PubMed

    Rodin, Sergey; Domogatskaya, Anna; Ström, Susanne; Hansson, Emil M; Chien, Kenneth R; Inzunza, José; Hovatta, Outi; Tryggvason, Karl

    2010-06-01

    We describe a system for culturing human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells on a recombinant form of human laminin-511, a component of the natural hES cell niche. The system is devoid of animal products and feeder cells and contains only one undefined component, human albumin. The hES cells self-renewed with normal karyotype for at least 4 months (20 passages), after which the cells could produce teratomas containing cell lineages of all three germ layers. When plated on laminin-511 in small clumps, hES cells spread out in a monolayer, maintaining cellular homogeneity with approximately 97% OCT4-positive cells. Adhesion of hES cells was dependent on alpha6beta1 integrin. The use of homogeneous monolayer hES or iPS cell cultures provides more controllable conditions for the design of differentiation methods. This xeno-free and feeder-free system may be useful for the development of cell lineages for therapeutic purposes.

  4. Efficient differentiation of human embryonic stem cells to definitive endoderm.

    PubMed

    D'Amour, Kevin A; Agulnick, Alan D; Eliazer, Susan; Kelly, Olivia G; Kroon, Evert; Baetge, Emmanuel E

    2005-12-01

    The potential of human embryonic stem (hES) cells to differentiate into cell types of a variety of organs has generated much excitement over the possible use of hES cells in therapeutic applications. Of great interest are organs derived from definitive endoderm, such as the pancreas. We have focused on directing hES cells to the definitive endoderm lineage as this step is a prerequisite for efficient differentiation to mature endoderm derivatives. Differentiation of hES cells in the presence of activin A and low serum produced cultures consisting of up to 80% definitive endoderm cells. This population was further enriched to near homogeneity using the cell-surface receptor CXCR4. The process of definitive endoderm formation in differentiating hES cell cultures includes an apparent epithelial-to-mesenchymal transition and a dynamic gene expression profile that are reminiscent of vertebrate gastrulation. These findings may facilitate the use of hES cells for therapeutic purposes and as in vitro models of development.

  5. Hetastarch and bleeding complications after coronary artery surgery.

    PubMed

    Avorn, Jerry; Patel, Minalkumar; Levin, Raisa; Winkelmayer, Wolfgang C

    2003-10-01

    Controversy persists concerning the potential association between intraoperative use of hetastarch (ie, hydroxyethyl starch [HES]) and postoperative bleeding in patients undergoing surgery. To determine whether intraoperative HES use is associated with an increased risk of postoperative bleeding following coronary artery bypass graft (CABG) surgery. Case-control study. A large academic medical center in the northeastern United States. A consecutive sample of 238 patients undergoing CABG surgery. Cases consisted of patients who had received either > or = 3 U packed RBCs, > or = 3 U platelets, > or= 3 U fresh frozen plasma, or any cryoprecipitate within 72 h after undergoing a CABG procedure, or who had undergone surgical revision for bleeding. All other CABG surgery patients served as control subjects. In multivariate models that controlled for a wide variety of demographic and clinical characteristics, we found that, compared to patients who did not receive any HES during surgery, those who received 1 U intraoperative HES had more than twice the risk of a bleeding outcome (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.10 to 4.91), and those who received 2 or 3 U HES had more than four times the risk of postoperative bleeding (OR, 4.57; 95% CI, 1.74 to 12.00). HES use in patients undergoing CABG surgery may be associated with a significant risk of postoperative bleeding. A double-blinded, randomized, controlled trial will be necessary to confirm this finding.

  6. Early warning signals of regime shifts in coupled human-environment systems.

    PubMed

    Bauch, Chris T; Sigdel, Ram; Pharaon, Joe; Anand, Madhur

    2016-12-20

    In complex systems, a critical transition is a shift in a system's dynamical regime from its current state to a strongly contrasting state as external conditions move beyond a tipping point. These transitions are often preceded by characteristic early warning signals such as increased system variability. However, early warning signals in complex, coupled human-environment systems (HESs) remain little studied. Here, we compare critical transitions and their early warning signals in a coupled HES model to an equivalent environment model uncoupled from the human system. We parameterize the HES model, using social and ecological data from old-growth forests in Oregon. We find that the coupled HES exhibits a richer variety of dynamics and regime shifts than the uncoupled environment system. Moreover, the early warning signals in the coupled HES can be ambiguous, heralding either an era of ecosystem conservationism or collapse of both forest ecosystems and conservationism. The presence of human feedback in the coupled HES can also mitigate the early warning signal, making it more difficult to detect the oncoming regime shift. We furthermore show how the coupled HES can be "doomed to criticality": Strategic human interactions cause the system to remain perpetually in the vicinity of a collapse threshold, as humans become complacent when the resource seems protected but respond rapidly when it is under immediate threat. We conclude that the opportunities, benefits, and challenges of modeling regime shifts and early warning signals in coupled HESs merit further research.

  7. Monitoring the use and outcomes of new devices and procedures: how does coding affect what Hospital Episode Statistics contribute? Lessons from 12 emerging procedures 2006-10.

    PubMed

    Patrick, Hannah; Sims, Andrew; Burn, Julie; Bousfield, Derek; Colechin, Elaine; Reay, Christopher; Alderson, Neil; Goode, Stephen; Cunningham, David; Campbell, Bruce

    2013-03-01

    New devices and procedures are often introduced into health services when the evidence base for their efficacy and safety is limited. The authors sought to assess the availability and accuracy of routinely collected Hospital Episodes Statistics (HES) data in the UK and their potential contribution to the monitoring of new procedures. Four years of HES data (April 2006-March 2010) were analysed to identify episodes of hospital care involving a sample of 12 new interventional procedures. HES data were cross checked against other relevant sources including national or local registers and manufacturers' information. HES records were available for all 12 procedures during the entire study period. Comparative data sources were available from national (5), local (2) and manufacturer (2) registers. Factors found to affect comparisons were miscoding, alternative coding and inconsistent use of subsidiary codes. The analysis of provider coverage showed that HES is sensitive at detecting centres which carry out procedures, but specificity is poor in some cases. Routinely collected HES data have the potential to support quality improvements and evidence-based commissioning of devices and procedures in health services but achievement of this potential depends upon the accurate coding of procedures.

  8. Characterization of left atrial dysfunction in hypereosinophilic syndrome - Insights from the Motion analysis of the heart and great vessels by three-dimensional speckle tracking echocardiography in pathological cases (MAGYAR-Path) Study.

    PubMed

    Nemes, Attila; Marton, Imelda; Domsik, Péter; Kalapos, Anita; Pósfai, Éva; Modok, Szabolcs; Borbényi, Zita; Forster, Tamás

    2016-05-01

    The present study was designed to compare three-dimensional speckle tracking echocardiography (3DSTE)-derived left atrial (LA) volumetric, volume-based functional and strain parameters between patients with hypereosinophilic syndrome (HES) and matched controls. A total of 10 HES patients and 19 age- and gender-matched healthy controls were included in the study. Complete two-dimensional Doppler echocardiography and 3DSTE were performed in all HES cases and controls. Significantly increased maximum (72.9±38.8 ml vs. 45.6±15.5 ml, p=0.01) and minimum (46.3±33.3 ml vs. 26.0±15.0 ml, p=0.03) LA volumes and LA volume before atrial contraction (62.0±36.0 ml vs. 36.5±16.6 ml, p=0.01) were found in HES patients compared to controls. Both peak global (18.3±6.7% vs. 25.6±9.0%, p=0.03) and mean segmental (22.2±6.0% vs. 31.0±12.1%, p=0.04) circumferential strains were significantly reduced in HES patients, suggesting decreased LA reservoir function. Increased LA volumes can be demonstrated in HES patients, accompanied by reduced LA peak circumferential strain as assessed by 3DSTE, suggesting LA remodeling. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  9. The effects of colloid solutions on renal proximal tubular cells in vitro.

    PubMed

    Neuhaus, Winfried; Schick, Martin A; Bruno, Raphael R; Schneiker, Bianca; Förster, Carola Y; Roewer, Norbert; Wunder, Christian

    2012-02-01

    Renal failure is a common complication of critically ill patients. Colloids such as hydroxyethyl starch (HES), gelatin, or albumin are regularly used for intravascular volume resuscitation, but there are increasing reports about the nephrotoxic side effects of synthetic colloids in septic patients. Therefore, we investigated the influence of colloids (HES130/0.4 (Voluven®), gelatin (Gelafundin®), human albumin, and the crystalloid Sterofundin® ISO on cell viability of human proximal tubular (HK-2) cells. HK-2 cells were incubated with colloids (0.1%-4%) and with equivalent volumes of the crystalloid solution Sterofundin ISO. After 21 hours, cell viability of HK-2 cells was measured by EZ4U assay (dye XTT). Application of HES130/0.4 decreased cell viability significantly in a concentration-dependent manner (86.80% ± 10.79% by 0.5% HES down to 24.02% ± 4.27% by 4% HES). Human albumin (>1.25%) as well as gelatin (>1%) also showed deleterious effects on HK-2 cells. Interestingly, in lower concentrations, human albumin and the crystalloid solution Sterofundin ISO were cytoprotective in comparison with the NaCl control. In conclusion, synthetic and natural colloids showed a harmful impact on HK-2 cells in higher concentrations without any prior proinflammatory stimulus. HES130/0.4 exhibited the most distinctive harmful impact, whereas the application of crystalloid Sterofundin ISO revealed cytoprotective effects.

  10. Human embryonic stem cells: isolation, maintenance, and differentiation.

    PubMed

    Turksen, Kursad; Troy, Tammy-Claire

    2006-01-01

    The isolation of pluripotent human embryonic stem (hES) cells having the capacity to differentiate in vitro to numerous cell types generated much excitement and promise in the field of regenerative medicine. However, along with great enthusiasm came hot controversy for stem cell research and researchers alike because available hES cell lines were isolated from "excess" embryos from in vitro fertilization clinics. Despite ethical and political debates, the methods and protocols to study diverse lineages are developing. Furthermore, strategies using specific growth factor combinations, cell-cell and cell-extracellular matrix induction systems are being explored for directed differentiation along a desired lineage. However, there is a great need to characterize the mechanisms that control self-renewal and differentiation and a necessity to improve methodologies and develop new purification protocols for the potential future clinical application of hES cells. After the scientific and political obstacles are overcome, it is anticipated that the hES cell field will make a tremendous difference in conditions, such as burn traumas and diabetic foot ulcers, as well a number of degenerative diseases such as Parkinson's disease, type 1 diabetes, rheumatoid arthritis, and myocardial infarction. In this introductory chapter, we will summarize and review recent progress in the field of hES cell differentiation protocols and discuss some of the current issues surrounding hES cell research.

  11. Human embryonic stem cells are pre-mitotically committed to self-renewal and acquire a lengthened G1 phase upon lineage programming.

    PubMed

    Becker, Klaus A; Stein, Janet L; Lian, Jane B; van Wijnen, Andre J; Stein, Gary S

    2010-01-01

    Self-renewal of human embryonic stem (hES) cells proceeds by a unique abbreviated cell cycle with a shortened G1 phase and distinctions in molecular cell cycle regulatory parameters. In this study, we show that early lineage-commitment of pluripotent hES cells modifies cell cycle kinetics. Human ES cells acquire a lengthened G1 within 72 h after lineage-programming is initiated, as reflected by loss of the pluripotency factor Oct4 and alterations in nuclear morphology. In hES cells that maintain the pristine pluripotent state, we find that autocrine mechanisms contribute to sustaining the abbreviated cell cycle. Our data show that naïve and mitotically synchronized pluripotent hES cells are competent to initiate two consecutive S phases in the absence of external growth factors. We conclude that short-term self-renewal of pluripotent hES cells occurs autonomously, in part due to secreted factors, and that pluripotency is functionally linked to the abbreviated hES cell cycle.

  12. Stochastic simulation of notch signaling reveals novel factors that mediate the differentiation of neural stem cells.

    PubMed

    Tzou, Wen-Shyong; Lo, Ying-Tsang; Pai, Tun-Wen; Hu, Chin-Hwa; Li, Chung-Hao

    2014-07-01

    Notch signaling controls cell fate decisions and regulates multiple biological processes, such as cell proliferation, differentiation, and apoptosis. Computational modeling of the deterministic simulation of Notch signaling has provided important insight into the possible molecular mechanisms that underlie the switch from the undifferentiated stem cell to the differentiated cell. Here, we constructed a stochastic model of a Notch signaling model containing Hes1, Notch1, RBP-Jk, Mash1, Hes6, and Delta. mRNA and protein were represented as a discrete state, and 334 reactions were employed for each biochemical reaction using a graphics processing unit-accelerated Gillespie scheme. We employed the tuning of 40 molecular mechanisms and revealed several potential mediators capable of enabling the switch from cell stemness to differentiation. These effective mediators encompass different aspects of cellular regulations, including the nuclear transport of Hes1, the degradation of mRNA (Hes1 and Notch1) and protein (Notch1), the association between RBP-Jk and Notch intracellular domain (NICD), and the cleavage efficiency of the NICD. These mechanisms overlap with many modifiers that have only recently been discovered to modulate the Notch signaling output, including microRNA action, ubiquitin-mediated proteolysis, and the competitive binding of the RBP-Jk-DNA complex. Moreover, we identified the degradation of Hes1 mRNA and nuclear transport of Hes1 as the dominant mechanisms that were capable of abolishing the cell state transition induced by other molecular mechanisms.

  13. Health Education Specialists' Knowledge, Attitudes, and Perceptions of the Patient Protection and Affordable Care Act.

    PubMed

    Strong, Jessica; Hanson, Carl L; Magnusson, Brianna; Neiger, Brad

    2016-03-01

    The changing landscape of health care as a result of the Patient Protection and Affordable Care Act (ACA) may provide new opportunities for health education specialists (HES). The purpose of this study was to survey HES in the United States on their knowledge and attitudes of the ACA and assess their perceptions of job growth under the law. A random sample of 220 (36% response rate) certified HES completed a 53-item cross sectional survey administered online through Qualtrics. Findings were compared to public opinion on health care reform. HES are highly favorable of the law (70%) compared to the general public (23%). A total of 85% of respondents were able to list a provision of the ACA, and most (81%) thought the ACA would be successful at increasing insured Americans. Over half (64.6%) believe job opportunities will increase. Those who viewed the law favorably were significantly more likely to score better on a knowledge scale related to the ACA. HES understand publicized provisions but are uncertain about common myths and specific provisions related to Title IV, "Prevention of Chronic Disease and Improving Public Health." Directed and continuing education to HES regarding the ACA is warranted. © 2015 Society for Public Health Education.

  14. Early warning signals of regime shifts in coupled human–environment systems

    PubMed Central

    Bauch, Chris T.; Sigdel, Ram; Pharaon, Joe; Anand, Madhur

    2016-01-01

    In complex systems, a critical transition is a shift in a system’s dynamical regime from its current state to a strongly contrasting state as external conditions move beyond a tipping point. These transitions are often preceded by characteristic early warning signals such as increased system variability. However, early warning signals in complex, coupled human–environment systems (HESs) remain little studied. Here, we compare critical transitions and their early warning signals in a coupled HES model to an equivalent environment model uncoupled from the human system. We parameterize the HES model, using social and ecological data from old-growth forests in Oregon. We find that the coupled HES exhibits a richer variety of dynamics and regime shifts than the uncoupled environment system. Moreover, the early warning signals in the coupled HES can be ambiguous, heralding either an era of ecosystem conservationism or collapse of both forest ecosystems and conservationism. The presence of human feedback in the coupled HES can also mitigate the early warning signal, making it more difficult to detect the oncoming regime shift. We furthermore show how the coupled HES can be “doomed to criticality”: Strategic human interactions cause the system to remain perpetually in the vicinity of a collapse threshold, as humans become complacent when the resource seems protected but respond rapidly when it is under immediate threat. We conclude that the opportunities, benefits, and challenges of modeling regime shifts and early warning signals in coupled HESs merit further research. PMID:27815533

  15. Rates of self-harm presenting to general hospitals: a comparison of data from the Multicentre Study of Self-Harm in England and Hospital Episode Statistics

    PubMed Central

    Turnbull, Pauline; Hawton, Keith; Geulayov, Galit; Waters, Keith; Ness, Jennifer; Townsend, Ellen; Khundakar, Kazem; Kapur, Nav

    2016-01-01

    Objective Rates of hospital presentation for self-harm in England were compared using different national and local data sources. Design The study was descriptive and compared bespoke data collection methods for recording self-harm presentations to hospital with routinely collected hospital data. Setting Local area data on self-harm from the 3 centres of the Multicentre Study of Self-harm in England (Oxford, Manchester and Derby) were used along with national and local routinely collected data on self-harm admissions and emergency department attendances from Hospital Episode Statistics (HES). Primary outcome Rate ratios were calculated to compare rates of self-harm generated using different data sources nationally and locally (between 2010 and 2012) and rates of hospital presentations for self-harm were plotted over time (between 2003 and 2012), based on different data sources. Results The total number of self-harm episodes between 2010 and 2012 was 13 547 based on Multicentre Study data, 9600 based on HES emergency department data and 8096 based on HES admission data. Nationally, routine HES data underestimated overall rates of self-harm by approximately 60% compared with rates based on Multicentre Study data (rate ratio for HES emergency department data, 0.41 (95% CI 0.35 to 0.49); rate ratio for HES admission data, 0.42 (95% CI 0.36 to 0.49)). Direct local area comparisons confirmed an overall underascertainment in the HES data, although the difference varied between centres. There was a general increase in self-harm over time according to HES data which contrasted with a fall and then a rise in the Multicentre Study data. Conclusions There was a consistent underestimation of presentations for self-harm recorded by HES emergency department data, and fluctuations in year-on-year figures. HES admission data appeared more reliable but missed non-admitted episodes. Routinely collected data may miss important trends in self-harm and cannot be used in isolation as

  16. Impairment of renal function using hyperoncotic colloids in a two hit model of shock: a prospective randomized study

    PubMed Central

    2012-01-01

    Introduction One of the therapeutic essentials in severe sepsis and septic shock is an adequate fluid replacement to restore and maintain circulating plasma volume, improve organ perfusion and nutritive microcirculatory flow. The type of solution to be used as a fluid replacement remains under discussion. The aim of the study was to evaluate the effects of clinically used fluid replacement solutions on renal function and inflammatory response. Methods A total of 23 anesthetized and ventilated female German Landrace pigs were investigated over 19 hours using a two-hit model that combined hemorrhagic and septic shock. The septic shock was induced using an Escherichia coli laden clot placed into the abdominal cavity. Infusions of 6% hydroxyethylstarch 130/0.42 in acetate (6% HES 130), 4% gelatin in acetate (4% gelatin) and 10% hydroxyethylstarch 200/0.5 in saline (10% HES200) compared to Ringer's acetate (RAc) were used for fluid replacement to maintain a central venous pressure of 12 mmHg. Ringer's acetate was also used in the sham-treated group (SHAM). Results At study end the cardiac output (10% HES200 143 ± 48 ml/kgBW; 6% HES130 171 ± 47 ml/kgBW; RAc 137 ± 32 ml/kgBW; 4% gelatin 160 ± 42 ml/kgBW), as well as mean arterial pressure did not differ between groups. N-acetyl-beta-D-glucosamidase was significantly higher in the hydroxyethylstarch 200 (157 ± 115 U/g creatinine; P < 0.05) group compared to hydroxyethylstarch 130 (24 ± 9 U/g creatinine), Ringer's acetate (2 ± 3 U/g creatinine) and SHAM (21 ± 15 U/g creatinine) at the study's end. Creatinine significantly increased by 87 ± 84 percent of baseline in the 10% HES200 group compared to RAc and 6% HES130. We demonstrated in the histology of the kidneys a significant increase in osmotic-nephrosis like lesions for 4% gelatin compared to RAc, 6% HES130 and SHAM. Urine output was lowest in the 10% HES200 and 4% gelatin group, however not significantly. Interleukin(IL)-6 levels were significantly elevated in

  17. The efficacy and safety of colloid resuscitation in the critically ill.

    PubMed

    Hartog, Christiane S; Bauer, Michael; Reinhart, Konrad

    2011-01-01

    Despite evidence from clinical studies and meta-analyses that resuscitation with colloids or crystalloids is equally effective in critically ill patients, and despite reports from high-quality clinical trials and meta-analyses regarding nephrotoxic effects, increased risk of bleeding, and a trend toward higher mortality in these patients after the use of hydroxyethyl starch (HES) solutions, colloids remain popular and the use of HES solutions is increasing worldwide. We investigated the major rationales for colloid use, namely that colloids are more effective plasma expanders than crystalloids, that synthetic colloids are as safe as albumin, that HES solutions have the best risk/benefit profile among the synthetic colloids, and that the third-generation HES 130/0.4 has fewer adverse effects than older starches. Evidence from clinical studies shows that comparable resuscitation is achieved with considerably less crystalloid volumes than frequently suggested, namely, <2-fold the volume of colloids. Albumin is safe in intensive care unit patients except in patients with closed head injury. All synthetic colloids, namely, dextran, gelatin, and HES have dose-related side effects, which are coagulopathy, renal failure, and tissue storage. In patients with severe sepsis, higher doses of HES may be associated with excess mortality. The assumption that third-generation HES 130/0.4 has fewer adverse effects is yet unproven. Clinical trials on HES 130/0.4 have notable shortcomings. Mostly, they were not performed in intensive care unit or emergency department patients, had short observation periods of 24 to 48 hours, used cumulative doses below 1 daily dose limit (50 mL/kg), and used unsuitable control fluids such as other HES solutions or gelatins. In conclusion, the preferred use of colloidal solutions for resuscitation of patients with acute hypovolemia is based on rationales that are not supported by clinical evidence. Synthetic colloids are not superior in critically ill

  18. Small volume resuscitation with 7.5% hypertonic saline, hydroxyethyl starch 130/0.4 solution and hypertonic sodium chloride hydroxyethyl starch 40 injection reduced lung injury in endotoxin shock rats: comparison with saline.

    PubMed

    Yu, Gaofeng; Chi, Xinjin; Hei, Ziqing; Shen, Ning; Chen, Jinghui; Zhang, Wenhua; Li, Shangrong

    2012-02-01

    The aim of this study was to investigate the effects of small volume resuscitation with 7.5% hypertonic sodium chloride (HSS), hydroxyethyl starch 130/0.4 solution (HES), and hypertonic sodium chloride hydroxyethyl starch 40 injection (HSH) on endotoxin shock rat lung. Thirty Sprague-Dawley (SD) rats were divided randomly into 5 groups ,Group C (negative control group), Group E (lipopolysaccharide, LPS +4 ml/kg saline), Group HSS (LPS +4 ml/kg HSS), Group HES (LPS +4 ml/kg HES) and Group HSH (LPS +4 ml/kg HSH). Endotoxin shock model of rat was produced by injection with LPS. Then small volume resuscitation with different fluids was implemented in each group, respectively. Compared to Group C(negative control group), lung injury in the other four groups was increased. Compared to Group E(LPS +4 ml/kg normal saline), lung injury of Group HSS(LPS +4 ml/kg HSS), HES(LPS +4 ml/kg HES), and HSH (LPS +4 ml/kg HSH)was lessened. Compared to Group C, oxygenation index in Groups E, HSS, HES, and HSH were decreased (P < 0.01). Compared to Group E, oxygenation indexes in Groups HSS, HES, and HSH were significantly increased (P < 0.01). Data of tumor necrosis factor (TNF)-α of lung tissue had similar results. However, protein concentration of bronchoalveolar lavage fluid and hydrogen sulfide (H(2)S) concentration indicated contrary results. Small volume resuscitation with 7.5% hypertonic sodium chloride, hydroxyethyl starch 130/0.4 solution, and hypertonic sodium chloride hydroxyethyl starch 40 injection could lessen lung injury caused by lipopolysaccharide. And this effect had relation to change of TNF-α and H(2)S. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. From Observation to Information: Data-Driven Understanding of on Farm Yield Variation.

    PubMed

    Jiménez, Daniel; Dorado, Hugo; Cock, James; Prager, Steven D; Delerce, Sylvain; Grillon, Alexandre; Andrade Bejarano, Mercedes; Benavides, Hector; Jarvis, Andy

    2016-01-01

    Agriculture research uses "recommendation domains" to develop and transfer crop management practices adapted to specific contexts. The scale of recommendation domains is large when compared to individual production sites and often encompasses less environmental variation than farmers manage. Farmers constantly observe crop response to management practices at a field scale. These observations are of little use for other farms if the site and the weather are not described. The value of information obtained from farmers' experiences and controlled experiments is enhanced when the circumstances under which it was generated are characterized within the conceptual framework of a recommendation domain, this latter defined by Non-Controllable Factors (NCFs). Controllable Factors (CFs) refer to those which farmers manage. Using a combination of expert guidance and a multi-stage analytic process, we evaluated the interplay of CFs and NCFs on plantain productivity in farmers' fields. Data were obtained from multiple sources, including farmers. Experts identified candidate variables likely to influence yields. The influence of the candidate variables on yields was tested through conditional forests analysis. Factor analysis then clustered harvests produced under similar NCFs, into Homologous Events (HEs). The relationship between NCFs, CFs and productivity in intercropped plantain were analyzed with mixed models. Inclusion of HEs increased the explanatory power of models. Low median yields in monocropping coupled with the occasional high yields within most HEs indicated that most of these farmers were not using practices that exploited the yield potential of those HEs. Varieties grown by farmers were associated with particular HEs. This indicates that farmers do adapt their management to the particular conditions of their HEs. Our observations confirm that the definition of HEs as recommendation domains at a small-scale is valid, and that the effectiveness of distinct

  20. Efficient derivation of Chinese human embryonic stem cell lines from frozen embryos.

    PubMed

    Li, Chunliang; Yang, Ying; Lu, Xiaowei; Sun, Yijuan; Gu, Junjie; Feng, Yun; Jin, Ying

    2010-04-01

    Human embryonic stem (hES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Their unique properties of self-renewal and pluripotency make them an attractive tool for basic research as well as a potential cell resource for therapy. However, each hES cell line demonstrates different identity. It is desirable to obtain more fully characterized hES cell lines with newly developed technologies associated with hES cell culture. Here, we report our experience of efficient derivation of three new Chinese hES cell lines (SHhES2, SHhES3, and SHhES4) from in vitro fertilization discarded embryos donated by women with polycystic ovary syndrome. These cell lines were derived under conditions minimizing exposure to animal components and maintained at an undifferentiated state for long-term culture. They retained a normal karyotype and expressed ALP, OCT4, SOX2, SSEA-4, TRA-1-60 and TRA-1-81. RT-PCR analysis also revealed high expression levels of pluripotency markers such as OCT4, LEFTY A, SOX2, TDGF-1, THY1, FGF4, NANOG, and REX1. When suspended in low-attachment culture dishes, embryoid bodies formed and were comprised of various differentiated cell types from all three embryonic germ layers. However, well-shaped teratomas were only harvested from line SHhES2, not from SHhES3 and SHhES4, indicating that the differentiation ability in vivo differs among the three cell lines. Collectively, the three new hES cell lines were established and fully characterized. The effort paves the way toward generating hES cell lines without contamination by animal components. All of these cell lines are available by contact Ying Jin at yjin@sibs.ac.cn.

  1. A chimeric vitronectin: IGF-I protein supports feeder-cell-free and serum-free culture of human embryonic stem cells.

    PubMed

    Manton, Kerry J; Richards, Sean; Van Lonkhuyzen, Derek; Cormack, Luke; Leavesley, David; Upton, Zee

    2010-09-01

    The therapeutic use of human embryonic stem (hES) cells is severely limited by safety concerns regarding their culture in media containing animal-derived or nondefined factors and on animal-derived feeder cells. Thus, there is a pressing need to develop culture techniques that are xeno-free, fully defined, and synthetic. Our laboratory has discovered that insulin-like growth factor (IGF) and vitronectin (VN) bind to each other resulting in synergistic short-term functional effects in several cell types, including keratinocytes and breast epithelial cells. We have further refined this complex into a single chimeric VN:IGF-I protein that functionally mimics the effects obtained upon binding of IGF-I to VN. The aim of the current study was to determine whether hES cells can be serially propagated in feeder-cell-free and serum-free conditions using medium containing our novel chimeric VN:IGF-I protein. Here we demonstrate that hES cells can be serially propagated and retain their undifferentiated state in vitro for up to 35 passages in our feeder-cell-free, serum-free, chemically defined media. We have utilized real-time polymerase chain reaction (PCR), immunofluorescence, and fluorescence-activated cell sorter (FACS) analysis to show that the hES cells have maintained an undifferentiated phenotype. In vitro differentiation assays demonstrated that the hES cells retain their pluripotent potential and the karyotype of the hES cells remains unchanged. This study demonstrates that the novel, fully defined, synthetic VN:IGF-I chimera-containing medium described herein is a viable alternative to media containing serum, and that in conjunction with laminin-coated plates facilitates feeder-cell-free and serum-free growth of hES.

  2. Significance of Stat3 Signaling in Epithelial Cell Differentiation of Fetal Mouse Lungs

    PubMed Central

    Kameyama, Hiroki; Kudoh, Shinji; Hatakeyama, Jun; Matuo, Akira; Ito, Takaaki

    2017-01-01

    To study the significance of signal transducer and activator of transcription (Stat) 3 in lung epithelial development of fetal mice, we examined fetal mouse lungs, focusing on the expression of Clara cell secretory protein (CCSP), Forkhead box protein J1 (Foxj1), calcitonin gene-related peptide (CGRP), phosphorylated Stat3 (Tyr705), and hairy/enhancer of split (Hes) 1, and observed cultured fetal lungs upon treatment with IL-6, a Stat3 activator, or cucurbitacin I, a Stat3 inhibitor. Moreover, the interaction of Stat3 signaling and Hes1 was studied using Hes1 gene-deficient mice. Phosphorylated Stat3 was detected in fetal lungs and, immunohistochemically, phosphorylated Stat3 was found to be co-localized in developing Clara cells, but not in ciliated cells. In the organ culture studies, upon treatment with IL-6, quantitative RT-PCR revealed that CCSP mRNA increased with increasing Stat3 phosphorylation, while cucurbitacin I decreased Hes1, CCSP, Foxj1 and CGRP mRNAs with decreasing Stat3 phosphorylation. In the lungs of Hes1 gene-deficient mice, Stat3 phosphorylation was not markedly different from wild-type mice, the expression of CCSP and CGRP was enhanced, and the treatment of IL-6 or cucurbitacin I induced similar effects on mouse lung epithelial differentiation regardless of Hes1 expression status. Stat3 signaling acts in fetal mouse lung development, and seems to regulate Clara cell differentiation positively. Hes1 could regulate Clara cell differentiation in a manner independent from Stat3 signaling. PMID:28386145

  3. Maintenance of pluripotency in human embryonic stem cells stably over-expressing enhanced green fluorescent protein.

    PubMed

    Liu, Yi-Ping; Dovzhenko, Oksana V; Garthwaite, Mark A; Dambaeva, Svetlana V; Durning, Maureen; Pollastrini, Leah M; Golos, Thaddeus G

    2004-12-01

    The availability of human embryonic stem (HES) cells with a readily evaluated genetic marker such as green fluorescent protein (GFP) could facilitate a number of experimental opportunities. We constructed a novel plasmid with two elongation factor-1alpha (EF-1alpha) promoters (YPL2) to obtain a vector with mammalian promoters for simultaneous transgene expression in HES cells. An enhanced green fluorescent protein (EGFP) cDNA was inserted under the control of the first EF-1alpha promoter to construct plasmid YPL2-EGFP. The second EF1-alpha promoter was upstream of the neomycin resistance gene. H1 HES cells were transfected with YPL2-EGFP using Fugene 6. Following 100 microg/ml neomycin selection, individual colonies demonstrating stable EGFP expression were observed. After 4 months of passage under neomycin selection, the cells continued to maintain typical HES cell morphology. Undifferentiated cells showed no change in EGFP expression as determined by FACS analysis. Immunostaining demonstrated maintenance of Oct-3/4 expression in undifferentiated H1EGFP cells that was indistinguishable from wild-type HES cells. Addition of 10 ng/ml bone morphogenic protein-4 (BMP-4) to the cells provoked morphological and functional differentiation to trophoblasts, but no loss of EGFP expression. Following injection of EGFP-HES cells into immunodeficient mice, there was robust formation of teratomas that demonstrated a broad range of morphological pluripotency with widespread EGFP expression. EGFP expression was also maintained in differentiating embryoid bodies formed from EGFP-HES cells. This report demonstrates that ES cells carrying EGFP will be useful in diverse areas of embryonic stem cell research.

  4. Fluid resuscitation with 6 % hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy.

    PubMed

    Gattas, David J; Dan, Arina; Myburgh, John; Billot, Laurent; Lo, Serigne; Finfer, Simon

    2013-04-01

    To determine whether fluid resuscitation of acutely ill adults with 6 % hydroxyethyl starch (6 % HES 130) with a molecular weight of 130 kD and a molar substitution ratio of approximately 0.4 (6 % HES 130) compared with other resuscitation fluids results in a difference in the relative risk of death or treatment with renal replacement therapy (RRT). Systematic review and meta-analysis of randomized controlled trials comparing intravascular fluids for resuscitation of hospitalised adults that reported mortality or treatment with RRT. The risk of bias was assessed independently by two reviewers and meta-analysis was performed using random effects. Thirty-five trials enrolling 10,391 participants were included. The three largest trials had the lowest risk of bias, were published (or completed) in 2012, and together enrolled 77 % of all participants. Death occurred in 928 of 4,691 patients (19.8 %) in the 6 % HES 130 group versus 871 of 4,720 (18.5 %) in the control fluid groups relative risk (RR) in the 6 % HES 130 group 1.08, 95 % confidence interval (CI) 1.00 to 1.17, I (2) = 0 %). Treatment with RRT occurred in 378 of 4,236 patients (8.9 %) in the 6 % HES 130 group versus 306 of 4,260 (7.2 %) in the control fluid group (RR in the 6 % HES 130 group 1.25, 95 % CI 1.08 to 1.44, I (2) = 0 %). The quality and quantity of data evaluating 6 % hydroxyethyl starch (130/0.4 and 130/0.42) as a resuscitation fluid has increased in the last 12 months. Patients randomly assigned to resuscitation with 6 %HES 130 are at significantly increased risk of being treated with RRT.

  5. Ionizing Radiation Alters Human Embryonic Stem Cell Properties and Differentiation Capacity by Diminishing the Expression of Activin Receptors.

    PubMed

    Luft, Sabine; Arrizabalaga, Onetsine; Kulish, Ireen; Nasonova, Elena; Durante, Marco; Ritter, Sylvia; Schroeder, Insa S

    2017-03-01

    Exposure of the embryo to ionizing radiation (IR) is detrimental as it can cause genotoxic stress leading to immediate and latent consequences such as functional defects, malformations, or cancer. Human embryonic stem (hES) cells can mimic the preimplantation embryo and help to assess the biological effects of IR during early development. In this study, we describe the alterations H9 hES cells exhibit after X-ray irradiation in respect to cell cycle progression, apoptosis, genomic stability, stem cell signaling, and their capacity to differentiate into definitive endoderm. Early postirradiation, hES cells responded with an arrest in G2/M phase, elevated apoptosis, and increased chromosomal aberrations. Significant downregulation of stem cell signaling markers of the TGF beta-, Wnt-, and Hedgehog pathways was observed. Most prominent were alterations in the expression of activin receptors. However, hES cells responded differently depending on the culture conditions chosen for maintenance. Enzymatically passaged cells were less sensitive to IR than mechanically passaged ones showing fewer apoptotic cells and fewer changes in the stem cell signaling 24 h after irradiation, but displayed higher levels of chromosomal aberrations. Even though many of the observed changes were transient, surviving hES cells, which were differentiated 4 days postirradiation, showed a lower efficiency to form definitive endoderm than their mock-irradiated counterparts. This was demonstrated by lower expression levels of SOX17 and microRNA miR-375. In conclusion, hES cells are a suitable tool for the IR risk assessment during early human development. However, careful choice of the culture methods and a vigorous monitoring of the stem cell quality are mandatory for the use of these cells. Exposure to IR influences the stem cell properties of hES cells even when immediate radiation effects are overcome. This warrants consideration in the risk assessment of radiation effects during the

  6. Efficacy and safety of 6% hydroxyethyl starch 130/0.4 (Voluven) for perioperative volume replacement in children undergoing cardiac surgery: a propensity-matched analysis.

    PubMed

    Van der Linden, Philippe; Dumoulin, Melanie; Van Lerberghe, Celine; Torres, Cristel Sanchez; Willems, Ariane; Faraoni, David

    2015-03-17

    Six percent hydroxyethyl starch (HES) 130/0.4 is considered an alternative to human albumin (HA) and crystalloids for volume replacement in children undergoing cardiac surgery. In this large propensity-matched analysis, we aimed to assess the efficacy and safety of replacing HA with HES for intraoperative volume therapy in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). We retrospectively reviewed our database, including children who underwent cardiac surgery between January 2002 and December 2010. Four percent HA was used until 2005; it was replaced by HES thereafter. Demographic data, intra- and postoperative blood loss and blood component transfusions were recorded, together with the incidence of postoperative complications and mortality. We performed a propensity-matched analysis using 13 possible confounding factors to compare children who received either HES or HA intraoperatively. The primary objectives included the effects of both fluids on intraoperative fluid balance (difference between fluids in and fluids out (efficacy)) and blood loss and exposure to allogeneic blood products (safety). Secondary safety outcomes were mortality and the incidence of postoperative renal dysfunction. Of 1,832 children reviewed, 1,495 were included in the analysis. Intraoperative use of HES was associated with a less positive fluid balance. Perioperative blood loss, volume of red blood cells and fresh frozen plasma administered, as well as the number of children who received transfusions, were also significantly lower in the HES group. No difference was observed regarding the incidence of postoperative renal failure requiring renal replacement therapy or of morbidity and mortality. These results confirm that the use of HES for volume replacement in children during cardiac surgery with CPB is as safe as HA. In addition, its use might be associated with less fluid accumulation. Further large studies are needed to assess whether the reduction in fluid

  7. Developmentally regulated HEART STOPPER, a mitochondrially targeted L18 ribosomal protein gene, is required for cell division, differentiation, and seed development in Arabidopsis

    PubMed Central

    Zhang, Hongyu; Luo, Ming; Day, Robert C.; Talbot, Mark J.; Ivanova, Aneta; Ashton, Anthony R.; Chaudhury, Abed M.; Macknight, Richard C.; Hrmova, Maria; Koltunow, Anna M.

    2015-01-01

    Evidence is presented for the role of a mitochondrial ribosomal (mitoribosomal) L18 protein in cell division, differentiation, and seed development after the characterization of a recessive mutant, heart stopper (hes). The hes mutant produced uncellularized endosperm and embryos arrested at the late globular stage. The mutant embryos differentiated partially on rescue medium with some forming callus. HES (At1g08845) encodes a mitochondrially targeted member of a highly diverged L18 ribosomal protein family. The substitution of a conserved amino residue in the hes mutant potentially perturbs mitoribosomal function via altered binding of 5S rRNA and/or influences the stability of the 50S ribosomal subunit, affecting mRNA binding and translation. Consistent with this, marker genes for mitochondrial dysfunction were up-regulated in the mutant. The slow growth of the endosperm and embryo indicates a defect in cell cycle progression, which is evidenced by the down-regulation of cell cycle genes. The down-regulation of other genes such as EMBRYO DEFECTIVE genes links the mitochondria to the regulation of many aspects of seed development. HES expression is developmentally regulated, being preferentially expressed in tissues with active cell division and differentiation, including developing embryos and the root tips. The divergence of the L18 family, the tissue type restricted expression of HES, and the failure of other L18 members to complement the hes phenotype suggest that the L18 proteins are involved in modulating development. This is likely via heterogeneous mitoribosomes containing different L18 members, which may result in differential mitochondrial functions in response to different physiological situations during development. PMID:26105995

  8. Trace levels of mitomycin C disrupt genomic integrity and lead to DNA damage response defect in long-term-cultured human embryonic stem cells.

    PubMed

    Zhou, Di; Lin, Ge; Zeng, Si-Cong; Xiong, Bo; Xie, Ping-Yuan; Cheng, De-Hua; Zheng, Qing; Ouyang, Qi; Zhou, Xiao-Ying; Tang, Wei-Ling; Sun, Yi; Lu, Guang-Ying; Lu, Guang-Xiu

    2015-01-01

    How to maintain the genetic integrity of cultured human embryonic stem (hES) cells is raising crucial concerns for future clinical use in regenerative medicine. Mitomycin C(MMC), a DNA damage agent, is widely used for preparation of feeder cells in many laboratories. However, to what extent MMC affects the karyotypic stability of hES cells is not clear. Here, we measured residual MMC using High Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry following each step of feeder preparation and found that 2.26 ± 0.77 and 3.50 ± 0.92 ng/ml remained in mouse feeder cells and human feeder cells, respectively. In addition, different amounts of MMC caused different chromosomal aberrations in hES cells. In particular, one abnormality, dup(1)(p32p36), was the same identical to one we previously reported in another hES cell line. Using Affymetrix SNP 6.0 arrays, the copy number variation changes of the hES cells maintained on MMC-inactivated feeders (MMC-feeder) were significantly more than those cultured on γ-inactivated feeder (IR-feeder) cells. Furthermore, DNA damage response (DDR) genes were down-regulated during long-term culture in the MMC-containing system, leading to DDR defect and shortened telomeres of hES cells, a sign of genomic instability. Therefore, MMC-feeder and MMC-induced genomic variation present an important safety problem that would limit such hES from being applied for future clinic use and drug screening.

  9. Effect of hyperosmolar sodium lactate infusion on haemodynamic status and fluid balance compared with hydroxyethyl starch 6% during the cardiac surgery.

    PubMed

    Boom, Cindy Elfir; Herdono, Poernomo; Koto, Chairil Gani; Hadi, Sjamsul; Permana, I Made Adi

    2013-11-01

    No solution has been determined ideal for fluid therapy during cardiac surgery. Previous studies have shown that hyperosmolar sodium lactate (HSL) infusion has improved cardiac performance with smaller volume infusion, which resulted in negative fluid balance. This study compared the effects between a patent-protected HSL infusion and hydroxyethyl starch (HES) 6% on haemodynamic status of the patients undergoing cardiac surgery. In this open-label prospective controlled randomized study, patients were randomly assigned to receive loading dose of either HSL or HES 6%, at 3 mL/kgBW within 15 min, at the beginning of surgery. Haemodynamic parameters and fluid balance were evaluated, while biochemical parameters and any adverse effect were also recorded. Haemodynamic and laboratory parameters were analyzed through repeated measures analysis of variance. Statistical assessment of fluid management was carried out through Student t-test. All statistical analyses were performed using the statistical package for the social sciences(®) version 15, 2006 (SPSS Inc., Chicago, IL). Out of 100 enrolled patients in this study (50 patients in each arm), 98 patients were included in analysis (50 in HSL group; 48 in HES group). Cardiac index increased higher in HSL group (P = 0.01), whereas systemic vascular resistance index decreased more in HSL than HES group (P = 0.002). Other haemodynamic parameters were comparable between HSL and HES group. Fluid balance was negative in HSL group, but it was positive in HES group (-445.94 ± 815.30 mL vs. +108.479 ± 1219.91 mL, P < 0.009). Administration of HSL solution during the cardiac surgery improved cardiac performance and haemodynamic status better than HES did.

  10. Six percent hydroxyethyl starch 130/0.4 impacts differently on blood glucose than 4% gelatine in a swine model of mixed acidaemia.

    PubMed

    Russ, Martin; Koch, Vera; Keckel, Tobias; Boemke, Willehad; Hiebl, Bernhard; Unger, Juliane K

    2009-12-01

    Tris-hydroxymethyl aminomethane can be used as a buffer in case of restricted ventilation, but hypoglycaemia is one adverse effect. The influence of a starch-based colloid [6% hydroxyethyl starch 130 kDa/0.4 (HES130)] vs. a gelatine-based colloid (4% polysuccinated gelatine) on blood glucose was investigated in a swine model of mixed acidaemia. Continuous colloid infusion was done in anaesthetized pigs with exogenously induced mixed acidaemia, which was maintained for 3 h. Pigs (approximately 40 kg, n = 6 in each group) were randomized to HES130 or 4% gelatine infusion (4 ml kg h(-1)). Infusion of an acid solution and low tidal volume ventilation induced mixed acidaemia. Treatment of mixed acidaemia with tris-hydroxymethyl aminomethane buffer, which is known to induce hypoglycaemia, prolonged anaesthesia, and volume support challenged the control of blood glucose. Hypoglycaemia was treated by individually dosed infusion of 5% glucose in sterile water. Bolus infusion of HES130 led to a moderate peak in blood glucose in four pigs. Four pigs in the 4% gelatine group and three in the HES130 group needed glucose infusion to prevent a drop in blood glucose levels below the set threshold (4 mmol l(-1)). The total amount of the glucose infusion was significantly lower in the HES130 group compared with the 4% gelatine group (100 vs. 295 ml per pig, median, P < 0.05). Generally, the HES130 pigs required glucose at later time points during anaesthesia. The first HES130 pig needed 5% glucose 2 h later than the first 4% gelatine pig to prevent a drop of blood glucose below 4 mmol l(-1). Volume support impacted specifically on blood glucose in this porcine model. Thus, an additional control of blood glucose seems recommendable whenever a change in the volume support occurs.

  11. From Observation to Information: Data-Driven Understanding of on Farm Yield Variation

    PubMed Central

    Jiménez, Daniel; Dorado, Hugo; Cock, James; Prager, Steven D.; Delerce, Sylvain; Grillon, Alexandre; Andrade Bejarano, Mercedes; Benavides, Hector; Jarvis, Andy

    2016-01-01

    Agriculture research uses “recommendation domains” to develop and transfer crop management practices adapted to specific contexts. The scale of recommendation domains is large when compared to individual production sites and often encompasses less environmental variation than farmers manage. Farmers constantly observe crop response to management practices at a field scale. These observations are of little use for other farms if the site and the weather are not described. The value of information obtained from farmers’ experiences and controlled experiments is enhanced when the circumstances under which it was generated are characterized within the conceptual framework of a recommendation domain, this latter defined by Non-Controllable Factors (NCFs). Controllable Factors (CFs) refer to those which farmers manage. Using a combination of expert guidance and a multi-stage analytic process, we evaluated the interplay of CFs and NCFs on plantain productivity in farmers’ fields. Data were obtained from multiple sources, including farmers. Experts identified candidate variables likely to influence yields. The influence of the candidate variables on yields was tested through conditional forests analysis. Factor analysis then clustered harvests produced under similar NCFs, into Homologous Events (HEs). The relationship between NCFs, CFs and productivity in intercropped plantain were analyzed with mixed models. Inclusion of HEs increased the explanatory power of models. Low median yields in monocropping coupled with the occasional high yields within most HEs indicated that most of these farmers were not using practices that exploited the yield potential of those HEs. Varieties grown by farmers were associated with particular HEs. This indicates that farmers do adapt their management to the particular conditions of their HEs. Our observations confirm that the definition of HEs as recommendation domains at a small-scale is valid, and that the effectiveness of distinct

  12. The implementation of an integrated information system for substance use screening in general medical settings.

    PubMed

    Shanahan, C W; Sorensen-Alawad, A; Carney, B L; Persand, I; Cruz, A; Botticelli, M; Pressman, K; Adams, W G; Brolin, M; Alford, D P

    2014-01-01

    The Massachusetts Screening, Brief Intervention and Referral to Treatment (MASBIRT) Program, a substance use screening program in general medical settings, created a web-based, point-of-care (POC), application--the MASBIRT Portal (the "Portal") to meet program goals. We report on development and implementation of the Portal. Five year program process outcomes recorded by an independent evaluator and an anonymous survey of Health Educator's (HEs) adoption, perceptions and Portal use with a modified version of the Technology Readiness Index are described. [8] Specific management team members, selected based on their roles in program leadership, development and implementation of the Portal and supervision of HEs, participated in semi-structured, qualitative interviews. At the conclusion of the program 73% (24/33) of the HEs completed a survey on their experience using the Portal. HEs reported that the Portal made recording screening information easy (96%); improved planning their workday (83%); facilitated POC data collection (84%); decreased time dedicated to data entry (100%); and improved job satisfaction (59%). The top two barriers to use were "no or limited wireless connectivity" (46%) and "the tablet was too heavy/bulky to carry" (29%). Qualitative management team interviews identified strategies for successful HIT implementation: importance of engaging HEs in outlining specifications and workflow needs, collaborative testing prior to implementation and clear agreement on data collection purpose, quality requirements and staff roles. Overall, HEs perceived the Portal favorably with regard to time saving ability and improved workflow. Lessons learned included identifying core requirements early during system development and need for managers to institute and enforce consistent behavioral work norms. Barriers and HEs' views of technology impacted the utilization of the MASBIRT Portal. Further research is needed to determine best approaches for HIT system

  13. The acute effects of acetate-balanced colloid and crystalloid resuscitation on renal oxygenation in a rat model of hemorrhagic shock.

    PubMed

    Almac, Emre; Aksu, Ugur; Bezemer, Rick; Jong, Willeke; Kandil, Asli; Yuruk, Koray; Demirci-Tansel, Cihan; Ince, Can

    2012-09-01

    Fluid resuscitation therapy is the initial step of treatment for hemorrhagic shock. In the present study we aimed to investigate the acute effects of acetate-balanced colloid and crystalloid resuscitation on renal oxygenation in a rat model of hemorrhagic shock. We hypothesized that acetate-balanced solutions would be superior in correcting impaired renal perfusion and oxygenation after severe hemorrhage compared to unbalanced solutions. In anesthetized, mechanically ventilated rats, hemorrhagic shock was induced by withdrawing blood from the femoral artery until mean arterial pressure (MAP) was reduced to 30 mmHg. One hour later, animals were resuscitated with either hydroxyethyl starch (HES, 130/0.42 kDa) dissolved in saline (HES-NaCl; n=6) or a acetate-balanced Ringer's solution (HES-RA; n=6), as well as with acetated Ringer's solution (RA; n=6) or 0.9% NaCl alone (NaCl; n=6) until a target MAP of 80 mmHg was reached. Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein were measured using phosphorimetry. Hemorrhagic shock (MAP=30 mmHg) significantly decreased renal oxygenation and oxygen consumption. Restoring the MAP to 80 mmHg required 24.8±1.7 ml of NaCl, 21.7±1.4 ml of RA, 5.9±0.5 ml of HES-NaCl (p<0.05 vs. NaCl and RA), and 6.0±0.4 ml of HES-RA (p<0.05 vs. NaCl and RA). NaCl, RA, and HES-NaCl resuscitation led to hyperchloremic acidosis, while HES-RA resuscitation did not. Only HES-RA resuscitation could restore renal blood flow back to ∼85% of baseline level (from 1.9±0.1 ml/min during shock to 5.1 ml±0.2 ml/min 60 min after HES-RA resuscitation) which was associated with an improved renal oxygenation (CμPO2 increased from 24±2 mmHg during shock to 50±2 mmHg 60 min after HES-RA resuscitation) albeit not to baseline level. At the end of the protocol, creatinine clearance was decreased in all groups with no differences between the different resuscitation groups. While resuscitation with the NaCl and RA (crystalloid

  14. Dynamic Analysis of Hybrid Energy Systems under Flexible Operation and Variable Renewable Generation -- Part I: Dynamic Performance Analysis and Part II: Dynamic Cost

    SciTech Connect

    Humberto E. Garcia; Amit Mohanty; Wen-Chiao Lin; Robert S. Cherry

    2013-04-01

    Dynamic analysis of hybrid energy systems (HES) under flexible operation and variable renewable generation is considered in order to better understand various challenges and opportunities associated with the high system variability arising from the integration of renewable energy into the power grid. Unique consequences are addressed by devising advanced HES solutions in which multiple forms of energy commodities, such as electricity and chemical products, may be exchanged. Dynamic models of various unit operations are developed and integrated within two different HES options. One HES option, termed traditional, produces electricity only and consists of a primary heat generator (PHG) (e.g., a small modular reactor), a steam turbine generator, a wind farm, and a battery storage. The other HES option, termed advanced, includes not only the components present in the traditional option but also a chemical plant complex to repurpose excess energy for non-electricity services, such as for the production of chemical goods (e.g., transportation fuel). In either case, a given HES is connected to the power grid at a point of common coupling and requested to deliver a certain electricity generation profile as dictated by a regional power grid operator based on a predicted demand curve. Dynamic analysis of these highly-coupled HES are performed to identify their key dynamical properties and limitations and to prescribe solutions for best managing and mitigating the high variability introduced from incorporating renewable energy into the energy mix. A comparative dynamic cost analysis is also conducted to determine best HES options. The cost function includes a set of metrics for computing fixed costs, such as fixed operations and maintenance (O&M) and overnight capital costs, and also variable operational costs, such as cost of variability, variable O&M cost, and cost of environmental impact, together with revenues. Assuming different options for implementing PHG (e

  15. Hyperoncotic colloids and acute kidney injury: a meta-analysis of randomized trials

    PubMed Central

    2010-01-01

    Introduction It has been hypothesized that hyperoncotic colloids might contribute to acute kidney injury (AKI). However, the validity of this hypothesis remains unclear. Methods A meta-analysis was conducted of randomized controlled trials evaluating AKI after infusion of hyperoncotic albumin and hydroxyethyl starch (HES) solutions. Mortality was a secondary endpoint. Eligible trials were sought by multiple methods, and the pooled odds ratios (OR) for AKI and death and 95% confidence intervals (CI) were computed under a random effects model. Results Eleven randomized trials with a total of 1220 patients were included: 7 evaluating hyperoncotic albumin and 4 hyperoncotic HES. Clinical indications were ascites, surgery, sepsis and spontaneous bacterial peritonitis. Hyperoncotic albumin decreased the odds of AKI by 76% (OR, 0.24; CI, 0.12-0.48; P < 0.0001), while hyperoncotic HES increased those odds by 92% (OR, 1.92; CI, 1.31-2.81; P = 0.0008). Parallel effects on mortality were observed, with hyperoncotic albumin reducing the odds of death by 48% (OR, 0.52; CI, 0.28-0.95; P = 0.035) and hyperoncotic HES raising those odds by 41% (OR, 1.41; CI, 1.01-1.96; P = 0.043). Conclusions This meta-analysis does not support the hypothesis that hyperoncotic colloid solutions per se injure the kidney. Renal effects appear instead to be colloid-specific, with albumin displaying renoprotection and HES showing nephrotoxicity. PMID:21029460

  16. Topology and dynamics of the zebrafish segmentation clock core circuit.

    PubMed

    Schröter, Christian; Ares, Saúl; Morelli, Luis G; Isakova, Alina; Hens, Korneel; Soroldoni, Daniele; Gajewski, Martin; Jülicher, Frank; Maerkl, Sebastian J; Deplancke, Bart; Oates, Andrew C

    2012-01-01

    During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel. To explain the observed single and double mutant phenotypes of her1, her7, and hes6 mutant embryos in our dynamic model, we postulate that the availability and effective stability of the dimers with DNA binding activity is controlled in a "dimer cloud" that contains all possible dimeric combinations between the three factors. This feature of our model predicts that Hes6 protein levels should oscillate despite constant hes6 mRNA production, which we confirm experimentally using novel Hes6 antibodies. The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks.

  17. Notch1 and its ligands Delta-like and Jagged are expressed and active in distinct cell populations in the postnatal mouse brain.

    PubMed

    Stump, Gila; Durrer, André; Klein, Anne-Laurence; Lütolf, Simone; Suter, Ueli; Taylor, Verdon

    2002-06-01

    Notch signaling plays a pivotal role in the regulation of vertebrate neurogenesis. However, in vitro experiments suggest that Notch1 may also be involved in the regulation of later stages of brain development. We have addressed putative roles in the central nervous system by examining the expression of Notch signaling cascade components in the postnatal mouse brain. In situ mRNA hybridization revealed that Notch1 is associated with cells in the subventricular zone, the dentate gyrus and the rostromigratory stream, all regions of continued neurogenesis in the postnatal brain. In addition, Notch1 is expressed at low levels throughout the cortex and olfactory bulb and shows striking expression in the cerebellar Purkinje cell layer. The Notch ligands, including Delta-like1 and 3 and Jagged1 and Jagged2, show distinct expression patterns in the developing and adult brain overlapping that of Notch1. In addition, the downstream targets of the Notch signaling cascade Hes1, Hes3, Hes5 and the intrinsic Notch regulatory proteins Numb and Numblike also show active signaling in distinct brain regions. Hes5 coincides with the majority of Notch1 expression and can be detected in the cerebral cortex, cerebellum and putative germinal zones. Hes3, on the other hand, shows a restricted expression in cerebellar Purkinje cells. The distribution of Notch1 and its putative ligands suggest distinct roles in specific subsets of cells in the postnatal brain including putative stem cells and differentiated neurons.

  18. Profiling TRA-1-81 antigen distribution on a human embryonic stem cell.

    PubMed

    Qiu, Dengli; Xiang, Jialing; Li, Zhaoxia; Krishnamoorthy, Aparna; Chen, Liaohai; Wang, Rong

    2008-05-02

    Human embryonic stem (hES) cells hold great promise in regenerative medicine. Although hES cells have unlimited self-renewal potential, they tend to differentiate spontaneously in culture. TRA-1-81 is a biomarker of undifferentiated hES cells. Quantitative characterization of TRA-1-81 expression level in a single cell helps capture the "turn-on" signal and understand the mechanism of early differentiation. Here, we report on our examination of TRA-1-81 distribution and association on a hES cell membrane using an atomic force microscope (AFM). Our results suggest that aggregated distribution of TRA-1-81 antigen is characteristic for undifferentiated hES cells. We also evaluated the TRA-1-81 expression level at approximately 17,800 epitopes and approximately 700 epitopes per cell on an undifferentiated cell and a spontaneously differentiated cell, respectively. The method in this study can be adapted in examining other surface proteins on various cell types, thus providing a general tool for investigating protein distribution and association at the single cell level.

  19. Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment.

    PubMed

    Rodin, Sergey; Antonsson, Liselotte; Niaudet, Colin; Simonson, Oscar E; Salmela, Elina; Hansson, Emil M; Domogatskaya, Anna; Xiao, Zhijie; Damdimopoulou, Pauliina; Sheikhi, Mona; Inzunza, José; Nilsson, Ann-Sofie; Baker, Duncan; Kuiper, Raoul; Sun, Yi; Blennow, Elisabeth; Nordenskjöld, Magnus; Grinnemo, Karl-Henrik; Kere, Juha; Betsholtz, Christer; Hovatta, Outi; Tryggvason, Karl

    2014-01-01

    Lack of robust methods for establishment and expansion of pluripotent human embryonic stem (hES) cells still hampers development of cell therapy. Laminins (LN) are a family of highly cell-type specific basement membrane proteins important for cell adhesion, differentiation, migration and phenotype stability. Here we produce and isolate a human recombinant LN-521 isoform and develop a cell culture matrix containing LN-521 and E-cadherin, which both localize to stem cell niches in vivo. This matrix allows clonal derivation, clonal survival and long-term self-renewal of hES cells under completely chemically defined and xeno-free conditions without ROCK inhibitors. Neither LN-521 nor E-cadherin alone enable clonal survival of hES cells. The LN-521/E-cadherin matrix allows hES cell line derivation from blastocyst inner cell mass and single blastomere cells without a need to destroy the embryo. This method can facilitate the generation of hES cell lines for development of different cell types for regenerative medicine purposes.

  20. Stemina biomarker discovery.

    PubMed

    Cezar, Gabriela G; Donley, Elizabeth L R

    2008-09-01

    Stemina Biomarker Discovery was established in 2006 to commercialize technology developed by Dr Gabriela Cezar at the University of Wisconsin (WI, USA). Stemina's cell-based assays arise from the strategic convergence of two cutting edge technologies: metabolomics and human embryonic stem (hES) cells. Stemina analyzes the small molecules secreted by hES cells and differentiated cell types such as neural and heart cells derived from hES cells by liquid chromatography mass spectrometry at its state-of-the-art facilities in Madison, WI, USA. Stemina's first technology platform has identified a dynamic set of small molecules in the extracellular secretome of hES cells secreted in response to exposure to a library of known teratogens. Alterations to small molecules in the biochemical pathway(s) of hES cells are mapped in silico to identify biomarkers of toxicity for drug screening and development in an all human system. These small human molecules may then be translated in vivo as biomarkers of toxic response and disease.

  1. A defined, controlled culture system for primary bovine chromaffin progenitors reveals novel biomarkers and modulators.

    PubMed

    Masjkur, Jimmy; Levenfus, Ian; Lange, Sven; Arps-Forker, Carina; Poser, Steve; Qin, Nan; Vukicevic, Vladimir; Chavakis, Triantafyllos; Eisenhofer, Graeme; Bornstein, Stefan R; Ehrhart-Bornstein, Monika; Androutsellis-Theotokis, Andreas

    2014-07-01

    We present a method to efficiently culture primary chromaffin progenitors from the adult bovine adrenal medulla in a defined, serum-free monolayer system. Tissue is dissociated and plated for expansion under support by the mitogen basic fibroblast growth factor (bFGF). The cultures, although not homogenous, contain a subpopulation of cells expressing the neural stem cell marker Hes3 that also propagate. In addition, Hes3 is also expressed in the adult adrenal medulla from where the tissue is taken. Differentiation is induced by bFGF withdrawal and switching to Neurobasal medium containing B27. Following differentiation, Hes3 expression is lost, and cells acquire morphologies and biomarker expression patterns of chromaffin cells and dopaminergic neurons. We tested the effect of different treatments that we previously showed regulate Hes3 expression and cell number in cultures of fetal and adult rodent neural stem cells. Treatment of the cultures with a combination of Delta4, Angiopoietin2, and a Janus kinase inhibitor increases cell number during the expansion phase without significantly affecting catecholamine content levels. Treatment with cholera toxin does not significantly affect cell number but reduces the ratio of epinephrine to norepinephrine content and increases the dopamine content relative to total catecholamines. These data suggest that this defined culture system can be used for target identification in drug discovery programs and that the transcription factor Hes3 may serve as a new biomarker of putative adrenomedullary chromaffin progenitor cells.

  2. Profiling TRA-1-81 antigen distribution on a human embryonic stem cell

    SciTech Connect

    Qiu Dengli; Xiang Jialing; Li Zhaoxia; Krishnamoorthy, Aparna; Chen Liaohai; Wang Rong

    2008-05-02

    Human embryonic stem (hES) cells hold great promise in regenerative medicine. Although hES cells have unlimited self-renewal potential, they tend to differentiate spontaneously in culture. TRA-1-81 is a biomarker of undifferentiated hES cells. Quantitative characterization of TRA-1-81 expression level in a single cell helps capture the 'turn-on' signal and understand the mechanism of early differentiation. Here, we report on our examination of TRA-1-81 distribution and association on a hES cell membrane using an atomic force microscope (AFM). Our results suggest that aggregated distribution of TRA-1-81 antigen is characteristic for undifferentiated hES cells. We also evaluated the TRA-1-81 expression level at {approx}17,800 epitopes and {approx}700 epitopes per cell on an undifferentiated cell and a spontaneously differentiated cell, respectively. The method in this study can be adapted in examining other surface proteins on various cell types, thus providing a general tool for investigating protein distribution and association at the single cell level.

  3. The Ultrastructural Signature of Human Embryonic Stem Cells.

    PubMed

    Underwood, Jean M; Becker, Klaus A; Stein, Gary S; Nickerson, Jeffrey A

    2017-04-01

    The epigenetics and molecular biology of human embryonic stem cells (hES cells) have received much more attention than their architecture. We present a more complete look at hES cells by electron microscopy, with a special emphasis on the architecture of the nucleus. We propose that there is an ultrastructural signature of pluripotent human cells. hES cell nuclei lack heterochromatin, including the peripheral heterochromatin, that is common in most somatic cell types. The absence of peripheral heterochromatin may be related to the absence of lamins A and C, proteins important for linking chromatin to the nuclear lamina and envelope. Lamins A and C expression and the development of peripheral heterochromatin were early steps in the development of embryoid bodies. While hES cell nuclei had abundant nuclear pores, they also had an abundance of nuclear pores in the cytoplasm in the form of annulate lamellae. These were not a residue of annulate lamellae from germ cells or the early embryos from which hES cells were derived. Subnuclear structures including nucleoli, interchromatin granule clusters, and Cajal bodies were observed in the nuclear interior. The architectural organization of human ES cell nuclei has important implications for cell structure-gene expression relationships and for the maintenance of pluripotency. J. Cell. Biochem. 118: 764-774, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Self-Contained Induction of Neurons from Human Embryonic Stem Cells

    PubMed Central

    Okuno, Tsuyoshi; Nakayama, Takashi; Konishi, Nae; Michibata, Hideo; Wakimoto, Koji; Suzuki, Yutaka; Nito, Shinji; Inaba, Toshio; Nakano, Imaharu; Muramatsu, Shin-ichi; Takano, Makoto; Kondo, Yasushi; Inoue, Nobuo

    2009-01-01

    Background Neurons and glial cells can be efficiently induced from mouse embryonic stem (ES) cells in a conditioned medium collected from rat primary-cultured astrocytes (P-ACM). However, the use of rodent primary cells for clinical applications may be hampered by limited supply and risk of contamination with xeno-proteins. Methodology/Principal Findings We have developed an alternative method for unimpeded production of human neurons under xeno-free conditions. Initially, neural stem cells in sphere-like clusters were induced from human ES (hES) cells after being cultured in P-ACM under free-floating conditions. The resultant neural stem cells could circumferentially proliferate under subsequent adhesive culture, and selectively differentiate into neurons or astrocytes by changing the medium to P-ACM or G5, respectively. These hES cell-derived neurons and astrocytes could procure functions similar to those of primary cells. Interestingly, a conditioned medium obtained from the hES cell-derived astrocytes (ES-ACM) could successfully be used to substitute P-ACM for induction of neurons. Neurons made by this method could survive in mice brain after xeno-transplantation. Conclusion/Significance By inducing astrocytes from hES cells in a chemically defined medium, we could produce human neurons without the use of P-ACM. This self-serving method provides an unlimited source of human neural cells and may facilitate clinical applications of hES cells for neurological diseases. PMID:19621077

  5. Self-contained induction of neurons from human embryonic stem cells.

    PubMed

    Okuno, Tsuyoshi; Nakayama, Takashi; Konishi, Nae; Michibata, Hideo; Wakimoto, Koji; Suzuki, Yutaka; Nito, Shinji; Inaba, Toshio; Nakano, Imaharu; Muramatsu, Shin-Ichi; Takano, Makoto; Kondo, Yasushi; Inoue, Nobuo

    2009-07-21

    Neurons and glial cells can be efficiently induced from mouse embryonic stem (ES) cells in a conditioned medium collected from rat primary-cultured astrocytes (P-ACM). However, the use of rodent primary cells for clinical applications may be hampered by limited supply and risk of contamination with xeno-proteins. We have developed an alternative method for unimpeded production of human neurons under xeno-free conditions. Initially, neural stem cells in sphere-like clusters were induced from human ES (hES) cells after being cultured in P-ACM under free-floating conditions. The resultant neural stem cells could circumferentially proliferate under subsequent adhesive culture, and selectively differentiate into neurons or astrocytes by changing the medium to P-ACM or G5, respectively. These hES cell-derived neurons and astrocytes could procure functions similar to those of primary cells. Interestingly, a conditioned medium obtained from the hES cell-derived astrocytes (ES-ACM) could successfully be used to substitute P-ACM for induction of neurons. Neurons made by this method could survive in mice brain after xeno-transplantation. By inducing astrocytes from hES cells in a chemically defined medium, we could produce human neurons without the use of P-ACM. This self-serving method provides an unlimited source of human neural cells and may facilitate clinical applications of hES cells for neurological diseases.

  6. Characterization of Notch Signalling Pathway Members in Normal Prostate, Prostatic Intraepithelial Neoplasia (PIN) and Prostatic Adenocarcinoma.

    PubMed

    Soylu, Hakan; Acar, Nuray; Ozbey, Ozlem; Unal, Betul; Koksal, Ismail Turker; Bassorgun, Ibrahim; Ciftcioglu, Akif; Ustunel, Ismail

    2016-01-01

    Prostate Cancer (PCa) holds the second place in terms of cancer-related mortality rate among men. The Notch signalling pathway regulates the proliferation and differentiation in embryonic and adult tissues and determines the cell fate. The body of knowledge in the present literature is currently controversial about the effect of the Notch pathway on prostatic cancer. Therefore, the present study aimed to examine the immunolocalization and expression levels of Notch1-4, Jagged1-2, Delta, HES1 and HES5 from among the members of the Notch signalling pathway in tissues of normal, prostatic intraepithelial neoplasia (PIN) and malignant prostate. The current study included a sample of 20 patients with localised prostatic adenocarcinoma, 18 patients with high grade PIN (H-PIN) and 18 normal prostatic tissue. Immunolocalisations of Notch1, 2, 3, 4, Jagged1, 2, Delta, HES1 and HES5 were identified through the immunohistochemical method. The findings of the present study showed that all in-scope members of the Notch signalling pathway were localised in PIN structures to a greater extent than in other tissues and from amongst these members, specifically Notch1, Notch4, Jagged1 and HES1 were at more significant levels. Consequently, the findings of the present study may indicate that the Notch signalling pathway can play a role especially in the formation of PIN structures.

  7. Hydroxyethyl starch-based polymers for the controlled release of biomacromolecules from hydrogel microspheres.

    PubMed

    Wöhl-Bruhn, Stefanie; Bertz, Andreas; Harling, Steffen; Menzel, Henning; Bunjes, Heike

    2012-08-01

    Hydrogels are promising delivery systems for the controlled release of biomacromolecules. Based on previous studies, hydrogels were prepared from crosslinkable hydroxyethyl starch with new linker groups to improve mechanical and release properties of the resulting hydrogels. Polyethylene glycol methacrylate with two different spacer lengths was used to obtain polymers (HES-P(EG)(n)MA) with increased hydrophilicity and degradability, whereas a polymer with methacrylate linker directly at the starch backbone (HES-MA) resulted in a less degradable polymer. Hydrogel disks were obtained by UV crosslinking and characterized by swelling and rheological measurements. The hydrogel strength was strongly influenced by the polymer concentration. Using a water-in-water emulsion process, hydrogel microspheres were prepared. The influence of the type of the linker, the degree of substitution and the phase ratio in the production process on the properties of the microspheres was investigated. Depending on the preparation parameters, particles with narrow particle size distribution and encapsulation efficiencies of up to more than 80% for FITC-dextran 70 kDa (FD70) were obtained. Incorporated FITC-labeled IgG showed a faster release from hydrogel microspheres than FD70. The release rate of incorporated FD70 could be adjusted by using different polymers (HES-P(EG)(10)MA>HES-P(EG)(6)MA>HES-MA).

  8. CONTRA: Hydroxyethyl starch solutions are unsafe in critically ill patients.

    PubMed

    Hartog, Christiane; Reinhart, Konrad

    2009-08-01

    To describe the risk-benefit profile of hydroxyethyl starch (HES). Narrative review. (1) EFFICACY: no single clinical study or systemic review has shown that administration of any HES solution confers a clinically relevant benefit compared to crystalloids in critically ill patients or surgical patients in need of volume replacement. Contrary to beliefs expecting a ratio of 4:1 or more for crystalloid to colloid volume need, recent studies of goal-directed resuscitation observed much lower ratios of between 1 and 1.6. (2) SAFETY: HES administration is associated with coagulopathy, nephrotoxicity, pruritus and increased long-term mortality. Clinical studies claiming that modern HES 130/0.4 is safe have serious methodological drawbacks and do not adequately address the safety concerns. Given the complete lack of superiority in clinical utility studies and the wide spectrum of severe side effects, the use of HES in the ICU should be stopped. The belief that four times as much crystalloid as colloid fluid volume is needed for successful resuscitation is being seriously questioned.

  9. Economic optimization of operations for hybrid energy systems under variable markets

    DOE PAGES

    Chen, Jen; Garcia, Humberto E.

    2016-05-21

    We prosed a hybrid energy systems (HES) which is an important element to enable increasing penetration of clean energy. Our paper investigates the operations flexibility of HES, and develops a methodology for operations optimization for maximizing economic value based on predicted renewable generation and market information. A multi-environment computational platform for performing such operations optimization is also developed. In order to compensate for prediction error, a control strategy is accordingly designed to operate a standby energy storage element (ESE) to avoid energy imbalance within HES. The proposed operations optimizer allows systematic control of energy conversion for maximal economic value. Simulationmore » results of two specific HES configurations are included to illustrate the proposed methodology and computational capability. These results demonstrate the economic viability of HES under proposed operations optimizer, suggesting the diversion of energy for alternative energy output while participating in the ancillary service market. Economic advantages of such operations optimizer and associated flexible operations are illustrated by comparing the economic performance of flexible operations against that of constant operations. Sensitivity analysis with respect to market variability and prediction error, are also performed.« less

  10. Economic optimization of operations for hybrid energy systems under variable markets

    SciTech Connect

    Chen, Jen; Garcia, Humberto E.

    2016-05-21

    We prosed a hybrid energy systems (HES) which is an important element to enable increasing penetration of clean energy. Our paper investigates the operations flexibility of HES, and develops a methodology for operations optimization for maximizing economic value based on predicted renewable generation and market information. A multi-environment computational platform for performing such operations optimization is also developed. In order to compensate for prediction error, a control strategy is accordingly designed to operate a standby energy storage element (ESE) to avoid energy imbalance within HES. The proposed operations optimizer allows systematic control of energy conversion for maximal economic value. Simulation results of two specific HES configurations are included to illustrate the proposed methodology and computational capability. These results demonstrate the economic viability of HES under proposed operations optimizer, suggesting the diversion of energy for alternative energy output while participating in the ancillary service market. Economic advantages of such operations optimizer and associated flexible operations are illustrated by comparing the economic performance of flexible operations against that of constant operations. Sensitivity analysis with respect to market variability and prediction error, are also performed.

  11. Tracking the Fate of Surface Plasmon Resonance-Generated Hot Electrons by In Situ SERS Surveying of Catalyzed Reaction.

    PubMed

    Liu, Rui; He, Zuoliang; Sun, Jiefang; Liu, Jingfu; Jiang, Guibin

    2016-12-01

    Plasmonic catalysis is an emerging process that utilizes surface plasmon resonance (SPR) process to harnesses solar energy for the promotion of catalyzed reactions. In most cases, SPR generated hot electrons (HEs) play an indispensable role in this solar-chemical energy shift process. Therefore, understanding the effectiveness of the HEs in promoting chemical reactions, and identifying the key factors that contribute to this utilization efficiency is of profound importance. Herein, the authors outline an in situ surface enhanced Raman spectroscopy protocol to track the fate of HEs. This is based on the unheeded HEs-acceleration nature of the p-nitirothiophenol hydrogenation reaction. By this way, the authors discover that unlike Au@Pd nanostructures which experience a 20-fold increase in rate constant, HEs primary leak to surrounding H(+) /O species through Ag pinholes in Ag@Pd. This work sheds light on why Ag is seldom employed as a plasmonic cocatalyst, and provides a new viewpoint to design plasmonic nanocatalysts with efficient light utilization.

  12. Standardization of physical measurements in European health examination surveys-experiences from the site visits.

    PubMed

    Tolonen, Hanna; Mäki-Opas, Johanna; Mindell, Jennifer S; Trichopoulou, Antonia; Naska, Androniki; Männistö, Satu; Giampaoli, Simona; Kuulasmaa, Kari; Koponen, Päivikki

    2017-01-23

    Health examination surveys (HESs) provide valuable data on health and its determinants at the population level. Comparison of HES results within and between countries and over time requires measurements which are free of bias due to differences in or adherence to measurement procedures and/or measurement devices. In the European HES (EHES) Pilot Project, 12 countries conducted a pilot HES in 2010-11 using standardized measurement protocols and centralized training. External evaluation visits (site visits) were performed by the EHES Reference Centre staff to evaluate the success of standardization and quality of data collection. In general, standardized EHES protocols were followed adequately in all the pilot surveys. Small deviations were observed in the posture of participants during the blood pressure and height measurement; in the use of a tourniquet when drawing blood samples; and in the calibration of measurement devices. Occasionally, problems with disturbing noise from outside or people coming into the room during the measurements were observed. In countries with an ongoing national HES or a long tradition of conducting national HESs at regular intervals, it was more difficult to modify national protocols to fulfil EHES requirements. The EHES protocols to standardize HES measurements and procedures for collection of blood samples are feasible in cross-country settings. The prerequisite for successful standardization is adequate training. External and internal evaluation activities during the survey fieldwork are also needed to monitor compliance to standards. © The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

  13. ROCK Inhibition Enhances the Recovery and Growth of Cryopreserved Human Embryonic Stem Cells and Human Induced Pluripotent Stem Cells

    PubMed Central

    Claassen, David A.; Desler, Michelle M.; Rizzino, Angie

    2012-01-01

    Poor recovery of cryopreserved human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells is a significant impediment to progress with pluripotent stem cells. In this study, we demonstrate that Y-27632, a specific inhibitor of Rho kinase (ROCK) activity, significantly enhances recovery of hES cells from cryopreserved stocks when cultured with or without a growth inactivated feeder layer. Furthermore, treatment with the ROCK inhibitor for several days increased the number of colonies and colony size of hES cells compared to shorter exposures. Remarkably, hES cells that had formed relatively few colonies five days after thawing exhibited rapid growth upon addition of Y-27632. Additionally, we determined that Y-27632 significantly improves the recovery of cryopreserved human iPS cells and their growth upon subculture. Thus, Y-27632 provides a means to “kick-start” slow-growing human pluripotent stem cells, especially after being thawed from frozen stocks. Together, these results argue that Y-27632 is a useful tool in overcoming obstacles to studies involving the cultivation of both hES cells and human iPS cells. PMID:19235204

  14. Nuclear Hybrid Energy Systems Regional Studies: West Texas & Northeastern Arizona

    SciTech Connect

    Garcia, Humberto E.; Chen, Jun; Kim, Jong Suk; McKellar, Michael George; Deason, Wesley R; Richard B. Vilim; Bragg-Sitton, Shannon M.; Boardman, Richard D.

    2015-04-01

    The primary objective of this study is to conduct a preliminary dynamic analysis of two realistic hybrid energy systems (HES) including a nuclear reactor as the main baseload heat generator (denoted as nuclear HES or nuclear hybrid energy systems [[NHES]) and to assess the local (e.g., HES owners) and system (e.g., the electric grid) benefits attainable by the application of NHES in scenarios with multiple commodity production and high penetration of renewable energy. It is performed for regional cases not generic examples based on available resources, existing infrastructure, and markets within the selected regions. This study also briefly addresses the computational capabilities developed to conduct such analyses, reviews technical gaps, and suggests some research paths forward.

  15. Nuclear Hybrid Energy Systems - Regional Studies. West Texas and Northeastern Arizona

    SciTech Connect

    Garcia, Humberto E.; Chen, Jun; Kim, Jong S.; McKellar, Michael G.; Deason, Wesley R.; Vilim, Richard B.; Bragg-Sitton, Shannon M.; Boardman, Richard D.

    2015-04-01

    The primary objective of this study is to conduct a preliminary dynamic analysis of two realistic hybrid energy systems (HES) including a nuclear reactor as the main baseload heat generator (denoted as nuclear HES or nuclear hybrid energy systems [NHES]) and to assess the local (e.g., HES owners) and system (e.g., the electric grid) benefits attainable by the application of NHES in scenarios with multiple commodity production and high penetration of renewable energy. It is performed for regional cases - not generic examples - based on available resources, existing infrastructure, and markets within the selected regions. This study also briefly addresses the computational capabilities developed to conduct such analyses, reviews technical gaps, and suggests some research paths forward.

  16. US hydropower resource assessment for Colorado

    SciTech Connect

    Francfort, J.E.

    1994-05-01

    The US Department of Energy is developing an estimate of the hydropower development potential in this country. Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE, menu-driven software application. HES allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the State of Colorado.

  17. U.S. Hydropower Resource Assessment Final Report

    SciTech Connect

    A. M. Conner; J. E. Francfort; B. N. Rinehart

    1998-12-01

    To provide a more accurate assessment of the domestic undeveloped hydropower capacity, the US Department of Energy's Hydropower Program developed a computer model, Hydropower Evaluation Software (HES). HES allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental, legal, and institutional attributes present, and generate reports based on these suitability factors. This report describes the development of HES, its data requirements, and its application to each state assessment; in addition, it summarizes the data derivation process and data for the states. Modeling of the undeveloped hydropower resources in the US, based on environmental, legal, and institutional constraints, has identified 5,677 sites that have a total undeveloped capacity of about 30,000 megawatts.

  18. U.S. Hydropower Resource Assessment Final Report

    SciTech Connect

    Conner, Alison M.; Francfort, James E.; Rinehart, Ben N.

    1998-12-01

    To provide a more accurate assessment of the domestic undeveloped hydropower capacity, the U.S. Department of Energy’s Hydropower Program developed a computer model, Hydropower Evaluation Software (HES). HES allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental, legal, and institutional attributes present, and generate reports based on these suitability factors. This report describes the development of HES, its data requirements, and its application to each state assessment; in addition, it summarizes the data derivation process and data for the states. Modeling of the undeveloped hydropower resources in the United States, based on environmental, legal, and institutional constraints, has identified 5,677 sites that have a total undeveloped capacity of about 30,000 megawatts.

  19. NEPRO: a novel Notch effector for maintenance of neural progenitor cells in the neocortex.

    PubMed

    Saito, Tetsuichiro

    2012-01-01

    The Notch pathway is essential for maintaining neural progenitor cells (NPCs) in the developing brain. Activation of the pathway is sufficient to maintain NPCs, whereas loss-of-function mutations in the critical components of the pathway cause precocious neuronal differentiation and NPC depletion. Hairy and Enhancer of split (Hes)-type transcription factors have long been thought to be the only Notch effectors for the maintenance of NPCs. Recently, a novel nuclear protein, Nepro, has been identified as another critical effector of Notch. The Notch pathway is bifurcated into Nepro and Hes-type proteins in the early development of the neocortex. The combination of Nepro and Hes-type proteins is necessary and sufficient for maintaining NPCs downstream of Notch.

  20. An Optimization Framework for Dynamic Hybrid Energy Systems

    SciTech Connect

    Wenbo Du; Humberto E Garcia; Christiaan J.J. Paredis

    2014-03-01

    A computational framework for the efficient analysis and optimization of dynamic hybrid energy systems (HES) is developed. A microgrid system with multiple inputs and multiple outputs (MIMO) is modeled using the Modelica language in the Dymola environment. The optimization loop is implemented in MATLAB, with the FMI Toolbox serving as the interface between the computational platforms. Two characteristic optimization problems are selected to demonstrate the methodology and gain insight into the system performance. The first is an unconstrained optimization problem that optimizes the dynamic properties of the battery, reactor and generator to minimize variability in the HES. The second problem takes operating and capital costs into consideration by imposing linear and nonlinear constraints on the design variables. The preliminary optimization results obtained in this study provide an essential step towards the development of a comprehensive framework for designing HES.

  1. [Human embryonic stem cell research in Germany. The scientific reviewing of applications for the import and use of human embryonic stem cells].

    PubMed

    Kiechle, M

    2008-09-01

    From July 2002 to May 2008, 36 applications for the import and use of human embryonic stem cells (hES) were reviewed by the German Central Ethics Committee for Stem Cell Research (ZES). A flood of applications anticipated by opponents to human embryonic stem cell research has not occurred since the enactment of the German Stem Cell Act in 2002. On the contrary, German hES cell research is below international average in terms of project numbers. The current restrictions for using hES cells in Germany might be causative for the opinion that this type of research is not considered to be very promising. This could hold true especially for research aiming at clinical applications. Consequently, potential research goals of premium importance, especially those of potential clinical relevance, could be seriously jeopardized.

  2. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells.

    PubMed

    Kehat, Izhak; Khimovich, Leonid; Caspi, Oren; Gepstein, Amira; Shofti, Rona; Arbel, Gil; Huber, Irit; Satin, Jonathan; Itskovitz-Eldor, Joseph; Gepstein, Lior

    2004-10-01

    Cell therapy is emerging as a promising strategy for myocardial repair. This approach is hampered, however, by the lack of sources for human cardiac tissue and by the absence of direct evidence for functional integration of donor cells into host tissues. Here we investigate whether cells derived from human embryonic stem (hES) cells can restore myocardial electromechanical properties. Cardiomyocyte cell grafts were generated from hES cells in vitro using the embryoid body differentiating system. This tissue formed structural and electromechanical connections with cultured rat cardiomyocytes. In vivo integration was shown in a large-animal model of slow heart rate. The transplanted hES cell-derived cardiomyocytes paced the hearts of swine with complete atrioventricular block, as assessed by detailed three-dimensional electrophysiological mapping and histopathological examination. These results demonstrate the potential of hES-cell cardiomyocytes to act as a rate-responsive biological pacemaker and for future myocardial regeneration strategies.

  3. A Rare Case of Aortic Valve Thrombosis in Patient with Idiopathic Hypereosinophilic Syndrome

    PubMed Central

    Grolla, Elisabetta; Dalla Vestra, Michele; Bonanni, Luca; Cutolo, Ada; Rigo, Fausto

    2015-01-01

    Idiopathic hypereosinophilic syndrome (HES) is characterized by persistent eosinophilia and eosinophil-mediated organ-system damage. Cardiac thrombosis and thromboembolic complications represent common causes of morbidity and mortality and usually involve cardiac ventricles or mitral and prosthetic valves, while the involvement of the aortic valve is extremely rare in HES. Here we report peculiar multimodality images of an atypical case of extended thrombosis of the aortic valve, complicated by myocardial ischemia and asymptomatic cerebral ischemia, likely due to thrombus embolization, occurring in a 48-year-old man with HES. Prompt anticoagulant and steroid therapy lead to rapid and complete resolution of the thrombotic lesions, allowing preserving the native valve and preventing further embolic events. PMID:26435854

  4. Hesperidin and rutin, antioxidant citrus flavonoids, attenuate cisplatin-induced nephrotoxicity in rats.

    PubMed

    Kamel, Kamel M; Abd El-Raouf, Ola M; Metwally, Salwa A; Abd El-Latif, Hekma A; El-sayed, Mostafa E

    2014-07-01

    This study aimed to assess the protective effect of hesperidin (HES) and rutin (RUT) against cisplatin-induced nephrotoxicity in male rats. Cisplatin (5 mg/kg, intraperitoneal) caused significant increases in serum sodium, blood urea nitrogen, serum creatinine, total sodium and potassium excreted in urine, urine volume, and lipid peroxides measured as the malondialdehyde content of kidney, with significant decreases in serum total protein, creatinine clearance, reduced glutathione content of kidney, and kidney superoxide dismutase activity as compared with the control group. On the other hand, administration of HES (200 mg/kg, per oral [p.o.]) or RUT (30 mg/kg, p.o.) for 14 days with a single cisplatin dose on the tenth day ameliorated the cisplatin-induced nephrotoxicity as indicated by the restoration of kidney function and oxidative stress biomarkers. Furthermore, the test drugs reduced the histopathological changes induced by cisplatin. In conclusion, HES and RUT showed protective effects against cisplatin-induced nephrotoxicity.

  5. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.

    PubMed

    D'Amour, Kevin A; Bang, Anne G; Eliazer, Susan; Kelly, Olivia G; Agulnick, Alan D; Smart, Nora G; Moorman, Mark A; Kroon, Evert; Carpenter, Melissa K; Baetge, Emmanuel E

    2006-11-01

    Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

  6. Success of short-term, higher-dose imatinib mesylate to induce clinical response in FIP1L1-PDGFRalpha-negative hypereosinophilic syndrome.

    PubMed

    Butterfield, Joseph H

    2009-08-01

    Presence of the oncogenic mutation FIP1L1-PDGFRalpha in hypereosinophilic patients is predictive of hematologic response to imatinib mesylate. However, most patients with hypereosinophilic syndrome (HES) do not have this mutation and have not responded to imatinib doses traditionally successful in patients who test positive for FIP1L1-PDGFRalpha. A patient with FIP1L1-PDGFRalpha-negative HES who had intolerance of interferon alpha-2b and hydroxyurea was treated with escalating doses of imatinib. At 800 mg of imatinib daily, eosinophilia was controlled, allowing prednisone tapering and control of clinical and laboratory-detected abnormalities. HES patients who test negative for FIP1L1-PDGFRalpha may benefit from a trial of higher-dose imatinib.

  7. Hypereosinophilic syndrome presenting with multiple organ infiltration and deep venous thrombosis

    PubMed Central

    Gao, Su-jun; Wei, Wei; Chen, Jiang-tao; Tan, Ye-hui; Yu, Cheng-bao; Litzow, Mark Robert; Liu, Qiu-ju

    2016-01-01

    Abstract Background: Hypereosinophilic syndrome (HES) can be fatal, particularly when eosinophils infiltrate vital organs and/or if extensive thrombosis develops. However there are no standard recommendations for the use of anticoagulant therapy of HES in the setting of thrombosis. Methods: We herein present a case of a 46-year-old female who presented with marked peripheral eosinophilia with symptoms of multi-organ infiltration and extensive deep venous thrombosis (DVT). In this case, evaluation was carried out before the diagnosis was established, and timely standard-dose corticosteroids combined with a new oral anticoagulant (NOAC) therapy were carried out. Results: These measures resulted in a rapid response and long-term disease control. Conclusion: Although there are no data to support which anticoagulant is preferred in this setting, this case indicates that the new oral anticoagulants may play an important role in the treatment of thrombosis in HES. PMID:27583887

  8. Structural, functional and evolutionary relationships between homing endonucleases and proteins from their host organisms

    PubMed Central

    Taylor, Gregory K.; Stoddard, Barry L.

    2012-01-01

    Homing endonucleases (HEs) are highly specific DNA-cleaving enzymes that are encoded by invasive DNA elements (usually mobile introns or inteins) within the genomes of phage, bacteria, archea, protista and eukaryotic organelles. Six unique structural HE families, that collectively span four distinct nuclease catalytic motifs, have been characterized to date. Members of each family display structural homology and functional relationships to a wide variety of proteins from various organisms. The biological functions of those proteins are highly disparate and include non-specific DNA-degradation enzymes, restriction endonucleases, DNA-repair enzymes, resolvases, intron splicing factors and transcription factors. These relationships suggest that modern day HEs share common ancestors with proteins involved in genome fidelity, maintenance and gene expression. This review summarizes the results of structural studies of HEs and corresponding proteins from host organisms that have illustrated the manner in which these factors are related. PMID:22406833

  9. Ethical issues of the research on human embryonic stem cells.

    PubMed

    Hotta, Yoshitaro

    2008-09-01

    This paper examines the debate on human embryonic stem cell (hES) research. In Japan, as in many Western countries, the moral status of the human embryo has been the main focus. There is a dichotomy between the advocates of research on hES cells and the advocates of the dignity of the embryos. Advocates of research on hES cells claim that the act of abandoning the embryo and the act of using it for research have the same moral status. Critics of research using embryos reject this position, claiming that the embryo has a status incommensurable with other values. This paper points out that the standpoint of the woman providing the embryos has been overlooked in this discussion.

  10. Relative Survival Benefit and Morbidity with Fluids in Severe Sepsis - A Network Meta-Analysis of Alternative Therapies

    PubMed Central

    Bansal, M.; Farrugia, A.; Balboni, S.; Martin, G.

    2013-01-01

    Background: Fluid resuscitation is widely practiced in intensive care units for the treatment of sepsis. A comparison of the evidence base of different fluids may inform therapeutic choice. Methods: The risks of mortality and morbidity (the need for renal replacement therapies (RRT)) were assessed in patients with severe sepsis. A network meta-analysis compared trials for crystalloids, albumin and hydroxyethyl starch (HES). A literature search of human randomized clinical trials was conducted in databases, the bibliographies of other recent relevant systematic reviews and data reported at recent conferences. Mortality outcomes and RRT data with the longest follow up period were compared. A Bayesian network meta-analysis assessed the risk of mortality and a pair-wise meta-analysis assessed RRT using crystalloids as the reference treatment. Results: 13 studies were identified. A fixed-effects meta-analysis of mortality data in the trials demonstrated an odds-ratio (OR) of 0.90 between crystalloids and albumin, 1.25 between crystalloids and HES and 1.40 between albumin and HES. The probability that albumin is associated with the highest survival was 96.4% followed by crystalloid at 3.6%, with a negligible probability for HES. Sub-group analyses demonstrated the robustness of this result to variations in fluid composition, study source and origin of septic shock. A random-effects pairwise comparison for the risk of RRT provided an OR of 1.52 favoring crystalloid over HES. Conclusion: Fluid therapy with albumin was associated with the highest survival benefit. The higher morbidity with HES may affect mortality and requires consideration by prescribers. PMID:23909705

  11. Early fluid resuscitation with hyperoncotic hydroxyethyl starch 200/0.5 (10%) in severe burn injury

    PubMed Central

    2010-01-01

    Introduction Despite large experience in the management of severe burn injury, there are still controversies regarding the best type of fluid resuscitation, especially during the first 24 hours after the trauma. Therefore, our study addressed the question whether hyperoncotic hydroxyethyl starch (HES) 200/0.5 (10%) administered in combination with crystalloids within the first 24 hours after injury is as effective as 'crystalloids only' in severe burn injury patients. Methods 30 consecutive patients were enrolled to this prospective interventional open label study and assigned either to a traditional 'crystalloids only' or to a 'HES 200/0.5 (10%)' volume resuscitation protocol. Total amount of fluid administration, complications such as pulmonary failure, abdominal compartment syndrome, sepsis, renal failure and overall mortality were assessed. Cox proportional hazard regression analysis was performed for binary outcomes and adjustment for potential confounders was done in the multivariate regression models. For continuous outcome parameters multiple linear regression analysis was used. Results Group differences between patients receiving crystalloids only or HES 200/0.5 (10%) were not statistically significant. However, a large effect towards increased overall mortality (adjusted hazard ratio 7.12; P = 0.16) in the HES 200/0.5 (10%) group as compared to the crystalloids only group (43.8% versus 14.3%) was present. Similarly, the incidence of renal failure was 25.0% in the HES 200/0.5 (10%) group versus 7.1% in the crystalloid only group (adjusted hazard ratio 6.16; P = 0.42). Conclusions This small study indicates that the application of hyperoncotic HES 200/0.5 (10%) within the first 24 hours after severe burn injury may be associated with fatal outcome and should therefore be used with caution. Trial registration NCT01120730. PMID:20584291

  12. Effects of crystalloids and colloids on liver and intestine microcirculation and function in cecal ligation and puncture induced septic rodents

    PubMed Central

    2012-01-01

    Background Septic acute liver and intestinal failure is associated with a high mortality. We therefore investigated the influence of volume resuscitation with different crystalloid or colloid solutions on liver and intestine injury and microcirculation in septic rodents. Methods Sepsis was induced by cecal ligation and puncture (CLP) in 77 male rats. Animals were treated with different crystalloids (NaCl 0.9% (NaCl), Ringer’s acetate (RA)) or colloids (Gelafundin 4% (Gel), 6% HES 130/0.4 (HES)). After 24 h animals were re-anesthetized and intestinal (n = 6/group) and liver microcirculation (n = 6/group) were obtained using intravital microscopy, as well as macrohemodynamic parameters were measured. Blood assays and organs were harvested to determine organ function and injury. Results HES improved liver microcirculation, cardiac index and DO2-I, but significantly increased IL-1β, IL-6 and TNF-α levels and resulted in a mortality rate of 33%. Gel infused animals revealed significant reduction of liver and intestine microcirculation with severe side effects on coagulation (significantly increased PTT and INR, decreased haemoglobin and platelet count). Furthermore Gel showed severe hypoglycemia, acidosis and significantly increased ALT and IL-6 with a lethality of 29%. RA exhibited no derangements in liver microcirculation when compared to sham and HES. RA showed no intestinal microcirculation disturbance compared to sham, but significantly improved the number of intestinal capillaries with flow compared to HES. All RA treated animals survided and showed no severe side effects on coagulation, liver, macrohemodynamic or metabolic state. Conclusions Gelatine 4% revealed devastated hepatic and intestinal microcirculation and severe side effects in CLP induced septic rats, whereas the balanced crystalloid solution showed stabilization of macro- and microhemodynamics with improved survival. HES improved liver microcirculation, but exhibited significantly

  13. Low molecular weight pentastarch is more effective than crystalloid solution in goal-directed fluid management in patients undergoing major gastrointestinal surgery.

    PubMed

    Kotake, Yoshifumi; Fukuda, Mitsue; Yamagata, Aya; Iwasaki, Ririko; Toyoda, Daisuke; Sato, Nobukazu; Ochiai, Ryoichi

    2014-04-01

    This prospective observational study compared the volume effect between hydroxyethyl starch (HES) and crystalloid solution and its context dependency in intraoperative goal-directed fluid management. With institutional review board (IRB) approval, 35 patients undergoing major gastrointestinal surgery were enrolled. Fluid challenge consisting of 250 ml of either bicarbonate Ringer solution (BRS) or low molecular weight pentastarch (HES 70/0.5) was given to maintain stroke volume index >35 ml/m2. The context of fluid challenge was classified as related to either epidural block (EB) or blood loss (BL) or as nonspecific. The primary end point was the interval between index fluid challenge and the next fluid challenge, and the secondary end point was the hemodynamic parameter at the end of fluid challenge. Differences in these parameters in each clinical context were compared between BRS and HES 70/0.5. A p value <0.05 was considered statistically significant. Eighty-eight, 77, and 127 fluid challenges were classified as related to EB and BL and as nonspecific, respectively. In the nonspecific condition, the median (range) interval after fluid challenge with HES 70/0.5 and BRS was 45 (11-162) min and 18 (8-44) min, respectively, and the difference was statistically significant. Also, mean arterial pressure and stroke volume index significantly increased, whereas stroke volume variation significantly decreased after fluid challenge with HES 70/0.5 compared with BRS. Such differences were not observed in the other situations. HES 70/0.5 exerted larger volume effects than did crystalloid under nonspecific conditions. However, similar volume effects were observed during volume loss and extensive sympathetic blockade.

  14. Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector

    PubMed Central

    2012-01-01

    Introduction Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of Aβ on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor κB (NF-κB) by impeding the tyrosine phosphorylation of I-κBα. As a result, the expression of the homologue of Enhancer-of split 1 (Hes1) gene is downregulated and ultimately, gamma-aminobutyric acid (GABA)-ergic connectivity is lost. Methods Hes1 activity was promoted in cultured hippocampal neurons by overexpressing a Hes1-encoding plasmid or by upregulating this gene by activating NF-κB through different approaches (overexpressing either the I-κB kinaseβ, or p65/RelA/NF-κB). Alternatively neurons were exposed to TGFβ1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-κB activation was measured using the dual-luciferase reporter assay. Results The expression of Hes1 abolished the effects of Aβ on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGFβ1, a known neuroprotector, could counteract the deleterious effects of Aβ by inducing NF-κB activation following the serine phosphorylation of I-κBα. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. Conclusion Our data define some of the mechanisms involved in Aβ-mediated cell death and they point to potential means to counteract this noxious activity. PMID:22849569

  15. Coding of Barrett's oesophagus with high-grade dysplasia in national administrative databases: a population-based cohort study.

    PubMed

    Chadwick, Georgina; Varagunam, Mira; Brand, Christian; Riley, Stuart A; Maynard, Nick; Crosby, Tom; Michalowski, Julie; Cromwell, David A

    2017-06-09

    The International Classification of Diseases 10th Revision (ICD-10) system used in the English hospital administrative database (Hospital Episode Statistics (HES)) does not contain a specific code for oesophageal high-grade dysplasia (HGD). The aim of this paper was to examine how patients with HGD were coded in HES and whether it was done consistently. National population-based cohort study of patients with newly diagnosed with HGD in England. The study used data collected prospectively as part of the National Oesophago-Gastric Cancer Audit (NOGCA). These records were linked to HES to investigate the pattern of ICD-10 codes recorded for these patients at the time of diagnosis. All patients with a new diagnosis of HGD between 1 April 2013 and 31 March 2014 in England, who had data submitted to the NOGCA. The main outcome assessed was the pattern of primary and secondary ICD-10 diagnostic codes recorded in the HES records at endoscopy at the time of diagnosis of HGD. Among 452 patients with a new diagnosis of HGD between 1 April 2013 and 31 March 2014, Barrett's oesophagus was the only condition coded in 200 (44.2%) HES records. Records for 59 patients (13.1%) contained no oesophageal conditions. The remaining 193 patients had various diagnostic codes recorded, 93 included a diagnosis of Barrett's oesophagus and 57 included a diagnosis of oesophageal/gastric cardia cancer. HES is not suitable to support national studies looking at the management of HGD. This is one reason for the UK to adopt an extended ICD system (akin to ICD-10-CM). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  16. Evaluation of intravenous hydroxylethyl starch, intravenous albumin 20%, and oral cabergoline for prevention of ovarian hyperstimulation syndrome in patients undergoing ovulation induction

    PubMed Central

    Ghahiri, Ataollah; Mogharehabed, Neda; Movahedi, Minoo; Hosseini, Naeimehossadat

    2015-01-01

    Background: The purpose of this study was to compare the three different strategies, intravenous (IV) hydroxylethyl starch (HES), IV human albumin (HA), and oral Cabergoline (Cb) in the prevention of ovarian hyperstimulation syndrome (OHSS). Materials and Methods: In this prospective randomized clinical trial, 91 women at high risk of developing OHSS were allocated into the three groups, group one received 2 vial (2 × 50 ml) IV HAs, in group two, 1000 ml of 6% HES was administered IV, both groups 30 min after oocyte retrieval within 4 h. Group three, 31 infertile patients received oral Cb 0.5 mg daily for 7 days after oocyte retrieval. Patients were visited 14 ± 1 days after in-vitro fertilization and if β-human chorionic gonadotropin level >10, transvaginal ultrasonography was performed 2 weeks later to confirm intrauterine pregnancy. Patients were followed up weekly for 3 months for signs of OHSS and were also informed about the signs of OHSS and asked to contact immediately if any symptoms of were detected. Results: None of the participants in group HES developed severe OHSS and only 3 patients (10%) developed mild to moderate OHSS. The incident of severe OHSS was significantly higher in albumin group compared to Cb and HES group (P = 0.033 and P < 0.001, respectively). Also, the probability of developing severe OHSS was higher in Cb group than group HES (P = 0.031). Conclusion: The findings from this study suggest that administration of 1000 ml of HES 6% has a higher prophylactic effect compared to administration of IV HA and oral Cb. PMID:26622260

  17. Impact of caregivers' education regarding respiratory infections on the health status of day-care children: a randomized trial.

    PubMed

    Alexandrino, Ana S; Santos, Rita; Melo, Cristina; Bastos, José M

    2016-10-01

    Acute respiratory infections are the most common illness in childhood, and caregivers often make an excessive use of medication and medical consultations. It is vital to design and implement educational interventions in order to minimize the burden of the disease. This study aimed to evaluate the impact of a health education session (HES) about respiratory infections on the indicators of individual health and health care utilization of day-care children. Randomized controlled trial in 10 day-care centres in Porto, including caregivers (parents or legal tutors) of children under 3 years of age. Children's caregivers were randomly distributed into an Intervention Group (IG), who attended a HES, and a Comparison Group (CG). Children's indicators of individual health and health care utilization were evaluated in both groups, during the month after HES. Children whose caregivers attended to the HES had fewer lower respiratory tract infections (IG = 5.8%; CG = 19.0%; P = 0.050) and fewer acute otitis media (IG = 9.5%; CG = 27.0%; P = 0.030), as well as fewer medical consultations (IG = 38.5% versus CG = 61.9%; P = 0.015) and less antibiotic consumption (IG = 11.5% versus CG = 29.5%; P = 0.022). They were also less absent from day care (IG = 21 days versus CG = 59 days; P = 0.037) and their caregivers were less absent from work (IG = 15 days versus CG = 44 days; P = 0.046). Caregivers who attended HES made more use of nasal irrigation (IG = 79.6% versus CG = 53.3%; P = 0.011). The HES about respiratory infections has positively influenced the indicators of individual health and health care utilization of children attending day-care centres in Porto. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Nutrition as a component of the performance triad: how healthy eating behaviors contribute to soldier performance and military readiness.

    PubMed

    Purvis, Dianna L; Lentino, Cynthia V; Jackson, Theresa K; Murphy, Kaitlin J; Deuster, Patricia A

    2013-01-01

    Nutrition is a critical element of Soldier health and performance. Food choices, meal timing, and dietary intake behaviors contribute to nutritional fitness. The objectives of this study were to describe Soldier dietary behaviors and quantify the association between healthy eating behaviors and demographic, lifestyle, and psychosocial factors. The Comprehensive Soldier and Family Fitness Global Assessment Tool (GAT) assesses emotional, social, family, and spiritual fitness. In 2012, 57 pilot questions were added to the GAT to create a physical dimension that included nutrition assessments. Participants included 13,858 Active Duty, Reserve, and National Guard Soldiers: 83% male; 85% enlisted; a mean age of 28±9 years. A Healthy Eating Score (HES-5) was calculated from 5 questions assessing frequency of fruit, vegetable, whole grain, dairy, and fish intake (Cronbach α=0.81). Associations between HES-5 and other dietary habits, physical activity patterns, and GAT psychosocial dimension scores were examined. Soldiers who ate breakfast regularly (6 times/week or more), drank 7 servings or more of water/day, and met weekly exercise recommendations were more likely to be in the highest HES-5 quartile than those who did not. Those who passed their Army Physical Fitness Test (APFT) in the top quartile were also more likely to report high HES-5 scores than those who failed (P<.001). Soldiers with healthy anthropometric measures and the highest emotional, social, family, and spiritual fitness scores were also more likely to be in the top HES-5 quartile than those with unhealthy measures and with the lowest fitness scores (P<.001). The HES-5 may be a useful index for characterizing dietary intake behaviors. Healthy dietary intake behaviors are associated with all dimensions of health, physical fitness, and psychosocial status.

  19. Evidence Linking Hypoglycemic Events to an Increased Risk of Acute Cardiovascular Events in Patients With Type 2 Diabetes

    PubMed Central

    Johnston, Stephen S.; Conner, Christopher; Aagren, Mark; Smith, David M.; Bouchard, Jonathan; Brett, Jason

    2011-01-01

    OBJECTIVE This retrospective study examined the association between ICD-9-CM–coded outpatient hypoglycemic events (HEs) and acute cardiovascular events (ACVEs), i.e., acute myocardial infarction, coronary artery bypass grafting, revascularization, percutaneous coronary intervention, and incident unstable angina, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Data were derived from healthcare claims for individuals with employer-sponsored primary or Medicare supplemental insurance. A baseline period (30 September 2006 to 30 September 2007) was used to identify eligible patients and collect information on their clinical and demographic characteristics. An evaluation period (1 October 2007 to 30 September 2008) was used to identify HEs and ACVEs. Patients aged ≥18 years with type 2 diabetes were selected for analysis by a modified Healthcare Effectiveness Data and Information Set algorithm. Data were analyzed with multiple logistic regression and backward stepwise selection (maximum P = 0.01) with adjustment for important confounding variables, including age, sex, geography, insurance type, comorbidity scores, cardiovascular risk factors, diabetes complications, total baseline medical expenditures, and prior ACVEs. RESULTS Of the 860,845 patients in the analysis set, 27,065 (3.1%) had ICD-9-CM–coded HEs during the evaluation period. The main model retained 17 significant independent variables. Patients with HEs had 79% higher regression-adjusted odds (HE odds ratio [OR] 1.79; 95% CI 1.69–1.89) of ACVEs than patients without HEs; results in patients aged ≥65 years were similar to those for the entire population (HE OR 1.78, 95% CI 1.65–1.92). CONCLUSIONS ICD-9-CM–coded HEs were independently associated with an increased risk of ACVEs. Further studies of the relationship between hypoglycemia and the risk of ACVEs are warranted. PMID:21421802

  20. Validating the use of Hospital Episode Statistics data and comparison of costing methodologies for economic evaluation: an end-of-life case study from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP)

    PubMed Central

    Thorn, Joanna C; Turner, Emma L; Hounsome, Luke; Walsh, Eleanor; Down, Liz; Verne, Julia; Donovan, Jenny L; Neal, David E; Hamdy, Freddie C; Martin, Richard M; Noble, Sian M

    2016-01-01

    Objectives To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies. Design Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes. Setting 7 UK secondary care centres. Population A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. Results Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months. Conclusions Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials. Trial registration number ISRCTN92187251

  1. Modeling the Zebrafish Segmentation Clock’s Gene Regulatory Network Constrained by Expression Data Suggests Evolutionary Transitions Between Oscillating and Nonoscillating Transcription

    PubMed Central

    Schwendinger-Schreck, Jamie; Kang, Yuan; Holley, Scott A.

    2014-01-01

    During segmentation of vertebrate embryos, somites form in accordance with a periodic pattern established by the segmentation clock. In the zebrafish (Danio rerio), the segmentation clock includes six hairy/enhancer of split-related (her/hes) genes, five of which oscillate due to negative autofeedback. The nonoscillating gene hes6 forms the hub of a network of 10 Her/Hes protein dimers, which includes 7 DNA-binding dimers and 4 weak or non-DNA-binding dimers. The balance of dimer species is critical for segmentation clock function, and loss-of-function studies suggest that the her genes have both unique and redundant functions within the clock. However, the precise regulatory interactions underlying the negative feedback loop are unknown. Here, we combine quantitative experimental data, in silico modeling, and a global optimization algorithm to identify a gene regulatory network (GRN) designed to fit measured transcriptional responses to gene knockdown. Surprisingly, we find that hes6, the clock gene that does not oscillate, responds to negative feedback. Consistent with prior in silico analyses, we find that variation in transcription, translation, and degradation rates can mediate the gain and loss of oscillatory behavior for genes regulated by negative feedback. Extending our study, we found that transcription of the nonoscillating Fgf pathway gene sef responds to her/hes perturbation similarly to oscillating her genes. These observations suggest a more extensive underlying regulatory similarity between the zebrafish segmentation clock and the mouse and chick segmentation clocks, which exhibit oscillations of her/hes genes as well as numerous other Notch, Fgf, and Wnt pathway genes. PMID:24663100

  2. Human embryonic stem cells form functional thyroid follicles.

    PubMed

    Ma, Risheng; Latif, Rauf; Davies, Terry F

    2015-04-01

    The molecular events that lead to human thyroid cell speciation remain incompletely characterized. It has been shown that overexpression of the regulatory transcription factors Pax8 and Nkx2-1 (ttf-1) directs murine embryonic stem (mES) cells to differentiate into thyroid follicular cells by initiating a transcriptional regulatory network. Such cells subsequently organized into three-dimensional follicular structures in the presence of extracellular matrix. In the current study, human embryonic stem (hES) cells were studied with the aim of recapitulating this scenario and producing functional human thyroid cell lines. Reporter gene tagged pEZ-lentiviral vectors were used to express human PAX8-eGFP and NKX2-1-mCherry in the H9 hES cell line followed by differentiation into thyroid cells directed by Activin A and thyrotropin (TSH). Both transcription factors were expressed efficiently in hES cells expressing either PAX8, NKX2-1, or in combination in the hES cells, which had low endogenous expression of these transcription factors. Further differentiation of the double transfected cells showed the expression of thyroid-specific genes, including thyroglobulin (TG), thyroid peroxidase (TPO), the sodium/iodide symporter (NIS), and the TSH receptor (TSHR) as assessed by reverse transcription polymerase chain reaction and immunostaining. Most notably, the Activin/TSH-induced differentiation approach resulted in thyroid follicle formation and abundant TG protein expression within the follicular lumens. On stimulation with TSH, these hES-derived follicles were also capable of dose-dependent cAMP generation and radioiodine uptake, indicating functional thyroid epithelial cells. The induced expression of PAX8 and NKX2-1 in hES cells was followed by differentiation into thyroid epithelial cells and their commitment to form functional three-dimensional neo-follicular structures. The data provide proof of principal that hES cells can be committed to thyroid cell speciation under

  3. From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

    PubMed Central

    Tiedemann, Hendrik B.; Schneltzer, Elida; Zeiser, Stefan; Hoesel, Bastian; Beckers, Johannes; Przemeck, Gerhard K. H.; de Angelis, Martin Hrabě

    2012-01-01

    The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice. PMID:22761566

  4. Hemospan improves outcome in a model of perioperative hemodilution and blood loss in the rat: comparison with hydroxyethyl starch.

    PubMed

    Young, Mark A; Lohman, Jeff; Malavalli, Ashok; Vandegriff, Kim D; Winslow, Robert M

    2009-06-01

    Hemospan (Sangart Inc, San Diego, CA) (MP4) is a hemoglobin-based oxygen carrier consisting of human hemoglobin modified with polyethylene glycol. This study evaluated the effects of MP4 on blood volume, hemodynamics, and metabolic stability in a rat model of hemodilution and hemorrhage. MP4 was compared with hydroxyethyl starch solutions of differing concentrations (ie, HES 260/0.45 and HES 130/0.4). An open-label, randomized comparison of treatments. Pharmaceutical industry. Sprague Dawley rats. Rats underwent 50% hemodilution with one of the solutions. Control rats were not hemodiluted. Blood volume was determined at baseline and 0, 60, and 120 minutes after exchange. In separate groups, hemodilution and subsequent 60% hemorrhage were examined to determine effectiveness of hemodilution. Endpoints were blood volume after hemodilution and survival, hemodynamics, and acid-base status during hemorrhage. Volume expansion was similar with MP4 (159% of infused volume) and HES 260/0.45 (145%) and less with HES 130/0.4 (104%). The duration of expansion was longest with MP4 (1-2 hours). In the hemorrhage studies, 2-hour survival was 90% with MP4, 50% with controls, and 10% and 0% with HES 260/0.45 and HES 130/0.4, respectively. The severity of hemodynamic and acid-base changes paralleled the survival, with the least disturbance observed in MP4-treated animals. Hemodilution with MP4 was more effective in maintaining hemodynamic and metabolic stability than starch solutions or no hemodilution before simulated intraoperative hemorrhage. The benefit of MP4 is not ascribed solely to volume expansion. The results suggest that perioperative administration of MP4 may improve outcomes in surgical settings.

  5. Crystalloid or colloid for goal-directed fluid therapy in colorectal surgery.

    PubMed

    Yates, D R A; Davies, S J; Milner, H E; Wilson, R J T

    2014-02-01

    Goal-directed fluid therapy has been shown to improve outcomes after colorectal surgery, but the optimal type of i.v. fluid to use is yet to be established. Theoretical advantages of using hydroxyethyl starch (HES) for goal-directed therapy include a reduction in the total volume of fluid required, resulting in less tissue oedema. Recent work has demonstrated that new generations of HES have a good safety profile, but their routine use in the perioperative setting has not been demonstrated to confer outcome benefit. We randomly assigned 202 medium to high-risk patients undergoing elective colorectal surgery to receive either balanced 6% HES (130/0.4, Volulyte) or balanced crystalloid (Hartmann's solution) as haemodynamic optimization fluid. The primary outcome measure was the incidence of gastrointestinal (GI) morbidity on postoperative day 5. Secondary outcome measures included the incidence of postoperative complications, hospital length of stay, and the effect of trial fluids on coagulation and inflammation. No difference was seen in the number of patients who suffered GI morbidity on postoperative day 5 [30% in the HES group vs 32% in the crystalloid group; adjusted odds ratio=0.96 (0.52-1.77)]. Subjects in the crystalloid group received more fluid [median (inter-quartile ranges) 3175 (2000-3700) vs 1875 (1500-3000) ml, P<0.001] and had a higher 24 h fluid balance [+4226 (3251-5779) vs +3610 (2443-4519) ml, P<0.001]. No difference in the incidence of postoperative complications was seen between the groups. Goal-directed fluid therapy is possible with either crystalloid or HES. There is no evidence of a benefit in using HES over crystalloid, despite its use resulting in a lower 24 h fluid balance.

  6. Hyperbranched polyglycerol as a colloid in cold organ preservation solutions.

    PubMed

    Gao, Sihai; Guan, Qiunong; Chafeeva, Irina; Brooks, Donald E; Nguan, Christopher Y C; Kizhakkedathu, Jayachandran N; Du, Caigan

    2015-01-01

    Hydroxyethyl starch (HES) is a common colloid in organ preservation solutions, such as in University of Wisconsin (UW) solution, for preventing graft interstitial edema and cell swelling during cold preservation of donor organs. However, HES has undesirable characteristics, such as high viscosity, causing kidney injury and aggregation of erythrocytes. Hyperbranched polyglycerol (HPG) is a branched compact polymer that has low intrinsic viscosity. This study investigated HPG (MW-0.5 to 119 kDa) as a potential alternative to HES for cold organ preservation. HPG was synthesized by ring-opening multibranching polymerization of glycidol. Both rat myocardiocytes and human endothelial cells were used as an in vitro model, and heart transplantation in mice as an in vivo model. Tissue damage or cell death was determined by both biochemical and histological analysis. HPG polymers were more compact with relatively low polydispersity index than HES in UW solution. Cold preservation of mouse hearts ex vivo in HPG solutions reduced organ damage in comparison to those in HES-based UW solution. Both size and concentration of HPGs contributed to the protection of the donor organs; 1 kDa HPG at 3 wt% solution was superior to HES-based UW solution and other HPGs. Heart transplants preserved with HPG solution (1 kDa, 3%) as compared with those with UW solution had a better functional recovery, less tissue injury and neutrophil infiltration in syngeneic recipients, and survived longer in allogeneic recipients. In cultured myocardiocytes or endothelial cells, significantly more cells survived after cold preservation with the HPG solution than those with the UW solution, which was positively correlated with the maintenance of intracellular adenosine triphosphate and cell membrane fluidity. In conclusion, HPG solution significantly enhanced the protection of hearts or cells during cold storage, suggesting that HPG is a promising colloid for the cold storage of donor organs and cells in

  7. Hyperbranched Polyglycerol as a Colloid in Cold Organ Preservation Solutions

    PubMed Central

    Gao, Sihai; Guan, Qiunong; Chafeeva, Irina; Brooks, Donald E.; Nguan, Christopher Y. C.; Kizhakkedathu, Jayachandran N.; Du, Caigan

    2015-01-01

    Hydroxyethyl starch (HES) is a common colloid in organ preservation solutions, such as in University of Wisconsin (UW) solution, for preventing graft interstitial edema and cell swelling during cold preservation of donor organs. However, HES has undesirable characteristics, such as high viscosity, causing kidney injury and aggregation of erythrocytes. Hyperbranched polyglycerol (HPG) is a branched compact polymer that has low intrinsic viscosity. This study investigated HPG (MW-0.5 to 119 kDa) as a potential alternative to HES for cold organ preservation. HPG was synthesized by ring-opening multibranching polymerization of glycidol. Both rat myocardiocytes and human endothelial cells were used as an in vitro model, and heart transplantation in mice as an in vivo model. Tissue damage or cell death was determined by both biochemical and histological analysis. HPG polymers were more compact with relatively low polydispersity index than HES in UW solution. Cold preservation of mouse hearts ex vivo in HPG solutions reduced organ damage in comparison to those in HES-based UW solution. Both size and concentration of HPGs contributed to the protection of the donor organs; 1 kDa HPG at 3 wt% solution was superior to HES-based UW solution and other HPGs. Heart transplants preserved with HPG solution (1 kDa, 3%) as compared with those with UW solution had a better functional recovery, less tissue injury and neutrophil infiltration in syngeneic recipients, and survived longer in allogeneic recipients. In cultured myocardiocytes or endothelial cells, significantly more cells survived after cold preservation with the HPG solution than those with the UW solution, which was positively correlated with the maintenance of intracellular adenosine triphosphate and cell membrane fluidity. In conclusion, HPG solution significantly enhanced the protection of hearts or cells during cold storage, suggesting that HPG is a promising colloid for the cold storage of donor organs and cells in

  8. Designing and evaluating a health education session on respiratory infections addressed to caregivers of children under three years of age attending day-care centres in Porto, Portugal: A community-based intervention.

    PubMed

    Alexandrino, Ana Manuela Ferreira da Silva; Santos, Rita Isabel Garrido Vieira Dos; Melo, Maria Cristina Damas Argel de; Bastos, José Adelino Mesquita

    2017-12-01

    Acute respiratory infections (ARI) are common in children, increasing the pressure on clinicians to prescribe antibiotics and affecting public health Objectives: This study aimed to design a health education session (HES) for caregivers of children, and to evaluate its effects on caregivers' needs, as well as on their knowledge and attitudes concerning ARI. A generalized model of developing, implementing and evaluating a community-based intervention was followed, including caregivers of children under three years of age. Caregivers were randomly distributed into an intervention group (IG) (n = 41) and a control group (CG) (n = 51) and the HES was administered to the IG. The caregivers' needs as well as knowledge of and attitudes to ARI were evaluated in both groups, before (M0) and two months after the HES (M1). At M0 the caregivers from both groups had 'some or great need' about all HES domains; at M1 the caregivers in the IG expressed 'no or low need', whereas the CG maintained 'some or great need' about all HES domains (0.011 ≤ P ≤ .047). Concerning caregivers' knowledge of and attitudes to ARI, at M1 there was a higher frequency of caregivers with right answers in the IG than in the CG (IG =7.5 ± 1 versus CG =6.0 ± 2; P = .000). Those differences occurred in domain (e) nasal clearance techniques, revealing a higher percentage of caregivers who used correctly nasal irrigation (P = .000), nasal aspirators (0.000 ≤P ≤ .001) and nebulization (P = .000) in IG. The HES met the caregivers' needs regarding ARI and increased their knowledge and attitudes towards ARI, especially regarding nasal clearance techniques.

  9. Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer's lactate on blood loss and coagulation after cardiac surgery.

    PubMed

    Skhirtladze, K; Base, E M; Lassnigg, A; Kaider, A; Linke, S; Dworschak, M; Hiesmayr, M J

    2014-02-01

    Infusion of 5% human albumin (HA) and 6% hydroxyethyl starch 130/0.4 (HES) during cardiac surgery expand circulating volume to a greater extent than crystalloids and would be suitable for a restrictive fluid therapy regimen. However, HA and HES may affect blood coagulation and could contribute to increased transfusion requirements. We randomly assigned 240 patients undergoing elective cardiac surgery to receive up to 50 ml kg(-1) day(-1) of either HA, HES, or Ringer's lactate (RL) as the main infusion fluid perioperatively. Study solutions were supplied in identical bottles dressed in opaque covers. The primary outcome was chest tube drainage over 24 h. Blood transfusions, thromboelastometry variables, perioperative fluid balance, renal function, mortality, intensive care unit, and hospital stay were also assessed. The median cumulative blood loss was not different between the groups (HA: 835, HES: 700, and RL: 670 ml). However, 35% of RL patients required blood products, compared with 62% (HA) and 64% (HES group; P=0.0003). Significantly, more study solution had to be administered in the RL group compared with the colloid groups. Total perioperative fluid balance was least positive in the HA group [6.2 (2.5) litre] compared with the HES [7.4 (3.0) litre] and RL [8.3 (2.8) litre] groups (P<0.0001). Both colloids affected clot formation and clot strength and caused slight increases in serum creatinine. Despite equal blood loss from chest drains, both colloids interfered with blood coagulation and produced greater haemodilution, which was associated with more transfusion of blood products compared with crystalloid use only.

  10. Molar substitution and C2/C6 ratio of hydroxyethyl starch: influence on blood coagulation.

    PubMed

    von Roten, I; Madjdpour, C; Frascarolo, P; Burmeister, M-A; Fisch, A; Schramm, S; Bombeli, T; Spahn, D R

    2006-04-01

    Development of hydroxyethyl starches (HES) with a low impact on blood coagulation but a long intravascular persistence is of clinical interest. A previous in vitro study showed that low substituted high molecular weight HES does not compromise blood coagulation more than medium molecular weight HES. In the present study we assessed the individual effects on blood coagulation of molar substitution and C2/C6 ratio of a high molecular weight HES. Blood was obtained from 30 healthy patients undergoing elective surgery and mixed with six high molecular weight (700 kDa) HES solutions differing in their molar substitution (0.42 and 0.51) and C2/C6 ratio (2.7, 7 and 14) to achieve 20, 40 and 60% dilution. Blood coagulation was assessed by Thrombelastograph analysis (TEG) and plasma coagulation tests. Data were compared using a three-way analysis of variance model with repeated measures on the three factors. Higher molar substitution compromised blood coagulation most (for all TEG parameters, P<0.05). The lowest C2/C6 ratio was associated with the lowest effect on blood coagulation; r (P<0.001), angle alpha (P=0.003) and coagulation index (P<0.001). No effect on k and maximum amplitude was observed (P for both >0.50). The higher molar substitution was associated with a lesser increase in PT (P=0.007) and a greater decrease in factor VIII (P=0.010). PTT, functional and antigenic von Willebrand factors were not significantly influenced by molar substitution (P for all >0.20). No significant differences between solutions with the same molar substitution but different C2/C6 ratios were found in plasma coagulation parameters (P for all >0.05). TEG analysis indicates that high molecular HES with a molar substitution of 0.42 and a C2/C6 ratio of 2.7 has the lowest effect on in vitro human blood coagulation.

  11. Marked and persistent eosinophilia in the absence of clinical manifestations

    PubMed Central

    Chen, Yun-Yun K.; Khoury, Paneez; Ware, JeanAnne M.; Holland-Thomas, Nicole C.; Stoddard, Jennifer L.; Gurprasad, Shakuntala; Waldner, Amy J.; Klion, Amy D.

    2013-01-01

    Background Although most patients with hypereosinophilic syndromes (HES) present with clinical signs and symptoms attributable to eosinophilic tissue infiltration, some untreated patients remain asymptomatic or have signs and symptoms, such as allergic rhinitis, for which the relationship to peripheral eosinophilia is unclear (hypereosinophilia of unknown significance [HEUS]). Objective To identify and characterize subjects with HEUS of 5 years duration or more as compared to untreated patients with symptomatic HES and healthy normal volunteers. Methods All subjects with eosinophilia underwent yearly evaluation, including a standardized clinical evaluation, whole blood flow cytometry to assess lymphocyte subsets and eosinophil activation, and serum collection. Peripheral blood mononuclear cells were cultured overnight with and without phorbol 12-myristate 13-acetate/ionomycin. Cytokines and chemokines were measured in serum and cell supernatants, and mRNA expression was assessed by using quantitative real-time PCR. Results Eight of the 210 subjects referred for the evaluation of eosinophilia (absolute eosinophil count [AEC] > 1500/µL) met the criteria for HEUS of 5 years duration or more (range, 7–29 years). Peak eosinophil count and surface expression of eosinophil activation markers were similar in subjects with HEUS and in untreated subjects with platelet-derived growth factor alpha–negative HES (n = 28). Aberrant or clonal T-cell populations were identified in 50% of the subjects with HEUS as compared to 29% of the subjects with HES (P = .12). Increased levels of IL-5, GM-CSF, IL-9, and IL-17A were also comparable in subjects with HEUS and HES. Serum levels of IgE and IL-13 were significantly increased only in subjects with HES. Conclusions A small number of patients with persistent peripheral eosinophilia (AEC > 1500/µL) appear to have clinically benign disease. PMID:23987798

  12. Marked and persistent eosinophilia in the absence of clinical manifestations.

    PubMed

    Chen, Yun-Yun K; Khoury, Paneez; Ware, JeanAnne M; Holland-Thomas, Nicole C; Stoddard, Jennifer L; Gurprasad, Shakuntala; Waldner, Amy J; Klion, Amy D

    2014-04-01

    Although most patients with hypereosinophilic syndromes (HES) present with clinical signs and symptoms attributable to eosinophilic tissue infiltration, some untreated patients remain asymptomatic or have signs and symptoms, such as allergic rhinitis, for which the relationship to peripheral eosinophilia is unclear (hypereosinophilia of unknown significance [HEUS]). To identify and characterize subjects with HEUS of 5 years duration or more as compared to untreated patients with symptomatic HES and healthy normal volunteers. All subjects with eosinophilia underwent yearly evaluation, including a standardized clinical evaluation, whole blood flow cytometry to assess lymphocyte subsets and eosinophil activation, and serum collection. Peripheral blood mononuclear cells were cultured overnight with and without phorbol 12-myristate 13-acetate/ionomycin. Cytokines and chemokines were measured in serum and cell supernatants, and mRNA expression was assessed by using quantitative real-time PCR. Eight of the 210 subjects referred for the evaluation of eosinophilia (absolute eosinophil count [AEC] > 1500/μL) met the criteria for HEUS of 5 years duration or more (range, 7-29 years). Peak eosinophil count and surface expression of eosinophil activation markers were similar in subjects with HEUS and in untreated subjects with platelet-derived growth factor alpha-negative HES (n = 28). Aberrant or clonal T-cell populations were identified in 50% of the subjects with HEUS as compared to 29% of the subjects with HES (P = .12). Increased levels of IL-5, GM-CSF, IL-9, and IL-17A were also comparable in subjects with HEUS and HES. Serum levels of IgE and IL-13 were significantly increased only in subjects with HES. A small number of patients with persistent peripheral eosinophilia (AEC > 1500/μL) appear to have clinically benign disease. Published by Mosby, Inc.

  13. The Implementation of an Integrated Information System for Substance Use Screening in General Medical Settings

    PubMed Central

    Sorensen-Alawad, A.; Carney, B.L.; Persand, I.; Cruz, A.; Botticelli, M.; Pressman, K.; Adams, W.G.; Brolin, M.; Alford, D.P.

    2014-01-01

    Summary The Massachusetts Screening, Brief Intervention and Referral to Treatment (MASBIRT) Program, a substance use screening program in general medical settings, created a web-based, point-of-care (POC), application – the MASBIRT Portal (the “Portal”) to meet program goals. Objectives We report on development and implementation of the Portal. Methods Five year program process outcomes recorded by an independent evaluator and an anonymous survey of Health Educator’s (HEs) adoption, perceptions and Portal use with a modified version of the Technology Readiness Index are described. [8] Specific management team members, selected based on their roles in program leadership, development and implementation of the Portal and supervision of HEs, participated in semi-structured, qualitative interviews. Results At the conclusion of the program 73% (24/33) of the HEs completed a survey on their experience using the Portal. HEs reported that the Portal made recording screening information easy (96%); improved planning their workday (83%); facilitated POC data collection (84%); decreased time dedicated to data entry (100%); and improved job satisfaction (59%). The top two barriers to use were “no or limited wireless connectivity” (46%) and “the tablet was too heavy/bulky to carry” (29%). Qualitative management team interviews identified strategies for successful HIT implementation: importance of engaging HEs in outlining specifications and workflow needs, collaborative testing prior to implementation and clear agreement on data collection purpose, quality requirements and staff roles. Discussion Overall, HEs perceived the Portal favorably with regard to time saving ability and improved workflow. Lessons learned included identifying core requirements early during system development and need for managers to institute and enforce consistent behavioral work norms. Conclusion Barriers and HEs’ views of technology impacted the utilization of the MASBIRT Portal

  14. The brain relaxation and cerebral metabolism in stroke volume variation-directed fluid therapy during supratentorial tumors resection: crystalloid solution versus colloid solution.

    PubMed

    Xia, Juan; He, Zhiyong; Cao, Xiaoying; Che, Xuehua; Chen, Liang; Zhang, Jun; Liang, Weimin

    2014-10-01

    Compared with goal-directed crystalloid therapy, goal-directed colloid therapy during high-risk surgery may improve postoperative outcome. Whether intraoperative fluid therapy based on goal-directed protocol with different types of fluid has distinctive effects on brain relaxation and cerebral metabolism during craniotomy remains unclear. Forty patients with supratentorial brain tumors undergoing craniotomy were randomly assigned to either a Ringer's Lactate-based goal-directed group (LR group, n=20) or a 6% hydroxyethyl starch-based goal-directed group (HES group, n=20). The goal was achieved by maintaining a target stroke volume variation (SVV<13%) by volume loading with LR or HES throughout the procedure. The primary outcome is brain relaxation scales, an indirect evaluation of ICP; secondary endpoints include cerebral metabolism variables (jugular venous oxygen saturation [SjvO(2)], arterial-jugular venous differences in oxygen [CajvO(2)], glucose [A-JvGD], lactate [A-JvLD], and cerebral extraction ratio for oxygen [CERO(2)]) and fluid volumes. There is no significant difference between the LR and HES groups on brain relaxation scales (P=0.845), or measures of cerebral oxygenation and metabolism. Intragroup comparisons showed that CERO(2) increased by 14.3% (P=0.009, LR group) and 13.2% (P=0.032, HES group), respectively, and SjvO(2) was decreased by 8.8% (P=0.016, LR group) and 8.1% (P=0.026, HES group), respectively, after tumor removal, compared with baseline. During surgery, the LR group (3070±1138 mL) received more fluid than the HES group (2041±758 mL, P=0.002). In patients undergoing supratentorial tumor resection, goal-directed HES therapy was not superior to goal-directed LR therapy for brain relaxation or cerebral metabolism, although less fluid was needed to maintain the target SVV in the HES-based group than in the LR-based group.

  15. Does small-volume resuscitation with crystalloids or colloids influence hemostasis and survival of rabbits subjected to lethal uncontrolled hemorrhage?

    PubMed

    Kheirabadi, Bijan Shams; Miranda, Nahir; Terrazas, Irasema B; Gonzales, Mary D; Grimm, Rose C; Dubick, Michael A

    2017-01-01

    Prehospital, small-volume resuscitation of combat casualties with a synthetic colloid (6% hydroxyethyl starch [HES] 670/0.75) has been recommended when blood or blood components are unavailable. We studied hemostatic effects of a newer synthetic colloid (6% HES, 130/0.4) compared with either a natural colloid (albumin) or to crystalloids in an uncontrolled hemorrhage model. Spontaneously breathing New Zealand white rabbits (3.4 ± 0.1 kg) were anesthetized, instrumented, and subjected to a splenic injury with uncontrolled bleeding. Fifteen minutes after injury, rabbits were in shock (mean arterial pressure [MAP] = 26 ± 1.3 mm Hg, and received colloids (6% HES, 130/0.4 or 5% albumin at 15 mL/kg), or crystalloids (normal saline at 30 mL/kg or 5% hypertonic saline at 7.5 mL/kg) for resuscitation in two intravenous bolus injections (15 minutes apart) to raise their MAP to 65 mm Hg, n = 9/group. Animals were monitored for 2.5 hours or until death, and blood losses were measured. Blood samples were analyzed for arterial blood gas, complete blood count, and coagulation measures. There were no differences among groups in baseline measures and initial hemorrhage volume (11.9 ± 0.6 mL/kg) at 15 minutes postinjury. Twenty minutes after fluid resuscitation (1 hour postinjury), MAP was higher, shock indices were lower, and blood pH was higher in colloids versus. crystalloids groups (p < 0.05). Administration of 6% HES 130/0.4 colloid produced the largest hemodilution (54% decrease in hematocrit, p < 0.05 vs. hypertonic saline). Activated partial thromboplastin time increased approximately 35% above baseline in all groups except in 6% HES 130/0.4 group in which it doubled. Clot strength was reduced (15%) only in the 6% HES 130/0.4 group. 6% HES 130/0.4 resuscitation produced the largest blood loss and 33% survival rate that was not different than the crystalloid groups. Albumin produced the best hemostatic and survival outcomes (78%). Small-volume resuscitation with

  16. Long Term Cryopreservation of Dog Granulocytes.

    DTIC Science & Technology

    1981-12-21

    using DINGO , HES and autologous plasma as the cryoprotectant. Our laboratory, employing CCE of whole blood and buffy coats, has also reported...cryopreservation of dog (1), baboon (3) and guinea pig granulocytes (4) using 5% DMSO, 6% HES, and 4% bovine serum albumin (BSA) formulated in Normosol-R pH 7.4...Hunt, S.M., Sehepis, R., Roy, A.J., Liss, R., Valeri, C.R.: In vitro distribution of cryopreserved guinea pig granulocytes. Cryobiology 1980; 17:1-11. S

  17. Value-Driven Design and Sensitivity Analysis of Hybrid Energy Systems using Surrogate Modeling

    SciTech Connect

    Wenbo Du; Humberto E. Garcia; William R. Binder; Christiaan J. J. Paredis

    2001-10-01

    A surrogate modeling and analysis methodology is applied to study dynamic hybrid energy systems (HES). The effect of battery size on the smoothing of variability in renewable energy generation is investigated. Global sensitivity indices calculated using surrogate models show the relative sensitivity of system variability to dynamic properties of key components. A value maximization approach is used to consider the tradeoff between system variability and required battery size. Results are found to be highly sensitive to the renewable power profile considered, demonstrating the importance of accurate renewable resource modeling and prediction. The documented computational framework and preliminary results represent an important step towards a comprehensive methodology for HES evaluation, design, and optimization.

  18. US hydropower resource assessment for Hawaii

    SciTech Connect

    Francfort, J.E.

    1996-09-01

    US DOE is developing an estimate of the undeveloped hydropower potential in US. The Hydropower Evaluation Software (HES) is a computer model developed by INEL for this purpose. HES measures the undeveloped hydropower resources available in US, using uniform criteria for measurement. The software was tested using hydropower information and data provided by Southwestern Power Administration. It is a menu-driven program that allows the PC user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes, and generate reports. This report describes the resource assessment results for the State of Hawaii.

  19. [A propose to suspend the use of hydroxyethyl starch for fluid resuscitation in shock phase of severe burns].

    PubMed

    Luo, Gao-xing; Peng, Yi-zhi; Wu, Jun

    2013-10-01

    Based on the result of randomized controlled trials and meta-analysis recently, the infusion of hydroxyethyl starch (HES) was not shown to over match routine crystalline solution in exerting resuscitation effect against hypovolemia of patients with burn shock, severe systematic infection, or other critical conditions, on the other hand, it may induce renal toxicity and other toxic and side effects. Since the pathological mechanism underlying hypovolemia during shock phase after burn is similar to that of severe systemic infection, we propose to suspend the use of HES for fluid resuscitation during the shock phase of severe burn until further elucidation.

  20. Postoperative Acute Kidney Injury and Blood Product Transfusion After Synthetic Colloid Use During Cardiac Surgery.

    PubMed

    Tobey, Rajika; Cheng, Hao; Gao, Mei; Li, Zhongmin; Young, J Nilas; Boyd, W Douglas; Ji, Fuhai; Liu, Hong

    2017-06-01

    This study assessed the effect of 2 types of hydroxyethyl starches (HES) on renal integrity and blood transfusion in cardiac surgery patients. Retrospective investigation. Patients from a single tertiary medical center. Inclusion criteria included coronary artery bypass graft (CABG) and/or valve surgery that included cardiopulmonary bypass with aortic cross-clamping. Intraoperative HES and blood product administration. The study comprised 1,265 patients who met inclusion criteria. Of these patients, 70% received HES, and of these, 47% received<1,000 mL and 53% received≥1,000 mL. There was no difference in the development of acute kidney injury between the 2 groups. A parsimonious propensity model for colloids showed that combined CABG and valve surgery were less likely to be associated with HES administration than was CABG alone (OR 0.68, confidence interval [CI] 0.46-0.97; p = 0.04). Intra-aortic balloon pump use was less likely to be associated with HES administration (OR 0.57, CI 0.38-0.86; p = 0.007). Patients with chronic kidney disease, stages 3 to 5, were less likely to receive HES, with an OR of 0.56 (CI 0.38-0.84; p = 0.004); 0.51 (CI 0.20-1.33; p = 0.170); and 0.23 (CI 0.12-0.44; p<0.0001), respectively, for each stage. No difference was noted in red blood cell transfusion. However, fresh frozen plasma, cryoprecipitate, and platelet transfusions were significantly higher with larger volumes of HES, with an OR of 2.03 (CI 1.64-2.52; p<0.001); 1.60 (CI 1.30-1.97; p<0.000); and 1.62 (CI 1.21-2.15; p = 0.006), respectively. No differences in surgical mortality were found between the colloid and noncolloid groups. This study showed no association of postoperative acute kidney injury and red blood cell transfusion between the colloid and noncolloid groups. Although the complication rate was higher with HES administration, there was no difference in surgery mortality between the 2 groups. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Hypercapnic encephalopathy syndrome: a new frontier for non-invasive ventilation?

    PubMed

    Scala, Raffaele

    2011-08-01

    According to the classical international guidelines, non-invasive ventilation is contraindicated in hypercapnic encephalopathy syndrome (HES) due to the poor compliance to ventilatory treatment of confused/agitated patients and the risk of aspirative pneumonia related to lack of airways protection. As a matter of fact, conventional mechanical ventilation has been recommended as "golden standard" in these patients. However, up to now there are not controlled data that have demonstrated in HES the advantage of conventional mechanical ventilation vs non-invasive ventilation. In fact, patients with altered mental status have been systematically excluded from the randomised and controlled trials performed with non-invasive ventilation in hypercapnic acute respiratory failure. Recent studies have clearly demonstrated that an initial cautious NPPV trial in selected HES patients may be attempt as long as there are no other contraindications and the technique is provided by experienced caregivers in a closely monitored setting where ETI is always readily available. The purpose of this review is to report the physiologic rationale, the clinical feasibility and the still open questions about the careful use of non-invasive ventilation in HES as first-line ventilatory strategy in place of conventional mechanical ventilation via endotracheal intubation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. 75 FR 6762 - Self-Regulatory Organizations; Chicago Board Options Exchange, Incorporated; Notice of Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-10

    ... amend its rules relating to the Penny Pilot Program. The text of the rule proposal is available on the... change. The text of these statements may be examined at the places specified in Item IV below. The self... Materials Inc. HES Hess Corp. WFT Weatherford International Ltd. HL Hecla Mining Co. WLP WellPoint Inc. HOG...

  3. Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and wnt-beta-catenin Pathways in CD44(+) Gastric Cancer Stem Cells.

    PubMed

    Barat, Samarpita; Chen, Xi; Cuong Bui, Khac; Bozko, Przemyslaw; Götze, Julian; Christgen, Matthias; Krech, Till; Malek, Nisar P; Plentz, Ruben R

    2017-02-03

    Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44(+) CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44(+) CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44(+) CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44(+) CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44(+) CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44(+) CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. © Stem Cells Translational Medicine 2017.

  4. Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

    EPA Science Inventory

    Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

  5. Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis.

    PubMed

    Zhang, Zhen; Gao, Feng; Kang, Xiaokui; Li, Jia; Zhang, Litong; Dong, Wentao; Jin, Zhangning; Li, Fan; Gao, Nannan; Cai, Xinwang; Yang, Shuyuan; Zhang, Jianning; Ren, Xinliang; Yang, Xinyu

    2015-04-01

    The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo.

  6. Idiopathic hypereosinophilic syndrome resulting in distal aortic thromboembolism in a dog.

    PubMed

    Madden, Valerie R; Schoeffler, Gretchen L

    2016-11-01

    To describe clinically significant thromboembolism as the result of idiopathic hypereosinophilic syndrome (HES) in a dog. A 3-year-old neutered female Boxer was evaluated for 2-week history of progressive respiratory difficulty and hemoptysis. A brief thoracic ultrasound performed shortly after presentation identified a presumed thrombus within the left atrium. Initial blood work revealed a marked eosinophilia 6.8 × 10(9) /L (6.8 × 10(3) /μL; reference interval, 0.1-2.1 × 10(9) /L [0.1-2.1 × 10(3) /μL]) and evidence of organ dysfunction. Within 24 hours of admission the patient developed acute paraparesis with absent femoral pulses and was euthanized. Necropsy findings included marked infiltration of multiple organs with large numbers of histologically normal eosinophils and numerous thrombi including a large aortic thrombus. This combination of findings resulted in a final diagnosis of HES with associated thromboembolism. Thromboembolism occurs relatively commonly in people with HES. While there are a few case reports of HES in the veterinary literature, this is the first to describe thromboembolism as a manifestation of this disease in a canine patient. © Veterinary Emergency and Critical Care Society 2016.

  7. Effects of polyethylene glycol and hydroxyethyl starch in University of Wisconsin preservation solution on human red blood cell aggregation and viscosity.

    PubMed

    Mosbah, I B; Franco-Gou, R; Abdennebi, H B; Hernandez, R; Escolar, G; Saidane, D; Rosello-Catafau, J; Peralta, C

    2006-06-01

    University of Wisconsin (UW) preservation solution is considered an effective flush and cold storage liquid. However, recent studies have provided evidence of the hyperaggregating effect on human red blood cells (RBC) of hydroxyethyl starch (HES), one of the components of the UW solution. In contrast, preservation solutions containing polyethylene glycol (PEG) have been found to be effective for organ preservation. The aim of this study was to compare the effects of HES (50 g/L); PEG 20 kDa (50 and 30 g/L), and PEG35 kDa (1.05 g/L) added to UW on the rheologic parameters of human RBC at 4 degrees C. Sedimentation rate was measured by the Westergren procedure and blood viscosity evaluated at high shear rates using a cone/plate viscometer. Alterations in RBC morphology and aggregation were evaluated by light microscopy. RBC sedimentation and viscosity were not affected by the inversion of Na+ and K+ concentrations in UW, but were increased by HES. PEGs appeared to reduce RBC deformability with concomitant inhibition of RBC aggregation. These results were consistent with reduced viscosity for PEG-containing solutions. In conclusion, the use of PEG did not change the physiologic function of human RBCs and thus may be an alternative to HES in UW liquids.

  8. Alternatives to the Fish Early Life-Stage Test: A Research Strategy for Discovering and Annotating Adverse Outcome Pathways During Fish Development

    EPA Science Inventory

    The OECD 210 fish early life]stage (FELS) test is the primary guideline test used to estimate chronic fish toxicity, as well as support ecological risk assessments and chemical management programs around the world. As a step toward developing alternatives to the FELS test, a HES...

  9. 77 FR 43601 - Risks and Benefits of Hydroxyethyl Starch Solutions; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-25

    ... HUMAN SERVICES Food and Drug Administration Risks and Benefits of Hydroxyethyl Starch Solutions; Public... Administration (FDA) is announcing a public workshop entitled: ``Risks and Benefits of Hydroxyethyl Starch... FDA-approved hydroxyethyl starch (HES) solutions. The public workshop has been planned in partnership...

  10. Investigating Students' Ideas about Buoyancy and the Influence of Haptic Feedback

    ERIC Educational Resources Information Center

    Minogue, James; Borland, David

    2016-01-01

    While haptics (simulated touch) represents a potential breakthrough technology for science teaching and learning, there is relatively little research into its differential impact in the context of teaching and learning. This paper describes the testing of a haptically enhanced simulation (HES) for learning about buoyancy. Despite a lifetime of…

  11. Suppression of OVA-alum induced allergy by Heligmosomoides polygyrus products is MyD88-, TRIF-, regulatory T- and B cell-independent, but is associated with reduced innate lymphoid cell activation.

    PubMed

    McSorley, Henry J; Blair, Natalie F; Robertson, Elaine; Maizels, Rick M

    2015-11-01

    The murine intestinal nematode Heligmosomoides polygyrus exerts multiple immunomodulatory effects in the host, including the suppression of allergic inflammation in mice sensitized to allergen presented with alum adjuvant. Similar suppression is attained by co-administration of H. polygyrus excretory/secretory products (HES) with the sensitizing dose of ovalbumin (OVA) in alum. We investigated the mechanism of suppression by HES in this model, and found it was maintained in MyD88xTRIF-deficient mice, implying no role for helminth- or host-derived TLR ligands, or IL-1 family cytokines that signal in a MyD88- or TRIF-dependent manner. We also found suppression was unchanged in µMT mice, which lack B2 B cells, and that suppression was not abrogated when regulatory T cells were depleted in Foxp3.LuciDTR-4 mice. However, reduced IL-5 production was seen in the first 12 h after injection of OVA-alum when HES was co-administered, associated with reduced activation of IL-5(+) and IL-13(+) group 2 innate lymphoid cells. Thus, the suppressive effects of HES on alum-mediated OVA sensitization are reflected in the very earliest innate response to allergen exposure in vivo.

  12. Spectroscopic investigation of Lambda hypernuclei in the wide mass region using the (e, e-prime K+) reaction

    SciTech Connect

    Satoshi N. Nakamura

    2011-09-01

    The third generation spectroscopic study of {Lambda} hypernuclei using (e,e'K{sup +}) reaction (JLab E05-115) was performed at JLab Hall-C in 2009. The experiment introduced the newly developed high-resolution electron spectrometer (HES) with the existing high-resolution kaon spectrometer (HKS). Experimental configuration, conditions, spectrometer designs and current status of analysis are presented.

  13. Reprogramming the pluripotent cell cycle: restoration of an abbreviated G1 phase in human induced pluripotent stem (iPS) cells

    PubMed Central

    Ghule, Prachi N.; Medina, Ricardo; Lengner, Chris J.; Mandeville, Matthew; Qiao, Meng; Dominski, Zbigniew; Lian, Jane B.; Stein, Janet L.; van Wijnen, Andre J.; Stein, Gary S.

    2011-01-01

    Induced pluripotent stem (iPS) cells derived from terminally differentiated human fibroblasts are re-programmed to possess stem cell like properties. However, the extent to which iPS cells exhibit unique properties of the human embryonic stem (hES) cell cycle remains to be established. Human ES cells are characterized by an abbreviated G1 phase (~2.5 h) and accelerated organization of subnuclear domains that mediate the assembly of regulatory machinery for histone gene expression [i.e., histone locus bodies (HLBs)]. We therefore examined cell cycle parameters of iPS cells in comparison to hES cells. Analysis of DNA synthesis (BrdU incorporation), cell cycle distribution (FACS analysis and Ki67 staining) and subnuclear organization of HLBs [immuno-fluorescence microscopy and fluorescence in situ hybridization (FISH)] revealed that human iPS cells have a short G1 phase (~2.5 h) and an abbreviated cell cycle (16–18 h). Furthermore, HLBs are formed and reorganized rapidly after mitosis (within0.5 to 1.5 h). Thus, reprogrammed iPS cells have cell cycle kinetics and dynamic subnuclear organization of regulatory machinery that are principal properties of pluripotent hES cells. Our findings support the concept that the abbreviated cell cycle of hES and iPS cells is functionally linked to pluripotency. PMID:20945438

  14. POPULATION EXPOSURES TO PARTICULATE MATTER: A COMPARISON OF EXPOSURE MODEL PREDICTIONS AND MEASUREMENT DATA

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) is currently developing an integrated human exposure source-to-dose modeling system (HES2D). This modeling system will incorporate models that use a probabilistic approach to predict population exposures to environmental ...

  15. Country's Competitiveness and Sustainability in the Context of the Higher Education System Reforms

    ERIC Educational Resources Information Center

    Jermolajeva, Elita; Aleksejeva, Ludmila

    2013-01-01

    The accumulation of knowledge and its use have become important factors that promote economic development as they contribute to a country's competitiveness in the global economy. The basic significance of research is obtained by defining new approaches in the organisation, function and efficiency of the higher education system (HES) by emphasising…

  16. Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro.

    PubMed

    Bruner-Tran, Kaylon L; Osteen, Kevin G; Taylor, Hugh S; Sokalska, Anna; Haines, Kaitlin; Duleba, Antoni J

    2011-01-01

    Endometriosis is a common gynecologic disorder characterized by ectopic attachment and growth of endometrial tissues. Resveratrol is a natural polyphenol with antiproliferative and anti-inflammatory properties. Our objective was to study the effects of resveratrol on human endometriotic implants in a nude mouse model and to examine its impact on human endometrial stromal (HES) cell invasiveness in vitro. Human endometrial tissues were obtained from healthy donors. Endometriosis was established in oophorectomized nude mice by intraperitoneal injection of endometrial tissues. Mice were treated with 17β-estradiol (8 mg, silastic capsule implants) alone (n = 16) or with resveratrol (6 mg/mouse; n = 20) for 10-12 and 18-20 days beginning 1 day after tissue injection. Mice were killed and endometrial implants were evaluated. A Matrigel invasion assay was used to examine the effects of resveratrol on HES cells. We assessed number and size of endometriotic implants in vivo and Matrigel invasion in vitro. Resveratrol decreased the number of endometrial implants per mouse by 60% (P < 0.001) and the total volume of lesions per mouse by 80% (P < 0.001). Resveratrol (10-30 μM) also induced a concentration-dependent reduction of invasiveness of HES by up to 78% (P < 0.0001). Resveratrol inhibits development of endometriosis in the nude mouse and reduces invasiveness of HES cells. These observations may aid in the development of novel treatments of endometriosis.

  17. Resveratrol Inhibits Development of Experimental Endometriosis In Vivo and Reduces Endometrial Stromal Cell Invasiveness In Vitro1

    PubMed Central

    Bruner-Tran, Kaylon L.; Osteen, Kevin G.; Taylor, Hugh S.; Sokalska, Anna; Haines, Kaitlin; Duleba, Antoni J.

    2010-01-01

    Endometriosis is a common gynecologic disorder characterized by ectopic attachment and growth of endometrial tissues. Resveratrol is a natural polyphenol with antiproliferative and anti-inflammatory properties. Our objective was to study the effects of resveratrol on human endometriotic implants in a nude mouse model and to examine its impact on human endometrial stromal (HES) cell invasiveness in vitro. Human endometrial tissues were obtained from healthy donors. Endometriosis was established in oophorectomized nude mice by intraperitoneal injection of endometrial tissues. Mice were treated with 17β-estradiol (8 mg, silastic capsule implants) alone (n = 16) or with resveratrol (6 mg/mouse; n = 20) for 10–12 and 18–20 days beginning 1 day after tissue injection. Mice were killed and endometrial implants were evaluated. A Matrigel invasion assay was used to examine the effects of resveratrol on HES cells. We assessed number and size of endometriotic implants in vivo and Matrigel invasion in vitro. Resveratrol decreased the number of endometrial implants per mouse by 60% (P < 0.001) and the total volume of lesions per mouse by 80% (P < 0.001). Resveratrol (10–30 μM) also induced a concentration-dependent reduction of invasiveness of HES by up to 78% (P < 0.0001). Resveratrol inhibits development of endometriosis in the nude mouse and reduces invasiveness of HES cells. These observations may aid in the development of novel treatments of endometriosis. PMID:20844278

  18. Enterprise Curriculum for Creative Industries Students: An Exploration of Current Attitudes and Issues

    ERIC Educational Resources Information Center

    Carey, Charlotte; Naudin, Annette

    2006-01-01

    Purpose: This paper seeks to report on the current state and attitudes towards Enterprise Curriculum within higher education (HE) for the creative industries sector. It is based on preliminary findings from the Creative Enterprise Conference (2006) held at UCE Birmingham, which examined the role of HEs in developing future entrepreneurs in this…

  19. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome.

    PubMed

    Griffin, John H; Leung, Joey; Bruner, Rebecca J; Caligiuri, Michael A; Briesewitz, Roger

    2003-06-24

    Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha (PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe-PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.

  20. Cultures of human embryonic stem cells: serum replacement medium or serum-containing media and the effect of basic fibroblast growth factor.

    PubMed

    Koivisto, Heidi; Hyvärinen, Marjukka; Strömberg, Anne-Marie; Inzunza, Jose; Matilainen, Eija; Mikkola, Milla; Hovatta, Outi; Teerijoki, Heli

    2004-09-01

    Human embryonic stem (hES) cells have traditionally been cultured in medium containing fetal calf serum (FCS) and mouse fibroblasts as feeder cells. The use of animal derived materials carries a risk of transmitting animal pathogens, and they are not optimal in cultures aimed at cell transplantation in humans. This technical study aiming at facilitating IVF units to establish new hES cell lines, has systematically compared the non-differentiated growth of the hES cell line HS237, originally derived and thereafter cultured using human foreskin fibroblasts as feeder cells, by culturing it in media containing serum replacement (SR; 10, 15, 20%), FCS, and human serum. In addition, optimal concentrations of insulin-transferrin-selenium (ITS) mixture and the effect of basic fibroblast growth factor (bFGF) have also been studied. Cellular growth was monitored daily and maintenance of their non-differentiated character was studied using antibodies against TRA-1-60, TRA-1-81 and SSEA-4 and expression of Oct-4. The hES cells proliferated fastest when 20% of SR was used. In human serum-containing medium, the cells underwent extensive spontaneous differentiation within a few passages. The FCS supported the non-differentiated growth poorly. Basic fibroblast growth factor supported non-differentiated growth, the highest concentration (8 ng/ml) giving the best result, while ITS was not beneficial.

  1. New Developments in Red Blood Cell Preservation Using Liquid and Freezing Procedures.

    DTIC Science & Technology

    1982-04-02

    protein fraction (PPF), hydroxyethyl starch (HES), dextran (high molecular weight (NNW) and low molecular weight (LMW)), and the gelatin -like ’.F .. RED...extent is the clinical use of dextran, gelatin , and hydroxyethyl starch influenced by the incidence and severity of anaphlactoid reactions. Vox Sang 36

  2. Schemas in Problem Solving: An Integrated Model of Learning, Memory, and Instruction

    DTIC Science & Technology

    1992-01-01

    u a schema. we coder execolon knowledge to be Mhe hes homesog, and we boo made li1t attemipt to model how Individuals learn the bodec wuec opematOLom... Margaret A., & Rose, Frederic E. (1989). STORY PROBLEM SOLVER: A schema-based system of instruction. Technical Rep. CRMSE 89-01 (ONR Contract N00014

  3. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability.

    PubMed

    Ong, Chin-Tong; Cheng, Hui-Teng; Chang, Li-Wei; Ohtsuka, Toshiyuki; Kageyama, Ryoichiro; Stormo, Gary D; Kopan, Raphael

    2006-02-24

    All four mammalian Notch proteins interact with a single DNA-binding protein (RBP-jkappa), yet they are not equivalent in activating target genes. Parallel assays of three Notch-responsive promoters in several cell lines revealed that relative activation strength is dependent on protein module and promoter context more than the cellular context. Each Notch protein reads binding site orientation and distribution on the promoter differently; Notch1 performs extremely well on paired sites, and Notch3 prefers single sites in conjunction with a proximal zinc finger transcription factor. Although head-head sites can elicit a Notch response on their own, use of CBS (CSL binding site) in tail-tail orientation is context-dependent. Bias for specific DNA elements is achieved by interplay between the N-terminal RAM (RBP-jkappa-associated molecule/ankyrin region), which interprets CBS proximity and orientation, and the C-terminal transactivation domain that interacts specifically with the transcription machinery or nearby factors. To confirm the prediction that modular design underscores the evolution of functional divergence between Notch proteins, we generated a synthetic Notch protein (Notch1 ankyrin with Notch3 transactivation domain) that displayed superior signaling strength on the hes5 promoter. Consistent with the prediction that "preferred" targets (Hes1) should respond faster and at lower Notch concentration than other targets, we showed that Hes5-GFP was extinguished fast and recovered slowly, whereas Hes1-GFP was inhibited late and recovered quickly after a pulse of DAPT in metanephroi cultures.

  4. POPULATION EXPOSURES TO PARTICULATE MATTER: A COMPARISON OF EXPOSURE MODEL PREDICTIONS AND MEASUREMENT DATA

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) is currently developing an integrated human exposure source-to-dose modeling system (HES2D). This modeling system will incorporate models that use a probabilistic approach to predict population exposures to environmental ...

  5. Applying GIS to Develop a Web-Based Spatial-Person-Temporal History Educational System

    ERIC Educational Resources Information Center

    Lo, Jia-Jiunn; Chang, Chuen-Jung; Tu, Hsiao-Han; Yeh, Shiou-Wen

    2009-01-01

    Developing interactive history learning materials to facilitate historical thinking is one of the challenges in history teaching and learning. This study developed a web-based history educational system, which has used the acronym HES-SPATO (history educational system based on SPATO), to increase the understandability of history learning…

  6. Evaluation of 1066 ToxCast Chemicals in a human stem cell assay for developmental toxicity (SOT)

    EPA Science Inventory

    To increase the diversity of assays used to assess potential developmental toxicity, the ToxCast chemical library was screened in the Stemina devTOX quickPREDICT assay using human embryonic stem (hES) cells. A model for predicting teratogenicity was based on a training set of 23 ...

  7. Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

    EPA Science Inventory

    Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

  8. Recovering Valuable Phosphates: Chemical Biotechnology as a Problem Solver for the Environment.

    PubMed

    Heinzelmann, Elsbeth

    2015-01-01

    Researchers from the HES-SO Valais/Wallis have demonstrated how to extract phosphate from sewage sludge on the laboratory scale using renewable energy sources from a microbial fuel cell. The mobilized phosphate barely contains heavy metals and can be used to produce fertilizer of marketable quality. The necessary energy comes from a sewage treatment plant and causes no additional costs.

  9. microRNA input into a neural ultradian oscillator controls emergence and timing of alternative cell states.

    PubMed

    Goodfellow, Marc; Phillips, Nicholas E; Manning, Cerys; Galla, Tobias; Papalopulu, Nancy

    2014-03-04

    Progenitor maintenance, timed differentiation and the potential to enter quiescence are three fundamental processes that underlie the development of any organ system. In the nervous system, progenitor cells show short-period oscillations in the expression of the transcriptional repressor Hes1, while neurons and quiescent progenitors show stable low and high levels of Hes1, respectively. Here we use experimental data to develop a mathematical model of the double-negative interaction between Hes1 and a microRNA, miR-9, with the aim of understanding how cells transition from one state to another. We show that the input of miR-9 into the Hes1 oscillator tunes its oscillatory dynamics, and endows the system with bistability and the ability to measure time to differentiation. Our results suggest that a relatively simple and widespread network of cross-repressive interactions provides a unifying framework for progenitor maintenance, the timing of differentiation and the emergence of alternative cell states.

  10. Commander’s Emergency Response Program: A Flawed Metric

    DTIC Science & Technology

    2012-12-06

    24 Hamlet Evaluation System...Escalation 1962- 1967 provides great detail on the shortcomings of such metric systems as the “body count” and the HES ( Hamlet Evaluation System).17...metrics, such as body counts and hamlet evaluations, did not reflect progress towards victory. Since its introduction, CERP has experienced

  11. Identification of seedling vigor-associated quantitative trait loci in temperate japonica rice

    USDA-ARS?s Scientific Manuscript database

    A quantitative trait loci (QTL) analysis of seedling vigor traits was conducted under dry-seeded conditions using 176 recombinant inbred lines developed from a cross of two California temperate japonica rice varieties M-203 and M-206. Height at early seedling (HES) and late seedling (HLS) stage, gro...

  12. The Use of Hydroxy-Ethyl Starch Sedimentation for Autologous Buffy Coat Preparation

    PubMed Central

    Gannon, Timothy; McConnell, Kristen; Riley, Jeffrey

    2005-01-01

    Abstract: The use of hydroxy-ethyl starch (HES) has been used in the cord blood banking industry for the separation of blood into its individual components. The focus of this study is to examine whether the use of HES is feasible in obtaining a buffy coat for the use in the construction of platelet gels. Blood was collected from seven canines into anticoagulant citrate dextrose at a ratio of 1:8. A sample of whole blood was used to obtain initial cell counts and a base line Thrombelastograph® (TEG®). 6% Hespan was added to the whole blood and allowed to sediment for 60 minutes. Cell counts and TEG®s were performed on the resulting layers: red blood cells (RBCs), buffy coat (BC), and plasma. The results of this study (see Table 1) suggest that the gravity sedimentation of whole blood with HES can significantly reduce the RBCs in the BC and plasma layers while increasing the platelet count in the plasma layer. These data also suggest that HES does not affect the clotting capabilities of the BC and plasma layers. PMID:16350387

  13. High Speed Video for Airborne Instrumentation Application

    NASA Technical Reports Server (NTRS)

    Tseng, Ting; Reaves, Matthew; Mauldin, Kendall

    2006-01-01

    A flight-worthy high speed color video system has been developed. Extensive system development and ground and environmental. testing hes yielded a flight qualified High Speed Video System (HSVS), This HSVS was initially used on the F-15B #836 for the Lifting Insulating Foam Trajectory (LIFT) project.

  14. Acute kidney injury in critically burned patients resuscitated with a protocol that includes low doses of Hydroxyethyl Starch.

    PubMed

    Sánchez-Sánchez, M; Garcia-de-Lorenzo, A; Cachafeiro, L; Herrero, E; Asensio, M J; Agrifoglio, A; Flores, E; Estebanez, B; Extremera, P; Iglesias, C; Martinez, J R

    2016-09-30

    Acute kidney injury (AKI) is an important complication in burn patients. Recently, it has been recommended that hydroxyethyl starch (HES) be avoided in burn patients because it increases the incidence of AKI. Our purpose was to study incidence of AKI in critically ill burn patients resuscitated with Ringer's solution and supplements of HES. We conducted an observational study of 165 patients admitted to the critical care burn unit (with 30 ± 15% TBSA burned). The main outcome measures were incidence of AKI, contributions of colloids and crystalloids, various severity scores, comorbidities, complications and mortality. According to the RIFLE criteria, 10 (6.1%) patients presented with Risk, 11 (6.7%) presented with Injury and 11 (6.7%) presented with Failure. According to the AKIN criteria, 9.7% presented stage I, 3% stage II and 10.3% stage III. Replacement therapy (RRT) was performed in 15 patients (9.1%), but in 6 of them RRT was employed in the final stages of multi-organ failure. The incidence of AKI in severe burn patients is high according to the RIFLE or AKIN criteria and these patients experience more complications and higher mortality. Our study suggests that the use of HES in low doses in the burn resuscitation phase does not cause more AKI than resuscitation without HES, but further evaluation is required. Further studies should be conducted.

  15. Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis

    PubMed Central

    Shimojo, Hiromi; Isomura, Akihiro; Ohtsuka, Toshiyuki; Kori, Hiroshi; Miyachi, Hitoshi; Kageyama, Ryoichiro

    2016-01-01

    Notch signaling regulates tissue morphogenesis through cell–cell interactions. The Notch effectors Hes1 and Hes7 are expressed in an oscillatory manner and regulate developmental processes such as neurogenesis and somitogenesis, respectively. Expression of the mRNA for the mouse Notch ligand Delta-like1 (Dll1) is also oscillatory. However, the dynamics of Dll1 protein expression are controversial, and their functional significance is unknown. Here, we developed a live-imaging system and found that Dll1 protein expression oscillated in neural progenitors and presomitic mesoderm cells. Notably, when Dll1 expression was accelerated or delayed by shortening or elongating the Dll1 gene, Dll1 oscillations became severely dampened or quenched at intermediate levels, as modeled mathematically. Under this condition, Hes1 and Hes7 oscillations were also dampened. In the presomitic mesoderm, steady Dll1 expression led to severe fusion of somites and their derivatives, such as vertebrae and ribs. In the developing brain, steady Dll1 expression inhibited proliferation of neural progenitors and accelerated neurogenesis, whereas optogenetic induction of Dll1 oscillation efficiently maintained neural progenitors. These results indicate that the appropriate timing of Dll1 expression is critical for the oscillatory networks and suggest the functional significance of oscillatory cell–cell interactions in tissue morphogenesis. PMID:26728556

  16. Significance of Notch1-signaling pathway in human pancreatic development and carcinogenesis.

    PubMed

    Hu, Huankai; Zhou, Lan; Awadallah, Amad; Xin, Wei

    2013-05-01

    In animal studies, Notch1-signaling pathway plays an important role in the pancreatic embryogenesis by promoting pancreatic progenitor cells self-renewal and exocrine linage development. The persistent activation of Notch pathway could arrest the organ development and keep cells at an undifferentiated stage. Studies have shown that Notch1-signaling pathway is upregulated in invasive pancreatic ductal adenocarcinoma (PDAC). Here we examined the expression pattern of Notch1 and Hes1 in human fetal pancreatic tissues to elucidate the role of Notch1 in human pancreatic embryonic development. We also compared Notch1 expression in tissues from PDAC, chronic pancreatitis and pancreatic intraepithelial neoplasm. Our data show that Notch1/Hes1-signaling pathway is activated during early pancreatic embryogenesis and reaches the highest at birth. After pancreas is fully developed, Notch1/Hes1 pathway is inactivated even though Notch1 protein cell-surface expression is upregulated. We also showed that the expression of both Notch1 and Hes1 are present in 50% (33/66) of PDACs, but not in pancreatic intraepithelial neoplasms. These findings indicate that Notch1 activation is only apparent in late stage of pancreatic carcinogenesis, suggesting that treatment with Notch-signaling inhibitors including γ-secretase should be selectively used for PDACs with confirmed Notch1-signaling activation.

  17. The Elementary and Secondary Education Act at Fifty: A Changing Federal Role in American Education

    ERIC Educational Resources Information Center

    Nelson, Adam R.

    2016-01-01

    For this first "History of Education Quarterly Policy Forum," we invited participants in the special Plenary Session at the 2015 Annual Meeting of the History of Education Society (HES) in St. Louis to publish their remarks on the historical significance of the Elementary and Secondary Education Act (ESEA) at fifty. Organized and…

  18. Durability of selected mulches, their ability to control weeds, and influence growth of loblolly pine seedlings

    Treesearch

    James D. Haywood

    1999-01-01

    Several mulc hes of natural, synthetic, or blends of natural and synthetic fibers were tested around newly planted loblolly pine (Pinus taeda L.) seedlings on a sheared and windrowed site in central Louisiana, U.S.A. The vegetation was primarily winter annuals, some residual grasses and forbs, and...

  19. Fire Season and Frequency Effects on Native Grass Bud Banks in the Northern Great Plains

    USDA-ARS?s Scientific Manuscript database

    Axillary buds, belowground meristematic tissue located on plant crowns, regulate productivity of perennial grasses. However, the impact of fire frequency and season-of-fire on quantity and viability of axillary buds is still unclear. We evaluated axillary bud populations of Bouteloua gracilis, Hes...

  20. Investigating Students' Ideas about Buoyancy and the Influence of Haptic Feedback

    ERIC Educational Resources Information Center

    Minogue, James; Borland, David

    2016-01-01

    While haptics (simulated touch) represents a potential breakthrough technology for science teaching and learning, there is relatively little research into its differential impact in the context of teaching and learning. This paper describes the testing of a haptically enhanced simulation (HES) for learning about buoyancy. Despite a lifetime of…

  1. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients.

    PubMed

    Reinhart, Konrad; Perner, Anders; Sprung, Charles L; Jaeschke, Roman; Schortgen, Frederique; Johan Groeneveld, A B; Beale, Richard; Hartog, Christiane S

    2012-03-01

    Colloids are administered to more patients than crystalloids, although recent evidence suggests that colloids may possibly be harmful in some patients. The European Society of Intensive Care Medicine therefore assembled a task force to compile consensus recommendations based on the current best evidence for the safety and efficacy of the currently most frequently used colloids--hydroxyethyl starches (HES), gelatins and human albumin. Meta-analyses, systematic reviews and clinical studies of colloid use were evaluated for the treatment of volume depletion in mixed intensive care unit (ICU), cardiac surgery, head injury, sepsis and organ donor patients. Clinical endpoints included mortality, kidney function and bleeding. The relevance of concentration and dosage was also assessed. Publications from 1960 until May 2011 were included. The quality of available evidence and strength of recommendations were based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We recommend not to use HES with molecular weight ≥ 200 kDa and/or degree of substitution >0.4 in patients with severe sepsis or risk of acute kidney injury and suggest not to use 6% HES 130/0.4 or gelatin in these populations. We recommend not to use colloids in patients with head injury and not to administer gelatins and HES in organ donors. We suggest not to use hyperoncotic solutions for fluid resuscitation. We conclude and recommend that any new colloid should be introduced into clinical practice only after its patient-important safety parameters are established.

  2. Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer's disease in Wistar rats.

    PubMed

    Justin Thenmozhi, Arokiasamy; Raja, Tharsius Raja William; Janakiraman, Udaiyappan; Manivasagam, Thamilarasan

    2015-04-01

    The present study was aimed to evaluate the protective effect of hesperidin (Hes) on aluminium chloride (AlCl3) induced neurobehavioral and pathological changes in Alzheimeric rats. Intraperitonial injection of AlCl3 (100 mg/kg body weight) for 60 days significantly elevated the levels of aluminium (Al), activity of acetylcholinesterase (AChE) and protein expressions of amyloid precursor protein (APP), β amyloid (Aβ 1-42), β and γ secretases as compared to control group in hippocampus and cortex of rat brain. Hes administration orally along with AlCl3 injection for 60 days, significantly revert the Al concentration, AChE activity and Aβ synthesis-related molecules in the studied brain regions. Our results showed that aluminum exposure was significantly reduced the spontaneous locomotor and exploratory activities in open field test and enhanced the learning and memory impairments in morris water maze test. The behavioral impairments caused by aluminum were significantly attenuated by Hes. The histopathological studies in the hippocampus and cortex of rat brain also supported that Hes (100 mg/kg) markedly reduced the toxicity of AlCl3 and preserved the normal histoarchitecture pattern of the hippocampus and cortex. From these results, it is concluded that hesperidin can reverse memory loss caused by aluminum intoxication through attenuating AChE activity and amyloidogenic pathway.

  3. A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences

    PubMed Central

    Smith, Julianne; Grizot, Sylvestre; Arnould, Sylvain; Duclert, Aymeric; Epinat, Jean-Charles; Chames, Patrick; Prieto, Jesús; Redondo, Pilar; Blanco, Francisco J.; Bravo, Jerónimo; Montoya, Guillermo; Pâques, Frédéric; Duchateau, Philippe

    2006-01-01

    Meganucleases, or homing endonucleases (HEs) are sequence-specific endonucleases with large (>14 bp) cleavage sites that can be used to induce efficient homologous gene targeting in cultured cells and plants. These findings have opened novel perspectives for genome engineering in a wide range of fields, including gene therapy. However, the number of identified HEs does not match the diversity of genomic sequences, and the probability of finding a homing site in a chosen gene is extremely low. Therefore, the design of artificial endonucleases with chosen specificities is under intense investigation. In this report, we describe the first artificial HEs whose specificity has been entirely redesigned to cleave a naturally occurring sequence. First, hundreds of novel endonucleases with locally altered substrate specificity were derived from I-CreI, a Chlamydomonas reinhardti protein belonging to the LAGLIDADG family of HEs. Second, distinct DNA-binding subdomains were identified within the protein. Third, we used these findings to assemble four sets of mutations into heterodimeric endonucleases cleaving a model target or a sequence from the human RAG1 gene. These results demonstrate that the plasticity of LAGLIDADG endonucleases allows extensive engineering, and provide a general method to create novel endonucleases with tailored specificities. PMID:17130168

  4. Evaluation of 1066 ToxCast Chemicals in a human stem cell assay for developmental toxicity (SOT)

    EPA Science Inventory

    To increase the diversity of assays used to assess potential developmental toxicity, the ToxCast chemical library was screened in the Stemina devTOX quickPREDICT assay using human embryonic stem (hES) cells. A model for predicting teratogenicity was based on a training set of 23 ...

  5. Computerized system for hospital engineering service management

    NASA Astrophysics Data System (ADS)

    Centeno, C. A.; Gonzalez, E. A.; Cagnolo, F. J.; Olmos, C. E.

    2007-11-01

    When a Hospital Engineering Service (HES) is implemented within a health care environment, the idea is to improve service conditions and costs as well as to provide timely responses to equipment preventive maintenance and infrastructure requirements. An HES must, within the shortest possible period of time, meet the above requirements at the cost necessary to provide the service quality sought. In many cases there is a lack of minimal materials and staff who are qualified to attain the objectives that have been set. Therefore, external assistance becomes necessary. In this context, actions are often taken which, because they are not recorded, cannot be assessed in order to evaluate the HES. Since all action taken is appraised from the purely economic point of view, in the final analysis the contributions from staff remain invisible. This situation works against the possibility of quantifying the convenience of possessing an internal HES. The software support system we have developed here is oriented toward providing all the necessary data to address this issue.

  6. Nonviral Reprogramming of Human Wharton's Jelly Cells Reveals Differences Between ATOH1 Homologues.

    PubMed

    Mellott, Adam J; Devarajan, Keerthana; Shinogle, Heather E; Moore, David S; Talata, Zsolt; Laurence, Jennifer S; Forrest, M Laird; Noji, Sumihare; Tanaka, Eiji; Staecker, Hinrich; Detamore, Michael S

    2015-06-01

    The transcription factor atonal homolog 1 (ATOH1) has multiple homologues that are functionally conserved across species and is responsible for the generation of sensory hair cells. To evaluate potential functional differences between homologues, human and mouse ATOH1 (HATH1 and MATH-1, respectively) were nonvirally delivered to human Wharton's jelly cells (hWJCs) for the first time. Delivery of HATH1 to hWJCs demonstrated superior expression of inner ear hair cell markers and characteristics than delivery of MATH-1. Inhibition of HES1 and HES5 signaling further increased the atonal effect. Transfection of hWJCs with HATH1 DNA, HES1 siRNA, and HES5 siRNA displayed positive identification of key hair cell and support cell markers found in the cochlea, as well as a variety of cell shapes, sizes, and features not native to hair cells, suggesting the need for further examination of other cell types induced by HATH1 expression. In the first side-by-side evaluation of HATH1 and MATH-1 in human cells, substantial differences were observed, suggesting that the two atonal homologues may not be interchangeable in human cells, and artificial expression of HATH1 in hWJCs requires further study. In the future, this line of research may lead to engineered systems that would allow for evaluation of drug ototoxicity or potentially even direct therapeutic use.

  7. Effects of albumin 5% and artificial colloids on clot formation in small infants.

    PubMed

    Haas, T; Preinreich, A; Oswald, E; Pajk, W; Berger, J; Kuehbacher, G; Innerhofer, P

    2007-10-01

    Albumin is often cited in textbooks as the gold standard for fluid replacement in paediatrics, but in practice artificial colloids are more frequently used. Although one concern with the use of artificial colloids is their intrinsic action on haemostasis, the available data in children are inconclusive for 6% hydroxyethyl starch 130/0.4 (HES) and no data exist for gelatine solution with respect to coagulation. A total of 42 children (3-15 kg) undergoing surgery and needing colloid replacement were randomly assigned to receive 15 mlxkg(-1) of either albumin 5%, 4% modified gelatine solution or 6% hydroxyethyl starch 130/0.4 solution. Standard coagulation tests and modified thrombelastography (ROTEM) were performed. After colloid administration, routine coagulation test results changed significantly and comparably in all groups, although activated partial thromboplastin time values increased more with gelatine and HES. Coagulation time was unchanged in the children who received albumin or gelatine but other activated modified thrombelastography values were significantly impaired in all groups. After gelatine and after albumin the median clot firmness decreased significantly but remained within the normal range. Following HES, coagulation time increased significantly, and clot formation time, alpha angle, clot firmness, and fibrinogen/fibrin polymerisation were significantly more impaired than for albumin or gelatine, reaching median values below the normal range. From a haemostatic point of view it might be preferable to use gelatine solution as an alternative to albumin; HES showed the greatest effects on the overall coagulation process.

  8. Toxcast Profiling in a Human Stem Cell Assay for Developmental Toxicity (SOT)

    EPA Science Inventory

    We correlated the ToxCast library in a metabolic biomarker-based in vitro assay (Stemina devTOXqP) utilizing human embryonic stem (hES) cells (H9 line). This assay identifies the concentration of a chemical that disrupts cellular metabolism in a manner indicative of teratogenic...

  9. 75 FR 6233 - Self-Regulatory Organizations; NASDAQ OMX PHLX, Inc.; Notice of Filing and Immediate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... Technologies Corp. 170 HBC HSBC Holdings PLC. 204 WFR MEMC Electronic Materials Inc. 197 HES Hess Corp. 115 WFT... 176 M Macy's Inc. Inc. 178 AMAT Applied Materials 155 MCO Moody's Corp. Inc. 117 AMR AMR Corp. 217 MET... Energy Inc. Nemours & Co. 146 ERTS Electronic Arts 207 TCK Teck Resources Inc. Ltd. 121 EWJ iShares...

  10. 75 FR 6239 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... HBC HSBC Holdings PLC 204 WFR MEMC Electronic Materials Inc. 197 HES Hess Corp 115 WFT Weatherford.... 181 AKAM Akamai 176 M Macy's Inc. Technologies Inc 178 AMAT Applied Materials 155 MCO Moody's Corp... Suncor Energy Nemours & Co Inc. 146 ERTS Electronic Arts 207 TCK Teck Resources Inc Ltd. 121 EWJ...

  11. 75 FR 6235 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... HSBC Holdings PLC. WFR MEMC Electronic Materials Inc. HES Hess Corp. WFT Weatherford International Ltd.... AMAT Applied Materials Inc. MCO Moody's Corp. AMR AMR Corp. MET MetLife Inc. ANF Abercrombie & Fitch Co... Seagate Technology. DD EI du Pont de Nemours & SU Suncor Energy Inc. Co. ERTS Electronic Arts Inc....

  12. Influence of magnetic field on aqueous two-phase extraction of horse ferritin in the polyethylene glycol/hydroxyethyl starch system.

    PubMed

    Zielińska-Dawidziak, Magdalena; Błaszak, Roman; Piasecka-Kwiatkowska, Dorota

    2012-02-24

    The presented experiments show the model of expectation of equine spleen ferritin extraction in a new aqueous two-phase system which was formed by mixing polyethylene glycol (PEG) and hydroxyethyl starch (HES). The tendency of the protein to migrate in the analyzed systems was dependent on the concentrations of HES and PEG as well as PEG molecular weight. The highest concentration of ferritin in the top phase (rich in PEG) was recorded in the system composed of 6% PEG 3000 and 3% HES. The obtained concentration was 0.88 mg mL(-1). The lowest concentration was 0.42 mg mL(-1) in the system composed of 5% PEG 6000 and 1% HES. Next the influence of the magnetic field on ferritin accumulation was analyzed. Selected samples were placed between homogeneous (S/S) or heterogeneous magnetic poles (N/S and S/N). It was observed that after the application of the magnetic field the extraction of ferritin into the PEG rich phase increased in every examined system. That increase was as high as 1.67-fold ferritin concentration in the PEG phase as compared with the total concentration of ferritin in the system before separation. Introduction of the magnetic field to two-phase extraction systems is shown as an effective method of changing the partition coefficient of ferritin.

  13. Invasive meningococcal disease in England: assessing disease burden through linkage of multiple national data sources.

    PubMed

    Ladhani, Shamez N; Waight, Pauline A; Ribeiro, Sonia; Ramsay, Mary E

    2015-12-01

    In England, Public Health England conducts enhanced surveillance of invasive meningococcal disease (IMD). The continuing decline in reported IMD cases has raised concerns that the MRU may be underestimating true IMD incidence. We linked five national datasets to estimate disease burden over five years, including PHE Meningococcal Reference Unit (MRU) confirmations, hospital episode statistics (HES), electronic reports of significant infections by National Health Service (NHS) Hospitals, death registrations and private laboratory reports. During 2007-11, MRU confirmed 5115 IMD cases and 4275 (84%) matched to HES, including 3935 (92%) with A39* (meningococcal disease) and 340 (8%) with G00* (bacterial meningo-encephalitis) ICD-10 codes. An additional 2792 hospitalised cases with an A39* code were identified in HES. Of these, 1465 (52%) matched to one of 53,806 samples tested PCR-negative for IMD by MRU and only 73 of the remaining 1327 hospitalised A39* cases were confirmed locally or by a private laboratory. The characteristics of hospitalised cases without laboratory confirmation were similar to PCR-negative than PCR-positive IMD cases. Interrogation of multiple national data sources identified very few laboratory confirmations in addition to the MRU-confirmed cases. The large number of unconfirmed and PCR-negative cases in HES suggests increased awareness among clinicians with low thresholds for hospitalising patients with suspected IMD.

  14. Alternatives to the Fish Early Life-Stage Test: A Research Strategy for Discovering and Annotating Adverse Outcome Pathways During Fish Development

    EPA Science Inventory

    The OECD 210 fish early life]stage (FELS) test is the primary guideline test used to estimate chronic fish toxicity, as well as support ecological risk assessments and chemical management programs around the world. As a step toward developing alternatives to the FELS test, a HES...

  15. Hypereosinophilic syndrome presenting as cutaneous necrotizing eosinophilic vasculitis and Raynaud's phenomenon complicated by digital gangrene.

    PubMed

    Jang, K A; Lim, Y S; Choi, J H; Sung, K J; Moon, K C; Koh, J K

    2000-09-01

    Cutaneous necrotizing eosinophilic vasculitis is a recently identified type of vasculitis that is characterized by an eosinophil-predominant necrotizing vasculitis affecting small dermal vessels. Clinically, it presents with pruritic erythematous and purpuric papules and plaques, peripheral eosinophilia and a good response to systemic steroid therapy. This vasculitis can be idiopathic or associated with connective tissue diseases. Although the pathogenic roles of eosinophil-derived granule proteins and interleukins have been documented in diseases associated with eosinophilia, a role of CD40 (a glycoprotein of the tumour necrosis factor receptor superfamily) has rarely been described. We describe two patients with idiopathic hypereosinophilic syndrome (HES) presenting with multiple erythematous patches and plaques on the lower extremities and Raynaud's phenomenon. They satisfied the criteria for the diagnosis of HES by clinical and laboratory investigations. Histopathology of the cutaneous lesions revealed prominent eosinophilic infiltration with local fibrinoid change in vessel walls in the dermis and subcutis. Immunohistochemical detection of CD3, CD4, CD8 and CD40 was performed. Infiltrating eosinophils were strongly stained by anti-CD40 monoclonal antibody. One patient improved with prednisolone, pentoxifylline and nifedipine, without recurrence. The other patient initially improved with steroids, but after self-withdrawal of steroid developed digital ischaemia that evolved to severe necrosis and required amputation. Cutaneous necrotizing eosinophilic vasculitis, Raynaud's phenomenon and digital gangrene may develop as cutaneous manifestations of HES. CD40 may play a part in the pathogenesis of eosinophilic vasculitis in HES.

  16. Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells.

    PubMed

    Becker, Klaus A; Ghule, Prachi N; Lian, Jane B; Stein, Janet L; van Wijnen, Andre J; Stein, Gary S

    2010-02-01

    Self-renewal of pluripotent human embryonic stem (hES) cells utilizes an abbreviated cell cycle that bypasses E2F/pRB-dependent growth control. We investigated whether self-renewal is alternatively regulated by cyclin/CDK phosphorylation of the p220(NPAT)/HiNF-P complex to activate histone gene expression at the G1/S phase transition. We show that cyclin D2 is prominently expressed in pluripotent hES cells, but cyclin D1 eclipses cyclin D2 during differentiation. Depletion of cyclin D2 or p220(NPAT) causes a cell cycle defect in G1 reflected by diminished phosphorylation of p220(NPAT), decreased cell cycle dependent histone H4 expression and reduced S phase progression. Thus, cyclin D2 and p220(NPAT) are principal cell cycle regulators that determine competency for self-renewal in pluripotent hES cells. While pRB/E2F checkpoint control is relinquished in human ES cells, fidelity of physiological regulation is secured by cyclin D2 dependent activation of the p220(NPAT)/HiNF-P mechanism that may explain perpetual proliferation of hES cells without transformation or tumorigenesis.

  17. Mineral nutrient recovery from pyrolysis systems

    USDA-ARS?s Scientific Manuscript database

    Bioenergy crops such as high-energy sorghum (HES), bioenergy rice, corn stover, and switchgrass can be thermo-chemically converted by pyrolysis to produce bio-oil, synthesis gas from non-condensable gases, and biochar. The biochar fraction can be recycled back to the production field to improve soil...

  18. THE CONTRIBUTION OF AMBIENT PM2.5 TO TOTAL PERSONAL EXPOSURES: RESULTS FROM A POPULATION EXPOSURE MODEL FOR PHILADELPHIA, PA

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) is currently developing an integrated human exposure source-to-dose modeling system (HES2D). This modeling system will incorporate population exposure modules that use a probabilistic approach to predict population exposu...

  19. The Elementary and Secondary Education Act at Fifty: A Changing Federal Role in American Education

    ERIC Educational Resources Information Center

    Nelson, Adam R.

    2016-01-01

    For this first "History of Education Quarterly Policy Forum," we invited participants in the special Plenary Session at the 2015 Annual Meeting of the History of Education Society (HES) in St. Louis to publish their remarks on the historical significance of the Elementary and Secondary Education Act (ESEA) at fifty. Organized and…

  20. Enzymatically catalyzed conjugation of a biodegradable polymer to proteins and small molecules using microbial transglutaminase.

    PubMed

    Besheer, Ahmed; Hertel, Thomas C; Kressler, Jörg; Mäder, Karsten; Pietzsch, Markus

    2011-01-01

    Hydroxyethyl starch (HES) is a water-soluble, biodegradable derivative of starch that is widely used in biomedicine as a plasma volume expander. Due to its favorable properties, HES is currently being investigated at the industrial and academic levels as a biodegradable polymer substitute for polyethylene glycol. To date, only chemical methods have been suggested for HESylation; unfortunately, however, these may have negative effects on protein stability. To address this issue, we have developed an enzymatic method for protein HESylation using recombinant microbial transglutaminase (rMTG). rMTG enzyme is able to catalyze the replacement of the amide ammonia at the γ-position in glutamine residues (acyl donors) with a variety of primary amines (acyl acceptors), including the amino group of lysine (Lys). To convert HES into a suitable substrate for rMTG, the polymer was derivatized with either N-carbobenzyloxy glutaminyl glycine (Z-QG) or hexamethylenediamine to act as an acyl donor or acyl acceptor, respectively. Using SDS-PAGE, it was possible to show that the modified HES successfully coupled to test compounds, proving that it is accepted as a substrate by rMTG. Overall, the enzymatic approach described in this chapter provides a facile route to produce biodegradable polymer-drug and polymer-protein conjugates under relatively mild reaction conditions.

  1. Nonviral Reprogramming of Human Wharton's Jelly Cells Reveals Differences Between ATOH1 Homologues

    PubMed Central

    Mellott, Adam J.; Devarajan, Keerthana; Shinogle, Heather E.; Moore, David S.; Talata, Zsolt; Laurence, Jennifer S.; Forrest, M. Laird; Noji, Sumihare; Tanaka, Eiji; Staecker, Hinrich

    2015-01-01

    The transcription factor atonal homolog 1 (ATOH1) has multiple homologues that are functionally conserved across species and is responsible for the generation of sensory hair cells. To evaluate potential functional differences between homologues, human and mouse ATOH1 (HATH1 and MATH-1, respectively) were nonvirally delivered to human Wharton's jelly cells (hWJCs) for the first time. Delivery of HATH1 to hWJCs demonstrated superior expression of inner ear hair cell markers and characteristics than delivery of MATH-1. Inhibition of HES1 and HES5 signaling further increased the atonal effect. Transfection of hWJCs with HATH1 DNA, HES1 siRNA, and HES5 siRNA displayed positive identification of key hair cell and support cell markers found in the cochlea, as well as a variety of cell shapes, sizes, and features not native to hair cells, suggesting the need for further examination of other cell types induced by HATH1 expression. In the first side-by-side evaluation of HATH1 and MATH-1 in human cells, substantial differences were observed, suggesting that the two atonal homologues may not be interchangeable in human cells, and artificial expression of HATH1 in hWJCs requires further study. In the future, this line of research may lead to engineered systems that would allow for evaluation of drug ototoxicity or potentially even direct therapeutic use. PMID:25760435

  2. Differences in Perceived Implementation of a Standard versus Peer-Led Interactive Substance Abuse Prevention Program

    ERIC Educational Resources Information Center

    Valente, Thomas W.; Okamoto, Janet; Pumpuang, Patchareeya; Okamoto, Paula; Sussman, Steve

    2007-01-01

    Objective: To assess perceived implementation of 2 substance-abuse prevention programs: a standard one and a peer-led interactive one. Methods: Data from 16 health educators were collected after 504 classroom sessions, 63 of which were observed by 24 monitors. Results: In the interactive program, health educators (HEs) followed the curriculum less…

  3. THE CONTRIBUTION OF AMBIENT PM2.5 TO TOTAL PERSONAL EXPOSURES: RESULTS FROM A POPULATION EXPOSURE MODEL FOR PHILADELPHIA, PA

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) is currently developing an integrated human exposure source-to-dose modeling system (HES2D). This modeling system will incorporate population exposure modules that use a probabilistic approach to predict population exposu...

  4. [Hydroxyethyl starch--an interim report].

    PubMed

    Weidhase, R; Faude, K; Weidhase, R

    1998-01-01

    Since the beginning of this century, a few biopolymers have been used as basic materials for volume substitution. Aside from gelatin and dextran, modified starch (hydroxyethyl starch, HES) is currently the first-choice means. Due to special manufacturing processes, different hydroxyethyl starches are now available. They have several different characteristics and produce different clinical effects. These clinical properties depend on the average molecular weight and the distribution of molecular weight as well as on the degree and pattern of substitution. The duration of volume effect, one of the most important parameters for the effectiveness of a volume substitute, depends to a large degree on the substitution. Elimination of HES from serum is delayed by a high degree of substitution and a high C2/C6 ratio of the substitution pattern. The molecular parameters of HES also influence other effects, such as cumulation in various organs and hemostasis. Critical reading of current HES literature shows that many questions still have to be answered. At the same time ways and means of optimizing differential volume substitution therapy and hemodilution therapy are emerging.

  5. Physicochemical properties and responses in microcirculation of native tapioca starch-based plasma expander.

    PubMed

    Chatpun, Surapong; Meesane, Jirut; Rujirojindakul, Pairaya

    2016-02-01

    Plasma expanders (PEs) such as hydroxyethyl strach are widely used for volume replacement. The plantation and production of tapioca in Thailand is abundant which may provide a new source for PEs starch with novel properties. This work investigated the properties and circulatory effects of native tapioca starch-based PE (TPE). Various formulations of mixture between native tapioca starch and 0.9% sodium chloride solution were prepared and characterized in order to obtain the proper physicochemical and rheological properties. About 1% concentration by weight per volume of TPE was compared with 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride (HES130/0.4) using an acute hemodilution by 40% of blood volume in an animal protocol. TPE had higher turbidity and viscosity but lower colloid osmotic pressure compared with HES 130/0.4. The in vivo study demonstrated that Golden Syrian hamsters hemodiluted with TPE maintained a mean arterial blood pressure and no significant difference compared to HES 130/0.4. The arterial vasodilation and functional capillary density in the animals hemodiluted with TPE had higher values than in the animals hemodiluted with HES 130/0.4. Although the in vivo study reported positive results using this native tapioca starch-based PE, the product needs work to improve some of its physiochemical properties.

  6. Applying GIS to Develop a Web-Based Spatial-Person-Temporal History Educational System

    ERIC Educational Resources Information Center

    Lo, Jia-Jiunn; Chang, Chuen-Jung; Tu, Hsiao-Han; Yeh, Shiou-Wen

    2009-01-01

    Developing interactive history learning materials to facilitate historical thinking is one of the challenges in history teaching and learning. This study developed a web-based history educational system, which has used the acronym HES-SPATO (history educational system based on SPATO), to increase the understandability of history learning…

  7. DEVELOPMENT OF VIBRATION RESISTANT PROPELLANTS FOR THE M91 PAD CARTRIDGE. INTEGRATED MOLDED CHARGE

    DTIC Science & Technology

    A case bonded, integrated, molded propellant charge (consisting of RDX- cellulose acetate ) was developed which met the ballistic requirements for the...containing the nitrate ester single base propellant previously used and similar to the ammonium perchlorate- cellulose acetate (HES 5808.7) propellant

  8. Post-transfusion survival of hydroxyethyl starch 450/0·70 in man: a long-term study

    PubMed Central

    Mishler, John Milton; Ricketts, Colin R; Parkhouse, Edward J

    1980-01-01

    Intravascular persistence concomitant with changes occurring in the circulating molecular size distribution were determined in five healthy normovolaemic men dosed with 7 ml/kg of a 6% (w/v) solution of a species of hydroxyethyl starch (HES 450/0·70) possessing a Mw- of 450 000 daltons combined with a molar hydroxyethyl group substitution (MS) of 0·70 (70 hydroxyethyl groups/100 glucose residues). The concentration of HES 450/0·70 in serum fell to 24% of its peak value (measured 2 minutes post injection) one week after the infusion. By 17 weeks after injection, < 1·0% remained in the intravascular space. The HES 450/0·70 material recovered from the bloodstream 2 minutes after injection was shown by gel filtration on a column of Sepharose CL-4B to be less polydisperse than the injected solution. The Kav calculated for the peak of material eluted after one week showed a definite shift of molecular size toward that of a lower molecular weight composition. However, at four weeks the value of Kav indicated a shift toward the high molecular weight region of the injected solution, and by seven weeks this movement was quite pronounced. These data clearly indicate the complex nature of the removal of HES 450/0·70 from the intravascular space of man and appear to substantiate previous clinical studies reporting that the MS plays the major role influencing the rate of elimination of this material from the bloodstream. PMID:6154064

  9. [Enzyme immunoassay for the determination of hexestrol in meat].

    PubMed

    Vdovenko, M M; Peng, C F; Xu, C L; Vylegzhanina, E S; Komarov, A A; Sakharov, I Iu

    2011-01-01

    An indirect competitive enzyme-linked immunosorbent assay (ELISA) of hexestrol (HES), an antibiotic forbidden for use in livestock farming, has been developed. Conditions of ELISA have been optimized by varying the concentrations of the coating conjugate (HES-ovalbumin), anti-HES antiserum, casein, and Tween 20. In the absence of Tween 20 in the reaction mixture, the detection limit (IC10) equaled 0.01 ng/ml, IC50 equaled 0.17 ng/ml, and the working range (IC20-IC80) equaled 0.03-0.86 ng/ml, while, in the presence of 0.05% Tween 20, these values equaled 0.05 ng/ml, 2.9 ng/ml, and 0.26-32.0 ng/ml, respectively. Standard deviation of the analysis results did not exceed 5.4%. If ELISA was performed in the absence of detergents, the recovery value upon HES determination in spiked beef samples ranged from 74 to 147%.

  10. Characterization and physiological effect of tapioca maltodextrin colloid plasma expander in hemorrhagic shock and resuscitation model.

    PubMed

    Chatpun, Surapong; Sawanyawisuth, Kittisak; Wansuksri, Rungtiva; Piyachomkwan, Kuakoon

    2016-05-01

    Plasma expanders (PEs) are administered fluids to replace blood volume when massive blood loss has occured. Maltodextrin from tapioca starch was selected as a study candidate to prepare a colloid PE due to an uncomplicated production process. The formulations of mixture between tapioca maltodextrin and 0.9 % sodium chloride solution were prepared and then characterized. This was to investigate the effects of a dextrose equivalent (DE) and the concentration on the physical properties. Storage stability of each formulation was also determined and compared with clinically used PE [6 % hydroxyethyl starch (HES), 130/0.4]. The effects on the circulatory system in hamsters with hemorrhagic shock and resuscitation using prepared PE were also investigated. The results showed that low DE value led to high retrogradation, turbidity and viscosity but low colloid osmotic pressure and poor solubility. Among the prepared solutions, tapioca maltodextrin with DE6 at 10 % w/v concentration had comparable properties with 6 % HES 130/0.4. Animals resuscitated with 10 % DE6 PE had improved mean arterial blood pressure similar to those resuscitated with 6 % HES 130/0.4. However, several parameters in animals resuscitated with 10 % DE6 PE were lower than those resuscitated with 6 % HES 130/0.4, i.e., heart rate, functional capillary density. Therefore, if using tapioca maltodextrin for PE, some properties have to be considered and efficiently optimized.

  11. Investigating increased admissions to neonatal intensive care in England between 1995 and 2006: data linkage study using Hospital Episode Statistics.

    PubMed

    Morgan, Andrei S; Marlow, Neil; Costeloe, Kate; Draper, Elizabeth S

    2016-05-20

    A 44 % increase was observed in admissions to neonatal intensive care of babies born ≤26 weeks completed gestational age in England between 1995 and 2006. Hospital Episode Statistics (HES) may provide supplementary information to investigate this. The methods and results of a probabilistic data linkage exercise are reported. Two data sets were linked for each year (1995 and 2006) using 3 different algorithms (Fellegi and Sunter, Contiero and estimation-maximisation). In 1995, linkage was performed between 668 EPICure and 486,705 HES records; 1,820 linked pairs were identified of which 422 (63.17 %) were confirmed. In 2006, from 2,750 EPICure and 631,401 HES records, 8,913 linked pairs were identified with 1,662 (60.40 %) confirmed as true. Reported births in HES at <26 weeks gestation increased 37.0 % from 867 to 1188. Results support the EPICure findings that there was an increase in the birth rate for extremely premature babies between 1995 and 2006. There were insufficient data available for detailed investigation. Routine data sources may not be suitable for investigations at the margins of viability.

  12. Conjugates of degraded and oxidized hydroxyethyl starch and sulfonylureas: synthesis, characterization, and in vivo antidiabetic activity.

    PubMed

    Abbas, Muhammad Azhar; Hameed, Shahid; Farman, Muhammad; Kressler, Jörg; Mahmood, Nasir

    2015-01-21

    Orally administered drugs usually face the problem of low water solubility, low permeability, and less retention in bloodstream leading to unsatisfactory pharmacokinetic profile of drugs. Polymer conjugation has attracted increasing interest in the pharmaceutical industry for delivering such low molecular weight (Mw) drugs as well as some complex compounds. In the present work, degraded and oxidized hydroxyethyl starch (HES), a highly biocompatible semisynthetic biopolymer, was used as a drug carrier to overcome the solubility and permeability problems. The HES was coupled with synthesized N-arylsulfonylbenzimidazolones, a class of sulfonylurea derivatives, by creating an amide linkage between the two species. The coupled products were characterized using GPC, FT-IR, (1)H NMR, and (13)C NMR spectroscopy. The experiments established the viability of covalent coupling between the biopolymer and N-arylsulfonylbenzimidazolones. The coupled products were screened for their in vivo antidiabetic potential on male albino rats. The coupling of sulfonylurea derivatives with HES resulted in a marked increase of the hypoglycemic activity of all the compounds. 2,3-Dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1H-benzimidazole coupled to HES10100 was found most potent with a 67% reduction in blood glucose level of the rats as compared to 41% reduction produced by tolbutamide and 38% by metformin.

  13. Safety evaluation on low-molecular-weight hydroxyethyl starch for volume expansion therapy in pediatric patients: a meta-analysis of randomized controlled trials.

    PubMed

    Li, Lixia; Li, Yongyang; Xu, Xiaoxing; Xu, Bo; Ren, Rongrong; Liu, Yan; Zhang, Jian; He, Bin

    2015-03-10

    Hydroxyethyl starch (HES) has been widely used for volume expansion, but its safety in adult patients has been questioned recently. The aim of this meta-analysis is to see whether or not HES has any adverse effect in pediatric patients. Randomized controlled trials (RCTs) involving pediatric patients who received 6% low-molecular-weight HES, published before January 2014, were searched for in Pubmed, Embase database and Cochrane Library. Two reviewers independently extracted the valid data, including the mortality, renal function, coagulation, blood loss, hemodynamic changes, and length of hospital and ICU stay. All data were analyzed by I (2)-test, and the results of statistical analysis were displayed in forest plots. Possible publication bias was tested by funnel plots. Bayesian analysis was performed using WinBUGS with fixed and random effects models. A total of 13 RCTs involving 1,156 pediatric patients were finally included in this meta-analysis. Compared with other fluids, HES did not significantly decrease the mortality (RR = -0.01; 95%CI: 0.05 to 0.03; P = 0.54; I(2) = 6%), creatinine level (I(2) -test: MD = 1.81; 95%CI: -0.35 to 3.98; P = 0.10;I(2)  = 0%; Bayesian analysis: Fixed effect model MD = 1.77; 95%CI: -0.07 to 3.6; Random effects model MD = 1.78; 95%CI: -1.86 to 5.33), activated partial thromboplastin time (MD = 0.01; 95%CI: -1.05 to 1.07; P = 0.99; I(2) = 42%), and blood loss (MD = 17.72; 95%CI: -41.27 to 5.82; P = 0.10; I(2) = 0%) in pediatric patients. However, HES significantly decreased the blood platelet count (MD = 20.99; 95%CI: -32.08 to -9.90; P = 0.0002; I(2) = 28%) and increased the length of ICU stay (MD = 0.94; 95%CI: 0.18 to 1.70; P = 0.02; I(2) = 46%). Volume expansion with 6% HES significantly decreased the platelet count and increased the length of ICU stay, also might have an adverse effect on renal function. Therefore HES is not recommended for

  14. Short-term effects of low-volume resuscitation with hypertonic saline and hydroxyethylstarch in an experimental model of lung contusion and haemorrhagic shock.

    PubMed

    Prunet, Bertrand; Cordier, Pierre-Yves; Prat, Nicolas; De Bourmont, Sophie; Couret, David; Lambert, Dominique; Michelet, Pierre

    2016-09-20

    This study aimed to assess the short-term respiratory tolerance and haemodynamic efficiency of low-volume resuscitation with hypertonic saline and hydroxyethylstarch (HS/HES) in a pig model of lung contusion and controlled haemorrhagic shock. We hypothesised that a low-volume of HS/HES after haemorrhagic shock did not impact contused lungs in terms of extravascular lung water 3hours after trauma. A lung contusion resulting from blunt chest trauma was induced in 28 anaesthetised female pigs with five bolt-shots to the right thoracic cage, followed by haemorrhagic shock and fluid resuscitation. Pigs were randomly allocated into two groups: fluid resuscitation by 4ml/kg of HS/HES, or fluid resuscitation by 10ml/kg of normal saline (NS). Monitoring was based on transpulmonary thermodilution and a pulmonary artery catheter. After 3h, animals were euthanized to measure extravascular lung water (EVLW) by gravimetry. Blunt chest trauma was followed by a transient collapse and hypoxaemia in both groups. Post-mortem gravimetric assessment demonstrated a significant difference between EVLW in the NS-group (8.1±0.7ml/kg) and in the HS/HES-group (6.2±0.6ml/kg, P=0.038). Based on a pathological EVLW threshold of > 7ml/kg, results indicated that only the NS-group experienced moderate pulmonary oedema, contrary to the HS/HES-group. After haemorrhagic shock, HS/HES infusion enabled the restoration of effective mean arterial pressure and cardiac index. Intrapulmonary shunting increased transiently after fluid resuscitation but there was no significant impairment of oxygenation. In this pig model of lung contusion, the short-term assessment of fluid resuscitation after haemorrhagic shock with 4ml/kg of HS/HES showed that pulmonary oedema was avoided compared to fluid resuscitation with 10ml/kg of NS. Copyright © 2016 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

  15. [Limited applications for hydroxyethyl starch : background and alternative concepts].

    PubMed

    Rehm, M

    2013-08-01

    Within the framework of a risk assessment procedure the Committee for Risk Assessment of Pharmacovigilance (PRAC) of the European Medicines Agency (EMA) came to the conclusion that the benefits of hydroxylethyl starch infusion solutions (HES) no longer outweighed the risks and on 14 June 2013 recommended that approval should be suspended. Until the procedure has finally been concluded, which could last several months, the Federal Institute for Drugs and Medical Products (BfArM) has recommended that HES should not be used. The aim of this article is to present the data situation in the most objective and compact way and to ultimately give the reader the foundations in order to be able to form a personal opinion. In addition an attempt will be made to describe a concept how infusion therapy can be carried out without using hydroxyethyl starch (HES). The background to this decision is given based on a review of the literature and the relevance for intensive care, emergency and perioperative medicine is assessed. Furthermore, a concept of infusion therapy without hydroxyethyl starch is formulated also based on the results of current studies. For infusion regimens without HES it should be noted that gelatin represents a considerable risk for anaphylactic reactions, that transfer of the new variants of Creutzfeldt-Jacob disease (bovine spongiform encephalopathy BSE) cannot fundamentally be excluded and that some evidence has been found that gelatin can cause kidney injury, probably in a similar way to HES. With respect to the cost-benefit analysis of infusion solutions, blood loss in adults of approximately 1-1.5 l can be substituted by balanced crystalloids (basic therapy 4-5 times compared to the amount of blood lost). For larger blood losses small amounts of hyperoncotic albumin solution (20 %) or alternatively 5 % albumin solution can be used. The 20 % albumin solution seems to have some advantages because it has a higher volume effect (approximately 200 %) and can

  16. Significance of Dynamic and Transient Analysis in the Design and Operation of Hybrid Energy Systems

    SciTech Connect

    Panwar, Mayank; Mohanpurkar, Manish; Hovsapian, Rob; Osorio, Julian D.

    2015-02-01

    Energy systems were historically designed and operated with a specific energy conversion objective, while managing loads and resources. In the recent years, the increased utilization of non-dispatchable renewable sources such as wind and solar has played a role in power quality and the reliability of power systems. In order to mitigate the risk associated with the non-dispatchable resources an integrated approach, such as Hybrid Energy Systems (HES), has to be taken, integrating the loads and resource management between the traditional thermal power plants and the non-dispatchable resources. As our electric energy becomes more diverse in its generation resources, the HES with its operational control system, its real-time view and its dynamic decisions making will become an essential part of the integrated energy systems and improve the overall grid reliability. The operational constraints of the energy sources on both the thermal power plants and the non-dispatchable resources in HES, plays a vital role in the planning and design stage. It is an established fact that the choice of energy source depends on the available natural resources and possible infrastructure. A critical component of decision-making depends on the complementary nature and controllability of the energy sources to supply the load demands with high reliability. Controllability of complex HES to achieve desired performance and flexibility is implemented via coordinated control systems while simultaneously generating electricity and other useful products such as useful heat or hydrogen. These systems are based on instrumentation, signal processing, control theory, and engineering system design. The entire HES along with the control systems are characterized by widely varying time constants. Hence, for a well-coordinated control and operation, we propose physics based modeling of the subsystems to assist in a dynamic and transient analysis. Dynamic and transient analysis in real and non-real time

  17. Effect of fluid loading with normal saline and 6% hydroxyethyl starch on stroke volume variability and left ventricular volume

    PubMed Central

    Kanda, Hirotsugu; Hirasaki, Yuji; Iida, Takafumi; Kanao, Megumi; Toyama, Yuki; Kunisawa, Takayuki; Iwasaki, Hiroshi

    2015-01-01

    Purpose The aim of this clinical trial was to investigate changes in stroke volume variability (SVV) and left ventricular end-diastolic volume (LVEDV) after a fluid bolus of crystalloid or colloid using real-time three-dimensional transesophageal echocardiography (3D-TEE) and the Vigileo-FloTrac™ system. Materials and methods After obtaining Institutional Review Board approval, and informed consent from the research participants, 22 patients undergoing scheduled peripheral vascular bypass surgery were enrolled in the study. The patients were randomly assigned to receive 500 mL of hydroxyethyl starch (HES; HES group, n=11) or normal saline (Saline group, n=11) for fluid replacement therapy. SVV was measured using the Vigileo-FloTrac system. LVEDV, stroke volume, and cardiac output were measured by 3D-TEE. The measurements were performed over 30 minutes before and after the fluid bolus in both groups. Results SVV significantly decreased after fluid bolus in both groups (HES group, 14.7%±2.6% to 6.9%±2.7%, P<0.001; Saline group, 14.3%±3.9% to 8.8%±3.1%, P<0.001). LVEDV significantly increased after fluid loading in the HES group (87.1±24.0 mL to 99.9±27.2 mL, P<0.001), whereas no significant change was detected in the Saline group (88.8±17.3 mL to 91.4±17.6 mL, P>0.05). Stroke volume significantly increased after infusion in the HES group (50.6±12.5 mL to 61.6±19.1 mL, P<0.01) but not in the Saline group (51.6±13.4 mL to 54.1±12.8 mL, P>0.05). Cardiac output measured by 3D-TEE significantly increased in the HES group (3.5±1.1 L/min to 3.9±1.3 L/min, P<0.05), whereas no significant change was seen in the Saline group (3.4±1.1 L/min to 3.3±1.0 L/min, P>0.05). Conclusion Administration of colloid and crystalloid induced similar responses in SVV. A higher plasma-expanding effect of HES compared to normal saline was demonstrated by the significant increase in LVEDV. PMID:26491368

  18. Computational enzyme design

    NASA Astrophysics Data System (ADS)

    Bolon, Daniel N.

    2002-08-01

    The long-term objective of computational enzyme design is the ability to generate efficient protein catalysts for any chemical reaction. This thesis develops and experimentally validates a general computational approach for the design of enzymes with novel function. In order to include catalytic mechanism in protein design, a high-energy state (HES) rotamer (side chain representation) was constructed. In this rotamer, substrate atoms are in a HES. In addition, at least one amino acid side chain is positioned to interact favorably with substrate atoms in their HES and facilitate the reaction. Including an amino acid side chain in the HES rotamer automatically positions substrate relative to a protein scaffold and allows protein design algorithms to search for sequences capable of interacting favorably with the substrate. Because chemical similarity exists between the transition state and the high-energy state, optimizing the protein sequence to interact favorably with the HES rotamer should lead to transition state stabilization. In addition, the HES rotamer model focuses the subsequent computational active site design on a relevant phase space where an amino acid is capable of interacting in a catalytically active geometry with substrate. Using a HES rotamer model of the histidine mediated nucleophilic hydrolysis of p-nitrophenyl acetate, the catalytically inert 108 residue E. coli thioredoxin as a scaffold, and the ORBIT protein design software to compute sequences, an active site scan identified two promising active site designs. Experimentally, both candidate ?protozymes? demonstrated catalytic activity significantly above background. In addition, the rate enhancement of one of these ?protozymes? was the same order of magnitude as the first catalytic antibodies. Because polar groups are frequently buried at enzyme-substrate interfaces, improved modeling of buried polar interactions may benefit enzyme design. By studying native protein structures, rules have been

  19. Distribution and differentiation of myeloid-derived suppressor cells after fluid resuscitation in mice with hemorrhagic shock*

    PubMed Central

    Jiang, Jiu-kun; Fang, Wen; Hong, Liang-jie; Lu, Yuan-qiang

    2017-01-01

    Objective: To investigate the distribution and differentiation of myeloid-derived suppressor cells (MDSCs) in hemorrhagic shock mice, which are resuscitated with normal saline (NS), hypertonic saline (HTS), and hydroxyethyl starch (HES). Methods: BALB/c mice were randomly divided into control, NS, HTS, and HES resuscitation groups. Three subgroups (n=8) in each resuscitation group were marked as 2, 24, and 72 h. Flow cytometry was used to detect the MDSCs, monocytic MDSCs (M-MDSCs), and granulocytic/neutrophilic MDSCs (G-MDSCs) in peripheral blood nucleated cells (PBNCs), spleen single-cell suspension, and bone marrow nucleated cells (BMNCs). Results: The MDSCs in BMNCs among three resuscitation groups were lower 2 h after shock, in PBNCs of the HTS group were higher, and in spleen of the NS group were lower (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios in PBNCs of the HTS and HES groups were lower (both P<0.05 vs. control). At 24 h, the MDSCs in PBNCs of the NS and HTS groups were higher, while the spleen MDSCs in the HTS group were higher (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios were all less in PBNCs, spleen, and BMNCs of the NS and HTS groups, and were lower in BMNCs of the HES group (all P<0.05 vs. control). At 72 h, the elevated MDSCs in PBNCs were presented in the HTS and HES groups, and in spleen the augment turned up in three resuscitation groups (all P<0.05 vs. control). The inclined ratios to M-MDSC were exhibited in spleen of the NS and HTS groups, and in PBNCs of the NS group; the inclination to G-MDSC in BMNCs was shown in the HES group (all P<0.05 vs. control). Conclusions: HTS induces the earlier elevation of MDSCs in peripheral blood and spleen, and influences its distribution and differentiation, while HES has a less effect on the distribution but a stronger impact on the differentiation of MDSCs, especially in bone marrow. PMID:28070996

  20. Platelet closure time in anesthetized Greyhounds with hemorrhagic shock treated with hydroxyethyl starch 130/0.4 or 0.9% sodium chloride infusions.

    PubMed

    McBride, Duana; Hosgood, Giselle; Raisis, Anthea; Smart, Lisa

    2016-07-01

    To measure platelet closure time (PCT) in dogs during controlled hemorrhagic shock and after fluid resuscitation with hydroxyethyl starch (HES) 130/0.4 or 0.9% sodium chloride. Experimental interventional study. University veterinary teaching hospital. Eleven healthy Greyhounds. Dogs were anesthetized and had 48 mL/kg of blood removed to induce hemorrhagic shock. Dogs received 20 mL/kg of HES 130/0.4 (n = 6) or 80 mL/kg of 0.9% sodium chloride (NaCl; n = 5) intravenously over 20 minutes. PCT was measured using the Platelet Function Analyzer-100 with collagen and adenosine-diphosphate cartridges at: T0 = 60 minutes after induction of anesthesia prior to hemorrhage, T1 = during hemorrhagic shock, and T2 = 40 minutes after completion of fluid bolus. Packed cell volume and platelet count were concurrently measured. Hemorrhagic shock did not significantly change PCT, with no difference between T0 and T1. Both the HES 130/0.4 and 0.9% NaCl group had a significantly increased mean PCT at T2 of 91.4 seconds (95% CI 69.3-113.4) and 95.5 seconds (95% CI 78.2-112.8), respectively, compared to T1. The magnitude of change was significantly greater for the 0.9% NaCl group than the HES 130/0.4 group. There was no difference in the magnitude of change in PCV and platelet count between the 2 groups. The PCV and platelet count were >25% and >100,000/μL, respectively, in all dogs, except for dogs in the HES 130/0.4 group at T2 where platelet counts were <100,000/μL. Controlled hemorrhagic shock in Greyhounds under anesthesia did not cause a significant change in PCT. Both HES 130/0.4 and 0.9% NaCl administration after induction of shock increased PCT. These results do not support that HES 130/0.4 causes relevant platelet dysfunction beyond hemodilution. © Veterinary Emergency and Critical Care Society 2016.

  1. Blood transfusion, colloid therapy and the possible saving of albumin volumes during surgery: data analysis of the survey for certified hospitals of the Japanese Society of Anesthesiologists.

    PubMed

    Miyao, Hideki

    2016-06-01

    Third-generation hydroxyethyl starch (HES) 130/0.4 has a larger dose limitation (up to 50 mL/kg/day) than HES 70/0.5 (up to 1000 mL/day) which has been used in Japan for 40 years. The aim of this study was to survey the current intraoperative blood transfusion and volume therapy and to predict the possible reduction of intraoperative albumin consumption assuming further replacement by HES 130/0.4 using data obtained from a survey by the Japanese Society of Anesthesiologists (JSA), although HES130/0.4 was not launched in Japan during this survey period. In a JSA survey conducted at JSA-certified hospitals, 12,856 patients with a certain amount of blood loss were analyzed for 1 month (April, 2012). The patients were divided into two groups-group A included patients aged ≥11 years and group B included patients aged <10 years. The possible lower volume of intraoperative albumin was calculated assuming that HES 130/0.4 was used up to a dose of 50 mL/kg. Blood loss (total 15,111 L; 15,057 L in group A and 54 L in group B) was treated with allogeneic transfusion (total 7970 L; 7893 L in group A and 77 L in group B) and auto-transfusion (total 1777 L; 1771 L in group A and 6 L in group B) in both groups (n = 11,670 and 119). Albumin (total 1391 L; 1376 L in group A and 15 L in group B), and HES 70/0.5 (total 7645 L; 7638 L in group A and 7 L in group B) were used in both groups (n = 10,850 and 116). Five percent and 4.4 % albumin (total 1189 L; 1180 L in group A and 9 L in group B) could be replaced by HES 130/0.4 if HES 130/0.4 had been used up to a dose of 50 mL/kg. Blood loss (15,111 L) was replaced with allogeneic transfusion (53 %), auto-transfusion (12 %), albumin (9 %) and HES 70/0.5 (51 %) during surgery in April 2012. The predicted volume of 5 and 4.4 % albumin saved during this 1-month period if HES 130/0.4 had been used up to a dose of 50 mL/kg was 1189 L (86 % of actual amount used).

  2. Effects of Simvastatin on Retinoic Acid System in Primary Human Endometrial Stromal Cells and in a Chimeric Model of Human Endometriosis

    PubMed Central

    Sokalska, Anna; Anderson, MariaPia; Villanueva, Jesus; Ortega, Israel; Bruner-Tran, Kaylon L.; Osteen, Kevin G.

    2013-01-01

    Context: Retinoic acid (RA) may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2), and cell survival-promoting fatty acid binding protein 5 (FABP5). Increased cellular uptake of retinol and altered actions of RA related to reduced expression of CRABP2 may contribute to the development of endometriosis. Recently statins have been shown to inhibit growth of human endometrial stromal (HES) cells and to reduce the number and size of endometriotic implants in experimental models of this disorder. Objective: The objective of the study was to determine whether effects of simvastatin on HES cells and experimental endometriotic implants are related to the modulation of the RA system. Methods: Effects of simvastatin and RA on proliferation and apoptosis of HES cells were evaluated. Expression of stimulated by RA 6 (STRA6), CRABP2, and FABP5 was determined by real-time PCR and Western blotting. Effects of simvastatin were also evaluated in a nude mouse model of human endometriosis. Results: Simvastatin potentiated an inhibitory effect of RA on growth of HES cells. In HES cells, simvastatin induced expression of STRA6 and CRABP2 but not FABP5. Similarly, simvastatin treatment of nude mice bearing human endometrial xenografts led to an increased expression of CRABP2 and STRA6 proteins in ectopic lesions. Conclusions: Simvastatin interacts with the RA system, inducing the expression of the key protein regulating the uptake of retinol (STRA6) and the expression of apoptosis-promoting CRABP2. These effects may contribute to cooperative apoptosis-inducing effects of simvastatin and RA and support the examination of these compounds in the treatment of endometriosis. PMID:23337719

  3. Systematically profiling and annotating long intergenic non-coding RNAs in human embryonic stem cell

    PubMed Central

    2013-01-01

    Background While more and more long intergenic non-coding RNAs (lincRNAs) were identified to take important roles in both maintaining pluripotency and regulating differentiation, how these lincRNAs may define and drive cell fate decisions on a global scale are still mostly elusive. Systematical profiling and comprehensive annotation of embryonic stem cells lincRNAs may not only bring a clearer big picture of these novel regulators but also shed light on their functionalities. Results Based on multiple RNA-Seq datasets, we systematically identified 300 human embryonic stem cell lincRNAs (hES lincRNAs). Of which, one forth (78 out of 300) hES lincRNAs were further identified to be biasedly expressed in human ES cells. Functional analysis showed that they were preferentially involved in several early-development related biological processes. Comparative genomics analysis further suggested that around half of the identified hES lincRNAs were conserved in mouse. To facilitate further investigation of these hES lincRNAs, we constructed an online portal for biologists to access all their sequences and annotations interactively. In addition to navigation through a genome browse interface, users can also locate lincRNAs through an advanced query interface based on both keywords and expression profiles, and analyze results through multiple tools. Conclusions By integrating multiple RNA-Seq datasets, we systematically characterized and annotated 300 hES lincRNAs. A full functional web portal is available freely at http://scbrowse.cbi.pku.edu.cn. As the first global profiling and annotating of human embryonic stem cell lincRNAs, this work aims to provide a valuable resource for both experimental biologists and bioinformaticians. PMID:24564552

  4. Colloid solutions for fluid resuscitation in patients with sepsis: systematic review of randomized controlled trials.

    PubMed

    Zhong, Jing-Zi; Wei, Dan; Pan, Hong-Fei; Chen, Yu-Jun; Liang, Xiu-An; Yang, Zhi-Yong; Tang, Hua-Bo

    2013-10-01

    Colloids are widely used for fluid resuscitation in patients with sepsis. But the optimal type of fluid remains unclear. Our aim was to assess the effects on mortality and safety of different colloid solutions in patients with sepsis requiring volume replacement by examining direct comparisons of colloid solutions. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, China Biological Medicine Database, VIP Chinese Journals Database, and CNKI China National Knowledge Infrastructure Whole Article Database. Randomized clinical trials comparing different colloids in septic patients needing fluid resuscitation were selected. Seventeen randomized clinical trials with a total 1281 participants met the inclusion criteria. Mortality was obtained in all trials. For intervention of albumin vs. hydroxyethyl starch solution (HES), the relative risk (RR) of death was 0.98 (95% confidence interval [CI] 0.74-1.30). For intervention of albumin vs. gelatin, the RR of death was 2.4 (95% CI 0.31-18.35). For intervention of gelatin vs. HES, the RR of death was 1.02 (95% CI 0.79-1.32). For the intervention of HES vs. dextran, the RR of death was 1.38 (95% CI 0.28-6.78). For the intervention of gelatin vs. dextran, RR of death was not estimable. For albumin vs. dextran, no trial was included. Four trials of intervention of albumin vs. HES recorded the change of severity score. There is no evidence that one colloid solution is more effective and safer than another for fluid resuscitation in sepsis. The severity score is improved in HES, but the confidence intervals are wide. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Cytogenetic and molecular cytogenetic characterization of 6 new cases of idiopathic hypereosinophilic syndrome.

    PubMed

    Bigoni, R; Cuneo, A; Roberti, M G; Milani, R; Bardi, A; Cavazzini, F; Minotto, C; Castoldi, G

    2000-05-01

    Idiopathic hypereosinophilic syndrome (HES) is defined as a peripheral blood eosiniphilia greater than 1, 500 cells/microL for longer than 6 months, absence of other apparent etiologies for eosinophilia and signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder but scanty information is available concerning its cytogenetic profile. Six patients with HES were studied by cytogenetic analysis. To increase the sensitivity of cytogenetic analysis, interphase FISH studies were performed to detect some cryptic chromosomal lesions involving the regions known to be frequently involved in myeloproliferative disorders (i.e. BCR/ABL, 5q31, 7q31.1, 11q23, 13q14, 17p13). Clinical parameters were recorded in all patients. A 3q deletion was detected in one patient; two unrelated clones with +14 and +11 were present in another patient who had a cryptic 5q31 deletion as disclosed by FISH; both patients had a mild clinical course. The 5q31 deletion was shown to involve the eosinophilic lineage and not the lymphoid cells. No chromosome abnormalities were found by karyotyping or interphase FISH in the remaining 4 cases. In two of these cases the clinical course was aggressive, with progressive leukocytosis and marked splenomegaly in one patient, central nervous system and cardiac involvement as well as bone marrow failure in the other. The 3q deletion, +11 and +14, and a cryptic 5q31 deletion involving the cells of the eosinophilic lineage are three novel chromosome abnormalities occurring in HES. We did not find a correlation between evolving or aggressive disease and the presence of chromosome anomalies. Our data confirm that HES is a clinically and biologically heterogeneous condition and suggest that more cases need to be studied to identify clinically significant chromosome changes in this rare condition. Some patients may benefit from treatment with interferon.

  6. Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients - a multidisciplinary statement

    PubMed Central

    2013-01-01

    Introduction Hydroxyethyl starch (HES) is a commonly used colloid in critically ill patients. However, its safety has been questioned in recent studies and meta-analyses. Methods We re-evaluated prospective randomised controlled trials (RCT) from four meta-analyses published in 2013 that compared the effect of HES with crystalloids in critically ill patients, focusing on the adherence to 'presumably correct indication'. Regarding the definition of 'presumably correct indication', studies were checked for the following six criteria (maximum six points): short time interval from shock to randomisation (<6 h), restricted use for initial volume resuscitation, use of any consistent algorithm for haemodynamic stabilisation, reproducible indicators of hypovolaemia, maximum dose of HES, and exclusion of patients with pre-existing renal failure or renal replacement therapy. Results Duration of fluid administration ranged from 90 min up to a maximum of 90 days. Four studies considered follow-up until 90-day mortality, three studies 28-/30-day mortality, whereas four studies reported only early mortality. Included studies showed a large heterogeneity of the indication score ranging between 1 and 4 points with a median (25%; 75% quartile) of 4 (2; 4). Conclusions The most important question, whether or not HES may be harmful when it is limited to immediate haemodynamic stabilisation, cannot be answered yet in the absence of any study sufficiently addressing this question. In order to overcome the limitations of most of the previous studies, we now suggest an algorithm emphasising the strict indication of HES. Additionally, we give a list of suggestions that should be adequately considered in any prospective RCT in the field of acute volume resuscitation in critically ill patients. PMID:23890518

  7. Comparison of dementia recorded in routinely collected hospital admission data in England with dementia recorded in primary care.

    PubMed

    Brown, Anna; Kirichek, Oksana; Balkwill, Angela; Reeves, Gillian; Beral, Valerie; Sudlow, Cathie; Gallacher, John; Green, Jane

    2016-01-01

    Electronic linkage of UK cohorts to routinely collected National Health Service (NHS) records provides virtually complete follow-up for cause-specific hospital admissions and deaths. The reliability of dementia diagnoses recorded in NHS hospital data is not well documented. For a sample of Million Women Study participants in England we compared dementia recorded in routinely collected NHS hospital data (Hospital Episode Statistics: HES) with dementia recorded in two separate sources of primary care information: a primary care database [Clinical Practice Research Datalink (CPRD), n = 340] and a survey of study participants' General Practitioners (GPs, n = 244). Dementia recorded in HES fully agreed both with CPRD and with GP survey data for 85% of women; it did not agree for 1 and 4%, respectively. Agreement was uncertain for the remaining 14 and 11%, respectively; and among those classified as having uncertain agreement in CPRD, non-specific terms compatible with dementia, such as 'memory loss', were recorded in the CPRD database for 79% of the women. Agreement was significantly better (p < 0.05 for all comparisons) for women with HES diagnoses for Alzheimer's disease (95 and 94% agreement with any dementia for CPRD and GP survey, respectively) and for vascular dementia (88 and 88%, respectively) than for women with a record only of dementia not otherwise specified (70 and 72%, respectively). Dementia in the same woman was first mentioned an average 1.6 (SD 2.6) years earlier in primary care (CPRD) than in hospital (HES) data. Age-specific rates for dementia based on the hospital admission data were lower than the rates based on the primary care data, but were similar if the delay in recording in HES was taken into account. Dementia recorded in routinely collected NHS hospital admission data for women in England agrees well with primary care records of dementia assessed separately from two different sources, and is sufficiently reliable for epidemiological

  8. Notch system is differentially expressed and activated in pituitary adenomas of distinct histotype, tumor cell lines and normal pituitaries

    PubMed Central

    Perrone, Sofia; Zubeldia-Brenner, Lautaro; Gazza, Elias; Demarchi, Gianina; Baccarini, Leticia; Baricalla, Agustin; Mertens, Freya; Luque, Guillermina; Vankelecom, Hugo; Berner, Silvia

    2017-01-01

    Pituitary adenomas are among the most frequent intracranial neoplasms and treatment depends on tumor subtype and clinical features. Unfortunately, non responder cases occur, then new molecular targets are needed. Notch system component expression and activation data are scarce in pituitary tumorigenesis, we therefore aimed to characterize Notch system in pituitary tumors of different histotype. In human pituitary adenomas we showed NOTCH1-4 receptors, JAGGED1 ligand and HES1 target gene expression with positive correlations between NOTCH1,2,4 and HES1, and NOTCH3 and JAGGED1 denoting Notch system activation in a subset of tumors. Importantly, NOTCH3 positive cells were higher in corticotropinomas and somatotropinomas compared to non functioning adenomas. In accordance, Notch activation was evidenced in AtT20 tumor corticotropes, with higher levels of NOTCH1-3 active domains, Jagged1 and Hes1 compared to normal pituitary. In the prolactinoma cell lines GH3 and MMQ, in vivo GH3 tumors and normal glands, Notch system activation was lower than in corticotropes. In MMQ cells only the NOTCH2 active domain was increased, whereas NOTCH1 active domain was higher in GH3 tumors. High levels of Jagged1 and Dll1 were found solely in GH3 cells, and Hes1, Hey1 and Hey2 were expressed in a model dependent pattern. Prolactinomas harbored by lacDrd2KO mice expressed high levels of NOTCH1 active domain and reduced Hes1. We show a differential expression of Notch system components in tumoral and normal pituitaries and specific Notch system involvement depending on adenoma histotype, with higher activation in corticotropinomas. These data suggest that targeting Notch pathway may benefit non responder pituitary adenomas. PMID:28915655

  9. Identification of the key genes implicated in the transformation of OLP to OSCC using RNA-sequencing.

    PubMed

    Yang, Qiaozhen; Guo, Bin; Sun, Hongying; Zhang, Jie; Liu, Shangfeng; Hexige, Saiyin; Yu, Xuedi; Wang, Xiaxia

    2017-04-01

    Oral lichen planus (OLP) is a chronic inflammatory disease that may transform to oral squamous cell carcinoma (OSCC), while its carcinogenesis mechanisms are not entirely clear. This study was designed to identify the important genes involved in the malignant transformation of OLP to OSCC. After RNA-sequencing, the differently expressed genes (DEGs) in OLP vs. normal and OSCC vs. normal groups, respectively, were identified by limma package in R language, and then clustering analysis were conducted by Pheatmap package in R language. Weighed gene co-expression network analysis (WGCNA) was performed for the DEGs to screen disease-associated modules. Using Cytoscape software, co-expression networks were constructed for the genes involved in the modules. Enrichment analysis was conducted for the genes involved in the co-expression networks using GOstat package in R language. Finally, quantitative real-time PCR (qRT-PCR) experiments were conducted to validate the key genes. There were, respectively, 223 and 548 DEGs in OLP vs. normal and OSCC vs. normal groups. WGCNA identified the blue modules for the DEGs in the two groups as disease-associated modules. Moreover, 19 common DEGs (including upregulated BCL9L, PER2 and TSPAN33, and downregulated GMPS and HES1) associated with both OLP and OSCC were identified. In the co-expression networks, BCL9L, HES1, PER2 and TSPAN33 might function in OLP via interactions (such as BCL9L-TSPAN33 and HES1-PER2). qRT-PCR analysis showed that BCL9L, PER2 and TSPAN33 were significantly upregulated, and GMP and HES1 were downregulated. These findings indicated that BCL9L, GMPS, HES1, PER2 and TSPAN33 affected the transformation of OLP to OSCC.

  10. Buffer capacity of 4% succinylated gelatin does not provide any advantages over acidic 6% hydroxyethyl starch 130/0.4 for acid-base balance during experimental mixed acidaemia in a porcine model.

    PubMed

    Esche, V; Russ, M; Melzer, S; Grossmann, B; Boemke, W; Unger, J K

    2008-11-01

    Four percent gelatine is an alkaline compound due to NH2 groups, whereas 6% hydroxyethyl starch 130/0.4 (HES130) has acidic features. We investigated whether these solutions lead to differences in acid-base balance in pigs during acidaemia and correction of pH. Anaesthetized pigs were randomized to HES130 or gelatine infusion (n = 5 per group). Animals received acid infusion (0.4 M solution of lactic acid and HCl diluted in normal saline) and low tidal volume ventilation (6-7 mL kg(-1), PaCO2 of 80-85 mmHg, pH 7.19-7.24). Measurements were made before and after induction of acidaemia, before and after correction of pH with haemofiltration (continuous venovenous haemofiltration) and tris-hydroxymethylaminomethane infusion. We measured parameters describing acid-base balance according to Stewart's approach, ketone body formation, oxygen delivery, haemodynamics, diuresis and urinary pH. Acid-base balance did not differ significantly between the groups. In HES130-treated pigs, the haemodilution-based drop of haemoglobin (1.4 +/- 1.0 g dL(-1), median +/- SD) was paralleled by an increase in the cardiac output (0.5 +/- 0.4 L min(-1). Lacking increases in cardiac output, gelatine-treated pigs demonstrated a reduction in oxygen delivery (149.4 +/- 106.0 mL min(-1)). Tris-hydroxymethylaminomethane volumes required for pH titration to desired values were significantly higher in the gelatine group (0.7 +/- 0.1 mL kg(-1) h(-1) vs. HES130: 0.5 +/- 0.2 mL kg(-1) h(-1)). The buffer capacity of gelatine did not lead to favourable differences in acid-base balance in comparison to HES130.

  11. Quantitative measurement of hard exudates in patients with diabetes and their associations with serum lipid levels.

    PubMed

    Sasaki, Mariko; Kawasaki, Ryo; Noonan, Jonathan E; Wong, Tien Yin; Lamoureux, Ecosse; Wang, Jie Jin

    2013-08-15

    To describe a reproducible method of quantifying macular hard exudates (HEs) in diabetic maculopathy and determine the associations of HEs with systemic risk factors. Patients with diabetes were recruited from a tertiary eye hospital in Melbourne, Australia. Total macular area covered by HEs (total HE area) and the distance from the foveal center to the nearest HE were measured in a semi-automated manner. Associations between HE parameters and diabetic complication risk factors were examined using multiple linear regression models. Of 593 participants (mean age 60.5-years old), 97 (16.4%) had HEs in at least one eye, due to diabetic maculopathy. The intraclass correlation coefficients (ICC) for inter- and intra-observer agreements were 0.982 and 0.999, respectively. Total HE area was positively associated with qualitative HE severity scale determined by photographic graders. The median of total HE area was 0.089 mm(2) (interquartile range, 0.027-0.246). The median distance between foveal center and the nearest HE was 791.1 μm (431.9-1385.4). After adjusting for age, sex, duration of diabetes, glycated hemoglobin, mean arterial pressure, diabetic retinopathy level, and use of lipid-lowering medication, low density lipoprotein (LDL) cholesterol (P = 0.009), and triglyceride levels (P = 0.036) were positively associated with total HE area. Higher triglyceride levels were associated with central involvement (P = 0.023). Quantitative measurement of HEs in patients with diabetes is associated with lipid levels, and higher triglyceride levels are associated with a higher risk of central involvement. Quantitative information may be useful to monitor HE progression or treatment response in persons with diabetic maculopathy.

  12. Elders Health Empowerment Scale

    PubMed Central

    2014-01-01

    Introduction: Empowerment refers to patient skills that allow them to become primary decision-makers in control of daily self-management of health problems. As important the concept as it is, particularly for elders with chronic diseases, few available instruments have been validated for use with Spanish speaking people. Objective: Translate and adapt the Health Empowerment Scale (HES) for a Spanish-speaking older adults sample and perform its psychometric validation. Methods: The HES was adapted based on the Diabetes Empowerment Scale-Short Form. Where "diabetes" was mentioned in the original tool, it was replaced with "health" terms to cover all kinds of conditions that could affect health empowerment. Statistical and Psychometric Analyses were conducted on 648 urban-dwelling seniors. Results: The HES had an acceptable internal consistency with a Cronbach's α of 0.89. The convergent validity was supported by significant Pearson's Coefficient correlations between the HES total and item scores and the General Self Efficacy Scale (r= 0.77), Swedish Rheumatic Disease Empowerment Scale (r= 0.69) and Making Decisions Empowerment Scale (r= 0.70). Construct validity was evaluated using item analysis, half-split test and corrected item to total correlation coefficients; with good internal consistency (α> 0.8). The content validity was supported by Scale and Item Content Validity Index of 0.98 and 1.0, respectively. Conclusions: HES had acceptable face validity and reliability coefficients; which added to its ease administration and users' unbiased comprehension, could set it as a suitable tool in evaluating elder's outpatient empowerment-based medical education programs. PMID:25767307

  13. Effect of the cellular-type artificial oxygen carrier hemoglobin vesicle as a resuscitative fluid for prehospital treatment: experiments in a rat uncontrolled hemorrhagic shock model.

    PubMed

    Seishi, Yasuhisa; Horinouchi, Hirohisa; Sakai, Hiromi; Kobayashi, Koichi

    2012-08-01

    The hemoglobin vesicle (Hb-vesicle) is a cellular-type artificial oxygen carrier showing a resuscitative effect comparable to that of blood transfusion in several animal models. However, the efficacy of Hb-vesicles for resuscitation when the hemorrhage cannot be controlled remains unclear. Therefore, we used Hb-vesicles in a rat hemorrhagic shock model caused by continuous bleeding. For inducing uncontrolled hemorrhage, animals were heparinized and bled from the caudal artery. Fluid resuscitation was subsequently performed with five materials: Hb-vesicle suspension in a 5% albumin (Alb) solution (HbV), washed red blood cells (wRBC) in a 6% hydroxyethyl starch (HES) solution, 5% Alb, 6% HES, and saline (Sal). During the experiment, all animals in the HbV and wRBC groups survived, whereas all those in the Alb and HES groups died. In the Sal group, five of seven animals died. In the HbV and wRBC groups, the heart rate, mean arterial pressure, and blood lactic acid levels were stabilized during resuscitation. Meanwhile, the hematocrit levels of the HbV, Alb, and HES groups showed sharp decreases (HbV: 6.8% ± 1.7%, Alb: 6.8% ± 0.8%, HES: 5.5% ± 0.7% at 100% total circulated blood volume; final hematocrit of the HbV group: 1.5% ± 0.5%). These results suggest that shocked animals can survive longer when the Hb-vesicle supply is maintained and that HbV showed a similar effect to wRBC in maintaining the circulating volume and oxygen metabolism. Continuous infusion of Hb-vesicles may extend the survival of trauma victims with uncontrolled hemorrhage until they have reached a trauma center.

  14. Effect of Culture Condition Variables on Human Endostatin Gene Expression in Escherichia coli Using Response Surface Methodology

    PubMed Central

    Mohajeri, Abbas; Pilehvar-Soltanahmadi, Yones; Abdolalizadeh, Jalal; Karimi, Pouran; Zarghami, Nosratollah

    2016-01-01

    Background Recombinant human endostatin (rhES) is an angiogenesis inhibitor used as a specific drug for the treatment of non-small-cell lung cancer. As mRNA concentration affects the recombinant protein expression level, any factor affecting mRNA concentration can alter the protein expression level. Response surface methodology (RSM) based on the Box-Behnken design (BBD) is a statistical tool for experimental design and for optimizing biotechnological processes. Objectives This investigation aimed to predict and develop the optimal culture conditions for mRNA expression of the synthetic human endostatin (hES) gene in Escherichia coli BL21 (DE3). Materials and Methods The hES gene was amplified, cloned, and expressed in the E. coli expression system. Three factors, including isopropyl β-D-1-thiogalactopyranoside (IPTG) concentration, post-induction time, and cell density before induction, were selected as important factors. The mRNA expression level was determined using real-time PCR. The expression levels of hES mRNA under the different growth conditions were analyzed. SDS-PAGE and western blot analyses were carried out for further confirmation of interest-gene expression. Results A maximum rhES mRNA level of 376.16% was obtained under the following conditions: 0.6 mM IPTG, 7 hours post-induction time, and 0.9 cell density before induction. The level of rhES mRNA was significantly correlated with post-induction time, IPTG concentration, and cell density before induction (P < 0.05). The expression of the hES gene was confirmed by western blot. Conclusions The obtained results indicate that RSM is an effective method for the optimization of culture conditions for hES gene expression in E. coli. PMID:27800134

  15. Self-renewal and pluripotency is maintained in human embryonic stem cells by co-culture with human fetal liver stromal cells expressing hypoxia inducible factor 1alpha.

    PubMed

    Ji, Lei; Liu, Yu-xiao; Yang, Chao; Yue, Wen; Shi, Shuang-shuang; Bai, Ci-xian; Xi, Jia-fei; Nan, Xue; Pei, Xue-Tao

    2009-10-01

    Human embryonic stem (hES) cells are typically maintained on mouse embryonic fibroblast (MEF) feeders or with MEF-conditioned medium. However, these xenosupport systems greatly limit the therapeutic applications of hES cells because of the risk of cross-transfer of animal pathogens. The stem cell niche is a unique tissue microenvironment that regulates the self-renewal and differentiation of stem cells. Recent evidence suggests that stem cells are localized in the microenvironment of low oxygen. We hypothesized that hypoxia could maintain the undifferentiated phenotype of embryonic stem cells. We have co-cultured a human embryonic cell line with human fetal liver stromal cells (hFLSCs) feeder cells stably expressing hypoxia-inducible factor-1 alpha (HIF-1alpha), which is known as the key transcription factor in hypoxia. The results suggested HIF-1alpha was critical for preventing differentiation of hES cells in culture. Consistent with this observation, hypoxia upregulated the expression of Nanog and Oct-4, the key factors expressed in undifferentiated stem cells. We further demonstrated that HIF-1alpha could upregulate the expression of some soluble factors including bFGF and SDF-1alpha, which are released into the microenvironment to maintain the undifferentiated status of hES cells. This suggests that the targets of HIF-1alpha are secreted soluble factors rather than a cell-cell contact mechanism, and defines an important mechanism for the inhibition of hESCs differentiation by hypoxia. Our findings developed a transgene feeder co-culture system and will provide a more reliable alternative for future therapeutic applications of hES cells.

  16. Hypereosinophilic syndrome, Churg-Strauss syndrome and parasitic diseases: possible links between eosinophilia and thrombosis.

    PubMed

    Maino, Alberto; Rossio, Raffaella; Cugno, Massimo; Marzano, Angelo V; Tedeschi, Alberto

    2012-09-01

    Throughout the past decade, a possible role of eosinophils in blood coagulation and thrombosis has been suggested. We conducted a Pubmed (MEDLINE) search of case and series referring to any kind of thrombotic events described in three conditions characterised by persistent blood eosinophilia, i.e. the hypereosinophilic syndrome (HES), the Churg Strauss syndrome (CSS), and parasitic infestations from 1966 to date. One hundred and ninety-two articles were found regarding thrombotic events in HES and CSS, and 209 cases of thrombosis were extracted. One hundred and seventy- seven articles dealing with parasitic diseases and thrombosis were found, but only 15 manuscripts reporting thrombosis of unknown origin in 22 patients were selected. In HES, arterial thromboses were more frequent than in CSS (p=0.006), representing almost half of the cases (45%), while venous and mixed artero-venous thrombosis were respectively 28% and 27%. In contrast, in CSS there was a predominance of venous thrombosis (56%, p=0.006), with arterial thrombosis representing 38% of total thrombotic events, and mixed thrombosis being the least frequent (4%). The higher incidence of arterial thrombosis in HES patients can be explained by the common cardiac involvement (64% of patients). In the 22 patients with parasitoses and thrombosis, 15 had arterial thrombosis (68%) and 7 had venous thrombosis (32 %). Literature analysis shows that there are numerous reports of thrombotic events in patients with eosinophil-related disorders supporting a role for eosinophils in thrombosis. This observation raises the problem of prevention and treatment of thromboembolism particularly in HES and CSS patients.

  17. Changes in blood coagulation after colloid administration in patients undergoing total hip arthroplasty: comparison between pentastarch and tetrastarches, a randomized trial.

    PubMed

    Shin, Hyun-Jung; Na, Hyo-Seok; Jeon, Young-Tae; Lee, Gwan Woo; Do, Sang-Hwan

    2015-08-01

    Hydroxyethyl starch (HES) solutions are used as plasma expanders for correcting hypovolemia, but can lead to impaired coagulation. We evaluated the changes in hematological and hemostatic profiles with three types of HES. Patients were randomized to receive volume replacement with 10% pentastarch 260/0.45 in 0.9% saline (Group-PEN, n = 25), 6% tetrastarch 130/0.4 in 0.9% saline (Group-TETS, n = 25), or 6% tetrastarch 130/0.4 in a balanced electrolyte solution (Group-TETB, n = 25). Coagulation was assessed using rotational thromboelastometry (ROTEM®) and other laboratory tests were performed, including measurements of hematological and hemostatic parameters and electrolytes. Post-operative ROTEM® parameters changed toward hypocoagulable states in all groups. The post-operative parameters of EXTEM and FIBTEM were more impaired in Group-PEN than in Group-TETB. The percentage change in INTEM clot formation time (P = 0.004) and α-angle (P = 0.003) were smaller in Group-TETS and Group-TETB than in Group-PEN. The percentage change in the FIBTEM maximum clot firmness was greatest in Group-PEN (P = 0.011). The international normalized ratio of prothrombin time (P < 0.001) and the activated partial thromboplastin time (P < 0.001) were significantly prolonged in Group-PEN compared to those of Group-TETB. The 6% HES 130/0.4 in a balanced electrolyte solution seemed to have less of an impact on blood coagulation than the 10% HES 260/0.45. No differences in hemostatic profile were observed between the balanced electrolyte and saline-based 6% HES 130/0.4.

  18. Changes in blood coagulation after colloid administration in patients undergoing total hip arthroplasty: comparison between pentastarch and tetrastarches, a randomized trial

    PubMed Central

    Shin, Hyun-Jung; Na, Hyo-Seok; Jeon, Young-Tae; Lee, Gwan Woo

    2015-01-01

    Background Hydroxyethyl starch (HES) solutions are used as plasma expanders for correcting hypovolemia, but can lead to impaired coagulation. We evaluated the changes in hematological and hemostatic profiles with three types of HES. Methods Patients were randomized to receive volume replacement with 10% pentastarch 260/0.45 in 0.9% saline (Group-PEN, n = 25), 6% tetrastarch 130/0.4 in 0.9% saline (Group-TETS, n = 25), or 6% tetrastarch 130/0.4 in a balanced electrolyte solution (Group-TETB, n = 25). Coagulation was assessed using rotational thromboelastometry (ROTEM®) and other laboratory tests were performed, including measurements of hematological and hemostatic parameters and electrolytes. Results Post-operative ROTEM® parameters changed toward hypocoagulable states in all groups. The post-operative parameters of EXTEM and FIBTEM were more impaired in Group-PEN than in Group-TETB. The percentage change in INTEM clot formation time (P = 0.004) and α-angle (P = 0.003) were smaller in Group-TETS and Group-TETB than in Group-PEN. The percentage change in the FIBTEM maximum clot firmness was greatest in Group-PEN (P = 0.011). The international normalized ratio of prothrombin time (P < 0.001) and the activated partial thromboplastin time (P < 0.001) were significantly prolonged in Group-PEN compared to those of Group-TETB. Conclusions The 6% HES 130/0.4 in a balanced electrolyte solution seemed to have less of an impact on blood coagulation than the 10% HES 260/0.45. No differences in hemostatic profile were observed between the balanced electrolyte and saline-based 6% HES 130/0.4. PMID:26257849

  19. Plasma volume and electrolyte changes following intravenous infusion of hypertonic hydroxyethyl starch versus mannitol in healthy dogs.

    PubMed

    Robinson, Rebecca; Schwendenwein, Ilse; Wacek, Sabine; Nell, Barbara; Mosing, Martina

    2011-11-01

    In a prospective cross-over study, the duration and magnitude of effect on the electrolyte and plasma volume changes of intravenous (IV) hypertonic hydroxyethyl starch (hyperHES) (7.5%/6%) and mannitol (20%) were compared. Eight Beagle dogs received an IV infusion of 4mL/kg hyperHES (group H) and 4mL/kg mannitol 20% (group M) on separate occasions. Urine and blood samples were taken in the first (T(60)) and second (T(120)) hour after infusion. Significant increases in plasma volume at each time point in group H and M were noted when compared to baseline (start of infusion=T(0)) level. There was no significant difference between groups. Both fluids resulted in diuresis, although no significant difference between groups was noted. A significant increase in plasma sodium (Na) was demonstrated in group H between T(0) and T(60) with a significant increase in the Na and chloride (Cl) fractional excretion (FE) between T(0), T(60) and T(120). In group M no changes in plasma electrolyte concentrations were detected, although FE of Na, Cl and K was increased significantly between T(0) and T(60). In conclusion, hyperHES and mannitol appear to have a volume expanding effect lasting at least 120 min. The hypernatraemia induced by hyperHES was minimal compared to previous reports of hypertonic saline use, and no clinical side effects were noted. HyperHES showed comparable effects to mannitol in increasing plasma volume and diuresis and could be considered for these applications. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Osmotic stress and membrane phase changes during freezing of stallion sperm: mode of action of cryoprotective agents.

    PubMed

    Oldenhof, Harriëtte; Gojowsky, Marina; Wang, Shangping; Henke, Samantha; Yu, Chaojie; Rohn, Karl; Wolkers, Willem F; Sieme, Harald

    2013-03-01

    The aim of this study was to determine how different membrane-permeable and -impermeable cryoprotective agents modulate tolerance of stallion sperm to osmotic stress and stabilize membranes during cryopreservation. Special emphasis was on hydroxyl ethylene starch (HES), which exposes cells to minimal osmotic stress due to its large molecular weight. Percentages of motile sperm post-thaw were found to be similar when glycerol, sucrose, and HES were used at their optimal concentrations. Percentages of plasma membrane intact sperm after return to isotonic medium were highest for HES. Fourier transform infrared spectroscopy studies were carried out to study subzero membrane phase and permeability behavior. Cryoprotectants were shown to decrease the initial rate of membrane dehydration during freezing, decrease the activation energy for water transport, and increase the total extent of freezing-induced dehydration. Freezing studies with liposomes as a model system showed that only the membrane-permeable cryoprotective agents glycerol and ethylene glycol protected membranes against leakage, whereas egg yolk, sucrose, and HES did not. Differential scanning calorimetry studies showed that sucrose and HES raise the glass transition temperature of the freezing extender and the difference in heat capacity associated with the glass transition. This indicates that these compounds enable formation of a stable glassy matrix at higher subzero temperatures. Sperm cryosurvival rates can be increased by combining different cryoprotectants with different protective functions; membrane permeable cryoprotective agents stabilize membranes and modulate the rate of cellular dehydration, whereas di- and polysaccharides increase the glass transition temperature and facilitate storage and handling at higher subzero temperatures.

  1. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes

    PubMed Central

    Roufosse, Florence E; Kahn, Jean-Emmanuel; Gleich, Gerald J; Schwartz, Lawrence B; Singh, Anish D; Rosenwasser, Lanny J; Denburg, Judah A; Ring, Johannes; Rothenberg, Marc E; Sheikh, Javed; Haig, Ann E; Mallett, Stephen A; Templeton, Deborah N; Ortega, Hector G; Klion, Amy D

    2012-01-01

    Background Hypereosinophilic syndromes (HES) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid-refractory or develop corticosteroid toxicity. Mepolizumab, a humanised monoclonal anti-interleukin-5 antibody, demonstrated corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HES. Objective To evaluate long-term safety and efficacy of mepolizumab (750 mg) in HES. Methods MHE100901 is an open-label extension study. The primary endpoint was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of anti-mepolizumab antibodies were also explored. Results Seventy-eight subjects received 1–66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range 4–302). The most common dosing interval was 9–12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including one death, were reported by the investigator as possibly due to mepolizumab in three subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone-free without other HES medications for ≥12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew prior to study completion for death (n=4), lack of efficacy (n=6), or other reasons. Conclusion Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES. PMID:23040887

  2. Notch pathway activation is associated with pancreatic cancer treatment failure.

    PubMed

    Lee, Jin Young; Song, Si Young; Park, Jeong Youp

    2014-01-01

    Pancreatic cancer is resistant to conventional treatment. The aim of the study was to confirm the hypothesis that changes in cancer stem cells (CSCs) and developmental pathway after treatment was responsible for treatment failure in pancreatic cancer. After recovery from a gemcitabine treatment, the percentage of pancreatic cancer CSCs and Notch pathway in BxPC3 and HPAC pancreatic cancer cell lines were analyzed by FACS (CD24 and CD44) and western blot (Notch1, Hes1, β-catenin, and pAKT). The effect of DAPT, a gamma-secretase inhibitor, was similarly investigated. The association between immunohistochemical expression of Hes1 and survival was analyzed. The percentage of CD24(+)CD44(+) cells was higher in gemcitabine-treated BxPC3 and HPAC cells than at pre-treatment. CD24(+)CD44(+) cells sorted from the gemcitabine-treated cell lines showed higher migration and invasion ability than CD24(-)CD44(-) or CD24(-)CD44(+) cells from the same cell lines. Western blot analysis showed an increased expression of Notch1 and Hes1 in gemcitabine-treated cell lines. The overall survival of pancreatic cancer patients with strong expression of Hes1 was shorter than that in patients with no or weak expression (11.1 vs. 21.6 months, P = 0.036). Treatment with DAPT reversed the increase in Hes1, β-catenin, and pAKT expression and the proportion of CD24(+)CD44(+) cells in gemcitabine-treated cell lines. The treatment also decreased migration and invasion ability. Our data suggested that an increase in CSCs and activation of the Notch pathway might contribute to the failure of treatment in pancreatic cancer. Notch pathway can be a potential target to overcome treatment failure. Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  3. Upfront immunohistochemistry improves specificity of Helicobacter pylori diagnosis. A French pathology laboratory point of view.

    PubMed

    Ginestet, Florent; Guibourg, Briac; Doucet, Laurent; Théreaux, Jérémie; Robaszkiewicz, Michel; Marcorelles, Pascale; Uguen, Arnaud

    2017-10-01

    There is no consensus about the histopathologic methods to detect Helicobacter pylori in gastric biopsies to date. We aimed to question about the value of upfront anti-H. pylori immunohistochemistry in this field. We led a retrospective study about the rate of H. pylori-positive gastric biopsies before and after the implementation of upfront immunohistochemistry, the inter-rater and intermethods agreements in H. pylori identification about Hematoxylin-Eosin Saffron (HES), Giemsa, and immunohistochemistry stains and the histopathologic features associated with low amounts of H. pylori. First, the rate of H. pylori-positive gastric biopsies significantly diminished after the implementation of upfront immunohistochemistry (from 21.15% to 12.56%, P<.0001), suggesting potential overdiagnosis of H. pylori infection before the use of immunohistochemistry. Secondly, immunohistochemistry was the most reproducible and performing stain (kappa values >0.80), but HES and Giemsa stains also presented good-to-very good agreements. Finally, less than 1% of gastric biopsies with inconspicuous H. pylori infection showed no mucosal injury pointing out that any HES-detected mucosal injury could help to preselect the gastric biopsies requiring ancillary stains for the detection of H. pylori. Albeit being considered as a gold standard in the detection of H. pylori, the interest of using immunohistochemistry as an upfront stain on gastric biopsies is still debated. In our opinion, its use in second line in case of ambiguous HE/HES-Giemsa result is more appropriate. Further effort is needed to optimize the inexpensive but feasible HE/HES-based detection of H. pylori. © 2017 John Wiley & Sons Ltd.

  4. Natural history of severe eosinophilia with uncertain aetiology and proposals on a practical approach to its management.

    PubMed

    Ang, A L; Wong, R X; Zhuang, Q Y; Linn, Y C

    2012-08-01

    Eosinophilia is commonly encountered during clinical practice. Some can be attributed to well-defined causes while others cannot. Optimal management of hypereosinophilia with unknown aetiology is uncertain as the natural history is not well described. We retrospectively studied patients with hypereosinophilia (>5 × 10(9)/L) and described the characteristics, natural history and treatment of those with eosinophilia of uncertain aetiology. There were 141 patients with hypereosinophilia: 87 with well-defined causes, 54 with uncertain aetiology. The latter was managed as hypereosinophilic syndrome (HES) (n = 5), idiopathic hypereosinophilia (IH) (n = 11), presumptive helminthic infection (n = 11) and reactive eosinophilia (n = 5), while 22 were insufficiently investigated and did not have definite working diagnoses. Their median age and peak eosinophil count were 64 (22 to 94) years and 10.0 (5.2-33.9) × 10(9)/L respectively. Forty-six per cent had symptoms attributable to eosinophilia, with the HES and insufficiently investigated groups having the highest (100%) and lowest (27%) percentages respectively. HES and IH patients were most extensively investigated. All 14 HES or IH patients who received steroids responded. All presumptive helminthic infection patients received mebendazole: nine responded, and two had unassessable responses. For the remaining patients, seven received steroids and all responded; one received mebendazole but defaulted; 19 were not treated: 11 resolved spontaneously. No non-HES patients developed eosinophilia-related organ dysfunction. No mortality was caused by hypereosinophilia. Patients with hypereosinophilia of uncertain aetiology can be empirically managed according to working diagnoses derived from history taking, examination and selective investigations. Most patients have benign short-term outcomes, but longer monitoring is required to assess long-term outcomes from untreated hypereosinophilia. © 2011 The Authors. Internal Medicine

  5. Comparison of the effect of hypertonic hydroxyethyl starch and mannitol on the intraocular pressure in healthy normotensive dogs and the effect of hypertonic hydroxyethyl starch on the intraocular pressure in dogs with primary glaucoma.

    PubMed

    Volopich, Sabine; Mosing, Martina; Auer, Ulrike; Nell, Barbara

    2006-01-01

    The purpose of this study was to determine if intravenous hypertonic hydroxyethyl starch (7.5%/6%) (HES) could decrease the intraocular pressure (IOP) in healthy normotensive dogs, and compare its effect with that of mannitol (20%) (experimental study). In addition, the potential IOP-lowering effect of hypertonic HES was evaluated in six dogs with primary glaucoma (clinical study). Experimental study: eight male ophthalmoscopically and clinically healthy Beagles were included in this study. The IOP of each dog was measured by applanation tonometry in both eyes to obtain control values at 10:00, 10:15, 10:30, 10:45, 11:00 a.m., and then every hour until 6:00 p.m. prior to the first treatment (control period). Each dog received, with at least 2-week intervals and in a random order, an intravenous (IV) infusion of 4 mL/kg hypertonic HES (1.2 g/kg NaCl; 0.96 g/kg HES) and 4 mL/kg mannitol 20% (1 g/kg) over a period of 15 min starting at 10:00 a.m. IOP was measured oculus uterque (OU) at the same time intervals as in the control study. The differences in IOP between the treatment groups and the baseline IOP (before the start of infusion), between oculus sinister (OS) and oculus dexter (OD) and between the same time points of all groups were determined with a Student's t-test for paired samples (P = 0.05). Clinical study: six dogs with primary glaucoma (representing seven eyes) received an IV infusion of 4 mL/kg hypertonic HES over a period of 15 min. IOP was measured before and 15 and 30 min after starting the infusion. Experimental study: no significant difference between IOP of both eyes was found. A significant decrease in IOP from baseline value was recorded at 15, 30, 45, and 60 min after the start of mannitol infusion (mean amplitude in IOP decrease 3.21 mmHg; P < 0.05) and at 15 and 30 min in dogs treated with HES (mean amplitude in IOP decrease 2.43 mmHg; P < 0.05). At 120 and 180 min there was a significantly higher IOP (P < 0.05) in HES treatment group

  6. Nuclear-Renewable Energy Systems Secondary Product Market Analysis Study

    SciTech Connect

    Deason, Wesley Ray

    2015-06-01

    In order to properly create a program surrounding the development of any technological concept it is necessary to fully understand the market in which it is being developed. In the case of Integrated Nuclear-Renewable Hybrid Energy Systems (HES), there are two economic markets in which it must be able to participate in: the electricity market and the secondary product market associated with the specific system. The purpose of the present report is to characterize the secondary product market in the U.S. and to provide recommendations for further developing the HES program. While HESs have been discussed in depth in many other reports, it is helpful to discuss them briefly in the present work [REF]. The concept of the HES can be deduced to a system, featuring a combination of a nuclear power plant, a renewable energy source, and an industrial manufacturing plant . The system is designed in a fashion that allows it either to produce electricity or to manufacture a secondary product as needed. The primary benefit of this concept lies in its ability to maximize economic performance of the integrated system and to manufacture products in a carbon-free manner. A secondary benefit is the enhanced supply-side flexibility gained by allowing the HES to economically provide grid services. A key tenant to nuclear power plant economics in today’s electricity market is their ability to operate at a very high capacity factor. Unfortunately, in regions with a high penetration of renewable energy, the carbon free energy produced by nuclear power may not be needed at all times. This forces the nuclear power plant to find a user for its excess capacity. This may include paying the electric grid to find a user, releasing energy to the environment by ‘dumping steam’, or reducing power. If the plant is unable to economically or safely do any of these actions, the plant is at risk of being shutdown. In order to allow for nuclear power plants to continue to contribute carbon free

  7. Validating the use of Hospital Episode Statistics data and comparison of costing methodologies for economic evaluation: an end-of-life case study from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

    PubMed

    Thorn, Joanna C; Turner, Emma L; Hounsome, Luke; Walsh, Eleanor; Down, Liz; Verne, Julia; Donovan, Jenny L; Neal, David E; Hamdy, Freddie C; Martin, Richard M; Noble, Sian M

    2016-04-29

    To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies. Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes. 7 UK secondary care centres. A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months. Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials. ISRCTN92187251; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use

  8. Hydroxyethyl starch - the importance of being earnest

    PubMed Central

    2013-01-01

    Despite ongoing controversial expert discussions the European Medicines Agency (EMA) recently recommended to suspend marketing authorisations for hydroxyethyl starch. This comment critically evaluates the line of arguments. Basically, the only indication for a colloid is intravascular hypovolemia. Crystalloid use appears reasonable to compensate ongoing extracellular losses beyond. In the hemodynamically instable patient this leads to the distinction between an initial resuscitation phase where colloids might be indicated and a crystalloidal maintenance phase thereafter. It is important to bear this in mind when reevaluating the studies the EMA referred to in the context of its recent decision: i) VISEP compared ringer’s lactate to 10% HES 200/0.5 in septic patients and found an increased incidence of renal failure in HES receivers. Unfortunately, study treatment was started only after initial stabilization with HES, randomizing hemodynamically stable patients into a rational (crystalloids) and an irrational (high dose starch until ICU discharge) maintenance treatment. ii) 6S compared ringer’s acetate to 6% HES 130/0.42 for fluid resuscitation in septic patients and found an increased need of renal replacement therapy and a higher mortality in the HES group. However, patients of both groups were again randomized only after initial stabilization with colloids, the actual comparison was, therefore, again rational vs. irrational. Beyond that, the documentation is partly fragmentary, leaving many important questions around the fate of the patients unanswered. iii) CHEST randomized ICU patients to receive saline or 6% HES 130/0.4 for fluid resuscitation. Actually, despite partly discussed in a different way, this trial showed no relevant differences in outcome. In all, two studies showed what happens to septic patients if starches are used in a way we do not observe in daily practice. The third one actually proves their safety. The benefit of perioperative goal

  9. Contribution of osmotic changes to disintegrative globulization of single cortical fibers isolated from rat lens.

    PubMed

    Wang, L F; Dhir, P; Bhatnagar, A; Srivastava, S K

    1997-08-01

    In this study the contribution of osmotic changes to disintegrative globulization of lens cortical fibers was examined. Single fiber cells were isolated by trypsinization of adult rat lens cortex, and morphological changes elicited by exposure to different external solutions were monitored optically. The survival of the fiber-shaped cells was analysed in accordance with the Weibull distribution. Changes in [Ca2+]i were measured using the fluorescent calcium-sensitive dye-Fluo-3. Exposure of isolated fiber cells to Ringer's solution (containing 2 mm Ca2+) led to an exponential increase in [Ca2+]i with a time constant of 10.2+/-0.8 min, and caused disintegrative globulization in 25+/-4 min (=Tg). The process of globulization as well as the rate of increase in [Ca2+]i was delayed by removing Cl- ions from the external media. Globulization was also delayed by adding 20% bovine serum albumin (Tg=107+/-3 min) or chloride channel inhibitors 5, nitro-2-(3-phenylpropylamino) benzoate (NPPB), dideoxyforskolin, niflumic acid, and tamoxifen. When the fiber cells were suspended in isotonic (280 mm sucrose) HEPES-sucrose (HS) or HEPES-EDTA-sucrose (HES) solution, no globulization was observed for an observation time of 120 min. However, exposure to hypotonic (180 mm) HES solution led to disintegration of fiber cells in 75+/-7 min. Disintegration of the fiber induced by hypotonic HES solution could be delayed by either 0. 05 mm leupeptin (Tg=97+/-6 min) or by pre-loading the fibers with BAPTA (Tg=100+/-4 min). Inhibition of membrane calcium transport by 0.5 mm La3+ had no effect on Tg in hypotonic HES. Addition of 2 mm Ca2+ to HES solution accelerated globulization, and Tg was 57+/-4, 69+/-5 and 102+/-6 min for hypo-, iso- and hyper- tonic solutions, respectively. Transient exposure to calcium also accelerated disintegrative globulization of fiber cells exposed subsequently to HES solution. These results suggest that in ionic media, part of the calcium influx in isolated fiber

  10. Evaluating Radioprotective Effect of Hesperidin on Acute Radiation Damage in the Lung Tissue of Rats

    PubMed Central

    Rezaeyan, A.; Fardid, R.; Haddadi, G.H.; Takhshid, M.A.; Hosseinzadeh, M.; Najafi, M.; Salajegheh, A.

    2016-01-01

    Background: Oxidative stress plays an important role in the pathogenesis and progression of γ-irradiation-induced cellular damage, Lung is a radiosensitive organ and its damage is a dose-limiting factor in radiotherapy. The administration of dietary antioxidants has been suggested to protect against the succeeding tissue damage. The present study aimed to evaluate the radioprotective efficacy of Hesperidin (HES) against γ-irradiation-induced tissue damage in the lung of male rats. Materials and Methods: Thirty two rats were divided into four groups. Rats in Group 1 received PBS and underwent sham irradiation. Rats in Group 2 received HES and underwent sham irradiation. Rats in Group 3 received PBS and underwent γ-irradiation. Rats in Group 4 received HES and underwent γ-irradiation. These rats were exposed to γ-radiation 18 Gy using a single fraction cobalt-60 unit, and were administered HES (100 mg/kg/d, b.w, orally) for 7 days prior to irradiation. Rats in each group were sacrificed 24 hours after radiotherapy (RT) for the determination of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and histopathological evaluations. Results: Compared to group 1, the level of SOD and GSH significantly decreased and MDA level significantly increased in group 3 at 24 h following irradiation, (p=0.001, p<0.001, p=0.001), respectively. A statistically significant difference in all parameters was observed for rats in group 4 as compared to group 3 (p<0.05). Histopathological results 24 hours after RT showed that radiation has increased inflammation, lymphocyte, macrophage and neutrophil compared to group 1 ( p<0.0125). Oral administration of HES before RT significantly decreased macrophage and neutrophil when compared to group 3 (p<0.0125), but partly there was inflammation and lymphocyte that indicated there was no significant difference when compared to group 3 (p>0.0125). Conclusion: Oral administration of HES was found to offer protection against

  11. Human Embryonic Stem Cells Form Functional Thyroid Follicles

    PubMed Central

    Latif, Rauf; Davies, Terry F.

    2015-01-01

    Objective: The molecular events that lead to human thyroid cell speciation remain incompletely characterized. It has been shown that overexpression of the regulatory transcription factors Pax8 and Nkx2-1 (ttf-1) directs murine embryonic stem (mES) cells to differentiate into thyroid follicular cells by initiating a transcriptional regulatory network. Such cells subsequently organized into three-dimensional follicular structures in the presence of extracellular matrix. In the current study, human embryonic stem (hES) cells were studied with the aim of recapitulating this scenario and producing functional human thyroid cell lines. Methods: Reporter gene tagged pEZ-lentiviral vectors were used to express human PAX8-eGFP and NKX2-1-mCherry in the H9 hES cell line followed by differentiation into thyroid cells directed by Activin A and thyrotropin (TSH). Results: Both transcription factors were expressed efficiently in hES cells expressing either PAX8, NKX2-1, or in combination in the hES cells, which had low endogenous expression of these transcription factors. Further differentiation of the double transfected cells showed the expression of thyroid-specific genes, including thyroglobulin (TG), thyroid peroxidase (TPO), the sodium/iodide symporter (NIS), and the TSH receptor (TSHR) as assessed by reverse transcription polymerase chain reaction and immunostaining. Most notably, the Activin/TSH-induced differentiation approach resulted in thyroid follicle formation and abundant TG protein expression within the follicular lumens. On stimulation with TSH, these hES-derived follicles were also capable of dose-dependent cAMP generation and radioiodine uptake, indicating functional thyroid epithelial cells. Conclusion: The induced expression of PAX8 and NKX2-1 in hES cells was followed by differentiation into thyroid epithelial cells and their commitment to form functional three-dimensional neo-follicular structures. The data provide proof of principal that hES cells can be

  12. Recording of hospitalizations for acute exacerbations of COPD in UK electronic health care records

    PubMed Central

    Rothnie, Kieran J; Müllerová, Hana; Thomas, Sara L; Chandan, Joht S; Smeeth, Liam; Hurst, John R; Davis, Kourtney; Quint, Jennifer K

    2016-01-01

    Background Accurate identification of hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) within electronic health care records is important for research, public health, and to inform health care utilization and service provision. We aimed to develop a strategy to identify hospitalizations for AECOPD in secondary care data and to investigate the validity of strategies to identify hospitalizations for AECOPD in primary care data. Methods We identified patients with chronic obstructive pulmonary disease (COPD) in the Clinical Practice Research Datalink (CPRD) with linked Hospital Episodes Statistics (HES) data. We used discharge summaries for recent hospitalizations for AECOPD to develop a strategy to identify the recording of hospitalizations for AECOPD in HES. We then used the HES strategy as a reference standard to investigate the positive predictive value (PPV) and sensitivity of strategies for identifying AECOPD using general practice CPRD data. We tested two strategies: 1) codes for hospitalization for AECOPD and 2) a code for AECOPD other than hospitalization on the same day as a code for hospitalization due to unspecified reason. Results In total, 27,182 patients with COPD were included. Our strategy to identify hospitalizations for AECOPD in HES had a sensitivity of 87.5%. When compared with HES, using a code suggesting hospitalization for AECOPD in CPRD resulted in a PPV of 50.2% (95% confidence interval [CI] 48.5%–51.8%) and a sensitivity of 4.1% (95% CI 3.9%–4.3%). Using a code for AECOPD and a code for hospitalization due to unspecified reason resulted in a PPV of 43.3% (95% CI 42.3%–44.2%) and a sensitivity of 5.4% (95% CI 5.1%–5.7%). Conclusion Hospitalization for AECOPD can be identified with high sensitivity in the HES database. The PPV and sensitivity of strategies to identify hospitalizations for AECOPD in primary care data alone are very poor. Primary care data alone should not be used to identify

  13. US hydropower resource assessment for Texas

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Texas.

  14. U.S. hydropower resource assessment for Pennsylvania

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-12-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Pennsylvania.

  15. US hydropower resource assessment for Wyoming

    SciTech Connect

    Francfort, J.E.

    1993-12-01