Science.gov

Sample records for acute phase genes

  1. Induction of acute phase gene expression by brain irradiation

    SciTech Connect

    Hong, Ji-Hong |; Sun, Ji-Rong; Withers, H.R.

    1995-10-15

    To investigate the in vivo acute phase molecular response of the brain to ionizing radiation, C3Hf/Sed/Kam mice were given midbrain or whole-body irradiation. Cerebral expression of interleukins (IL-1{alpha}, IL-1{beta}, IL-2, IL-3, IL-4, IL-5, IL-6), interferon (IFN-{gamma}), tumor necrosis factors (TNF-{alpha} and TNF-{beta}), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthetase (iNOS), von Willebrand factor (vWF), {alpha}1-antichymotrypsin (EB22/5.3), and glial fibrillary acidic protein (GFAP) was measured at various times after various radiation doses by ribonuclease (RNase) protection assay. The effects of dexamethasone or pentoxifylline treatment of mice on radiation-induced gene expression were also examined. Levels of TNF-{alpha}, IL-1{beta}, ICAM-1, EB22/5.3, and to a lesser extent IL-1{alpha} and GFAP, messenger RNA were increased in the brain after irradiation, whether the dose was delivered to the whole body or only to the midbrain. Responses were radiation dose dependent, but were not found below 7 Gy; the exception being ICAM-1, which was increased by doses as low as 2 Gy. Most responses were rapid, peaking within 4-8 h, but antichymotrypsin and GFAP responses were delayed and still elevated at 24 h, by which time the others had subsided. Pretreatment of mice with dexamethasone or pentoxifylline suppressed radiation-induced gene expression, either partially or completely. Dexamethasone was more inhibitory than pentoxifylline at the doses chosen. The initial response of the brain to irradiation involves expression of inflammatory gene products, which are probably responsible for clinically observed early symptoms of brain radiotherapy. This mechanism explains the beneficial effects of the clinical use of steroids in such circumstances. 64 refs., 4 figs.

  2. The acute phase response of cod (Gadus morhua L.): expression of immune response genes.

    PubMed

    Audunsdottir, Sigridur S; Magnadottir, Bergljot; Gisladottir, Berglind; Jonsson, Zophonias O; Bragason, Birkir Th

    2012-02-01

    An acute phase response (APR) was experimentally induced in Atlantic cod (Gadus morhua L.) by intramuscular injection of turpentine oil. The change in the expression of immune related genes was monitored in the anterior kidney and the spleen over a period of 7 days. The genes examined were two types of pentraxins, apolipoprotein A1 (ApoA-I), the complement component C3, interleukin-1β (IL-1β), transferrin, cathelicidin, and hepcidin. All genes were constitutively expressed in both organs and their expression amplified by the turpentine injection. A pattern of response was observed both with respect to the organ preference and to the timing of a maximum response. The increased gene expression of the pentraxins, ApoA-I and C3 was restricted to the anterior kidney, the gene expression of IL-1β, cathelicidin, and transferrin increased in both organs, while hepcidin gene expression was only significantly increased in the spleen. The pentraxins and ApoA-I appear to be early mediators of APR in cod, possibly stimulating C3 and IL-1β response, while the antimicrobial peptides may play a minor role. The increase in transferrin gene expression in both organs, and apparent indifference to cortisol release associated with the turpentine injection, suggests that this could be a typical acute phase protein in cod.

  3. Induction of several acute-phase protein genes by heavy metals: A new class of metal-responsive genes

    SciTech Connect

    Yiangou, Minas; Ge, Xin; Carter, K.C.; Papaconstantinou, J. Shriners Burns Institute, Galveston, TX )

    1991-04-16

    Acute-phase reactants, metallothioneins, and heat-shock proteins are the products of three families of genes that respond to glucocorticoids and cytokines. Metallothioneins and heat-shock proteins, however, are also stimulated by heavy metals whereas very little is known about the effect of heavy metals on acute-phase-reactant genes. The authors have studied the effect of heavy metals (Hg, Cd, Pb, Cu, Ni, and Zn) and Mg on the acute-phase reactants {alpha}{sub 1}-acid glycoprotein, C-reactive protein, {alpha}{sub 1}-antitrypsin and {alpha}{sub 1}-antichymotrypsin. {alpha}{sub 1}-Acid glycoprotein and C-reactive protein mRNA levels were increased severalfold in livers of heavy-metal-treated Balb/c mice. The strongest induction was mediated by Hg, followed in order of response by Cd > Pb > Cu > Ni > Zn > Mg. None of the metals affected the mRNA levels of albumin, {alpha}{sub 1}-antitrypsin, and {alpha}{sub 1}-antichymotrypsin. Furthermore, failure to repress albumin, a negative acute-phase reactant, indicated that the induction of these genes was not due to a metal-mediated inflammatory response. The metals also induced {alpha}{sub 1}-acid glycoprotein and C-reactive protein in adrenalectomized animals, indicating that induction by the heavy metals is not mediated by the glucocorticoid induction pathway. Sequence analysis has revealed a region of homology to metal-responsive elements in the {alpha}{sub 1}-acid glycoprotein and C-reactive protein promoters. The studies indicate that the induction of {alpha}{sub 1}-acid glycoprotein and C-reactive protein by heavy metals may be regulated by these metal-responsive elements at the level of transcription.

  4. Acute phase reaction and acute phase proteins*

    PubMed Central

    Gruys, E.; Toussaint, M.J.M.; Niewold, T.A.; Koopmans, S.J.

    2005-01-01

    A review of the systemic acute phase reaction with major cytokines involved, and the hepatic metabolic changes, negative and positive acute phase proteins (APPs) with function and associated pathology is given. It appears that APPs represent appropriate analytes for assessment of animal health. Whereas they represent non-specific markers as biological effect reactants, they can be used for assessing nutritional deficits and reactive processes, especially when positive and negative acute phase variables are combined in an index. When such acute phase index is applied to separate healthy animals from animals with some disease, much better results are obtained than with single analytes and statistically acceptable results for culling individual animals may be reached. Unfortunately at present no cheap, comprehensive and easy to use system is available for assessing various acute phase proteins in serum or blood samples at the same time. Protein microarray or fluid phase microchip technology may satisfy this need; and permit simultaneous analysis of numerous analytes in the same small volume sample and enable integration of information derived from systemic reactivity and nutrition with disease specific variables. Applying such technology may help to solve health problems in various countries not only in animal husbandry but also in human populations. PMID:16252337

  5. Two genes controlling acute phase responses by the antitumor polysacch aride, lentinan.

    PubMed

    Maeda, Y Y; Takahama, S; Kohara, Y; Yonekawa, H

    1996-01-01

    Lentinan, a beta-1,6;1,3-glucan, is tumor-specific for transplantable mouse solid-type tumors and it also stimulates the production of acute phase proteins (APPs). The APP response to lentinan is of the delayed type (DT-APR) and differs from that to lipopolysaccharide, which is acute. We found that the responses were genetically controlled in mice and that low responsiveness is dominant (Maeda et al. 1991). Using 123 segregants of crosses between SWR/J (a high responder) and Mus spretus (a low responder), we analyzed the linkage between DT-APR responsiveness and the DNA polymerase chain reaction-simple sequence length polymorphism (PCR-SSLP) phenotype using 80 chromosome-specific microsatellite markers. We identified two loci (ltn1.1 and ltn1.2) responsible for DT-APR. ltn1.1 is closely linked to D3Mit11 on chromosome 3 and ltn1.2 to D11Nds9 on chromosome 11 (P <0.001). The linkage analysis also suggested that ltn1.2 is the major determinant for DT-APR. Correlation between lentinan-specific IL-6 mRNA expression (the late expression) controlled recessively and DT-APR induction suggests that the ltn1 loci control some process(es) of IL-6 expression in the regulation step before NF-IL6.

  6. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration.

    PubMed

    Zhang, Lisheng; Huang, Xiongfei; Meng, Zhipeng; Dong, Bingning; Shiah, Steven; Moore, David D; Huang, Wendong

    2009-02-01

    Cholesterol 7alpha-hydroxylase (CYP7a1) is the rate-limiting enzyme in the classic pathway of bile acid synthesis. Expression of CYP7a1 is regulated by a negative feedback pathway of bile acid signaling. Previous studies have suggested that bile acid signaling is also required for normal liver regeneration, and CYP7a1 expression is strongly repressed after 70% partial hepatectomy (PH). Both the effect of CYP7a1 suppression on liver regrowth and the mechanism by which 70% PH suppresses CYP7a1 expression are unknown. Here we show that liver-specific overexpression of an exogenous CYP7a1 gene impaired liver regeneration after 70% PH, which was accompanied by increased hepatocyte apoptosis and liver injury. CYP7a1 expression was initially suppressed after 70% PH in an farnesoid X receptor/ small heterodimer partner-independent manner; however, both farnesoid X receptor and small heterodimer partner were required to regulate CYP7a1 expression at the later stage of liver regeneration. c-Jun N-terminus kinase and hepatocyte growth factor signaling pathways are activated during the acute phase of liver regeneration. We determined that hepatocyte growth factor and c-Jun N-terminus kinase pathways were involved in the suppressing of the CYP7a1 expression in the acute phase of live regeneration. Taken together, our results provide the significance that CYP7a1 suppression is required for liver protection after 70% PH and there are two distinct phases of CYP7a1 gene regulation during liver regeneration.

  7. Regulation of the acute phase and immune responses

    SciTech Connect

    Sehgal, P.B.; Grieninger, G.; Tosato, G.

    1989-01-01

    This book contains the conference entitled Regulation of the acute phase and immune responses: Interleukin-L. Topics covered include: Interferon-B{sub 2}/26kDa Protein, Regulation of acute phase liver gene expression, and Genetics and regulation of expression of IL-6.

  8. Kinetic modeling and mathematical analysis indicate that acute phase gene expression in Hep 3B cells is regulated by both transcriptional and posttranscriptional mechanisms.

    PubMed Central

    Jiang, S L; Samols, D; Rzewnicki, D; Macintyre, S S; Greber, I; Sipe, J; Kushner, I

    1995-01-01

    To evaluate the possible role of posttranscriptional mechanisms in the acute phase response, we determined the kinetics of transcription (by nuclear run-on assay) and mRNA accumulation of five human acute phase genes in Hep 3B cells incubated with conditioned medium from LPS-stimulated monocytes. Increase in mRNA accumulation was comparable to increase in transcription rate for fibrinogen-alpha and alpha-1 protease inhibitor, suggesting largely transcriptional regulation. In contrast, mRNA accumulation was about 10-20-fold greater than transcriptional increase for serum amyloid A, C3, and factor B, suggesting participation of posttranscriptional mechanisms. Since finding a disparity between the magnitudes of increase in mRNA and transcription does not definitively establish involvement of posttranscriptional mechanisms, we subjected our data to modeling studies and dynamic mathematical analysis to evaluate this possibility more rigorously. In modeling studies, accumulation curves resembling those observed for these three mRNAs could be generated from the nuclear run-on results only if posttranscriptional regulation was assumed. Dynamic mathematical analysis of relative transcription rates and relative mRNA abundance also strongly supported participation of posttranscriptional mechanisms. These observations suggest that posttranscriptional regulation plays a substantial role in induction of some, but not all acute phase proteins. Images PMID:7883974

  9. Increases in the serum acute phase proteins after ozone exposure are associated with induction of genes in the lung but not liver

    EPA Science Inventory

    Acute Phase Response (APR), a systemic reaction to infection, trauma, and inflammation, is characterized by increases and decreases in plasma levels of positive and negative acute phase proteins (APP), respectively. Although the liver has been shown to contribute to APR in variou...

  10. Rapid Sequential Changeover of Expressed p44 Genes during the Acute Phase of Anaplasma phagocytophilum Infection in Horses

    PubMed Central

    Wang, Xueqi; Rikihisa, Yasuko; Lai, Tzung-Hui; Kumagai, Yumi; Zhi, Ning; Reed, Stephen M.

    2004-01-01

    Anaplasma phagocytophilum immunodominant polymorphic major surface protein P44s have been hypothesized to go through antigenic variation, but the within-host dynamics of p44 expression has not been demonstrated. In the present study we investigated the composition and changes of p44 transcripts in the blood during the acute phase of well-defined laboratory A. phagocytophilum infections in naïve equine hosts. Three traveling waves of sequential population changeovers of the p44 transcript species were observed within a single peak of rickettsemia of less than 1 month. During the logarithmic increase, the rapid switch-off of the initial dominant transcript p44-18 occurred regardless of whether the bacterium was transmitted by ticks or by intravenous inoculation. Each of the subsequently dominant p44 transcript species was phylogenetically dissimilar from p44-18. Development of antibody to the hypervariable region of P44-18 during the rickettsemia suggests the suppression of dominance of immuno-cross-reactive p44 populations. When A. phagocytophilum was preincubated with plasma from the infected horse and then coincubated with HL-60 cells, the dominance of the p44-18 transcript was rapidly suppressed in vitro and most of the newly emerged p44 transcript species were previously undetected in this horse. This work provides experimental evidence of within-host p44 antigenic variation. Results suggest that the rapid and synchronized switch of expression is an intrinsic property of p44s reinitiated after transmission to naïve mammalian hosts and shaped upon exposure to immune plasma. PMID:15557606

  11. A cDNA microarray analysis to identify genes involved in the acute-phase response pathway of the olive flounder after infection with Edwardsiella tarda.

    PubMed

    Moon, Ji Young; Hong, Yong-Ki; Kong, Hee Jeong; Kim, Dong-Gyun; Kim, Young-Ok; Kim, Woo-Jin; Ji, Young Joo; An, Cheul Min; Nam, Bo-Hye

    2014-09-15

    The acute-phase response (APR) is an important systemic reaction that occurs within hours of an inflammatory signal caused by physical bodily injury or microbial infection. To investigate the APR of the olive flounder (Paralichthys olivaceus) following infection with a pathogen, we established an expressed sequence tag (EST)-based cDNA microarray chip composed of 13,061 PCR-amplified cDNAs encoding unique genes selected from an olive flounder EST analysis. Microarray analyses showed that the set of genes involved in the APR was strongly up-regulated in the liver of the olive flounder after infection with Edwardsiella tarda. Among the up-regulated genes, catechol-O-methyltransferase domain-containing protein 1, six-transmembrane prostate protein, haptoglobin precursor, and toll-like receptor 5 soluble form were particularly strongly up-regulated. Interestingly, the toll-like receptor 5 soluble form, which has not yet been detected in mammals, was up-regulated as much as 250-fold upon E. tarda infection. These results suggest that the APR mechanism of fish may be regulated differently from that of mammals. The data described here contribute toward our collective understanding of APR, especially in fish.

  12. Pulmonary Response to Surface-Coated Nanotitanium Dioxide Particles Includes Induction of Acute Phase Response Genes, Inflammatory Cascades, and Changes in MicroRNAs: A Toxicogenomic Study

    PubMed Central

    Halappanavar, Sabina; Jackson, Petra; Williams, Andrew; Jensen, Keld A; Hougaard, Karin S; Vogel, Ulla; Yauk, Carole L; Wallin, Håkan

    2011-01-01

    Titanium dioxide nanoparticles (nanoTiO2) are used in various applications including in paints. NanoTiO2 inhalation may induce pulmonary toxicity and systemic effects. However, the underlying molecular mechanisms are poorly understood. In this study, the effects of inhaled surface-coated nanoTiO2 on pulmonary global messenger RNA (mRNA) and microRNA (miRNA) expression in mouse were characterized to provide insight into the molecular response. Female C57BL/6BomTac mice were exposed for 1 hr daily to 42.4 ± 2.9 (SEM) mg surface-coated nanoTiO2/m3 for 11 consecutive days by inhalation and were sacrificed 5 days following the last exposure. Physicochemical properties of the particles were determined. Pulmonary response to nanoTiO2 was characterized using DNA microarrays and pathway-specific PCR arrays and related to data on pulmonary inflammation from bronchial lavages. NanoTiO2 exposure resulted in increased levels of mRNA for acute phase markers serum amyloid A-1 (Saa1) and serum amyloid A-3 (Saa3), several C-X-C and C-C motif chemokines, and cytokine tumor necrosis factor genes. Protein analysis of Saa1 and 3 showed selective upregulation of Saa3 in lung tissues. Sixteen miRNAs were induced by more than 1.2-fold (adjusted P-value < 0.05) following exposure. Real time polymerase chain reaction confirmed the upregulation of miR-1, miR-449a and revealed dramatic induction of miR-135b (60-fold). Thus, inhalation of surface-coated nanoTiO2 results in changes in the expression of genes associated with acute phase, inflammation and immune response 5 days post exposure with concomitant changes in several miRNAs. The role of these miRNAs in pulmonary response to inhaled particles is unknown and warrants further research. Environ. Mol. Mutagen., 2011. © 2011 Wiley-Liss, Inc.† PMID:21259345

  13. [Acute-phase proteins in inflammation].

    PubMed

    Engler, R

    1995-01-01

    The acute phase proteins (APPs) have been empirically defined as those whose plasma concentration changes following inflammatory reaction. Those proteins whose concentrations increase are referred to as positive APP, while those whose levels decline are termed negative APP. In man, positive APP are: alpha 1 acid glycoprotein, alpha 1 protease inhibitor, alpha 1 antichymotrypsin, haptoglobin, ceruloplasmin, fibrinogen, C-reactive protein, serum amyloid A. Great variability in the APP response between different species is observed. The principal functions of APP, result from the interaction of these proteins with ligands of various origins which give "protein-ligands" complexes. These complexes are cleared by the RES or by the hepatocyte. The results are protease inhibition, neutralization of toxic molecules such as hemoglobin or the superoxide anion, clearance of cell membranes and chromatin. The drop of the plasma concentration of negative APP during an inflammatory reaction carries a rise of free ligands (fatty acids, hormones, vitamins, trace elements). IL6 has been recognized as the principal regulator of most APP genes. The response of the hepatic cell to IL6 is characterized by the enhanced production of type 2 or IL6 specific APPs. The biochemical process of signal transduction is IL6--JAK2--APRF The set of APP genes regulated by IL1 type cytokines (type 1 APPs) is distinct from that regulated by IL6 type cytokine. IL1 and TNF alpha mediated stimulation of type 1 APP genes is synergistically enhanced by IL6 type cytokines. The biochemical process of signal transduction is IL1, IL6--Ras--MAP kinase--NFIL6 The targeted inflammatory proteic profile including the assay of C-reactive protein, haptoglobin and alpha 1 acid glycoprotein produces a "biological tool" to the clinician in order to manage an inflammatory response. IL6, a proteic marker for the future, connected with CRP, will be assayed during early inflammatory reaction.

  14. [Acute phase reaction and immunocompetence in sepsis and SIRS].

    PubMed

    Burdon, Dan; Zabel, Peter

    2002-01-01

    The incidence of sepsis and SIRS, respectively is still rising. Mortality is 40 to 70% and, thus, remains very high in spite of major advances in intensive care medicine. Numerous experimental data have helped to explain isolated aspects of the pathophysiology of these disease states but the complex patho-mechanism remains to be elucidated. The discovery of the toll-like receptors and of the endotoxin-binding proteins LBP and BPI have substantially contributed to the understanding of the bacterial toxin-host interactions and may stimulate the development of new therapeutic strategies in the future. Pro- and anti-inflammatory cytokines play a central role in disease evolution, however the concept of organ-derived and organ-specific damage is gaining importance. Both inflammation and counter-regulation can occur at the same time in the circulation thus, making the evaluation of the patients' immunological status difficult. Additionally, several gene polymorphisms have been detected for example within the toll-like receptor genes and TNF genes. These polymorphisms document the existence of pre-disposing factors, which influence acute phase reaction as well as immuno-competence in sepsis. Both genes and gender will play an important role in the future to identify patients at risk and potentially, to design a specific and individualized immuno-therapies.

  15. Acute Phase Reactants as Novel Predictors of Cardiovascular Disease

    PubMed Central

    Ahmed, M. S.; Jadhav, A. B.; Hassan, A.; Meng, Qing H.

    2012-01-01

    Acute phase reaction is a systemic response which usually follows a physiological condition that takes place in the beginning of an inflammatory process. This physiological change usually lasts 1-2 days. However, the systemic acute phase response usually lasts longer. The aim of this systemic response is to restore homeostasis. These events are accompanied by upregulation of some proteins (positive acute phase reactants) and downregulation of others (negative acute phase reactants) during inflammatory reactions. Cardiovascular diseases are accompanied by the elevation of several positive acute phase reactants such as C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, white blood cell count, secretory nonpancreatic phospholipase 2-II (sPLA2-II), ferritin, and ceruloplasmin. Cardiovascular disease is also accompanied by the reduction of negative acute phase reactants such as albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, and transcortin. In this paper, we will be discussing the biological activity and diagnostic and prognostic values of acute phase reactants with cardiovascular importance. The potential therapeutic targets of these reactants will be also discussed. PMID:24049653

  16. Acrolein-Induced Dyslipidemia and Acute Phase Response Independenly of HMG-CoA Reductase

    PubMed Central

    Conklin, Daniel J.; Prough, Russell A.; Juvan, Peter; Rezen, Tadeja; Rozman, Damjana; Haberzettl, Petra; Srivastava, Sanjay; Bhatnagar, Aruni

    2012-01-01

    Scope Aldehydes are ubiquitous natural constituents of foods, water and beverages. Dietary intake represents the greatest source of exposure to acrolein and related aldehydes. Oral acrolein induces dyslipidemia acutely and chronically increases atherosclerosis in mice, yet the mechanisms are unknown. Because lipid synthesis and trafficking are largely under hepatic control, we examined hepatic genes in murine models of acute and chronic oral acrolein exposure. Methods and results Changes in hepatic gene expression were examined using a Steroltalk microarray. Acute acrolein feeding modified plasma and hepatic proteins and increased plasma triglycerides within 15 min. By 6h, acrolein altered hepatic gene expression including Insig1, Insig2 and Hmgcr genes and stimulated an acute phase response (APR) with up-regulation of serum amyloid A genes (Saa) and systemic hypoalbuminemia. To test if decreased HMG-CoA reductase activity could modify acrolein-induced dyslipidemia or the APR, mice were pretreated with simvastatin. Statin treatment, however, did not alter acrolein-induced dyslipidemia or hypoalbuminemia associated with an APR. Few hepatic genes were dysregulated by chronic acrolein feeding in apoE-null mice. These studies confirmed that acute acrolein exposure altered expression of hepatic genes involved with lipid synthesis and trafficking and APR, and thus, indicated a hepatic locus of acrolein-induced dyslipidemia and APR that was independent of HMG CoA-reductase. Conclusion Dietary intake of acrolein could contribute to cardiovascular disease risk by disturbing hepatic function. PMID:21812109

  17. Murine heart gene expression during acute Chagasic myocarditis

    PubMed Central

    Henao-Martínez, Andrés F.; Parra-Henao, Gabriel

    2015-01-01

    Chagas disease is transmitted by the parasite, Trypanosoma cruzi. Acute infection is characterized by acute myocarditis, although it is largely asymptomatic. Initial cardiac insult could be a determinant to the posterior development of chronic Chagasic cardiomyopathy, usually after 10 years in only approximately 30% of chronically infected patients. Herein, we characterized the acute gene expression profiling in heart tissue of two strains of mice infected with T. cruzi (tulahuen strain) at 4 weeks and their respective controls. Gene sequence data are available at NCBI under GEO accession number: GSE63847. The output of the genes expression suggests differences in involvement of protein kinase B (AKT), NCAM1, HLA-DRA, and ubiquitin C genes networks. These gene activation differences may correlate with myocardial contractility during the acute infection. PMID:26484182

  18. Tipifarnib and Bortezomib in Treating Patients With Acute Leukemia or Chronic Myelogenous Leukemia in Blast Phase

    ClinicalTrials.gov

    2015-04-14

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Blastic Phase; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  19. Hox gene dysregulation in acute myeloid leukemia.

    PubMed

    De Braekeleer, Etienne; Douet-Guilbert, Nathalie; Basinko, Audrey; Le Bris, Marie-Josée; Morel, Frédéric; De Braekeleer, Marc

    2014-02-01

    In humans, class I homeobox genes (HOX genes) are distributed in four clusters. Upstream regulators include transcriptional activators and members of the CDX family of transcription factors. HOX genes encode proteins and need cofactor interactions, to increase their specificity and selectivity. HOX genes contribute to the organization and regulation of hematopoiesis by controlling the balance between proliferation and differentiation. Changes in HOX gene expression can be associated with chromosomal rearrangements generating fusion genes, such as those involving MLL and NUP98, or molecular defects, such as mutations in NPM1 and CEBPA for example. Several miRNAs are involved in the control of HOX gene expression and their expression correlates with HOX gene dysregulation. HOX genes dysregulation is a dominant mechanism of leukemic transformation. A better knowledge of their target genes and the mechanisms by which their dysregulated expression contributes to leukemogenesis could lead to the development of new drugs.

  20. Acute exercise does not induce an acute phase response (APR) in Standardbred trotters.

    PubMed

    Kristensen, Lena; Buhl, Rikke; Nostell, Katarina; Bak, Lars; Petersen, Ellen; Lindholm, Maria; Jacobsen, Stine

    2014-04-01

    The purpose of the study was to investigate whether acute strenuous exercise (1600- to 2500-m race) would elicit an acute phase response (APR) in Standardbred trotters. Blood levels of several inflammatory markers [serum amyloid A (SAA), haptoglobin, fibrinogen, white blood cell count (WBC), and iron], muscle enzymes [creatinine kinase (CK) and aspartate transaminase (AST)], and hemoglobin were assessed in 58 Standardbred trotters before and after racing. Hemoglobin levels increased and iron levels decreased 12 to 14 h after racing and haptoglobin concentrations, white blood cell counts, and iron levels were decreased 2 and/or 7 d after racing. Concentrations of CK, AST, SAA, and fibrinogen were unaltered in response to racing. Acute strenuous exercise did not elicit an acute phase reaction. The observed acute increase in hemoglobin levels and decreases in haptoglobin and iron levels may have been caused by exercise-induced hemolysis, which indicates that horses might experience a condition similar to athlete's anemia in humans. The pathogenesis and clinical implications of the hematological and blood-biochemical changes elicited by acute exercise in Standardbred trotters in the present study warrant further investigation.

  1. Roles of STAT3 in Protein Secretion Pathways during the Acute-Phase Response

    PubMed Central

    Ahyi, Ayele-Nati N.; Quinton, Lee J.; Jones, Matthew R.; Ferrari, Joseph D.; Pepper-Cunningham, Zachary A.; Mella, Juan R.; Remick, Daniel G.

    2013-01-01

    The acute-phase response is characteristic of perhaps all infections, including bacterial pneumonia. In conjunction with the acute-phase response, additional biological pathways are induced in the liver and are dependent on the transcription factors STAT3 and NF-κB, but these responses are poorly understood. Here, we demonstrate that pneumococcal pneumonia and other severe infections increase expression of multiple components of the cellular secretory machinery in the mouse liver, including the endoplasmic reticulum (ER) translocon complex, which mediates protein translation into the ER, and the coat protein complexes (COPI and COPII), which mediate vesicular transport of proteins to and from the ER. Hepatocyte-specific mutation of STAT3 prevented the induction of these secretory pathways during pneumonia, with similar results observed following pharmacological activation of ER stress by using tunicamycin. These findings implicate STAT3 in the unfolded protein response and suggest that STAT3-dependent optimization of secretion may apply broadly. Pneumonia also stimulated the binding of phosphorylated STAT3 to promoter regions of secretion-related genes in the liver, supporting a direct role for STAT3 in their transcription. Altogether, these results identify a novel function of STAT3 during the acute-phase response, namely, the induction of secretory machinery in hepatocytes. This may facilitate the processing and delivery of newly synthesized loads of acute-phase proteins, enhancing innate immunity and preventing liver injury during infection. PMID:23460517

  2. Normal Caloric Responses during Acute Phase of Vestibular Neuritis

    PubMed Central

    Lee, Sun-Uk; Park, Seong-Ho; Kim, Hyo-Jung; Koo, Ja-Won

    2016-01-01

    Background and Purpose We report a novel finding of caloric conversion from normal responses into unilateral paresis during the acute phase of vestibular neuritis (VN). Methods We recruited 893 patients with a diagnosis of VN at Dizziness Clinic of Seoul National University Bundang Hospital from 2003 to 2014 after excluding 28 patients with isolated inferior divisional VN (n=14) and those without follow-up tests despite normal caloric responses initially (n=14). We retrospectively analyzed the neurotological findings in four (0.5%) of the patients who showed a conversion from initially normal caloric responses into unilateral paresis during the acute phase. Results In those four patients, the initial caloric tests were performed within 2 days of symptom onset, and conversion into unilateral caloric paresis was documented 1–4 days later. The clinical and laboratory findings during the initial evaluation were consistent with VN in all four patients except for normal findings in bedside head impulse tests in one of them. Conclusions Normal findings in caloric tests should be interpreted with caution during the acute phase of suspected VN. Follow-up evaluation should be considered when the findings of the initial caloric test are normal, but VN remains the most plausible diagnosis. PMID:26932259

  3. Acute phase protein response in the capybara (Hydrochoerus hydrochaeris).

    PubMed

    Bernal, Luis; Feser, Mariane; Martínez-Subiela, Silvia; García-Martínez, Juan D; Cerón, José J; Tecles, Fernando

    2011-10-01

    We evaluated the acute phase protein response in capybaras (Hydrochoerus hydrochaeris). Three animal groups were used: 1) healthy animals (n=30), 2) a group in which experimental inflammation with turpentine was induced (n=6), and 3) a group affected with sarcoptic scabies (n=14) in which 10 animals were treated with ivermectin. Haptoglobin (Hp), acid-soluble glycoprotein (ASG) and albumin were analyzed in all animals. In those treated with turpentine, Hp reached its maximum value at 2 wk with a 2.7-fold increase, whereas ASG increased 1.75-fold and albumin decreased 0.87-fold 1 wk after the induction of inflammation. Capybaras affected with sarcoptic scabies presented increases in Hp and ASG of 4.98- and 3.18-fold, respectively, and a 0.87-fold decrease in albumin, compared with healthy animals. Haptoglobin and ASG can be considered as moderate, positive acute phase proteins in capybaras because they showed less than 10-fold increases after an inflammatory process and reached their peak concentrations 1 wk after the induction of inflammation. Conversely, albumin can be considered a negative acute phase protein in capybaras because it showed a reduction in concentration after inflammatory stimulus.

  4. Elimination Half-Lives of Acute Phase Proteins in Rats and Beagle Dogs During Acute Inflammation.

    PubMed

    Kuribayashi, Takashi; Seita, Tetsuro; Momotani, Eiichi; Yamazaki, Shunsuke; Hagimori, Kohei; Yamamoto, Shizuo

    2015-08-01

    The half-lives of typical acute phase proteins in rats and beagle dogs during acute inflammation were investigated. Acute inflammation was induced by injection of turpentine oil in rats and administration of indomethacin in beagle dogs. Serum concentrations of α2-macroglobulin (α2M) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assay and α1-acid glycoprotein (AAG) was measured by single radial immunodiffusion. Half-life was calculated as 0.693/elimination rate constant (K). The mean half-lives in the terminal elimination phase of α2M and AAG were 68.1 and 164.8 h, respectively. The half-life of AAG was significantly longer than that of α2M. Mean half-lives in the terminal elimination phase of CRP and AAG were 161.9 and 304.4 h, respectively. The half-life of AAG was significantly longer than that of CRP in beagle dogs. No significant differences in the half-life of AAG were observed between rats and beagle dogs. Furthermore, serum concentrations in the terminal elimination phase could be simulated with the K data acquired in this study.

  5. Early phase of acute pancreatitis: Assessment and management

    PubMed Central

    Phillip, Veit; Steiner, Jörg M; Algül, Hana

    2014-01-01

    Acute pancreatitis (AP) is a potentially life-threatening disease with a wide spectrum of severity. The overall mortality of AP is approximately 5%. According to the revised Atlanta classification system, AP can be classified as mild, moderate, or severe. Severe AP often takes a clinical course with two phases, an early and a late phase, which should both be considered separately. In this review article, we first discuss general aspects of AP, including incidence, pathophysiology, etiology, and grading of severity, then focus on the assessment of patients with suspected AP, including diagnosis and risk stratification, followed by the management of AP during the early phase, with special emphasis on fluid therapy, pain management, nutrition, and antibiotic prophylaxis. PMID:25133018

  6. Host gene expression classifiers diagnose acute respiratory illness etiology

    PubMed Central

    Nichols, Marshall; Burke, Thomas; Ko, Emily R.; McClain, Micah T.; Hudson, Lori L.; Mazur, Anna; Freeman, Debra H.; Veldman, Tim; Langley, Raymond J.; Quackenbush, Eugenia B.; Glickman, Seth W.; Cairns, Charles B.; Jaehne, Anja K.; Rivers, Emanuel P.; Otero, Ronny M.; Zaas, Aimee K.; Kingsmore, Stephen F.; Lucas, Joseph; Fowler, Vance G.; Carin, Lawrence; Ginsburg, Geoffrey S.; Woods, Christopher W.

    2016-01-01

    Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational, cohort study determined whether host gene expression patterns discriminate non-infectious from infectious illness, and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or non-infectious illness as well as 44 healthy controls was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a non-infectious cause of illness (26 probes). Overall accuracy was 87% (238/273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, p<0.03) and three published classifiers of bacterial vs. viral infection (78-83%). The classifiers developed here externally validated in five publicly available datasets (AUC 0.90-0.99). A sixth publically available dataset included twenty-five patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI; viral ARI; co-infection; and neither a bacterial nor viral response. These findings create an opportunity to develop and utilize host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance. PMID:26791949

  7. [Plasmapheresis in acute phase of multiple sclerosis and neuromyelitis optica].

    PubMed

    Matsuo, Hidenori

    2014-11-01

    In acute phase of multiple sclerosis (MS) and neuromyelitis optica (NMO), plasmapheresis (PP) should be considered as the 2nd choice treatment when corticosteroid pulse therapy results in unsuccessful. It is believed that the beneficial effects of PP occur through the elimination of pathogenic humoral and plasma factors, including autoantibodies, complement components, and cytokines. In MS, several clinical trials have shown the efficacy. However, there have been no randomized controlled trials that demonstrated the efficacy of PP in NMO. There are three methods of PP, plasma exchange, double filtration plasmapheresis and immunoadsorption plasmapheresis, available in Japan. But the difference of efficacy among these 3 methods has not been fully evaluated.

  8. Acute exercise regulates adipogenic gene expression in white adipose tissue.

    PubMed

    Shen, Y; Zhou, H; Jin, W; Lee, H J

    2016-12-01

    White adipose tissue expansion is associated with both hypertrophy and hyperplasia of adipocytes. Exercise training results in adipocyte hypotrophy by activating lipolysis, but it is poorly understood whether exercise regulates adipogenesis by altering adipogenic gene expression. The purpose of this study was to evaluate the effect of a single bout of swimming exercise on adipogenic gene expression in white adipose tissue (WAT). Male C57BL/6J mice were divided into two groups: a sedentary control group and a 120-minute swimming exercise group. Immediately after acute exercise, adipogenic gene expression in WAT was analysed by RT-PCR, and tdTomato positive cells in WAT from UCP1-cre-tdTomato mice were observed under a confocal microscope. In epididymal white adipose tissue (eWAT), PPARγ2 and C/EBPα expression at the mRNA level was significantly decreased with high induction of Wnt10b and KLFs (KLF2, KLF3, KLF7, KLF6, KLF9 and KLF15), whereas PPARγ2, not C/EBPα, was decreased with high induction of Wnt6 and KLFs (KLF2, KLF3, KLF7, KLF6 and KLF9) in inguinal white adipose tissue (iWAT) after acute exercise. The expression of C/EBPβ and C/EBPδ was upregulated in both WATs with a high level of PGC-1α expression. Expression level of UCP1 was increased only in adipocytes of eWAT, while beige cell specific gene expression was comparable between groups and tdTomato positive cells were not found in WAT of UCP1-cre-tdTomato reporter mouse immediately after acute exercise. These results suggest that acute exercise suppresses adipogenic gene expression and may regulate thermogenesis by activating C/EBPβ, PGC-1α and UCP1 in WAT.

  9. Acute phase response in cattle infected with Anaplasma marginale.

    PubMed

    Nazifi, S; Razavi, S M; Kaviani, F; Rakhshandehroo, E

    2012-03-23

    This study was undertaken to evaluate the acute phase responses via the assessment of the concentration of serum sialic acids (total, lipid bound and protein bound), inflammatory mediators (IFN-γ and TNF-α) and acute phase proteins (Hp and SAA) in 20 adult crossbred cattle naturally infected by Anaplasma marginale. The infected animals were divided into 2 subgroups on the basis of parasitemia rate (<20% and >20%). Also, as a control group, 10 clinically healthy cattle from the same farms were sampled. Our data revealed significant decreases in red blood cell count (RBC), hematocrite (PCV) and hemoglobine (Hb) in infected cattle compared to healthy ones. Conversely, the concentrations of Hp, SAA, ceruloplasmin, fibrinogen, serum sialic acids and the circulatory IFN-γ and TNF-α were increased in the diseased cattle (P<0.05). In addition, it was evident that the progression of parasitemia in infected cattle did not induce any significant alterations in the hematological indices (RBCs, PCV and Hb) and the concentrations of Hp, SAA, ceruloplasmin and fibrinogen. SAA was the most sensitive factor to change in the diseased cattle. Therefore, increase in SAA concentration may be a good indicator of inflammatory process in cattle naturally infected with Anaplasma marginale.

  10. Relationship between Acute Phase of Chronic Periodontitis and Meteorological Factors in the Maintenance Phase of Periodontal Treatment: A Pilot Study

    PubMed Central

    Takeuchi, Noriko; Ekuni, Daisuke; Tomofuji, Takaaki; Morita, Manabu

    2015-01-01

    The acute phase of chronic periodontitis may occur even in patients during supportive periodontal therapy. However, the details are not fully understood. Since the natural environment, including meteorology affects human health, we hypothesized that weather conditions may affect occurrence of acute phase of chronic periodontitis. The aim of this study was to investigate the relationship between weather conditions and acute phase of chronic periodontitis in patients under supportive periodontal therapy. Patients who were diagnosed with acute phase of chronic periodontitis under supportive periodontal therapy during 2011–2013 were selected for this study. We performed oral examinations and collected questionnaires and meteorological data. Of 369 patients who experienced acute phase of chronic periodontitis, 153 had acute phase of chronic periodontitis without direct-triggered episodes. When using the autoregressive integrated moving average model of time-series analysis, the independent covariant of maximum hourly range of barometric pressure, maximum hourly range of temperature, and maximum daily wind speed were significantly associated with occurrence of acute phase of chronic periodontitis (p < 0.05), and 3.1% of the variations in these occurrence over the study period were explained by these factors. Meteorological variables may predict occurrence of acute phase of chronic periodontitis. PMID:26251916

  11. Relationship between Acute Phase of Chronic Periodontitis and Meteorological Factors in the Maintenance Phase of Periodontal Treatment: A Pilot Study.

    PubMed

    Takeuchi, Noriko; Ekuni, Daisuke; Tomofuji, Takaaki; Morita, Manabu

    2015-08-05

    The acute phase of chronic periodontitis may occur even in patients during supportive periodontal therapy. However, the details are not fully understood. Since the natural environment, including meteorology affects human health, we hypothesized that weather conditions may affect occurrence of acute phase of chronic periodontitis. The aim of this study was to investigate the relationship between weather conditions and acute phase of chronic periodontitis in patients under supportive periodontal therapy. Patients who were diagnosed with acute phase of chronic periodontitis under supportive periodontal therapy during 2011-2013 were selected for this study. We performed oral examinations and collected questionnaires and meteorological data. Of 369 patients who experienced acute phase of chronic periodontitis, 153 had acute phase of chronic periodontitis without direct-triggered episodes. When using the autoregressive integrated moving average model of time-series analysis, the independent covariant of maximum hourly range of barometric pressure, maximum hourly range of temperature, and maximum daily wind speed were significantly associated with occurrence of acute phase of chronic periodontitis (p < 0.05), and 3.1% of the variations in these occurrence over the study period were explained by these factors. Meteorological variables may predict occurrence of acute phase of chronic periodontitis.

  12. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes.

    PubMed Central

    Janssen, J W; Steenvoorden, A C; Lyons, J; Anger, B; Böhlke, J U; Bos, J L; Seliger, H; Bartram, C R

    1987-01-01

    We report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization we additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case. Images PMID:3122217

  13. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes

    SciTech Connect

    Janssen, J.W.G.; Steenvoorden, A.C.M.; Lyons, J.; Anger, B.; Boehlke, J.U.; Bos, J.L.; Seliger, H.; Bartram, C.R.

    1987-12-01

    The authors report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization they additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case.

  14. Acute megakaryoblastic leukemia and loss of the RUNX1 gene.

    PubMed

    Berger, Roland; Busson, Maryvonne; Dastugue, Nicole; Radford-Weiss, Isabelle; Michaux, Lucienne; Hagemeijer, Anne; Quilichini, Benoît; Benattar, Laurence; Bernard, Olivier; Romana, Serge P

    2006-01-01

    Since the RUNX1 gene contributes to megakaryopoiesis and acquired trisomy 21 is the most frequent numerical chromosome anomaly in acute megakaryoblastic leukemia (AMLK), a systematic study of RUNX1 abnormalities was performed by fluorescence in situ hybridization in AMLK patients. Four abnormalities were detected among 15 patients. One copy of RUNX1 was completeley or partially lost in three patients and translocated onto Xq24 in the fourth. The possible consequences of RUNX1 haploinsufficiency are discussed.

  15. Acute phase response in lame crossbred dairy cattle

    PubMed Central

    Bagga, A.; Randhawa, Swaran Singh; Sharma, S.; Bansal, B. K.

    2016-01-01

    Aim: The study was undertaken to study acute phase response based on acute phase proteins (APPs) such as C-reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA), and fibrinogen in lame crossbred dairy cattle. Materials and Methods: Lame animals (n=30) were selected within 3-7 days of being noticed as lame by the farm veterinarian, from a local dairy farm in southeast Ludhiana over a period of 6 months, stratified proportionately with respect to stage of lactation with non-lame healthy cows (n=10). All the cows were otherwise healthy and did not have any other inflammatory problems such as pneumonia, enteritis, mastitis, or any kind of acute uterine inflammation. Blood samples were collected from all the animals; serum and plasma samples were separated and stored at −20°C. The levels of CRP, Hp, and SAA were estimated using Sandwich ELISA, whereas fibrinogen was estimated by heat precipitation method. Results: SAA levels in lame cows were significantly higher (22.19±0.85 µg/ml), approximately 3 times as compared to non-lame cows (8.89±0.72 µg/ml), whereas serum Hp concentration was approximately 20 times higher in the lame cattle (21.71±3.32 mg/dl) as compared to non-lame cows (1.17±0.07 mg/dl). Fibrinogen also increased in the lame cattle (3.97±0.22 g/L) as compared to non-lame group (1.40±0.17 g/L). Serum CRP levels analyzed in the lame cattle for the first time in the present study, and significant high concentration was appreciated in lame cattle (4.41±0.33 mg/L) as compared to non-lame cattle (0.61±0.14 mg/L). Lame cattle were having more of sole hemorrhages, sole ulcers, and white line lesions as compared to non-lame cattle. Conclusion: It can be concluded that lame cattle exhibit high levels of APPs including CRP, Hp, SAA, and fibrinogen as compared to non-lame cattle. PMID:27956769

  16. Conserved gene regulation during acute inflammation between zebrafish and mammals.

    PubMed

    Forn-Cuní, G; Varela, M; Pereiro, P; Novoa, B; Figueras, A

    2017-02-03

    Zebrafish (Danio rerio), largely used as a model for studying developmental processes, has also emerged as a valuable system for modelling human inflammatory diseases. However, in a context where even mice have been questioned as a valid model for these analysis, a systematic study evaluating the reproducibility of human and mammalian inflammatory diseases in zebrafish is still lacking. In this report, we characterize the transcriptomic regulation to lipopolysaccharide in adult zebrafish kidney, liver, and muscle tissues using microarrays and demonstrate how the zebrafish genomic responses can effectively reproduce the mammalian inflammatory process induced by acute endotoxin stress. We provide evidence that immune signaling pathways and single gene expression is well conserved throughout evolution and that the zebrafish and mammal acute genomic responses after lipopolysaccharide stimulation are highly correlated despite the differential susceptibility between species to that compound. Therefore, we formally confirm that zebrafish inflammatory models are suited to study the basic mechanisms of inflammation in human inflammatory diseases, with great translational impact potential.

  17. T Helper Subsets, Peripheral Plasticity, and the Acute Phase Protein, α1-Antitrypsin

    PubMed Central

    Baranovski, Boris M.; Freixo-Lima, Gabriella S.; Lewis, Eli C.; Rider, Peleg

    2015-01-01

    The traditional model of T helper differentiation describes the naïve T cell as choosing one of several subsets upon stimulation and an added reciprocal inhibition aimed at maintaining the chosen subset. However, to date, evidence is mounting to support the presence of subset plasticity. This is, presumably, aimed at fine-tuning adaptive immune responses according to local signals. Reprograming of cell phenotype is made possible by changes in activation of master transcription factors, employing epigenetic modifications that preserve a flexible mode, permitting a shift between activation and silencing of genes. The acute phase response represents an example of peripheral changes that are critical in modulating T cell responses. α1-antitrypsin (AAT) belongs to the acute phase responses and has recently surfaced as a tolerogenic agent in the context of adaptive immune responses. Nonetheless, AAT does not inhibit T cell responses, nor does it shutdown inflammation per se; rather, it appears that AAT targets non-T cell immunocytes towards changing the cytokine environment of T cells, thus promoting a regulatory T cell profile. The present review focuses on this intriguing two-way communication between innate and adaptive entities, a crosstalk that holds important implications on potential therapies for a multitude of immune disorders. PMID:26583093

  18. [Occurrence of acute infectious diarrhea during the lunar phases].

    PubMed

    Mikulecký, M; Schréter, I

    1993-08-23

    A chronobiometric analysis of 753 cases of acute infectious diarrhoea in adults in 1981-1990 in Kosice confirmed to a surprising extent recently reached conclusions of an investigation made by authors from Bratislava. The Kosice group comprised 352 cases of bacillary dysentery, 305 patients with salmonellosis, 72 with campylobacteriosis and 24 with yersiniosis. Statistically significantly fewer patients (p < 0.0001) were hospitalized during full moon, moon quarterly and new moon. In the intervals there were periods with a short-term increase of the daily admissions by cca 25%. This 7.38-day periodicity cannot be explained by the influence of the social 7-day week, as during observations extending over several years this rhythm is eliminated by a gradual shift across different phases of the moon. The authors did not find similar reports in the literature. For explanation, not only the organism of the host (variable immunity?) but also the infectious agent must be taken into account. More profound understanding of the mechanism may open the road to practical application of the described lunar relationship. Its knowledge can help already now to improve the organization of the health service.

  19. Molecular Diagnosis of Chagas Disease in Colombia: Parasitic Loads and Discrete Typing Units in Patients from Acute and Chronic Phases

    PubMed Central

    Hernández, Carolina; Cucunubá, Zulma; Flórez, Carolina; Olivera, Mario; Valencia, Carlos; Zambrano, Pilar; León, Cielo; Ramírez, Juan David

    2016-01-01

    Background The diagnosis of Chagas disease is complex due to the dynamics of parasitemia in the clinical phases of the disease. The molecular tests have been considered promissory because they detect the parasite in all clinical phases. Trypanosoma cruzi presents significant genetic variability and is classified into six Discrete Typing Units TcI-TcVI (DTUs) with the emergence of foreseen genotypes within TcI as TcIDom and TcI Sylvatic. The objective of this study was to determine the operating characteristics of molecular tests (conventional and Real Time PCR) for the detection of T. cruzi DNA, parasitic loads and DTUs in a large cohort of Colombian patients from acute and chronic phases. Methodology/Principal Findings Samples were obtained from 708 patients in all clinical phases. Standard diagnosis (direct and serological tests) and molecular tests (conventional PCR and quantitative PCR) targeting the nuclear satellite DNA region. The genotyping was performed by PCR using the intergenic region of the mini-exon gene, the 24Sa, 18S and A10 regions. The operating capabilities showed that performance of qPCR was higher compared to cPCR. Likewise, the performance of qPCR was significantly higher in acute phase compared with chronic phase. The median parasitic loads detected were 4.69 and 1.33 parasite equivalents/mL for acute and chronic phases. The main DTU identified was TcI (74.2%). TcIDom genotype was significantly more frequent in chronic phase compared to acute phase (82.1% vs 16.6%). The median parasitic load for TcIDom was significantly higher compared with TcI Sylvatic in chronic phase (2.58 vs.0.75 parasite equivalents/ml). Conclusions/Significance The molecular tests are a precise tool to complement the standard diagnosis of Chagas disease, specifically in acute phase showing high discriminative power. However, it is necessary to improve the sensitivity of molecular tests in chronic phase. The frequency and parasitemia of TcIDom genotype in chronic

  20. The onset of the progression of acute phase response mechanisms induced by extreme impacts can be followed by the decrease in blood levels of positive acute phase proteins.

    NASA Astrophysics Data System (ADS)

    Larina, Olga; Bekker, Anna

    Studies performed at space flights and earth-based simulation models detected the plasma indices of acute phase reaction (APR), i.e. the increase of APR cytokine mediators and alterations in the production of blood acute phase proteins (APP) at the initial stages of adaptation to altered gravity conditions. Acute phase response is the principal constituent of the functional activity of innate immunity system. Changes in plasma APPs contents are considered to serve the restoration of homeostasis state. According to trends of their concentration shifts at the evolving of acute phase reaction APPs are denoted as positive, neutral, or negative. Plasma concentrations of positive acute phase proteins α1-acid glycoprotein (α1-AGP), α1-antitrypsin (α1-AT), and neutral α2-macroglobulin (α2-M) were measured in human study at 12-hour antiorthostatic position (AOP) with 15° head down tilt and hypoxia experiments at 14% oxygen in pressure chamber. Both of these impacts were shown to produce alterations in the APP levels indicative for acute phase response. Nevertheless, in AOP experiment noticeable decrease in α1-AGP concentration occurred by hour 12, and even more pronounced decline of α1-AGP and α1-AT were found on hypoxia hours 12 and 36. Acute phase proteins α1-AGP and α2-M possess the features of proteinase inhibitors. This function is implemented by the formation of complexes with the molecules of proteolytic enzymes which subsequently are removed from the blood flow. Transient decrease in plasma concentrations of protease inhibitors on early phases of APR development was reported to result from the growth of plasma protease activity due to cathepsin release from activated leukocytes, which had not yet been compensated by enhanced APP synthesis. Being a carrier protein for positively charged and neutral substances, α1-AGP shows pronounced elevation in its blood content during APR development. As assumed, it is required for the transportation of the increased

  1. Complement-dependent acute-phase expression of C-reactive protein and serum amyloid P-component.

    PubMed

    Szalai, A J; van Ginkel, F W; Wang, Y; McGhee, J R; Volanakis, J E

    2000-07-15

    The acute-phase response (APR) is regulated by TNF-alpha, IL-1beta, and IL-6 acting alone, in combination, or in concert with hormones. The anaphylotoxin C5a, generated during complement activation, induces in vitro the synthesis of these cytokines by leukocytes and of acute-phase proteins by HepG2 cells. However, there is no clear evidence for a role of C5a or any other complement activation product in regulation of the APR in vivo. In this study, using human C-reactive protein (CRP) transgenic mice deficient in C3 or C5, we investigated whether complement activation contributes to induction of the acute-phase proteins CRP and serum amyloid P-component (SAP). Absence of C3 or C5 resulted in decreased LPS-induced up-regulation of the CRP transgene and the mouse SAP gene. Also, LPS induced both the IL-1beta and IL-6 genes in normocomplementemic mice, but in complement-deficient mice it significantly induced only IL-6. Like LPS injection, activation of complement by cobra venom factor led to significant elevation of serum CRP and SAP in normocomplementemic mice but not in complement-deficient mice. Injection of recombinant human C5a into human CRP transgenic mice induced the IL-1beta gene and caused significant elevation of both serum CRP and SAP. However, in human CRP transgenic IL-6-deficient mice, recombinant human C5a did not induce the CRP nor the SAP gene. Based on these data, we conclude that during the APR, C5a generated as a consequence of complement activation acts in concert with IL-6 and/or IL-1beta to promote up-regulation of the CRP and SAP genes.

  2. [Management of coronary artery disease at the acute phase].

    PubMed

    Chatot, Marion; Schiele, François

    2015-03-01

    In patients with acute coronary syndrome (ACS), early management is of prime importance. However, the median time taken by the patient to call the emergency services is often very long, up to 2 hours. The presence of a physician as first responder ensures good quality resuscitation in case of cardiac arrest, and allows recording of a first ECG, which can be very informative, especially in ACS without ST segment elevation. Treatment at this stage is limited to sublingual nitroglycerin and aspirin. If the first ECG shows ST segment elevation, the patient should be immediately oriented for reperfusion, usually by percutaneous coronary intervention. in the absence of ST segment elevation, the diagnosis of ACS remains unconfirmed. This does not imply that the risk is lesser, but rather that the risk cannot be evaluated accurately in the pre-hospital setting. The use of risk scores can guide the choice of management towards an invasive strategy, including coronary angiography (immediately, or within 24-72 hours). Low-risk patients are candidates for an invasive strategy, provided non-invasive tests demonstrate the presence of ischemia. During the hospital phase, antiplatelet treatment should be initiated and must be adapted to the patient bleeding and thrombotic risk. Clopidogrel is recommended only in patients who are not amenable to prasugrel or ticagrelor. Statin therapy should be initiated from day one, regardless of the initial cholesterol level, preferably with 80 mg atorvastatin. Angiotensin-converting enzyme inhibitors and beta-blockers should also be prescribed to complete the medical prescription both in-hospital and in the long term.

  3. Conserved gene regulation during acute inflammation between zebrafish and mammals

    PubMed Central

    Forn-Cuní, G.; Varela, M.; Pereiro, P.; Novoa, B.; Figueras, A.

    2017-01-01

    Zebrafish (Danio rerio), largely used as a model for studying developmental processes, has also emerged as a valuable system for modelling human inflammatory diseases. However, in a context where even mice have been questioned as a valid model for these analysis, a systematic study evaluating the reproducibility of human and mammalian inflammatory diseases in zebrafish is still lacking. In this report, we characterize the transcriptomic regulation to lipopolysaccharide in adult zebrafish kidney, liver, and muscle tissues using microarrays and demonstrate how the zebrafish genomic responses can effectively reproduce the mammalian inflammatory process induced by acute endotoxin stress. We provide evidence that immune signaling pathways and single gene expression is well conserved throughout evolution and that the zebrafish and mammal acute genomic responses after lipopolysaccharide stimulation are highly correlated despite the differential susceptibility between species to that compound. Therefore, we formally confirm that zebrafish inflammatory models are suited to study the basic mechanisms of inflammation in human inflammatory diseases, with great translational impact potential. PMID:28157230

  4. Hepatic acute phase proteins--regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signaling.

    PubMed

    Bode, Johannes G; Albrecht, Ute; Häussinger, Dieter; Heinrich, Peter C; Schaper, Fred

    2012-01-01

    The function of the liver as an important constituent of the immune system involved in innate as well as adaptive immunity is warranted by different highly specialized cell populations. As the major source of acute phase proteins, including secreted pathogen recognition receptors (PRRs), short pentraxins, components of the complement system or regulators of iron metabolism, hepatocytes are essential constituents of innate immunity and largely contribute to the control of a systemic inflammatory response. The production of acute phase proteins in hepatocytes is controlled by a variety of different cytokines released during the inflammatory process with IL-1- and IL-6-type cytokines as the leading regulators operating both as a cascade and as a network having additive, inhibitory, or synergistic regulatory effects on acute phase protein expression. Hence, IL-1β substantially modifies IL-6-induced acute phase protein production as it almost completely abrogates production of acute phase proteins such as γ-fibrinogen, α(2)-macroglobulin or α(1)-antichymotrypsin, whereas production of for example hepcidin, C-reactive protein and serum amyloid A is strongly up-regulated. This switch-like regulation of IL-6-induced acute phase protein production by IL-1β is due to a complex processing of the intracellular signaling events activated in response to IL-6 and/or IL-1β, with the crosstalk between STAT3- and NF-κB-mediated signal transduction being of particular importance. Recent data suggest that in this context complex formation between STAT3 and the p65 subunit of NF-κB might be of key importance. The present review summarizes the regulation of acute phase protein production focusing on the role of the crosstalk of STAT3- and NF-κB-driven pathways for transcriptional control of acute phase gene expression.

  5. ACUTE PHASE IMMUNE GENE PROFILING OF SPLEEN AND PEYER’S PATCH IN NAÏVE AND VACCINATED CHICKENS FOLLOWING AVIAN INFLUENZA A (H5N1) VIRUS INFECTION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, we applied functional genomics tools to investigate the early immunological response of chickens to highly pathogenic (HP) avian influenza virus (AIV). Infection with HPAIV usually results in the rapid death of poultry. The aim of this study was to identify host immune genes which a...

  6. Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase.

    PubMed

    Kobayashi, Masatake; Nanri, Kazunori; Taguchi, Takeshi; Ishiko, Tomoko; Yoshida, Masaharu; Yoshikawa, Noriko; Sugisaki, Kentaro; Tanaka, Nobuyuki

    2015-02-01

    Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti-aquaporin-4-positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice.

  7. Acute-phase reactants in periodontal disease: current concepts and future implications.

    PubMed

    Archana, Vilasan; Ambili, Ranjith; Nisha, Krishnavilasam Jayakumary; Seba, Abraham; Preeja, Chandran

    2015-05-01

    Periodontal disease has been linked to adverse cardiovascular events by unknown mechanisms. C-reactive protein is a systemic marker released during the acute phase of an inflammatory response and is a prognostic marker for cardiovascular disease, with elevated serum levels being reported during periodontal disease. Studies also reported elevated levels of various other acute-phase reactants in periodontal disease. It has been reported extensively in the literature that treatment of periodontal infections can significantly lower serum levels of C-reactive protein. Therefore, an understanding of the relationship between acute-phase response and the progression of periodontal disease and other systemic health complications would have a profound effect on the periodontal treatment strategies. In view of this fact, the present review highlights an overview of acute-phase reactants and their role in periodontal disease.

  8. Predictors of Longitudinal Outcomes after Unstable Response to Acute Phase Cognitive Therapy for Major Depressive Disorder

    PubMed Central

    Vittengl, Jeffrey R.; Clark, Lee Anna; Thase, Michael E.; Jarrett, Robin B.

    2015-01-01

    After patients with major depressive disorder (MDD) respond to acute-phase cognitive therapy (CT), continuation-phase treatments may be applied to improve long-term outcomes. We clarified which CT responders experience remission, recovery, relapse, and recurrence by testing baseline demographic, clinical, and personality variables. The sample of CT responders at higher risk of relapse (N = 241) was randomized to 8 months of continuation-phase CT (C-CT), double-blinded fluoxetine or pill placebo, and followed 24 months (Jarrett & Thase, 2010). Patients with lower positive emotionality and behavioral activation at the end of acute-phase CT showed increased risk for relapse/recurrence of MDD. In addition, patients with lower positive emotionality and behavioral activation, as well as higher residual depression (including emotional, cognitive, and social facets), showed decreased probability of remission (≥6 continuous weeks of minimal or absent symptoms) after acute-phase CT. Finally, patients with greater residual depression, as well as younger age and earlier MDD onset, showed decreased probability of recovery (≥35 continuous weeks of minimal or absent symptoms) after acute-phase CT. Moderator analyses did not reveal differential prediction across the continuation phase treatment arms. These results may help clinicians gauge the prognoses and need for continuation treatment among MDD patients who respond to acute-phase CT. PMID:25985046

  9. RNA-Seq Characterization of Spinal Cord Injury Transcriptome in Acute/Subacute Phases: A Resource for Understanding the Pathology at the Systems Level

    PubMed Central

    Chen, Kenian; Deng, Shuyun; Lu, Hezuo; Zheng, Yiyan; Yang, Guodong; Kim, Dong; Cao, Qilin; Wu, Jia Qian

    2013-01-01

    Spinal cord injury (SCI) is a devastating neurological disease without effective treatment. To generate a comprehensive view of the mechanisms involved in SCI pathology, we applied RNA-Sequencing (RNA-Seq) technology to characterize the temporal changes in global gene expression after contusive SCI in mice. We sequenced tissue samples from acute and subacute phases (2 days and 7 days after injury) and systematically characterized the transcriptomes with the goal of identifying pathways and genes critical in SCI pathology. The top enriched functional categories include “inflammation response,” “neurological disease,” “cell death and survival” and “nervous system development.” The top enriched pathways include LXR/RXR Activation and Atherosclerosis Signaling, etc. Furthermore, we developed a systems-based analysis framework in order to identify key determinants in the global gene networks of the acute and sub-acute phases. Some candidate genes that we identified have been shown to play important roles in SCI, which demonstrates the validity of our approach. There are also many genes whose functions in SCI have not been well studied and can be further investigated by future experiments. We have also incorporated pharmacogenomic information into our analyses. Among the genes identified, the ones with existing drug information can be readily tested in SCI animal models. Therefore, in this study we have described an example of how global gene profiling can be translated to identifying genes of interest for functional tests in the future and generating new hypotheses. Additionally, the RNA-Seq enables splicing isoform identification and the estimation of expression levels, thus providing useful information for increasing the specificity of drug design and reducing potential side effect. In summary, these results provide a valuable reference data resource for a better understanding of the SCI process in the acute and sub-acute phases. PMID:23951329

  10. Acute phase response induced following tumor treatment by photodynamic therapy: relevance for the therapy outcome

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Merchant, Soroush; Stott, Brandon; Cecic, Ivana; Payne, Peter; Sun, Jinghai

    2006-02-01

    Acute phase response is an effector process orchestrated by the innate immune system for the optimal mobilization of the resources of the organism distant from the local insult site needed in the execution of a host-protecting reaction. Our research has shown that mice bearing tumors treated by photodynamic therapy (PDT) exhibit the three major hallmarks of acute phase response: release of acute phase reactants, neutrophilia, and pituitary/adrenal axis activation. Of particular interest in this study were acute phase proteins that have a pivotal role in the clearance of dead cells, since the occurrence of this process in PDT-treated tumors emerges as a critical event in the course of PDT-associated host response. It is shown that this type of acute phase reactants, including complement proteins (C3, C5, C9, mannose-binding lectin, and ficolin A) and related pentraxins (serum amyloid P component and PTX3), are upregulated following tumor PDT and accumulate in the targeted lesions. Based on the recently accumulated experimental evidence it is definitely established that the acute phase response is manifested in the hosts bearing PDT-treated tumors and it is becoming clear that this effector process is an important element of PDT-associated host response bearing in impact on the eventual outcome of this therapy.

  11. PS-341 in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia in Blast Phase, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  12. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia.

    PubMed

    Raponi, Mitch; Lancet, Jeffrey E; Fan, Hongtao; Dossey, Lesley; Lee, Grace; Gojo, Ivana; Feldman, Eric J; Gotlib, Jason; Morris, Lawrence E; Greenberg, Peter L; Wright, John J; Harousseau, Jean-Luc; Löwenberg, Bob; Stone, Richard M; De Porre, Peter; Wang, Yixin; Karp, Judith E

    2008-03-01

    At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.

  13. THE ACUTE PHASE RESPONSE INDUCED BY BRONCHOSCOPY WITH LAVAGE

    EPA Science Inventory

    Bronchoscopy has been used to evaluate the inflammatory responses in vitro and in vivo. The procedure may affect acute inflammation in the lower respiratory tract. We reviewed consecutive bronchoscopies done in normal healthy non-smokers between April, 1998 and April, 2004. The...

  14. Validity of Sudden Gains in Acute Phase Treatment of Depression

    ERIC Educational Resources Information Center

    Vittengl, Jeffrey R.; Clark, Lee Anna; Jarrett, Robin B.

    2005-01-01

    The authors examined the validity of sudden gains identified with T. Z. Tang and R. J. DeRubeis's (1999) method in 2 clinical data sets that involved treatment of major depressive disorder (N=227). Sudden gains replicated among self- and clinician reports of depressive symptoms and predicted better psychosocial functioning at the acute phase…

  15. Monocyte-conditioned medium, interleukin-1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro

    PubMed Central

    1986-01-01

    Human hepatoma cells mimic the acute phase response after treatment with monocyte-conditioned medium. Levels of secreted fibrinogen, alpha- 1 acid glycoprotein, C-reactive protein, haptoglobin, and the third component of complement were elevated compared with control levels after 48 h of incubation with conditioned supernatant medium from an enriched fraction of normal peripheral monocytes. Albumin levels declined and alpha-1 antitrypsin remained unchanged. Levels of specific mRNA were measured by hybridization to slot blots and Northern blots and changed in correspondence with protein alterations. Interleukin-1 and tumor necrosis factor stimulated the third component of complement, but did not elevate any other member of the acute phase group and were therefore only partially active in this system. The identification of an in vitro model of the human acute phase response will permit analysis of the molecular basis for coordinate regulation of this group of facultative genes. PMID:3017995

  16. Bcl-2 associated with positive symptoms of schizophrenic patients in an acute phase.

    PubMed

    Tsai, Meng-Chang; Liou, Chia-Wei; Lin, Tsu-Kung; Lin, I-Mei; Huang, Tiao-Lai

    2013-12-30

    B cell lymphoma protein-2 (Bcl-2) may contribute to the pathophysiology of schizophrenia in the brain. The aim of this study was to investigate the serum levels of Bcl-2 in schizophrenic patients in an acute phase, and evaluate Bcl-2 level changes after antipsychotic treatment. We consecutively enrolled 41 schizophrenia patients in an acute phase; 28 were followed up with a 4-week antipsychotic treatment. Serum Bcl-2 levels were measured with assay kits. All patients were evaluated by examining the correlation between Bcl-2 levels and Positive and Negative Syndrome Scale (PANSS) scores, using Pearson correlation coefficients. In schizophrenic patients in an acute phase, positive PANSS subscores were significantly negatively correlated with Bcl-2 levels. In addition, we found Bcl-2 levels had a significantly negative correlation with PANSS total scores and positive subscores in male patients in an acute phase. Using the paired t-test, we found no significant changes in Bcl-2 levels in schizophrenia patients who had received the 4-week treatment with antipsychotic drugs (n=28). In conclusion, our results suggest that Bcl-2 might be an indicator of schizophrenia severity in the acute phase. In addition, Bcl-2 levels might be associated with positive symptoms in male patients with schizophrenia.

  17. Sorafenib in Treating Patients With Refractory or Relapsed Acute Leukemia, Myelodysplastic Syndromes, or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-04-27

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  18. Presence of acute phase changes in zinc, iron, and copper metabolism in turkey embryos

    SciTech Connect

    Klasing, K.C.; Richards, M.P.; Darcey, S.E.; Laurin, D.E.

    1987-01-01

    Acute phase changes in trace mineral metabolism were examined in turkey embryos. An endotoxin injection resulted in increased concentrations of serum copper and liver zinc and decreased concentrations of serum zinc in embryos incubated either in ovo or ex ovo. Changes in zinc and copper metabolism occurred when endotoxin either was injected intramuscularly, into the amnionic fluid, or administered onto the chorioallantoic membrane. Unlike poults, embryos did not respond to an inflammatory challenge with decreased serum iron concentrations. Acute phase changes in embryo serum zinc and copper as well as liver zinc concentrations were similar to those in poults. Increased liver zinc concentrations were associated with increased zinc in metallothionein (MT). An injection of a crude interleukin 1 preparation into embryos resulted in similar increases in hepatic zinc and MT concentrations as an endotoxin injection, suggesting a role for this cytokine in mediating the acute phase changes in embryonic zinc metabolism.

  19. Upregulation of interferon-induced genes in infants with virus-associated acute bronchiolitis.

    PubMed

    Scagnolari, Carolina; Midulla, Fabio; Trombetti, Simona; Pierangeli, Alessandra; Tromba, Valeria; Grossi, Rosanna; Di Marco, Paola; Dianzani, Caterina; Girardi, Enrico; Antonelli, Guido

    2007-11-01

    To determine whether there is an airway IFN response in infants with acute bronchiolitis and to establish whether the rate of such a response is related to the severity of illness, the expression of some IFN-induced genes was measured in nasopharyngeal washes from 39 infants with acute bronchiolitis. The results indicate that in infants with a virus-associated acute bronchiolitis there is a strong activation of IFN system and that the severity of illness is inversely related to the level of expression of IFN-induced genes. This suggests that the IFN response plays an important role in determining virus-associated respiratory disease in early life.

  20. Poliomyelitis: immunoglobulin-containing cells in the central nervous system in acute and convalescent phases of the human disease.

    PubMed Central

    Esiri, M M

    1980-01-01

    The immunoperoxidase method has been used to demonstrate the presence of immunoglobulin-containing cells in the central nervous system in acute and convalescent phases of poliomyelitis. These cells were found in considerable numbers in the areas of damage during the acute phase, and persisted at the same sites, though in smaller numbers, during the convalescent phase for at least 8 months. Most of the positively stained cells were plasma cells. IgA was the commonest heavy chain type demonstrated, with lesser amounts also of IgG and, during the acute phase, IgM. In the acute phase more lambda than kappa light chain was demonstrated but in the convalescent phase this ratio was reversed. More light chain than heavy chain was demonstrable during the acute phase. The significance of these results is briefly discussed. Images Fig. 2 PMID:6771081

  1. Phase I and Phase II Therapies for Acute Ischemic Stroke: An Update on Currently Studied Drugs in Clinical Research

    PubMed Central

    Reis, Cesar; Akyol, Onat; Ho, Wing Mann; Araujo, Camila; Huang, Lei; Applegate II, Richard

    2017-01-01

    Acute ischemic stroke is a devastating cause of death and disability, consequences of which depend on the time from ischemia onset to treatment, the affected brain region, and its size. The main targets of ischemic stroke therapy aim to restore tissue perfusion in the ischemic penumbra in order to decrease the total infarct area by maintaining blood flow. Advances in research of pathological process and pathways during acute ischemia have resulted in improvement of new treatment strategies apart from restoring perfusion. Additionally, limiting the injury severity by manipulating the molecular mechanisms during ischemia has become a promising approach, especially in animal research. The purpose of this article is to review completed and ongoing phases I and II trials for the treatment of acute ischemic stroke, reviewing studies on antithrombotic, thrombolytic, neuroprotective, and antineuroinflammatory drugs that may translate into more effective treatments. PMID:28286764

  2. Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6.

    PubMed

    Ramadori, Pierluigi; Ahmad, Ghayyor; Ramadori, Giuliano

    2010-09-01

    The source of circulating erythropoietin (EPO), the mediators and the mechanisms involved in the upregulation of EPO gene expression during acute-phase reaction are still poorly understood. Acute-phase reaction was induced by either intramuscular turpentine oil (TO) or intraperitoneal lipopolysaccharide (LPS) administration into wild-type and interleukin (IL)-6 knockout (KO) mice. Animals were killed at different time points and blood, liver and muscle tissue were collected. Serum levels of EPO were measured by enzyme-linked immunoadsorbent assay; liver and injured muscle samples were processed for RNA isolation and for protein analysis. EPO, hypoxia-inducible factors 1alpha and 2alpha (HIF-1alpha and HIF-2alpha) mRNA were analyzed by RT-PCR and the protein levels were analyzed by western blot and electrophoretic mobility shift assay. HIF-1alpha and HIF-2alpha localization was performed through immunofluorescence staining. EPO, HIF-1 and HIF-2 gene and protein expression levels were also analyzed in isolated mouse hepatocytes after stimulation with IL-6. In the wild-type animals, EPO serum levels increased dramatically at 12 h after the insults together with the hepatic gene expression. In TO-treated animals, the EPO gene expression reached an 8.2-fold increase at 12 h, and in LPS-treated mice a similar induction was recorded at 6 h (about 4.5-fold increase). In the IL-6KO strain, the upregulation after the inflammatory stimuli was much lower (only 2.0-fold increase). A progressive upregulation of HIF-1alpha and HIF-2alpha was detectable until 6 h after the insults, but only HIF-1alpha upregulation was reduced in IL-6KO mice. In isolated hepatocytes, stimulation with a single dose of IL-6 induced a nuclear accumulation of HIF-1alpha, in parallel with an increase of EPO mRNA. No effect on HIF-2alpha expression was found. IL-6 appears to be the main regulator of EPO gene expression and a major contributor for HIF-1alpha induction in hepatocytes and Kupffer cells

  3. Clinical characteristics and prognosis of acute myeloid leukemia associated with DNA-methylation regulatory gene mutations

    PubMed Central

    Ryotokuji, Takeshi; Yamaguchi, Hiroki; Ueki, Toshimitsu; Usuki, Kensuke; Kurosawa, Saiko; Kobayashi, Yutaka; Kawata, Eri; Tajika, Kenji; Gomi, Seiji; Kanda, Junya; Kobayashi, Anna; Omori, Ikuko; Marumo, Atsushi; Fujiwara, Yusuke; Yui, Shunsuke; Terada, Kazuki; Fukunaga, Keiko; Hirakawa, Tsuneaki; Arai, Kunihito; Kitano, Tomoaki; Kosaka, Fumiko; Tamai, Hayato; Nakayama, Kazutaka; Wakita, Satoshi; Fukuda, Takahiro; Inokuchi, Koiti

    2016-01-01

    In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations – mutations of the genes that regulate gene expression through DNA methylation – is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (P<0.0001) and in patients with intermediate cytogenetic risk (P<0.0001) accompanied by a high white blood cell count (P=0.0032). DNA-methylation regulatory gene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged ≤70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA-methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia. PMID:27247325

  4. The developmental and acute phases of insulin-induced laminitis involve minimal metalloproteinase activity.

    PubMed

    de Laat, M A; Kyaw-Tanner, M T; Nourian, A R; McGowan, C M; Sillence, M N; Pollitt, C C

    2011-04-15

    Metalloproteinases have been implicated in the pathogenesis of equine laminitis and other inflammatory conditions, through their role in the degradation and remodelling of the extracellular matrix environment. Matrix metalloproteinases (MMPs) and their inhibitors are present in normal equine lamellae, with increased secretion and activation of some metalloproteinases reported in horses with laminitis associated with systemic inflammation. It is unknown whether these enzymes are involved in insulin-induced laminitis, which occurs without overt systemic inflammation. In this study, gene expression of MMP-2, MMP-9, MT1-MMP, ADAMTS-4 and TIMP-3 was determined in the lamellar tissue of normal control horses (n=4) and horses that developed laminitis after 48 h of induced hyperinsulinaemia (n=4), using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Protein concentrations of MMP-2 and MMP-9 were also examined using gelatin zymography in horses subject to prolonged hyperinsulinaemia for 6h (n=4), 12h (n=4), 24h (n=4) and 48 h (n=4), and in normal control horses (n=4). The only change in gene expression observed was an upregulation of MMP-9 (p<0.05) in horses that developed insulin-induced laminitis (48 h). Zymographical analysis showed an increase (p<0.05) in pro MMP-9 during the acute phase of laminitis (48 h), whereas pro MMP-2 was present in similar concentration in the tissue of all horses. Thus, MMP-2, MT1-MMP, TIMP-3 and ADAMTS-4 do not appear to play a significant role in the pathogenesis of insulin-induced laminitis. The increased expression of MMP-9 may be associated with the infiltration of inflammatory leukocytes, or may be a direct result of hyperinsulinaemia. The exact role of MMP-9 in basement membrane degradation in laminitis is uncertain as it appears to be present largely in the inactive form.

  5. GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-12-03

    Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  6. Feasibility and safety of acute phase rehabilitation after stroke using the hybrid assistive limb robot suit.

    PubMed

    Ueba, Tetsuya; Hamada, Omi; Ogata, Toshiyasu; Inoue, Tooru; Shiota, Etsuji; Sankai, Yoshiyuki

    2013-01-01

    Acute phase rehabilitation is an important treatment for improving the functional outcome of patients after stroke. The present cohort study analyzed the feasibility and safety of acute phase rehabilitation using the hybrid assistive limb robot suit in 22 patients, 7 males and 15 females (mean age 66.6 ± 17.7 years). Neurological deterioration, mortality, or other accidents were recorded as adverse events. Baseline characteristics of each patient were recorded at the first hybrid assistive limb rehabilitation. Hybrid assistive limb rehabilitation was conducted for 12.1 ± 7.0 days with the patients in stable condition. Acute phase hybrid assistive limb rehabilitation was performed a total of 84 times with no adverse events recorded except for orthostatic hypotension. Good functional outcomes were obtained in 14 patients. Orthostatic hypotension was observed during the first hybrid assistive limb rehabilitation in four patients, and was significantly associated with intracerebral hemorrhage (p = 0.007) and lower Brunnstrom stage (p = 0.033). Acute phase rehabilitation using the hybrid assistive limb suit is feasible and safe. Patients with intracerebral hemorrhage and lower Brunnstrom stage should be carefully monitored for orthostatic hypotension.

  7. Natural variations in the stress and acute phase responses of cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The initial response of the innate immune system upon activation has been defined as the acute phase response (APR). Activation of the APR results in several responses that include fever, metabolic adaptations, and changes in behavior. The APR can be modulated by many factors, with stress being th...

  8. Modulation of the acute phase response in feedlot steers supplemented with Saccharomyces cerevisiae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine the effect of supplementing feedlot steers with Saccharomyces cerevisiae CNCM I-1079 (SC) on the acute phase response to a lipopolysaccharide (LPS) challenge. Steers (n = 18; 266 ± 4 kilograms body weight) were separated into three treatment groups (n = 6/treatm...

  9. Changes in the Neuropsychological Correlates of Clinical Dimensions between the Acute and Stable Phase of Schizophrenia

    ERIC Educational Resources Information Center

    Guillem, F.; Ganeva, E.; Pampoulova, T.; Stip, E.; Lalonde, P.; Sasseville, M.

    2005-01-01

    This study was designed to investigate whether the neuropsychological correlates of the symptom dimensions of schizophrenia vary with the clinical state in patients followed from the acute to stable the phase of the illness. Fifteen patients were assessed for symptoms (SAPS-SANS) and undergone a complete neuropsychological assessment at two…

  10. In Utero Exposure to Lipopolysaccharide Alters the Postnatal Acute Phase Response in Beef Heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine the potential effect of prenatal lipopolysaccharide (LPS) exposure on the postnatal acute phase response (APR) to an LPS challenge in heifers. Pregnant crossbred cows (n = 50) were separated into prenatal immune stimulation (PIS; n = 25; administered 0.1 microgr...

  11. C-reactive protein and the acute phase reaction in geriatric patients.

    PubMed

    Bertsch, Thomas; Triebel, Jakob; Bollheimer, Cornelius; Christ, Michael; Sieber, Cornel; Fassbender, Klaus; Heppner, Hans Jürgen

    2015-10-01

    The C-reactive protein (CRP), first described as a serum component capable of precipitating the C-polysaccharide of pneumococci, is one of the most important proteins because the serum concentration rises in the acute phase reaction. The acute phase reaction is the nonspecific reaction of the body to noxious stimuli of the most varied kinds, such as infections, burns, neoplasms and tissue trauma. The CRP is synthesized in liver parenchymal cells by cytokines which are derived from stimulated leucocytes and released into the circulation. Because of its molecular structure and in synergy with the complement system, it is able to precipitate and/or lyse microorganisms, thereby rendering them harmless. Measurement of the serum CRP concentration can provide important information with respect to the diagnosis and monitoring of treatment. Due to immunosenescence in geriatric patients the synthesis of CRP appears to be limited to inflammatory stimuli; however, this phenomenon does not appear to be of major clinical relevance. Despite the introduction of new parameters of the acute phase reaction, sometimes with better performance, such as interleukin-6, procalcitonin and the soluble endotoxin receptor sCD14, measurement of CRP for diagnosis and treatment monitoring is still justified even in geriatric patients as testing is rapid, economic and nearly ubiquitously available round the clock. Biochemical markers of the acute phase reaction should always be interpreted together with the clinical picture and their specific limitations.

  12. The effect of chronic ammonia exposure on acute phase proteins, immunoglobulin and cytokines in laying hens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ammonia is a potential health hazard to both humans and animals, causing systemic low-grade inflammation based on its levels and durations. The objective of this study was to examine the effect of 45 weeks of exposure to 30 ppm NH3 on the concentrations of acute phase proteins, immunoglobulins and c...

  13. The diagnostic accuracy of acute phase proteins and proinflammatory cytokines in sheep with pneumonic pasteurellosis

    PubMed Central

    Elmoslemany, Ahmed M.

    2016-01-01

    The goal of this study was to assess the diagnostic accuracy of acute phase proteins and proinflammatory cytokines in sheep with pneumonic pasteurellosis. Blood samples were collected from 56 sheep (36 naturally infected with Pasteurella multocida and 20 healthy controls) belonging to one farm in Eastern region, Saudi Arabia. Serum samples were evaluated for acute phase proteins (Haptoglobin (Hp), serum amyloid A (SAA) and fibrinogen (Fb)), and the proinflammatory cytokines (interleukins (IL-1α, IL-1β, and IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-ϒ)). Additionally, nasopharyngeal swabs and bronchoalveolar lavages were collected from all animals for bacteriological examinations. Receiver operating characteristic curve was used to assess the diagnostic performance of each parameter. All parameters showed moderate to high degree of positive correlation with case-control status. There was no significant difference in the area under the curve (AUC) among acute phase proteins; however, both Hp and SAA showed better sensitivity and specificity than Fb. The proinflammatory cytokines (IL1-α, IL1-β, and IL6) showed similar and highly accurate diagnostic performance (AUC > 0.9), whereas IFN-ϒ was moderately accurate (AUC = 0.79). In conclusion, this study confirms the value of acute phase proteins and cytokines as diagnostic biomarkers of naturally occuring pneumonic pasteurellosis in sheep. PMID:27547520

  14. Monitoring the acute phase response to vaso-occlusive crisis in sickle cell disease.

    PubMed Central

    Stuart, J; Stone, P C; Akinola, N O; Gallimore, J R; Pepys, M B

    1994-01-01

    AIMS--To identify suitable acute phase proteins as objective markers of tissue ischaemia during painful vaso-occlusive crises in sickle cell disease. METHODS--The prodromal and established phases of 14 vaso-occlusive crises were studied longitudinally in 10 patients with sickle cell anaemia. Automated solid phase enzyme immunoassays were used to measure the fast responding acute phase proteins C-reactive protein and serum amyloid A protein. Slower responding glycoproteins (fibrinogen, orosomucoid, sialic acid and concanavalin-A binding) were measured in parallel. RESULTS--C-reactive protein and serum amyloid A protein increased early in crisis, sometimes within the early (prodromal) phase. Crises that resolved within 24 hours in hospital showed a minor and transient rise compared with crises that required treatment for four days or more. In eight crises treated by patients at home the acute phase response ranged from minor to a level consistent with extensive tissue ischaemia. CONCLUSIONS--Sensitive enzyme immunoassays for C-reactive protein and serum amyloid A protein are of potential value for monitoring the onset of tissue ischaemia in sickle cell crisis and for confirming subsequent resolution. PMID:7510726

  15. A potentially novel overlapping gene in the genomes of Israeli acute paralysis virus and its relatives

    PubMed Central

    Sabath, Niv; Price, Nicholas; Graur, Dan

    2009-01-01

    The Israeli acute paralysis virus (IAPV) is a honeybee-infecting virus that was found to be associated with colony collapse disorder. The IAPV genome contains two genes encoding a structural and a nonstructural polyprotein. We applied a recently developed method for the estimation of selection in overlapping genes to detect purifying selection and, hence, functionality. We provide evolutionary evidence for the existence of a functional overlapping gene, which is translated in the +1 reading frame of the structural polyprotein gene. Conserved orthologs of this putative gene, which we provisionally call pog (predicted overlapping gene), were also found in the genomes of a monophyletic clade of dicistroviruses that includes IAPV, acute bee paralysis virus, Kashmir bee virus, and Solenopsis invicta (red imported fire ant) virus 1. PMID:19761605

  16. Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-10-29

    B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  17. Gene expression analysis during acute hepatitis C virus infection associates dendritic cell activation with viral clearance.

    PubMed

    Zabaleta, Aintzane; Riezu-Boj, Jose-Ignacio; Larrea, Esther; Villanueva, Lorea; Lasarte, Juan Jose; Guruceaga, Elizabeth; Fisicaro, Paola; Ezzikouri, Sayeh; Missale, Gabriele; Ferrari, Carlo; Benjelloun, Soumaya; Prieto, Jesús; Sarobe, Pablo

    2016-05-01

    Viral clearance during acute hepatitis C virus (HCV) infection is associated with the induction of potent antiviral T-cell responses. Since dendritic cells (DC) are essential in the activation of primary T-cell responses, gene expression was analyzed in DC from patients during acute HCV infection. By using microarrays, gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from patients who become chronically infected (ANR), as well as in healthy individuals (CTRL) and chronically-infected patients (CHR). For pDC, a high number of upregulated genes was found in AR patients, irrespective of DC stimulation. However, for mDC, most evident differences were detected after DC stimulation, again corresponding to upregulated genes in AR patients. Divergent behavior of ANR was also observed when analyzing DC from CTRL and CHR, with ANR patients clustering again apart from these groups. These differences corresponded to metabolism-associated genes and genes belonging to pathways relevant for DC activation and cytokine responses. Thus, upregulation of relevant genes in DC during acute HCV infection may determine viral clearance, suggesting that dysfunctional DC may be responsible for the lack of efficient T-cell responses which lead to chronic HCV infection.

  18. Development of Gene Expression Markers of Acute Heat-Light Stress in Reef-Building Corals of the Genus Porites

    PubMed Central

    Kenkel, Carly D.; Aglyamova, Galina; Alamaru, Ada; Bhagooli, Ranjeet; Capper, Roxana; Cunning, Ross; deVillers, Amanda; Haslun, Joshua A.; Hédouin, Laetitia; Keshavmurthy, Shashank; Kuehl, Kristin A.; Mahmoud, Huda; McGinty, Elizabeth S.; Montoya-Maya, Phanor H.; Palmer, Caroline V.; Pantile, Raffaella; Sánchez, Juan A.; Schils, Tom; Silverstein, Rachel N.; Squiers, Logan B.; Tang, Pei-Ciao; Goulet, Tamar L.; Matz, Mikhail V.

    2011-01-01

    Coral reefs are declining worldwide due to increased incidence of climate-induced coral bleaching, which will have widespread biodiversity and economic impacts. A simple method to measure the sub-bleaching level of heat-light stress experienced by corals would greatly inform reef management practices by making it possible to assess the distribution of bleaching risks among individual reef sites. Gene expression analysis based on quantitative PCR (qPCR) can be used as a diagnostic tool to determine coral condition in situ. We evaluated the expression of 13 candidate genes during heat-light stress in a common Caribbean coral Porites astreoides, and observed strong and consistent changes in gene expression in two independent experiments. Furthermore, we found that the apparent return to baseline expression levels during a recovery phase was rapid, despite visible signs of colony bleaching. We show that the response to acute heat-light stress in P. astreoides can be monitored by measuring the difference in expression of only two genes: Hsp16 and actin. We demonstrate that this assay discriminates between corals sampled from two field sites experiencing different temperatures. We also show that the assay is applicable to an Indo-Pacific congener, P. lobata, and therefore could potentially be used to diagnose acute heat-light stress on coral reefs worldwide. PMID:22046408

  19. Quantitative Evaluation and Selection of Reference Genes for Quantitative RT-PCR in Mouse Acute Pancreatitis

    PubMed Central

    Yan, Zhaoping; Gao, Jinhang; Lv, Xiuhe; Yang, Wenjuan; Wen, Shilei; Tong, Huan; Tang, Chengwei

    2016-01-01

    The analysis of differences in gene expression is dependent on normalization using reference genes. However, the expression of many of these reference genes, as evaluated by quantitative RT-PCR, is upregulated in acute pancreatitis, so they cannot be used as the standard for gene expression in this condition. For this reason, we sought to identify a stable reference gene, or a suitable combination, for expression analysis in acute pancreatitis. The expression stability of 10 reference genes (ACTB, GAPDH, 18sRNA, TUBB, B2M, HPRT1, UBC, YWHAZ, EF-1α, and RPL-13A) was analyzed using geNorm, NormFinder, and BestKeeper software and evaluated according to variations in the raw Ct values. These reference genes were evaluated using a comprehensive method, which ranked the expression stability of these genes as follows (from most stable to least stable): RPL-13A, YWHAZ > HPRT1 > GAPDH > UBC > EF-1α > 18sRNA > B2M > TUBB > ACTB. RPL-13A was the most suitable reference gene, and the combination of RPL-13A and YWHAZ was the most stable group of reference genes in our experiments. The expression levels of ACTB, TUBB, and B2M were found to be significantly upregulated during acute pancreatitis, whereas the expression level of 18sRNA was downregulated. Thus, we recommend the use of RPL-13A or a combination of RPL-13A and YWHAZ for normalization in qRT-PCR analyses of gene expression in mouse models of acute pancreatitis. PMID:27069927

  20. Protective effect of resveratrol in endotoxemia-induced acute phase response in rats.

    PubMed

    Sebai, Hichem; Ben-Attia, Mossadok; Sani, Mamane; Aouani, Ezzedine; Ghanem-Boughanmi, Néziha

    2009-04-01

    Lipopolysaccharide (LPS), a glycolipid component of the cell wall of gram-negative bacteria can elicit a systemic inflammatory process leading to septic shock and death. Acute phase response is characterized by fever, leucocytosis, thrombocytopenia, altered metabolic responses and redox balance by inducing excessive reactive oxygen species (ROS) generation. Resveratrol (trans-3,5,4' trihydroxystilbene) is a natural polyphenol exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effect of resveratrol on endotoxemia-induced acute phase response in rats. When acutely administered by i.p. route, resveratrol (40 mg/kg b.w.) counteracted the effect of a single injection of LPS (4 mg/kg b.w.) which induced fever, a decrease in white blood cells (WBC) and platelets (PLT) counts. When i.p. administered during 7 days at 20 mg/kg per day (subacute treatment), resveratrol abrogated LPS-induced erythrocytes lipoperoxidation and catalase (CAT) activity depression to control levels. In the plasma compartment, LPS increased malondialdehyde (MDA) via nitric monoxide (NO) elevation and decreased iron level. All these deleterious LPS effects were reversed by a subacute resveratrol pre-treatment via a NO independent way. Resveratrol exhibited potent protective effect on LPS-induced acute phase response in rats.

  1. Ferroportin-1 is a 'nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins.

    PubMed

    Naz, Naila; Malik, Ihtzaz A; Sheikh, Nadeem; Ahmad, Shakil; Khan, Sajjad; Blaschke, Martina; Schultze, Frank; Ramadori, Giuliano

    2012-06-01

    Liver is the central organ of iron metabolism. During acute-phase-response (APR), serum iron concentration rapidly decreases. The current study aimed to compare expression and localization of iron transport protein ferroportin-1 (Fpn-1) and of other iron import proteins after experimental tissue damage induced by injecting turpentine oil in the hind limbs of rats and mice. Serum and spleen iron concentration decreased with an increase in total liver, cytoplasmic and nuclear iron concentration. In liver, mRNA amount of Fpn-1, Fpn-1a, Fpn-1b, HFE, hemojuvelin (HJV) and hephaestin (heph) genes showed a rapid decrease. Hepcidin, divalent metal transporter-1 (DMT-1), transferrin (Tf) and Tf-receptor-1 (TfR1), TfR-2 (TfR2) gene expression was increased. Western blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2, and an increase in hepcidin was observed. Immunohistochemistry of DMT-1 and TfR2 were mainly detected in the nucleus of rat liver and spleen, whereas TfR1 was clearly localized in the plasma membrane. Fpn-1 was mostly found in the nuclei of liver cells, whereas in spleen, the protein was mainly detected in the cell membrane. Western blot analysis of liver fractions confirmed immunohistochemical results. In livers of wild-type mice, gene expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated, whereas hepcidin gene expression was increased. In contrast, these changes were less pronounced in IL-6ko-mice. Cytokine (IL-6, IL-1b and TNF-a) treatment of rat hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b, and upregulation of hepcidin gene expression. Moreover, western blot analysis of cell lysate of IL-6-treated hepatocytes detected, as expected, an increase of a2-macroglobulin (positive acute-phase protein), whereas albumin (negative acute-phase protein) and Fpn-1 were downregulated. Our results demonstrate that liver

  2. ACUTE ETHANOL DISRUPTS PHOTIC AND SEROTONERGIC CIRCADIAN CLOCK PHASE-RESETTING IN THE MOUSE

    PubMed Central

    Brager, Allison J.; Ruby, Christina L.; Prosser, Rebecca A.; Glass, J. David

    2011-01-01

    Background Alcohol abuse is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: 1) characterize the SCN pharmacokinetics of acute systemic ethanol administration; 2) explore the effects of acute ethanol on photic and non-photic phase-resetting; and 2) determine if the SCN is a direct target for photic effects. Methods First, microdialysis was used to characterize the pharmacokinetics of acute i.p. injections of 3 doses of ethanol (0.5, 1.0 and 2.0 g/kg) in the mouse suprachiasmatic (SCN) circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase-delays and serotonergic ([+]8-OH-DPAT-induced) phase-advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized. Results Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20–40 min post-injection with half-lives for clearance ranging from 0.6–1.8 hr. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase-delays. Conclusions These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and non-photic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism. PMID:21463340

  3. Muscle Contraction Induces Acute Hydroxymethylation of the Exercise-Responsive Gene Nr4a3

    PubMed Central

    Pattamaprapanont, Pattarawan; Garde, Christian; Fabre, Odile; Barrès, Romain

    2016-01-01

    Exercise training triggers numerous positive adaptations through the regulation of genes controlling muscle structure and function. Epigenetic modifications, including DNA methylation, participate in transcriptional activation by allowing the recruitment of the transcription machinery to gene promoters. Exercise induces dynamic DNA demethylation at gene promoters; however, the contribution of the demethylation precursor hydroxymethylcytosine is unknown. Given the evanescent nature of hydroxymethylcytosine, a muscle contraction model that allows for the collection of samples that are repeatedly stimulated over time is required to determine whether contraction-induced demethylation is preceded by changes in the hydroxymethylcytosine level. Here, we established an acute skeletal muscle contraction model to mimic the effects of acute exercise on gene expression. We used this model to investigate the effect of muscle contraction on DNA demethylation and hydroxymethylation. First, we performed an acute exercise study in healthy humans to identify an exercise-responsive gene that we could study in culture. We identified the nuclear receptor subfamily 4 group A member 3 (Nr4a3) gene with the highest fold-expression increase after acute exercise. We then refined an electrical pulse stimulation (EPS) protocol that could induce expression of the Nr4a3 gene in C2C12 myotubes. Using targeted bisulfite sequencing, we found that in response to EPS, a region of the Nr4a3 promoter is rapidly demethylated at 60 min and re-methylated at 120 min. Of interest, hydroxymethylation of the differentially methylated region of Nr4a3 promoter after EPS was elevated immediately after EPS, with lowest levels reached at 60 min after EPS. In conclusion, we have established a cell culture-based protocol to mimic the acute transcriptional responses to exercise. Furthermore, we provide insight into the mechanism by which the exercise-responsive gene Nr4a3 is demethylated after muscle

  4. Effect of the consumption of ethanol on the microcirculation of the human optic nerve head in the acute phase

    PubMed

    Kojima; Sugiyama; Kojima; Azuma; Ito

    2000-05-01

    Purpose: The effect of the consumption of ethanol on the circulation of the optic nerve head (ONH) in the human eye in the acute phase and its mechanism were studied.Methods: Eleven volunteers drank a bottle of beer (633 mL) with or without ethanol (29.5 g). Normalized blur (NB), a quantitative index of blood flow velocity, was measured in the temporal site of the ONH. NB, blood pressure (BP) and pulse rate (PR) were measured before, immediately after, and every 15 minutes for 90 minutes after consumption. Intraocular pressure (IOP) and plasma ethanol concentration were measured before, and 30 and 90 minutes after consumption. Genotyping of the aldehyde dehydrogenase (ALDH) 2 gene was also performed.Results: NB in the ONH increased significantly from 15 to 45 minutes after consumption of ethanol and the maximum increase was 14% at 15 minutes. IOP was lowered at 90 minutes after consumption, but it was not significant. Mean BP was lowered significantly after 60 minutes. PR and ocular perfusion pressure did not change. A significant correlation was found between plasma ethanol concentration at 30 minutes and maximum NB. NB in the ALDH 2-deficient group was significantly larger from 15 to 45 minutes after consumption than in the proficient group.Conclusions: It appeared that the consumption of ethanol can increase the blood flow in the human ONH in the acute phase through decreased resistance in blood vessels induced by acetaldehyde, a metabolite of ethanol.

  5. Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice.

    PubMed

    Baker, Jessica A; Li, Jingxin; Zhou, Diana; Yang, Ming; Cook, Melloni N; Jones, Byron C; Mulligan, Megan K; Hamre, Kristin M; Lu, Lu

    2017-02-01

    Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intraperitoneal (i.p.) injection of 1.8 g/kg ethanol or saline, and subsets of both groups were exposed to acute restraint stress for 15 min or controls. Gene expression in the hippocampus was examined using microarray analysis. Genes that were significantly (p < 0.05, q < 0.1) differentially expressed were further evaluated. Bioinformatic analyses were predominantly performed using tools available at GeneNetwork.org, and included gene ontology, presence of cis-regulation or polymorphisms, phenotype correlations, and principal component analyses. Comparisons of differential gene expression between groups showed little overlap. Gene Ontology demonstrated distinct biological processes in each group with the combined exposure (RSE) being unique from either the ethanol (NOE) or stress (RSS) group, suggesting that the interaction between these variables is mediated through diverse molecular pathways. This supports the hypothesis that exposure to stress alters ethanol-induced gene expression changes and that exposure to alcohol alters stress-induced gene expression changes. Behavior was profiled in all groups following treatment, and many of the differentially expressed genes are correlated with behavioral variation within experimental groups. Interestingly, in each group several genes were correlated with the same phenotype, suggesting that these genes are the potential origins of significant genetic networks. The distinct sets of differentially expressed genes within each group provide the basis for identifying molecular networks that may aid in understanding the complex interactions between stress and ethanol, and potentially provide relevant therapeutic targets. Using Ptp4

  6. Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease

    PubMed Central

    Bouquet, Jerome; Soloski, Mark J.; Swei, Andrea; Cheadle, Chris; Federman, Scot; Billaud, Jean-Noel; Rebman, Alison W.; Kabre, Beniwende; Halpert, Richard; Boorgula, Meher

    2016-01-01

    ABSTRACT Lyme disease is a tick-borne illness caused by the bacterium Borrelia burgdorferi, and approximately 10 to 20% of patients report persistent symptoms lasting months to years despite appropriate treatment with antibiotics. To gain insights into the molecular basis of acute Lyme disease and the ensuing development of post-treatment symptoms, we conducted a longitudinal transcriptome study of 29 Lyme disease patients (and 13 matched controls) enrolled at the time of diagnosis and followed for up to 6 months. The differential gene expression signature of Lyme disease following the acute phase of infection persisted for at least 3 weeks and had fewer than 44% differentially expressed genes (DEGs) in common with other infectious or noninfectious syndromes. Early Lyme disease prior to antibiotic therapy was characterized by marked upregulation of Toll-like receptor signaling but lack of activation of the inflammatory T-cell apoptotic and B-cell developmental pathways seen in other acute infectious syndromes. Six months after completion of therapy, Lyme disease patients were found to have 31 to 60% of their pathways in common with three different immune-mediated chronic diseases. No differential gene expression signature was observed between Lyme disease patients with resolved illness to those with persistent symptoms at 6 months post-treatment. The identification of a sustained differential gene expression signature in Lyme disease suggests that a panel of selected human host-based biomarkers may address the need for sensitive clinical diagnostics during the “window period” of infection prior to the appearance of a detectable antibody response and may also inform the development of new therapeutic targets. PMID:26873097

  7. Temporal gene expression profile after acute electroconvulsive stimulation in the rat.

    PubMed

    Dyrvig, Mads; Christiansen, Søren H; Woldbye, David P D; Lichota, Jacek

    2014-04-10

    Electroconvulsive therapy (ECT) remains one of the most effective treatments of major depression. It has been suggested that the mechanisms of action involve gene expression. In recent decades there have been several investigations of gene expression following both acute and chronic electroconvulsive stimulation (ECS). These studies have focused on several distinct gene targets but have generally included only few time points after ECS for measuring gene expression. Here we measured gene expression of three types of genes: Immediate early genes, synaptic proteins, and neuropeptides at six time points following an acute ECS. We find significant increases for c-Fos, Egr1, Neuritin 1 (Nrn 1), Bdnf, Snap29, Synaptotagmin III (Syt 3), Synapsin I (Syn 1), and Psd95 at differing time points after ECS. For some genes these changes are prolonged whereas for others they are transient. Npy expression significantly increases whereas the gene expression of its receptors Npy1r, Npy2r, and Npy5r initially decreases. These decreases are followed by a significant increase for Npy2r, suggesting anticonvulsive adaptations following seizures. In summary, we find distinct changes in mRNA quantities that are characteristic for each gene. Considering the observed transitory and inverse changes in expression patterns, these data underline the importance of conducting measurements at several time points post-ECS.

  8. Gene expression in cortex and hippocampus during acute pneumococcal meningitis

    PubMed Central

    Coimbra, Roney S; Voisin, Veronique; de Saizieu, Antoine B; Lindberg, Raija LP; Wittwer, Matthias; Leppert, David; Leib, Stephen L

    2006-01-01

    Background Pneumococcal meningitis is associated with high mortality (~30%) and morbidity. Up to 50% of survivors are affected by neurological sequelae due to a wide spectrum of brain injury mainly affecting the cortex and hippocampus. Despite this significant disease burden, the genetic program that regulates the host response leading to brain damage as a consequence of bacterial meningitis is largely unknown. We used an infant rat model of pneumococcal meningitis to assess gene expression profiles in cortex and hippocampus at 22 and 44 hours after infection and in controls at 22 h after mock-infection with saline. To analyze the biological significance of the data generated by Affymetrix DNA microarrays, a bioinformatics pipeline was used combining (i) a literature-profiling algorithm to cluster genes based on the vocabulary of abstracts indexed in MEDLINE (NCBI) and (ii) the self-organizing map (SOM), a clustering technique based on covariance in gene expression kinetics. Results Among 598 genes differentially regulated (change factor ≥ 1.5; p ≤ 0.05), 77% were automatically assigned to one of 11 functional groups with 94% accuracy. SOM disclosed six patterns of expression kinetics. Genes associated with growth control/neuroplasticity, signal transduction, cell death/survival, cytoskeleton, and immunity were generally upregulated. In contrast, genes related to neurotransmission and lipid metabolism were transiently downregulated on the whole. The majority of the genes associated with ionic homeostasis, neurotransmission, signal transduction and lipid metabolism were differentially regulated specifically in the hippocampus. Of the cell death/survival genes found to be continuously upregulated only in hippocampus, the majority are pro-apoptotic, while those continuously upregulated only in cortex are anti-apoptotic. Conclusion Temporal and spatial analysis of gene expression in experimental pneumococcal meningitis identified potential targets for therapy. PMID

  9. Early downregulation of acute phase proteins after doxorubicin exposition in patients with breast cancer.

    PubMed

    Panis, Carolina; Pizzatti, Luciana; Bufalo, Aedra Carla; Herrera, Ana Cristina; Victorino, Vanessa Jacob; Cecchini, Rubens; Abdelhay, Eliana

    2016-03-01

    Chemotherapy remains the first-choice option for adjuvant therapy in breast cancer. Here, we investigated the impact of the first chemotherapic cycle of doxorubicin on the plasmatic-proteomic profiling of women diagnosed with breast cancer (n = 87). Blood samples were obtained from the same patient before and after doxorubicin infusion (1 h, 60 mg/m(2)) and processed for label-free LC-MS proteomic screening. A total of 80 proteins were downregulated after chemotherapy. In silico analysis revealed that the main biological process enrolled was inflammation and canonical pathways involving acute phase proteins. TNF-α, IL-1β, IL-12, TGF-β1, clusterin, and gelsolin were chosen as relevant for further validation. All selected targets presented reduced plasmatic levels after treatment. Our results indicate that doxorubicin downregulated acute phase proteins immediately after its infusion. Since such proteins are cancer promoting, its downregulation could support the effectiveness of doxorubicin along treatment.

  10. Levels of complement components, immunoglobulins and acute phase proteins in plasma during aging in Nigeria.

    PubMed

    Oyeyinka, G O; Salimonu, L S

    1999-01-01

    Plasma samples from Nigerians aged 6-95 years were examined for their content of complement components (C3, C4, factor B-Bf), immuloglobins (IgG, IgA, IgM IgD) and acute phase proteins (transferrin, albumin, C-reactive protein--CRP, alpha-2-macroglobulin). Albumin, was estimated colorimetrically and the other components by the single radial immunodiffusion techniques. No significant age-related changes in mean values of the four immunobulins and the four acute phase proteins could be demonstrated. Also, the mean values for C3 and Bf did not change significantly with age but C4 values rose significantly with increasing age (r -0.232: P < 0.01).

  11. Meta-Analysis of Gene Expression Profiles in Acute Promyelocytic Leukemia Reveals Involved Pathways

    PubMed Central

    Jalili, Mahdi; Salehzadeh-Yazdi, Ali; Mohammadi, Saeed; Yaghmaie, Marjan; Ghavamzadeh, Ardeshir; Alimoghaddam, Kamran

    2017-01-01

    Background: Acute promyelocytic leukemia (APL) is a unique subtype of acute leukemia. APL is a curable disease; however, drug resistance, early mortality, disease relapse and treatment-related complications remain challenges in APL patient management. One issue underlying these challenges is that the molecular mechanisms of the disease are not sufficiently understood. Materials and Methods: In this study, we performed a meta-analysis of gene expression profiles derived from microarray experiments and explored the background of disease by functional and pathway analysis. Results: Our analysis revealed a gene signature with 406 genes that are up or down-regulated in APL. The pathway analysis determined that MAPK pathway and its involved elements such as JUN gene and AP-1 play important roles in APL pathogenesis along with insulin-like growth factor–binding protein-7. Conclusion: The results of this meta-analysis could be useful for developing more effective therapy strategies and new targets for diagnosis and drugs. PMID:28286608

  12. Circulating Microbial Products and Acute Phase Proteins as Markers of Pathogenesis in Lymphatic Filarial Disease

    PubMed Central

    Anuradha, R.; George, P. Jovvian; Pavan Kumar, N.; Fay, Michael P.; Kumaraswami, V.; Nutman, Thomas B.; Babu, Subash

    2012-01-01

    Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Dysregulated host inflammatory responses leading to systemic immune activation are thought to play a central role in filarial disease pathogenesis. We measured the plasma levels of microbial translocation markers, acute phase proteins, and inflammatory cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection; with clinically asymptomatic infections (INF); and in those without infection (endemic normal [EN]). Comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN) were used preliminarily to identify markers of pathogenesis. Thereafter, we tested for group effects among all the four groups using linear models on the log transformed responses of the markers. Our data suggest that circulating levels of microbial translocation products (lipopolysaccharide and LPS-binding protein), acute phase proteins (haptoglobin and serum amyloid protein-A), and inflammatory cytokines (IL-1β, IL-12, and TNF-α) are associated with pathogenesis of disease in lymphatic filarial infection and implicate an important role for circulating microbial products and acute phase proteins. PMID:22685406

  13. Presence of an acute phase response in sheep with clinical classical scrapie

    PubMed Central

    2012-01-01

    Background Work with experimental scrapie in sheep has been performed on-site for many years including studies on PrPSc dissemination and histopathology of organs and tissues both at preclinical and clinical stages. In this work serum was sampled at regular intervals from lambs which were infected immediately after birth and from parallel healthy controls, and examined for acute phase proteins. In contrast to earlier experiments, which extensively studied PrPSc dissemination and histopathology in peripheral tissues and brain, this experiment is focusing on examination of serum for non-PrPSc markers that discriminates the two groups, and give insight into other on-going processes detectable in serum samples. Results There was clear evidence of an acute phase response in sheep with clinical scrapie, both experimental and natural. All the three proteins, ceruloplasmin, haptoglobin and serum amyloid A, were increased at the clinical stage of scrapie. Conclusion There was evidence of a systemic measurable acute phase response at the clinical terminal end-stage of classical scrapie. PMID:22805457

  14. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD.

    PubMed

    Socié, Gérard; Vigouroux, Stéphane; Yakoub-Agha, Ibrahim; Bay, Jacques-Olivier; Fürst, Sabine; Bilger, Karin; Suarez, Felipe; Michallet, Mauricette; Bron, Dominique; Gard, Philippe; Medeghri, Zakaria; Lehert, Philippe; Lai, Chinglin; Corn, Tim; Vernant, Jean-Paul

    2017-02-02

    Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.

  15. The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia

    PubMed Central

    Cuartero, María Isabel; de la Parra, Juan; García-Culebras, Alicia; Ballesteros, Iván; Lizasoain, Ignacio; Moro, María Ángeles

    2016-01-01

    Kynurenines are a wide range of catabolites which derive from tryptophan through the “Kynurenine Pathway” (KP). In addition to its peripheral role, increasing evidence shows a role of the KP in the central nervous system (CNS), mediating both physiological and pathological functions. Indeed, an imbalance in this route has been associated with several neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases. Altered KP catabolism has also been described during both acute and chronic phases of stroke; however the contribution of the KP to the pathophysiology of acute ischemic damage and of post-stroke disorders during the chronic phase including depression and vascular dementia, and the exact mechanisms implicated in the regulation of the KP after stroke are not well established yet. A better understanding of the regulation and activity of the KP after stroke could provide new pharmacological tools in both acute and chronic phases of stroke. In this review, we will make an overview of CNS modulation by the KP. We will detail the KP contribution in the ischemic damage, how the unbalance of the KP might trigger an alteration of the cognitive function after stroke as well as potential targets for the development of new drugs. PMID:25248805

  16. The effect of lunar phases on the occurrence of acute cardiovascular diseases

    NASA Astrophysics Data System (ADS)

    Chertoprud, V. E.; Gurfinkel', Yu. I.; Goncharova, E. E.; Ivanov-Kholodnyi, G. S.; Kanonidi, H. D.; Mitrofanova, T. A.; Trubina, M. A.

    2012-12-01

    This paper analyzes the possible impact of lunar phases on the dynamics of acute cardiovascular diseases: acute myocardial infarctions (MIs) and acute brain strokes (BSs) at different levels of heliogeomagnetic activity. The superposed epoch analysis (SEA) has been applied with dates of the new moon and full moon used as reference days. A statistical analysis of a 14-year-long (1992 to 2005) series of everyday medical data from the Central Clinical Hospital no. 1 of Russian Railways (Moscow) and the parameters of heliogeomagnetic activity was carried out. It was found that daily occurrences of MIs and BSs vary with the phase of the moon. These variations are significant; they continue at different levels of heliogeomagnetic activity and are not related to the variations in geomagnetic activity identified by the same method. The effect of lunar phases on MIs and BSs is quite different. New moons and full moons have qualitatively the same effect on MIs; however, there are significant differences in the incidence of BSs during new moons and full moons.

  17. Manifestation of Latent Left Ventricular Outflow Tract Obstruction in the Acute Phase of Takotsubo Cardiomyopathy

    PubMed Central

    Ozaki, Kazuyuki; Okubo, Takeshi; Tanaka, Komei; Hosaka, Yukio; Tsuchida, Keiichi; Takahashi, Kazuyoshi; Oda, Hirotaka; Minamino, Tohru

    2016-01-01

    Objective Left ventricular outflow tract (LVOT) obstruction is a complication in 15-25% of patients with Takotsubo cardiomyopathy and sometimes leads to catastrophic outcomes, such as cardiogenic shock or cardiac rupture. However, the underlying mechanisms have not been clarified. Methods and Results We experienced 22 cases of Takotsubo cardiomyopathy during 3 years, and 4 of these 22 cases were complicated with LVOT obstruction in the acute phase (mean age 79±5 years, 1 man, 21 women). The LVOT pressure gradient in the acute phase was 100±17 mmHg. Transthoracic echocardiogram (TTE) revealed left ventricular hypertrophy (LVH) in one case and sigmoid-shaped septum without LVH in three cases. The complete resolution of the LVOT obstruction was achieved in a few days with normalization of the left ventricular wall motion following administration of beta-blockers. A dobutamine provocation test after normalization of the left ventricular wall motion reproduced the LVOT obstruction in all cases and revealed the presence of latent LVOT obstruction. Conclusion The manifestation of latent LVOT obstruction in the acute phase of Takotsubo cardiomyopathy is one potential reason for the complication of LVOT obstruction with Takotsubo cardiomyopathy. PMID:27904102

  18. Insufficient secretion of atrial natriuretic peptide at acute phase of myocardial infarction.

    PubMed

    Maeda, K; Tsutamoto, T; Wada, A; Mabuchi, N; Hayashi, M; Hisanaga, T; Kamijo, T; Kinoshita, M

    2000-08-01

    To investigate the secretion of the plasma levels of atrial natriuretic peptide (ANP) in patients with acute myocardial infarction (AMI), we evaluated the relationship between plasma levels of ANP and pulmonary capillary wedge pressure (PCWP) in 45 consecutive patients during the acute phase of AMI ( approximately 12 h after the attack) (group 1) and compared data with those obtained after 1 mo (group 2). In both groups 1 and 2, plasma ANP levels significantly correlated with PCWP. The slope of the linear regression line between the PCWP and ANP in group 1 was significantly lower, by about one-third, than that in group 2. In addition, we examined changes in ANP levels and left ventricular end-diastolic pressure (LVEDP) over 180 min after AMI induced by injection of microspheres into the left coronary arteries of three dogs. The LVEDP and ANP levels 30 min after AMI were significantly higher than those before; however, despite the persistent high LVEDP during the 180 min after AMI, ANP levels decreased gradually and significantly to 63% of the peak level at 150 min. These findings suggest that the secretion of ANP during the acute phase of myocardial infarction may be insufficient relative to the chronic phase.

  19. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation.

    PubMed

    Nannya, Yasuhito; Shinohara, Akihito; Ichikawa, Motoshi; Kurokawa, Mineo

    2014-03-01

    Currently, we utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving hematopoietic stem cell transplantation (HSCT), and adequacy of this strategy has not been evaluated. We prospectively measured blood level of vitamins and trace elements in 15 patients once per week at 6 time points around the acute phase of allogeneic HSCT. We provided standard nutrition support, including administration of parenteral nutrition with vitamin and trace elements formulation in case of impairment of oral intake. Most patients had vitamin B1 deficiency from the start of preparative regimens. Vitamin C deficiency was prominent throughout the acute phase of HSCT and this was significantly associated with high inflammatory markers, C-reactive protein and ferritin. Remarkable vitamin K overload associated with administration of parenteral supplementation and ferritin overload caused by repeated transfusions was observed. Moderate deficiency of zinc was at least partially linked to gastrointestinal loss by diarrhea. We revealed several features of vitamin and trace element status in the acute phase of HSCT and provided a basis for attempts to improve the nutritional condition in HSCT recipients.

  20. Placental thrombosis in acute phase abortions during experimental Toxoplasma gondii infection in sheep

    PubMed Central

    2014-01-01

    After oral administration of ewes during mid gestation with 2000 freshly prepared sporulated oocysts of T. gondii isolate M4, abortions occurred between days 7 and 11 in 91.6% of pregnant and infected ewes. Afterwards, a further infection was carried out at late gestation in another group of sheep with 500 sporulated oocysts. Abortions happened again between days 9 and 11 post infection (pi) in 58.3% of the infected ewes. Classically, abortions in natural and experimental ovine toxoplasmosis usually occur one month after infection. Few experimental studies have reported the so-called acute phase abortions as early as 7 to 14 days after oral inoculation of oocysts, and pyrexia was proposed to be responsible for abortion, although the underline mechanism was not elucidated. In the present study, all placentas analysed from ewes suffering acute phase abortions showed infarcts and thrombosis in the caruncullar villi of the placentomes and ischemic lesions (periventricular leukomalacia) in the brain of some foetuses. The parasite was identified by PCR in samples from some placentomes of only one sheep, and no antigen was detected by immunohistochemical labelling. These findings suggest that the vascular lesions found in the placenta, and the consequent hypoxic damage to the foetus, could be associated to the occurrence of acute phase abortions. Although the pathogenesis of these lesions remains to be determined, the infectious dose or virulence of the isolate may play a role in their development. PMID:24475786

  1. Altered Gene Expression in Cerulein-Stimulated Pancreatic Acinar Cells: Pathologic Mechanism of Acute Pancreatitis

    PubMed Central

    Yu, Ji Hoon; Lim, Joo Weon

    2009-01-01

    Acute pancreatitis is a multifactorial disease associated with the premature activation of digestive enzymes. The genes expressed in pancreatic acinar cells determine the severity of the disease. The present study determined the differentially expressed genes in pancreatic acinar cells treated with cerulein as an in vitro model of acute pancreatitis. Pancreatic acinar AR42J cells were stimulated with 10-8 M cerulein for 4 h, and genes with altered expression were identified using a cDNA microarray for 4,000 rat genes and validated by real-time PCR. These genes showed a 2.5-fold or higher increase with cerulein: lithostatin, guanylate cyclase, myosin light chain kinase 2, cathepsin C, progestin-induced protein, and pancreatic trypsin 2. Stathin 1 and ribosomal protein S13 showed a 2.5-fold or higher decreases in expression. Real-time PCR analysis showed time-dependent alterations of these genes. Using commercially available antibodies specific for guanylate cyclase, myosin light chain kinase 2, and cathepsin C, a time-dependent increase in these proteins were observed by Western blotting. Thus, disturbances in proliferation, differentiation, cytoskeleton arrangement, enzyme activity, and secretion may be underlying mechanisms of acute pancreatitis. PMID:20054485

  2. Bioinforrnatics of Gene Expression Profiling Data Provide Mechanistic Understanding of Acute Ozone-Induced Lung injury

    EPA Science Inventory

    Acute ozone-induced pulmonary injury and inflammation are well characterized. A few studies have used gene expression profiling to determine the types of changes induced by ozone; however the mechanisms or the pathways involved are less well understood. We presumed that robust bi...

  3. Prognostic value of quantitative analysis of WT1 gene transcripts in adult acute lymphoblastic leukemia.

    PubMed

    Chiusa, Luigi; Francia di Celle, Paola; Campisi, Paola; Ceretto, Cristina; Marmont, Filippo; Pich, Achille

    2006-02-01

    We quantified Wilm's tumor gene (WT1) using a real time quantitative polymerase chain reaction in 20 adult patients with acute lymphoblastic leukemia at presentation. A WT1 level greater than 906 (median value for the whole series) was a significant predictor of a poor disease-free and overall survival in uni- and multivariate analyses.

  4. Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

    PubMed Central

    Ham, Claire; Ferguson, Deborah; Tudor, Hannah; Mattiuzzo, Giada; Klaver, Bep; Page, Mark; Stebbings, Richard; Das, Atze T.; Berkhout, Ben; Almond, Neil; Cranage, Martin P.

    2016-01-01

    In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity. PMID:28002473

  5. Hierarchy in gene expression is predictive of risk, progression, and outcome in adult acute myeloid leukemia

    NASA Astrophysics Data System (ADS)

    Tripathi, Shubham; Deem, Michael W.

    2015-02-01

    Cancer progresses with a change in the structure of the gene network in normal cells. We define a measure of organizational hierarchy in gene networks of affected cells in adult acute myeloid leukemia (AML) patients. With a retrospective cohort analysis based on the gene expression profiles of 116 AML patients, we find that the likelihood of future cancer relapse and the level of clinical risk are directly correlated with the level of organization in the cancer related gene network. We also explore the variation of the level of organization in the gene network with cancer progression. We find that this variation is non-monotonic, which implies the fitness landscape in the evolution of AML cancer cells is non-trivial. We further find that the hierarchy in gene expression at the time of diagnosis may be a useful biomarker in AML prognosis.

  6. Assessment of Expression of Genes Coding GABAA Receptors during Chronic and Acute Intoxication of Laboratory Rats with Ethanol.

    PubMed

    Osechkina, N S; Ivanov, M B; Nazarov, G V; Batotsyrenova, E G; Lapina, N V; Babkin, A V; Berdinskikh, I S; Melekhova, A S; Voitsekhovich, K O; Lisitskii, D S; Kashina, T V

    2016-02-01

    Expression of genes encoding the individual subunits of ionotropic GABAA receptor was assessed after acute and chronic intoxication of rats with ethanol. The chronic 1-month-long exposure to ethanol signifi cantly decreased (by 38%) expression of Gabrb1 gene in the hippocampus. Acute exposure to ethanol elevated expression of genes Gabrb1 (by 1.7 times), Gabra1 (by 3.8 times), and Gabra4 (by 6.5 times), although it diminished expression of Gabra2 gene by 1.4 times. In preliminarily alcoholized rats, acute intoxication with ethanol enhanced expression of genes Gabrb1 and Gabra5 by 1.7 and 8.7 times, respectively. There was neither acute nor chronic effect of ethanol on expression of gene Gabra3.

  7. Acute stress and cardiovascular health: is there an ACE gene connection?

    PubMed

    Holman, E Alison

    2012-10-01

    Cardiovascular disorders (CVD) are associated with acute and posttraumatic stress responses, yet biological processes underlying this association are poorly understood. This study examined whether renin-angiotensin-aldosterone system activity, as indicated by a functional single nucleotide polymorphism (SNP) in the angiotensin converting enzyme (ACE) gene, is associated with both CVD and acute stress related to the September 11, 2001 (9/11) terrorist attacks. European-American respondents (N = 527) from a nationally representative longitudinal study of coping following 9/11 provided saliva for genotyping. Respondents had completed health surveys before 9/11 and annually for 3 years after, and acute stress assessments 9 to 23 days after 9/11. Respondents with rs4291 AA or TT genotypes reported high acute stress twice as often as those with the AT genotype. Individuals with the TT genotype were 43% more likely to report increased physician-diagnosed CVD over 3 years following 9/11, when the following variables were included in the model: (a) pre-9/11 CVD, mental health, and non-CVD ailments; (b) cardiac risk factors; (c) ongoing endocrine disorders; and (d) significant demographics. The ACE rs4291 TT genotype, which has been associated with HPA axis hyperactivity and higher levels of serum angiotensin converting enzyme (ACE), predicted acute stress response and reports of physician-diagnosed CVD in a national sample following collective stress. ACE gene function may be associated with both mental and physical health disorders following collective stress.

  8. Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant

    SciTech Connect

    Liu Zhilin; Ukomadu, Chinweike

    2008-01-25

    Fibrinogen-like protein 1 (FGL1) is a hepatocyte derived protein that is upregulated in regenerating rodent livers following partial hepatectomy. It has been implicated as a mitogen for liver cell proliferation. In this study, we show that recombinant human IL-6 induces FGL1 expression in Hep G2 cells in a pattern similar to those of acute phase reactants. Following induction of acute inflammation in rats by subcutaneous injection of turpentine oil, serum FGL1 levels are also enhanced. Although, a recent report suggests that FGL1 associates almost exclusively with the fibrin matrix, we report here that approximately 20% of the total plasma FGL1 remains free. The enhancement of FGL1 levels in vitro by IL-6 and its induction after turpentine oil injection suggest that it is an acute phase reactant. Its presence in bound and free forms in the blood also implies biological roles that extend beyond the proposed autocrine effect it has on hepatocytes during regeneration.

  9. Pulmonary function of children with acute leukemia in maintenance phase of chemotherapy☆

    PubMed Central

    de Macêdo, Thalita Medeiros Fernandes; Campos, Tania Fernandes; Mendes, Raquel Emanuele de França; França, Danielle Corrêa; Chaves, Gabriela Suéllen da Silva; de Mendonça, Karla Morganna Pereira Pinto

    2014-01-01

    OBJECTIVE: The aim of this study was to assess the pulmonary function of children with acute leukemia. METHODS: Cross-sectional observational analytical study that enrolled 34 children divided into groups A (17 with acute leukemia in the maintenance phase of chemotherapy) and B (17 healthy children). The groups were matched for sex, age and height. Spirometry was measured using a spirometer Microloop Viasys(r) in accordance with American Thoracic Society and European Respiratory Society guidelines. Maximal respiratory pressures were measured with an MVD300 digital manometer (Globalmed(r)). Maximal inspiratory pressures and maximal expiratory pressures were measured from residual volume and total lung capacity, respectively. RESULTS: Group A showed a significant decrease in maximal inspiratory pressures when compared to group B. No significant difference was found between the spirometric values of the two groups, nor was there any difference between maximal inspiratory pressure and maximal expiratory pressure values in group A compared to the lower limit values proposed as reference. CONCLUSION: Children with acute leukemia, myeloid or lymphoid, during the maintenance phase of chemotherapy exhibited unchanged spirometric variables and maximal expiratory pressure; However, there was a decrease in inspiratory muscle strength. PMID:25510995

  10. Phase transitions in the evolution of gene regulatory networks

    NASA Astrophysics Data System (ADS)

    Skanata, Antun; Kussell, Edo

    The role of gene regulatory networks is to respond to environmental conditions and optimize growth of the cell. A typical example is found in bacteria, where metabolic genes are activated in response to nutrient availability, and are subsequently turned off to conserve energy when their specific substrates are depleted. However, in fluctuating environmental conditions, regulatory networks could experience strong evolutionary pressures not only to turn the right genes on and off, but also to respond optimally under a wide spectrum of fluctuation timescales. The outcome of evolution is predicted by the long-term growth rate, which differentiates between optimal strategies. Here we present an analytic computation of the long-term growth rate in randomly fluctuating environments, by using mean-field and higher order expansion in the environmental history. We find that optimal strategies correspond to distinct regions in the phase space of fluctuations, separated by first and second order phase transitions. The statistics of environmental randomness are shown to dictate the possible evolutionary modes, which either change the structure of the regulatory network abruptly, or gradually modify and tune the interactions between its components.

  11. An accurate two-phase approximate solution to the acute viral infection model

    SciTech Connect

    Perelson, Alan S

    2009-01-01

    During an acute viral infection, virus levels rise, reach a peak and then decline. Data and numerical solutions suggest the growth and decay phases are linear on a log scale. While viral dynamic models are typically nonlinear with analytical solutions difficult to obtain, the exponential nature of the solutions suggests approximations can be found. We derive a two-phase approximate solution to the target cell limited influenza model and illustrate the accuracy using data and previously established parameter values of six patients infected with influenza A. For one patient, the subsequent fall in virus concentration was not consistent with our predictions during the decay phase and an alternate approximation is derived. We find expressions for the rate and length of initial viral growth in terms of the parameters, the extent each parameter is involved in viral peaks, and the single parameter responsible for virus decay. We discuss applications of this analysis in antiviral treatments and investigating host and virus heterogeneities.

  12. [Dynamics of interferon production during different phases of the pathological process in children with acute pneumonia and relapsing bronchitis].

    PubMed

    Koval'chuk, O L

    2001-01-01

    With the purpose of gaining further insight into regularities of changes that take place in indices for the interferon status in children with acute pneumonia and current bronchitis depending on the phase of the pathological process, 112 children were examined in whom the level of serum interferon was measured together with production of alpha- and gamma-interferon by leucocytes of the peripheral blood in vitro. It is shown that in the examined patients with acute pneumonia and relapsing bronchitis in the acute period and during the phase of reparation there are differences in functioning of indices for the system of interferon.

  13. Prognostic implications of cardiac scintigraphic parameters obtained in the early phase of acute myocardial infarction

    SciTech Connect

    Suzuki, A.; Matsushima, H.; Satoh, A.; Hayashi, H.; Sotobata, I.

    1988-06-01

    A cohort of 76 patients with acute myocardial infarction was studied with infarct-avid scan, radionuclide ventriculography, and thallium-201 myocardial perfusion scintigraphy. Infarct area, left ventricular ejection fraction, and defect score were calculated as radionuclide indices of the extent of myocardial infarction. The correlation was studied between these indices and cardiac events (death, congestive heart failure, postinfarction angina, and recurrence of myocardial infarction) in the first postinfarction year. High-risk patients (nonsurvivors and patients who developed heart failure) had a larger infarct area, a lower left ventricular ejection fraction, and a larger defect score than the others. Univariate linear discriminant analysis was done to determine the optimal threshold of these parameters for distinguishing high-risk patients from others. Radionuclide parameters obtained in the early phase of acute myocardial infarction were useful for detecting both patients with grave complications and those with poor late prognosis during a mean follow-up period of 2.6 years.

  14. Phase I Trial of AZD1775 and Belinostat in Treating Patients With Relapsed or Refractory Myeloid Malignancies or Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2017-02-03

    Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  15. Are the unenhanced and excretory CT phases necessary for the evaluation of acute pyelonephritis?

    PubMed

    Taniguchi, Lincoln S; Torres, Ulysses S; Souza, Saulo M; Torres, Lucas R; D'Ippolito, Giuseppe

    2017-05-01

    Background The most widely accepted computed tomography (CT) protocol for diagnosis of acute pyelonephritis (APN) includes at least a pre- and post-contrast scan, which may expose patients to higher doses of ionizing radiation. Purpose To establish the accuracy, reproducibility, and degree of confidence in CT diagnosis of acute pyelonephritis (APN) and urolithiasis using only images obtained during the nephrographic phase. Material and Methods A retrospective study of 100 consecutive patients (88 women; age range, 19-70 years) with clinical and laboratory suspicion of APN and who underwent triphasic abdominal CT scans (non-contrast, nephrographic, and excretory phases) was performed. Two readers first evaluated independently only the nephrographic phase of scans, and, in a second session, the entire study. The diagnostic reference standard was settled by a third experienced radiologist who reviewed all triphasic scans and clinical data. Results The accuracy of only nephrographic phase for diagnosis of APN and urolithiasis was in the range of 90.3-91.78% and 96.27-99.25%, respectively. There was no significant difference in comparison with the triphasic reading (z: -0.4 - 0.2; P = 0.34-0.83). The average degree of confidence for APN also showed no significant variation for both readers ( P = 0.4 and 0.08). Almost perfect inter-observer agreements for the diagnosis of APN (k = 0.86, P < 0.001) and for urolithiasis (k = 0.84, P < 0.001) were observed when considering only the nephrographic phase. Conclusion CT assessment of APN and urolithiasis can be accurately performed using only the late nephrographic phase, with consequent dose reduction.

  16. Restoration of energy level in the early phase of acute pediatric pancreatitis

    PubMed Central

    Mosztbacher, Dóra; Farkas, Nelli; Solymár, Margit; Pár, Gabriella; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Márta, Katalin; Mikó, Alexandra; Rumbus, Zoltán; Varjú, Péter; Hegyi, Péter; Párniczky, Andrea

    2017-01-01

    Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatment of acute pediatric pancreatitis. The preferred reporting items for systematic review (PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (PubMed: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly (SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better

  17. Prostate Hypofractionated Radiation Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study

    SciTech Connect

    Chapet, Olivier; Decullier, Evelyne; Bin, Sylvie; Faix, Antoine; Ruffion, Alain; Jalade, Patrice; Fenoglietto, Pascal; Udrescu, Corina; Enachescu, Ciprian; Azria, David

    2015-03-15

    Purpose: Hypofractionated radiation therapy (RT) in prostate cancer can be developed only if the risk of rectal toxicity is controlled. In a multicenter phase 2 trial, hypofractionated irradiation was combined with an injection of hyaluronic acid (HA) to preserve the rectal wall. Tolerance of the injection and acute toxicity rates are reported. Methods and Materials: The study was designed to assess late grade 2 toxicity rates. The results described here correspond to the secondary objectives. Acute toxicity was defined as occurring during RT or within 3 months after RT and graded according to the Common Terminology Criteria for Adverse Events version 4.0. HA tolerance was evaluated with a visual analog scale during the injection and 30 minutes after injection and then by use of the Common Terminology Criteria at each visit. Results: From 2010 to 2012, 36 patients with low-risk to intermediate-risk prostate cancer were included. The HA injection induced a mean pain score of 4.6/10 ± 2.3. Thirty minutes after the injection, 2 patients still reported pain (2/10 and 3/10), which persisted after the intervention. Thirty-three patients experienced at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities. Conclusions: The injection of HA makes it possible to deliver hypofractionated irradiation over 4 weeks with a dose per fraction of > 3 Gy, with limited acute rectal toxicity.

  18. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

    SciTech Connect

    Shannahan, Jonathan H.; Alzate, Oscar; Winnik, Witold M.; Andrews, Debora; Schladweiler, Mette C.; Ghio, Andrew J.; Gavett, Stephen H.; Kodavanti, Urmila P.

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. -- Highlights: ► Biomarkers of asbestos exposure are required for disease diagnosis. ► Libby amphibole exposure is associated with increased human mortality. ► Libby amphibole increases circulating proteins involved

  19. Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress

    PubMed Central

    Li, Sisi; Papale, Ligia A.; Zhang, Qi; Madrid, Andy; Chen, Li; Chopra, Pankaj; Keleş, Sündüz; Jin, Peng; Alisch, Reid S.

    2015-01-01

    Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here, we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. PMID:26598390

  20. Scintigraphic evaluation of digital circulation during the developmental and acute phases of equine laminitis

    SciTech Connect

    Trout, D.R.

    1987-01-01

    Using nuclear isotopic imaging, digital circulation was sequentially evaluated at 24-hour intervals in 11 control horses and in 9 horses affected with acute laminitis, created by administration of a high-starch ration. Following intra-arterial injection of /sup 99m/Tc macroaggregated albumin into the brachiocephalic trunk, a gamma camera and dedicated nuclear medicine computer were used to acquire static images of the right front foot. Dynamic vascular-phase and static interstitial-phase images were also obtained after jugular vein injection of /sup 99m/Tc diethylenetriamine pentaacetic acid. These procedures were performed on standing horses, using either minimal or no tranquilization. The images were quantitatively analyzed for parameters indicative of circulation to the foot as a whole and to specific regions of interest within the foot. There was no evidence of reduced total blood flow to the lamellae during either the developmental or acute phases of laminitis. Although total flow tended to increase throughout the peripheral/external regions of the foot, statistically significant elevations were consistently present only within the lamellae. Changes indicative of decreased total blood flow were noted in the central/internal regions of the foot. These alterations usually occurred coincident with or after the onset of clinical lameness.

  1. Thromboembolism in the Sub-Acute Phase of Spinal Cord Injury: A Systematic Review of the Literature

    PubMed Central

    Belci, Maurizio; Van Middendorp, Joost J; Al Halabi, Ahmed; Meagher, Tom M

    2016-01-01

    To review the evidence of thromboembolism incidence and prophylaxis in the sub-acute phase of spinal cord injury (SCI) 3–6 months post injury. All observational and experimental studies with any length of follow-up and no limitations on language or publication status published up to March 2015 were included. Two review authors independently selected trials for inclusion and extracted data. Outcomes studied were incidence of pulmonary embolism (PE) and deep vein thrombosis (DVT) in the sub-acute phase of SCI. The secondary outcome was type of thromboprophylaxis. Our search identified 4305 references and seven articles that met the inclusion criteria. Five papers reported PE events and three papers reported DVT events in the sub-acute phase of SCI. Studies were heterogeneous in populations, design and outcome reporting, therefore a meta-analysis was not performed. The included studies report a PE incidence of 0.5%–6.0% and DVT incidence of 2.0%–8.0% in the sub-acute phase of SCI. Thromboprophylaxis was poorly reported. Spinal patients continue to have a significant risk of PE and DVT after the acute period of their injury. Clinicians are advised to have a low threshold for suspecting venous thromboembolism in the sub-acute phase of SCI and to continue prophylactic anticoagulation therapy for a longer period of time. PMID:27790330

  2. Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia.

    PubMed

    van Rijn, Bas B; Bruinse, Hein W; Veerbeek, Jan H; Post Uiterweer, Emiel D; Koenen, Steven V; van der Bom, Johanna G; Rijkers, Ger T; Roest, Mark; Franx, Arie

    2016-02-01

    Preeclampsia is an inflammatory-mediated hypertensive disorder of pregnancy and seems to be an early indicator of increased cardiovascular risk, but mechanisms underlying this association are unclear. In this study, we identified levels of circulating inflammatory markers and dynamic changes in the systemic acute-phase response in 44 women with a history of severe early-onset preeclampsia, compared with 29 controls with only uneventful pregnancies at 1.5 to 3.5 years postpartum. Models used were in vivo seasonal influenza vaccination and in vitro whole-blood culture with T-cell stimulants and the toll-like receptor-4 ligand lipopolysaccharide. Outcome measures were C-reactive protein, interleukin-6 (IL-6), IL-18, fibrinogen, myeloperoxidase, and a panel of 13 cytokines representative of the innate and adaptive inflammatory response, in addition to established cardiovascular markers. The in vivo acute-phase response was higher for women with previous preeclampsia than that for controls without such a history, although only significant for C-reactive protein (P=0.04). Preeclampsia was associated with higher IL-1β (P<0.05) and IL-8 (P<0.01) responses to T-cell activation. Hierarchical clustering revealed 2 distinct inflammatory clusters associated with previous preeclampsia: an adaptive response cluster associated with increased C-reactive protein and IL-6 before and after vaccination, increased weight, and low high-density lipoprotein cholesterol; and a toll-like receptor-4 mediated the cluster associated with increased IL-18 before and after vaccination but not associated with other cardiovascular markers. Furthermore, we found interactions between previous preeclampsia, common TLR4 gene variants, and the IL-18 response to vaccination. In conclusion, preeclampsia is associated with alterations in the inflammatory response postpartum mostly independent of other established cardiovascular risk markers.

  3. Glutamate transporter type 3 mediates isoflurane preconditioning-induced acute phase of neuroprotection in mice.

    PubMed

    Li, Liaoliao; Deng, Jiao; Zuo, Zhiyi

    2013-09-01

    A pre-exposure to isoflurane reduces ischemic brain injury in rodents (isoflurane preconditioning). This neuroprotection has acute and delayed phases. Our previous in vitro studies suggest that the acute phase may involve excitatory amino acid transporters (EAATs). We determine whether this protection involves EAAT3, the major neuronal EAAT. Adult male EAAT3 knockout mice and their wild-type littermates were exposed or were not exposed to 1.5% isoflurane for 30 min. Sixty minutes later, they were subjected to a 90- or 60-min middle cerebral arterial occlusion (MCAO). Their neurological outcomes were evaluated 24h after the MCAO. In another experiment, cerebral cortex was harvested for Western blotting at 30 min after animals were exposed to 1.5% isoflurane for 30 min. Here, we showed that isoflurane reduced brain infarct volumes and improved neurological functions of wild-type mice after a 90-min MCAO. However, isoflurane pre-exposure did not change the neurological outcome of EAAT3 knockout mice no matter whether the MCAO was for 90 min or 60 min. Isoflurane increased phospho-Akt, a survival-promoting protein, in the wild-type mice but not in the EAAT3 knockout mice. The isoflurane-induced neuroprotection in the wild-type mice was abolished by LY294004, an Akt activation inhibitor. LY294004 alone did not affect the neurological outcome of the wild-type or EAAT3 knockout mice after focal brain ischemia. These results suggest that the isoflurane preconditioning-induced acute phase of neuroprotection involves EAAT3. The downstream event includes Akt activation.

  4. [Mechanism of thiol-dependence of acute phase proteins and serology of monospecific antisera in vitro].

    PubMed

    Kostiushov, V V; Kostiushova, N V; Pavlovich, S I; Sakhno, Iu P; Tymchyshyn, O L

    2001-01-01

    For the donors and for the patients with inflammatory processes is thiol-dependent the gear of immune responses in vitro an antigen--antibody on dynamics(changes) of change (+/- delta) of the contents SH- and S-S-group reaction mixtures. Thus, is conducted the analysis of interplay of proteins of an acute phase (CRP, orosomucoid and transferin) serums of a blood of the donors and patients with serology by related diagnostic (complementary) monospecific serums (MSS) against CRP (Anti-CRP), against Oroso (Anti-Oroso) i against Transf (Anti-Transf). Is established, that as against the donors, for the patients with inflammatory processes these reacting are accompanied by a phenomenon of a liberation of energy of Ag(+)-sensing non proteins SH-groups and they occur in supernatants of deprotheinized of reaction mixtures. At the same time, both for the donors, and for the patients, these reacting are accompanied modification by changes kept in repair (+/- delta) proteins SH- and S-S-rpy[symbol: see text], in integral reaction mixtures (in which one protein did not deposit). Such data testify, that the inflammatory process, apparently, can be accompanied by such rearrangement of a structurally functional condition of proteins of an acute phase, that under operating MSS in reaction mixtures descends labelised blended disulfide of communications between them and low molecular weight thiols. As a result of it there is a liberation of energy of Ag(+)-sensing non proteins SH-groups. This parameter can be used for an estimation of functional activity of proteins of an acute phase.

  5. Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve.

    PubMed

    Rankin, James; Walker, Jamie J; Windle, Richard; Lightman, Stafford L; Terry, John R

    2012-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a dynamic oscillatory hormone signalling system that regulates the pulsatile secretion of glucocorticoids from the adrenal glands. In addition to regulation of basal levels of glucocorticoids, the HPA axis provides a rapid hormonal response to stress that is vitally important for homeostasis. Recently it has become clear that glucocorticoid pulses encode an important biological signal that regulates receptor signalling both in the central nervous system and in peripheral tissues. It is therefore important to understand how stressful stimuli disrupt the pulsatile dynamics of this system. Using a computational model that incorporates the crucial feed-forward and feedback components of the axis, we provide novel insight into experimental observations that the size of the stress-induced hormonal response is critically dependent on the timing of the stress. Further, we employ the theory of Phase Response Curves to show that an acute stressor acts as a phase-resetting mechanism for the ultradian rhythm of glucocorticoid secretion. Using our model, we demonstrate that the magnitude of an acute stress is a critical factor in determining whether the system resets via a Type 1 or Type 0 mechanism. By fitting our model to our in vivo stress-response data, we show that the glucocorticoid response to an acute noise stress in rats is governed by a Type 0 phase-resetting curve. Our results provide additional evidence for the concept of a deterministic sub-hypothalamic oscillator regulating the ultradian glucocorticoid rhythm, which constitutes a highly responsive peripheral hormone system that interacts dynamically with hypothalamic inputs to regulate the overall hormonal response to stress.

  6. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis.

    PubMed Central

    Hamid, Q; Boguniewicz, M; Leung, D Y

    1994-01-01

    The mechanisms involved in the initiation and maintenance of skin inflammation in atopic dermatitis (AD) are poorly understood. Recent data suggest that the pattern of cytokines expressed locally plays a critical role in modulating the nature of tissue inflammation. In this study, we used in situ hybridization to investigate the expression of interleukin 4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) messenger RNA (mRNA) in skin biopsies from acute and chronic skin lesions of patients with AD. As compared with normal control skin or uninvolved skin of patients with AD, acute and chronic skin lesions had significantly greater numbers of cells that were positive for mRNA, IL-4 (P < 0.01), and IL-5 (P < 0.01), but not for IFN-gamma mRNA expressing cells. However, as compared with acute AD skin lesions, chronic AD skin lesions had significantly fewer IL-4 mRNA-expressing cells (P < 0.01), but significantly greater IL-5 mRNA (P < 0.01). T cells constituted the majority of IL-5-expressing cells in acute and chronic AD lesions. Chronic lesions also expressed significantly greater numbers of activated EG2+ eosinophils than acute lesions (P < 0.01). These data indicate that although acute and chronic AD lesions are associated with increased activation of IL-4 and IL-5 genes, initiation of acute skin inflammation in AD is associated with a predominance of IL-4 expression whereas maintenance of chronic inflammation is predominantly associated with increased IL-5 expression and eosinophil infiltration. Images PMID:8040343

  7. Gene expression changes in female zebrafish (Danio rerio) brain in response to acute exposure to methylmercury

    USGS Publications Warehouse

    Richter, Catherine A.; Garcia-Reyero, Natàlia; Martyniuk, Chris; Knoebl, Iris; Pope, Marie; Wright-Osment, Maureen K.; Denslow, Nancy D.; Tillitt, Donald E.

    2011-01-01

    Methylmercury (MeHg) is a potent neurotoxicant and endocrine disruptor that accumulates in aquatic systems. Previous studies have shown suppression of hormone levels in both male and female fish, suggesting effects on gonadotropin regulation in the brain. The gene expression profile in adult female zebrafish whole brain induced by acute (96 h) MeHg exposure was investigated. Fish were exposed by injection to 0 or 0.5(mu or u)g MeHg/g. Gene expression changes in the brain were examined using a 22,000-feature zebrafish microarray. At a significance level of pgenes were up-regulated and 76 genes were down-regulated in response to MeHg exposure. Individual genes exhibiting altered expression in response to MeHg exposure implicate effects on glutathione metabolism in the mechanism of MeHg neurotoxicity. Gene ontology (GO) terms significantly enriched among altered genes included protein folding, cell redox homeostasis, and steroid biosynthetic process. The most affected biological functions were related to nervous system development and function, as well as lipid metabolism and molecular transport. These results support the involvement of oxidative stress and effects on protein structure in the mechanism of action of MeHg in the female brain. Future studies will compare the gene expression profile induced in response to MeHg with that induced by other toxicants and will investigate responsive genes as potential biomarkers of MeHg exposure.

  8. GENE EXPRESSION CHANGES IN FEMALE ZEBRAFISH (DANIO RERIO) BRAIN IN RESPONSE TO ACUTE EXPOSURE TO METHYLMERCURY

    PubMed Central

    Richter, Catherine A.; Garcia-Reyero, Natàlia; Martyniuk, Chris; Knoebl, Iris; Pope, Marie; Wright-Osment, Maureen K.; Denslow, Nancy D.; Tillitt, Donald E.

    2010-01-01

    Methylmercury (MeHg) is a potent neurotoxicant and endocrine disruptor that accumulates in aquatic systems. Previous studies have shown suppression of hormone levels in both male and female fish, suggesting effects on gonadotropin regulation in the brain. The gene expression profile in adult female zebrafish whole brain induced by acute (96 hr) MeHg exposure was investigated. Fish were exposed by injection to 0 or 0.5 μg MeHg/g. Gene expression changes in the brain were examined using a 22,000 feature zebrafish microarray. At a significance level of p<0.01, 79 genes were up-regulated and 76 genes were down-regulated in response to MeHg exposure. Individual genes exhibiting altered expression in response to MeHg exposure implicate effects on glutathione metabolism in the mechanism of MeHg neurotoxicity. Gene ontology (GO) terms significantly enriched among altered genes included protein folding, cell redox homeostasis, and steroid biosynthetic process. The most affected biological functions were related to the nervous system development and function, as well as lipid metabolism and molecular transport. These results support the involvement of oxidative stress and effects on protein structure in the mechanism of action of MeHg in the female brain. Future studies will compare the gene expression profile induced in response to MeHg with that induced by other toxicants and investigate responsive genes as potential biomarkers of MeHg exposure. PMID:21082716

  9. Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor β

    PubMed Central

    Wesselkamper, Scott C.; Case, Lisa M.; Henning, Lisa N.; Borchers, Michael T.; Tichelaar, Jay W.; Mason, John M.; Dragin, Nadine; Medvedovic, Mario; Sartor, Maureen A.; Tomlinson, Craig R.; Leikauf, George D.

    2005-01-01

    Rationale: Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain. Objectives: To integrate molecular pathways and investigate the role of transforming growth factor β (TGF-β) in acute lung injury in mice. Methods: cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-β1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-β, was assessed in nickel-exposed mice. The effect of TGF-β on surfactant-associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells. Measurements and Main Results: Genes that decreased the most after nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-β signaling. MAPPFinder analysis further established TGF-β signaling to be significantly altered. TGF-β–inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-β1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-β attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-β1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-β–responsive region in the Sftpb promoter was identified. Conclusions: These data suggest that TGF-β acts as a central mediator of acute lung injury through the alteration of several different molecular pathways. PMID:16100012

  10. Cytokine kinetics of Zika virus-infected patients from acute to reconvalescent phase.

    PubMed

    Tappe, Dennis; Pérez-Girón, José Vicente; Zammarchi, Lorenzo; Rissland, Jürgen; Ferreira, Davis F; Jaenisch, Thomas; Gómez-Medina, Sergio; Günther, Stephan; Bartoloni, Alessandro; Muñoz-Fontela, César; Schmidt-Chanasit, Jonas

    2016-06-01

    Zika virus is an emerging mosquito-borne flavivirus currently causing large epidemics in the Pacific Ocean region and Brazil. Clinically, Zika fever resembles dengue fever, but is less severe. Whereas the clinical syndrome and laboratory diagnostic procedures have been described, little attention was paid to the immunology of the disease and its possible use for clinical follow-up of patients. Here, we investigate the role of cytokines in the pathogenesis of Zika fever in travelers returning from Asia, the Pacific, and Brazil. Polyfunctional T cell activation (Th1, Th2, Th9, and Th17 response) was seen during the acute phase characterized by respective cytokine level increases, followed by a decrease in the reconvalescent phase.

  11. Transcription factor AP-2α regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression.

    PubMed

    Ding, Xiaofeng; Yang, Zijian; Zhou, Fangliang; Wang, Fangmei; Li, Xinxin; Chen, Cheng; Li, Xiaofeng; Hu, Xiang; Xiang, Shuanglin; Zhang, Jian

    2013-08-01

    Transcription factor AP-2α mediates transcription of a number of genes implicated in mammalian development, cell proliferation and carcinogenesis. In the current study, we identified Hoxa7, Hoxa9 and Hox cofactor Meis1 as AP-2α target genes, which are involved in myeloid leukemogenesis. Luciferase reporter assays revealed that overexpression of AP-2α activated transcription activities of Hoxa7, Hoxa9 and Meis1, whereas siRNA of AP-2α inhibited their transcription activities. We found that AP-2 binding sites in regulatory regions of three genes activated their transcription by mutant analysis and AP-2α could interact with AP-2 binding sites in vivo by chromatin immunoprecipitation (ChIP). Further results showed that the AP-2α shRNA efficiently inhibited mRNA and protein levels of Hoxa7, Hoxa9 and Meis1 in AML cell lines U937 and HL60. Moreover, decreased expression of AP-2α resulted in a significant reduction in the growth and proliferation of AML cells in vitro. Remarkably, AP-2α knockdown leukemia cells exhibit decreased tumorigenicity in vivo compared with controls. Finally, AP-2α and target genes in clinical acute myeloid leukemia samples of M5b subtype revealed variable expression levels and broadly paralleled expression. These data support a role of AP-2α in mediating the expression of Hoxa genes in acute myeloid leukemia to influence the proliferation and cell survival.

  12. Sex differences in acute hormonal and subjective response to naltrexone: The impact of menstrual cycle phase.

    PubMed

    Roche, Daniel J O; King, Andrea C

    2015-02-01

    Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n=46 women) participated in two morning sessions in which they received 50mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n=23) or luteal phase of the MC. Serum cortisol, salivary cortisol, prolactin, luteinizing hormone (LH), and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women.

  13. Undernutrition, the Acute Phase Response to Infection, and Its Effects on Micronutrient Status Indicators12

    PubMed Central

    Bresnahan, Kara A.; Tanumihardjo, Sherry A.

    2014-01-01

    Infection and undernutrition are prevalent in developing countries and demonstrate a synergistic relation. Undernutrition increases infection-related morbidity and mortality. The acute phase response (APR) is an innate, systemic inflammatory reaction to a wide array of disruptions in a host’s homeostasis, including infection. Released from immune cells in response to deleterious stimuli, proinflammatory cytokines act on distant tissues to induce behavioral (e.g., anorexia, weakness, and fatigue) and systemic effects of the APR. Cytokines act to increase energy and protein requirements to manifest fever and support hepatic acute phase protein (APP) production. Blood concentrations of glucose and lipid are augmented to provide energy to immune cells in response to cytokines. Additionally, infection decreases intestinal absorption of nutrients and can cause direct loss of micronutrients. Traditional indicators of iron, zinc, and vitamin A status are altered during the APR, leading to inaccurate estimations of deficiency in populations with a high or unknown prevalence of infection. Blood concentrations of APPs can be measured in nutrition interventions to assess the time stage and severity of infection and correct for the APR; however, standardized cutoffs for nutrition applications are needed. Protein-energy malnutrition leads to increased gut permeability to pathogens, abnormal immune cell populations, and impaired APP response. Micronutrient deficiencies cause specific immune impairments that affect both innate and adaptive responses. This review describes the antagonistic interaction between the APR and nutritional status and emphasizes the need for integrated interventions to address undernutrition and to reduce disease burden in developing countries. PMID:25398733

  14. Acute phase protein concentrations after limited distance and long distance endurance rides in horses.

    PubMed

    Cywińska, Anna; Szarska, Ewa; Górecka, Renata; Witkowski, Lucjan; Hecold, Mateusz; Bereznowski, Andrzej; Schollenberger, Antoni; Winnicka, Anna

    2012-12-01

    Acute phase proteins (APP) have been described as useful for assessing health in human and animal patients, as they closely reflect the acute phase reaction (APR). In humans and dogs a reaction analogous to APR has also been described after prolonged or strenuous exercise. The aim of this study was to determine, if similar reactions occur in endurance horses after limited and long distance rides. Seventeen horses that successfully completed various distance competitions were tested. Routine haematological and biochemical tests were performed and the concentrations of serum amyloid A (SAA), C-reactive protein (CRP) and haptoglobin were measured. Typical endurance exercise-induced haematological and biochemical changes were observed in all horses, regardless the distance. After long distance rides, the level of SAA markedly increased, but CRP and haptoglobin concentrations remained unchanged. After limited distance rides no changes in the levels of APPs were noted. Exercise-induced APR in horses occurred only after prolonged, strenuous exertion, and differed from APR in inflammation in that only SAA concentration was increased.

  15. Relationship between production of acute-phase proteins and strength of inflammatory stimulation in rats.

    PubMed

    Kuribayashi, Takashi; Tomizawa, Misaki; Seita, Tetsurou; Tagata, Kazutoshi; Yamamoto, Shizuo

    2011-07-01

    The relationship between intensity of inflammatory stimulation and production of α(2)-macroglobulin (α2M) and α(1)-acid glycoprotein (AAG) in rats was investigated. Sprague-Dawley rats were injected with turpentine oil at doses of 0.05, 0.2 or 0.4 mL/rat. Serum levels of α2M, interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured by enzyme-linked immunosorbent assay, and AAG was measured by single radial immunodiffusion. Peak serum levels of α2M and AAG in rats injected at 0.05 mL/rat were significantly lower than those at 0.2 or 0.4 mL/rat. However, no significant differences were observed for peak serum levels of these acute-phase proteins between 0.2 and 0.4 mL/rat. Furthermore, peak serum levels of IL-6 and CINC-1 in rats injected at 0.05 mL/rat were significantly lower than those at 0.2 or 0.4 mL/rat. Thus, the production of these acute-phase proteins has upper limits, even under increased strength of inflammatory stimulation in rats injected with turpentine oil.

  16. ACUTE PHASE PROTEIN AND ELECTROPHORESIS PROTEIN FRACTION VALUES FOR CAPTIVE AMERICAN FLAMINGOS (PHOENICOPTERUS RUBER).

    PubMed

    Delk, Katie W; Wack, Raymund F; Burgdorf-Moisuk, Anne; Kass, Philip H; Cray, Carolyn

    2015-12-01

    Protein electrophoresis has recognized applications in determining the health status of various species. While reference intervals for electrophoresis have been determined for psittacine and raptor species, there are none reported for Phoenicopteriformes species. Reference intervals for haptoglobin and protein fractions obtained by electrophoresis were determined for the American flamingo (Phoenicopterus ruber) based on plasma samples from 39 captive birds. The reference intervals were as follows: haptoglobin, 0.17-0.8 mg/ml; total protein, 3.65-6.38 g/dl; prealbumin, 0.26-1.9 g/dl; albumin, 1.51-3.12 g/dl; α-1 globulin, 0.06-0.38 g/dl; α-2 globulin, 0.17-0.67 g/dl; β globulin, 0.38-1.33 g/dl; γ globulin, 0.26-0.68 g/dl; albumin : globulin ratio, 0.93-2.17. As captive flamingos often suffer from pododermatitis, feet of all flamingos were scored to determine if pododermatitis would be reflected in the acute phase proteins. Spearman rank correlation was performed on each of the protein fractions and pododermatitis scores, and only albumin had a significant correlation. This indicates that albumin, as a negative acute phase protein, may be a marker for this disease process.

  17. Acute-phase responses vary with pathogen identity in house sparrows (Passer domesticus).

    PubMed

    Coon, Courtney A C; Warne, Robin W; Martin, Lynn B

    2011-06-01

    Pathogens may induce different immune responses in hosts contingent on pathogen characteristics, host characteristics, or interactions between the two. We investigated whether the broadly effective acute-phase response (APR), a whole body immune response that occurs in response to constitutive immune receptor activation and includes fever, secretion of immune peptides, and sickness behaviors such as anorexia and lethargy, varies with pathogen identity in the house sparrow (Passer domesticus). Birds were challenged with a subcutaneous injection of either a glucan at 0.7 mg/kg (to simulate fungal infection), a synthetic double-stranded RNA at 25 mg/kg (to simulate viral infection), or LPS at 1 mg/kg (to simulate a gram-negative bacterial infection), and then body mass, core body temperature changes, sickness behaviors, and secretion of an acute-phase protein, haptoglobin, were compared. Despite using what are moderate-to-high pyrogen doses for other vertebrates, only house sparrows challenged with LPS showed measurable APRs. Febrile, behavioral, and physiological responses to fungal and viral mimetics had minimal effects.

  18. Neurohormonal activation in ischemic stroke: effects of acute phase disturbances on long-term mortality.

    PubMed

    Anne, Mäkikallio; Juha, Korpelainen; Timo, Mäkikallio; Mikko, Tulppo; Olli, Vuolteenaho; Kyösti, Sotaniemi; Heikki, Huikuri; Vilho, Myllylä

    2007-08-01

    A stress response consisting of elevated levels of cortisol and catecholamines is common after acute stroke. The plasma levels of natriuretic peptides are known to be elevated after ischemic stroke, but the relations of these neurohormonal systems in the acute phase of stroke and their impact on long-term prognosis have not been studied previously. A series of 51 consecutive patients (mean age 68+/-11 years) with an ischemic first-ever stroke underwent a comprehensive clinical investigation, scoring of their neurologic deficit by Scandinavian Stroke Scale (SSS), Barthel Index (BI) and Modified Ranking Scale (MRS) as well as measurements of plasma cortisol, norepinephrine, epinephrine, ACTH and atrial (N-ANP) and brain (N-BNP) natriuretic peptides on the 2nd and 7th days after ischemic stroke. The patients were followed up for 44+/-21 months. Higher levels of cortisol, ACTH and natriuretic peptides were observed in the stroke patients who died (n=22) during the follow-up than in the stroke survivors. Cortisol levels associated significantly with the 2nd and 7th day N-ANP and N-BNP levels, catecholamine levels (r= 0.55 - 0.94, p<0.01 for all) and measures of neurologic deficit (r= 0.36 - -0.44, p<0.05). High acute phase cortisol levels assessed either in the morning (RR=5.4, p<0.05) or in the evening (RR=5.8, p<0.05) predicted long-term mortality after stroke in multivariate analysis. Activation of the hypothalamus-pituitary-adrenal axis in ischemic stroke is associated with elevated levels of natriuretic peptides. High cortisol and natriuretic peptide values predict long-term mortality after ischemic stroke, suggesting that this profound neurohumoral disturbance is prognostically unfavourable.

  19. Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington's disease.

    PubMed

    Bouwens, J A; Hubers, A A M; van Duijn, E; Cobbaert, C M; Roos, R A C; van der Mast, R C; Giltay, E J

    2014-08-01

    Activation of the innate immune system has been postulated in the pathogenesis of Huntington's disease (HD). We studied serum concentrations of C-reactive protein (CRP) and low albumin as positive and negative acute-phase proteins in HD. Multivariate linear and logistic regression was used to study the association between acute-phase protein levels in relation to clinical, neuropsychiatric, cognitive, and psychotropic use characteristics in a cohort consisting of 122 HD mutation carriers and 42 controls at first biomarker measurement, and 85 HD mutation carriers and 32 controls at second biomarker measurement. Significant associations were found between acute-phase protein levels and Total Functioning Capacity (TFC) score, severity of apathy, cognitive impairment, and the use of antipsychotics. Interestingly, all significant results with neuropsychiatric symptoms disappeared after additional adjusting for antipsychotic use. High sensitivity CRP levels were highest and albumin levels were lowest in mutation carriers who continuously used antipsychotics during follow-up versus those that had never used antipsychotics (mean difference for CRP 1.4 SE mg/L; P=0.04; mean difference for albumin 3 SE g/L; P<0.001). The associations found between acute-phase proteins and TFC score, apathy, and cognitive impairment could mainly be attributed to the use of antipsychotics. This study provides evidence that HD mutation carriers who use antipsychotics are prone to develop an acute-phase response.

  20. Current status of gene expression profiling in the diagnosis and management of acute leukaemia.

    PubMed

    Bacher, Ulrike; Kohlmann, Alexander; Haferlach, Torsten

    2009-06-01

    Gene expression profiling (GEP) enables the simultaneous investigation of the expression of tens of thousands of genes and was successfully introduced in leukaemia research a decade ago. Aiming to better understand the diversity of genetic aberrations in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), pioneer studies investigated and confirmed the predictability of many cytogenetic and molecular subclasses in AML and ALL. In addition, GEP can define new prognostic subclasses within distinct leukaemia subgroups, as illustrated in AML with normal karyotype. Another approach is the development of treatment-specific sensitivity assays, which might contribute to targeted therapy studies. Finally, GEP might enable the detection of new molecular targets for therapy in patients with acute leukaemia. Meanwhile, large multicentre studies, e.g. the Microarray Innovations in LEukaemia (MILE) study, prepare for a standardised introduction of GEP in leukaemia diagnostic algorithms, aiming to translate this novel methodology into clinical routine for the benefit of patients with the complex disorders of AML and ALL.

  1. Microarray and functional analysis of growth phase-dependent gene regulation in Bordetella bronchiseptica.

    PubMed

    Nicholson, Tracy L; Buboltz, Anne M; Harvill, Eric T; Brockmeier, Susan L

    2009-10-01

    Growth phase-dependent gene regulation has recently been demonstrated to occur in Bordetella pertussis, with many transcripts, including known virulence factors, significantly decreasing during the transition from logarithmic to stationary-phase growth. Given that B. pertussis is thought to have derived from a Bordetella bronchiseptica-like ancestor, we hypothesized that growth phase-dependent gene regulation would also occur in B. bronchiseptica. Microarray analysis revealed and quantitative real-time PCR (qRT-PCR) confirmed that growth phase-dependent gene regulation occurs in B. bronchiseptica, resulting in prominent temporal shifts in global gene expression. Two virulence phenotypes associated with these gene expression changes were tested. We found that growth-dependent increases in expression of some type III secretion system (TTSS) genes led to a growth phase-dependent increase in a TTSS-dependent function, cytotoxicity. Although the transcription of genes encoding adhesins previously shown to mediate adherence was decreased in late-log and stationary phases, we found that the adherence of B. bronchiseptica did not decrease in these later phases of growth. Microarray analysis revealed and qRT-PCR confirmed that growth phase-dependent gene regulation occurred in both Bvg(+) and Bvg(-) phase-locked mutants, indicating that growth phase-dependent gene regulation in B. bronchiseptica can function independently from the BvgAS regulatory system.

  2. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.

    PubMed

    Yeoh, Eng-Juh; Ross, Mary E; Shurtleff, Sheila A; Williams, W Kent; Patel, Divyen; Mahfouz, Rami; Behm, Fred G; Raimondi, Susana C; Relling, Mary V; Patel, Anami; Cheng, Cheng; Campana, Dario; Wilkins, Dawn; Zhou, Xiaodong; Li, Jinyan; Liu, Huiqing; Pui, Ching-Hon; Evans, William E; Naeve, Clayton; Wong, Limsoon; Downing, James R

    2002-03-01

    Treatment of pediatric acute lymphoblastic leukemia (ALL) is based on the concept of tailoring the intensity of therapy to a patient's risk of relapse. To determine whether gene expression profiling could enhance risk assignment, we used oligonucleotide microarrays to analyze the pattern of genes expressed in leukemic blasts from 360 pediatric ALL patients. Distinct expression profiles identified each of the prognostically important leukemia subtypes, including T-ALL, E2A-PBX1, BCR-ABL, TEL-AML1, MLL rearrangement, and hyperdiploid >50 chromosomes. In addition, another ALL subgroup was identified based on its unique expression profile. Examination of the genes comprising the expression signatures provided important insights into the biology of these leukemia subgroups. Further, within some genetic subgroups, expression profiles identified those patients that would eventually fail therapy. Thus, the single platform of expression profiling should enhance the accurate risk stratification of pediatric ALL patients.

  3. Gene Signature of High White Blood Cell Count in B-Precursor Acute Lymphoblastic Leukemia.

    PubMed

    Edwards, Holly; Rubenstein, Mara; Dombkowski, Alan A; Caldwell, J Timothy; Chu, Roland; Xavier, Ana C; Thummel, Ryan; Neely, Melody; Matherly, Larry H; Ge, Yubin; Taub, Jeffrey W

    2016-01-01

    In this study we sought to identify genetic factors associated with the presenting white blood cell (WBC) count in B-precursor acute lymphoblastic leukemia (BP-ALL). Using ETV6-RUNX1-positive BP-ALL patient samples, a homogeneous subtype, we identified 16 differentially expressed genes based on the presenting WBC count (< 50,000/cumm vs > 50,000). We further confirmed that IL1R1, BCAR3, KCNH2, PIR, and ZDHHC23 were differentially expressed in a larger cohort of ETV6-RUNX1-negative BP-ALL patient samples. Statistical analysis demonstrated that expression levels of these genes could accurately categorize high and low WBC count subjects using two independent patient sets, representing positive and negative ETV6-RUNX1 cases. Further studies in leukemia cell line models will better delineate the role of these genes in regulating the white blood cell count and potentially identify new therapeutic targets.

  4. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure.

    PubMed

    Shannahan, Jonathan H; Alzate, Oscar; Winnik, Witold M; Andrews, Debora; Schladweiler, Mette C; Ghio, Andrew J; Gavett, Stephen H; Kodavanti, Urmila P

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA.

  5. [Acute-phase proteins in the saliva of workers engaged in processing natural gas and condensate high in hydrogen sulfide].

    PubMed

    Boĭko, V I; Dotsenko, Iu I; Boĭko, O V

    2011-06-01

    The paper considers current methods for assessing the workers' health status. It shows it possible to identify increased quantities of acute-phase serum proteins upon exposure to the negative factors characteristic of the Astrakhan gas processing plant. A wider range of tests for acute-phase tissue and serum proteins is proposed to be included in order to gain a fuller insight into the influence of unfavorable industrial factors on man and to make monitoring that enables the existing health risks and the efficiency of preventive measures to be controlled.

  6. Effective factors on linguistic disorder during acute phase following traumatic brain injury in adults.

    PubMed

    Chabok, Shahrokh Yousefzadeh; Kapourchali, Sara Ramezani; Leili, Ehsan Kazemnezhad; Saberi, Alia; Mohtasham-Amiri, Zahra

    2012-06-01

    Traumatic brain injury (TBI) has been known to be the leading cause of breakdown and long-term disability in people under 45 years of age. This study highlights the effective factors on post-traumatic (PT) linguistic disorder and relations between linguistic and cognitive function after trauma in adults with acute TBI. A cross-sectional design was employed to study 60 post-TBI hospitalized adults aged 18-65 years. Post-traumatic (PT) linguistic disorder and cognitive deficit after TBI were respectively diagnosed using the Persian Aphasia Test (PAT) and Persian version of Mini-Mental State Examination (MMSE) at discharge. Primary post-resuscitation consciousness level was determined using the Glasgow Coma Scale (GCS). Paracilinical data was obtained by CT scan technique. Multiple logistic regression analysis illustrated that brain injury severity was the first powerful significant predictor of PT linguistic disorder after TBI and frontotemporal lesion was the second. It was also revealed that cognitive function score was significantly correlated with score of each language skill except repetition. Subsequences of TBI are more commonly language dysfunctions that demand cognitive flexibility. Moderate, severe and fronto-temporal lesion can increase the risk of processing deficit in linguistic macrostructure production and comprehension. The dissociation risk of cortical and subcortical pathways related to cognitive-linguistic processing due to intracranial lesions can augment possibility of lexical-semantic processing deficit in acute phase which probably contributes to later cognitive-communication disorder.

  7. The cerebrovascular CO2 reactivity during the acute phase of brain injury.

    PubMed

    Cold, G E; Jensen, F T; Malmros, R

    1977-01-01

    Using the intra-arterial 133xenon (133Xe) method, the cerebrovascular response to acute Paco2 reduction was studied in 26 unconscious, brain-injured patients subjected to controlled ventilation. The CO2 reactivity was calculated as delta in CBF/delta Paco2. The perfusion pressure was defined as the difference between mean arterial pressure and mean intraventricular pressure. Although the CO2 reactivities did not differ significantly from that in awake, normocapnic subjects, it was low in the acute phase of injury, especially in those patients with severe outcome in whom the brain-stem reflexes were often affected. An increase of the CO2 reactivity with time was observed, indicating normal response after 1-2 weeks. Chronic hypocapnia in six unconscious patients resulted in sustained CSF pH adaptation. The question whether a delay in CSF pH adapation exerts an influence on the CO2 reactivity, and the influence of cerebral lactacidosis on the CO2 response are discussed.

  8. [Acute phase reaction of different macromolecule vascular grafts healing in rat muscle].

    PubMed

    Wang, Weici; Jin, Bi; Ouyang, Chenxi; Li, Yiqing; Xu, Weilin; Yang, Hongjun; Xu, Haiye

    2010-01-01

    To find out which biomaterial had the best biocompatibility, we compared the acute phase reaction of common biomaterials preparing for vascular grafts with the material of polyurethane modified by silk fibroin (SF-PU(1:1)). After transplanted the materials of dacron, polyterafluoroethylene (e-PTFE), polyurethane (PU), SF-PU(1:1) in rat muscle for one week, we studied the influence of different biomaterials on the histocompatibility by using rat acute toxicity test, test of local reaction in muscle, tissue section staining, WBC and PLT count. As a result, dacron had the worst histocompatibility. The other biomaterials had slight local inflammatory reaction. The WBC and PLT was nearly the same with the blank except dacron. e-PTFE, pure PU and SF-PU(1:1) had the better histocompatibility than traditional dacron. Especially SF-PU(1:1) had the best histocompatibility. Because of the better physical properties and histocompatibility of SF-PU( 1:1), the prospect of preparing small-diameter vascular grafts with SF-PU was cheerful.

  9. Telemedicine in Acute-Phase Injury Management: A Review of Practice and Advancements

    PubMed Central

    Lewis, Erin R.; Thomas, Carlos A.; Mbarika, Victor W.A.

    2012-01-01

    Abstract Objectives: To offer a systematic review of the body of literature in the emerging field of telemedicine in the management of acute-phase injuries. Materials and Methods: We conducted a literature review. Results: Telemedicine has only recently been applied to the specialties of trauma, emergency care, and surgery. The potential benefits of telemedicine include a decrease in travel expenses, enhanced continuity of care, and increased access to specialized consultants in medically underserved and rural areas. Conclusions: There still exist barriers to the use of teletechnologies in medicine that limit their wider adoption. Poor infrastructure, limited equipment availability, and insufficient access to training and education for medical personnel have prevented wider use. PMID:22694296

  10. Body composition and phase angle in Russian children in remission from acute lymphoblastic leukemia

    NASA Astrophysics Data System (ADS)

    Tseytlin, G. Ja; Khomyakova, I. A.; Nikolaev, D. V.; Konovalova, M. V.; Vashura, A. Yu; Tretyak, A. V.; Godina, E. Z.; Rudnev, S. G.

    2010-04-01

    Elevated degree of body fatness and changes in other body composition parameters are known to be common effects of treatment for acute lymphoblastic leukemia (ALL) in children. In order to study peculiarities of somatic growth and development in ALL survivors, we describe the results of BIA body composition analysis of 112 boys and 108 girls aged 5-18 years in remission from ALL (remission time range 1-13 years) compared to data from the same number of age- and sex-matched healthy controls (n=220). Detrimental effect on height in ALL boys was observed, whereas girls experienced additional weight gain compared to healthy subjects. In ALL patients, resistance, body fat, and percent body fat were significantly increased. The reactance, phase angle, absolute and relative values of skeletal muscle and body cell mass were significantly decreased. Principal component analysis revealed an early prevalence of adiposity traits in the somatic growth and development of ALL girls compared to healthy controls.

  11. Acupuncture as a primary and independent treatment in the acute phases of sudden sensorineural hearing loss

    PubMed Central

    Jin, Yuanyuan; Lu, Ming

    2016-01-01

    Abstract Sudden sensorineural hearing loss (SSHL) is an otological emergency defined as a rapid hearing loss, seriously affects patient's social life. To data, no study has reported the treatment by acupuncture alone in the acute phase. In this report, Acupuncture and Moxibustion therapy of excitation-focus transfer is outlined. The patient was a 26-year-old young woman who had an SSHL coupled with ear fullness. The patient had no past medical history, but she had undergone variable emotions and had a history of excessive noise exposure. The patient refused to receive any medicine especially steroids and hyperbaric oxygen therapy. She just only received acupuncture treatment. Her symptoms and outcome measurements were improved every week and completely recovered after the last week. Even though the article presents a single case and is based on self-reports, there are very clear trends on how patients with SSHL responded to acupuncture treatments. PMID:27368045

  12. Dynamics of cellular immune responses in the acute phase of dengue virus infection.

    PubMed

    Yoshida, Tomoyuki; Omatsu, Tsutomu; Saito, Akatsuki; Katakai, Yuko; Iwasaki, Yuki; Kurosawa, Terue; Hamano, Masataka; Higashino, Atsunori; Nakamura, Shinichiro; Takasaki, Tomohiko; Yasutomi, Yasuhiro; Kurane, Ichiro; Akari, Hirofumi

    2013-06-01

    In this study, we examined the dynamics of cellular immune responses in the acute phase of dengue virus (DENV) infection in a marmoset model. Here, we found that DENV infection in marmosets greatly induced responses of CD4/CD8 central memory T and NKT cells. Interestingly, the strength of the immune response was greater in animals infected with a dengue fever strain than in those infected with a dengue hemorrhagic fever strain of DENV. In contrast, when animals were re-challenged with the same DENV strain used for primary infection, the neutralizing antibody induced appeared to play a critical role in sterilizing inhibition against viral replication, resulting in strong but delayed responses of CD4/CD8 central memory T and NKT cells. The results in this study may help to better understand the dynamics of cellular and humoral immune responses in the control of DENV infection.

  13. Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets

    PubMed Central

    Cafaro, Caterina; Nadeem, Aftab; Butler, Daniel S. C.; Rydström, Gustav; Filenko, Nina A.; Wullt, Björn; Miethke, Thomas; Svanborg, Catharina

    2016-01-01

    Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. Trial Registration The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www

  14. Pituitary dysfunction in traumatic brain injury: Is evaluation in the acute phase worthwhile?

    PubMed Central

    Dalwadi, Pradip P.; Bhagwat, Nikhil M.; Tayde, Parimal S.; Joshi, Ameya S.; Varthakavi, Premlata K.

    2017-01-01

    Introduction: Traumatic brain injury (TBI) is an under-recognized cause of hypopituitarism. According to recent data, it could be more frequent than previously known. However, there is a scarcity of data in Indian population. Aims: The main aim of the study was to determine the prevalence of pituitary hormone deficiencies in the acute phase of TBI. The secondary objectives were to correlate the severity of trauma with basal hormone levels and to determine whether initial hormone deficiencies predict mortality. Subjects and Methods: Forty-nine TBI patients (41 men and 8 women) were included in this study. Pituitary functions were evaluated within 24 h of admission. Results: Gonadotropin deficiency was found in 65.3% patient while 46.9% had low insulin-like growth factor-1, 12.24% had cortisol level <7 mcg/dl. Cortisol and prolactin level were positively correlated with the severity of TBI suggestive of stress response. Free triiodothyronine (fT3) and free thyroxine were significantly lower in patients with increasing severity of tuberculosis. Logistic regression analysis revealed that mortality after TBI was unrelated to the basal pituitary hormone levels except low T3 level, which was found to be positively related to mortality. Conclusions: Pituitary dysfunction is common after TBI and the most commonly affected axes are growth hormone and gonadotropin axis. Low fT3 correlates best with mortality. During the acute phase of TBI, at least an assessment of cortisol is vital as undetected cortisol deficiency can be life-threatening PMID:28217503

  15. Effects of competition on acute phase proteins and lymphocyte subpopulations - oxidative stress markers in eventing horses.

    PubMed

    Valle, E; Zanatta, R; Odetti, P; Traverso, N; Furfaro, A; Bergero, D; Badino, P; Girardi, C; Miniscalco, B; Bergagna, S; Tarantola, M; Intorre, L; Odore, R

    2015-10-01

    The aim of the study was to evaluate markers of the acute phase response (APR) in eventing horses by measuring acute phase proteins (APP) (haptoglobin, Hp, and serum amyloid A, SAA), lysozyme, protein adducts such as pentosidine-like adducts (PENT), malondialdehyde adducts (MDA), hydroxynonenal adducts (HNE) and total advanced glycation/glycoxidation end products (AGEs), complete blood count and lymphocyte subpopulations (CD4+, CD8+ and CD21+) both at rest and at the end of an eventing competition. Blood samples were collected from eight Warmblood horses (medium age 10 ± 3) during an official national 2-day event competition at rest (R) and 10 min after the arrival of the cross-country test on the second day. Exercise caused a significant increase in red blood cell number, haemoglobin, packed cell volume, neutrophils, white blood cell and lymphocyte number; however, these values remained within the normal range. The CD4+ and CD8+ cells significantly increased, whereas the CD21+ lymphocytes decreased; a significant increase in serum SAA, lysozyme and protein carbonyl derivates was also observed. Two-day event causes significant changes in APR markers such as lysozyme, protein carbonyl derivates (HNE, AGEs, PENT) and lymphocyte subpopulations. The data support the hypothesis that 2-day event may alter significantly APR markers. Limitations of the study were the relatively small sample size and sampling time conditioned by the official regulations of the event. Therefore, further studies are needed to investigate the time required for recovery to basal values in order to define the possible effects on the immune function of the athlete horse.

  16. Serotonergic genes and depressive disorder in acute coronary syndrome: The Korean depression in ACS (K-DEPACS) study.

    PubMed

    Kim, Jae-Min; Stewart, Robert; Kang, Hee-Ju; Bae, Kyung-Yeol; Kim, Sung-Wan; Shin, Il-Seon; Hong, Young Joon; Ahn, Youngkeun; Jeong, Myung Ho; Park, Sung-Woo; Kim, Young-Hoon; Yoon, Jin-Sang

    2015-06-01

    Genes coding for the serotonergic pathway have been associated with depressive disorders. However, these associations have rarely been tested in acute coronary syndrome (ACS) patients vulnerable to depression. This study aimed to investigate whether polymorphisms of serotonin transporter (5-HTT) and serotonin 2a receptor (5-HTR2a) genes are associated with occurrence of depressive disorder in ACS. 969 patients with recently developed ACS were recruited at baseline, and 711 were followed 1 year thereafter. Depressive disorder was diagnosed according to DSM-IV criteria, and analysed as an outcome at baseline (prevalence), and follow up (incidence and persistence). Genotypes were ascertained for 5-HTTLPR, STin2 VNTR, 5-HTR2a 102T/C, and 5-HTR2a 1438A/G. Logistic regression models were used to investigate associations. The 5-HTTLPR s/s genotype was independently associated with depressive disorder prevalence and persistence following ACS, but no significant associations were found with the other polymorphisms. ACS patients with the 5-HTTLPR s allele are thus potentially susceptible to depressive disorder in the early phase after ACS, and with its persistence over the subsequent year.

  17. Use of a 15 k gene microarray to determine gene expression changes in response to acute and chronic methylmercury exposure in the fathead minnow Pimephales promelas Rafinesque

    USGS Publications Warehouse

    Klaper, R.; Carter, Barbara J.; Richter, C.A.; Drevnick, P.E.; Sandheinrich, M.B.; Tillitt, D.E.

    2008-01-01

    This study describes the use of a 15 000 gene microarray developed for the toxicological model species, Pimephales promelas, in investigating the impact of acute and chronic methylmercury exposures in male gonad and liver tissues. The results show significant differences in the individual genes that were differentially expressed in response to each treatment. In liver, a total of 650 genes exhibited significantly (P < 0.05) altered expression with greater than two-fold differences from the controls in response to acute exposure and a total of 267 genes were differentially expressed in response to chronic exposure. A majority of these genes were downregulated rather than upregulated. Fewer genes were altered in gonad than in liver at both timepoints. A total of 212 genes were differentially expressed in response to acute exposure and 155 genes were altered in response to chronic exposure. Despite the differences in individual genes expressed across treatments, the functional categories that altered genes were associated with showed some similarities. Of interest in light of other studies involving the effects of methylmercury on fish, several genes associated with apoptosis were upregulated in response to both acute and chronic exposures. Induction of apoptosis has been associated with effects on reproduction seen in the previous studies. This study demonstrates the utility of microarray analysis for investigations of the physiological effects of toxicants as well as the time-course of effects that may take place. In addition, it is the first publication to demonstrate the use of this new 15 000 gene microarray for fish biology and toxicology. ?? 2008 The Authors.

  18. Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice

    SciTech Connect

    Yin Huquan; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2007-09-15

    Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p < 0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayed {>=} 2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1.

  19. Acute-phase response to benzo[a]pyrene and induction of rat ALDH3A1.

    PubMed

    Pappas, Periklis; Sotiropoulou, Marianthi; Karamanakos, Petros; Kostoula, Aggeliki; Levidiotou, Stamatia; Marselos, Marios

    2003-02-01

    The aldehyde dehydrogenase-3A1 (ALDH3A1) enzyme, encoded by a member of the [Ah]-gene family, is dramatically increased (more than 100-fold) by benzo[a]pyrene (BaP) and other polycyclic hydrocarbons. Although much is known regarding the mechanism for the drug-metabolizing enzymes up-regulated by the Ah receptor, the physiological role of that tremendously increased ALDH3A1 enzyme activity is not yet fully clarified. The aim of this study was to identify a possible acute-phase response to different classes of xenobiotics affecting the metabolic capacity of the hepatocyte, by studying possible changes of serum acute-phase proteins (APPs) of hepatic origin, before and after BaP administration. Male Wistar rats were used in different series of experiments. The effects of BaP were estimated in terms of dose-response and time-response, with regard to the serum level of several APPs such as alpha-1-acid-glycoprotein (AAG), alpha-1-antitrypsin (AAT), C-reactive protein (CRP), and haptoglobin (HPT). In parallel experiments, levels of the same proteins have been determined after a time-dependent treatment with lipopolysaccharide (LPS). The changes in serum proteins were compared with the results of BaP or LPS administration on both hepatic ALDH3A1 and total ALDH enzyme activities. The results showed that BaP induced CRP and HPT in a time-dependent way, proportional to that caused by LPS. Additionally, ALDH3A1, CRP, and HPT were induced by BaP subacute treatment, whereas another type of ALDH inducer, phenobarbital, did not affect the levels of APPs or ALDH3A1, but did increase ALDH1A3 activity. Former studies of our group have shown that the inhibitory effects of different non-steroidal anti-inflammatory drugs (NSAIDs) on the ALDH3A1 induction were most possibly due to a decreased formation of arachidonic products like prostaglandins. Considering the changes of APPs caused by BaP, this study further supports the suggestion that the induction of ALDH3A1 is related to an

  20. Minimal residual disease detection in Tunisian B-acute lymphoblastic leukemia based on immunoglobulin gene rearrangements

    PubMed Central

    Besbes, S.; Hamadou, W.S.; Boulland, M.L.; Youssef, Y.B.; Achour, B.; Regaieg, H.; Khelif, A.; Fest, T.; Soua, Z.

    2017-01-01

    IGH gene rearrangement and IGK-Kde gene deletion can be used as molecular markers for the assessment of B lineage acute lymphoblastic leukemia (B-ALL). Minimal residual disease detected based on those markers is currently the most reliable prognosis factor in B-ALL. The aim of this study was to use clonal IGH/IGK-Kde gene rearrangements to confirm B-ALL diagnosis and to evaluate the treatment outcome of Tunisian leukemic patients by monitoring the minimal residual disease (MRD) after induction chemotherapy. Seventeen consecutive newly diagnosed B-ALL patients were investigated by multiplex PCR assay and real time quantitative PCR according to BIOMED 2 conditions. The vast majority of clonal VH-JH rearrangements included VH3 gene. For IGK deletion, clonal VK1f/6-Kde recombinations were mainly identified. These rearrangements were quantified to follow-up seven B-ALL after induction using patient-specific ASO. Four patients had an undetectable level of MRD with a sensitivity of up to 10-5. This molecular approach allowed identification of prognosis risk group and adequate therapeutic decision. The IGK-Kde and IGH gene rearrangements might be used for diagnosis and MRD monitoring of B-ALL, introduced for the first time in Tunisian laboratories. PMID:28099581

  1. Identification of Differentially Expressed Genes Associated with Prognosis of B Acute Lymphoblastic Leukemia

    PubMed Central

    Jaime-Perez, Jose Carlos; Carrillo-Sanchez, Karol; Ramos-Del Hoyo, Maria Guadalupe; Lugo-Trampe, Angel; Gutierrez-Aguirre, Cesar Homero; Gonzalez-Llano, Oscar; Salazar-Riojas, Rosario; Hidalgo-Miranda, Alfredo; Gomez-Almaguer, David

    2015-01-01

    Background. Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder with high mortality rates. The aim of this study was to validate the expression profile of 45 genes associated with signaling pathways involved in leukemia and to evaluate their association with the prognosis of B-ALL. Methods. 219 samples of peripheral blood mononuclear cells obtained from 73 B-ALL patients were studied at diagnosis, four, and eight weeks after starting treatment. Gene expression was analyzed by quantitative real-time polymerase chain reaction. Results. Normalized delta Cq values of 23 genes showed differences between B-ALL and controls at diagnosis time (P values < 0.05). There were significant associations between B-ALL patients relapse/death and the expression levels of IL2RA, SORT1, DEFA1, and FLT3 genes at least in one of the times evaluated (P values < 0.05 and odds ratio ranges: 3.73–27). The association between FLT3 deregulation and relapse/death was a constant in the times studied and their overexpression significantly increased the odds of relapse/death in a range of 3.73 and 6.05 among study population (P values < 0.05). Conclusions. Overexpression of FLT3 and DEFA1 genes retained independent prognostic significance for B-ALL outcome, reflected as increased risks of relapse/death among the study population. PMID:25802479

  2. [Analysis of gene expression and DNA methylation patterns in childhood acute lymphoblastic leukemia].

    PubMed

    Iijima, Kazutoshi; Kiyokawa, Nobutaka

    2016-04-01

    The 5-year survival rate of patients with childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) now exceeds 90%, though there are still patients who fail to achieve remission or relapse early. To improve the outcomes of these cases, new diagnostic markers for stratification of those with unfavorable outcomes and novel targets for treatment have been investigated based on data from the OMICs analysis. We performed gene expression analysis of leukemic cells from 91 near-diploid BCP-ALL cases without specific fusion genes enrolled in Tokyo Children's Cancer Study Group (TCCSG)-L0416 & L0616 clinical trials employing the Affymetrix Human Genome U133 Plus 2.0 Array. Among them, DNA methylation status was analyzed in 24 cases by using the Infinium HumanMethylation450 BeadChip. Herein, initially, the current situations of gene expression analysis and DNA methylation analysis of childhood BCP-ALL are reviewed. Then, our analyses of gene expressions and DNA methylation related to the prognosis of childhood ALL without fusion genes are presented.

  3. Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2[S

    PubMed Central

    Annema, Wijtske; Nijstad, Niels; Tölle, Markus; de Boer, Jan Freark; Buijs, Ruben V. C.; Heeringa, Peter; van der Giet, Markus; Tietge, Uwe J. F.

    2010-01-01

    Atherosclerosis is linked to inflammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol efflux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute inflammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [3H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol efflux toward plasma and HDL were significantly decreased (P < 0.001). In mice, acute inflammation (75 µg/mouse lipopolysaccharide) decreased [3H]cholesterol appearance in plasma (P < 0.05) and tracer excretion into feces both within bile acids (−84%) and neutral sterols (−79%, each P < 0.001). In the absence of systemic inflammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT (P < 0.05), whereas secretory phospholipase A2 (sPLA2, transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma (P < 0.05) as well as RCT (−36%, P < 0.05). Hepatic expression of bile acid synthesis genes (P < 0.01) and transporters mediating biliary sterol excretion (P < 0.01) was decreased by inflammation. In conclusion, our data demonstrate that acute inflammation impairs cholesterol efflux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during inflammation but not sPLA2. However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in inflammation. PMID:20061576

  4. DO ACUTE PHASE PROTEINS REFLECT SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

    EPA Science Inventory

    Title: DO ACUTE PHASE PROTEINS REFLECT THE SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

    M. C. Schladweiler, BS 1, P. S. Gilmour, PhD 2, D. L. Andrews, BS 1, D. L. Costa, ScD 1, A. D. Ledbetter, BS 1, K. E. Pinkerton, PhD 3 and U. P. Kodavanti, ...

  5. Acute-phase protein concentration and metabolic status affect the outcome of treatment in cows with clinical and subclinical endometritis.

    PubMed

    Heidarpour, M; Mohri, M; Fallah-Rad, A H; Dehghan Shahreza, F; Mohammadi, M

    2012-09-01

    The aim of this study was to investigate the role of acute-phase protein concentration and metabolic status in the establishment and resistance of clinical endometritis (CE) and subclinical endometritis (SE) in dairy cows. We also characterised the treatment-related changes in the concentration of acute-phase proteins and metabolic variables in dairy cows affected by CE and SE. Cows of the SE and CE groups presented a significantly higher β-hydroxybutyrate (BHB), haptoglobin and total sialic acid (TSA) concentrations compared with a healthy group of animals. A significantly lower serum calcium concentration, and a significantly higher serum aspartate aminotransferase activity in the CE group, were observed when compared with SE and healthy groups. The comparison of parameters before treatment indicated that cows suffering from CE or SE with lower concentrations of hepatic and inflammatory markers showed a better response to further treatment, and endometritis was not detected in the second examination. Moreover, decreased concentrations of BHB, acute-phase proteins and hepatic markers were observed after successful treatment for endometritis in CE and SE cows. The results obtained in this study suggest that improved liver function and a decrease in the acute-phase protein concentration might favour the resolution of endometritis after treatment.

  6. The acute phase inflammatory response to maximal exercise testing in children and young adults with sickle cell anaemia.

    PubMed

    Liem, Robert I; Onyejekwe, Kasiemobi; Olszewski, Marie; Nchekwube, Chisalu; Zaldivar, Frank P; Radom-Aizik, Shlomit; Rodeghier, Mark J; Thompson, Alexis A

    2015-12-01

    Although individuals with sickle cell anaemia (SCA) have elevated baseline inflammation and endothelial activation, the acute phase response to maximal exercise has not been evaluated among children with SCA. We measured the acute phase response to maximal exercise testing for soluble vascular cell adhesion molecule (sVCAM) as well as interleukin 6 (IL6), total white blood cell (WBC) count, C-reactive protein (CRP) and D-dimer in a cohort of children with SCA and matched controls at baseline, immediately after, and 30, 60 and 120 min following exercise. Despite higher baseline levels of all biomarkers except CRP, the acute phase response from baseline to immediately after exercise was significantly greater in subjects versus controls for CRP (2·1 vs. 0·2 mg/l, P = 0·02) and D-dimer (160 vs. 10 μg/l, P < 0·01) only. Similar between-group trends were observed over time for all biomarkers, including sVCAM, IL6, total WBC, CRP and D-dimer. Lower fitness, defined by peak oxygen consumption (VO2 ), was independently associated with greater acute phase responses to exercise for sVCAM. Our results suggest maximal exercise may not be associated with any greater escalation of endothelial activation or inflammation in SCA and provide preliminary biomarker evidence for the safety of brief, high-intensity physical exertion in children with SCA.

  7. Prenatal transportation alters the acute phase response (APR) of bull calves exposed to a lipopolysaccharide (LPS) challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine if prenatal transportation influences the acute phase response (APR) to a postnatal Lipopolysaccharide (LPS) challenge. Pregnant Brahman cows (n=96) matched by age and parity were separated into transported (TRANS; n=48; transported for 2 hours on gestational day...

  8. Supplementation of Lactobacillus acidophilus fermentation product can attenuate the acute phase response following a lipopolysaccharide challenge in pigs.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine if feeding a Lactobacillus acidophilus fermentation product to weaned pigs would reduce stress and acute phase responses (APR) following a lipopolysaccharide (LPS) challenge. Pigs (n=30; 6.4±0.1 kilograms body weight) were housed individually in pens with ad libi...

  9. Yeast cell wall supplementation alters the physiological and acute phase responses of crossbred heifers to an endotoxin challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study was conducted to determine the effect of feeding yeast cell wall (YCW) products on the physiological and acute phase responses of crossbred newly-received heifers to an endotoxin challenge. Heifers (n = 24; 219 ± 2.4 kg) were separated into treatment groups receiving a Control diet (n = 8), ...

  10. The effect of yeast cell wall supplementation on the physiological and acute phase responses of crossbred heifers to endotoxin challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study was conducted to determine the effect of feeding yeast cell wall (YCW) products on the physiological and acute phase responses of crossbred newly-received heifers to endotoxin (lipopolysaccharide; LPS) challenge. Heifers (n=24; 218.9+/-2.4 kg) were obtained from commercial sale barns and tra...

  11. OmniGen-AF supplementation modulated the physiological and acute phase responses of Brahman heifers to an endotoxin challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study examined the effect of feeding OmniGen-AF (OG; Prince Agri Products) on the physiological and acute phase responses (APR) of newly-weaned heifers to an endotoxin (lipopolysaccharide; LPS) challenge. Brahman heifers (n=24; 183±5 kilograms) from the Texas AgriLife Research Center in Overton...

  12. Dried citrus pulp modulates the physiological and acute phase responses of crossbred heifers to an endotoxin challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study examined the effect of feeding dried citrus pulp (CP) pellets on the physiological and acute phase responses (APR) of newly-received crossbred heifers to an endotoxin (lipopolysaccharide; LPS) challenge. Heifers (n=24; 218.3±2.4 kg) were obtained from commercial sale barns and transported...

  13. Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia.

    PubMed

    Gomes, Rachel Novaes; Castro-Faria-Neto, Hugo C; Bozza, Patricia T; Soares, Milena B P; Shoemaker, Charles B; David, John R; Bozza, Marcelo T

    2005-12-01

    Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPS-induced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 mug of CGRP protects against a lethal dose of LPS. The CGRP-induced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-alpha and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-alpha released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.

  14. Acute exposure to 2G phase shifts the rat circadian timing system

    NASA Technical Reports Server (NTRS)

    Hoban-Higgins, T. M.; Murakami, D. M.; Tandon, T.; Fuller, C. A.

    1995-01-01

    The circadian timing system (CTS) provides internal and external temporal coordination of an animal's physiology and behavior. In mammals, the generation and coordination of these circadian rhythms is controlled by a neural pacemaker, the suprachiasmatic nucleus (SCN), located within the hypothalamus. The pacemaker is synchronized to the 24 hour day by time cures (zeitgebers) such as the light/dark cycle. When an animal is exposed to an environment without time cues, the circadian rhythms maintain internal temporal coordination, but exhibit a 'free-running' condition in which the period length is determined by the internal pacemaker. Maintenance of internal and external temporal coordination are critical for normal physiological and psychological function in human and non-human primates. Exposure to altered gravitational environments has been shown to affect the amplitude, mean, and timing of circadian rhythms in species ranging from unicellular organisms to man. However, it has not been determined whether altered gravitational fields have a direct effect on the neural pacemaker, or affect peripheral parameters. In previous studies, the ability of a stimulus to phase shift circadian rhythms was used to determine whether a stimulus has a direct effect on the neural pacemaker. The present experiment was performed in order to determine whether acute exposure to a hyperdynamic field could phase shift circadian rhythms.

  15. Involvement of activated leukocytes in the regulation of plasma levels of acute phase proteins in microgravity simulation experiments

    NASA Astrophysics Data System (ADS)

    Larina, Olga; Bekker, Anna; Turin-Kuzmin, Alexey

    2016-07-01

    Earth-based studies of microgravity effects showed the induction of the mechanisms of acute phase reaction (APR). APR comprises the transition of stress-sensitive protein kinases of macrophages and other responsive cells into the active state and the phosphorylation of transcription factors which in turn stimulate the production of acute-phase reaction cytokines. Leukocyte activation is accompanied by the acceleration of the formation of oxygen radicals which can serve a functional indice of leukocyte cell state. The series of events at acute phase response result in selective changes in the synthesis of a number of secretory blood proteins (acute phase proteins, APPs) in liver cells thus contributing the recovery of homeostasis state in the organism. Earlier experiment with head-down tilt showed the increase in plasma concentrations of two cytokine mediators of acute phase response, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) being the outcome of the activation of producer cells, foremost, leukocytes. In experiment with 4-day dry immersion chemiluminescent (ChL) reply of the whole blood samples to a test stimulus were studied along with the measurements of plasma levels of APPs, namely, alpha1-antitrypsin (alpha1-AT), alpha1-acid glycoprotein (alpha1-AGP), alpha2-macroglobulin (alpha2-M), ceruloplasmin (Cer), haptoglobin (Hp), C3-complement component (C3), C-reactive protein (CRP). Eight individuals aged 21.2 ± 3.2 years were the test subjects in the investigation. Protein studies showed a noticeable increase in the mean plasma levels of all APPs measured in experiment thus producing the evidence of the activation of acute phase response mechanisms while individual patterns revealed variability during the immersion period. The overall trends were similar to these in the previous immersion series. The augment in the strength of signal in stimulated light emission tests was higher after 1- and 2-day of immersion exposure than before the

  16. Mimicking acute and chronic stress exposure in naive beef steers alters the acute phase response (APR) associated with vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine the effect of an acute versus chronic stress model on the APR associated with vaccination in naïve beef steers. Steers (n=32; 209 +/- 8 kg) were blocked by body weight and assigned to 1 of 3 treatments: 1) Chronic stress (CHR), 0.5 mg/kg body weight dexamethasone...

  17. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.

    PubMed

    Wan, Liling; Wen, Hong; Li, Yuanyuan; Lyu, Jie; Xi, Yuanxin; Hoshii, Takayuki; Joseph, Julia K; Wang, Xiaolu; Loh, Yong-Hwee E; Erb, Michael A; Souza, Amanda L; Bradner, James E; Shen, Li; Li, Wei; Li, Haitao; Allis, C David; Armstrong, Scott A; Shi, Xiaobing

    2017-03-09

    Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.

  18. The acute phase reactant, fibrinogen, as a guide to plasma exchange therapy for acute Guillain-Barré syndrome.

    PubMed

    Sanjay, Rashmi; Flanagan, Janice; Sodano, Donata; Gorson, Kenneth C; Ropper, Allan H; Weinstein, Robert

    2006-07-01

    The Guillian Barré syndrome is an acute inflammatory disorder for which plasma exchange is effective treatment. Up to 10% relapse after plasma exchange suggesting that treatment sometimes finishes before disease activity has resolved. We studied whether plasma fibrinogen, an inflammatory marker, might be used to determine when to discontinue plasma exchange in patients with acute Guillain-Barré syndrome. We conducted a post-hoc analysis of apheresis database and hospital records of patients treated with plasma exchange for acute Guillain-Barré syndrome during 1999-2004. Data were analyzed from 28 patients who underwent a total of 29 courses of plasma exchange for acute Guillain-Barré syndrome. The mean (+/-SD) plasma fibrinogen concentration was 422.5 (+/-96.4) mg/dl at the time of presentation and, in 17 of the 29, it was above 400 mg/dl (reference range 200-400). Twenty of the 21 patients whose fibrinogen fell by more than 30% from baseline by the time of the final plasma exchange treatment had neurological improvement. There was improvement in only 3 of the 8 instances where fibrinogen decreased by less than 30% by the end of plasma exchange therapy. A > or =30% decrease in fibrinogen by the conclusion of plasma exchange was significantly associated with sustained neurological improvement (P = 0.0025). The plasma fibrinogen level appears to reflect disease activity in acute Guillain-Barré syndrome. A <30% fall in fibrinogen level despite plasma exchange may indicate the need to continue plasma exchange to maximize the benefit of treatment or minimize the risk of relapse. Therapeutic plasma exchange need not be extended when plasma fibrinogen remains > or =30% below its level at presentation by the time of the final planned plasma exchange procedure.

  19. Behavioral phenotypes of impulsivity related to the ANKK1 gene are independent of an acute stressor

    PubMed Central

    White, Melanie J; Morris, C Phillip; Lawford, Bruce R; Young, Ross McD

    2008-01-01

    Background The A1 allele of the ANKK1 TaqIA polymorphism (previously reported as located in the D2 dopamine receptor (DRD2) gene) is associated with reduced DRD2 density in the striatum and with clinical disorders, particularly addiction. It was hypothesized that impulsivity represents an endophenotype underlying these associations with the TaqIA and that environmental stress would moderate the strength of the gene-behavior relationship. Methods TaqIA genotyping was conducted on 72 healthy young adults who were randomly allocated to either an acute psychosocial stress or relaxation induction condition. Behavioral phenotypes of impulsivity were measured using a card-sorting index of reinforcement sensitivity and computerized response inhibition and delay discounting tasks. Results Separate analyses of variance revealed associations between the A1 allele and two laboratory measures of impulsivity. The presence of the TaqIA allele (A1+) was associated with slower card-sorting in the presence of small financial reinforcers, but was overcome in a second administration after either a five-minute rest or psychosocial stress induction. A1+ participants also demonstrated significantly poorer response inhibition and faster response times on a computerized stop inhibition task, independent of acute stress exposure. Conclusion These findings indicate the A1 allele is associated with an endophenotype comprising both a "rash impulsive" behavioral style and reinforcement-related learning deficits. These effects are independent of stress. PMID:19025655

  20. Preventive effect of the microalga Chlamydomonas debaryana on the acute phase of experimental colitis in rats.

    PubMed

    Avila-Román, Javier; Talero, Elena; Alcaide, Antonio; Reyes, Carolina de Los; Zubía, Eva; García-Mauriño, Sofía; Motilva, Virginia

    2014-10-14

    Inflammatory bowel diseases (IBD) are characterised by chronic uncontrolled inflammation of intestinal mucosa. Diet and nutritional factors have emerged as possible interventions for IBD. Microalgae are rich sources of n-3 PUFA and derived oxylipins. Oxylipins are lipid mediators involved in the resolution of many inflammatory disorders. The aim of the present study was to investigate the effects of the oxylipin-containing biomass of the microalga Chlamydomonas debaryana and its major oxylipin constituent, (9Z,11E,13S,15Z)-13-hydroxyoctadeca-9,11,15-trienoic acid ((13S)-HOTE), on acute 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Lyophilised microalgal biomass and (13S)-HOTE were administered by oral route 48, 24 and 1 h before the induction of colitis and 24 h later, and the rats were killed after 48 h. The treatment with the lyophilised microalga and (13S)-HOTE improved body-weight loss and colon shortening, as well as attenuated the extent of colonic damage and increased mucus production. Cellular neutrophil infiltration, with the subsequent increase in myeloperoxidase levels induced by TNBS, were also reduced after the administration of the lyophilised microalga or (13S)-HOTE. The anti-inflammatory effects of these treatments were confirmed by the inhibition of colonic TNF-α production. Moreover, lyophilised microalga or (13S)-HOTE down-regulated cyclo-oxygenase-2 and inducible nitric oxide synthase expression. The present study was the first to show the prophylactic effects of a lyophilised biomass sample of the microalga C. debaryana and the oxylipin (13S)-HOTE on TNBS-induced acute colitis in rats. Our findings suggest that the microalga C. debaryana or derived oxylipins could be used as nutraceuticals in the treatment of the active phase of IBD.

  1. Fasa Registry on Acute Myocardial Infarction (FaRMI): Feasibility Study and Pilot Phase Results

    PubMed Central

    Askari, Alireza; Zakeri, Habib; Farjam, Mojtaba; Dehghan, Azizallah; Zendehdel, Kazem

    2016-01-01

    Background Myocardial infarction (MI) is the leading cause of death in Iran. Every attempt to improve treatment patterns and patient outcomes needs a surveillance system to both consider the efficacy and safety measures. Fasa Registry on Myocardial Infarction (FaRMI) is the first population-based registry for acute MI in Iran targeted to provide meticulous description of patients’ characteristics, to explore the management patterns of these patients, to discover the degree of adherence to the practice guidelines, and to investigate the determinants of poor in-hospital and later outcomes. Methods A diagnosis of acute MI (type I, II and III) was made upon the accepted criteria by the attending cardiologists and types IV and V MI were excluded. Two registrar nurses gathered data on demographics, place of residence and ethnicity, past medical history, risk factors, and the clinical course. Management patterns in the pre-hospital setting, during the hospital stay and at the discharge time were recorded. Routine laboratory results and cardiac biomarkers on three consecutive days were registered. Results pilot phase included the first 95 patients, 63.5% of whom were men and 31.5% were women. With a mean age of 62.89±13.75 years among participants, the rate of premature MI was 31.8%. ST segment elevation MI accounted for 68.2% cases and inferior wall was the most prevalent region involved followed by anterior and posterior walls. Discussion Obtained data on the characteristics of patients suffering an MI event revealed the major determinants of delay in initiation of therapies and contributors of poor outcome. Completeness of data was guaranteed upon involvement of multiple checkpoints and data quality was secured by means of automatic validation processes in addition to weekly physicians’ roundups. Conclusion Execution of FaRMI in the form presented is feasible and it will build up a comprehensive population-based registry for MI in the region. PMID:27907128

  2. Acute Phase Proteins in Cerebrospinal Fluid from Dogs with Naturally-Occurring Spinal Cord Injury

    PubMed Central

    Anderson, Kimberly M.; Welsh, C. Jane; Young, Colin; Levine, Gwendolyn J.; Kerwin, Sharon C.; Boudreau, C. Elizabeth; Reyes, Ismael; Mondragon, Armando; Griffin, John F.; Cohen, Noah D.

    2015-01-01

    Abstract Spinal cord injury (SCI) affects thousands of people each year and there are no treatments that dramatically improve clinical outcome. Canine intervertebral disc herniation is a naturally-occurring SCI that has similarities to human injury and can be used as a translational model for evaluating therapeutic interventions. Here, we characterized cerebrospinal fluid (CSF) acute phase proteins (APPs) that have altered expression across a spectrum of neurological disorders, using this canine model system. The concentrations of C-reactive protein (CRP), haptoglobin (Hp), alpha-1-glycoprotein, and serum amyloid A were determined in the CSF of 42 acutely injured dogs, compared with 21 healthy control dogs. Concentrations of APPs also were examined with respect to initial injury severity and motor outcome 42 d post-injury. Hp concentration was significantly higher (p<0.0001) in the CSF of affected dogs, compared with healthy control dogs. Additionally, the concentrations of CRP and Hp were significantly (p=0.0001 and p=0.0079, respectively) and positively associated with CSF total protein concentration. The concentrations of CRP and Hp were significantly higher (p=0.0071 and p=0.0197, respectively) in dogs with severe injury, compared with those with mild-to-moderate SCI, but there was no significant correlation between assessed CSF APP concentrations and 42 d motor outcome. This study demonstrated that CSF APPs were dysregulated in dogs with naturally-occurring SCI and could be used as markers for SCI severity. As Hp was increased following severe SCI and is neuroprotective across a number of model systems, it may represent a viable therapeutic target. PMID:26186466

  3. Cord Blood Acute Phase Reactants Predict Early Onset Neonatal Sepsis in Preterm Infants

    PubMed Central

    Palac, Hannah L.; Yogev, Ram; Ernst, Linda M.; Mestan, Karen K.

    2017-01-01

    Background Early onset sepsis (EOS) is a major cause of morbidity and mortality in preterm infants, yet diagnosis remains inadequate resulting in missed cases or prolonged empiric antibiotics with adverse consequences. Evaluation of acute phase reactant (APR) biomarkers in umbilical cord blood at birth may improve EOS detection in preterm infants with intrauterine infection. Methods In this nested case-control study, infants (29.7 weeks gestation, IQR: 27.7–32.2) were identified from a longitudinal cohort with archived cord blood and placental histopathology. Patients were categorized using culture, laboratory, clinical, and antibiotic treatment data into sepsis groups: confirmed sepsis (cEOS, n = 12); presumed sepsis (PS, n = 30); and no sepsis (controls, n = 30). Nine APRs were measured in duplicate from cord blood using commercially available multiplex immunoassays (Bio-Plex Pro™). In addition, placental histopathologic data were linked to biomarker results. Results cEOS organisms were Escherichia coli, Streptococcus agalactiae, Proteus mirabilis, Haemophilus influenzae and Listeria monocytogenes. C-reactive protein (CRP), serum amyloid A (SAA), haptoglobin (Hp), serum amyloid P and ferritin were significantly elevated in cEOS compared to controls (p<0.01). SAA, CRP, and Hp were elevated in cEOS but not in PS (p<0.01) and had AUCs of 99%, 96%, and 95% respectively in predicting cEOS. Regression analysis revealed robust associations of SAA, CRP, and Hp with EOS after adjustment for covariates. Procalcitonin, fibrinogen, α-2-macroglobulin and tissue plasminogen activator were not significantly different across groups. Placental acute inflammation was associated with APR elevation and was present in all cEOS, 9 PS, and 17 control infants. Conclusion This study shows that certain APRs are elevated in cord blood of premature infants with EOS of intrauterine origin. SAA, CRP, and Hp at birth have potential diagnostic utility for risk stratification and

  4. Prolonged QT interval at onset of acute myocardial infarction in predicting early phase ventricular tachycardia

    SciTech Connect

    Taylor, G.J.; Crampton, R.S.; Gibson, R.S.; Stebbins, P.T.; Waldman, M.T.; Beller, G.A.

    1981-07-01

    The prospectively assessed time course of changes in ventricular repolarization during acute myocardial infarction (AMI) is reported in 32 patients admitted 2.0 +/- 1.8 (SD) hours after AMI onset. The initial corrected QT interval (QTc) upon hospitalization was longer in the 14 patients developing ventricular tachycardia (VT) within the first 48 hours as compared to QTc in the eight patients with frequent ventricular premature beats (VPBs) and to QTc in the 10 patients with infrequent VPBs. By the fifth day after AMI onset, the QTc shortened significantly only in the VT group, suggesting a greater initial abnormality of repolarization in these patients. All 32 patients had coronary angiography, radionuclide ventriculography, and myocardial perfusion scintigraphy before hospital discharge. Significant discriminating factors related to early phase VT in AMI included initially longer QT and QTc intervals, faster heart rate, higher peak serum levels of creatine kinase, acute anterior infarction, angiographically documented proximal stenosis of the left anterior descending coronary artery, and scintigraphic evidence of hypoperfusion of the interventricular septum. Prior infarction, angina pectoris, hypertension, multivessel coronary artery disease, and depressed left ventricular ejection fraction did not provide discrimination among the three different ventricular arrhythmia AMI groups. Researchers conclude that (1) the QT interval is frequently prolonged early in AMI, (2) the initial transiently prolonged ventricular repolarization facilitates and predicts complex ventricular tachyarrhythmias within the first 48 hours of AMI, (3) jeopardized blood supply to the interventricular septum frequently coexists, and (4) therapeutic enhancement of rapid recovery of the ventricular repolarization process merits investigation for prevention of VT in AMI.

  5. A Five-Gene Peripheral Blood Diagnostic Test for Acute Rejection in Renal Transplantation

    PubMed Central

    Li, Li; Khatri, Purveshkumar; Sigdel, Tara K.; Tran, Tim; Ying, Lihua; Vitalone, Matthew; Chen, Amery; Hsieh, Szu-chuan; Dai, Hong; Zhang, Meixia; Naesens, Maarten; Zarkhin, Valeriya; Sansanwal, Poonam; Chen, Rong; Mindrinos, Michael; Xiao, Wenzhong; Benfield, Mark; Ettenger, Robert; Dharnidharka, Vikas; Mathias, Robert; Portale, Anthony; McDonald, Ruth; Harmon, William; Kershaw, David; Vehaskari, V. Matti; Kamil, Elaine; Baluarte, H. Jorge; Warady, Brad; Davis, Ron; Butte, Atul J.; Salvatierra, Oscar; Sarwal, Minnie

    2012-01-01

    Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in gthe NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n=47) and validated on independent test-set (n=198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool. PMID:23009139

  6. Major histocompatibility complex gene product expression on pancreatic beta cells in acutely diabetic BB rats.

    PubMed Central

    Issa-Chergui, B.; Yale, J. F.; Vigeant, C.; Seemayer, T. A.

    1988-01-01

    Type I diabetes mellitus was induced in young, diabetes-prone BB rats by the passive transfer of concanavalin A-activated T lymphocytes from the spleens of acutely diabetic BB rats. The pancreas of the recipients was examined 1-2 days after the onset of glycosuria by immunocytochemistry by means of monoclonal antibodies for determining whether 1) Class I and/or II major histocompatibility gene complex (MHC) products were expressed on beta cells and 2) the mononuclear cell infiltrates were represented by T cells. Marked expression of Class I MHC gene products was evident on beta cells. In contrast, Class II MHC gene products were not identified on normal-appearing beta cells. Dendritic cells dispersed throughout the acinar and interstitial pancreas were markedly increased in number. The mononuclear cell infiltrate contained few cells (1-15%) recognized by a pan-T cell marker. Although it is possible that this passive transfer model might differ considerably from the spontaneously occurring diabetic state in the rat, this study suggests that 1) Class I, rather than Class II, MHC gene expression may be pivotal to beta-cell injury in diabetic rats, and 2) non-T cells may constitute an effector cell population central to beta-cell necrosis in Type I diabetes mellitus. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3276208

  7. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair

    PubMed Central

    Alcalay, Myriam; Meani, Natalia; Gelmetti, Vania; Fantozzi, Anna; Fagioli, Marta; Orleth, Annette; Riganelli, Daniela; Sebastiani, Carla; Cappelli, Enrico; Casciari, Cristina; Sciurpi, Maria Teresa; Mariano, Angela Rosa; Minardi, Simone Paolo; Luzi, Lucilla; Muller, Heiko; Di Fiore, Pier Paolo; Frosina, Guido; Pelicci, Pier Giuseppe

    2003-01-01

    Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities. Expression of AML fusion proteins in transgenic mice increases the risk of myeloid leukemias, suggesting that they induce a preleukemic state. The underlying molecular and biological mechanisms are, however, unknown. To address this issue, we performed a systematic analysis of fusion protein transcriptional targets. We expressed AML1/ETO, PML/RAR, and PLZF/RAR in U937 hemopoietic precursor cells and measured global gene expression using oligonucleotide chips. We identified 1,555 genes regulated concordantly by at least two fusion proteins that were further validated in patient samples and finally classified according to available functional information. Strikingly, we found that AML fusion proteins induce genes involved in the maintenance of the stem cell phenotype and repress DNA repair genes, mainly of the base excision repair pathway. Functional studies confirmed that ectopic expression of fusion proteins constitutively activates pathways leading to increased stem cell renewal (e.g., the Jagged1/Notch pathway) and provokes accumulation of DNA damage. We propose that expansion of the stem cell compartment and induction of a mutator phenotype are relevant features underlying the leukemic potential of AML-associated fusion proteins. PMID:14660751

  8. Genome-Wide Expression Analysis Reveals Diverse Effects of Acute Nicotine Exposure on Neuronal Function-Related Genes and Pathways

    PubMed Central

    Wang, Ju; Cui, Wenyan; Wei, Jinxue; Sun, Dongxiao; Gutala, Ramana; Gu, Jun; Li, Ming D.

    2011-01-01

    Previous human and animal studies demonstrate that acute nicotine exposure has complicated influences on the function of the nervous system, which may lead to long-lasting effects on the behavior and physiology of the subject. To determine the genes and pathways that might account for long-term changes after acute nicotine exposure, a pathway-focused oligoarray specifically designed for drug addiction research was used to assess acute nicotine effect on gene expression in the neuron-like SH-SY5Y cells. Our results showed that 295 genes involved in various biological functions were differentially regulated by 1 h of nicotine treatment. Among these genes, the expression changes of 221 were blocked by mecamylamine, indicating that the majority of nicotine-modulated genes were altered through the nicotinic acetylcholine receptors (nAChRs)-mediated signaling process. We further identified 14 biochemical pathways enriched among the nicotine-modulated genes, among which were those involved in neural development/synaptic plasticity, neuronal survival/death, immune response, or cellular metabolism. In the genes significantly regulated by nicotine but blocked by mecamylamine, 13 enriched pathways were detected. Nine of these pathways were shared with those enriched in the genes regulated by nicotine, including neuronal function-related pathways such as glucocorticoid receptor signaling, p38 MAPK signaling, PI3K/AKT signaling, and PTEN signaling, implying that nAChRs play important roles in the regulation of these biological processes. Together, our results not only provide insights into the mechanism underlying the acute response of neuronal cells to nicotine but also provide clues to how acute nicotine exposure exerts long-term effects on the nervous system. PMID:21556275

  9. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease.

    PubMed

    Mittermeyer, Gabriele; Christine, Chadwick W; Rosenbluth, Kathryn H; Baker, Suzanne L; Starr, Philip; Larson, Paul; Kaplan, Paul L; Forsayeth, John; Aminoff, Michael J; Bankiewicz, Krystof S

    2012-04-01

    We report the results of a long-term follow-up of subjects in a phase 1 study of AAV2-hAADC (adeno-associated virus type 2-human aromatic L-amino acid decarboxylase) gene therapy for the treatment of Parkinson's disease (PD). Ten patients with moderately advanced PD received bilateral putaminal infusions of either a low or a high dose of AAV2-hAADC vector. An annual positron emission tomography (PET) imaging with [(18)F]fluoro-L-m-tyrosine tracer was used for evaluation of AADC expression, and a standard clinical rating scale [Unified Parkinson's Disease Rating Scale (UPDRS)] was used to assess effect. Our previous analysis of the 6-month data suggested that this treatment was acutely safe and well tolerated. We found that the elevated PET signal observed in the first 12 months persisted over 4 years in both dose groups. A significantly increased PET value compared with the presurgery baseline was maintained over the 4-year monitoring period. The UPDRS in all patients off medication for 12 hr improved in the first 12 months, but displayed a slow deterioration in subsequent years. This analysis demonstrates that apparent efficacy continues through later years with an acceptable safety profile. These data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose.

  10. TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia.

    PubMed

    Jamil, A; Theil, K S; Kahwash, S; Ruymann, F B; Klopfenstein, K J

    2000-10-15

    TEL gene rearrangement due to the 12;21 chromosome translocation is believed to be the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL). A study was conducted to investigate the frequency and prognostic significance of TEL/AML-1 fusion gene resulting from a cryptic t(12;21)(p13;q22). Bone marrow samples from 86 patients diagnosed over the past 5 years at Columbus Children's Hospital were analyzed by fluorescence in situ hybridization (FISH) technique for TEL/AML-1 fusion gene, using LSI((R)) DNA probes. The positive cases were analyzed for clinical outcome. Patients in this study received treatment according to Children's Cancer Group (CCG) protocols. Fifteen of the 86 cases (17%) were positive for the fusion gene. All were B-cell lineage and except for one, all were CD10 positive. TEL/AML-1 was not found in any T-cell ALL. The mean overall survival (OS) following diagnosis for the TEL/AML-1-positive group was significantly longer than for the TEL/AML-1-negative group by log-rank = 7.84, P = 0.005. Similarly, the event-free survival (EFS) after remission for the positive group (median 94.5 months) was longer than the negative group (median 57 months) by log-rank = 7.19, P = 0.007. This study confirms that the TEL/AML-1 fusion gene may be the most common genetic event in childhood ALL, occurring in 17% of the patients. It appears restricted to the B-cell lineage. In this study, the presence of a TEL/AML-1 fusion gene was statistically significant in predicting both OS and EFS, indicating a favorable clinical outcome for these patients. Screening for TEL/AML-1 should become routine at diagnosis and a useful biological variable for risk stratification in future clinical trials.

  11. Identification of genes associated with heat tolerance in Arctic charr exposed to acute thermal stress.

    PubMed

    Quinn, Nicole L; McGowan, Colin R; Cooper, Glenn A; Koop, Ben F; Davidson, William S

    2011-06-15

    Arctic charr is an especially attractive aquaculture species given that it features the desirable tissue traits of other salmonids and is bred and grown at inland freshwater tank farms year round. It is of interest to develop upper temperature tolerant (UTT) strains of Arctic charr to increase the robustness of the species in the face of climate change and to enable production in more southern regions. We used a genomics approach that takes advantage of the well-studied Atlantic salmon genome to identify genes that are associated with UTT in Arctic charr. Specifically, we conducted an acute temperature trial to identify temperature tolerant and intolerant Arctic charr individuals, which were subject to microarray and qPCR analysis to identify candidate UTT genes. These were compared with genes annotated in a quantitative trait locus (QTL) region that was previously identified as associated with UTT in rainbow trout and Arctic charr and that we sequenced in Atlantic salmon. Our results suggest that small heat shock proteins as well as HSP-90 genes are associated with UTT. Furthermore, hemoglobin expression was significantly downregulated in tolerant compared with intolerant fish. Finally, QTL analysis and expression profiling identified COUP-TFII as a candidate UTT gene, although its specific role is unclear given the identification of two transcripts, which appear to have different expression patterns. Our results highlight the importance of using more than one approach to identify candidate genes, particularly when examining a complicated trait such as UTT in a highly complex genome for which there is no reference genome.

  12. Integrative Gene Regulatory Network Analysis Reveals Light-Induced Regional Gene Expression Phase Shift Programs in the Mouse Suprachiasmatic Nucleus

    PubMed Central

    Zhu, Haisun; Vadigepalli, Rajanikanth; Rafferty, Rachel; Gonye, Gregory E.; Weaver, David R.; Schwaber, James S.

    2012-01-01

    We use the multigenic pattern of gene expression across suprachiasmatic nuclei (SCN) regions and time to understand the dynamics within the SCN in response to a circadian phase-resetting light pulse. Global gene expression studies of the SCN indicate that circadian functions like phase resetting are complex multigenic processes. While the molecular dynamics of phase resetting are not well understood, it is clear they involve a “functional gene expression program”, e.g., the coordinated behavior of functionally related genes in space and time. In the present study we selected a set of 89 of these functionally related genes in order to further understand this multigenic program. By use of high-throughput qPCR we studied 52 small samples taken by anatomically precise laser capture from within the core and shell SCN regions, and taken at time points with and without phase resetting light exposure. The results show striking regional differences in light response to be present in the mouse SCN. By using network-based analyses, we are able to establish a highly specific multigenic correlation between genes expressed in response to light at night and genes normally activated during the day. The light pulse triggers a complex and highly coordinated network of gene regulation. The largest differences marking neuroanatomical location are in transmitter receptors, and the largest time-dependent differences occur in clock-related genes. Nighttime phase resetting appears to recruit transcriptional regulatory processes normally active in the day. This program, or mechanism, causes the pattern of core region gene expression to transiently shift to become more like that of the shell region. PMID:22662235

  13. Gene-gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children.

    PubMed

    Petra, Bohanec Grabar; Janez, Jazbec; Vita, Dolzan

    2007-04-01

    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation and repair. We analysed common genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MS) and methionine synthase reductase (MTRR) in 68 children with ALL and 258 healthy controls to investigate their influence on the risk for ALL. No significant differences in frequencies of separate polymorphisms were observed between both groups. Combined MTHFR 677CT/TT and MS 2756AG/GG genotypes showed a nonsignificant tendency to reduce the risk for ALL 2.24-fold (CI: 0.191 - 1.037, P: 0.061). The risk was significantly reduced in carriers of combined MTHFR 677CT/TT, MS 2756AG/GG and MTRR 66AG/GG genotypes (OR: 0.312; CI: 0.107 - 0.907; P: 0.032). Our results suggest that gene - gene interactions that may decrease the methylation capacity might have a protective effect on the risk for childhood ALL.

  14. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.

    PubMed

    Konopleva, Marina; Thall, Peter F; Yi, Cecilia Arana; Borthakur, Gautam; Coveler, Andrew; Bueso-Ramos, Carlos; Benito, Juliana; Konoplev, Sergej; Gu, Yongchuan; Ravandi, Farhad; Jabbour, Elias; Faderl, Stefan; Thomas, Deborah; Cortes, Jorge; Kadia, Tapan; Kornblau, Steven; Daver, Naval; Pemmaraju, Naveen; Nguyen, Hoang Q; Feliu, Jennie; Lu, Hongbo; Wei, Caimiao; Wilson, William R; Melink, Teresa J; Gutheil, John C; Andreeff, Michael; Estey, Elihu H; Kantarjian, Hagop

    2015-07-01

    We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.1 to 4 g/m(2). The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62%, neutropenia 50%, thrombocytopenia 46%), febrile neutropenia (40%), infection (24%), and enterocolitis (14%). Ten of 31 patients with acute myeloid leukemia (32%) and 2 of 10 patients with acute lymphoblastic leukemia (20%) who received 3 g/m(2) or 4 g/m(2) had a response (complete response, n=1; complete response without platelet recovery, n=5; morphological leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at clinicaltrials.gov identifier: 01037556.

  15. Influence of transportation on serum concentrations of acute phase proteins in horse.

    PubMed

    Casella, S; Fazio, F; Giannetto, C; Giudice, E; Piccione, G

    2012-10-01

    The modifications of Haptoglobin (Hp), Serum Amyloid A (SAA), Fibrinogen (Fbg) and White Blood Cells (WBCs) were evaluated in 15 Saddle Italian horses. Ten horses were transported covering a distance of about 320 km within 4 h with an average speed of 80 km/h (experimental group) and five horses were not subject to transportation (control group). Blood was collected via jugular venipuncture before the transportation (T0), immediately after the transportation (T1), 12 (T12), 24 (T24) and 48 (T48)hours after the transportation in experimental group and at the same time point in control group. For each parameter statistical analysis of different groups and sampling time was performed using a two-way analysis of covariance, with the data before the transportation (T0) as the covariate, by the GLM procedure of SAS. For all parameters the interaction (Group × Time) was tested and it was resulted no significant. The application of statistical analysis showed significant differences between the control group and horses subjected to transportation (P<0.01), and the influence of sampling time (P<0.05) on Hp, SAA and WBCs. These modifications appeared to be innovative showing that equine Hp, generally considered as moderate acute phase protein, increases more rapidly than the SAA after transportation-induced stress.

  16. Swimming Exercise in the Acute or Late Phase after Sciatic Nerve Crush Accelerates Nerve Regeneration

    PubMed Central

    Teodori, Rosana Macher; Betini, Joice; de Oliveira, Larissa Salgado; Sobral, Luciane Lobato; Takeda, Sibele Yoko Mattozo; Montebelo, Maria Imaculada de Lima

    2011-01-01

    There is no consensus about the best time to start exercise after peripheral nerve injury. We evaluated the morphological and functional characteristics of the sciatic nerves of rats that began to swim immediately after crush nerve injury (CS1), those that began to swim 14 days after injury (CS14), injured rats not submitted to swimming (C), and uninjured rats submitted to swimming (S). After 30 days the number of axons in CS1 and CS14 was lower than in C (P < 0.01). The diameter of axons and nerve fibers was larger in CS1 (P < 0.01) and CS14 (P < 0.05) than in C, and myelin sheath thickness was lower in all crushed groups (P < 0.05). There was no functional difference between CS1 and CS14 (P > 0.05). Swimming exercise applied during the acute or late phase of nerve injury accelerated nerve regeneration and synaptic elimination after axonotmesis, suggesting that exercise may be initiated immediately after injury. PMID:21876821

  17. The Acute-Phase Proteins Serum Amyloid A and C Reactive Protein in Transudates and Exudates

    PubMed Central

    Okino, Alessandra M.; Bürger, Cristiani; Cardoso, Jefferson R.; Lavado, Edson L.; Lotufo, Paulo A.; Campa, Ana

    2006-01-01

    The distinction between exudates and transudates is very important in the patient management. Here we evaluate whether the acute-phase protein serum amyloid A (SAA), in comparison with C reactive protein (CRP) and total protein (TP), can be useful in this discrimination. CRP, SAA, and TP were determined in 36 exudate samples (27 pleural and 9 ascitic) and in 12 transudates (9 pleural and 3 ascitic). CRP, SAA, and TP were measured. SAA present in the exudate corresponded to 10% of the amount found in serum, that is, the exudate/serum ratio (E/S) was 0.10 ± 0.13. For comparison, the exudate/serum ratio for CRP and TP was 0.39 ± 0.37 and 0.68 ± 0.15, respectively. There was a strong positive correlation between serum and exudate SAA concentration (r = 0.764;p < 0.0001). The concentration of SAA in transudates was low and did not overlap with that found in exudates (0.02-0.21 versus 0.8–360.5 g/mL). SAA in pleural and ascitic exudates results mainly from leakage of the serum protein via the inflamed membrane. A comparison of the E/S ratio of SAA and CRP points SAA as a very good marker in discriminating between exudates and transudates. PMID:16864904

  18. NRF2 and the Phase II Response in Acute Stress Resistance Induced by Dietary Restriction

    PubMed Central

    Hine, Christopher M.; Mitchell, James R.

    2013-01-01

    Dietary restriction (DR) as a means to increase longevity is well-established in a number of model organisms from yeast to primates. DR also improves metabolic fitness and increases resistance to acute oxidative, carcinogenic and toxicological stressors - benefits with more immediate potential for clinical translation than increased lifespan. While the detailed mechanism of DR action remains unclear, a conceptual framework involving an adaptive, or hormetic response to the stress of nutrient/energy deprivation has been proposed. A key prediction of the hormesis hypothesis of DR is that beneficial adaptations occur in response to an increase in reactive oxygen/nitrogen species (ROS). These ROS may be derived either from increased mitochondrial respiration or increased xenobiotic metabolism in the case of some DR mimetics. This review will focus on the potential role of the redox-sensing transcription factor NF-E2-related factor 2 (NRF2) and its control of the evolutionarily conserved antioxidant/redox cycling and detoxification systems, collectively known as the Phase II response, in the adaptive response to DR. PMID:23505614

  19. [The measurement of CoQ10 in the acute phase of a myocardial infarct].

    PubMed

    Puletti, M; Trappolini, M; Di Palma, A; Curione, M; Schiavone, R A; Matteoli, S; Borgia, C

    1991-05-01

    The authors have studied the behaviour of ubidecorenone (Co Q10) in the acute phase of myocardial infarction in 24 patients, 19 male and 5 female, mean age 56.8 +/- 3.3. Ubidecorenone level was determined on admittance, after 48 hours and on the 7th and 30th days. A significant decrease was observed from the first to the 3rd day (mean values 0.90 +/- 0.18 microgram/ml vs 0.72 +/- 0.22, p less than 0.01). Thereafter a progressive rise was observed, but at the 30th day mean values were still below the basal ones. No significant differences were observed between patients treated with fibrinolytic agents and those not so treated, nor between those in whom reperfusion was obtained and the others. Nor was there a proven correlation with changes in creatinkinase. The behaviour of ubidecorenone may be associated with increased consumption for metabolic needs and increased destruction in scavenger action, and also to a lesser extent to decreased production due to lower food intake.

  20. Intestinal pathogens, diarrhoea and acute phase proteins in naturally infected dairy calves.

    PubMed

    Seppä-Lassila, Leena; Orro, Toomas; Lassen, Brian; Lasonen, Riikka; Autio, Tiina; Pelkonen, Sinikka; Soveri, Timo

    2015-08-01

    In this study, the association between Eimeria spp. related signs and innate immune response in dairy calves was examined. Calves (n=100) aged 15-60 days were clinically examined and faecal samples, blood samples and deep nasopharyngeal swabs obtained. The samples were analysed for intestinal pathogens, acute phase proteins and WBC count, and respiratory tract pathogens, respectively. Diarrhoea was diagnosed in 32.6% (23.3-43.0%, 95% CI) of calves. An association between the pathogenic Eimeria spp. and diarrhoea was detected by multiple correspondence analysis. Eimeria related signs (diarrhoea, presence of pathogenic species and total oocyst count) were combined resulting a four level variable. Calves with weak signs of eimeriosis had decreased haptoglobin concentrations (p=0.02) and increased fibrinogen concentrations (p=0.048) compared to no signs. Increased haptoglobin and fibrinogen concentrations were associated with respiratory tract infection and umbilical infection. Serum amyloid A and WBC counts showed no association with signs of eimeriosis or clinical diagnoses.

  1. Oxidative Status and Acute Phase Reactants in Patients with Environmental Asbestos Exposure and Mesothelioma

    PubMed Central

    Sezgi, Cengizhan; Taylan, Mahsuk; Selimoglu Sen, Hadice; Evliyaoğlu, Osman; Kaya, Halide; Abakay, Ozlem; Abakay, Abdurrahman; Tanrıkulu, Abdullah Cetin; Senyiğit, Abdurrahman

    2014-01-01

    Background and Objectives. The aim of this study was to investigate inflammatory indicators and oxidative status in patients with asbestos exposure with and without mesothelioma and to compare results with data from healthy subjects. Methods. Eighty people with exposure to environmental asbestos and without any disease, 46 mesothelioma patients, and a control group of 50 people without exposure to environmental asbestos were enrolled in this prospective study. Serum total oxidant level (TOL), total antioxidant capacity (TAC), and oxidative stress index (OSI), CRP, transferrin, ceruloplasmin, α-1 antitrypsin, ferritin, and copper levels were measured. Results. Mesothelioma group exhibited higher TOL, OSI, α1-antitrypsin, ferritin and copper levels as compared to the other groups (P < 0.001, P = 0.007, P < 0.0001, P < 0.001, and P < 0.001, resp.). Transferrin was lower in the mesothelioma group than in the other two groups (P < 0.001). The asbestos group had higher TOL, TAC, α1-antitrypsin, and transferrin levels (P < 0.001, P < 0.001, P < 0.001, and P < 0.001, resp.), as well as lower OSI and ferritin levels as compared to the control group (P < 0.001 and P < 0.001). Conclusions. We believe that elevated acute phase reactants and oxidative stress markers (TOL and OSI) in the mesothelioma group can be used as predictive markers for the development of asbestos-related malignancy. PMID:24592197

  2. Transport proteins and acute phase reactant proteins in children with sickle cell anemia.

    PubMed Central

    Warrier, R. P.; Kuvibidila, S.; Gordon, L.; Humbert, J.

    1994-01-01

    Transport proteins, acute-phase reactant proteins (APRP), hematology, and anthropometry were studied in 34 sickle cell disease (SCD) children (20 boys, 14 girls) and 27 controls without growth deficits (13 boys, 14 girls) [corrected]. The age range was 1/2 to 16 1/2 years. Weight deficits (< 80%) by Waterlow's classification were observed in 41% of SCD boys and 25% of SCD girls, and height deficits (< 90%) were observed in 25% SCD boys and 25% girls. Mean white blood cell counts were significantly higher (P < .001) and hematocrit and hemoglobin (Hb) lower (P < .005) in SCD children than in controls. Although both groups had similar mean levels of albumin, transferrin, and APRP, SCD children had significantly lower mean levels of retinol-binding protein (RBP) (P < .001) and retinol-prealbumin (P < .001). Retinol-binding protein levels were abnormal in 18 (53%) SCD children and in only 23% controls (chi 2 = 14.06; P < 0.005); transferrin levels were abnormal in 20% of SCD children and in none of the controls. Children with SC and SF Hb phenotype had normal mean levels of RBP, whereas those with S beta thal and SS phenotype had levels below normal. Growth-retarded children by weight and height had reduced mean levels of RBP and prealbumin compared with growth-normal SCD children. The implication of primary protein-energy malnutrition on growth retardation in SCD children is under study. PMID:7512147

  3. Acute-phase protein behavior in dairy cattle herd naturally infected with Trypanosoma vivax.

    PubMed

    Sampaio, Paulo Henrique; Fidelis Junior, Otavio Luiz; Marques, Luiz Carlos; Machado, Rosangela Zacarias; Barnabé, Patrícia de Athayde; André, Marcos Rogério; Balbuena, Tiago Santana; Cadioli, Fabiano Antonio

    2015-07-30

    Trypanosoma vivax is a hemoprotozoon that causes disease in cattle and is difficult to diagnose. The host-parasite relationship in cattle that are infected by T. vivax has only been poorly studied. In the present study, a total of 429 serum proteinograms were produced from naturally infected animals (NIF) and were compared with 50 samples from control animals (C). The total protein, IgA band, complement C3 β chain band, albumin band, antitrypsin band, IgG band, haptoglobin band, complement C3c α chain band and protein HP-20 band presented higher levels in the serum proteinograms of the NIF group. Inter-alpha-trypsin inhibitor heavy chain H4, α2-macroglobulin, complement C6, ceruloplasmin, transferrin band and apolipoprotein A1 band presented lower levels in this group. There was no significant difference (p<0.05) in acid glycoprotein serum concentration between the NIF and C groups. Acute phase proteins may be useful for understanding the host-parasite relationship, since the antitrypsin band was only present in the NIF group. This can be used as an indicator for infection in cattle that are naturally infected by T. vivax.

  4. Determination of ceruloplasmin, some other acute phase proteins, and biochemical parameters in cows with endometritis

    PubMed Central

    Kaya, S.; Merhan, O.; Kacar, C.; Colak, A.; Bozukluhan, K.

    2016-01-01

    Aim: The aim of this study is to determine serum ceruloplasmin levels in cows with endometritis of varying degrees of severity and to establish whether or not there is a correlation between acute phase protein (APP) levels and biochemical parameters. Material and Methods: The study was conducted with 100 Brown Swiss cows (3-8 years of age) on days 28-32 postpartum. Cows were divided into endometritis (mild, moderate, and severe endometriosis) and healthy groups based on ultrasonography, vaginoscopy, and cytological examination. Blood samples were collected from all cows. Levels of haptoglobin (Hp), serum amyloid A (SAA), ceruloplasmin, albumin, and some biochemical parameters were analyzed. Results: Hp, SAA, and ceruloplasmin levels were higher in cows with endometritis than in healthy cows (p=0.001), and the levels of these APPs increased as endometritis became more severe (p=0.001). Some significant correlations were found between APPs and the biochemical parameters that were analyzed. In conclusion, it was determined that ceruloplasmin levels increase significantly in the presence of endometritis and proportionate to the severity of endometritis. A significant correlation was found between ceruloplasmin levels and Hp and SAA levels. Conclusion: It was concluded that ceruloplasmin levels can be used in the diagnosis of endometritis as an alternative to Hp and SAA levels. PMID:27847413

  5. Controversial results of therapy with mesenchymal stem cells in the acute phase of canine distemper disease.

    PubMed

    Pinheiro, A O; Cardoso, M T; Vidane, A S; Casals, J B; Passarelli, D; Alencar, A L F; Sousa, R L M; Fantinato-Neto, P; Oliveira, V C; Lara, V M; Ambrósio, C E

    2016-05-23

    Distemper disease is an infectious disease reported in several species of domestic and wild carnivores. The high mortality rate of animals infected with canine distemper virus (CDV) treated with currently available therapies has driven the study of new efficacious treatments. Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic option for many degenerative, hereditary, and inflammatory diseases. Therefore, the aim of this study was to characterize stem cells derived from the canine fetal olfactory epithelium and to assess the systemic response of animals infected with CDV to symptomatic therapy and treatment with MSCs. Eight domestic mongrel dogs (N = 8) were divided into two groups: support group (SG) (N = 5) and support group + cell therapy (SGCT) (N = 3), which were monitored over 15 days. Blood samples were collected on days 0, 6, 9, 12, and 15 to assess blood count and serum biochemistry (urea, creatinine, alanine transferase, alkaline phosphatase, gamma-glutamyl transferase, total protein, albumin, and globulin), and urine samples were obtained on days 0 and 15 for urinary evaluation (urine I). The results showed a high mortality rate (SG = 4 and SGCT = 2), providing inadequate data on the clinical course of CDV infection. MSC therapy resulted in no significant improvement when administered during the acute phase of canine distemper disease, and a prevalence of animals with high mortality rate was found in both groups due to the severity of symptoms.

  6. Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

    PubMed Central

    Rivory, L P; Slaviero, K A; Clarke, S J

    2002-01-01

    Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C20min measure and the recently proposed 1/TMAX values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1β, TNFα and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg l−1, n=26) had reduced metabolism as measured with the erythromycin breath test 1/TMAX (Kruskal–Wallis Anova, P=0.0062) as compared to controls (C-reactive protein ⩽10 mg l−1, n=14). Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=−0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population. British Journal of Cancer (2002) 87, 277–280. doi:10.1038/sj.bjc.6600448 www.bjcancer.com © 2002 Cancer Research UK PMID:12177794

  7. The rat acute-phase protein α2-macroglobulin plays a central role in amifostine-mediated radioprotection.

    PubMed

    Mirjana, Mihailović; Goran, Poznanović; Nevena, Grdović; Melita, Vidaković; Svetlana, Dinić; Ilijana, Grigorov; Desanka, Bogojević

    2010-09-01

    Previously we reported that elevated circulating concentrations of the acute-phase (AP) protein α(2)-macroglobulin (α(2)M), either as typically occurring in pregnant female rats or after administration to male rats, provides radioprotection, displayed as 100% survival of experimental animals exposed to total-body irradiation with 6.7 Gy (LD(50/30)) x-rays, that is as effective as that afforded by the synthetic radioprotector amifostine. The finding that amifostine administration induces a 45-fold increase in α(2)M in the circulation led us to hypothesise that α(2)M assumes an essential role in both natural and amifostine-mediated radioprotection in the rat. In the present work we examined the activation of cytoprotective mechanisms in rat hepatocytes after the exogenous administration of α(2)M and amifostine. Our results showed that the IL6/JAK/STAT3 hepatoprotective signal pathway, described in a variety of liver-injury models, upregulated the α(2)M gene in amifostine-pretreated animals. In both α(2)M- and amifostine-pretreated rats we observed the activation of the Akt signalling pathways that mediate cellular survival. At the cellular level this was reflected as a significant reduction of irradiation-induced DNA damage that allowed for the rapid and complete restoration of liver mass and ultimately at the level of the whole organism the complete restoration of body weight. We conclude that the selective upregulation of α(2)M plays a central role in amifostine-provided radioprotection.

  8. Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

    PubMed

    Tucker, James D; Divine, George W; Grever, William E; Thomas, Robert A; Joiner, Michael C; Smolinski, Joseph M; Auner, Gregory W

    2013-01-01

    Rapid and reliable methods for performing biological dosimetry are of paramount importance in the event of a large-scale nuclear event. Traditional dosimetry approaches lack the requisite rapid assessment capability, ease of use, portability and low cost, which are factors needed for triaging a large number of victims. Here we describe the results of experiments in which mice were acutely exposed to (60)Co gamma rays at doses of 0 (control) to 10 Gy. Blood was obtained from irradiated mice 0.5, 1, 2, 3, 5, and 7 days after exposure. mRNA expression levels of 106 selected genes were obtained by reverse-transcription real time PCR. Stepwise regression of dose received against individual gene transcript expression levels provided optimal dosimetry at each time point. The results indicate that only 4-7 different gene transcripts are needed to explain ≥ 0.69 of the variance (R(2)), and that receiver-operator characteristics, a measure of sensitivity and specificity, of ≥ 0.93 for these statistical models were achieved at each time point. These models provide an excellent description of the relationship between the actual and predicted doses up to 6 Gy. At doses of 8 and 10 Gy there appears to be saturation of the radiation-response signals with a corresponding diminution of accuracy. These results suggest that similar analyses in humans may be advantageous for use in a field-portable device designed to assess exposures in mass casualty situations.

  9. Gene Expression-Based Dosimetry by Dose and Time in Mice Following Acute Radiation Exposure

    PubMed Central

    Tucker, James D.; Divine, George W.; Grever, William E.; Thomas, Robert A.; Joiner, Michael C.; Smolinski, Joseph M.; Auner, Gregory W.

    2013-01-01

    Rapid and reliable methods for performing biological dosimetry are of paramount importance in the event of a large-scale nuclear event. Traditional dosimetry approaches lack the requisite rapid assessment capability, ease of use, portability and low cost, which are factors needed for triaging a large number of victims. Here we describe the results of experiments in which mice were acutely exposed to 60Co gamma rays at doses of 0 (control) to 10 Gy. Blood was obtained from irradiated mice 0.5, 1, 2, 3, 5, and 7 days after exposure. mRNA expression levels of 106 selected genes were obtained by reverse-transcription real time PCR. Stepwise regression of dose received against individual gene transcript expression levels provided optimal dosimetry at each time point. The results indicate that only 4–7 different gene transcripts are needed to explain ≥ 0.69 of the variance (R2), and that receiver-operator characteristics, a measure of sensitivity and specificity, of ≥ 0.93 for these statistical models were achieved at each time point. These models provide an excellent description of the relationship between the actual and predicted doses up to 6 Gy. At doses of 8 and 10 Gy there appears to be saturation of the radiation-response signals with a corresponding diminution of accuracy. These results suggest that similar analyses in humans may be advantageous for use in a field-portable device designed to assess exposures in mass casualty situations. PMID:24358280

  10. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia.

    PubMed

    Kontro, M; Kumar, A; Majumder, M M; Eldfors, S; Parsons, A; Pemovska, T; Saarela, J; Yadav, B; Malani, D; Fløisand, Y; Höglund, M; Remes, K; Gjertsen, B T; Kallioniemi, O; Wennerberg, K; Heckman, C A; Porkka, K

    2017-02-01

    Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.

  11. Gene copy number alteration profile and its clinical correlation in B-cell acute lymphoblastic leukemia.

    PubMed

    Gupta, Sanjeev Kumar; Bakhshi, Sameer; Kumar, Lalit; Kamal, Vineet Kumar; Kumar, Rajive

    2017-02-01

    The genes related to B-cell development are frequently altered in B-cell acute lymphoblastic leukemia (B-ALL). One hundred sixty-two newly diagnosed B-ALL cases, median age 8.5 years (2 months-67 years), were prospectively analyzed for copy number alterations (CNAs) in CDKN2A/B, IKZF1, PAX5, RB1, ETV6, BTG1, EBF1, and pseudoautosomal region genes (CRLF2, CSF2RA, IL3RA) using multiplex ligation-dependent probe amplification. The CNAs were detected in 114 (70.4%) cases; most commonly affected genes being CDKN2A/B-55 (34%), PAX5-51 (31.5%), and IKZF1-43 (26.5%). IKZF1 and RB1 deletions correlated with higher induction failure. Patients classified as good-risk, according to the integrated CNA profile and cytogenetic criteria, had lower induction failure [5 (8.6%) vs. 20 (25.3%); p = 0.012]. Those classified as good-risk, based on CNA profile irrespective of cytogenetics, also showed lower induction failure [6 (9.4%) vs. 19 (26%); p = 0.012]. The CNA profile identified patients with better induction outcome and has a potential role in better risk stratification of B-ALL.

  12. Exposure of Lactating Dairy Cows to Acute Pre-Ovulatory Heat Stress Affects Granulosa Cell-Specific Gene Expression Profiles in Dominant Follicles

    PubMed Central

    Vanselow, Jens; Vernunft, Andreas; Koczan, Dirk; Spitschak, Marion; Kuhla, Björn

    2016-01-01

    High environmental temperatures induce detrimental effects on various reproductive processes in cattle. According to the predicted global warming the number of days with unfavorable ambient temperatures will further increase. The objective of this study was to investigate effects of acute heat stress during the late pre-ovulatory phase on morphological, physiological and molecular parameters of dominant follicles in cycling cows during lactation. Eight German Holstein cows in established lactation were exposed to heat stress (28°C) or thermoneutral conditions (15°C) with pair-feeding for four days. After hormonal heat induction growth of the respective dominant follicles was monitored by ultrasonography for two days, then an ovulatory GnRH dose was given and follicular steroid hormones and granulosa cell-specific gene expression profiles were determined 23 hrs thereafter. The data showed that the pre-ovulatory growth of dominant follicles and the estradiol, but not the progesterone concentrations tended to be slightly affected. mRNA microarray and hierarchical cluster analysis revealed distinct expression profiles in granulosa cells derived from heat stressed compared to pair-fed animals. Among the 255 affected genes heatstress-, stress- or apoptosis associated genes were not present. But instead, we found up-regulation of genes essentially involved in G-protein coupled signaling pathways, extracellular matrix composition, and several members of the solute carrier family as well as up-regulation of FST encoding follistatin. In summary, the data of the present study show that acute pre-ovulatory heat stress can specifically alter gene expression profiles in granulosa cells, however without inducing stress related genes and pathways and suggestively can impair follicular growth due to affecting the activin-inhibin-follistatin system. PMID:27532452

  13. ETS-related gene is a novel prognostic factor in childhood acute lymphoblastic leukemia.

    PubMed

    Zhao, Hai-Zhao; Jia, Ming; Luo, Ze-Bin; Xu, Xiao-Jun; Li, Si-Si; Zhang, Jing-Ying; Guo, Xiao-Ping; Tang, Yong-Min

    2017-01-01

    The ETS-related gene (ERG) has been demonstrated to be associated with overall survival in cytogenetically normal acute myeloid leukemia and acute T cell-lymphoblastic leukemia (T-ALL) in adult patients. However, there are no data available regarding the impact of ERG expression on childhood ALL. In the present study, ERG expression levels were analyzed in bone marrow samples from 119 ALL pediatric patients. ALL patients demonstrated higher ERG expression compared with the controls (P<0.0001). In addition, low ERG expression identified a group of patients with higher white blood cell counts (P=0.011), higher percentages of T-ALL immunophenotype (P=0.027), and higher relapse rates (P=0.009). Survival analyses demonstrated that low ERG expression was associated with inferior relapse-free survival (RFS) in childhood ALL (P=0.036) and was an independent prognostic factor in multivariable analyses for RFS. In conclusion, low ERG expression is associated with poor outcomes and may be used to serve as a molecular prognostic marker to identify patients with a high risk of relapse in childhood ALL.

  14. Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

    PubMed

    Klafke, J Z; da Silva, M A; Rossato, M F; de Prá, S Dal Toé; Rigo, F K; Walker, C I B; Bochi, G V; Moresco, R N; Ferreira, J; Trevisan, G

    2016-02-01

    Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

  15. Effects of repetitive stress during the acute phase of Trypanosoma cruzi infection on chronic Chagas' disease in rats.

    PubMed

    Caetano, Leony Cristina; Brazão, Vânia; Filipin, Marina Del Vecchio; Santello, Fabricia Helena; Caetano, Luana Naiara; Toldo, Miriam Paula Alonso; Caldeira, Jerri C; do Prado, José Clóvis

    2009-03-01

    The effect of repetitive stress during acute infection with Trypanosoma cruzi (T. cruzi) on the chronic phase of ensuing Chagas' disease was the focus of this investigation. The aim of this study was to evaluate in Wistar rats the influence of repetitive stress during the acute phase of infection (7 days) with the Y strain of T. cruzi on the chronic phase of the infection (at 180 days). Exposure to ether vapor for 1 min twice a day was used as a stressor. Repetitive stress enhanced the number of circulating parasites and cardiac tissue disorganization, from a moderate to a severe diffuse mononuclear inflammatory process and the presence of amastigote burden in the cardiac fibers. Immunological parameters revealed that repetitive stress triggered a reduced concanavalin A induced splenocyte proliferation in vitro with major effects on the late chronic phase. Serum interleukin-12 concentration decreased in both stressed and infected rats in the early phase of infection although it was higher on 180 days post-infection. These results suggest that repetitive stress can markedly impair the host's immune system and enhance the pathological process during the chronic phase of Chagas' disease.

  16. Identification and expression of mutations in the hydroxymethylbilane synthase gene causing acute intermittent porphyria (AIP).

    PubMed Central

    Solis, C.; Lopez-Echaniz, I.; Sefarty-Graneda, D.; Astrin, K. H.; Desnick, R. J.

    1999-01-01

    BACKGROUND: Acute intermittent porphyria (AIP), an autosomal dominant inborn error, results from the half-normal activity of the heme biosynthetic enzyme hydroxymethylbilane synthase (EC 4.3.1.8; HMB-synthase). This disease is characterized by acute, life-threatening neurologic attacks that are precipitated by various drugs, hormones, and other factors. The enzymatic and/or biochemical diagnosis of AIP heterozygotes is problematic; therefore, efforts have focused on the identification of HMB-synthase mutations so that heterozygotes can be identified and educated to avoid the precipitating factors. In Spain, the occurrence of AIP has been reported, but the nature of the HMB-synthase mutations causing AIP in Spanish families has not been investigated. Molecular analysis was therefore undertaken in nine unrelated Spanish AIP patients. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and family members of nine unrelated Spanish families with AIP. The HMB-synthase gene was amplified by long-range PCR and the nucleotide sequence of each exon was determined by cycle sequencing. RESULTS: Three new mutations, a missense, M212V; a single base insertion, g4715insT; and a deletion/insertion, g7902ACT-->G, as well as five previously reported mutations (G111R, R116W, R149X R167W, and R173W) were detected in the Spanish probands. Expression of the novel missense mutation M212V in E. coli revealed that the mutation was causative, having <2% residual activity. CONCLUSIONS: These studies identified the first mutations in the HMB-synthase gene causing AIP in Spanish patients. Three of the mutations were novel, while five previously reported lesions were found in six Spanish families. These findings enable accurate identification and counseling of presymptomatic carriers in these nine unrelated Spanish AIP families and further demonstrate the genetic heterogeneity of mutations causing AIP. Images Fig. 1 PMID:10602775

  17. Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers.

    PubMed

    Kim, Min S; Kim, Yoo R; Yoo, Nam J; Lee, Sug H

    2013-02-01

    DNMT3A, a DNA methyltransferase that functions for de novo methylation, is important in development and many cellular processes related to tumorigenesis. Somatic mutations of DNMT3A gene, including recurrent mutations in its Arg-882, were recently reported in acute myelogenous leukemia (AML), strongly suggesting its role in development of AML. To see whether DNMT3A mutation occurs in other malignancies as well, we analyzed DNMT3A in 916 cancer tissues from 401 hematologic malignancies (AML, acute lymphoblastic leukemias (ALL), multiple myelomas and lymphomas) and 515 carcinomas (lung, breast, prostate, colorectal and gastric carcinomas) using a single-strand conformation polymorphism (SSCP) assay. We identified DNMT3A mutations, especially the Arg-882 mutations, in adulthood AML (9.4%). In addition, we found DNMT3A mutations in pre-B-ALL and three lung cancers at lower frequencies. Allelic loss of DNMT3A was frequently observed in most cancer types analyzed, including lymphomas (48.1%), gastric cancers (23.5%) and lung cancers (18.3%) irrespective of DNMT3A mutation. Also, loss of DNMT3A expression was common in lung cancers (46.4%), and was associated with the allelic loss. Our data indicate that DNMT3A gene is mutated mainly in AML, but it occurs in other cancers, such as ALL and lung cancer, despite the lower incidences. Also, the data suggest that DNMT3A is altered in many cancer types by various ways, including somatic mutations, allelic loss and loss of expression that might play roles in tumorigenesis.

  18. Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction

    PubMed Central

    Cyr, Derek D.; Lucas, Joseph E.; Zaas, Aimee K.; Woods, Christopher W.; Newby, L. Kristin; Kraus, William E.; Ginsburg, Geoffrey S.

    2015-01-01

    Background Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. Methods A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. Results In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). Conclusions A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection

  19. Diminished acute phase response and increased hepatic inflammation of aged rats in response to intraperitoneal injection of lipopolysaccharide.

    PubMed

    Gomez, Christian R; Acuña-Castillo, Claudio; Pérez, Claudio; Leiva-Salcedo, Elías; Riquelme, Denise M; Ordenes, Gamaliel; Oshima, Kiyoko; Aravena, Mauricio; Pérez, Viviana I; Nishimura, Sumiyo; Sabaj, Valeria; Walter, Robin; Sierra, Felipe

    2008-12-01

    Aging is associated with a deterioration of the acute phase response to inflammatory challenges. However, the nature of these defects remains poorly defined. We analyzed the hepatic inflammatory response after intraperitoneal administration of lipopolysaccharide (LPS) given to Fisher 344 rats aged 6, 15, and 22-23 months. Induction of the acute phase proteins (APPs), haptoglobin, alpha-1-acid glycoprotein, and T-kininogen was reduced and/or retarded with aging. Initial induction of interleukin-6 in aged rats was normal, but the later response was increased relative to younger counterparts. An exacerbated hepatic injury was observed in aged rats receiving LPS, as evidenced by the presence of multiple microabscesses in portal tracts, confluent necrosis, higher neutrophil accumulation, and elevated serum levels of alanine aminotransferase, relative to younger animals. Our results suggest that aged rats displayed a reduced expression of APPs and increased hepatic injury in response to the inflammatory insult.

  20. Plasma-exchange as a "rescue therapy" for dermato/polymyositis in acute phase. Experience in three young patients.

    PubMed

    Cozzi, Franco; Marson, Piero; Pigatto, Erika; Tison, Tiziana; Polito, Pamela; Galozzi, Paola; De Silvestro, Giustina; Punzi, Leonardo

    2015-12-01

    There are few data in the literature supporting the efficacy of plasma-exchange in dermato/polymyositis. The authors report three cases of patients with acute disease phase showing severe pharyngo-esophageal muscle weakness unresponsive to conventional therapy (corticosteroids and immunosuppressant agents) who were treated with plasma-exchange. As the patients were at high risk of "aspiration pneumonia", tracheostomy and PEG tubes were placed. The patients underwent a series of plasma-exchange for a mean of 15 weeks, during which time they progressively recovered muscle strength, their serum muscle enzyme values returned to normal levels, and MRI showed resolution of muscle edema. The tracheostomy and PEG tubes could be removed. Our findings suggest that plasma-exchange in association with immunosuppressant agents could play a relevant role in the management of dermato/polymyositis in acute phase.

  1. RAD51 and XRCC3 gene polymorphisms and the risk of developing acute myeloid leukemia.

    PubMed

    Hamdy, Mona S; El-Haddad, Alaa M; Bahaa El-Din, Neveen M; Makhlouf, Manal Mohamed; Abdel-Hamid, Samah M

    2011-10-01

    RAD51 (Rec A homolog of E. coli) is a polymorphic gene and one of the central proteins in homologous recombination-DNA-double-stand breaks (HR-DNA-DSB) repair pathway, which is vital in maintaining genetic stability within a cell. The x-ray repair cross complementing (XRCC3) protein also functions in HR-DNA-DSB repair pathway and directly interacts with and stabilizes RAD51 and the closely related RAD51C. The aim of this study was to determine the prevalence of the RAD51 and XRCC3 repair gene polymorphisms among acute myeloid leukemia (AML) patients and to define their role in development of AML and its correlation with the clinical presentation, laboratory data as well as treatment outcome using polymerase chain reaction-restriction fragment length polymorphism assay in 50 de novo AML patients as well as 30 healthy subjects as a control group. Our study revealed that RAD51 G135C and XRCC3 Thr241Met alleles were associated with increased risk of AML with odds ratio (OR) of 2.833 and 2.909 and 95% confidence interval (CI) of 1.527 to 8.983 and 1.761 to 9.788, respectively. Moreover, when combining the 2 genes polymorphisms, a significant elevation of the risk of AML was found with OR of 3.124 and 95% CI of 1.872 to 11.243. As regards treatment outcome, a highly statistical significant difference was found between XRCC3 genotypes with P value of 0.001, whereas no significant difference was present between RAD51 genotypes with P value of 0.29. This clarifies that XRCC3 gene polymorphisms was found to have a significant impact on the risk of treatment failure with OR of 3.560 and 95% CI of 1.167 to 10.875; however, RAD51 gene polymorphism was not found to have an equivalent effect with OR of 2.813 and 95% CI of 0.933 to 10.828. So XRCC3 gene polymorphism might be considered as a prognostic marker in AML. In conclusion, RAD51 and XRCC3 genes polymorphisms may play an important role in the development of AML.

  2. Chronic and Acute Stress, Gender, and Serotonin Transporter Gene-Environment Interactions Predicting Depression Symptoms in Youth

    ERIC Educational Resources Information Center

    Hammen, Constance; Brennan, Patricia A.; Keenan-Miller, Danielle; Hazel, Nicholas A.; Najman, Jake M.

    2010-01-01

    Background: Many recent studies of serotonin transporter gene by environment effects predicting depression have used stress assessments with undefined or poor psychometric methods, possibly contributing to wide variation in findings. The present study attempted to distinguish between effects of acute and chronic stress to predict depressive…

  3. Paediatric Dengue Fever diagnosed through parents' epidemiologic report and preventive strategy during the acute phase of infection.

    PubMed

    Poddighe, Dimitri; Bonomelli, Irene; Giardinetti, Silvia; Nedbal, Marco; Bruni, Paola

    2016-01-01

    In Europe, Dengue Fever is one of the most frequent imported diseases and also autochthonous cases occurred in areas where the insect vector is present. Here, we describe a child returning from Philippines and diagnosed with Dengue Fever, through the information provided by parents about an ongoing outbreak in their municipality. An appropriate clinical management in the hospital was established to monitor the occurrence of complications and to cancel the risk of dengue virus transmission in the acute phase of infection.

  4. The Concentration of Apolipoprotein A-I Decreases during Experimentally Induced Acute-Phase Processes in Pigs

    PubMed Central

    Carpintero, R.; Piñeiro, M.; Andrés, M.; Iturralde, M.; Alava, M. A.; Heegaard, P. M. H.; Jobert, J. L.; Madec, F.; Lampreave, F.

    2005-01-01

    In this work, apolipoprotein A-I (ApoA-I) was purified from pig sera. The responses of this protein after sterile inflammation and in animals infected with Actinobacillus pleuropneumoniae or Streptococcus suis were investigated. Decreases in the concentrations of ApoA-I, two to five times lower than the initial values, were observed at 2 to 4 days. It is concluded that ApoA-I is a negative acute-phase protein in pigs. PMID:15845530

  5. Serum protein capillary electrophoresis and measurement of acute phase proteins in a captive cheetah (Acinonyx jubatus) population.

    PubMed

    Depauw, Sarah; Delanghe, Joris; Whitehouse-Tedd, Katherine; Kjelgaard-Hansen, Mads; Christensen, Michelle; Hesta, Myriam; Tugirimana, Pierrot; Budd, Jane; Dermauw, Veronique; Janssens, Geert P J

    2014-09-01

    Renal and gastrointestinal pathologies are widespread in the captive cheetah (Acinonyx jubatus) population but are often diagnosed at a late stage, because diagnostic tools are limited to the evaluation of clinical signs or general blood examination. Presently, no data are available on serum proteins and acute-phase proteins in cheetahs during health or disease, although they might be important to improve health monitoring. This study aimed to quantify serum proteins by capillary electrophoresis in 80 serum samples from captive cheetahs, categorized according to health status and disease type. Moreover, serum amyloid A concentrations were measured via a turbidimetric immunoassay validated in domestic cats, whereas haptoglobin and C-reactive protein were determined by non-species-specific functional tests. Cheetahs classified as healthy had serum protein and acute phase protein concentrations within reference ranges for healthy domestic cats. In contrast, unhealthy cheetahs had higher (P < 0.001) serum amyloid A, alpha2-globulin, and haptoglobin concentrations compared with the healthy subgroup. Moreover, serum amyloid A (P = 0.020), alpha2-globulin (P < 0.001) and haptoglobin (P = 0.001) concentrations in cheetahs suffering from chronic kidney disease were significantly greater compared to the reportedly healthy cheetahs. Our study indicates that serum proteins in the cheetah can be analyzed by routine capillary electrophoresis, whereas acute-phase proteins can be measured using available immunoassays or non-species-specific techniques, which are also likely to be applicable in other exotic felids. Moreover, results suggest that serum amyloid A and haptoglobin are important acute-phase proteins in the diseased cheetah and highlight the need to evaluate their role as early-onset markers for disease.

  6. Lower Methylation of the ANGPTL2 Gene in Leukocytes from Post-Acute Coronary Syndrome Patients

    PubMed Central

    Nguyen, Albert; Mamarbachi, Maya; Turcot, Valérie; Lessard, Samuel; Yu, Carol; Luo, Xiaoyan; Lalongé, Julie; Hayami, Doug; Gayda, Mathieu; Juneau, Martin; Thorin-Trescases, Nathalie; Lettre, Guillaume; Nigam, Anil; Thorin, Eric

    2016-01-01

    DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation quantification. The functionality of ANGPTL2 methylation was assessed by an in vitro luciferase assay. In post-ACS patients, C-reactive protein and ANGPTL2 circulating levels increased significantly when compared to healthy controls. Decreased methylation of specific CpGs were found in the promoter of ANGPTL2 and allowed to discriminate age vs. disease associated methylation. In vitro DNA methylation of specific CpG lead to inhibition of ANGPTL2 promoter activity. Reduced leukocyte DNA methylation in the promoter region of ANGPTL2 is associated with the pro-inflammatory environment that characterizes patients with post-ACS differently from age-matched healthy controls. Methylation of different CpGs in ANGPTL2 gene may prove to be a reliable biomarker of coronary disease. PMID:27101308

  7. Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B

    2014-01-01

    Alpha-1-antitrypsin (AAT) is a hepatic stress protein with protease inhibitor activity. Recent evidence indicates that ischemic or toxic injury can evoke selective changes within kidney that resemble a hepatic phenotype. Hence, we tested the following: i) Does acute kidney injury (AKI) up-regulate the normally renal silent AAT gene? ii) Does rapid urinary AAT excretion result? And iii) Can AAT's anti-protease/anti-neutrophil elastase (NE) activity protect injured proximal tubule cells? CD-1 mice were subjected to ischemic or nephrotoxic (glycerol, maleate, cisplatin) AKI. Renal functional and biochemical assessments were made 4-72 hrs later. Rapidly following injury, 5-10 fold renal cortical and isolated proximal tubule AAT mRNA and protein increases occurred. These were paralleled by rapid (>100 fold) increases in urinary AAT excretion. AKI also induced marked increases in renal cortical/isolated proximal tubule NE mRNA. However, sharp NE protein levels declines resulted, which strikingly correlated (r, -0.94) with rising AAT protein levels (reflecting NE complexing by AAT/destruction). NE addition to HK-2 cells evoked ∼95% cell death. AAT completely blocked this NE toxicity, as well as Fe induced oxidant HK-2 cell attack. Translational relevance of experimental AAT gene induction was indicated by ∼100-1000 fold urinary AAT increases in 22 AKI patients (matching urine NGAL increases). We conclude: i) AKI rapidly up-regulates the renal cortical/proximal tubule AAT gene; ii) NE gene induction also results; iii) AAT can confer cytoprotection, potentially by blocking/reducing cytotoxic NE accumulation; and iv) marked increases in urinary AAT excretion in AKI patients implies clinical relevance of the AKI- AAT induction pathway.

  8. Modulation of C4b-binding protein isoforms during the acute phase response caused by orthopedic surgery.

    PubMed

    Criado-García, O; González-Rubio, C; López-Trascasa, M; Pascual-Salcedo, D; Munuera, L; Rodríguez de Córdoba, S

    1997-01-01

    Orthopedic surgery is described as an event with a high risk of thromboembolic diseases. This is probably a consequence of a synergistic combination of different risk factors in the patients subjected to this type of surgery, including age, immobilization, anesthesia and different hypercoagulable states. After surgery patients develop an acute-phase response that leads to changes in several plasma proteins. One of these proteins is the complement regulator C4b-binding protein (C4BP). We have recently shown that in some acute-phase patients C4BP is incorrectly controlled (with elevation of the C4BP beta-containing isoforms), leading to a potential hypercoagulable state by decreasing the plasma levels of free (active) protein S. Here we have studied whether patients subjected to orthopedic surgery have an appropriate modulation of the C4BP isoforms during their postoperative acute-phase responses. We have analyzed the evolution of the C4BP isoforms in serial samples from 11 patients who have undergone knee (or hip) prosthesis surgery (mean age 70 years), or scoliosis surgery (mean age 18 years). Our data suggest a similar evolution of C4BP isoforms in all these patients, with an almost exclusive increase of C4BP isoforms lacking C4BP beta polypeptides and steady levels of free protein S.

  9. PLASMA PROTEIN ELECTROPHORESIS AND SELECT ACUTE PHASE PROTEINS IN HEALTHY BONNETHEAD SHARKS (SPHYRNA TIBURO) UNDER MANAGED CARE.

    PubMed

    Hyatt, Michael W; Field, Cara L; Clauss, Tonya M; Arheart, Kristopher L; Cray, Carolyn

    2016-12-01

    Preventative health care of elasmobranchs is an important but understudied field of aquatic veterinary medicine. Evaluation of inflammation through the acute phase response is a valuable tool in health assessments. To better assess the health of bonnethead sharks ( Sphyrna tiburo ) under managed care, normal reference intervals of protein electrophoresis (EPH) and the acute phase proteins, C-reactive protein (CRP) and haptoglobin (HP), were established. Blood was collected from wild caught, captive raised bonnethead sharks housed at public aquaria. Lithium heparinized plasma was either submitted fresh or stored at -80°C prior to submission. Electrophoresis identified protein fractions with migration characteristics similar to other animals with albumin, α-1 globulin, α-2 globulin, β globulin, and γ globulin. These fractions were classified as fractions 1-5 as fractional contents are unknown in this species. Commercial reagents for CRP and HP were validated for use in bonnethead sharks. Reference intervals were established using the robust method recommended by the American Society for Veterinary Clinical Pathology for the calculation of 90% reference intervals. Once established, the diagnostic and clinical applicability of these reference intervals was used to assess blood from individuals with known infectious diseases that resulted in systemic inflammation and eventual death. Unhealthy bonnethead sharks had significantly decreased fraction 2, fraction 3, and fraction 3:4 ratio and significantly increased fraction 5, CRP, and HP. These findings advance our understanding of elasmobranch acute phase inflammatory response and health and aid clinicians in the diagnosis of inflammatory disease in bonnethead sharks.

  10. Metabolizable protein supply modulated the acute-phase response following vaccination of beef steers.

    PubMed

    Moriel, P; Arthington, J D

    2013-12-01

    Our objective was to evaluate the effects of MP supply, through RUP supplementation, on the acute-phase response of beef steers following vaccination. On d 0, Brangus-crossbred steers (n = 24; 173 ± 31 kg; 175 ± 16 d of age) were randomly assigned to receive 1 of 3 isocaloric diets formulated to provide 85, 100, and 115% of the daily MP requirements of a beef steer gaining 0.66 kg of BW daily. Diets were limit-fed at 1.8% of BW (DM basis) and individually provided to steers once daily (0800 h) from d 0 to 29. Steers were weighed on d 0 and 29, following a 12-h period of feed and water withdrawal. On d 7, steers were vaccinated against Mannheimia haemolytica (OneShot, Pfizer), and blood samples were collected on d 0, 7, 8, 10, 14, 21, and 30. Plasma metabolites were analyzed as repeated measures using the MIXED procedure of SAS. Final BW and ADG were similar (P ≥ 0.50) among treatments (mean = 184 ± 9 kg and 0.5 ± 0.08 kg/d, respectively). Effects of time were detected (P < 0.01) for plasma concentrations of all acute-phase proteins, which peaked between d 7 to 14, returning to baseline concentrations by d 29. Treatment effects were not detected (P ≥ 0.19) for plasma concentrations of acid-soluble protein, albumin, fibrinogen, IGF-1 and serum amyloid-A. Plasma concentrations of total protein (TP) and plasma urea nitrogen (PUN) increased (P ≤ 0.05) with increasing supply of MP (87.1, 89.6, and 90.1 ± 1.09 mg TP/mL and 6.1, 8.3, and 10.3 ± 0.41 mg PUN/dL for 85, 100, and 115% MP steers, respectively). From d 10 to 29, steers provided 115% MP had less (P < 0.001) plasma concentrations of ceruloplasmin than steers fed 85 and 100% MP, which had similar plasma ceruloplasmin concentrations. On d 14, plasma concentrations of haptoglobin were greatest (P ≤ 0.06) for steers fed 115% MP, intermediate for 100% MP, and least for 85% MP (0.98, 0.71 and 0.44 ± 0.099 mg/mL, respectively). On d 10, plasma concentrations of creatinine were greater (P = 0.01) for steers

  11. The Fusarium toxin deoxynivalenol (DON) modulates the LPS induced acute phase reaction in pigs.

    PubMed

    Dänicke, Sven; Brosig, Bianca; Kersten, Susanne; Kluess, Jeannette; Kahlert, Stefan; Panther, Patricia; Diesing, Anne-Kathrin; Rothkötter, Hermann-Josef

    2013-07-04

    The systemic effects of the Fusarium toxin deoxynivalenol (DON) and of bacterial lipopolysaccharides (LPS) were studied in male castrated pigs (40.4 ± 3.7 kg) infused intravenously with either DON or LPS alone (100 μg DON/kg/h, 7.5 μg/LPS/kg/h), or together (100 μg DON plus 7.5 μg/LPS/kg/h). The Control group received a saline infusion (n=6/treatment, 24h observation period). An additional DON infusion did not exacerbate the clinical signs observed in LPS-infused pigs. For example, rectal temperature climaxed after 4h (40.4 ± 0.2°C) and 5h (40.1 ± 0.3°C), in the LPS and LPS+DON group, respectively. Saline and DON alone did not induce an acute phase reaction as indicated by unaltered plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) while LPS caused a significant rise of both cytokines. TNF-alpha plasma peak concentrations were significantly higher in the LPS compared to the DON+LPS group (94.3 ± 17.2 ng/mL vs. 79.2 ± 15.7 ng/mL) while IL-6 climaxed earlier in the latter group (3h p.i. vs. 2h p.i.). From the tested clinical-chemical plasma characteristics the total bilirubin concentration and the ASAT activity were strongly elevated by the LPS infusion and additionally increased and decreased by DON, respectively. In conclusion, the LPS-induced effects were only marginally modified by DON.

  12. Influence of induction of parturition on the neonatal acute phase response in foals.

    PubMed

    Duggan, Vivienne E; Holyoak, G Reed; MaCallister, Charles G; Confer, Anthony W

    2007-01-15

    The objectives of the present study were to determine whether induction of parturition in mares at term with low doses of oxytocin (2.5 i.u. i.v. every 20 min) affected the incidence of peri-partum complications or inflammatory responses in the neonatal foal. Parturition was induced in 11 of 26 mares and the remainder foaled spontaneously. Serum concentrations of amyloid A (AA; an acute phase protein) were measured (with a commercial ELISA) from 0 to 72 h postpartum in 18 of the neonatal foals. The incidence of dystocia and premature placental separation was higher in induced mares (2 of 11 and 1 of 11 versus 0 of 15 and 0 of 15, respectively), whereas retained fetal membranes were more common in spontaneous foalings (2 of 15 versus 0 of 11). When abnormal foals were excluded (to decrease the influence of endogenous serum AA elevations), serum concentrations of AA increased to the same extent over time in foals with induced versus spontaneous parturition; foals with spontaneous parturition had a mean serum AA concentration of 7.8 microg/mL at birth that increased to a maximum of 58.9 microg/mL at 36 h; foals with induced parturition had a mean serum AA concentration of 5.4 microg/mL at birth that increased to a maximum of 41.4 microg/mL at 48 h. Baseline serum AA concentrations were lower in induced foals. We concluded that inducing parturition with low doses of oxytocin in mares at term did not affect (relative to spontaneous parturition) the temporal dynamics of serum AA concentrations in the normal foal in the first 72 h of life. However, the induction procedure may lead to complications during parturition that, if not detected early, could result in the development of an inflammatory response in the neonate.

  13. Estimating mortality risk in preoperative patients using immunologic, nutritional, and acute-phase response variables.

    PubMed Central

    Christou, N V; Tellado-Rodriguez, J; Chartrand, L; Giannas, B; Kapadia, B; Meakins, J; Rode, H; Gordon, J

    1989-01-01

    We measured the delayed type hypersensitivity (DTH) skin test response, along with additional variables of host immunocompetence in 245 preoperative patients to determine which variables are associated with septic-related deaths following operation. Of the 14 deaths (5.7%), 12 were related to sepsis and in 2 sepsis was contributory. The DTH response (p less than 0.00001), age (p less than 0.0002), serum albumin (p less than 0.003), hemoglobin (p less than 0.02), and total hemolytic complement (p less than 0.03), were significantly different between those who died and those who lived. By logistic regression analysis, only the DTH skin test response (log likelihood = 41.7, improvement X2 = 6.24, p less than 0.012) and the serum albumin (log likelihood = 44.8, improvement X2 = 17.7, p less than 0.001) were significantly and independently associated with the deaths. The resultant probability of mortality calculation equation was tested in a separate validation group of 519 patients (mortality = 5%) and yielded a good predictive capability as assessed by (1) X2 = 0.08 between observed and expected deaths, NS; (2) Goodman-Kruskall G statistic = 0.673) Receiver-Operating-Characteristic (ROC) curve analysis with an area under the ROC curve, Az = 0.79 +/- 0.05. We conclude that a reduced immune response (DTH skin test anergy) plus a nutritional deficit and/or acute-phase response change are both associated with increased septic-related deaths in elective surgical patients. PMID:2472781

  14. Telemedicine Approaches to Evaluating Acute-phase Retinopathy of Prematurity: Study Design

    PubMed Central

    2016-01-01

    Purpose Detecting sight-threatening retinopathy of prematurity (ROP) relies on a diagnostic examination (DE) performed by an experienced ophthalmologist. An alternative may be a telemedicine system where retinal images of at-risk infants are graded by readers to determine features of ROP indicating the need for a DE. Methods The multicenter “Telemedicine Approaches to Evaluating Acute-phase ROP” (e-ROP) Study is a cohort study of 2,000 infants with birth weights <1251g. At each visit, ophthalmologists perform DEs and non-physician imagers obtain iris and five retinal images with the disc positioned in the center, right, left, up anddown. Images are uploaded to a secure server for grading by non-physician readers for the detection of plus disease, stage 3 ROP and/or zone I disease, any of which indicates “referral-warranted ROP (RW-ROP).” Images from all infants with RW-ROP and a random sample of infants without RW-ROP (based on DEs) are selected for grading. Gradings are compared to DEs to determine the validity and evaluate reliability, feasibility, safety, and cost-effectiveness of the telemedicine system. Results e-ROP is conducted in 12 Clinical Centers in the US and Canada with Study Headquarters, the Data Coordinating Center and the Image Reading Center in Philadelphia and the ROP Data Center in Oklahoma City. 27 Study Center Coordinators, 34 ophthalmologists; 26 imagers, and 4 readers have been certified. All study data are submitted using a secure web-based system. Conclusion The design and findings of this study will be useful to conduct other ROP studies or evaluate telemedicine for other diseases. PMID:24955738

  15. Gene expression profiles of four heat shock proteins in response to different acute stresses in shrimp, Litopenaeus vannamei.

    PubMed

    Qian, Zhaoying; Liu, Xiaolin; Wang, Lijun; Wang, Xianzong; Li, Yang; Xiang, Jianhai; Wang, Ping

    2012-11-01

    Heat shock proteins (HSPs) are a suite of highly conserved proteins well known for their quick responses to environmental stresses. However, the respective roles of different HSPs in response to a particular environmental stress have not received adequate scientific attentions to date. In this study, the expression profiles of four HSP genes (Lvhsp60, Lvhsp70, Lvhsc70, and Lvhsp90) of the Pacific white shrimp, Litopenaeus vannamei under acute thermal stress, pH challenge, and heavy metal exposure were investigated, respectively, using the quantitative real-time reverse transcription polymerase chain reaction technique. Results showed that the four genes exhibited quite different expression profiles when the shrimp were subjected to each of the above stressors. Under acute thermal stress, the messenger RNA (mRNA) levels of all the four genes were significantly induced, and the transcription level of Lvhsp70 was the most sensitive to temperature fluctuations. Under acute pH challenge, the relative mRNA expression of the four genes was shown to be time and pH dependent, and the strongest response occurred in Lvhsp60. Under acute heavy metal exposure, transcripts of each of the four genes varied depending on metal type and exposure time. Lvhsp60 displayed particularly high sensitivity to cadmium and manganese exposure, while Lvhsp70 showed the most sensitive response to iron and zinc treatments. The results obtained suggest that different LvHSP genes may play different roles in mediating cell stress caused by a specific environmental stressor. Given the response sensitivity and intensity of LvHSP genes to environmental stresses, Lvhsp70 may be most suitable to act as a biomarker indicating thermal stress, iron and zinc stimulation, while Lvhsp60 may be a promising candidate marker of pH stress, cadmium and manganese exposure in shrimp.

  16. Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia

    PubMed Central

    Vener, Tatiana I.; Raponi, Mitch; Ritchie, Ellen K.; Smith, B. Douglas; Gore, Steven D.; Morris, Lawrence E.; Feldman, Eric J.; Greer, Jacqueline M.; Malek, Sami; Carraway, Hetty E.; Ironside, Valerie; Galkin, Steven; Levis, Mark J.; McDevitt, Michael A.; Roboz, Gail R.; Gocke, Christopher D.; Derecho, Carlo; Palma, John; Wang, Yixin; Kaufmann, Scott H.; Wright, John J.; Garret-Mayer, Elizabeth

    2012-01-01

    Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771. PMID:22001391

  17. Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia.

    PubMed

    Karp, Judith E; Vener, Tatiana I; Raponi, Mitch; Ritchie, Ellen K; Smith, B Douglas; Gore, Steven D; Morris, Lawrence E; Feldman, Eric J; Greer, Jacqueline M; Malek, Sami; Carraway, Hetty E; Ironside, Valerie; Galkin, Steven; Levis, Mark J; McDevitt, Michael A; Roboz, Gail R; Gocke, Christopher D; Derecho, Carlo; Palma, John; Wang, Yixin; Kaufmann, Scott H; Wright, John J; Garret-Mayer, Elizabeth

    2012-01-05

    Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.

  18. Temporal Changes in Rat Liver Gene Expression after Acute Cadmium and Chromium Exposure

    PubMed Central

    Madejczyk, Michael S.; Baer, Christine E.; Dennis, William E.; Minarchick, Valerie C.; Leonard, Stephen S.; Jackson, David A.; Stallings, Jonathan D.; Lewis, John A.

    2015-01-01

    U.S. Service Members and civilians are at risk of exposure to a variety of environmental health hazards throughout their normal duty activities and in industrial occupations. Metals are widely used in large quantities in a number of industrial processes and are a common environmental toxicant, which increases the possibility of being exposed at toxic levels. While metal toxicity has been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify candidate biomarkers, rats were exposed via a single intraperitoneal injection to three concentrations of CdCl2 and Na2Cr2O7, with livers harvested at 1, 3, or 7 days after exposure. Cd and Cr accumulated in the liver at 1 day post exposure. Cd levels remained elevated over the length of the experiment, while Cr levels declined. Metal exposures induced ROS, including hydroxyl radical (•OH), resulting in DNA strand breaks and lipid peroxidation. Interestingly, ROS and cellular damage appeared to increase with time post-exposure in both metals, despite declines in Cr levels. Differentially expressed genes were identified via microarray analysis. Both metals perturbed gene expression in pathways related to oxidative stress, metabolism, DNA damage, cell cycle, and inflammatory response. This work provides insight into the temporal effects and mechanistic pathways involved in acute metal intoxication, leading to the identification of candidate biomarkers. PMID:25993096

  19. Systematic analysis of hematopoietic gene expression profiles for prognostic prediction in acute myeloid leukemia

    PubMed Central

    Varn, Frederick S.; Andrews, Erik H.; Cheng, Chao

    2015-01-01

    Acute myeloid leukemia (AML) is a hematopoietic disorder initiated by the leukemogenic transformation of myeloid cells into leukemia stem cells (LSCs). Preexisting gene expression programs in LSCs can be used to assess their transcriptional similarity to hematopoietic cell types. While this relationship has previously been examined on a small scale, an analysis that systematically investigates this relationship throughout the hematopoietic hierarchy has yet to be implemented. We developed an integrative approach to assess the similarity between AML patient tumor profiles and a collection of 232 murine hematopoietic gene expression profiles compiled by the Immunological Genome Project. The resulting lineage similarity scores (LSS) were correlated with patient survival to assess the relationship between hematopoietic similarity and patient prognosis. This analysis demonstrated that patient tumor similarity to immature hematopoietic cell types correlated with poor survival. As a proof of concept, we highlighted one cell type identified by our analysis, the short-term reconstituting stem cell, whose LSSs were significantly correlated with patient prognosis across multiple datasets, and showed distinct patterns in patients stratified by traditional clinical variables. Finally, we validated our use of murine profiles by demonstrating similar results when applying our method to human profiles. PMID:26598031

  20. Systematic analysis of hematopoietic gene expression profiles for prognostic prediction in acute myeloid leukemia.

    PubMed

    Varn, Frederick S; Andrews, Erik H; Cheng, Chao

    2015-11-24

    Acute myeloid leukemia (AML) is a hematopoietic disorder initiated by the leukemogenic transformation of myeloid cells into leukemia stem cells (LSCs). Preexisting gene expression programs in LSCs can be used to assess their transcriptional similarity to hematopoietic cell types. While this relationship has previously been examined on a small scale, an analysis that systematically investigates this relationship throughout the hematopoietic hierarchy has yet to be implemented. We developed an integrative approach to assess the similarity between AML patient tumor profiles and a collection of 232 murine hematopoietic gene expression profiles compiled by the Immunological Genome Project. The resulting lineage similarity scores (LSS) were correlated with patient survival to assess the relationship between hematopoietic similarity and patient prognosis. This analysis demonstrated that patient tumor similarity to immature hematopoietic cell types correlated with poor survival. As a proof of concept, we highlighted one cell type identified by our analysis, the short-term reconstituting stem cell, whose LSSs were significantly correlated with patient prognosis across multiple datasets, and showed distinct patterns in patients stratified by traditional clinical variables. Finally, we validated our use of murine profiles by demonstrating similar results when applying our method to human profiles.

  1. Expression pattern of the RAR alpha-PML fusion gene in acute promyelocytic leukemia.

    PubMed Central

    Alcalay, M; Zangrilli, D; Fagioli, M; Pandolfi, P P; Mencarelli, A; Lo Coco, F; Biondi, A; Grignani, F; Pelicci, P G

    1992-01-01

    Two chimeric genes, PML-RAR alpha and RAR alpha-PML, are formed as a consequence of the acute promyelocytic leukemia (APL)-specific reciprocal translocation of chromosomes 15 and 17 [t(15;17)]. PML-RAR alpha is expressed as a fusion protein. We investigated the organization and expression pattern of the RAR alpha-PML gene in a series of APL patients representative of the molecular heterogeneity of the t(15;17) and found (i) two types of RAR alpha-PML mRNA junctions (RAR alpha exon 2/PML exon 4 or RAR alpha exon 2/PML exon 7) that maintain the RAR alpha and PML longest open reading frames aligned and are the result of chromosome 15 breaking at two different sites; and (ii) 10 different RAR alpha-PML fusion transcripts that differ for the assembly of their PML coding exons. A RAR alpha-PML transcript was present in most, but not all, APL patients. Images PMID:1317574

  2. Acute intermittent porphyria: A single-base deletion and a nonsense mutation in the human hydroxymethylbilane synthase gene, predicting truncations of the enzyme polypeptide

    SciTech Connect

    Lee, G.L.; Astrin, K.H.; Desnick, R.J.

    1995-08-28

    Acute intermittent porphyria (AIP) is an autosomal-dominant inborn error of metabolism that results from the half-normal activity of the third enzyme in the heme biosynthetic pathway, hydroxymethylbilane synthase (HMB-synthase). AIP is an ecogenetic condition, since the life-threatening acute attacks are precipitated by various factors, including drugs, alcohol, fasting, and certain hormones. Biochemical diagnosis is problematic, and the identification of mutations in the HMB-synthase gene provides accurate detection of presymptomatic heterozygotes, permitting avoidance of the acute precipitating factors. By direct solid-phase sequencing, two mutations causing AIP were identified, an adenine deletion at position 629 in exon 11(629delA), which alters the reading frame and predicts premature truncation of the enzyme protein after amino acid 255, and a nonsense mutation in exon 12 (R225X). These mutations were confirmed by either restriction enzyme analysis or family studies of symptomatic patients, permitting accurate presymptomatic diagnosis of affected relatives. 29 refs., 2 figs.

  3. Modulation of the acute phase response following a lipopolysaccharide challenge in pigs supplemented with an all-natural Saccharomyces cerevisiae fermentation product

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine if feeding a Saccharomyces cerevisiae fermentation product to weaned pigs would reduce the stress and acute phase responses (APR) following an acute lipopolysaccharide (LPS) challenge. Pigs (n = 20; 6.4 +/- 0.2 kg body weight) were obtained and transported to an ...

  4. Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice.

    PubMed

    Poulsen, Sarah S; Knudsen, Kristina B; Jackson, Petra; Weydahl, Ingrid E K; Saber, Anne T; Wallin, Håkan; Vogel, Ulla

    2017-01-01

    Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been linked to an increased risk of developing cardiovascular disease in addition to the well-documented physicochemical-dependent adverse lung effects. A proposed mechanism is through a strong and sustained pulmonary secretion of acute phase proteins to the blood. We identified physicochemical determinants of MWCNT-induced systemic acute phase response by analyzing effects of pulmonary exposure to 14 commercial, well-characterized MWCNTs in female C57BL/6J mice pulmonary exposed to 0, 6, 18 or 54 μg MWCNT/mouse. Plasma levels of acute phase response proteins serum amyloid A1/2 (SAA1/2) and SAA3 were determined on day 1, 28 or 92. Expression levels of hepatic Saa1 and pulmonary Saa3 mRNA levels were assessed to determine the origin of the acute phase response proteins. Pulmonary Saa3 mRNA expression levels were greater and lasted longer than hepatic Saa1 mRNA expression. Plasma SAA1/2 and SAA3 protein levels were related to time and physicochemical properties using adjusted, multiple regression analyses. SAA3 and SAA1/2 plasma protein levels were increased after exposure to almost all of the MWCNTs on day 1, whereas limited changes were observed on day 28 and 92. SAA1/2 and SAA3 protein levels did not correlate and only SAA3 protein levels correlated with neutrophil influx. The multiple regression analyses revealed a protective effect of MWCNT length on SAA1/2 protein level on day 1, such that a longer length resulted in lowered SAA1/2 plasma levels. Increased SAA3 protein levels were positively related to dose and content of Mn, Mg and Co on day 1, whereas oxidation and diameter of the MWCNTs were protective on day 28 and 92, respectively. The results of this study reveal very differently controlled pulmonary and hepatic acute phase responses after MWCNT exposure. As the responses were influenced by the physicochemical properties of the MWCNTs, this study provides the first step towards designing

  5. EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells.

    PubMed

    Yaguchi, Akinori; Ishibashi, Takeshi; Terada, Kazuki; Ueno-Yokohata, Hitomi; Saito, Yuya; Fujimura, Junya; Shimizu, Toshiaki; Ohki, Kentaro; Manabe, Atsushi; Kiyokawa, Nobutaka

    2017-04-04

    ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.

  6. Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia.

    PubMed

    Safavi, Setareh; Hansson, Markus; Karlsson, Karin; Biloglav, Andrea; Johansson, Bertil; Paulsson, Kajsa

    2015-01-01

    In contrast to acute lymphoblastic leukemia in children, adult cases of this disease are associated with a very poor prognosis. In order to ascertain whether the frequencies and patterns of submicroscopic changes, identifiable with single nucleotide polymorphism array analysis, differ between childhood and adult acute lymphoblastic leukemia, we performed single nucleotide polymorphism array analyses of 126 adult cases, the largest series to date, including 18 paired diagnostic and relapse samples. Apart from identifying characteristic microdeletions of the CDKN2A, EBF1, ETV6, IKZF1, PAX5 and RB1 genes, the present study uncovered novel, focal deletions of the BCAT1, BTLA, NR3C1, PIK3AP1 and SERP2 genes in 2-6% of the adult cases. IKZF1 deletions were associated with B-cell precursor acute lymphoblastic leukemia (P=0.036), BCR-ABL1-positive acute lymphoblastic leukemia (P<0.001), and higher white blood cell counts (P=0.005). In addition, recurrent deletions of RASSF3 and TOX were seen in relapse samples. Comparing paired diagnostic/relapse samples revealed identical changes at diagnosis and relapse in 27%, clonal evolution in 22%, and relapses evolving from ancestral clones in 50%, akin to what has previously been reported in pediatric acute lymphoblastic leukemia and indicating that the mechanisms of relapse may be similar in adult and childhood cases. These findings provide novel insights into the leukemogenesis of adult acute lymphoblastic leukemia, showing similarities to childhood disease in the pattern of deletions and the clonal relationship between diagnostic and relapse samples, but with the adult cases harboring additional aberrations that have not been described in pediatric acute lymphoblastic leukemia.

  7. A 17-gene stemness score for rapid determination of risk in acute leukaemia.

    PubMed

    Ng, Stanley W K; Mitchell, Amanda; Kennedy, James A; Chen, Weihsu C; McLeod, Jessica; Ibrahimova, Narmin; Arruda, Andrea; Popescu, Andreea; Gupta, Vikas; Schimmer, Aaron D; Schuh, Andre C; Yee, Karen W; Bullinger, Lars; Herold, Tobias; Görlich, Dennis; Büchner, Thomas; Hiddemann, Wolfgang; Berdel, Wolfgang E; Wörmann, Bernhard; Cheok, Meyling; Preudhomme, Claude; Dombret, Herve; Metzeler, Klaus; Buske, Christian; Löwenberg, Bob; Valk, Peter J M; Zandstra, Peter W; Minden, Mark D; Dick, John E; Wang, Jean C Y

    2016-12-15

    Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC(+) and 89 LSC(-) cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.

  8. Novel Polymorphisms in the Myosin Light Chain Kinase Gene Confer Risk for Acute Lung Injury

    PubMed Central

    Gao, Li; Grant, Audrey; Halder, Indrani; Brower, Roy; Sevransky, Jonathan; Maloney, James P.; Moss, Marc; Shanholtz, Carl; Yates, Charles R.; Meduri, Gianfranco Umberto; Shriver, Mark D.; Ingersoll, Roxann; Scott, Alan F.; Beaty, Terri H.; Moitra, Jaideep; Ma, Shwu Fan; Ye, Shui Q.; Barnes, Kathleen C.; Garcia, Joe G. N.

    2006-01-01

    The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon–intron boundaries, and 2 kb of 5′ UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P < 0.001), with an additional SNP associated with the ALI phenotype (P = 0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P = 0.002) and with ALI (P = 0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P < 0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5′ of the MYLK gene in both European and African Americans and an additional 3′ region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI. PMID:16399953

  9. A host-based RT-PCR gene expression signature to identify acute respiratory viral infection.

    PubMed

    Zaas, Aimee K; Burke, Thomas; Chen, Minhua; McClain, Micah; Nicholson, Bradly; Veldman, Timothy; Tsalik, Ephraim L; Fowler, Vance; Rivers, Emanuel P; Otero, Ronny; Kingsmore, Stephen F; Voora, Deepak; Lucas, Joseph; Hero, Alfred O; Carin, Lawrence; Woods, Christopher W; Ginsburg, Geoffrey S

    2013-09-18

    Improved ways to diagnose acute respiratory viral infections could decrease inappropriate antibacterial use and serve as a vital triage mechanism in the event of a potential viral pandemic. Measurement of the host response to infection is an alternative to pathogen-based diagnostic testing and may improve diagnostic accuracy. We have developed a host-based assay with a reverse transcription polymerase chain reaction (RT-PCR) TaqMan low-density array (TLDA) platform for classifying respiratory viral infection. We developed the assay using two cohorts experimentally infected with influenza A H3N2/Wisconsin or influenza A H1N1/Brisbane, and validated the assay in a sample of adults presenting to the emergency department with fever (n = 102) and in healthy volunteers (n = 41). Peripheral blood RNA samples were obtained from individuals who underwent experimental viral challenge or who presented to the emergency department and had microbiologically proven viral respiratory infection or systemic bacterial infection. The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively. We validated this host gene expression signature in a cohort of 102 individuals arriving at the emergency department. The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%). These results show that RT-PCR-based detection of a host gene expression signature can classify individuals with respiratory viral infection and sets the stage for prospective evaluation of this diagnostic approach in a clinical setting.

  10. Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

    PubMed Central

    Bolli, Niccolò; Manes, Nicla; McKerrell, Thomas; Chi, Jianxiang; Park, Naomi; Gundem, Gunes; Quail, Michael A.; Sathiaseelan, Vijitha; Herman, Bram; Crawley, Charles; Craig, Jenny I. O.; Conte, Natalie; Grove, Carolyn; Papaemmanuil, Elli; Campbell, Peter J.; Varela, Ignacio; Costeas, Paul; Vassiliou, George S.

    2015-01-01

    Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples. Consequently, we were able to detect copy number changes, such as an interstitial deletion of BCOR, three MLL partial tandem duplications, and a novel KRAS amplification. With regards to coding mutations, we identified likely oncogenic variants in 41 of 42 samples. NPM1 mutations were the most frequent, followed by FLT3, DNMT3A and TET2. NPM1 and FLT3 indels were reported with good efficiency. We also showed that DNMT3A mutations can persist post-chemotherapy and in 2 cases studied at diagnosis and relapse, we were able to delineate the dynamics of tumor evolution and give insights into order of acquisition of variants. HaloPlex is a quick and reliable target enrichment method that can aid diagnosis and prognostic stratification of acute myeloid leukemia patients. PMID:25381129

  11. IL-8 gene polymorphism in acute biliary and non biliary pancreatitis: probable cause of high level parameters?

    PubMed Central

    Ozen, Filiz; Yildirim, Ibrahim Halil; Ozemir, Ibrahim Ali; Ozlu, Can; Alimoglu, Orhan

    2017-01-01

    Backgrounds/Aims Inflammatory mediators of the innate immune response play fundamental roles in the pathogenesis of acute pancreatitis. The correlation between interleukin-8 (IL-8) gene polymorphism with types of acute pancreatitis and severity of pancreatitis, was evaluated in this study. Methods According to the diagnostic criteria, 176 patients with acute pancreatitis were grouped into biliary (n=83) and nonbiliary pancreatitis (n=93). Healthy blood donors (n=100) served as controls. Serum alanine transaminase, aspartate transaminase, total and direct bilirubin, amylase, lypase, white blood cell count and c-reactive protein levels were evaluated to correlate with IL-8 rs4073 (-251T/A) polymorphism, which was analyzed using a real-time polymerase chain reaction method with melting point analysis. Results The IL-8 AA genotype was detected with a significantly higher frequency among the patients with acute biliary pancreatitis having higher alanine transaminase levels than the median range. Homozygote alleles were significantly higher among patients with acute biliary pancreatitis having amylase levels higher than the median range. Conclusions Determination of the frequency of IL-8 polymorphism in acute pancreatitis is informative and provides further evidence concerning the role of IL-8 in laboratory tests. PMID:28317043

  12. Exercise, sex, menstrual cycle phase, and 17beta-estradiol influence metabolism-related genes in human skeletal muscle.

    PubMed

    Fu, Ming-hua H; Maher, Amy C; Hamadeh, Mazen J; Ye, Changhua; Tarnopolsky, Mark A

    2009-12-30

    Higher fat and lower carbohydrate and amino acid oxidation are observed in women compared with men during endurance exercise. We hypothesized that the observed sex difference is due to estrogen and that menstrual cycle phase or supplementation of men with 17beta-estradiol (E(2)) would coordinately influence the mRNA content of genes involved in lipid and/or carbohydrate metabolism in skeletal muscle. Twelve men and twelve women had muscle biopsies taken before and immediately after 90 min of cycling at 65% peak oxygen consumption (Vo(2peak)). Women were studied in the midfollicular (Fol) and midluteal (Lut) phases, and men were studied after 8 days of E(2) or placebo supplementation. Targeted RT-PCR was used to compare mRNA content for genes involved in transcriptional regulation and lipid, carbohydrate, and amino acid metabolism. Sex was the greatest predictor of substrate metabolism gene content. Sex affected the mRNA content of FATm, FABPc, SREBP-1c, mtGPAT, PPARdelta, PPARalpha, CPTI, TFP-alpha, GLUT4, HKII, PFK, and BCOADK (P < 0.05). E(2) administration significantly (P < 0.05) affected the mRNA content of PGC-1alpha, PPARalpha, PPARdelta, TFP-alpha, CPTI, SREBP-1c, mtGPAT, GLUT4, GS-1, and AST. Acute exercise increased the mRNA abundance for PGC-1alpha, HSL, FABPc, CPTI, GLUT4, HKII, and AST (P < 0.05). Menstrual cycle had a small effect on PPARdelta, GP, and glycogenin mRNA content. Overall, women have greater mRNA content for several genes involved in lipid metabolism, which is partially due to an effect of E(2).

  13. Microarray and functional analysis of growth-phase dependent gene regulation in Bordetella bronchiseptica

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Growth-phase dependent gene regulation has recently been demonstrated to occur in B. pertussis, with many transcripts, including known virulence factors, significantly decreasing during the transition from logarithmic to stationary-phase growth. Given that B. pertussis is thought to have derived fro...

  14. Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children.

    PubMed

    Chan, Jason Yong-Sheng; Ugrasena, Dewa G; Lum, Danny Wai-Kiong; Lu, Yi; Yeoh, Allen Eng-Juh

    2011-09-01

    Xenobiotic and folate metabolic pathways are important for the maintenance of genetic stability and may influence susceptibility to the development of childhood acute lymphoblastic leukaemia (ALL). In this study, we investigated 10 polymorphisms in 6 genes (GSTM1-present/null, GSTT1-present/null, GSTP1 1578A > G, NQO1 609C > T, MTHFR 677C > T, MTHFR 1298A > C, MTHFD1 1958G > A, 3'-TYMS 1494 6bp-deletion/insertion, 5'-TYMS 28bp-tandem repeats, and SLC19A1 80G > A) in a cohort of 185 Javanese children with ALL and 177 healthy controls. In ALL patients, none of the polymorphisms demonstrated a statistically significant association with ALL after correcting for multiple comparisons. Gender-stratified analysis showed that in girls, GSTT1-null genotype was associated with increased ALL risk (OR = 2.20; p = 0.027), while GSTP1 1578AG genotype was associated with reduced risk (OR = 0.43; p = 0.031). Strong linkage disequilibrium between the MTHFR 677C > T and 1298A > C polymorphisms was observed (D' = 1.0; r(2) = 0.072). The haplotypes 677C-1298C and 677T-1298A were associated with a reduced risk of ALL (OR = 0.68 and 0.64, respectively; gender-adjusted global p = 0.028). Classification and regression tree (CART) analysis was employed to identify potential high-order gene-gene interactions and cluster subjects into susceptibility groups. SLC19A1 80G > A emerged as the predominant polymorphism associated with risk of ALL. Individuals simultaneously carrying MTHFR 1298AA, 3'-TYMS 6bp deletion(s) and SLC19A1 80A-allele(s) were at higher disease risk (OR = 2.21; p < 0.001). On the contrary, simultaneous possession of MTHFR 1298CC, 3'-TYMS 6bp homozygosity and SLC19A1 80A-allele(s) conferred lower risk (OR = 0.25; p = 0.004). Carriage of NQO1 609C-allele amongst SLC19A1 80GG genotype was associated with lower risk (OR = 0.47; p = 0.003). In conclusion, our study has demonstrated the importance of gender and gene-gene interaction within the xenobiotic and folate pathways in

  15. Role of mga in growth phase regulation of virulence genes of the group A streptococcus.

    PubMed Central

    McIver, K S; Scott, J R

    1997-01-01

    To determine whether growth phase affects the expression of mga and other virulence-associated genes in the group A streptococcus (GAS), total RNA was isolated from the serotype M6 GAS strain JRS4 at different phases of growth and transcript levels were quantitated by hybridization with radiolabeled DNA probes. Expression of mga (which encodes a multiple gene regulator) and the Mga-regulated genes emm (which encodes M protein) and scpA (which encodes a complement C5a peptidase) was found to be maximal in exponential phase and shut off as the bacteria entered stationary phase, while the housekeeping genes recA and rpsL showed constant transcript levels over the same period of growth. Expression of mga from a foreign phage promoter in a mga-deleted GAS strain (JRS519) altered the wild-type growth phase-dependent transcription profile seen for emm and scpA, as well as for mga. Therefore, the temporal control of mga expression requires its upstream promoter region, and the subsequent growth phase regulation of emm and scpA is Mga dependent. A number of putative virulence genes in JRS4 were shown not to require Mga for their expression, although several exhibited growth phase-dependent regulation that was similar to mga, i.e., slo (which encodes streptolysin O) and plr (encoding the plasmin receptor/glyceraldehyde-3-phosphate dehydrogenase). Still others showed a markedly different pattern of expression (the genes for the superantigen toxins MF and SpeC). These results suggest the existence of complex levels of global regulation sensitive to growth phase that directly control the expression of virulence genes and mga in GAS. PMID:9260962

  16. Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke

    PubMed Central

    Stein, Efrat Shavit; Itsekson-Hayosh, Zeev; Aronovich, Anna; Reisner, Yair; Bushi, Doron; Pick, Chaim G.; Tanne, David; Chapman, Joab; Vlachos, Andreas; Maggio, Nicola

    2015-01-01

    Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke. PMID:25604482

  17. Growth Phase dependent gene regulation in Bordetella bronchiseptica

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bordetellae are Gram negative bacterial respiratory pathogens. Bordetella pertussis, the causative agent of whooping cough, is a human-restricted variant of Bordetella bronchiseptica, which infects a broad range of mammals causing chronic and often asymptomatic infections. Growth phase dependent gen...

  18. Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats

    SciTech Connect

    Ray, Anamika; Liu Jing; Ayoubi, Patricia; Pope, Carey

    2010-10-15

    Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2 mg/kg) gene expression profiles and changes in cell signaling pathways 24 h following acute CPF exposure in 7-day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0 mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clustering while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis (registered) . Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276 to 905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2 mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2 mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2 mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2 mg/kg CPF (MAPK, oxidative stress, NF{Kappa}B, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse

  19. Effects of Combined Phase III and Phase II Cardiac Exercise Therapy for Middle-aged Male Patients with Acute Myocardial Infarction.

    PubMed

    Lee, Chih-Wei; Wang, Ji-Hung; Hsieh, Jen-Che; Hsieh, Tsung-Cheng; Huang, Chien-Hui

    2013-11-01

    [Purpose] To investigate the effects of cardiac exercise therapy (CET) on exercise capacity and coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Methods] Patients who participated in an 8-week supervised, hospital-based phase II and 6-month home-based phase III CET with monthly telephone and/or home visits were defined as the exercise group (EG) (n=20), while those who did not receive phase II or phase III CET were defined as the no-exercise group (NEG) (n=10). CRFs were evaluated pre- and post-phase II and eight months after discharge. One and two-way repeated measures ANOVA were used to perform intra- and inter-group comparisons. [Results] Thirty men with AMI aged 49.3 ± 8.3 years were studied. EG increased their exercise capacity (METs) (6.8 ± 1.6 vs.10.0 ± 1.9) after phase II CET and was able to maintain it at 8-month follow-up. Both groups had significantly fewer persons who kept on smoking compared to the first examination. High density lipoprotein cholesterol (HDL-C) increased from 38.1 ± 11.0 to 43.7 ± 8.7 mg/dl at follow-up in EG while no significant difference was noted in NEG. [Conclusion] After phase III CET subjects had maintained the therapeutic effects of smoking cessation, and increasing exercise capacity obtained in phase II CET. HDL-C in EG continued to improve during phase III CET.

  20. Evidence for a protective role of tumor necrosis factor in the acute phase of Trypanosoma cruzi infection in mice.

    PubMed Central

    Lima, E C; Garcia, I; Vicentelli, M H; Vassalli, P; Minoprio, P

    1997-01-01

    A possible role for tumor necrosis factor (TNF) alpha during Trypanosoma cruzi infection was explored by using transgenic mice expressing in blood high levels of a soluble TNFR1-FcIgG3 fusion protein, which neutralizes the effects of TNF in vivo. Nontransgenic littermates were used as controls. The transgenic mice showed high susceptibility to T. cruzi infection. Inocula sublethal for control mice resulted in over 80% mortality associated with higher levels of parasites in the blood. In histological sections of the hearts of transgenic mice, large parasitic clusters without inflammatory cell infiltrates around the parasites were seen, while smaller parasitic clusters associated with leukocytes were seen in control mice. No difference in specific antibody response or lymphocyte composition of the spleen was found between transgenic and control mice, although the unresponsiveness of spleen cells to concanavalin A stimulation in vitro, typical of the acute phase of T. cruzi infection, was less pronounced in transgenic mice. Infected transgenic mice produced higher levels of gamma interferon than did control mice. These results confirm that TNF is involved in mechanisms leading to parasite clearance and protection from death in the acute phase of T. cruzi infection. More importantly, the data reveal that TNF is necessary for the establishment of effective tissue inflammation and parasite load control in acute experimental Chagas' disease myocarditis. PMID:9009297

  1. Elevation of Intact and Proteolytic Fragments of Acute Phase Proteins Constitutes the Earliest Systemic Antiviral Response in HIV-1 Infection

    PubMed Central

    Kramer, Holger B.; Lavender, Kerry J.; Qin, Li; Stacey, Andrea R.; Liu, Michael K. P.; di Gleria, Katalin; Simmons, Alison; Gasper-Smith, Nancy; Haynes, Barton F.; McMichael, Andrew J.; Borrow, Persephone; Kessler, Benedikt M.

    2010-01-01

    The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, β-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5–7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha–1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies. PMID:20463814

  2. Systemic acute phase proteins response in calves experimentally infected with Eimeria zuernii.

    PubMed

    Lassen, Brian; Bangoura, Berit; Lepik, Triin; Orro, Toomas

    2015-09-15

    Acute phase proteins (APPs) have been demonstrated to be useful in evaluating general health stress and diseases in cattle. Serum amyloid A (SAA) and haptoglobin (Hp) are APPs that are produced during inflammation, and likely play a role in host immunological defence against Eimeria infection and the associated intestinal tissue damage. We investigated the involvement of SAA and HP in an experimental study, including three groups of calves: a control group (group 0, n=11), and two groups infected with either 150,000 or 250,000 Eimeria zuernii oocysts (group 1 (n=11) and group 2 (n=12), respectively). The calves were monitored for 28 days and data was collected on oocyst excretion, faecal score, animal weight, and SAA and Hp serum concentrations. Generalized linear mixed models showed that the clinical symptoms, indicated by an increase in the number of oocysts in the faeces and severe diarrhoea, manifested at patency for group 1 and 2. Serum Hp and SAA levels also increased during this period. Hp appeared to be a more sensitive marker than SAA, and differences between groups 1 and 2 were observed only for Hp. Linear regression models showed a negative association between weight gain and Hp concentrations, calculated as the area under the curve (AUC) during the overall experimental period and the patency period. A similar result was seen for SAA only during the patency period. This result supports the assumption that reduced weight gain due to E. zuernii infection is an immunologically driven process that involves an increase in APPs. A random intercept regression model of oocyst shedding groups showed that calves shedding 1-500 oocysts had reduced concentrations of Hp, indicating that a different immunological reaction occurs during mild shedding of E. zuernii oocysts than during more intensive shedding. A similar model was used to examine associations between faecal scores and Hp concentrations for each group. Group 2 calves with haemorrhagic diarrhoea displayed

  3. Epstein-Barr virus IL-10 gene expression by a recombinant murine gammaherpesvirus in vivo enhances acute pathogenicity but does not affect latency or reactivation

    PubMed Central

    2014-01-01

    Background Many viral genes affect cytokine function within infected hosts, with interleukin 10 (IL-10) as a commonly targeted mediator. Epstein-Barr virus (EBV) encodes an IL-10 homologue (vIL-10) expressed during productive (lytic) infection and induces expression of cellular IL-10 (cIL-10) during latency. This study explored the role of vIL-10 in a murine gammaherpesvirus (MHV) model of viral infection. Methods The EBV vIL-10 gene was inserted into MHV-76, a strain which lacks the ability to induce cIL-10, by recombination in transfected mouse cells. Mice were infected intranasally with the recombinant, vIL-10-containing MHV-76 or control virus strains and assayed at various days post infection for lung virus titer, spleen cell number, percentage of latently infected spleen cells and ability to reactivate virus from spleen cells. Results Recombinant murine gammaherpesvirus expressing EBV vIL-10 rose to significantly higher titers in lungs and promoted an increase in spleen cell number in infected mice in comparison to MHV strains lacking the vIL-10 gene. However, vIL-10 expression did not alter the quantity of latent virus in the spleen or its ability to reactivate. Conclusions In this mouse model of gammaherpesvirus infection, EBV vIL-10 appears to influence acute-phase pathogenicity. Given that EBV and MHV wild-type strains contain other genes that induce cIL-10 expression in latency (e.g. LMP-1 and M2, respectively), vIL-10 may have evolved to serve the specific role in acute infection of enlarging the permissive host cell population, perhaps to facilitate initial survival and dissemination of viral-infected cells. PMID:25324959

  4. Regulation of postsynaptic plasticity genes' expression and topography by sustained dopamine perturbation and modulation by acute memantine: relevance to schizophrenia.

    PubMed

    Iasevoli, Felice; Buonaguro, Elisabetta F; Sarappa, Chiara; Marmo, Federica; Latte, Gianmarco; Rossi, Rodolfo; Eramo, Anna; Tomasetti, Carmine; de Bartolomeis, Andrea

    2014-10-03

    A relevant role for dopamine-glutamate interaction has been reported in the pathophysiology and treatment of psychoses. Dopamine and glutamate may interact at multiple levels, including the glutamatergic postsynaptic density (PSD), an electron-dense thickening that has gained recent attention as a switchboard of dopamine-glutamate interactions and for its role in synaptic plasticity. Recently, glutamate-based strategies, such as memantine add-on to antipsychotics, have been proposed for refractory symptoms of schizophrenia, e.g. cognitive impairment. Both antipsychotics and memantine regulate PSD transcripts but sparse information is available on memantine's effects under dopamine perturbation. We tested gene expression changes of the Homer1 and PSD-95 PSD proteins in models of sustained dopamine perturbation, i.e. subchronic treatment by: a) GBR-12909, a dopamine receptor indirect agonist; b) haloperidol, a D2R antagonist; c) SCH-23390, a dopamine D1 receptor (D1R) antagonist; and d) SCH-23390+haloperidol. On the last day of treatment, rats were acutely treated with vehicle or memantine. The Homer1a immediate-early gene was significantly induced by haloperidol and by haloperidol+SCH-23390. The gene was not induced by SCH-23390 per se or by GBR-12909. Expression of the constitutive genes Homer1b/c and PSD-95 was less affected by these dopaminergic paradigms. Acute memantine administration significantly increased Homer1a expression by the dopaminergic compounds used herein. Both haloperidol and haloperidol+SCH-23390 shifted Homer1a/Homer1b/c ratio of expression toward Homer1a. This pattern was sharpened by acute memantine. Dopaminergic compounds and acute memantine also differentially affected topographic distribution of gene expression and coordinated expression of Homer1a among cortical-subcortical regions. These results indicate that dopaminergic perturbations may affect glutamatergic signaling in different directions. Memantine may help partially revert dopamine

  5. The role and importance of glycosylation of acute phase proteins with focus on alpha-1 antitrypsin in acute and chronic inflammatory conditions.

    PubMed

    McCarthy, Cormac; Saldova, Radka; Wormald, Mark R; Rudd, Pauline M; McElvaney, Noel G; Reeves, Emer P

    2014-07-03

    Acute phase proteins (APPs) are a group of circulating plasma proteins which undergo changes quantitatively or qualitatively at the time of inflammation. Many of these APPs are glycosylated, and it has been shown that alterations in glycosylation may occur in inflammatory and malignant conditions. Changes in glycosylation have been studied as potential biomarkers in cancer and also in chronic inflammatory conditions and have been shown to correlate with disease severity in certain conditions. Serine protease inhibitors (serpins), many of which are also APPs, are proteins involved in the control of proteases in numerous pathways. Alpha-1 Antitrypsin (AAT) is the most abundant serpin within the circulation and is an APP which has been shown to increase in response to inflammation. The primary role of AAT is maintaining the protease/antiprotease balance in the lung, but it also possesses important anti-inflammatory and immune-modulating properties. Several glycoforms of AAT exist, and they possess differing properties in regard to plasma half-life and stability. Glycosylation may also be important in determining the immune modulatory properties of AAT. The review will focus on the role and importance of glycosylation in acute phase proteins with particular attention to AAT and its use as a biomarker of disease. The review describes the processes involved in glycosylation, how glycosylation changes in differing disease states, and the alterations that occur to glycans of APPs with disease and inflammation. Finally, the review explores the importance of changes in glycosylation of AAT at times of inflammation and in malignant conditions and how this may impact upon the functions of AAT.

  6. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia.

    PubMed

    Garzon, R; Pichiorri, F; Palumbo, T; Visentini, M; Aqeilan, R; Cimmino, A; Wang, H; Sun, H; Volinia, S; Alder, H; Calin, G A; Liu, C-G; Andreeff, M; Croce, C M

    2007-06-14

    MicroRNAs (miRNAs) are small non-coding RNAs of 19-25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time-polymerase chain reaction (qRT-PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-kappaB) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NF-kappaB binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/miR-16-1, respectively.

  7. Gene transfer corrects acute GM2 gangliosidosis--potential therapeutic contribution of perivascular enzyme flow.

    PubMed

    Cachón-González, M Begoña; Wang, Susan Z; McNair, Rosamund; Bradley, Josephine; Lunn, David; Ziegler, Robin; Cheng, Seng H; Cox, Timothy M

    2012-08-01

    The GM2 gangliosidoses are fatal lysosomal storage diseases principally affecting the brain. Absence of β-hexosaminidase A and B activities in the Sandhoff mouse causes neurological dysfunction and recapitulates the acute Tay-Sachs (TSD) and Sandhoff diseases (SD) in infants. Intracranial coinjection of recombinant adeno-associated viral vectors (rAAV), serotype 2/1, expressing human β-hexosaminidase α (HEXA) and β (HEXB) subunits into 1-month-old Sandhoff mice gave unprecedented survival to 2 years and prevented disease throughout the brain and spinal cord. Classical manifestations of disease, including spasticity-as opposed to tremor-ataxia-were resolved by localized gene transfer to the striatum or cerebellum, respectively. Abundant biosynthesis of β-hexosaminidase isozymes and their global distribution via axonal, perivascular, and cerebrospinal fluid (CSF) spaces, as well as diffusion, account for the sustained phenotypic rescue-long-term protein expression by transduced brain parenchyma, choroid plexus epithelium, and dorsal root ganglia neurons supplies the corrective enzyme. Prolonged survival permitted expression of cryptic disease in organs not accessed by intracranial vector delivery. We contend that infusion of rAAV into CSF space and intraparenchymal administration by convection-enhanced delivery at a few strategic sites will optimally treat neurodegeneration in many diseases affecting the nervous system.

  8. Evaluation of the prevalence of stress and its phases in acute myocardial infarction in patients active in the labor market

    PubMed Central

    Lucinda, Luciane Boreki; Prosdócimo, Ana Claudia Merchan Giaxa; de Carvalho, Katherine Athayde Teixeira; Francisco, Julio Cesar; Baena, Cristina Pellegrino; Olandoski, Marcia; do Amaral, Vivian Ferreira; Faria, José Rocha; Guarita-Souza, Luiz César

    2015-01-01

    Introduction Acute myocardial infarction is a social health problem of epidemiological relevance, with high levels of morbidity and mortality. Stress is one of the modifiable risk factors that triggers acute myocardial infarction. Stress is a result of a set of physiological reactions, which when exaggerated in intensity or duration can lead to imbalances in one's organism, resulting in vulnerability to diseases. Objective To identify the presence of stress and its phases in hospitalized and active labor market patients with unstable myocardial infarction and observe its correlation with the life of this population with stress. Methods The methodology used was a quantitative, descriptive and transversal research approach conducted with a total of 43 patients, who were still active in the labor market, presenting or not morbidities. Data collection occurred on the fourth day of their hospitalization and patients responded to Lipp's Stress Symptom Inventory for adults. Results Thirty-one patients (72.1%) presented stress and twelve (27.8%) did not. In patients with stress, the identified phases were: alert - one patient (3.2%); resistance -twenty-two patients (71.0%); quasi-exhaustion - six patients (19.4%) and exhaustion - two patients (6.5%). All women researched presented stress. Conclusion The results suggest a high level of stress, especially in the resistance phase, in the male infarcted population, hospitalized and active in the labor market. PMID:25859863

  9. Regulatory and ethical issues for phase I in utero gene transfer studies.

    PubMed

    Strong, Carson

    2011-11-01

    Clinical gene transfer research has involved adult and child subjects, and it is expected that gene transfer in fetal subjects will occur in the future. Some genetic diseases have serious adverse effects on the fetus before birth, and there is hope that prenatal gene therapy could prevent such disease progression. Research in animal models of prenatal gene transfer is actively being pursued. The prospect of human phase I in utero gene transfer studies raises important regulatory and ethical issues. One issue not previously addressed arises in applying U.S. research regulations to such studies. Specifically, current regulations state that research involving greater than minimal risk to the fetus and no prospect of direct benefit to the fetus or pregnant woman is not permitted. Phase I studies will involve interventions such as needle insertions through the uterus, which carry risks to the fetus including spontaneous abortion and preterm birth. It is possible that these risks will be regarded as exceeding minimal. Also, some regard the probability of therapeutic benefit in phase I studies to be so low that these studies do not satisfy the regulatory requirement that they "hold out the prospect of direct benefit" to subjects. On the basis of these considerations, investigators and institutional review boards might reasonably conclude that some phase I in utero studies are not to be permitted. This paper identifies considerations that are relevant to such judgments and explores ethically acceptable ways in which phase I studies can be designed so that they are permitted by the regulations.

  10. Restriction of histone gene transcription to S phase by phosphorylation of a chromatin boundary protein

    PubMed Central

    Kurat, Christoph F.; Lambert, Jean-Philippe; van Dyk, Dewald; Tsui, Kyle; van Bakel, Harm; Kaluarachchi, Supipi; Friesen, Helena; Kainth, Pinay; Nislow, Corey; Figeys, Daniel; Fillingham, Jeffrey; Andrews, Brenda J.

    2011-01-01

    The cell cycle-regulated expression of core histone genes is required for DNA replication and proper cell cycle progression in eukaryotic cells. Although some factors involved in histone gene transcription are known, the molecular mechanisms that ensure proper induction of histone gene expression during S phase remain enigmatic. Here we demonstrate that S-phase transcription of the model histone gene HTA1 in yeast is regulated by a novel attach–release mechanism involving phosphorylation of the conserved chromatin boundary protein Yta7 by both cyclin-dependent kinase 1 (Cdk1) and casein kinase 2 (CK2). Outside S phase, integrity of the AAA-ATPase domain is required for Yta7 boundary function, as defined by correct positioning of the histone chaperone Rtt106 and the chromatin remodeling complex RSC. Conversely, in S phase, Yta7 is hyperphosphorylated, causing its release from HTA1 chromatin and productive transcription. Most importantly, abrogation of Yta7 phosphorylation results in constitutive attachment of Yta7 to HTA1 chromatin, preventing efficient transcription post-recruitment of RNA polymerase II (RNAPII). Our study identified the chromatin boundary protein Yta7 as a key regulator that links S-phase kinases with RNAPII function at cell cycle-regulated histone gene promoters. PMID:22156209

  11. Restriction of histone gene transcription to S phase by phosphorylation of a chromatin boundary protein.

    PubMed

    Kurat, Christoph F; Lambert, Jean-Philippe; van Dyk, Dewald; Tsui, Kyle; van Bakel, Harm; Kaluarachchi, Supipi; Friesen, Helena; Kainth, Pinay; Nislow, Corey; Figeys, Daniel; Fillingham, Jeffrey; Andrews, Brenda J

    2011-12-01

    The cell cycle-regulated expression of core histone genes is required for DNA replication and proper cell cycle progression in eukaryotic cells. Although some factors involved in histone gene transcription are known, the molecular mechanisms that ensure proper induction of histone gene expression during S phase remain enigmatic. Here we demonstrate that S-phase transcription of the model histone gene HTA1 in yeast is regulated by a novel attach-release mechanism involving phosphorylation of the conserved chromatin boundary protein Yta7 by both cyclin-dependent kinase 1 (Cdk1) and casein kinase 2 (CK2). Outside S phase, integrity of the AAA-ATPase domain is required for Yta7 boundary function, as defined by correct positioning of the histone chaperone Rtt106 and the chromatin remodeling complex RSC. Conversely, in S phase, Yta7 is hyperphosphorylated, causing its release from HTA1 chromatin and productive transcription. Most importantly, abrogation of Yta7 phosphorylation results in constitutive attachment of Yta7 to HTA1 chromatin, preventing efficient transcription post-recruitment of RNA polymerase II (RNAPII). Our study identified the chromatin boundary protein Yta7 as a key regulator that links S-phase kinases with RNAPII function at cell cycle-regulated histone gene promoters.

  12. Double trisomy 8 and 21 in acute myelocytic leukemias, one with rearrangement of the RUNX1 gene.

    PubMed

    Berger, Roland; Coniat, Maryvonne Busson-Le

    2003-04-15

    Fluorescence in situ hybridization analysis was carried out in five patients with acute myeloblastic leukemia of various French-American-British subtypes and with double trisomy of chromosomes 8 and 21. PML-RARA fusion was detected with appropriate molecular probes in one patient with acute promyelocytic leukemia without t(15;17). Two PAC probes covering the 5' and 3' part of the RUNX1 gene were used in the four other patients. While three copies were present in three patients, as expected from conventional karyotype analysis, only two hybridization signals were present in the fifth patient. This was due to the apparent loss of the 3' part of RUNX1. Since chromosome number abnormalities may be associated with submicroscopic gene rearrangements, it should be important to search for them for a better understanding of mechanisms of leukemogenesis, and to understand the prognostic heterogeneity in leukemic patients with aneusomies without apparent chromosome structure rearrangements.

  13. Acute-phase protein α1-antitrypsin--a novel regulator of angiopoietin-like protein 4 transcription and secretion.

    PubMed

    Frenzel, Eileen; Wrenger, Sabine; Immenschuh, Stephan; Koczulla, Rembert; Mahadeva, Ravi; Deeg, H Joachim; Dinarello, Charles A; Welte, Tobias; Marcondes, A Mario Q; Janciauskiene, Sabina

    2014-06-01

    The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator-activated receptor [PPAR]γ-induced angiopoietin-related protein) is a multifunctional protein associated with acute-phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study shows that human α1-antitrypsin (A1AT) upregulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1 h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2- to 174-fold, respectively, relative to controls. In endothelial cells, the maximal effect on angptl4 expression was achieved at 8 h with 2 mg/ml A1AT (11-fold induction versus controls). In 10 emphysema patients receiving A1AT therapy (Prolastin), plasma angptl4 levels were higher relative to patients without therapy (nanograms per milliliter, mean [95% confidence interval] 127.1 [99.5-154.6] versus 76.8 [54.8-98.8], respectively, p = 0.045) and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pretreated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARγ antagonist (GW9662), or genistein, a ligand for PPARγ. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARγ is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of HIF-1α, an upregulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute-phase protein A1AT is a physiological regulator of angptl4, another acute-phase protein.

  14. Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene.

    PubMed

    Milewicz, Dianna; Hostetler, Ellen; Wallace, Stephanie; Mellor-Crummey, Lauren; Gong, Limin; Pannu, Hariyadarshi; Guo, Dong-chuan; Regalado, Ellen

    2016-04-01

    Almost one-quarter of patients presenting with thoracic aortic aneurysms (TAAs) or acute aortic dissections (TAADs) have an underlying mutation in a specific gene. A subset of these patients will have systemic syndromic features, for example, skeletal features in patients with Marfan Syndrome. It is important to note that the majority of patients with thoracic aortic disease will not have these syndromic features but many will have a family history of the disease. The genes predisposing to these thoracic aortic diseases are inherited in an autosomal dominant manner, and thirteen genes have been identified to date. As the clinical phenotype associated with each specific gene is defined, the data indicate that the underlying gene dictates associated syndromic features. More importantly, the underlying gene also dictates the aortic disease presentation, the risk for dissection at a given range of aortic diameters, the risk for additional vascular diseases and what specific vascular diseases occur associated with the gene. These results lead to the recommendation that the medical and surgical management of these patients be dictated by the underlying gene, and for patients with mutations in ACTA2, the specific mutation in the gene.

  15. Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease

    SciTech Connect

    Poulsen, Sarah S.; Saber, Anne T.; Mortensen, Alicja; Szarek, Józef; Wu, Dongmei; Williams, Andrew; Andersen, Ole; Jacobsen, Nicklas R.; Yauk, Carole L.; Wallin, Håkan; Halappanavar, Sabina; Vogel, Ulla

    2015-03-15

    Adverse lung effects following pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) are well documented in rodents. However, systemic effects are less understood. Epidemiological studies have shown increased cardiovascular disease risk after pulmonary exposure to airborne particles, which has led to concerns that inhalation exposure to MWCNTs might pose similar risks. We analyzed parameters related to cardiovascular disease, including plasma acute phase response (APR) proteins and plasma lipids, in female C57BL/6 mice exposed to a single intratracheal instillation of 0, 18, 54 or 162 μg/mouse of small, entangled (CNT{sub Small}, 0.8 ± 0.1 μm long) or large, thick MWCNTs (CNT{sub Large}, 4 ± 0.4 μm long). Liver tissues and plasma were harvested 1, 3 and 28 days post-exposure. In addition, global hepatic gene expression, hepatic cholesterol content and liver histology were used to assess hepatic effects. The two MWCNTs induced similar systemic responses despite their different physicochemical properties. APR proteins SAA3 and haptoglobin, plasma total cholesterol and low-density/very low-density lipoprotein were significantly increased following exposure to either MWCNTs. Plasma SAA3 levels correlated strongly with pulmonary Saa3 levels. Analysis of global gene expression revealed perturbation of the same biological processes and pathways in liver, including the HMG-CoA reductase pathway. Both MWCNTs induced similar histological hepatic changes, with a tendency towards greater response following CNT{sub Large} exposure. Overall, we show that pulmonary exposure to two different MWCNTs induces similar systemic and hepatic responses, including changes in plasma APR, lipid composition, hepatic gene expression and liver morphology. The results link pulmonary exposure to MWCNTs with risk of cardiovascular disease. - Highlights: • Systemic and hepatic alterations were evaluated in female mice following MWCNT instillation. • Despite being physicochemically

  16. Regression Analysis of Combined Gene Expression Regulation in Acute Myeloid Leukemia

    PubMed Central

    Li, Yue; Liang, Minggao; Zhang, Zhaolei

    2014-01-01

    Gene expression is a combinatorial function of genetic/epigenetic factors such as copy number variation (CNV), DNA methylation (DM), transcription factors (TF) occupancy, and microRNA (miRNA) post-transcriptional regulation. At the maturity of microarray/sequencing technologies, large amounts of data measuring the genome-wide signals of those factors became available from Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA). However, there is a lack of an integrative model to take full advantage of these rich yet heterogeneous data. To this end, we developed RACER (Regression Analysis of Combined Expression Regulation), which fits the mRNA expression as response using as explanatory variables, the TF data from ENCODE, and CNV, DM, miRNA expression signals from TCGA. Briefly, RACER first infers the sample-specific regulatory activities by TFs and miRNAs, which are then used as inputs to infer specific TF/miRNA-gene interactions. Such a two-stage regression framework circumvents a common difficulty in integrating ENCODE data measured in generic cell-line with the sample-specific TCGA measurements. As a case study, we integrated Acute Myeloid Leukemia (AML) data from TCGA and the related TF binding data measured in K562 from ENCODE. As a proof-of-concept, we first verified our model formalism by 10-fold cross-validation on predicting gene expression. We next evaluated RACER on recovering known regulatory interactions, and demonstrated its superior statistical power over existing methods in detecting known miRNA/TF targets. Additionally, we developed a feature selection procedure, which identified 18 regulators, whose activities clustered consistently with cytogenetic risk groups. One of the selected regulators is miR-548p, whose inferred targets were significantly enriched for leukemia-related pathway, implicating its novel role in AML pathogenesis. Moreover, survival analysis using the inferred activities identified C-Fos as a potential AML

  17. Clinical Courses of Two Pediatric Patients with Acute Megakaryoblastic Leukemia Harboring the CBFA2T3-GLIS2 Fusion Gene

    PubMed Central

    Ishibashi, Mayu; Yokosuka, Tomoko; Yanagimachi, Masakatsu D.; Iwasaki, Fuminori; Tsujimoto, Shin-ichi; Sasaki, Koji; Takeuchi, Masanobu; Tanoshima, Reo; Kato, Hiromi; Kajiwara, Ryosuke; Tanaka, Fumiko; Goto, Hiroaki; Yokota, Shumpei

    2016-01-01

    Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome (DS) has an extremely poor outcome with 3-year survival of less than 40%, whereas AMKL in children with DS has an excellent survival rate. Recently, a novel recurrent translocation involving CBFA2T3 and GLIS2 was identified in about 30% of children with non-DS AMKL, and the fusion gene was reported as a strong poor prognostic factor in pediatric AMKL. We report the difficult clinical courses of pediatric patients with AMKL harboring the CBFA2T3-GLIS2 fusion gene. PMID:27094503

  18. Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia-A case-control study from Iran.

    PubMed

    Eskandari-Nasab, Ebrahim; Hashemi, Mohammad; Hasani, Seyed-Shahab-Adin; Naderi, Majid; Sadeghi-Bojd, Simin; Taheri, Mohsen

    2017-03-04

    We examined the possible relationship between three RAGE polymorphisms, -429C/T, -374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE -374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.

  19. Production of thyrotropin receptor antibodies in acute phase of infectious mononucleosis due to Epstein-Barr virus primary infection: a case report of a child.

    PubMed

    Nagata, Keiko; Okuno, Keisuke; Ochi, Marika; Kumata, Keisuke; Sano, Hitoshi; Yoneda, Naohiro; Ueyama, Jun-Ichi; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Kanzaki, Susumu; Hayashi, Kazuhiko

    2015-01-01

    Various autoantibodies have been reported to be detected during the progression of infectious mononucleosis. We observed a case of infectious mononucleosis due to Epstein-Barr virus primary infection for 2 months, and noticed the transiently increased titer of thyrotropin receptor autoantibodies detected at the acute phase on the 3rd day after admission. At that time, real-time quantitative PCR also revealed the mRNA expressions of an immediate early lytic gene, BZLF1, and a latent gene, EBNA2. The expression of BZLF1 mRNA means that Epstein-Barr virus infects lytically, and EBNA2 protein has an important role in antibody production as well as the establishment of Epstein-Barr virus latency. These results suggest that Epstein-Barr virus lytic infection is relevant to thyrotropin receptor autoantibody production. Thyrotropin receptor autoantibodies stimulate thyroid follicular cells to produce excessive thyroid hormones and cause Graves' disease. Recently, we reported the thyrotropin receptor autoantibody production from thyrotropin receptor autoantibody-predisposed Epstein-Barr virus-infected B cells by the induction of Epstein-Barr virus lytic infection in vitro. This case showed in vivo findings consistent with our previous reports, and is important to consider the pathophysiology of Graves' disease and one of the mechanisms of autoimmunity.

  20. Blood pressure lowering in acute phase of stroke: latest evidence and clinical implications

    PubMed Central

    Patarroyo, Sully Xiomara Fuentes

    2012-01-01

    Persistent controversy exists as to whether there are worthwhile beneficial effects of early, rapid lowering of elevated blood pressure (BP) in acute stroke. Elevated BP or ‘hypertension’ (i.e. systolic >140 mmHg) is common in stroke, especially in patients with pre-existing hypertension and large strokes, due to variable ‘autonomic stress’ and raised intracranial pressure. While positive associations between BP levels and poor outcomes are evident across a range of studies, very low BP levels and large reductions in BP have also been shown to predict death and dependence, more so for ischaemic stroke (IS) than intracerebral haemorrhage (ICH). Accumulating evidence indicates that early BP lowering can reduce haematoma expansion in ICH, but there is uncertainty over whether this translates into improved clinical outcomes, particularly since such an effect was not evident from haemostatic therapy in clinical trials. Guidelines generally recommend control of high systolic BP (>180 mmHg), but recent evidence indicates that even more modest elevation (>140 mmHg) increases risks of cerebral oedema and haemorrhagic transformation following thrombolysis in IS. Thus, any potential benefits of rapid BP lowering in acute stroke, particularly in IS, must be balanced against the potential risks of worsening cerebral ischaemia from altered autoregulation/perfusion. This paper explores current knowledge regarding the management of hypertension in acute stroke and introduces ongoing clinical trials aimed at resolving such a critical issue in the care of patients with acute stroke. PMID:23342232

  1. Investigation of deregulated genes of Notch signaling pathway in human T cell acute lymphoblastic leukemia cell lines and clinical samples.

    PubMed

    Paryan, Mahdi; Mohammadi-Yeganeh, Samira; Samiee, Siamak Mirab; Soleimani, Masoud; Arefian, Ehsan; Azadmanesh, Keyhan; Poopak, Behzad; Mostafavi, Ehsan; Karimipoor, Morteza; Mahdian, Reza

    2013-10-01

    In diagnostic research challenges, quantitative real-time PCR (QPCR) has been widely utilized in gene expression analysis because of its sensitivity, accuracy, reproducibility, and most importantly, quantitativeness. Real-time PCR base kits are wildly applicable in cancer signaling pathways, especially in cancer investigations. T-cell acute lymphoblastic leukemia (T-ALL) is a type of leukemia that is more common in older children and teenagers. Deregulation of the Notch signaling pathway promotes proliferation and inhibits apoptosis of the lymphoblastic T cells. The aim of this study was to investigate the effect of Notch signaling activation on the expression of target genes using real-time QPCR and further use this method in clinical examination after validation. Two T-ALL cell lines, Jurkat and Molt-4, were used as models for activation of the Notch signaling via over-expression of the Notch1 intracellular domain. Expression analysis was performed for six downstream target genes (NCSTN, APH1, PSEN1, ADAM17, NOTCH1 and C-MYC) which play critical roles in the Notch signaling pathway. The results showed significant difference in the expression of target genes in the deregulated Notch signaling pathway. These results were also verified in 12 clinical samples bearing over-expression of the Notch signaling pathway. Identification of such downstream Notch target genes, which have not been studied inclusively, provides insights into the mechanisms of the Notch function in T cell leukemia, and may help identify novel diagnoses and therapeutic targets in acute lymphoblastic leukemia.

  2. Serum acute phase proteins in control and Theileria annulata infected water buffaloes (Bubalus bubalis).

    PubMed

    El-Deeb, Wael M; Iacob, Olimpia C

    2012-11-23

    This study was carried out to ascertain the changes in acute phase proteins (APPs) and pro-inflammatory cytokines in Theileria annulata infected water buffalo. Thirty infected water buffaloes and 20 parasitologically free were used. In the present study there was significant (P ≤ 0.05) increase in haptoglobin (Hp), serum amyloid A (SAA), ceruloplasmin, α1-acid glycoprotein (AGP) and fibrinogen levels (2.18 ± 0.29 g/l, 156.58 ± 3.48 mg/l, 31.23 ± 1.25mg/dl, 370.23 ± 33.21 mg/l and 16.17 ± 1.18 g/l, respectively) in T. annulata infected water buffaloes when compared to healthy ones (0.13 ± 0.01 g/l, 23.9 ± 0.56 mg/l, 21.23 ± 1.21 mg/dl, 240.53 ± 22.45 mg/l and 4.2 ± 0.1 6g/l, respectively). Moreover, there was significant (P ≤ 0.05) increase in the levels of TNF-α, IL-1α, IL-6, IL-12, IL-1β and IFN-γ (2.55 ± 0.12 ng/ml, 98.32 ± 4.21 pg/ml, 152.32 ± 5.62 pg/ml, 26.44 ± 1.43 ng/ml, 240.33 ± 20.45 pg/ml and 123.65 ± 5.67 pg/ml, respectively) in T. annulata infected water buffaloes when compared to healthy ones (0.42 ± 0.04 ng/ml, 55.32 ± 3.21 pg/ml, 88.23 ± 3.21 pg/ml, 7.45 ± 0.67 ng/ml, 98.33 ± 3.45 pg/ml and 34.76 ± 1.56 pg/ml, respectively). There was also significant decrease (P ≤ 0.05) in the Hb content, PCV%, RBCs and WBCs counts in the diseased water buffaloes compared to the control ones. Neutropenia, eosinopenia, lymphopenia, monocytopenia and thrombocytopenia were also recorded. The biochemical changes revealed significant (P ≤ 0.05) elevation in the levels of AST, ALT, ALP, LDL-c, VLDL-c, BHBA and NEFA, with significant (P ≤ 0.05) decrease in the levels of total proteins, albumin, globulins, cholesterol, triglyceride, glucose, G6PD, calcium and phosphorus in T. annulata infected water buffaloes when compared to healthy ones. It could be concluded that APPs and pro-inflammatory cytokines could be used as a valuable biomarkers in T. annulata infected water buffaloes (Bubalus bubalis).

  3. An observational study on electrolyte disorders in the acute phase of ischemic stroke and their prognostic value.

    PubMed

    Fofi, Luisa; Dall'armi, Valentina; Durastanti, Laura; Valenza, Alessandro; Lorenzano, Svetlana; Prencipe, Massimiliano; Toni, Danilo

    2012-04-01

    Data on electrolyte disorders in neurological conditions and in acute stroke are somewhat scanty and not easily compared. In our Stroke Unit we studied patients hospitalized within six hours of the onset of an acute ischemic stroke and recorded their demographic and clinical data. Blood test results were recorded before any pharmacological therapy. A total of 475 individuals (256 M, 219 F; range: 14-96 years) treated over a period of 18 consecutive months, were selected. According to multiple logistic regression analysis, the baseline National Institute of Health Stroke Scale (NIHSS) score (odds ratio [OR]=1.33; 95% confidence interval [CI]: 1.22-1.44) and natremia alterations (OR=6.89; 95% CI=1.94-24.40) were associated with higher odds of death. Based on the ordinal logistic regression analysis, the baseline NIHSS score (OR=1.07; 95% CI=1.03-1.10) and baseline hypernatremia (OR=9.69; 95% CI=1.55-60.69) were related to early neurological worsening. Our work suggests an association between serum sodium alterations and mortality, and between high sodium levels and neurological clinical impairment, in the acute phase of an ischemic stroke.

  4. Mutational analysis of NOTCH1, 2, 3 and 4 genes in common solid cancers and acute leukemias.

    PubMed

    Lee, Sung Hak; Jeong, Eun Goo; Yoo, Nam Jin; Lee, Sug Hyung

    2007-12-01

    NOTCH proteins (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) play crucial roles in embryonic development. Also, mounting evidence indicates that NOTCH contributes to the pathogenesis of hematopoietic and solid malignancies. Recent studies reported a high incidence of gain-of-function mutations of the NOTCH1 gene in T-cell acute lymphoblastic leukemias (ALL). To see whether NOTCH1 mutation occurs in other malignancies, we analyzed NOTCH1 for the detection of somatic mutations in 334 malignancies, including 48 lung, 48 breast, 48 colorectal and 48 gastric carcinomas, and 142 acute leukemias (105 acute myelogenous leukemias, 32 B-ALLs and 4 T-ALLs) by single-strand conformation polymorphism assay. Also, to see whether other NOTCH genes harbor somatic mutations, we analyzed NOTCH2, NOTCH3 and NOTCH4 genes in the same tissue samples. Overall, we detected three NOTCH mutations in the cancers, which consisted of one NOTCH1 mutation in the T-ALLs (25.0%), one NOTCH2 mutation in the breast carcinomas (2.1%), and one NOTCH3 mutation in the colorectal carcinomas (2.0%). There was no NOTCH mutation in other malignancies analyzed. Our data indicate that NOTCH1 is mutated in T-ALL, but not in other common human cancers, and that NOTCH2, NOTCH3 and NOTH4 genes are rarely mutated in common human cancers. Despite the importance of NOTCH activation in many types of human cancers, mutation of NOTCH genes, except for NOTCH1 mutation in T-ALL, may not play an important role in the tumorigenesis of common cancers.

  5. Modifying the acute phase response of Jersey calves by supplementing milk replacer with omega-3 fatty acids from fish oil.

    PubMed

    Ballou, M A; Cruz, G D; Pittroff, W; Keisler, D H; DePeters, E J

    2008-09-01

    Fifty-one Jersey bull calves (5 +/- 1 d old) were assigned to 1 of 3 milk replacers to determine the effects of increasing doses of n-3 fatty acids from fish oil on the acute phase response after an endotoxin challenge. All calves were fed a 22.5% crude protein and 18% lipid milk replacer (Calva Products, Acampo, CA) supplemented with an additional 2% fatty acids. Treatments differed only in the supplemental lipid source and included a 3:1 mix of corn and canola oils, a 1:1 blend of fish oil (Omega Proteins, Houston, TX) and the 3:1 mix of corn and canola oils, and fish oil only. On d 23, each calf was injected subcutaneously with 4 microg/kg of body weight of Salmonella Typhimurium endotoxin. Clinical, hematological, and biochemical parameters were measured at 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24, and 72 h post endotoxin challenge. Endotoxin caused a dramatic rise in respiratory rate; feeding fish oil significantly attenuated the increase. Heart rate and rectal temperature were not affected by treatment. Feeding fish oil attenuated the change in serum iron concentration over time. Endotoxin caused severe hypoglycemia, reaching a nadir at 4 h. Calves supplemented with fish oil had reduced concentrations of serum glucose for 8 to 24 h. Furthermore, calves supplemented with fish oil alone had reduced serum insulin at 12, 28, and 24 h. In contrast, endotoxin caused an acute increase in blood urea nitrogen and nonesterified fatty acids; there were significant linear effects of fish oil on both blood urea nitrogen and nonesterified fatty acids. Serum triglycerides were elevated beginning at 12 h after the endotoxin challenge and returned to baseline values within 72 h. Fish oil suppressed the rise in triglycerides during this period, and the effect was linear with increasing fish oil. Serum concentrations of leptin decreased after the endotoxin challenge; however, the treatment did not influence the response. There was no treatment effect on serum aspartate

  6. Phase I and Pharmacologic Trial of Cytosine Arabinoside with the Selective Checkpoint 1 Inhibitor Sch 900776 in Refractory Acute Leukemias

    PubMed Central

    Karp, Judith E.; Thomas, Brian M.; Greer, Jacqueline M.; Sorge, Christopher; Gore, Steven D.; Pratz, Keith W.; Smith, B. Douglas; Flatten, Karen S.; Peterson, Kevin; Schneider, Paula; Mackey, Karen; Freshwater, Tomoko; Levis, Mark J.; McDevitt, Michael A.; Carraway, Hetty E.; Gladstone, Douglas E.; Showel, Margaret M.; Loechner, Sabine; Parry, David A.; Horowitz, Jo Ann; Isaacs, Randi; Kaufmann, Scott H.

    2013-01-01

    Purpose Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. Experimental Design Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m2 over 72 hours (667 mg/m2/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m2/dose. Results Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m2). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m2 or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m2, consistent with unrepaired DNA damage. Conclusions These data support a randomized phase II trial of cytarabine +/− SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m2) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT #00907517. PMID:23092873

  7. The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons

    PubMed Central

    Jones, Jeff R.

    2016-01-01

    The brain’s biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping. PMID:27602274

  8. Amplification of thermostable lipase genes fragment from thermogenic phase of domestic waste composting process

    NASA Astrophysics Data System (ADS)

    Nurhasanah, Nurbaiti, Santi; Madayanti, Fida; Akhmaloka

    2015-09-01

    Lipases are lipolytic enzymes, catalyze the hydrolysis of fatty acid ester bonds of triglycerides to produce free fatty acids and glycerol. The enzyme is widely used in various fields of biotechnological industry. Hence, lipases with unique properties (e.g.thermostable lipase) are still being explored by variation methods. One of the strategy is by using metagenomic approach to amplify the gene directly from environmental sample. This research was focused on amplification of lipase gene fragment directly from the thermogenic phase of domestic waste composting in aerated trenches. We used domestic waste compost from waste treatment at SABUGA, ITB for the sample. Total chromosomal DNA were directly extracted from several stages at thermogenic phase of compost. The DNA was then directly used as a template for amplification of thermostable lipase gene fragments using a set of internal primers namely Flip-1a and Rlip-1a that has been affixed with a GC clamp in reverse primer. The results showed that the primers amplified the gene from four stages of thermogenic phase with the size of lipase gene fragment of approximately 570 base pairs (bp). These results were further used for Denaturing Gradient Gel Electrophoresis (DGGE) analysis to determine diversity of thermostable lipase gene fragments.

  9. Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation

    SciTech Connect

    Daila S. Gridley, PhD

    2012-03-30

    FINAL TECHNICAL REPORT Supported by the Low Dose Radiation Research Program, Office of Science U.S. Department of Energy Grant No. DE-FG02-07ER64345 Project ID: 0012965 Award Register#: ER64345 Project Manager: Noelle F. Metting, Sc.D. Phone: 301-903-8309 Division SC-23.2 noelle.metting@science.doe.gov Submitted March 2012 To: https://www.osti.gov/elink/241.3.jsp Title: Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation PI: Daila S. Gridley, Ph.D. Human low dose radiation data have been derived primarily from studies of space and airline flight personnel, nuclear plant workers and others exposed occupationally, as well as victims in the vicinity of atomic bomb explosions. The findings remain inconclusive due to population inconsistencies and complex interactions among total dose, dose rate, radiation quality and age at exposure. Thus, safe limits for low dose occupational irradiation are currently based on data obtained with doses far exceeding the levels expected for the general population and health risks have been largely extrapolated using the linear-nonthreshold dose-response model. The overall working hypothesis of the present study is that priming with low dose, low-linear energy transfer (LET) radiation can ameliorate the response to acute high-dose radiation exposure. We also propose that the efficacy of low-dose induced protection will be dependent upon the form and regimen of the high-dose exposure: photons versus protons versus simulated solar particle event protons (sSPE). The emphasis has been on gene expression and function of CD4+ T helper (Th) lymphocytes harvested from spleens of whole-body irradiated C57BL/6 mice, a strain that provides the genetic background for many genetically engineered strains. Evaluations of the responses of other selected cells, tissues such as skin, and organs such as lung, liver and brain were also initiated (partially funded by other sources). The long-term goal is to provide information

  10. Is the serum amyloid A protein in acute phase plasma high density lipoprotein the precursor of AA amyloid fibrils?

    PubMed Central

    Baltz, M L; Rowe, I F; Caspi, D; Turnell, W G; Pepys, M B

    1986-01-01

    Serum amyloid A protein (SAA), an apolipoprotein of high density lipoprotein (HDL), is generally considered to be the precursor of AA protein, which forms the fibrils in reactive systemic amyloidosis in man and animals. This view is based on amino acid sequence identity between AA and the amino-terminal portion of SAA. However, in extensive and well-controlled studies of experimentally induced murine AA amyloidosis, we were unable to demonstrate a direct precursor-product relationship between SAA, in SAA-rich HDL preparations from acute phase or amyloidotic mouse or human serum, and AA protein in the amyloid deposits. This raises the possibility that SAA in its usual form, as an apolipoprotein of HDL synthesized during the acute phase response, may not be the major precursor of AA fibrils. The amyloidogenic forms of circulating SAA molecules may not be isolated during the preparation of HDL. Alternatively, particularly in the light of recent evidence that SAA mRNA is expressed in many different tissues throughout the body of appropriately stimulated animals, amyloidogenic SAA may be derived from sources other than the liver cells in which SAA-rich HDL is synthesized. PMID:3105937

  11. Glutamate excitoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

    PubMed

    Campos, Francisco; Pérez-Mato, María; Agulla, Jesús; Blanco, Miguel; Barral, David; Almeida, Angeles; Brea, David; Waeber, Christian; Castillo, José; Ramos-Cabrer, Pedro

    2012-01-01

    Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33°C, normothermia at 37°C and hyperthermia at 39°C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

  12. Latex-protein complexes from an acute phase recombinant antigen of Toxoplasma gondii for the diagnosis of recently acquired toxoplasmosis.

    PubMed

    Peretti, Leandro E; Gonzalez, Verónica D G; Marcipar, Iván S; Gugliotta, Luis M

    2014-08-01

    The synthesis and characterization of latex-protein complexes (LPC), from the acute phase recombinant antigen P35 (P35Ag) of Toxoplasma gondii and "core-shell" carboxylated or polystyrene (PS) latexes (of different sizes and charge densities) are considered, with the aim of producing immunoagglutination reagents able to detect recently acquired toxoplasmosis. Physical adsorption (PA) and chemical coupling (CC) of P35Ag onto latex particles at different pH were investigated. Greater amounts of adsorbed protein were obtained on PS latexes than on carboxylated latexes, indicating that hydrophobic forces govern the interactions between the protein and the particle surface. In the CC experiments, the highest amount of bound protein was obtained at pH 6, near the isoelectric point of the protein (IP=6.27). At this pH, it decreased both the repulsion between particle surface and protein, and the repulsion between neighboring molecules. The LPC were characterized and the antigenicity of the P35Ag protein coupled on the particles surface was evaluated by Enzyme-Linked ImmunoSorbent Assay (ELISA). Results from ELISA showed that the P35Ag coupled to the latex particles surface was not affected during the particles sensitization by PA and CC and the produced LPC were able to recognize specific anti-P35Ag antibodies present in the acute phase of the disease.

  13. Acute phase protein response during subclinical infection of pigs with H1N1 swine influenza virus.

    PubMed

    Pomorska-Mól, Małgorzata; Markowska-Daniel, Iwona; Pejsak, Zygmunt

    2012-10-12

    In the present study acute phase proteins (APPs) responses in pigs after subclinical infection with H1N1 swine influenza virus (SwH1N1) were evaluated. Fourteen 5 weeks old, seronegative piglets, both sexes were used. Ten of them were infected intranasally with SwH1N1. C-reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA) and pig major acute phase protein (Pig-MAP) concentrations in serum were measured using commercial ELISAs. No significant clinical signs were observed in any of the infected pigs, however, all infected animals developed specific antibodies against SwH1N1 and viral shedding was observed from 2 to 5 dpi. Only concentrations of Hp and SAA were significantly induced after infection, with mean maximum levels from days 1 to 2 post infection (dpi). The concentrations of CRP and Pig-MAP remained generally unchanged, however in half of infected pigs the concentration of CRP tended to increase at 1 dpi (but without statistical significance). The results of our study confirmed that monitoring of APPs may be useful for detection of subclinically infected pigs. The use of SAA or Hp and Pig-MAP may be a valuable in combination [i.e. Hp (increased concentration) and Pig-MAP (unchanged concentration)] to detect subclinically SIV infected pigs, or to identify pigs actually producing a large amount of virus. Additional studies need to be done in order to confirm these findings.

  14. [Cerebroprotective effect of 3-oxypyridine and succinic acid derivatives in acute phase of alloxan-induced diabetes mellitus in rats].

    PubMed

    Volchegorskiĭ, I A; Rassokhina, L M; Miroshnichenko, I Iu

    2011-01-01

    The effects of original domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin, and mexidol) on cellular composition of cortical and diencephalic structures in rat brain were studied in parallel with monitoring of behavioral, conditional learning, and metabolic disorders in acute phase of alloxan-induced diabetes in rats. The efficiency of 3-oxypyridine derivatives was compared to the results of alpha-lipoic acid administration. Single administration of emoxipine, reamberin, and mexidol in optimal doses prevented lipofuscin deposition in CA1 field neurocytes in hippocampus and/or increased the amount of terminally differentiated cells ofneuroectodermal lineage (oligodendrocytes, pyramid and basket cells) in this zone ofpaleocortex. Concurrently conditional learning capacity in morbid animals was restored. The cerebroprotective and nootropic effects of emoxipine and reamberin were associated with increased exploration motivation in the open field and were independent of their effects on carbohydrate and lipid metabolism dysfunction. On the contrary, the neuroprotective and nootropic effects of mexidol were associated with additional inhibition of morbid rat activity in the open field and a decrease in the level of circulating products of lipid peroxidation. It is established that 3-oxypyridine and succinic acid derivatives significantly exceed alpha-lipoic acid in terms of neuroprotective effects but exhibit significantly lower hypolipdemic activity in acute phase of alloxan diabetes.

  15. Effects of glutamine supplementation on gut barrier, glutathione content and acute phase response in malnourished rats during inflammatory shock

    PubMed Central

    Belmonte, Liliana; Coëffier, Moïse; Pessot, Florence Le; Miralles-Barrachina, Olga; Hiron, Martine; Leplingard, Antony; Lemeland, Jean-François; Hecketsweiler, Bernadette; Daveau, Maryvonne; Ducrotté, Philippe; Déchelotte, Pierre

    2007-01-01

    AIM: To evaluate the effect of glutamine on intestinal mucosa integrity, glutathione stores and acute phase response in protein-depleted rats during an inflammatory shock. METHODS: Plasma acute phase proteins (APP), jejunal APP mRNA levels, liver and jejunal glutathione concentrations were measured before and one, three and seven days after turpentine injection in 4 groups of control, protein-restricted, protein-restricted rats supplemented with glutamine or protein powder. Bacterial translocation in mesenteric lymph nodes and intestinal morphology were also assessed. RESULTS: Protein deprivation and turpentine injection significantly reduced jejunal villus height, and crypt depths. Mucosal glutathione concentration significantly decreased in protein-restricted rats. Before turpentine oil, glutamine supplementation restored villus heights and glutathione concentration (3.24 ± 1.05 vs 1.72 ± 0.46 μmol/g tissue, P < 0.05) in the jejunum, whereas in the liver glutathione remained low. Glutamine markedly increased jejunal α1-acid glycoprotein mRNA level after turpentine oil but did not affect its plasma concentration. Bacterial translocation in protein-restricted rats was not prevented by glutamine or protein powder supplementation. CONCLUSION: Glutamine restored gut glutathione stores and villus heights in malnourished rats but had no preventive effect on bacterial translocation in our model. PMID:17569119

  16. The acute phase of mild traumatic brain injury is characterized by a distance-dependent neuronal hypoactivity.

    PubMed

    Johnstone, Victoria P A; Shultz, Sandy R; Yan, Edwin B; O'Brien, Terence J; Rajan, Ramesh

    2014-11-15

    The consequences of mild traumatic brain injury (TBI) on neuronal functionality are only now being elucidated. We have now examined the changes in sensory encoding in the whisker-recipient barrel cortex and the brain tissue damage in the acute phase (24 h) after induction of TBI (n=9), with sham controls receiving surgery only (n=5). Injury was induced using the lateral fluid percussion injury method, which causes a mixture of focal and diffuse brain injury. Both population and single cell neuronal responses evoked by both simple and complex whisker stimuli revealed a suppression of activity that decreased with distance from the locus of injury both within a hemisphere and across hemispheres, with a greater extent of hypoactivity in ipsilateral barrel cortex compared with contralateral cortex. This was coupled with an increase in spontaneous output in Layer 5a, but only ipsilateral to the injury site. There was also disruption of axonal integrity in various regions in the ipsilateral but not contralateral hemisphere. These results complement our previous findings after mild diffuse-only TBI induced by the weight-drop impact acceleration method where, in the same acute post-injury phase, we found a similar depth-dependent hypoactivity in sensory cortex. This suggests a common sequelae of events in both diffuse TBI and mixed focal/diffuse TBI in the immediate post-injury period that then evolve over time to produce different long-term functional outcomes.

  17. The Acute Phase of Mild Traumatic Brain Injury Is Characterized by a Distance-Dependent Neuronal Hypoactivity

    PubMed Central

    Johnstone, Victoria P.A.; Shultz, Sandy R.; Yan, Edwin B.; O'Brien, Terence J.

    2014-01-01

    Abstract The consequences of mild traumatic brain injury (TBI) on neuronal functionality are only now being elucidated. We have now examined the changes in sensory encoding in the whisker-recipient barrel cortex and the brain tissue damage in the acute phase (24 h) after induction of TBI (n=9), with sham controls receiving surgery only (n=5). Injury was induced using the lateral fluid percussion injury method, which causes a mixture of focal and diffuse brain injury. Both population and single cell neuronal responses evoked by both simple and complex whisker stimuli revealed a suppression of activity that decreased with distance from the locus of injury both within a hemisphere and across hemispheres, with a greater extent of hypoactivity in ipsilateral barrel cortex compared with contralateral cortex. This was coupled with an increase in spontaneous output in Layer 5a, but only ipsilateral to the injury site. There was also disruption of axonal integrity in various regions in the ipsilateral but not contralateral hemisphere. These results complement our previous findings after mild diffuse-only TBI induced by the weight-drop impact acceleration method where, in the same acute post-injury phase, we found a similar depth-dependent hypoactivity in sensory cortex. This suggests a common sequelae of events in both diffuse TBI and mixed focal/diffuse TBI in the immediate post-injury period that then evolve over time to produce different long-term functional outcomes. PMID:24927383

  18. Serum acute phase proteins as biomarkers of pleuritis and cranio-ventral pulmonary consolidation in slaughter-aged pigs.

    PubMed

    Saco, Yolanda; Fraile, Lorenzo; Giménez, Mercè; Alegre, Ana; López-Jimenez, Rosa; Cortey, Martí; Segalés, Joaquim; Bassols, Anna

    2011-08-01

    The purpose of this study was to investigate the relationship between the existence of lung lesions in pigs at slaughter and the concentration of the serum acute phase proteins (APP), haptoglobin (Hp), pig-major acute protein (Pig-MAP) and C-reactive protein (CRP). A total of 24 pig farms were selected out of a larger farm database previously screened to study risk factors associated with pleuritis and cranio-ventral pulmonary consolidation (CVPC) lesions at slaughter-aged pigs in Spain. The farms were classified as "pleuritis negative (P-) or positive (P+)" and as "CVPC negative (M-) or positive (M+)" and divided into four groups according to a 2X2 factorial design (P-M-, P-M+, P+M-, P+M+). Also at slaughter, blood from 20 randomly selected pigs from each farm was collected. Obtained serum samples were used to measure acute phase proteins. All APP concentrations were significantly higher for M+ farms than for M- ones. However, only Hp and Pig-MAP showed significantly higher concentrations for P+ farms than for P- ones. Pig-MAP was the most sensitive biomarker since it was able to clearly discriminate between P-/P+ and M-/M+ groups (p<0.001 in both cases). Hp was an excellent marker for pleuritis and good for CVPC lesions. CRP was able to discriminate for CVPC lesions but not for pleuritis. The present results indicate that Pig-MAP and, possibly Hp, may be used as potential markers to characterise and discriminate respiratory lesions in swine herds at slaughter.

  19. Acute modulation of cytokine gene expression in bovine peripheral blood mononuclear cells (PBMCs) by endogenous cortisol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cortisol suppresses many aspects of immune function. However, recent publications suggest acute cortisol exposure may actually enhance immune function (Dhabhar. 2009. Neuroimmunomod. 16:300). The objective of this study was to determine the influence of acute increases in endogenous cortisol on expr...

  20. Acute modulation of cytokine gene expression in bovine PBMCs by endogenous cortisol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cortisol suppresses many aspects of immune function. However, recent publications suggest acute cortisol exposure may actually enhance immune function (Dhabhar, Neuroimmunomod 2009;16:300). The objective of this study was to determine the influence of acute increases in endogenous cortisol on expres...

  1. Endogenous Cortisol: Acute Modulation of Cytokine Gene Expression in Bovine PBMCs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cortisol suppresses many aspects of immune function. However, recent publications suggest acute cortisol exposure may actually enhance immune function (Dhabhar, Neuroimmunomod 2009;16:300). The objective of this study was to determine the influence of acute increases in endogenous cortisol on expres...

  2. Acute Toluene Exposure alters expression of genes associated with synaptic structure and function

    EPA Science Inventory

    Toluene (TOL), a volatile organic compound, is a ubiquitous air pollutant of interest to EPA regulatory programs. Whereas its acute functional effects are well described, several potential modes of action in the CNS have been proposed. Therefore, the genomic response to acute TOL...

  3. Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure.

    PubMed

    Court, Michael H; Peter, Inga; Hazarika, Suwagmani; Vasiadi, Magdalini; Greenblatt, David J; Lee, William M

    2014-01-01

    Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a single-time-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophen-metabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients. This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminophen-induced ALF.

  4. Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis

    PubMed Central

    Karki, Anju; Humphrey, Sean E.; Steele, Rebecca E.; Hess, David A.; Taparowsky, Elizabeth J.; Konieczny, Stephen F.

    2015-01-01

    Acinar cells of the exocrine pancreas are tasked with synthesizing, packaging and secreting vast quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Because the synthesis of high levels of hydrolases is potentially dangerous, the pancreas is prone to acute pancreatitis (AP), a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM), inflammation and fibrosis—events that can transition into the earliest stages of pancreatic ductal adenocarcinoma. Despite a wealth of information concerning the broad phenotype associated with pancreatitis, little is understood regarding specific transcriptional regulatory networks that are susceptible to AP and the role these networks play in acinar cell and exocrine pancreas responses. In this study, we examined the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery. Analysis of wild-type and Mist1 conditional null mice revealed that Mist1 gene transcription and protein accumulation were dramatically reduced as acinar cells underwent ADM alterations during AP episodes. To test if loss of MIST1 function was primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible Mist1 transgene (iMist1) were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Unexpectedly, constitutive iMist1 expression during AP led to a dramatic increase in organ damage followed by acinar cell death. We conclude that the transient silencing of Mist1 expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer. PMID:26717480

  5. Identification of gene variants related to the nitric oxide pathway in patients with acute coronary syndrome.

    PubMed

    Umman, B; Cakmakoglu, B; Cincin, Z B; Kocaaga, M; Emet, S; Tamer, S; Gokkusu, C

    2015-12-10

    Dysfunction of vascular endothelium is known to have an essential role in the atherosclerotic process by releasing mediators including nitric oxide (NO). Nitric oxide maintains endothelial balance by controlling cellular processes of vascular smooth muscle cells. Evidence suggests that variations in the NO pathway could include atherosclerotic events. The objective of this study was to determine the possible effects of genes on the nitric oxide pathway in the development of acute coronary syndrome (ACS). The blood samples of 100 patients with ACS and 100 controls were collected at Istanbul University, Department of Cardiology. DNA samples were genotyped by using Illumina Cyto-SNP-12 BeadChip. The additive model and Correlation/Trend Test were selected for association analysis. Afterwards, a Q-Q graphic was drawn to compare expected and obtained values. A Manhattan plot was produced to display p-values that were generated by -log10(P) function for each SNP. The p-values under 1×10(-4) were selected as statistically significant SNPs while p-values under 5×10(-2) were considered as suspicious biomarker candidates. Nitric oxide pathway analysis was then used to find the single nucleotide polymorphisms (SNPs) related to ACS. As a result, death-associated protein kinase 3 (DAPK) (rs10426955) was found to be most statistically significant SNP. The most suspicious biomarker candidates associated with the nitric oxide pathway analysis were vascular endothelial growth factor A (VEGFA), methionine sulfoxide reductase A (MSRA), nitric oxide synthase 1 (NOS1), and GTP cyclohydrolase I (GCH-1). Further studies with large sample groups are necessary to clarify the exact role of nitric oxide in the development of disease.

  6. Genome-Wide Transcriptional Analysis of Genes Associated with Acute Desiccation Stress in Anopheles gambiae

    PubMed Central

    Wang, Mei-Hui; Marinotti, Osvaldo; Vardo-Zalik, Anne; Boparai, Rajni; Yan, Guiyun

    2011-01-01

    Malaria transmission in sub-Saharan Africa varies seasonally in intensity. Outbreaks of malaria occur after the beginning of the rainy season, whereas, during the dry season, reports of the disease are less frequent. Anopheles gambiae mosquitoes, the main malaria vector, are observed all year long but their densities are low during the dry season that generally lasts several months. Aestivation, seasonal migration, and local adaptation have been suggested as mechanisms that enable mosquito populations to persist through the dry season. Studies of chromosomal inversions have shown that inversions 2La, 2Rb, 2Rc, 2Rd, and 2Ru are associated with various physiological changes that confer aridity resistance. However, little is known about how phenotypic plasticity responds to seasonally dry conditions. This study examined the effects of desiccation stress on transcriptional regulation in An. gambiae. We exposed female An. gambiae G3 mosquitoes to acute desiccation and conducted a genome-wide analysis of their transcriptomes using the Affymetrix Plasmodium/Anopheles Genome Array. The transcription of 248 genes (1.7% of all transcripts) was significantly affected in all experimental conditions, including 96 with increased expression and 152 with decreased expression. In general, the data indicate a reduction in the metabolic rate of mosquitoes exposed to desiccation. Transcripts accumulated at higher levels during desiccation are associated with oxygen radical detoxification, DNA repair and stress responses. The proportion of transcripts within 2La and 2Rs (2Rb, 2Rc, 2Rd, and 2Ru) (67/248, or 27%) is similar to the percentage of transcripts located within these inversions (31%). These data may be useful in efforts to elucidate the role of chromosomal inversions in aridity tolerance. The scope of application of the anopheline genome demonstrates that examining transcriptional activity in relation to genotypic adaptations greatly expands the number of candidate regions

  7. Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations.

    PubMed

    Abbas, Saman; Sanders, Mathijs A; Zeilemaker, Annelieke; Geertsma-Kleinekoort, Wendy M C; Koenders, Jasper E; Kavelaars, Francois G; Abbas, Zabiollah G; Mahamoud, Souad; Chu, Isabel W T; Hoogenboezem, Remco; Peeters, Justine K; van Drunen, Ellen; van Galen, Janneke; Beverloo, H Berna; Löwenberg, Bob; Valk, Peter J M

    2014-05-01

    Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia.

  8. Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations

    PubMed Central

    Abbas, Saman; Sanders, Mathijs A.; Zeilemaker, Annelieke; Geertsma-Kleinekoort, Wendy M.C.; Koenders, Jasper E.; Kavelaars, Francois G.; Abbas, Zabiollah G.; Mahamoud, Souad; Chu, Isabel W.T.; Hoogenboezem, Remco; Peeters, Justine K.; van Drunen, Ellen; van Galen, Janneke; Beverloo, H. Berna; Löwenberg, Bob; Valk, Peter J.M.

    2014-01-01

    Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia. PMID:24441149

  9. Delivery of glutamine synthetase gene by baculovirus vectors: a proof of concept for the treatment of acute hyperammonemia.

    PubMed

    Torres-Vega, M A; Vargas-Jerónimo, R Y; Montiel-Martínez, A G; Muñoz-Fuentes, R M; Zamorano-Carrillo, A; Pastor, A R; Palomares, L A

    2015-01-01

    Hyperammonemia, a condition present in patients with urea cycle disorders (UCDs) or liver diseases, can cause neuropsychiatric complications, which in the worst cases result in brain damage, coma or death. Diverse treatments exist for the treatment of hyperammonemia, but they have limited efficacy, adverse effects and elevated cost. Gene therapy is a promising alternative that is explored here. A baculovirus, termed Bac-GS, containing the glutamine synthetase (GS) gene was constructed for the in vitro and in vivo treatment of hyperammonemia. Transduction of MA104 epithelial or L6 myoblast/myotubes cells with Bac-GS resulted in a high expression of the GS gene, an increase in GS concentration, and a reduction of almost half of exogenously added ammonia. When Bac-GS was tested in an acute hyperammonemia rat model by intramuscularly injecting the rear legs, the concentration of ammonia in blood decreased 351 μM, in comparison with controls. A high GS concentration was detected in gastrocnemius muscles from the rats transduced with Bac-GS. These results show that gene delivery for overexpressing GS in muscle tissue is a promising alternative for the treatment of hyperammonemia in patients with acute or chronic liver diseases and hepatic encephalopathy or UCD.

  10. Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation

    SciTech Connect

    Corral, J.; Forster, A.; Thompson, S.; Rabbitts, T.H. ); Lampert, F. ); Kaneko, Y. ); Slater, R.; Kroes, W.G. ); Van Der Schoot, C.E. ); Ludwig, W.D. ); Karpas, A. ); Pocock, C.; Cotter, F. )

    1993-09-15

    The MLL gene, on human chromosome 11q23, undergoes chromosomal translocation in acute leukemias, resulting in gene fusion with AF4 (chromosome 4) and ENL (chromosome 19). The authors report here translocation of MLL with nine different chromosomes and two paracentric chromosome 11 deletions in early B cell, B- or T-cell lineage, or nonlymphocytic acute leukemias. The mRNA translocation junction from 22t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL genes, irrespective of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important component in leukemogenesis. Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heterogeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH[sub 2] terminus of MLL, lacking the zinc-finger region, and that translocation occurs in early hematopoietic cells, before commitment to distinct lineages. 36 refs., 2 figs.

  11. Investor Outlook: Significance of the Positive LCA2 Gene Therapy Phase III Results.

    PubMed

    Schimmer, Joshua; Breazzano, Steven

    2015-12-01

    Spark Therapeutics recently reported positive phase III results for SPK-RPE65 targeting the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders), marking an important inflection point for the field of gene therapy. The results highlight the ability to successfully design and execute a randomized trial of a gene therapy and also reinforce the potentially predictive nature of early preclinical and clinical data. The results are expected to pave the way for the first approved gene therapy product in the United States and should sustain investor interest and confidence in gene therapy for many approaches, including retina targeting and beyond.

  12. Methylation of tumour suppressor gene promoters in the presence and absence of transcriptional silencing in high hyperdiploid acute lymphoblastic leukaemia.

    PubMed

    Paulsson, Kajsa; An, Qian; Moorman, Anthony V; Parker, Helen; Molloy, Gael; Davies, Teresa; Griffiths, Mike; Ross, Fiona M; Irving, Julie; Harrison, Christine J; Young, Bryan D; Strefford, Jon C

    2009-03-01

    Promoter methylation is a common phenomenon in tumours, including haematological malignancies. In the present study, we investigated 36 cases of high hyperdiploid (>50 chromosomes) acute lymphoblastic leukaemia (ALL) with methylation-specific multiplex ligase-dependent probe amplification to determine the extent of aberrant methylation in this subgroup. The analysis, which comprised the promoters of 35 known tumour suppressor genes, showed that 16 genes displayed abnormal methylation in at least one case each. The highest number of methylated gene promoters seen in a single case was thirteen, with all but one case displaying methylation for at least one gene. The most common targets were ESR1 (29/36 cases; 81%), CADM1 (IGSF4, TSLC1; 25/36 cases; 69%), FHIT (24/36 cases; 67%) and RARB (22/36 cases; 61%). Interestingly, quantitative reverse transcription-polymerase chain reaction showed that although methylation of the CADM1 and RARB promoters resulted in the expected pattern of downregulation of the respective genes, no difference could be detected in FHIT expression between methylation-positive and -negative cases. Furthermore, TIMP3 was not expressed regardless of methylation status, showing that aberrant methylation does not always lead to gene expression changes. Taken together, our findings suggest that aberrant methylation of tumour suppressor gene promoters is a common phenomenon in high hyperdiploid ALL.

  13. Supervised Phase II Cardiac Exercise Therapy Shortens the Recovery of Exercise Capacity in Patients with Acute Myocardial Infarction

    PubMed Central

    Lee, Chih-Wei; Wang, Ji-Hung; Hsieh, Jen-Che; Hsieh, Tsung-Cheng; Wu, Yu-Zu; Chen, Tung-Wei; Huang, Chien-Hui

    2014-01-01

    [Purpose] To investigate the effects of Phase II cardiac exercise therapy (CET) on exercise capacity and changes in coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Subjects] Thirty male subjects with AMI were divided into an experimental group (EG) and a control group (CG). Another 30 age-matched subjects with patent coronary arteries served as a normal-control group (NCG). [Methods] Subjects in EG (n=20) trained using a stationary bicycle for 30 min at their target heart rate twice a week for 8 weeks. Exercise capacity was defined as the maximal metabolic equivalents (METs) that subjects reached during the symptom-limited maximal exercise test. HR, BP and RPP were recorded. Subjects in EG and CG received exercise tests and screening for CRFs at the beginning of, end of, and 3 months after Phase II CET, while subjects in NCG participated only in the 1st test. [Results] METs of CG did not improve until the 3rd test, while RPP at the 2nd test showed a significant increase. However, EG showed increased METs at the 2nd test without increase of RPP, and increased their high density lipoprotein cholesterol (HDL-C) during the follow-up period between the 2nd and 3rd tests. [Conclusion] Phase II CET shortens the recovery time of exercise capacity, helps to maintain the gained exercise capacity and increases HDL-C in phase III. PMID:25276046

  14. Delta 9-tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew.

    PubMed

    Ray, Andrew P; Griggs, Lisa; Darmani, Nissar A

    2009-01-03

    Cisplatin chemotherapy frequently causes severe vomiting in two temporally separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both the emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB(1), CB(2)), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10mg/kg i.p.), and one of vehicle, Delta(9)-THC, or both Delta(9)-THC and the CB(1) receptor antagonist SR141716A (2mg/kg i.p.), and monitored for vomiting. Delta(9)-THC-pretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fos-immunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB(1) receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB(2) receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin- and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Delta(9)-THC mediated by CB(1) receptors.

  15. Acute stress enhances the expression of neuroprotection- and neurogenesis-associated genes in the hippocampus of a mouse restraint model

    PubMed Central

    Sannino, Giuseppina; Pasqualini, Lorenza; Ricciardelli, Eugenia; Montilla, Patricia; Soverchia, Laura; Ruggeri, Barbara; Falcinelli, Silvia; Renzi, Alessandra; Ludka, Colleen; Kirchner, Thomas; Grünewald, Thomas G. P.; Ciccocioppo, Roberto; Ubaldi, Massimo; Hardiman, Gary

    2016-01-01

    Stress arises from an external demand placed on an organism that triggers physiological, cognitive and behavioural responses in order to cope with that request. It is thus an adaptive response useful for the survival of an organism. The objective of this study was to identify and characterize global changes in gene expression in the hippocampus in response to acute stress stimuli, by employing a mouse model of short-term restraint stress. In our experimental design mice were subjected to a one time exposure of restraint stress and the regulation of gene expression in the hippocampus was examined 3, 12 and 24 hours thereafter. Microarray analysis revealed that mice which had undergone acute restraint stress differed from non-stressed controls in global hippocampal transcriptional responses. An up-regulation of transcripts contributing directly or indirectly to neurogenesis and neuronal protection including, Ttr, Rab6, Gh, Prl, Ndufb9 and Ndufa6, was observed. Systems level analyses revealed a significant enrichment for neurogenesis, neuron morphogenesis- and cognitive functions-related biological process terms and pathways. This work further supports the hypothesis that acute stress mediates a positive action on the hippocampus favouring the formation and the preservation of neurons, which will be discussed in the context of current data from the literature. PMID:26863456

  16. Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease.

    PubMed

    Poulsen, Sarah S; Saber, Anne T; Mortensen, Alicja; Szarek, Józef; Wu, Dongmei; Williams, Andrew; Andersen, Ole; Jacobsen, Nicklas R; Yauk, Carole L; Wallin, Håkan; Halappanavar, Sabina; Vogel, Ulla

    2015-03-15

    Adverse lung effects following pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) are well documented in rodents. However, systemic effects are less understood. Epidemiological studies have shown increased cardiovascular disease risk after pulmonary exposure to airborne particles, which has led to concerns that inhalation exposure to MWCNTs might pose similar risks. We analyzed parameters related to cardiovascular disease, including plasma acute phase response (APR) proteins and plasma lipids, in female C57BL/6 mice exposed to a single intratracheal instillation of 0, 18, 54 or 162μg/mouse of small, entangled (CNTSmall, 0.8±0.1μm long) or large, thick MWCNTs (CNTLarge, 4±0.4μm long). Liver tissues and plasma were harvested 1, 3 and 28days post-exposure. In addition, global hepatic gene expression, hepatic cholesterol content and liver histology were used to assess hepatic effects. The two MWCNTs induced similar systemic responses despite their different physicochemical properties. APR proteins SAA3 and haptoglobin, plasma total cholesterol and low-density/very low-density lipoprotein were significantly increased following exposure to either MWCNTs. Plasma SAA3 levels correlated strongly with pulmonary Saa3 levels. Analysis of global gene expression revealed perturbation of the same biological processes and pathways in liver, including the HMG-CoA reductase pathway. Both MWCNTs induced similar histological hepatic changes, with a tendency towards greater response following CNTLarge exposure. Overall, we show that pulmonary exposure to two different MWCNTs induces similar systemic and hepatic responses, including changes in plasma APR, lipid composition, hepatic gene expression and liver morphology. The results link pulmonary exposure to MWCNTs with risk of cardiovascular disease.

  17. Analysis of gene expression during the transition to climacteric phase in carnation flowers (Dianthus caryophyllus L.).

    PubMed

    In, Byung-Chun; Binder, Brad M; Falbel, Tanya G; Patterson, Sara E

    2013-11-01

    It has been generally thought that in ethylene-sensitive plants such as carnations, senescence proceeds irreversibly once the tissues have entered the climacteric phase. While pre-climacteric petal tissues have a lower sensitivity to ethylene, these tissues are converted to the climacteric phase at a critical point during flower development. In this study, it is demonstrated that the senescence process initiated by exogenous ethylene is reversible in carnation petals. Petals treated with ethylene for 12h showed sustained inrolling and senescence, while petals treated with ethylene for 10h showed inrolling followed by recovery from inrolling. Reverse transcription-PCR analysis revealed differential expression of genes involved in ethylene biosynthesis and ethylene signalling between 10h and 12h ethylene treatment. Ethylene treatment at or beyond 12h (threshold time) decreased the mRNA levels of the receptor genes (DcETR1, DcERS1, and DcERS2) and DcCTR genes, and increased the ethylene biosynthesis genes DcACS1 and DcACO1. In contrast, ethylene treatment under the threshold time caused a transient decrease in the receptor genes and DcCTR genes, and a transient increase in DcACS1 and DcACO1. Sustained DcACS1 accumulation is correlated with decreases in DcCTR genes and increase in DcEIL3 and indicates that tissues have entered the climacteric phase and that senescence proceeds irreversibly. Inhibition of ACS (1-aminocyclopropane-1-carboxylic acid synthase) prior to 12h ethylene exposure was not able to prevent reduction in transcripts of DcCTR genes, yet suppressed transcript of DcACS1 and DcACO1. This leads to the recovery from inrolling of the petals, indicating that DcACS1 may act as a signalling molecule in senescence of flowers.

  18. Deletion and deletion/insertion mutations in the juxtamembrane domain of the FLT3 gene in adult acute myeloid leukemia

    PubMed Central

    Deeb, Kristin K.; Smonskey, Matthew T.; DeFedericis, HanChun; Deeb, George; Sait, Sheila N.J.; Wetzler, Meir; Wang, Eunice S.; Starostik, Petr

    2014-01-01

    In contrast to FLT3 ITD mutations, in-frame deletions in the FLT3 gene have rarely been described in adult acute leukemia. We report two cases of AML with uncommon in-frame mutations in the juxtamembrane domain of the FLT3 gene: a 3-bp (c.1770_1774delCTACGinsGT; p.F590_V592delinsLF) deletion/insertion and a 12-bp (c.1780_1791delTTCAGAGAATAT; p.F594_Y597del) deletion. We verified by sequencing that the reading frame of the FLT3 gene was preserved and by cDNA analysis that the mRNA of the mutant allele was expressed in both cases. Given the recent development of FLT3 inhibitors, our findings may be of therapeutic value for AML patients harboring similar FLT3 mutations. PMID:25379410

  19. Mutation profiling of 19 candidate genes in acute myeloid leukemia suggests significance of DNMT3A mutations

    PubMed Central

    Shin, Sang-Yong; Lee, Seung-Tae; Kim, Hee-Jin; Cho, Eun Hae; Kim, Jong-Won; Park, Silvia; Jung, Chul Won; Kim, Sun-Hee

    2016-01-01

    We selected 19 significantly-mutated genes in AMLs, including FLT3, DNMT3A, NPM1, TET2, RUNX1, CEBPA, WT1, IDH1, IDH2, NRAS, ASXL1, SETD2, PTPN11, TP53, KIT, JAK2, KRAS, BRAF and CBL, and performed massively parallel sequencing for 114 patients with acute myeloid leukemias, mainly including those with normal karyotypes (CN-AML). More than 80% of patients had at least one mutation in the genes tested. DNMT3A mutation was significantly associated with adverse outcome in addition to conventional risk stratification such as the European LeukemiaNet (ELN) classification. We observed clinical usefulness of mutation testing on multiple target genes and the association with disease subgroups, clinical features and prognosis in AMLs. PMID:27359055

  20. Altered Circadian Rhythm and Metabolic Gene Profile in Rats Subjected to Advanced Light Phase Shifts

    PubMed Central

    Herrero, Laura; Valcarcel, Lorea; da Silva, Crhistiane Andressa; Albert, Nerea; Diez-Noguera, Antoni; Cambras, Trinitat; Serra, Dolors

    2015-01-01

    The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT), brown adipose tissue (BAT) and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level. PMID:25837425

  1. p21 as a Transcriptional Co-Repressor of S-Phase and Mitotic Control Genes

    PubMed Central

    Ferrándiz, Nuria; Caraballo, Juan M.; García-Gutierrez, Lucía; Devgan, Vikram; Rodriguez-Paredes, Manuel; Lafita, M. Carmen; Bretones, Gabriel; Quintanilla, Andrea; Muñoz-Alonso, M. Jose; Blanco, Rosa; Reyes, Jose C.; Agell, Neus; Delgado, M. Dolores; Dotto, G. Paolo; León, Javier

    2012-01-01

    It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes. PMID:22662213

  2. Predicting value of cerebrospinal fluid proinflammatory factors in acute phase of ischemic stroke.

    PubMed

    Beridze, M; Shakarishvili, R

    2006-03-01

    Study purposed to establish the correlation between proinflammatory cytokines' initial CSF levels and neurological outcome on 7th day of acute ischemic stroke. 58 patients with acute ischemic stroke have been investigated. Neurological impairment assessed in 48 hours and on 7th day of stroke applying the international scales NIHSS and GCS. Patients divided into two groups: with severe stroke (GCS>9, NIHSS>15) and stroke with moderate severity (GCS=14,15; NIHSS=10-15). On 7th day increase of NIHSS score and decrease of GCS score at least 1 point was considered as deterioration and decrease of NIHSS score and increase of GCS score at least 1 point was considered as amelioration. CSF levels of proinflamatory cytokines determined using the enzyme-linked immunosorbent assay (ELISA). Control consisted with 15 patients, which were taken CSF in relation with vertebral discopathies. Means calculated by t-paired test. Pearson correlation and multivariate logistic regression were used. In 48 hours of stroke onset the CSF levels of interleukine-1beta (IL-1beta), interleukine-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were elevated compared to control. Statistical differences were not found between groups regarding the initial CSF levels of IL-1beta and TNF-alpha (p<0,5), while the significant statistical differences were found in regard with IL-6 CSF levels (p<0,05) between groups and against control. Significant positive correlation was found between initial CSF IL-6 levels and ischemic lesion size and neurological outcome at 1 week as well (r=+0,48 p<0,05 and r=+0,54 p<0,01 respectively). Thus, the IL-6 CSF levels in acute stage of ischemic stroke might be considered as the relatively stable prognostic indicator of clinical course of the disease.

  3. Effects of Acupuncture on mRNA Levels of Apoptotic Factors in Perihematomal Brain Tissue During the Acute Phase of Cerebral Hemorrhage.

    PubMed

    Li, Zuowei; Zheng, Xiaonan; Li, Ping; Itoua, Eudes Saturnin Régis; Moukassa, Donatien; Ndinga Andely, Françoise

    2017-03-30

    BACKGROUND To explore the time-dependent effects of acupuncture on mRNA levels of the apoptotic factors BCL-2 and BAX in a rat cerebral hemorrhage model, slow injection of autologous blood to the caudate nucleus was used to generate the cerebral hemorrhage model. MATERIAL AND METHODS A sham surgery control group, groups with acupuncture applied 3, 9, 24, and 48 hours after model induction, and time-matched model-only control groups were used. In situ hybridization was used to detect BCL-2 and BAX mRNA expression, and semi-quantitative RT-PCR was used to measure the expression. RESULTS The number of BCL-2 and BAX mRNA-positive cells significantly increased during the acute phase of cerebral hemorrhage. BCL-2 mRNA was significantly upregulated in acupuncture groups compared to other groups, whereas BAX mRNA levels in the acupuncture groups were lower in the other groups, except for the sham surgery group. Additionally, earlier acupuncture intervention was associated with a lower ratio of expression between the two genes. Changes in BCL-2 and BAX mRNA expression were consistent with changes in the number of cells positive for BCL-2 and BAX mRNA; however, the change in the expression ratio was consistent with the change in the number of cells positive for BCL-2 mRNA, but opposite to the change in the number of cells positive for BAX mRNA. CONCLUSIONS Acupuncture ameliorated changes in expression of apoptotic factors in the brain induced by acute cerebral hemorrhage and may thus protect the brain, with greater efficacy when the delay before acupuncture was minimized.

  4. Effects of Acupuncture on mRNA Levels of Apoptotic Factors in Perihematomal Brain Tissue During the Acute Phase of Cerebral Hemorrhage

    PubMed Central

    Li, Zuowei; Zheng, Xiaonan; Li, Ping; Itoua, Eudes Saturnin Régis; Moukassa, Donatien; Andely, Françoise Ndinga

    2017-01-01

    Background To explore the time-dependent effects of acupuncture on mRNA levels of the apoptotic factors BCL-2 and BAX in a rat cerebral hemorrhage model, slow injection of autologous blood to the caudate nucleus was used to generate the cerebral hemorrhage model. Material/Methods A sham surgery control group, groups with acupuncture applied 3, 9, 24, and 48 hours after model induction, and time-matched model-only control groups were used. In situ hybridization was used to detect BCL-2 and BAX mRNA expression, and semi-quantitative RT-PCR was used to measure the expression. Results The number of BCL-2 and BAX mRNA-positive cells significantly increased during the acute phase of cerebral hemorrhage. BCL-2 mRNA was significantly upregulated in acupuncture groups compared to other groups, whereas BAX mRNA levels in the acupuncture groups were lower in the other groups, except for the sham surgery group. Additionally, earlier acupuncture intervention was associated with a lower ratio of expression between the two genes. Changes in BCL-2 and BAX mRNA expression were consistent with changes in the number of cells positive for BCL-2 and BAX mRNA; however, the change in the expression ratio was consistent with the change in the number of cells positive for BCL-2 mRNA, but opposite to the change in the number of cells positive for BAX mRNA. Conclusions Acupuncture ameliorated changes in expression of apoptotic factors in the brain induced by acute cerebral hemorrhage and may thus protect the brain, with greater efficacy when the delay before acupuncture was minimized. PMID:28357997

  5. BAYESIAN SEMIPARAMETRIC ANALYSIS FOR TWO-PHASE STUDIES OF GENE-ENVIRONMENT INTERACTION

    PubMed Central

    Ahn, Jaeil; Mukherjee, Bhramar; Gruber, Stephen B.; Ghosh, Malay

    2013-01-01

    The two-phase sampling design is a cost-efficient way of collecting expensive covariate information on a judiciously selected sub-sample. It is natural to apply such a strategy for collecting genetic data in a sub-sample enriched for exposure to environmental factors for gene-environment interaction (G × E) analysis. In this paper, we consider two-phase studies of G × E interaction where phase I data are available on exposure, covariates and disease status. Stratified sampling is done to prioritize individuals for genotyping at phase II conditional on disease and exposure. We consider a Bayesian analysis based on the joint retrospective likelihood of phase I and phase II data. We address several important statistical issues: (i) we consider a model with multiple genes, environmental factors and their pairwise interactions. We employ a Bayesian variable selection algorithm to reduce the dimensionality of this potentially high-dimensional model; (ii) we use the assumption of gene-gene and gene-environment independence to trade-off between bias and efficiency for estimating the interaction parameters through use of hierarchical priors reflecting this assumption; (iii) we posit a flexible model for the joint distribution of the phase I categorical variables using the non-parametric Bayes construction of Dunson and Xing (2009). We carry out a small-scale simulation study to compare the proposed Bayesian method with weighted likelihood and pseudo likelihood methods that are standard choices for analyzing two-phase data. The motivating example originates from an ongoing case-control study of colorectal cancer, where the goal is to explore the interaction between the use of statins (a drug used for lowering lipid levels) and 294 genetic markers in the lipid metabolism/cholesterol synthesis pathway. The sub-sample of cases and controls on which these genetic markers were measured is enriched in terms of statin users. The example and simulation results illustrate that the

  6. Peripheral Inflammatory Markers and Antioxidant Response during the Post-Acute and Chronic Phase after Severe Traumatic Brain Injury

    PubMed Central

    Licastro, Federico; Hrelia, Silvana; Porcellini, Elisa; Malaguti, Marco; Di Stefano, Cristina; Angeloni, Cristina; Carbone, Ilaria; Simoncini, Laura; Piperno, Roberto

    2016-01-01

    Traumatic brain injury (TBI) is a mechanical insult to the brain caused by external forces and associated with inflammation and oxidative stress. The patients may show different profiles of neurological recovery and a combination of oxidative damage and inflammatory processes can affect their courses. It is known that an overexpression of cytokines can be seen in peripheral blood in the early hours/days after the injury, but little is known about the weeks and months encompassing the post-acute and chronic phases. In addition, no information is available about the antioxidant responses mediated by the major enzymes that regulate reactive oxygen species levels: superoxide dismutase, catalase, peroxidases, and GSH-related enzymes. This study investigates the 6-month trends of inflammatory markers and antioxidant responses in 22 severe TBI patients with prolonged disorders of consciousness, consecutively recruited in a dedicated neurorehabilitation facility. Patients with a high degree of neurological impairment often show an uncertain outcome. In addition, the profiles of plasma activities were related to the neurological recovery after 12 months. Venous peripheral blood samples were taken blindly as soon as clinical signs and laboratory markers confirmed the absence of infections, 3 and 6 months later. The clinical and neuropsychological assessment continued up to 12 months. Nineteen patients completed the follow-up. In the chronic phase, persistent high plasma levels of cytokines can interfere with cognitive functioning and higher post-acute levels of cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL1b, IL6] are associated with poorer cognitive recoveries 12 months later. Moreover, higher IFN-γ, higher TNF-α, and lower glutathione peroxidase activity are associated with greater disability. The results add evidence of persistent inflammatory response, provide information about long-term imbalance of antioxidant activity, and suggest that

  7. Immunomodulatory properties of gamithromycin and ketoprofen in lipopolysaccharide-challenged calves with emphasis on the acute-phase response.

    PubMed

    Plessers, Elke; Wyns, Heidi; Watteyn, Anneleen; Pardon, Bart; De Baere, Siegrid; Sys, Stanislas U; De Backer, Patrick; Croubels, Siska

    2016-03-01

    Macrolide antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to be modulators of the innate immune response, irrespectively of their antimicrobial and anti-inflammatory actions. Therefore, it was our objective to evaluate whether the macrolide gamithromycin (GAM) and the NSAID ketoprofen (KETO) attenuate the acute-phase response in calves, and whether their combined administration is beneficial due to synergistic and/or additive effects. To this end, both drugs, as well as their combination, were studied in a previously developed inflammation model, i.e., the induction of an acute-phase response by an intravenous lipopolysaccharide (LPS) challenge (0.5 μg/kg body weight). Sixteen 4-week-old Holstein-Friesian calves were randomized into 4 groups: a positive control (+CONTR) group, receiving LPS but no pharmacological treatment (n=4) and a GAM (n=4), a KETO (n=4) and a GAM-KETO (n=4) group, receiving the respective drugs 1h prior to LPS administration. Clinical scoring and blood collection were performed at regular time points until 72 h post LPS challenge. Plasma concentrations of the selected cytokines (tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)), acute-phase protein (serum amyloid A (SAA)) and prostaglandin E2 (PGE2) were subsequently quantified. Pre-treatment with GAM had no effect in the inflammation model compared to the +CONTR group. KETO, on the other hand, completely inhibited depression, anorexia and fever. This remarkable influence was associated with a significant reduction of PGE2 synthesis by KETO, while the effect on TNF-α, IL-6 and SAA was not straightforward. The combined administration of GAM and KETO provided no synergistic or additive effects in this model, neither clinically nor regarding the studied inflammatory mediators. In conclusion, KETO entirely inhibited PGE2 synthesis, fever development and depression, while GAM did not exert any effect in this model. These results promote the concomitant

  8. Peripheral Inflammatory Markers and Antioxidant Response during the Post-Acute and Chronic Phase after Severe Traumatic Brain Injury.

    PubMed

    Licastro, Federico; Hrelia, Silvana; Porcellini, Elisa; Malaguti, Marco; Di Stefano, Cristina; Angeloni, Cristina; Carbone, Ilaria; Simoncini, Laura; Piperno, Roberto

    2016-01-01

    Traumatic brain injury (TBI) is a mechanical insult to the brain caused by external forces and associated with inflammation and oxidative stress. The patients may show different profiles of neurological recovery and a combination of oxidative damage and inflammatory processes can affect their courses. It is known that an overexpression of cytokines can be seen in peripheral blood in the early hours/days after the injury, but little is known about the weeks and months encompassing the post-acute and chronic phases. In addition, no information is available about the antioxidant responses mediated by the major enzymes that regulate reactive oxygen species levels: superoxide dismutase, catalase, peroxidases, and GSH-related enzymes. This study investigates the 6-month trends of inflammatory markers and antioxidant responses in 22 severe TBI patients with prolonged disorders of consciousness, consecutively recruited in a dedicated neurorehabilitation facility. Patients with a high degree of neurological impairment often show an uncertain outcome. In addition, the profiles of plasma activities were related to the neurological recovery after 12 months. Venous peripheral blood samples were taken blindly as soon as clinical signs and laboratory markers confirmed the absence of infections, 3 and 6 months later. The clinical and neuropsychological assessment continued up to 12 months. Nineteen patients completed the follow-up. In the chronic phase, persistent high plasma levels of cytokines can interfere with cognitive functioning and higher post-acute levels of cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL1b, IL6] are associated with poorer cognitive recoveries 12 months later. Moreover, higher IFN-γ, higher TNF-α, and lower glutathione peroxidase activity are associated with greater disability. The results add evidence of persistent inflammatory response, provide information about long-term imbalance of antioxidant activity, and suggest that

  9. Proteogenomics of selective susceptibility to endotoxin using circulating acute phase biomarkers and bioassay development in sheep: a review

    PubMed Central

    2014-01-01

    Scientists have injected endotoxin into animals to investigate and understand various pathologies and novel therapies for several decades. Recent observations have shown that there is selective susceptibility to Escherichia coli lipopolysaccharide (LPS) endotoxin in sheep, despite having similar breed characteristics. The reason behind this difference is unknown, and has prompted studies aiming to explain the variation by proteogenomic characterisation of circulating acute phase biomarkers. It is hypothesised that genetic trait, biochemical, immunological and inflammation marker patterns contribute in defining and predicting mammalian response to LPS. This review discusses the effects of endotoxin and host responses, genetic basis of innate defences, activation of the acute phase response (APR) following experimental LPS challenge, and the current approaches employed in detecting novel biomarkers including acute phase proteins (APP) and micro-ribonucleic acids (miRNAs) in serum or plasma. miRNAs are novel targets for elucidating molecular mechanisms of disease because of their differential expression during pathological, and in healthy states. Changes in miRNA profiles during a disease challenge may be reflected in plasma. Studies show that gel-based two-dimensional electrophoresis (2-DE) coupled with either matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) or liquid chromatography–mass spectrometry (LC-MS/MS) are currently the most used methods for proteome characterisation. Further evidence suggests that proteomic investigations are preferentially shifting from 2-DE to non-gel based LC-MS/MS coupled with data extraction by sequential window acquisition of all theoretical fragment-ion spectra (SWATH) approaches that are able to identify a wider range of proteins. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and most recently proteomic methods have been used to

  10. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia

    PubMed Central

    Xiang, Zhifu; Walgren, Richard; Zhao, Yu; Kasai, Yumi; Miner, Tracie; Ries, Rhonda E.; Lubman, Olga; Fremont, Daved H.; McLellan, Michael D.; Payton, Jacqueline E.; Westervelt, Peter; DiPersio, John F.; Link, Daniel C.; Walter, Matthew J.; Graubert, Timothy A.; Watson, Mark; Baty, Jack; Heath, Sharon; Shannon, William D.; Nagarajan, Rakesh; Bloomfield, Clara D.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.

    2008-01-01

    Activating mutations in tyrosine kinase (TK) genes (eg, FLT3 and KIT) are found in more than 30% of patients with de novo acute myeloid leukemia (AML); many groups have speculated that mutations in other TK genes may be present in the remaining 70%. We performed high-throughput resequencing of the kinase domains of 26 TK genes (11 receptor TK; 15 cytoplasmic TK) expressed in most AML patients using genomic DNA from the bone marrow (tumor) and matched skin biopsy samples (“germline”) from 94 patients with de novo AML; sequence variants were validated in an additional 94 AML tumor samples (14.3 million base pairs of sequence were obtained and analyzed). We identified known somatic mutations in FLT3, KIT, and JAK2 TK genes at the expected frequencies and found 4 novel somatic mutations, JAK1V623A, JAK1T478S, DDR1A803V, and NTRK1S677N, once each in 4 respective patients of 188 tested. We also identified novel germline sequence changes encoding amino acid substitutions (ie, nonsynonymous changes) in 14 TK genes, including TYK2, which had the largest number of nonsynonymous sequence variants (11 total detected). Additional studies will be required to define the roles that these somatic and germline TK gene variants play in AML pathogenesis. PMID:18270328

  11. [Analysis of DEK-CAN fusion gene expression in acute myeloid leukemia patients with 6; 9 chromosome translocation].

    PubMed

    Wang, Ya-Lun; Wang, Tong; Xu, Feng; Gang, Yan; Wang, Jie

    2006-04-01

    This study was aimed to explore the relationship of 6; 9 chromosome translocation with DEK-CAN fusion gene expression in patients with acute myeloid leukemia (AML) and its clinical significance. Chromosome specimens were prepared by routine method after short-term culture of bone marrow cells; karyotype analysis was performed by R banding technique; the expression of fusion gene DEK-CAN was analyzed by RT-nested-PCR in mononuclear cells of bone marrow or peripheral blood of 4 AML patients, for 3 patients received allo-BMT out of 4 patients the dynamic follow-up was performed. The results indicated that t (6; 9) (p23; q34) was confirmed by chromosome karyotype analysis in the four AML patients. The DEK-CAN fusion gene was found during in all four de novo, relapsed and CR patients (100%). And the expression of DEK-CAN fusion gene enhanced apparently in de novo and relapsed patients, and weakened in CR patient. DEK-CAN mRNA was found in the three patients during 1-24 months after allo-BMT. Clinical data showed 2 patients relapsed and died after CR for 1-24 months; the other two patients received allo-BMT got CR and still survive. It is concluded that DEK-CAN fusion gene is the molecular basis in pathogenesis of AML. The detection of DEK-CAN fusion gene is significant for diagnosis of AML, evaluation of curative effect, and predication of prognosis.

  12. Evaluation of BAALC gene expression in normal cytogenetic acute myeloid leukemia patients in north-east of Iran

    PubMed Central

    Amirpour, Mojgan; Ayatollahi, Hossein; Sheikhi, Maryam; Azarkerdar, Somaye; Shams, Seyyede Fatemeh

    2016-01-01

    Background: Acute myeloid leukemia (AML) is known as one of the most common leukemia among adults. Environmental and different genetic factors affect disease process, prognosis and treatment. Among different genetic factors NPM1, FLT3, MLL and BAALC genes are the most effective on patient's survival rate. The aim of this study was to assess amount of BAALC gene expression in AML patients, and its relation to survival rate. Methods: In this case-control study, from all 94 individuals referred to Ghaem Medical Center during 2012-2015, 47 cases were normal cytogenetic AML and others were healthy individuals that were studied as control group. Real-time PCR method was applied for gene expression evaluation. Other information of patients was extracted from medical documents. SPSS v.21 was used for data processing. Results: Mean age of studied cases was 31.50 years. The most of BAALC gene expression was seen in M1 and M2 subtypes, and the less was in M5. A significant relation was found between amount of gene expression and patient's survival rate. Conclusion: BAALC gene expression was increased significantly in AML cases. BAALC expression had reverse relation with patients' survival rate in North-East of Iran. PMID:28210583

  13. Acute-Phase Inflammatory Response to Single-Bout HIIT and Endurance Training: A Comparative Study

    PubMed Central

    Kaspar, Felix; Jelinek, Herbert F.; Perkins, Steven; Al-Aubaidy, Hayder A.; deJong, Bev; Butkowski, Eugene

    2016-01-01

    Objective. This study compared acute and late effect of single-bout endurance training (ET) and high-intensity interval training (HIIT) on the plasma levels of four inflammatory cytokines and C-reactive protein and insulin-like growth factor 1. Design. Cohort study with repeated-measures design. Methods. Seven healthy untrained volunteers completed a single bout of ET and HIIT on a cycle ergometer. ET and HIIT sessions were held in random order and at least 7 days apart. Blood was drawn before the interventions and 30 min and 2 days after the training sessions. Plasma samples were analyzed with ELISA for the interleukins (IL), IL-1β, IL-6, and IL-10, monocyte chemoattractant protein-1 (MCP-1), insulin growth factor 1 (IGF-1), and C-reactive protein (CRP). Statistical analysis was with Wilcoxon signed-rank tests. Results. ET led to both a significant acute and long-term inflammatory response with a significant decrease at 30 minutes after exercise in the IL-6/IL-10 ratio (−20%; p = 0.047) and a decrease of MCP-1 (−17.9%; p = 0.03). Conclusion. This study demonstrates that ET affects the inflammatory response more adversely at 30 minutes after exercise compared to HIIT. However, this is compensated by a significant decrease in MCP-1 at two days associated with a reduced risk of atherosclerosis. PMID:27212809

  14. [Asystolias in the acute phase of brain stroke. Report of a case].

    PubMed

    Belvis, R; Marti-Fàbregas, J; Franquet, E; Cocho, D; Valencia, C; Martí-Vilalta, J L

    2003-04-01

    Brain areas involved in heart autonomic control are not well characterized. Insulae have been proposed as control centers. A lesion in these areas may induce a cardiac autonomic dysfunction (arrhythmias, atrioventricular conduction abnormalities). Asystolia has not been previously reported. A 65-year-old man suffered an acute ischemia of the right middle cerebral artery (MCA) territory. NIHSS score was 19 points. Brain CT scan was normal. Transcranial Doppler (TCD) showed occlusion of the right MCA. Fibrinolysis was initiated 135 minutes after stroke onset with TCD monitoring. Twenty minutes later he suffered cardiac arrest with asystolia trace in the ECG monitor. Fibrinolysis was stopped during resuscitation. Four minutes later, he recovered with the same NIHSS score. Aggressive resuscitation maneuvers were not necessary. A repeated brain CT scan showed infarct signs in the whole MCA territory and a new TCD did not show any change. Serial blood analyses including cardiac nzymes were normal. The patient experienced four brief cardiac arrests in the next nine hours, so a temporary cardiac pacemaker was placed for four days. He was treated with aspirin and was discharged 14 days after admission. He has not experienced recurrences during a 6-month follow-up. We could not diagnose the etiology of the cardiac arrests. All the episodes occurred in the acute stroke stage and arrhythmia, atrioventricular block, myocardial ischemia or structural lesions were not found in the cardiac study. We propose that ischemia in the right insula induced sudden and transitory interruptions of the sympathetic cardiac tone.

  15. Biphasic CD8+ T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization

    PubMed Central

    Iseda, Sumire; Takahashi, Naofumi; Poplimont, Hugo; Nomura, Takushi; Seki, Sayuri; Nakane, Taku; Nakamura, Midori; Shi, Shoi; Ishii, Hiroshi; Furukawa, Shota; Harada, Shigeyoshi; Naruse, Taeko K.; Kimura, Akinori; Matano, Tetsuro

    2016-01-01

    ABSTRACT Identifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recent in vivo studies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8+ cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIVmac239-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8+ cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)hi/phosphorylated AMP-activated protein kinase (AMPK)lo subpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control. IMPORTANCE In early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally

  16. Cystathionine-gamma-lyase gene silencing with siRNA in monocytes/macrophages protects mice against acute pancreatitis.

    PubMed

    Badiei, A; Chambers, S T; Gaddam, R R; Fraser, R; Bhatia, M

    2016-01-01

    Hydrogen sulphide (H2S) is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in monocytes/macrophages. To determine the role of H2S and macrophages in inflammation, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of acute pancreatitis. Acute pancreatitis is characterised by increased levels of plasma amylase, myeloperoxidase (MPO) activity and pro-inflammatory cytokines and chemokines in the pancreas and lung. SiRNA treatment attenuated inflammation in the pancreas and lungs of mice following caerulein-induced acute pancreatitis. MPO activity increased in caerulein-induced acute pancreatitis (16.21 ± 3.571 SD fold increase over control) and treatment with siRNA significantly reduced this (mean 3.555 ± 2.522 SD fold increase over control) (p < 0.0001). Similarly, lung MPO activity increased following treatment with caerulein (3.56 ± 0.941 SD fold increase over control) while siRNA treatment significantly reduced MPO activity (0.8243 ± 0.4353 SD fold increase over control) (p < 0.0001). Caerulein treatment increased plasma amylase activity (7094 ± 207 U/l) and this significantly decreased following siRNA administration (5895 ± 115 U/l) (p < 0.0001). Cytokine and chemokine levels in caerulein-induced acute pancreatitis reduced following treatment with siRNA. For example, siRNA treatment significantly decreased pancreatic and lung monocyte chemoattractant protein (MCP)-1 (169.8 ± 59.75 SD; 90.01 ± 46.97 SD pg/ml, respectively) compared to caerulein-treated mice (324.7 ± 103.9 SD; 222.8 ± 85.37 SD pg/ml, pancreas and lun,g respectively) (p < 0.0001). These findings show a crucial pro-inflammatory role for H2S synthesised by CSE in macrophages in acute pancreatitis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.

  17. Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats.

    PubMed

    Balakrishnan, Anita; Stearns, Adam T; Ashley, Stanley W; Tavakkolizadeh, Ali; Rhoads, David B

    2010-05-01

    The intestine exhibits striking diurnal rhythmicity in glucose uptake, mediated by the sodium glucose cotransporter (SGLT1); however, regulatory pathways for these rhythms remain incompletely characterized. We hypothesized that SGLT1 rhythmicity is linked to the circadian clock. To investigate this, we examined rhythmicity of Sglt1 and individual clock genes in rats that consumed food ad libitum (AL). We further compared phase shifts of Sglt1 and clock genes in a second group of rats following restricted feeding to either the dark (DF) or light (LF) phase. Rats fed during the DF were pair-fed to rats fed during the LF. Jejunal mucosa was harvested across the diurnal period to generate expression profiles of Sglt1 and clock genes Clock, Bmal1 (brain-muscle Arnt-like 1), ReverbA/B, Per(Period) 1/2, and Cry (Cryptochrome) 1/2. All clock genes were rhythmic in AL rats (P < 0.05). Sglt1 also exhibited diurnal rhythmicity, with peak expression preceding nutrient arrival (P < 0.05). Light-restricted feeding shifted the expression rhythms of Sglt1 and most clock genes (Bmal1, ReverbA and B, Per1, Per2, and Cry1) compared with dark-restricted feeding (P < 0.05). The Sglt1 rhythm shifted in parallel with rhythms of Per1 and ReverbB. These effects of restricted feeding highlight luminal nutrients as a key Zeitgeber in the intestine, capable of simultaneously shifting the phases of transporter and clock gene expression, and suggest a role for clock genes in regulating Sglt1 and therefore glucose uptake. Understanding the regulatory cues governing rhythms in intestinal function may allow new therapeutic options for conditions of dysregulated absorption such as diabetes and obesity.

  18. Proteins involved on TGF-β pathway are up-regulated during the acute phase of experimental Chagas disease.

    PubMed

    Ferreira, Roberto Rodrigues; de Souza, Elen Mello; de Oliveira, Fabiane Loiola; Ferrão, Patrícia Mello; Gomes, Leonardo Henrique Ferreira; Mendonça-Lima, Leila; Meuser-Batista, Marcelo; Bailly, Sabine; Feige, Jean Jacques; de Araujo-Jorge, Tania Cremonini; Waghabi, Mariana Caldas

    2016-05-01

    Studies developed by our group in the last years have shown the involvement of TGF-β in acute and chronic Chagas heart disease, with elevated plasma levels and activated TGF-β cell signaling pathway as remarkable features of patients in the advanced stages of this disease, when high levels of cardiac fibrosis is present. Imbalance in synthesis and degradation of extracellular matrix components is the basis of pathological fibrosis and TGF-β is considered as one of the key regulators of this process. In the present study, we investigated the activity of the TGF-β signaling pathway, including receptors and signaling proteins activation in the heart of animals experimentally infected with Trypanosoma cruzi during the period that mimics the acute phase of Chagas disease. We observed that T. cruzi-infected animals presented increased expression of TGF-β receptors. Overexpression of receptors was followed by an increased phosphorylation of Smad2/3, p38 and ERK. Furthermore, we correlated these activities with cellular factors involved in the fibrotic process induced by TGF-β. We observed that the expression of collagen I, fibronectin and CTGF were increased in the heart of infected animals on day 15 post-infection. Correlated with the increased TGF-β activity in the heart, we found that serum levels of total TGF-β were significantly higher during acute infection. Taken together, our data suggest that the commitment of the heart associates with increased activity of TGF-β pathway and expression of its main components. Our results, confirm the importance of this cytokine in the development and maintenance of cardiac damage caused by T. cruzi infection.

  19. Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia.

    PubMed

    Stein, Anthony; Palmer, Joycelynne; Tsai, Ni-Chun; Al Malki, Monzr M; Aldoss, Ibrahim; Ali, Haris; Aribi, Ahmed; Farol, Len; Karanes, Chatchada; Khaled, Samer; Liu, An; O'Donnell, Margaret; Parker, Pablo; Pawlowska, Anna; Pullarkat, Vinod; Radany, Eric; Rosenthal, Joseph; Sahebi, Firoozeh; Salhotra, Amandeep; Sanchez, James F; Schultheiss, Tim; Spielberger, Ricardo; Thomas, Sandra H; Snyder, David; Nakamura, Ryotaro; Marcucci, Guido; Forman, Stephen J; Wong, Jeffrey

    2017-04-01

    Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.

  20. [Lymphocyte metabolism in patients with acute pancreatitis with different genotypes of GSTM1 and GSTT1 genes].

    PubMed

    Markova, E V; Zotova, N V; Savchenko, A A; Titova, N M; Slepov, E V; Cherdantsev, D V; Konovalenko, A N

    2006-01-01

    In this study, we have investigated correlation between enzymatic activity of NAD(P)-dependent dehydrogenases of lymphocytes and polymorphic variants of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes in the group of unrelated patients with acute pancreatitis in comparison with healthy Russians from Krasnoyarsk. Thus, genotype GSTM1 0/0 is the marker of predisposition to the acute pancreatitis, wheras polymorphism of the GSTT1 gene is not involved in the development of the pancreatitis, at least in our group. The bioluminescence analysis showed statistically significant decrease of the levels of G3PD, NAD(+)MDH and the increase of NADH(+)LDH, NAD(+)GDH, NADH(+)GDH in lymphocytes of pancreatic group. Development of pancreatitis in patients with different genotypes GSTM1 and GSTT1 genes showed the rearrangement of the basic intracellular processes: dominance of a plastic metabolism in the patients with GSTM1--deletions and predominance of energetic processes at GSTT1 0 - pancreatitis.

  1. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response

    PubMed Central

    2010-01-01

    Background Ciguatoxins (CTXs) are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO) and molecular pathway enrichment of the gene expression data. Results A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p < 0.0001) with microarray results. Conclusions Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against

  2. Zoledronic acid exerts antitumor effects in NB4 acute promyelocytic leukemia cells by inducing apoptosis and S phase arrest.

    PubMed

    Liu, Shou-Sheng; Wang, Xiao-Pai; Li, Xiu-Bo; Liang, Jia-Yi; Liu, Ling-Ling; Lu, Ying; Zhong, Xue-Yun; Chen, Yun-Xian

    2014-10-01

    The aim of this study was to investigate the antitumor effect of zoledronic acid (ZOL) in the NB4 human acute promyelocytic leukemia (APL) cell line and explore the potential mechanism of action of this compound. NB4 cells were exposed to various concentrations (0-200μM) of ZOL. Cell viability was measured by MTS assay. The extent of cell apoptosis and distribution of cells in the different phases of the cell cycle were analyzed with flow cytometry. The expression of apoptosis- and cell cycle-related proteins was assayed by Western blot. The combined effect of ZOL and arsenic trioxide (ATO) on the proliferation of NB4 cells was also determined. The results of this study indicate that ZOL inhibits cell proliferation in a time- and dose-dependent fashion and also induces apoptosis and S phase arrest in a dose-dependent manner. The Western blot analysis confirmed the induction of apoptosis and S phase arrest, revealing that the pro-apoptosis proteins Bax, Puma and activated caspase-9 were upregulated and the anti-apoptosis proteins Bcl-2 and Bcl-xL were downregulated. ZOL at a concentration of 50μM synergized with 0.5μM ATO on the growth inhibition of NB4 cells. Taken together, our data indicate that ZOL exerts a potent antitumor effect on NB4 cells by inducing apoptosis and cell cycle arrest, and that ZOL can synergize with the traditional chemotherapy drug ATO.

  3. Alterations in oxidant/antioxidant balance, high-mobility group box 1 protein and acute phase response in cross-bred suckling piglets suffering from rotaviral enteritis.

    PubMed

    Kumar De, Ujjwal; Mukherjee, Reena; Nandi, Sukdeb; Patel, Bhimnere Hanumatnagouda Manjunatha; Dimri, Umesh; Ravishankar, Chintu; Verma, Ashok Kumar

    2014-10-01

    Rotaviral enteritis has emerged as a major cause of morbidity and mortality in piglets during their post-natal life. The present study was carried out to examine high-mobility group box 1 (HMGB1) protein, acute phase response and oxidative stress indices in the serum of suckling piglets suffering from enteritis with or without association of porcine group A rotavirus infection. The present investigation utilized 23 clinical cases with signs of acute enteritis and 12 more healthy piglets of a similar age group as control animals. Out of 23 enteritis cases, 12 cases were found to be positive for porcine group A rotavirus infection as confirmed by reverse transcription-polymerase chain reaction (RT-PCR) using specific primers for group A rotavirus, and the rest were found negative. The acute enteritis cases in piglets were associated with an elevated level of HMGB1 protein and serum haptoglobin and ceruloplasmin suggestive of an acute phase response. Among the oxidative stress indices, the concentrations of malondialdehyde (MDA) and nitric oxide (NO) in serum were significantly increased. A pronounced drop of total antioxidant capacity and the activity of antioxidant enzymes such as catalase and superoxide dismutase in the serum of piglets suffering from acute enteritis compared to healthy ones were also noticed. The alterations in HMGB1 protein, acute phase response and oxidative stress indices were more pronounced in cases with the involvement of porcine rotavirus as compared to rotavirus-negative cases. It is concluded that HMGB1 protein, markers of oxidative stress and acute phase proteins might play an important role in the aetiopathogenesis of porcine diarrhoea caused by rotavirus and might be true markers in diagnosing the conditions leading to the extension of the prompt and effective therapeutic care.

  4. [Anaemia, iron index status and acute phase proteins in malaria (Abidjan, Côte d'Ivoire)].

    PubMed

    Ahiboh, H; Oga, A S; Yapi, H F; Kouakou, G; Boua, K D; Edjeme, N; Monnet, D

    2008-02-01

    Clinical signs of malaria are the combined expression of several biological mechanisms. During this parasite infection, anaemia can be the consequence of several different pathogenic mechanisms. It can be an acute haemolytic anaemia due to a mechanical and immune action of the parasite or an inflammation. Besides, in Africa malaria matches with iron deficiency area. So, malarial anaemia in tropical area can be a characteristic of iron deficiency The purpose of this survey was to define the features of malarial anaemia and elucidate the link of all biological processes involved. A black population living in tropical urban areas, with fever and diagnosed Plasmodium-infection was assessed. Parasitaemia, haemoglobin, hematocrit, average corpuscular volume and average corpuscular haemoglobin were determined. For each patient, iron index status and acute phase protein were assessed with the plasmatic iron, ferritin, haptoglobin, transferrin and C-reactive protein. Regardless of gender and age, the characteristics of malarial anaemia are microcythaemia and hypochromia. Anaemia occurs as frequently as parasitaemia is high. When parasitaemia is low anaemia gets a haemolytic feature. When parasitaemia is high, anaemia gets haemolytic and inflammatory features. Anaemia occurs more often with a good iron index status.

  5. Individuals with hematological malignancies before undergoing chemotherapy present oxidative stress parameters and acute phase proteins correlated with nutritional status.

    PubMed

    Camargo, Carolina de Quadros; Borges, Dayanne da Silva; de Oliveira, Paula Fernanda; Chagas, Thayz Rodrigues; Del Moral, Joanita Angela Gonzaga; Durigon, Giovanna Steffanello; Dias, Bruno Vieira; Vieira, André Guedes; Gaspareto, Patrick; Trindade, Erasmo Benício Santos de Moraes; Nunes, Everson Araújo

    2015-01-01

    Hematological malignancies present abnormal blood cells that may have altered functions. This study aimed to evaluate nutritional status, acute phase proteins, parameters of cell's functionality, and oxidative stress of patients with hematological malignancies, providing a representation of these variables at diagnosis, comparisons between leukemias and lymphomas and establishing correlations. Nutritional status, C-reactive protein (CRP), albumin, phagocytic capacity and superoxide anion production of mononuclear cells, lipid peroxidation and catalase activity in plasma were evaluated in 16 untreated subjects. Main diagnosis was acute leukemia (n = 9) and median body mass index (BMI) indicated overweight (25.6 kg/m(2)). Median albumin was below (3.2 g/dL) and CRP above (37.45 mg/L) the reference values. Albumin was inversely correlated with BMI (r = -0.53). Most patients were overweight before the beginning of treatment and had a high CRP/albumin ratio, which may indicate a nutrition inflammatory risk. BMI values correlated positively with lipid peroxidation and catalase activity. A strong correlation between catalase activity and lipid peroxidation was found (r = 0.75). Besides the elevated BMI, these patients also have elevated CRP values and unexpected relations between nutritional status and albumin, reinforcing the need for nutritional counseling during the course of chemotherapy, especially considering the correlations between oxidative stress parameters and nutritional status evidenced here.

  6. Transcriptional expression levels of cell stress marker genes in the Pacific oyster Crassostrea gigas exposed to acute thermal stress

    PubMed Central

    Farcy, Émilie; Voiseux, Claire; Lebel, Jean-Marc

    2008-01-01

    During the annual cycle, oysters are exposed to seasonal slow changes in temperature, but during emersion at low tide on sunny summer days, their internal temperature may rise rapidly, resulting in acute heat stress. We experimentally exposed oysters to a 1-h acute thermal stress and investigated the transcriptional expression level of some genes involved in cell stress defence mechanisms, including chaperone proteins (heat shock proteins Hsp70, Hsp72 and Hsp90 (HSP)), regulation of oxidative stress (Cu-Zn superoxide dismutase, metallothionein (MT)), cell detoxification (glutathione S-transferase sigma, cytochrome P450 and multidrug resistance (MDR1)) and regulation of the cell cycle (p53). Gene mRNA levels were quantified by reverse transcription-quantitative polymerase chain reaction and expressed as their ratio to actin mRNA, used as a reference. Of the nine genes studied, HSP, MT and MDR1 mRNA levels increased in response to thermal stress. We compared the responses of oysters exposed to acute heat shock in summer and winter and observed differences in terms of magnitude and kinetics. A larger increase was observed in September, with recovery within 48 h, whereas in March, the increase was smaller and lasted more than 2 days. The results were also compared with data obtained from the natural environment. Though the functional molecule is the protein and information at the mRNA level only has limitations, the potential use of mRNAs coding for cell stress defence proteins as early sensitive biomarkers is discussed. PMID:19002605

  7. β1-Na(+),K(+)-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury.

    PubMed

    Lin, X; Barravecchia, M; Kothari, P; Young, J L; Dean, D A

    2016-06-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with diverse disorders and characterized by disruption of the alveolar-capillary barrier, leakage of edema fluid into the lung, and substantial inflammation leading to acute respiratory failure. Gene therapy is a potentially powerful approach to treat ALI/ARDS through repair of alveolar epithelial function. Herein, we show that delivery of a plasmid expressing β1-subunit of the Na(+),K(+)-ATPase (β1-Na(+),K(+)-ATPase) alone or in combination with epithelial sodium channel (ENaC) α1-subunit using electroporation not only protected from subsequent lipopolysaccharide (LPS)-mediated lung injury, but also treated injured lungs. However, transfer of α1-subunit of ENaC (α1-ENaC) alone only provided protection benefit rather than treatment benefit although alveolar fluid clearance had been remarkably enhanced. Gene transfer of β1-Na(+),K(+)-ATPase, but not α1-ENaC, not only enhanced expression of tight junction protein zona occludins-1 (ZO-1) and occludin both in cultured cells and in mouse lungs, but also reduced pre-existing increase of lung permeability in vivo. These results demonstrate that gene transfer of β1-Na(+),K(+)-ATPase upregulates tight junction formation and therefore treats lungs with existing injury, whereas delivery of α1-ENaC only maintains pre-existing tight junction but not for generation. This indicates that the restoration of epithelial/endothelial barrier function may provide better treatment of ALI/ARDS.

  8. SHARED, NOT UNIQUE, COMPONENTS OF PERSONALITY AND PSYCHOSOCIAL FUNCTIONING PREDICT DEPRESSION SEVERITY AFTER ACUTE-PHASE COGNITIVE THERAPY

    PubMed Central

    Clark, Lee Anna; Vittengl, Jeffrey R.; Kraft, Dolores; Jarrett, Robin B.

    2005-01-01

    In a sample of 100 patients with recurrent major depression, we collected depression severity data early and late in acute-phase cognitive therapy, plus a wide range of psychosocial variables that have been studied extensively in depression research, including measures of interpersonal, cognitive, and social functioning, and personality traits using an inventory that is linked with the Big-Three tradition in personality assessment theory. By assessing this broad range of variables in a single study, we could examine the extent to which relations of these variables with depression were due to (a) a common factor shared across this diverse set of constructs, (b) factors shared among each type of construct (personality vs. psychosocial measures), or (c) specific aspects of the individual measures. Only the most general factor shared across the personality and psychosocial variables predicted later depression. PMID:14632375

  9. Early Diagnosis of Congenital Trypanosoma cruzi Infection, Using Shed Acute Phase Antigen, in Ushuaia, Tierra del Fuego, Argentina

    PubMed Central

    Mallimaci, María Cristina; Sosa-Estani, Sergio; Russomando, Graciela; Sanchez, Zunilda; Sijvarger, Carina; Alvarez, Isabel Marcela; Barrionuevo, Lola; Lopez, Carlos; Segura, Elsa Leonor

    2010-01-01

    Chagas' disease, or American trypanosomiasis, is caused by the protozoan parasite Trypanasoma cruzi. It is estimated that 15,000 new cases of congenital T. cruzi transmission occur in the Americas each year. The aim of this study was to estimate the rate of congenital T. cruzi infection in infants born to infected women living in Ushuaia, Argentina, as well to assess a serologic test using Shed Acute Phase Antigen (SAPA) for a timely diagnosis of congenital infection. The rate of congenital infection among children in the study was 4.4% (3/68). Our results show that for infants younger than 30 days of age, matched blood samples from mother and infant were capable of identifying congenital transmission of infection using an enzyme-linked immunosorbent assay with SAPA. For infants older than 3 months, congenital infection could be ruled out using the same procedure. PMID:20064996

  10. Plastic Change along the Intact Crossed Pathway in Acute Phase of Cerebral Ischemia Revealed by Optical Intrinsic Signal Imaging

    PubMed Central

    Guo, Xiaoli; He, Yongzhi; Lu, Hongyang; Li, Yao; Su, Xin; Jiang, Ying; Tong, Shanbao

    2016-01-01

    The intact crossed pathway via which the contralesional hemisphere responds to the ipsilesional somatosensory input has shown to be affected by unilateral stroke. The aim of this study was to investigate the plasticity of the intact crossed pathway in response to different intensities of stimulation in a rodent photothrombotic stroke model. Using optical intrinsic signal imaging, an overall increase of the contralesional cortical response was observed in the acute phase (≤48 hours) after stroke. In particular, the contralesional hyperactivation is more prominent under weak stimulations, while a strong stimulation would even elicit a depressed response. The results suggest a distinct stimulation-response pattern along the intact crossed pathway after stroke. We speculate that the contralesional hyperactivation under weak stimulations was due to the reorganization for compensatory response to the weak ipsilateral somatosensory input. PMID:27144032

  11. Role of lysosomal enzymes released by alveolar macrophages in the pathogenesis of the acute phase of hypersensitivity pneumonitis

    PubMed Central

    Barrios, M. N.; Martín, T.; Sánchez, M. L.; Buitrago, J. M. González; Jiménez, A.

    1995-01-01

    Hydrolytic enzymes are the major constituents of alveolar macrophages (AM) and have been shown to be involved in many aspects of the inflammatory pulmonary response. The aim of this study was to evaluate the role of lysosomal enzymes in the acute phase of hypersensitivity pneumonitis (HPs). An experimental study on AM lysosomal enzymes of an HP-guinea-pig model was performed. The results obtained both in vivo and in vitro suggest that intracellular enzymatic activity decrease is, at least partly, due to release of lysosomal enzymes into the medium. A positive but slight correlation was found between extracellular lysosomal activity and four parameters of lung lesion (lung index, bronchoalveolar fluid total (BALF) protein concentration, BALF LDH and BALF alkaline phosphatase activities). All the above findings suggest that the AM release of lysosomal enzymes during HP is a factor involved, although possibly not the only one, in the pulmonary lesions appearing in this disease. PMID:18475615

  12. Phase sensitive detection of light reflected from a Fabry{endash}P{acute e}rot interferometer

    SciTech Connect

    Bava, E.; Massari, F.

    1996-05-01

    We present an analysis of the Fabry{endash}P{acute e}rot response to a phase-modulated light in the reflection mode, by considering the general problem of the lock-in detection at the {ital p}th harmonics of the rf modulating frequency. Suitable frequency modulation conditions for servo-locking purposes are obtained and the values of modulation index which maximize the sensitivity for the first, third, and fifth harmonics are found. Moreover, we investigate the effects of the residual amplitude modulation introduced by the electro-optic frequency modulator, the presence of laser amplitude and frequency noise, and the dependence of the achievable closed-loop frequency fluctuation spectrum on the modulation index and detection noise. {copyright} {ital 1996 American Institute of Physics.}

  13. Early diagnosis of congenital Trypanosoma cruzi infection, using shed acute phase antigen, in Ushuaia, Tierra del Fuego, Argentina.

    PubMed

    Mallimaci, María Cristina; Sosa-Estani, Sergio; Russomando, Graciela; Sanchez, Zunilda; Sijvarger, Carina; Alvarez, Isabel Marcela; Barrionuevo, Lola; Lopez, Carlos; Segura, Elsa Leonor

    2010-01-01

    Chagas' disease, or American trypanosomiasis, is caused by the protozoan parasite Trypanasoma cruzi. It is estimated that 15,000 new cases of congenital T. cruzi transmission occur in the Americas each year. The aim of this study was to estimate the rate of congenital T. cruzi infection in infants born to infected women living in Ushuaia, Argentina, as well to assess a serologic test using Shed Acute Phase Antigen (SAPA) for a timely diagnosis of congenital infection. The rate of congenital infection among children in the study was 4.4% (3/68). Our results show that for infants younger than 30 days of age, matched blood samples from mother and infant were capable of identifying congenital transmission of infection using an enzyme-linked immunosorbent assay with SAPA. For infants older than 3 months, congenital infection could be ruled out using the same procedure.

  14. Association of cytotoxic T-lymphocyte antigen 4 +49A/G gene polymorphism with acute rejection risk in renal transplantation.

    PubMed

    Yang, Chun-Hua; Chen, Xue-Xia; Chen, Li; Zheng, Dong-Hua; Liu, Qiong-Shan; Xie, Wen-Feng

    2017-03-23

    The conclusions on the association between cytotoxic T-lymphocyte antigen 4 (CTLA4) +49A/G gene polymorphism and acute rejection risk in renal transplantation are still debated. This meta-analysis was performed to update the association between CTLA4 +49A/G and acute rejection risk in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Fourteen reports were included into this meta-analysis for the association of CTLA4 A/G gene polymorphism and acute rejection risk in renal transplantation, consisting of 962 acute rejection patients and 2084 non-acute rejection controls. The association between CTLA4 G allele/GG genotype and acute rejection risk in renal transplantation was found in this meta-analysis (G allele: OR=1.21, 95% CI: 1.03-1.44, P=.02; GG genotype: OR=1.37, 95% CI: 1.10-1.69, P=.004). However, the AA genotype was not associated with acute rejection risk in renal transplantation. In conclusion, CTLA4 G allele/GG genotype is associated with the acute rejection risk in renal transplantation.

  15. The diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in Urinary Tract Infection (UTI) in camels.

    PubMed

    El-Deeb, Wael M; Buczinski, Sébastien

    2015-01-01

    The present study aimed to investigate the diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in urinary tract infection (UTI) in camels. We describe the clinical, bacteriological and biochemical findings in 89 camels. Blood and urine samples from diseased (n = 74) and control camels (n = 15) were submitted to laboratory investigations. The urine analysis revealed high number of RBCS and pus cells. The concentrations of serum and erythrocytic malondialdehyde (sMDA & eMDA), Haptoglobin (Hp), serum amyloid A (SAA), Ceruloplasmin (Cp), fibrinogen (Fb), albumin, globulin and interleukin 6 (IL-6) were higher in diseased camels when compared to healthy ones. Catalase, super oxide dismutase and glutathione levels were lower in diseased camels when compared with control group. Forty one of 74 camels with UTI were successfully treated. The levels of malondialdehyde, catalase, super oxide dismutase, glutathione, Hp, SAA, Fb, total protein, globulin and IL-6 were associated with the odds of treatment failure. The MDA showed a great sensitivity (Se) and specificity (Sp) in predicting treatment failure (Se 85%/Sp 100%) as well as the SAA (Se 92%/Sp 87%) and globulin levels (Se 85%/Sp 100%) when using the cutoffs that maximizes the sum of Se + Sp. Multivariate logistic regression analysis revealed that two models had a high accuracy to predict failure with the first model including sex, sMDA and Hp as covariates (area under the receiver operating characteristic curve (AUC) = 0.92) and a second model using sex, SAA and Hp (AUC = 0.89). Conclusively, the oxidative stress biomarkers and acute phase proteins could be used as diagnostic and prognostic biomarkers in camel UTI management. Efforts should be forced to investigate such biomarkers in other species with UTI.

  16. Complement Factor H Binds at Two Independent Sites to C-reactive Protein in Acute Phase Concentrations*♦

    PubMed Central

    Okemefuna, Azubuike I.; Nan, Ruodan; Miller, Ami; Gor, Jayesh; Perkins, Stephen J.

    2010-01-01

    Factor H (FH) regulates the activation of C3b in the alternative complement pathway, both in serum and at host cell surfaces. It is composed of 20 short complement regulator (SCR) domains. The Y402H polymorphism in FH is a risk factor for age-related macular degeneration. C-reactive protein (CRP) is an acute phase protein that binds Ca2+. We established the FH-CRP interaction using improved analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), and synchrotron x-ray scattering methods. Physiological FH and CRP concentrations were used in 137 mm NaCl and 2 mm Ca2+, in which the occurrence of denatured CRP was avoided. In solution, AUC revealed FH-CRP binding. The FH-CRP interaction inhibited the formation of higher FH oligomers, indicating that CRP blocked FH dimerization sites at both SCR-6/8 and SCR-16/20. SPR confirmed the FH-CRP interaction and its NaCl concentration dependence upon using either immobilized FH or CRP. The SCR-1/5 fragment of FH did not bind to CRP. In order of increasing affinity, SCR-16/20, SCR-6/8 (His-402), and SCR-6/8 (Tyr-402) fragments bound to CRP. X-ray scattering showed that FH became more compact when binding to CRP, which is consistent with CRP binding at two different FH sites. We concluded that FH and CRP bind at elevated acute phase concentrations of CRP in physiological buffer. The SCR-16/20 site is novel and indicates the importance of the FH-CRP interaction for both age-related macular degeneration and atypical hemolytic uremic syndrome. PMID:19850925

  17. The diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in Urinary Tract Infection (UTI) in camels

    PubMed Central

    Buczinski, Sébastien

    2015-01-01

    The present study aimed to investigate the diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in urinary tract infection (UTI) in camels. We describe the clinical, bacteriological and biochemical findings in 89 camels. Blood and urine samples from diseased (n = 74) and control camels (n = 15) were submitted to laboratory investigations. The urine analysis revealed high number of RBCS and pus cells. The concentrations of serum and erythrocytic malondialdehyde (sMDA & eMDA), Haptoglobin (Hp), serum amyloid A (SAA), Ceruloplasmin (Cp), fibrinogen (Fb), albumin, globulin and interleukin 6 (IL-6) were higher in diseased camels when compared to healthy ones. Catalase, super oxide dismutase and glutathione levels were lower in diseased camels when compared with control group. Forty one of 74 camels with UTI were successfully treated. The levels of malondialdehyde, catalase, super oxide dismutase, glutathione, Hp, SAA, Fb, total protein, globulin and IL-6 were associated with the odds of treatment failure. The MDA showed a great sensitivity (Se) and specificity (Sp) in predicting treatment failure (Se 85%/Sp 100%) as well as the SAA (Se 92%/Sp 87%) and globulin levels (Se 85%/Sp 100%) when using the cutoffs that maximizes the sum of Se + Sp. Multivariate logistic regression analysis revealed that two models had a high accuracy to predict failure with the first model including sex, sMDA and Hp as covariates (area under the receiver operating characteristic curve (AUC) = 0.92) and a second model using sex, SAA and Hp (AUC = 0.89). Conclusively, the oxidative stress biomarkers and acute phase proteins could be used as diagnostic and prognostic biomarkers in camel UTI management. Efforts should be forced to investigate such biomarkers in other species with UTI. PMID:26587339

  18. Gene conversion accounts for pilin structural changes and for reversible piliation "phase" changes in gonococci.

    PubMed

    Swanson, J; Bergstrom, S; Boslego, J; Koomey, M

    1987-01-01

    Pilus+ "wild-type" gonococci (Gc) frequently display gene conversion of their expressed complete pilin gene (CPG); a copy of DNA derived from one of the Gc genome's multiple silent partial pilin genes (PPG) is recombinationally-inserted into the CPG's central and 3' portions with formation of a new, chimeric CPG. Expression of that new CPG leads to either 1) retention of pilus+ phenotype but change in pilin primary structure/antigenicity, or 2) phase change to pilus- phenotype capable of reverting. This study utilizes pilus revertants of P-rp +/- Gc and P+ colony morphotype variants spawned by P++ Gc to examine pilin gene conversion in strain MS11mk Gc in greater detail. Each revertant's and variant's expressed pilin gene's sequence (as pilin mRNA) was defined to learn whether their differences are due to gene conversion by different PPGs, or by varying stretches from the same PPG, or both. Gene conversion by PPG pilS1 copy 2 has been documented in Gc recovered from a human volunteer's urethra previously inoculated with pilus Gc (strain MS11). The pilus+ Gc isolated expressed structurally/antigenically distinct pilins.

  19. Identification of differentially expressed genes in parasitic phase Miamiensis avidus (Ciliophora: Scuticociliatia) using suppression subtractive hybridization.

    PubMed

    Lee, Eun Hye; Kim, Ki Hong

    2011-04-06

    Miamiensis avidus, a causative agent of scuticociliatosis in cultured marine fish, can live not only in seawater as a free-living organism but also in fish as a parasite. In this study, a cDNA library of representative mRNAs more specific to parasitic phase M. avidus was generated using suppression subtractive hybridization (SSH), and 520 clones selected from the SSH library were single-run sequenced. The differential gene expression patterns were confirmed by semi-quantitative reverse-transcription PCR. Of the 510 SSH clones, 21 clones of 6 putative genes did not match sequences in the public database. The expectation values (E-values) of 117 clones encoding 9 putative genes were greater than 1 x 10(-5). The other 372 clones that met the criterion of E value <1 x 10-5 were matched to 26 known sequences in the database. Genes associated with signal transduction, cell proliferation, membrane transportation, protein translocation, and transcription regulation were preferentially expressed in parasitic phase M. avidus. The differential gene expression may be needed for the ciliates to survive in the host fish, and the corresponding proteins might be used as antigen candidates for development of scuticociliatosis vaccines.

  20. GeneLab Phase 2: Integrated Search Data Federation of Space Biology Experimental Data

    NASA Technical Reports Server (NTRS)

    Tran, P. B.; Berrios, D. C.; Gurram, M. M.; Hashim, J. C. M.; Raghunandan, S.; Lin, S. Y.; Le, T. Q.; Heher, D. M.; Thai, H. T.; Welch, J. D.; Caldwell, S. M.; Stotzky, O. G.; Skidmore, M. G.

    2016-01-01

    The GeneLab project is a science initiative to maximize the scientific return of omics data collected from spaceflight and from ground simulations of microgravity and radiation experiments, supported by a data system for a public bioinformatics repository and collaborative analysis tools for these data. The mission of GeneLab is to maximize the utilization of the valuable biological research resources aboard the ISS by collecting genomic, transcriptomic, proteomic and metabolomic (so-called omics) data to enable the exploration of the molecular network responses of terrestrial biology to space environments using a systems biology approach. All GeneLab data are made available to a worldwide network of researchers through its open-access data system. GeneLab is currently being developed by NASA to support Open Science biomedical research in order to enable the human exploration of space and improve life on earth. Open access to Phase 1 of the GeneLab Data Systems (GLDS) was implemented in April 2015. Download volumes have grown steadily, mirroring the growth in curated space biology research data sets (61 as of June 2016), now exceeding 10 TB/month, with over 10,000 file downloads since the start of Phase 1. For the period April 2015 to May 2016, most frequently downloaded were data from studies of Mus musculus (39) followed closely by Arabidopsis thaliana (30), with the remaining downloads roughly equally split across 12 other organisms (each 10 of total downloads). GLDS Phase 2 is focusing on interoperability, supporting data federation, including integrated search capabilities, of GLDS-housed data sets with external data sources, such as gene expression data from NIHNCBIs Gene Expression Omnibus (GEO), proteomic data from EBIs PRIDE system, and metagenomic data from Argonne National Laboratory's MG-RAST. GEO and MG-RAST employ specifications for investigation metadata that are different from those used by the GLDS and PRIDE (e.g., ISA-Tab). The GLDS Phase 2 system

  1. [Clinical course of acute coronary syndrome in dependence on containing of homozystein and С677Т methylenetetrahydrofolate reductase gene polymorphism].

    PubMed

    Pristupa, L N; Grek, A V; Ataman, Iu A; Orlovskiy, A V; Opolonska, N A

    2015-01-01

    Nowadays to a numerous factors of IHD development risks hyperhomocysteinemia (HHc), C-reactive protein, fibrogen, as well as genetic disorders are relating. With development of IHD and its complications associated methylentetrahudrofolate reductase gene mutation of С677Т polymorphism. The purpose of the investigation was studying the connection between acute coronary syndrome severity (ACS) in dependence on plasma homocysteine containing and genotype by С677Т polymorphism MTHFR gene. Examined: 161 patients with ACS and 87 almost healthy people. Identification of 4th exon allelic polymorphism MTHFR С677Т gene (rs1801133) was conducted with method of polymerase chain reaction, the investigation of homocysteine containing with immunoenzymated method. The statistic analyze was performed with using of SPSS - 17 programme. According to results of study patients with ACS of homozygote by minor allele T С677Т MTHFR gene polymorphism by main allele C and heterozygote were associated with high homocysteine containing in plasma. While frequencies of T/T genotype was reliably higher in patients with ACS with segment ST elevation and complicated course compare with patients with ACS with segment ST elevation and non-complicated course and ACS without climbs of segment ST. Also, statistically reliable difference in genotypes distribution by C677T MTHFR gene polymorphism in dependence on homocysteine plasma level and clinical course of ACS severity were established.

  2. The gene expression signature of relapse in paediatric acute lymphoblastic leukaemia: implications for mechanisms of therapy failure.

    PubMed

    Beesley, Alex H; Cummings, Aaron J; Freitas, Joseph R; Hoffmann, Katrin; Firth, Martin J; Ford, Jette; de Klerk, Nicolas H; Kees, Ursula R

    2005-11-01

    Despite significant improvements in the treatment of childhood acute lymphoblastic leukaemia (ALL), the prognosis for relapsing patients remains poor. The aim of this study was to generate a transcriptional profile of relapsed ALL to increase our understanding of the mechanisms involved in therapy failure. RNA was extracted from 11 pairs of cryopreserved pre-B ALL bone marrow specimens taken from the same patients at diagnosis and relapse, and analysed using HG-U133A microarrays. Relapse specimens overexpressed genes that are involved with cell growth and proliferation, in keeping with their aggressive phenotype. When tested in 72 independent specimens of pre-B ALL and T-ALL, the identified genes could successfully differentiate between diagnosis and relapse in either lineage, indicating the existence of relapse mechanisms common to both. These genes have functions relevant for oncogenesis, drug resistance and metastasis, but are not related to classical multidrug-resistance pathways. Increased expression of the top-ranked gene (BSG) at diagnosis was significantly associated with adverse outcome. Several chromosomal loci, including 19p13, were identified as potential hotspots for aberrant gene expression in relapsed ALL. Our results provide evidence for a link between drug resistance and the microenvironment that has previously only been considered in the context of solid tumour biology.

  3. Investor Outlook: Focus on Upcoming LCA2 Gene Therapy Phase III Results.

    PubMed

    Schimmer, Joshua; Breazzano, Steven

    2015-09-01

    Investor interest in gene therapy has increased substantially over the past few years, and the next major catalyst for the field is likely to be Spark Therapeutics's phase III trial for the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders). Analysis of the approach from the basic genetics, underlying visual mechanisms, clinical data, and commercialization considerations helps frame investor expectations and the potential implications for the broader field.

  4. Genetic Variants of Cytochrome b-245, Alpha Polypeptide Gene and Premature Acute Myocardial Infarction Risk in an Iranian Population

    PubMed Central

    Amin, Fatemeh; Jahani, Mohammad Mehdi; Ghaedi, Hamid; Alipoor, Behnam; Fatemi, Ahmad; Tajik, Michael; Sharifi, Zohreh; Golmohammadi, Taghi; Askari, Mohammad; Azarnejad, Asaad; Alipoor, Sadegh; Valipour, Aliasghar; Mousavizadeh, Kazem

    2015-01-01

    Summary Background Oxidative stress induced by superoxide anion plays critical roles in the pathogenesis of coronary artery disease (CAD) and hence acute myocardial infarction (AMI). The major source of superoxide production in vascular smooth muscle and endothelial cells is the NADPH oxidase complex. An essential component of this complex is p22phox, that is encoded by the cytochrome b-245, alpha polypeptide (CYBA) gene. The aim of this study was to investigate the association of CYBA variants (rs1049255 and rs4673) and premature acute myocardial infarction risk in an Iranian population. Methods The study population consisted of 158 patients under the age of 50 years, with a diagnosis of premature AMI, and 168 age-matched controls with normal coronary angiograms. Genotyping of the polymorphisms was performed by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results There was no association between the genotypes and allele frequencies of rs4673 polymorphism and premature acute myocardial infarction (P>0.05). A significant statistical association was observed between the genotypes distribution of rs1049255 polymorphism and AMI risk (P=0.037). Furthermore, the distribution of AA+AG/GG genotypes was found to be statistically significant between the two groups (P=0.011). Conclusions Our findings indicated that rs1049255 but not rs4673 polymorphism is associated with premature AMI. PMID:28356848

  5. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia

    SciTech Connect

    Barker, G.F.; Golub, T.R.; Gilliland, D.G.; Bohlander, S.K.; Rowley, J.D.; Heibert, S.W.; Raimondi, S.C.; Ward, D.C.; Bray-Ward, P.; Morgan, E.

    1995-05-23

    Chromosomal rearrangements involving band 12p13 are found in a wide variety of human leukemias but are particularly common in childhood acute lymphoblastic leukemia. The genes involved in these rearrangements, however, have not been identified. We now report the cloning of a t(12;21) translocation breakpoint involving 12p13 and 21q22 in two cases of childhood pre-B acute lymphoblastic leukemia, in which t(12;21) rearrangements were not initially apparent. The consequence of the translocation is fusion of the helix-loop-helix domain of TEL, an ETS-like putative transcription factor, to the DNA-binding and transactivation domains of the transcription factor AML1. These data show that TEL, previously shown to be fused to the platelet-derived growth factor receptor {beta} in chronic myelomonocytic leukemia, can be implicated in the pathogenesis of leukemia through its fusion to either a receptor tyrosine kinase or a transcription factor. The TEL-AML1 fusion also indicates that translocations affecting the AML1 gene can be associated with lymphoid, as well as myeloid, malignancy. 23 refs., 5 figs.

  6. The Acute Phase Reactant Orosomucoid-1 Is a Bimodal Regulator of Angiogenesis with Time- and Context-Dependent Inhibitory and Stimulatory Properties

    PubMed Central

    Ligresti, Giovanni; Aplin, Alfred C.; Dunn, Bruce E.; Morishita, Ann; Nicosia, Roberto F.

    2012-01-01

    Background Tissues respond to injury by releasing acute phase reaction (APR) proteins which regulate inflammation and angiogenesis. Among the genes upregulated in wounded tissues are tumor necrosis factor-alpha (TNFα) and the acute phase reactant orosomucoid-1 (ORM1). ORM1 has been shown to modulate the response of immune cells to TNFα, but its role on injury- and TNFα-induced angiogenesis has not been investigated. This study was designed to characterize the role of ORM1 in the angiogenic response to injury and TNFα. Methods and Results Angiogenesis was studied with in vitro, ex vivo, and in vivo angiogenesis assays. Injured rat aortic rings cultured in collagen gels produced an angiogenic response driven by macrophage-derived TNFα. Microarray analysis and qRT-PCR showed that TNFα and ORM1 were upregulated prior to angiogenic sprouting. Exogenous ORM1 delayed the angiogenic response to injury and inhibited the proangiogenic effect of TNFα in cultures of aortic rings or isolated endothelial cells, but stimulated aortic angiogenesis over time while promoting VEGF production and activity. ORM1 inhibited injury- and TNFα-induced phosphorylation of MEK1/2 and p38 MAPK in aortic rings, but not of NFκB. This effect was injury/TNFα-specific since ORM1 did not inhibit VEGF-induced signaling, and cell-specific since ORM1 inhibited TNFα-induced phosphorylation of MEK1/2 and p38 MAPK in macrophages and endothelial cells, but not mural cells. Experiments with specific inhibitors demonstrated that the MEK/ERK pathway was required for angiogenesis. ORM1 inhibited angiogenesis in a subcutaneous in vivo assay of aortic ring-induced angiogenesis, but stimulated developmental angiogenesis in the chorioallantoic membrane (CAM) assay. Conclusion ORM1 regulates injury-induced angiogenesis in a time- and context-dependent manner by sequentially dampening the initial TNFα-induced angiogenic response and promoting the downstream stimulation of the angiogenic process by VEGF

  7. Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver.

    PubMed

    Peng, Lai; Piekos, Stephanie; Guo, Grace L; Zhong, Xiao-Bo

    2016-09-01

    The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation. Farnesoid X receptor (FXR) is critical for bile acid and lipid homeostasis in liver. However, the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear. Hence, we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 and Fxr-null mice at 6 different ages from prenatal to adult were used. The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression, including cytochrome P450s at neonatal ages. Among the 185 phase-I genes from 12 different families, 136 were expressed, and differential expression during development occurred in genes from all 12 phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldoketo reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). The data also suggested new phase-I genes potentially targeted by FXR. These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.

  8. Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality.

    PubMed

    Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof; Volinia, Stefano; Blachly, James S; Nicolet, Deedra; Oakes, Christopher; Kroll, Karl; Orwick, Shelley; Carroll, Andrew J; Stone, Richard M; Byrd, John C; de la Chapelle, Albert; Bloomfield, Clara D

    2017-01-01

    Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had less mutations in the methylation and spliceosome groups compared with patients ≥60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207-18. ©2016 AACR.

  9. Mutational landscape and gene-expression patterns in adult acute myeloid leukemias with monosomy 7 as a sole abnormality

    PubMed Central

    Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof; Volinia, Stefano; Blachly, James S.; Nicolet, Deedra; Oakes, Christopher; Kroll, Karl; Orwick, Shelley; Carroll, Andrew J.; Stone, Richard M.; Byrd, John C.; de la Chapelle, Albert; Bloomfield, Clara D.

    2016-01-01

    Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML) which may give insights into the basis for its poor prognosis have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and microRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors and tumor suppressors. Gene mutations in the activated signaling and chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had more mutations in the methylation and spliceosome groups compared to patients {greater than or equal to} 60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients {greater than or equal to} 60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (p=0.03). RNA sequencing revealed distinct gene and microRNA expression patterns between the sole -7 and non-7 AML cases, with reduced expression as expected of many genes and microRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. PMID:27784745

  10. [Auriculoventricular blocks in the acute phase of myocardial infarction. Course and prognosis. Apropos of 90 cases].

    PubMed

    Hannachi, N; Derbel, F; Ben Ismail, M

    1988-03-01

    The objective is to study the clinical and electrocardiographic characteristics as well as the course of myocardial infarction complicated by atrio-ventricular block (AVB), and to propose a management to acute myocardial infarction with A-V block. This study concerns 90 patients (78 men and 12 women), with a mean age of 58 years. The overall frequency of AVB is 7.6 p. cent. The infarction is most of the time found posteriorly (51 p. cent of the cases). Syncopes are essentially seen in complete AVB (81 p. cent) and with deep antero-septal necrosis (73 p. cent). Heart failure is especially the complication of anterior (73 p. cent) and deep septal (78 p. cent) necrosis. The mortality of myocardial infarction complicated by A-V block (41 p. cent) is higher than that of uncomplicated necroses (15 p. cent). The prognosis is usually favorable in posteriorly located infarctions where the A-V block is usually regressive and benign while it is much more severe in other locations where the conduction disorders associated with severe myocardial lesions. Temporary and/or permanent electrosystolic stimulation must be well codified in its indications which should be broadened, especially in case of anterior or deep septal necrosis.

  11. Dexrazoxane Shows No Protective Effect in the Acute Phase of Reperfusion during Myocardial Infarction in Pigs

    PubMed Central

    Kamat, Pranitha; Vandenberghe, Stijn; Christen, Stephan; Bongoni, Anjan K.; Meier, Bernhard; Rieben, Robert; Khattab, Ahmed A.

    2016-01-01

    Calcium and iron overload participate in the mechanisms of ischemia/reperfusion (I/R) injury during myocardial infarction (MI). Calcium overload induces cardiomyocyte death by hypercontraction, while iron catalyses generation of reactive oxygen species (ROS). We therefore hypothesized that dexrazoxane, an intracellular metal chelator, would attenuate I/R injury. MI was induced in pigs by occlusion of the left anterior descending artery for 1 hour followed by 2 hours reperfusion. Thirty minutes before reperfusion either 5 mg/ml dexrazoxane (n = 5) or saline (n = 5) was infused intravenously. Myocardial necrosis as percentage of the area at ischemic risk was found to be similar in both groups (77.2 ± 18% for dexrazoxane and 76.4 ± 14% for saline group) as determined by triphenyl tetrazolium chloride staining of the ischemic myocardium. Also, serum levels of troponin-I were similar in both groups. A conductance catheter was used to measure left ventricular pressure and volume at all times. Markers for tissue damage due to ROS (HNE), endothelial cell activation (CD31) and inflammation (IgG, C3b/c, C5b9, MCP-1) were assessed on tissue and/or in serum. No significant differences were observed between the groups for the parameters analyzed. To conclude, in this clinically relevant model of early reperfusion after acute myocardial ischemia, dexrazoxane lacked attenuating effects on I/R injury as shown by the measured parameters. PMID:28002439

  12. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

    PubMed Central

    Ongaro, Alessia; De Mattei, Monica; Della Porta, Matteo Giovanni; Rigolin, GianMatteo; Ambrosio, Cristina; Di Raimondo, Francesco; Pellati, Agnese; Masieri, Federica Francesca; Caruso, Angelo; Catozzi, Linda; Gemmati, Donato

    2009-01-01

    Background The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and Methods The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. Results Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. PMID:19648163

  13. Factors associated with acute-phase response of bisphosphonate-naïve or pretreated women with osteoporosis receiving an intravenous first dose of zoledronate or ibandronate.

    PubMed

    Popp, A W; Senn, R; Curkovic, I; Senn, C; Buffat, H; Popp, P F; Lippuner, K

    2017-03-15

    A first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity.

  14. ROLE OF THE MATERNAL ACUTE PHASE RESPONSE AND TUMOR NECROSIS FACTOR ALPHA IN THE DEVELOPMENTAL TOXICITY OF LIPOPOLYSACCHARIDE IN THE CD-1 MOUSE

    EPA Science Inventory

    ABSTRACT
    The acute phase response (APR) functions to reset metabolic homeostasis following infectious, toxic or traumatic insult. TNF- , a putative mediator of the APR, has been associated with fetal death in rodents and preterm labor and delivery in humans. We hypothesized...

  15. Guidelines on selection of laboratory tests for monitoring the acute phase response. International Committee for Standardization in Haematology (expert panel on blood rheology).

    PubMed Central

    1988-01-01

    These guidelines refer to laboratory tests for monitoring changes in acute phase proteins in patients with an inflammatory response to tissue damage. Quantitative measurements of acute phase proteins are a valuable indicator of the presence, extent, and response of inflammation to treatment. When short term (less than 24 hours) changes in the inflammatory response are expected, quantitative assay of C reactive protein is the test of choice. The hyperproteinaemia that develops in response to a longer term (more than 24 hours) inflammatory response is complex and may vary from one disease to another. A test that is sensitive to the combined effect of several plasma proteins is therefore indicated, and appropriate tests include the erythrocyte sedimentation rate and plasma viscosity--the latter having several advantages. Tests for monitoring short term and long term changes in acute phase proteins are complementary and should be used for different clinical purposes; no one test is ideal for all clinical situations. A quality control programme is an essential component of laboratory tests for monitoring the acute phase response. PMID:2463272

  16. Acute physiological stress down-regulates mRNA expressions of growth-related genes in coho salmon.

    PubMed

    Nakano, Toshiki; Afonso, Luis O B; Beckman, Brian R; Iwama, George K; Devlin, Robert H

    2013-01-01

    Growth and development in fish are regulated to a major extent by growth-related factors, such as liver-derived insulin-like growth factor (IGF) -1 in response to pituitary-secreted growth hormone (GH) binding to the GH receptor (GHR). Here, we report on the changes in the expressions of gh, ghr, and igf1 genes and the circulating levels of GH and IGF-1 proteins in juvenile coho salmon (Oncorhynchus kisutch) in response to handling as an acute physiological stressor. Plasma GH levels were not significantly different between stressed fish and prestressed control. Plasma IGF-1 concentrations in stressed fish 1.5 h post-stress were the same as in control fish, but levels in stressed fish decreased significantly 16 h post-stress. Real-time quantitative PCR (qPCR) analysis showed that ghr mRNA levels in pituitary, liver, and muscle decreased gradually in response to the stressor. After exposure to stress, hepatic igf1 expression transiently increased, whereas levels decreased 16 h post-stress. On the other hand, the pituitary gh mRNA level did not change in response to the stressor. These observations indicate that expression of gh, ghr, and igf1 responded differently to stress. Our results show that acute physiological stress can mainly down-regulate the expressions of growth-related genes in coho salmon in vivo. This study also suggests that a relationship between the neuroendocrine stress response and growth-related factors exists in fish.

  17. Acute Physiological Stress Down-Regulates mRNA Expressions of Growth-Related Genes in Coho Salmon

    PubMed Central

    Nakano, Toshiki; Afonso, Luis O. B.; Beckman, Brian R.; Iwama, George K.; Devlin, Robert H.

    2013-01-01

    Growth and development in fish are regulated to a major extent by growth-related factors, such as liver-derived insulin-like growth factor (IGF) -1 in response to pituitary-secreted growth hormone (GH) binding to the GH receptor (GHR). Here, we report on the changes in the expressions of gh, ghr, and igf1 genes and the circulating levels of GH and IGF-1 proteins in juvenile coho salmon (Oncorhynchus kisutch) in response to handling as an acute physiological stressor. Plasma GH levels were not significantly different between stressed fish and prestressed control. Plasma IGF-1 concentrations in stressed fish 1.5 h post-stress were the same as in control fish, but levels in stressed fish decreased significantly 16 h post-stress. Real-time quantitative PCR (qPCR) analysis showed that ghr mRNA levels in pituitary, liver, and muscle decreased gradually in response to the stressor. After exposure to stress, hepatic igf1 expression transiently increased, whereas levels decreased 16 h post-stress. On the other hand, the pituitary gh mRNA level did not change in response to the stressor. These observations indicate that expression of gh, ghr, and igf1 responded differently to stress. Our results show that acute physiological stress can mainly down-regulate the expressions of growth-related genes in coho salmon in vivo. This study also suggests that a relationship between the neuroendocrine stress response and growth-related factors exists in fish. PMID:23990952

  18. ET-1 and ecNOS gene polymorphisms andsusceptibility to acute chest syndrome and painful vaso-occlusive crises in children with sickle cell anemia.

    PubMed

    Chaar, Vicky; Tarer, Vanessa; Etienne-Julan, Maryse; Diara, Jean Pierre; Elion, Jacques; Romana, Marc

    2006-09-01

    The association of endothelin 1 (ET-1) and endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphisms (G5665T and T8002C, VNTR and T-786C respectively) with the occurrence of acute chest syndrome and painful vaso-occlusive crises was evaluated in homozygous SS children. This retrospective study reveals that ET-1 T8002 and ecNOS C-786 alleles are associated with, respectively, an increased and a decreased risk of acute chest syndrome.

  19. A phase I study of intermediate dose cytarabine in combination with lenalidomide in relapsed/refractory acute myeloid leukemia.

    PubMed

    Griffiths, Elizabeth A; Brady, William E; Tan, Wei; Vigil, Carlos E; Thompson, James E; Ford, Laurie A; Dickey, Noelle M; L Bashaw, Heather; Sperrazza, Jill; Wetzler, Meir; Wang, Eunice S

    2016-04-01

    Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Cytarabine arabinoside (AraC) forms the backbone of most regimens, with complete responses (CR) ranging from 17 to 20%. Lenalidomide (Len) is approved by the FDA for multiple myeloma and myelodysplasia and has demonstrated activity in AML. We developed a phase I study to evaluate the safety and tolerability of Len in combination with intermediate dose AraC (1.5 g/m(2)/day given on days 1-5) in adults with r/r AML. The maximally tolerated dose for this combination was 10mg daily on days 6-26 of a 28 day cycle. Dose de-escalation from 25mg was required due to rash, liver function abnormalities, and hypokalemia. Of 32 evaluable patients, five achieved CR (16%), 5CRi (16%) and 3 had hematological improvements for an overall response rate of 41% (13/32). Median overall survival (95% confidence interval) for patients treated on study was 5.8 (2.5-10.6) months and disease free survival was 3.4 (2.3-6.2) months. This single institute phase I trial of Len and intermediate dose AraC was associated with marked skin and other toxicities. At the dose and schedule tested, this combination did not appear to result in improved CR over single agent AraC for r/r AML.

  20. The Diagnostic Usefulness of Serum Total Bile Acid Concentrations in the Early Phase of Acute Pancreatitis of Varied Etiologies

    PubMed Central

    Maleszka, Aleksandra; Dumnicka, Paulina; Matuszyk, Aleksandra; Pędziwiatr, Michał; Mazur-Laskowska, Małgorzata; Sporek, Mateusz; Ceranowicz, Piotr; Olszanecki, Rafał; Kuźniewski, Marek; Kuśnierz-Cabala, Beata

    2017-01-01

    The most common causes of acute pancreatitis (AP) are biliary tract diseases with cholestasis and alcohol consumption. In 10%–15% of patients, etiology determination is difficult. Identification of the etiology allows for the implementation of adequate treatment. The aim of this study was to assess the utility of the serum concentrations of total bile acids (TBA) to diagnose AP etiology in the early phase of the disease. We included 66 patients with AP, admitted within the first 24 h from the onset of symptoms. TBA were measured in serum at 24, 48, and 72 h from the onset of AP, using an automated fifth generation assay. The bilirubin-to-TBA ratio (B/TBA) was calculated. TBA was highest on the first day of AP and decreased subsequently. In patients with biliary etiology, serum TBA was significantly higher compared to those with alcoholic and other etiologies. B/TBA was significantly higher in patients with alcoholic etiology. At admission, the cut-off values of 4.7 µmol/L for TBA and 4.22 for the B/TBA ratio allowed for a differentiation between biliary and other etiologies of AP with a diagnostic accuracy of 85 and 83%. Both TBA and B/TBA may help in the diagnosis of AP etiology in the early phase of AP. PMID:28067818

  1. ACUTE PHASE DEATHS FROM MURINE POLYMICROBIAL SEPSIS ARE CHARACTERIZED BY INNATE IMMUNE SUPPRESSION RATHER THAN EXHAUSTION1

    PubMed Central

    Chiswick, Evan L.; Mella, Juan R.; Bernardo, John; Remick, Daniel

    2015-01-01

    Sepsis, a leading cause of death in the U.S., has poorly understood mechanisms of mortality. To address this, our model of Cecal Ligation and Puncture (CLP) induced sepsis stratifies mice as predicted to Live (Live-P) or Die (Die-P) based on plasma IL-6. Six hours post-CLP, both Live-P and Die-P groups have equivalent peritoneal bacterial colony forming units and recruitment of phagocytes. By 24hr, however, Die-P mice have increased bacterial burden, despite increased neutrophil recruitment, suggesting Die-P phagocytes have impaired bacterial killing. Peritoneal cells were used to study multiple bactericidal processes: bacterial killing, Reactive Oxygen Species (ROS) generation, and phagocytosis. Total phagocytosis and intra-phagosomal processes were determined with triple-labeled E.coli, covalently labeled with ROS and pH sensitive probes, and an ROS/pH insensitive probe for normalization. While similar proportions of Live-P and Die-P phagocytes responded to exogenous stimuli, Die-P phagocytes showed marked deficits in all parameters measured, thus suggesting immunosuppression rather than exhaustion. This contradicts the prevailing sepsis paradigm that acute phase sepsis deaths (<5 days) result from excessive inflammation, whereas chronic phase deaths (>5 days) are characterized by insufficient inflammation and immunosuppression. These data suggest that suppression of cellular innate immunity in sepsis occurs within the first six hours. PMID:26371253

  2. Constitutive gene expression in monocytes from chronic HIV-1 infection overlaps with acute Toll-like receptor induced monocyte activation profiles.

    PubMed

    Gekonge, Bethsebah; Giri, Malavika S; Kossenkov, Andrew V; Nebozyhn, Michael; Yousef, Malik; Mounzer, Karam; Showe, Louise; Montaner, Luis J

    2012-01-01

    Elevated TLR expression/signalling in monocyte/macrophages has been shown to mediate systemic immune activation, a hallmark of progressive HIV-1 infection. Here we show, via differential gene expression comparisons, the presence of a constitutive in vivo TLR-like gene activation signature in steady-state circulating monocytes from chronically HIV-1 infected subjects. The TLR2-like gene signature was defined as an 82 gene subset of the 376 genes constitutively modulated in in vivo HIV-1 monocytes, based on their overlap with de novo TLR2-induced genes in uninfected subjects' monocytes following acute ex vivo stimulation with Staphylococcus Aureus Cowan (SAC). Additional comparison of in vivo gene networks with available datasets from acute TLR activations in M/M expanded the overlap to 151-gene concordance among the 376 differential genes with emphasis on ERK/MAPK, TNF/IL6 (NFκB) and p53 gene networks. TLR2 stimulation of monocytes from HIV-1 infected subjects resulted in further upregulation of inflammatory genes indicative of a sustained transcriptional potential upon stimulation. In summary, our data support the presence of a sustained TLR-like gene activation profile in circulating monocyte from steady-state viremia in HIV-1 infected subjects.

  3. Decreased DNA repair gene XRCC1 expression is associated with radiotherapy-induced acute side effects in breast cancer patients.

    PubMed

    Batar, Bahadir; Guven, Gulgun; Eroz, Seda; Bese, Nuran Senel; Guven, Mehmet

    2016-05-10

    DNA repair plays a critical role in response to ionizing radiation (IR) and developing of radiotherapy induced normal tissue reactions. In our study, we investigated the association of radiotherapy related acute side effects, with X-ray repair cross complementing group 1 (XRCC1) and Poly (ADP-ribose) polymerase 1 (PARP1) DNA repair gene expression levels, their changes in protein expression and DNA damage levels in breast cancer patients. The study included 40 women with newly diagnosed breast cancer; an experimental case group (n=20) with acute side effects and the control group (n=20) without side effects. For gene and protein expression analysis, lymphocytes were cultured for 72 h and followed by in vitro 2 Gray (Gy) gamma-irradiation. For detection of DNA damage levels, lymphocytes were irradiated with in vitro 2 Gy gamma-rays and followed by incubation for 72 h. XRCC1 mRNA and protein expression levels were significantly higher in controls than in experimental cases (P=0.020). In terms of DNA damage levels, an increased frequency of micronucleus (MN) was observed in experimental cases versus controls, but this association was not significant (P=0.206). We also observed a significant negative correlation between MN frequency and XRCC1 protein levels in experimental (r=-0.469, P=0.037) vs control (r=-0.734, P<0.001). Our results suggested that decreased XRCC1 expression levels might be associated with the increased risk of therapeutic IR-related acute side effects in patients with breast cancer.

  4. INHALATION OF OZONE AND DIESEL EXHAUST PARTICLES (DEP) INDUCES ACUTE AND REVERSIBLE CARDIAC GENE EXPRESSION CHANGES

    EPA Science Inventory

    We have recently shown that episodic but not acute exposure to ozone or DEP induces vascular effects that are associated with the loss of cardiac mitochondrial phospholipid fatty acids (DEP 2.0 mg/m3 > ozone, 0.4 ppm). In this study we determined ozone and DEP-induced cardiac gen...

  5. PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

    EPA Science Inventory

    Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

  6. Polymorphism of HDAC9 Gene Is Associated with Increased Risk of Acute Coronary Syndrome in Chinese Han Population.

    PubMed

    Han, Zhenhua; Dong, Xin; Zhang, Chaoying; Wu, Yue; Yuan, Zuyi; Wang, Xinhong

    2016-01-01

    Recent genome-wide association studies (GWAS) have indicated an association of histone deacetylase 9 (HDAC9) genetic variant with large-vessel stroke and coronary artery disease, among the European population. However, whether HDAC9 gene is associated with an increased susceptibility to acute coronary syndrome (ACS) in Chinese Han population is not known. A total of 472 patients, including patients with ACS (N = 309), and those with chest pain syndrome (controls, N = 163) were enrolled. Genotyping for HDAC9 gene was performed using the ligation detection reaction assay. A series of statistical analyses were performed to investigate the correlation between HDAC9 gene SNPs and the susceptibility to ACS. The results revealed a significant association of rs2240419 with ACS risk in which the A allele (P = 0.047) and the A allele carriers (AA + AG) (P = 0.037) were more likely to be in ACS group as compared to those in the control group. None of two other SNPs, rs2389995 and rs2107595, were significantly associated with ACS risk (P > 0.05). Logistic regression analyses further revealed an increased risk for ACS in A allele carrier among rs2240419 genotypes, as compared to those with GG homozygotes (odds ratio: 1.869, 95% CI 1.143, 3.056, P = 0.013). A significant correlation between rs2240419 polymorphism of HDAC9 gene and the susceptibility to ACS in Chinese Han population was observed in this study.

  7. Early changes in gene expression induced by acute UV exposure in leaves of Psychotria brachyceras, a bioactive alkaloid accumulating plant.

    PubMed

    do Nascimento, Naíla Cannes; Menguer, Paloma Koprovski; Sperotto, Raul Antonio; de Almeida, Márcia Rodrigues; Fett-Neto, Arthur Germano

    2013-05-01

    UV-B radiation can damage biomolecules, such as DNA, RNA, and proteins, halting essential cellular processes; this damage is partly due to ROS generation. Plant secondary metabolites may protect against UV-B. Psychotria brachyceras Müll. Arg. (Rubiaceae), a subtropical shrub, produces brachycerine, a monoterpene indole alkaloid mainly accumulated in leaf tissues, which displays antioxidant and antimutagenic activities. Exposure of P. brachyceras cuttings to UV-B radiation significantly increases leaf brachycerine concentration. It has been suggested that this alkaloid might contribute to protection against UV-B damage both through its quenching activity on ROS and as UV shield. To identify differentially expressed genes of P. brachyceras in response to UV-B and investigate a possible influence of this stimulus on putative brachycerine-related genes, suppressive subtractive hybridization was applied. Complementary DNA from UV-B-treated leaves for 24 h was used as tester, and cDNA from untreated leaves, as driver. After BLASTX alignments, 134 sequences matched plant genes. Using quantitative RT-PCR, selected genes potentially related to brachycerine showed significant increases in transcription after UV-B exposure: tryptophan decarboxylase, ACC oxidase, UDP-glucose glucosyltransferase, lipase, and serine/threonine kinase. Results suggest a possible involvement of brachycerine in acute UV-B responses and show that alkaloid accumulation seems at least partly regulated at transcriptional level.

  8. High frequency of clonal immunoglobulin or T cell receptor gene rearrangements in acute myelogenous leukemia expressing terminal deoxyribonucleotidyltransferase

    PubMed Central

    1987-01-01

    Ig and T cell receptor rearrangements have been used as irreversible markers of lineage and clonality in the study of B- and T-lymphoid populations. We have addressed the issue of lymphoid lineage specificity of these rearrangements by analyzing a panel of 25 TdT- acute myelogenous leukemias, 13 TdT+ AMLs, and 4 TdT+ undifferentiated leukemias. We report that while gene rearrangements represent extremely rare events in classical TdT- AML (less than 8%), rearrangements of either the Ig or T beta locus or both were detectable in the majority of the TdT+ AMLs (greater than 60%), and rearrangements of both loci were detectable in all of the TdT+ undifferentiated leukemias. These data demonstrate a significant association between TdT expression and Ig or T beta gene rearrangements even outside the lymphoid lineage, further supporting a role for TdT in Ig and T cell receptor gene assembly. These data also indicate that a coordinated program of lymphoid gene expression involving TdT-CD7-expression and Ig/T beta rearrangements can be activated before myeloid commitment. Whether the activation of this program represents a normal, albeit rare, event in early myelopoiesis or a transformation-related event present only in leukemic cells remains to be determined. PMID:3473183

  9. Mild sensory stimulation re-establishes cortical function during the acute phase of ischemia

    PubMed Central

    Lay, Christopher C.; Davis, Melissa F.; Chen-Bee, Cynthia H.; Frostig, Ron D.

    2011-01-01

    When delivered within 1 and in most cases 2 hours of permanent middle cerebral artery occlusion (pMCAO), mild sensory stimulation (intermittent single whisker stimulation) was shown to be completely neuroprotective according to assessment with multiple techniques 24 hours after pMCAO in a rodent model of ischemic stroke (Lay et al., 2010). The acute effect of stimulation treatment on the ischemic cortex however, had yet to be reported. Here we characterize cortical function and perfusion during the 120 minute whisker stimulation period in four experimental groups with treatment initiated 0, 1, 2 hours (protected groups) or 3 hours post-pMCAO (unprotected group) using multiple techniques. According to functional imaging, a gradual return of evoked whisker functional representation to baseline levels was initiated with treatment onset and completed within the treatment period. Evoked neuronal activity and reperfusion to the ischemic area also showed a gradual recovery in protected animals. Surprisingly, a similar recovery profile was observed in response to treatment in all protected animals, irrespective of treatment onset time. Non-stimulated pMCAO control group data demonstrate that reperfusion is not spontaneous. This makes the complete protection observed in the majority of animals stimulated at 2 hours post-pMCAO even more surprising as these animals recovered despite having been in this severely ischemic state for two full hours. In summary, when delivered within a 2 hour window post- pMCAO, whisker stimulation treatment initiated reperfusion and a gradual recovery of cortical function that was completed or nearly completed within the treatment period. PMID:21832179

  10. The einkorn wheat (Triticum monococcum) mutant, maintained vegetative phase, is caused by a deletion in the VRN1 gene.

    PubMed

    Shitsukawa, Naoki; Ikari, Chihiro; Shimada, Sanae; Kitagawa, Satoshi; Sakamoto, Koichi; Saito, Hiroyuki; Ryuto, Hiromichi; Fukunishi, Nobuhisa; Abe, Tomoko; Takumi, Shigeo; Nasuda, Shuhei; Murai, Koji

    2007-04-01

    The einkorn wheat (Triticum monococcum) mutant, maintained vegetative phase (mvp), was induced by nitrogen ion-beam treatment and was identified by its inability to transit from the vegetative to reproductive phase. In our previous study, we showed that WAP1 (wheat APETALA1) is a key gene in the regulatory pathway that controls phase transition from vegetative to reproductive growth in common wheat. WAP1 is an ortholog of the VRN1 gene that is responsible for vernalization insensitivity in einkorn wheat. The mvp mutation resulted from deletion of the VRN1 coding and promoter regions, demonstrating that WAP1/VRN1 is an indispensable gene for phase transition in wheat. Expression analysis of flowering-related genes in mvp plants indicated that wheat GIGANTIA (GI), CONSTANS (CO) and SUPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) genes either act upstream of or in a different pathway to WAP1/VRN1.

  11. Quantifying factors determining the rate of CTL escape and reversion during acute and chronic phases of HIV infection

    SciTech Connect

    Ganusov, Vitaly V; Korber, Bette M; Perelson, Alan S

    2009-01-01

    Human immunodeficiency virus (HIV) often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. However, the importance and quantitative details of CTL escape in humans are poorly understood. In part, this is because most studies looking at escape of HIV from CTL responses are cross-sectional and are limited to early or chronic phases of the infection. We use a novel technique of single genome amplification (SGA) to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We find that HIV escapes from virus-specific CTL responses as early as 30-50 days since the infection, and the rates of viral escapes during acute phase of the infection are much higher than was estimated in previous studies. However, even though with time virus acquires additional escape mutations, these late mutations accumulate at a slower rate. A poor correlation between the rate of CTL escape in a particular epitope and the magnitude of the epitope-specific CTL response suggests that the lower rate of late escapes is unlikely due to a low efficacy of the HIV-specific CTL responses in the chronic phase of the infection. Instead, our results suggest that late and slow escapes are likely to arise because of high fitness cost to the viral replication associated with such CTL escapes. Targeting epitopes in which virus escapes slowly or does not escape at all by CTL responses may, therefore, be a promising direction for the development of T cell based HIV vaccines.

  12. First Generation Gene Expression Signature for Early Prediction of Late Occurring Hematological Acute Radiation Syndrome in Baboons.

    PubMed

    Port, M; Herodin, F; Valente, M; Drouet, M; Lamkowski, A; Majewski, M; Abend, M

    2016-07-01

    We implemented a two-stage study to predict late occurring hematologic acute radiation syndrome (HARS) in a baboon model based on gene expression changes measured in peripheral blood within the first two days after irradiation. Eighteen baboons were irradiated to simulate different patterns of partial-body and total-body exposure, which corresponded to an equivalent dose of 2.5 or 5 Gy. According to changes in blood cell counts the surviving baboons (n = 17) exhibited mild (H1-2, n = 4) or more severe (H2-3, n = 13) HARS. Blood samples taken before irradiation served as unexposed control (H0, n = 17). For stage I of this study, a whole genome screen (mRNA microarrays) was performed using a portion of the samples (H0, n = 5; H1-2, n = 4; H2-3, n = 5). For stage II, using the remaining samples and the more sensitive methodology, qRT-PCR, validation was performed on candidate genes that were differentially up- or down-regulated during the first two days after irradiation. Differential gene expression was defined as significant (P < 0.05) and greater than or equal to a twofold difference above a H0 classification. From approximately 20,000 genes, on average 46% appeared to be expressed. On day 1 postirradiation for H2-3, approximately 2-3 times more genes appeared up-regulated (1,418 vs. 550) or down-regulated (1,603 vs. 735) compared to H1-2. This pattern became more pronounced at day 2 while the number of differentially expressed genes decreased. The specific genes showed an enrichment of biological processes coding for immune system processes, natural killer cell activation and immune response (P = 1 × E-06 up to 9 × E-14). Based on the P values, magnitude and sustained differential gene expression over time, we selected 89 candidate genes for validation using qRT-PCR. Ultimately, 22 genes were confirmed for identification of H1-3 classifications and seven genes for identification of H2-3 classifications using qRT-PCR. For H1-3 classifications, most genes were

  13. Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response.

    PubMed

    Yang, Yang; Zhang, Yan; Wang, Zhaotao; Wang, Shanshan; Gao, Mou; Xu, Ruxiang; Liang, Chunyang; Zhang, Hongtian

    2016-04-01

    The outcome of intracerebral hemorrhage (ICH) is mainly determined by the volume of the hemorrhage core and the secondary brain damage to penumbral tissues due to brain swelling, microcirculation disturbance and inflammation. The present study aims to investigate the protective effects of cerebrolysin on brain edema and inhibition of the inflammation response surrounding the hematoma core in the acute stage after ICH. The ICH model was induced by administration of type VII bacterial collagenase into the stratum of adult rats, which were then randomly divided into three groups: ICH + saline; ICH + Cerebrolysin (5 ml/kg) and sham. Cerebrolysin or saline was administered intraperitoneally 1 h post surgery. Neurological scores, extent of brain edema content and Evans blue dye extravasation were recorded. The levels of pro-inflammatory factors (IL-1β, TNF-α and IL-6) were assayed by Real-time PCR and Elisa kits. Aquaporin-4 (AQP4) and tight junction proteins (TJPs; claudin-5, occludin and zonula occluden-1) expression were measured at multiple time points. The morphological and intercellular changes were characterized by Electron microscopy. It is found that cerebrolysin (5 ml/kg) improved the neurological behavior and reduced the ipsilateral brain water content and Evans blue dye extravasation. After cerebrolysin treated, the levels of pro-inflammatory factors and AQP4 in the peri-hematomal areas were markedly reduced and were accompanied with higher expression of TJPs. Electron microscopy showed the astrocytic swelling and concentrated chromatin in the ICH group and confirmed the cell junction changes. Thus, early cerebrolysin treatment ameliorates secondary injury after ICH and promotes behavioral performance during the acute phase by reducing brain edema, inflammatory response, and blood-brain barrier permeability.

  14. Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

    PubMed Central

    Yan, Han; Wen, Lu; Tan, Dan; Xie, Pan; Pang, Feng-mei; Zhou, Hong-hao; Zhang, Wei; Liu, Zhao-qian; Tang, Jie; Li, Xi; Chen, Xiao-ping

    2017-01-01

    The prognosis of cytogenetically normal acute myeloid leukemia (CN-AML) varies greatly among patients. Achievement of complete remission (CR) after chemotherapy is indispensable for a better prognosis. To develop a gene signature predicting overall survival (OS) in CN-AML, we performed data mining procedure based on whole genome expression data of both blood cancer cell lines and AML patients from open access database. A gene expression signature including 42 probes was derived. These probes were significantly associated with both cytarabine half maximal inhibitory concentration values in blood cancer cell lines and OS in CN-AML patients. By using cox regression analysis and linear regression analysis, a chemo-sensitive score calculated algorithm based on mRNA expression levels of the 42 probes was established. The scores were associated with OS in both the training sample (p=5.13 × 10−4, HR=2.040, 95% CI: 1.364-3.051) and the validation sample (p=0.002, HR=2.528, 95% CI: 1.393-4.591) of the GSE12417 dataset from Gene Expression Omnibus. In The Cancer Genome Atlas (TCGA) CN-AML patients, higher scores were found to be associated with both worse OS (p=0.013, HR=2.442, 95% CI: 1.205-4.950) and DFS (p=0.015, HR=2.376, 95% CI: 1.181-4.779). Results of gene ontology (GO) analysis showed that all the significant GO Terms were correlated with cellular component of mitochondrion. In summary, a novel gene set that could predict prognosis of CN-AML was identified presently, which provided a new way to identify genes impacting AML chemo-sensitivity and prognosis. PMID:27903973

  15. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

    PubMed Central

    Vijayakrishnan, Jayaram; Houlston, Richard S.

    2010-01-01

    To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996–July 2009). Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04–1.30), MTRR A66G (OR=0.73, 95%CI:0.59–0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65–0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11–1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11–1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32–3.00) NQO1 C609T (OR=1.24, 95%CI:1.02–1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32–2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design. PMID:20511665

  16. Randomised phase 2 trial of intra-coronary nitrite during acute myocardial infarction

    PubMed Central

    Jones, Daniel A; Pellaton, Cyril; Velmurugan, Shanti; Rathod, Krishnaraj Sinha; Andiapen, Mervyn; Antoniou, Sotiris; van Eijl, Sven; Webb, Andrew J; Westwood, Mark A; Parmar, Mahesh K; Mathur, Anthony; Ahluwalia, Amrita

    2015-01-01

    Rationale Pre-clinical evidence demonstrates that inorganic nitrite, following its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. Objective We investigated whether intra-coronary injection of nitrite during primary percutaneous coronary intervention (PCI) might improve infarct size in ST-elevated myocardial infarction (STEMI). Methods and Results Patients undergoing primary PCI (n=80) were randomised to receive intracoronary (10mL) sodium nitrite (1.8μmol) or NaCl (placebo) before balloon inflation. The primary endpoint was infarct size assessed by measuring creatine kinase (CK) release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac magnetic resonance imaging (CMR) on day 2. Baseline characteristics were similar between the groups. No evidence of differences in CK release (p=0.92), troponin T (p=0.85) or CMR-assessed infarct size (p=0.254) were evident. In contrast there was an improvement in myocardial salvage index (p=0.05) and reduction in MACE at 1 year (2.6% vs 15.8%, p=0.04) in the nitrite group. In a 66-patient sub-group with TIMI≤1 flow there was reduced serum CK (p=0.030) and a 19% reduction in CMR-determined infarct size (p=0.034) with nitrite. No adverse effects of nitrite were detected. Conclusions In this phase II study intra-coronary nitrite infusion did not alter infarct size although a trend to improved myocardial salvage index and a significant reduction in MACE was evident. In a sub-group of patients with TIMI flow≤1 nitrite reduced infarct size and MACE and improved myocardial salvage index indicating that a phase III clinical trial assessing intra-coronary nitrite administration as an adjunct to PCI in STEMI patients is warranted. Clinical Trial Registration URL: http://clinicaltrials.gov NCT01584453. PMID:25512434

  17. C-reactive protein, haptoglobin and Pig-Major acute phase protein profiles of pigs infected experimentally by different isolates of porcine reproductive and respiratory syndrome virus.

    PubMed

    Saco, Y; Martínez-Lobo, F; Cortey, M; Pato, R; Peña, R; Segalés, J; Prieto, C; Bassols, A

    2016-02-01

    Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) is the etiologic agent of PRRS, one of the most important diseases in swine worldwide. In the present work, the effects of different PRRSV strains were tested on a piglet experimental model to study the induced acute phase response. For this purpose, pigs (n=15 for each group) were intranasally inoculated with one of five PRRSV strains (isolates EU10, 12, 17, 18 from genotype 1 and isolate JA-142 from genotype 2). The acute phase response was monitored by measuring acute phase proteins (APPs). Specifically, the serum concentration of haptoglobin (Hp), C-reactive protein (CRP) and Pig-Major Acute Protein (Pig-MAP) was determined at 0, 3, 6, 9, 12, 15, 18 and 21 days p.i. Clinical signs and growth performance were also monitored during the experiment. All animals became viremic after inoculation during the study period. The APP response was heterogeneous and dependent on the strain, being strains EU10, EU 18 and JA-142 those that induced the highest response and the strongest clinical signs. In general, Hp was the most sensitive biomarker for PRRSV infection, CRP behaved as moderate and Pig-MAP was the less responsive during the course of PRRSV experimental infection. Hp and CRP were significantly discriminatory between infected and control pigs, but not Pig-MAP.

  18. The expression of plasticity-related genes in an acute model of stress is modulated by chronic desipramine in a time-dependent manner within medial prefrontal cortex.

    PubMed

    Nava, Nicoletta; Treccani, Giulia; Müller, Heidi Kaastrup; Popoli, Maurizio; Wegener, Gregers; Elfving, Betina

    2017-01-01

    It is well established that stress plays a major role in the pathogenesis of neuropsychiatric diseases. Stress-induced alteration of synaptic plasticity has been hypothesized to underlie the morphological changes observed by neuroimaging in psychiatric patients in key regions such as hippocampus and prefrontal cortex (PFC). We have recently shown that a single acute stress exposure produces significant short-term alterations of structural plasticity within medial PFC. These alterations were partially prevented by previous treatment with chronic desipramine (DMI). In the present study we evaluated the effects of acute Foot-shock (FS)-stress and pre-treatment with the traditional antidepressant DMI on the gene expression of key regulators of synaptic plasticity and structure. Expression of Homer, Shank, Spinophilin, Densin-180, and the small RhoGTPase related gene Rac1 and downstream target genes, Limk1, Cofilin1 and Rock1 were investigated 1 day (1d), 7 d and 14d after FS-stress exposure. We found that DMI specifically increases the short-term expression of Spinophilin, as well as Homer and Shank family genes, and that both acute stress and DMI exert significant long-term effects on mRNA levels of genes involved in spine plasticity. These findings support the knowledge that acute FS stress and antidepressant treatment induce both rapid and sustained time-dependent alterations in structural components of synaptic plasticity in rodent medial PFC.

  19. Lunar Phase Modulates Circadian Gene Expression Cycles in the Broadcast Spawning Coral Acropora millepora.

    PubMed

    Brady, Aisling K; Willis, Bette L; Harder, Lawrence D; Vize, Peter D

    2016-04-01

    Many broadcast spawning corals in multiple reef regions release their gametes with incredible temporal precision just once per year, using the lunar cycle to set the night of spawning. Moonlight, rather than tides or other lunar-regulated processes, is thought to be the proximate factor responsible for linking the night of spawning to the phase of the Moon. We compared patterns of gene expression among colonies of the broadcast spawning coral Acropora millepora at different phases of the lunar cycle, and when they were maintained under one of three experimentally simulated lunar lighting treatments: i) lunar lighting conditions matching those on the reef, or lunar patterns mimicking either ii) constant full Moon conditions, or iii) constant new Moon conditions. Normal lunar illumination was found to shift both the level and timing of clock gene transcription cycles between new and full moons, with the peak hour of expression for a number of genes occurring earlier in the evening under a new Moon when compared to a full Moon. When the normal lunar cycle is replaced with nighttime patterns equivalent to either a full Moon or a new Moon every evening, the normal monthlong changes in the level of expression are destroyed for most genes. In combination, these results indicate that daily changes in moonlight that occur over the lunar cycle are essential for maintaining normal lunar periodicity of clock gene transcription, and this may play a role in regulating spawn timing. These data also show that low levels of light pollution may have an impact on coral biological clocks.

  20. A stationary-phase gene in Saccharomyces cerevisiae is a member of a novel, highly conserved gene family.

    PubMed Central

    Braun, E L; Fuge, E K; Padilla, P A; Werner-Washburne, M

    1996-01-01

    The regulation of cellular growth and proliferation in response to environmental cues is critical for development and the maintenance of viability in all organisms. In unicellular organisms, such as the budding yeast Saccharomyces cerevisiae, growth and proliferation are regulated by nutrient availability. We have described changes in the pattern of protein synthesis during the growth of S. cerevisiae cells to stationary phase (E. K. Fuge, E. L. Braun, and M. Werner-Washburne, J. Bacteriol. 176:5802-5813, 1994) and noted a protein, which we designated Snz1p (p35), that shows increased synthesis after entry into stationary phase. We report here the identification of the SNZ1 gene, which encodes this protein. We detected increased SNZ1 mRNA accumulation almost 2 days after glucose exhaustion, significantly later than that of mRNAs encoded by other postexponential genes. SNZ1-related sequences were detected in phylogenetically diverse organisms by sequence comparisons and low-stringency hybridization. Multiple SNZ1-related sequences were detected in some organisms, including S. cerevisiae. Snz1p was found to be among the most evolutionarily conserved proteins currently identified, indicating that we have identified a novel, highly conserved protein involved in growth arrest in S. cerevisiae. The broad phylogenetic distribution, the regulation of the SNZ1 mRNA and protein in S. cerevisiae, and identification of a Snz protein modified during sporulation in the gram-positive bacterium Bacillus subtilis support the hypothesis that Snz proteins are part of an ancient response that occurs during nutrient limitation and growth arrest. PMID:8955308

  1. Growth phase-dependent transcription of the Streptomyces ramocissimus tuf1 gene occurs from two promoters.

    PubMed Central

    Tieleman, L N; van Wezel, G P; Bibb, M J; Kraal, B

    1997-01-01

    The str operon of Streptomyces ramocissimus contains the genes for ribosomal proteins S12 (rpsL) and S7 (rpsG) and for the polypeptide chain elongation factors G (EF-G) (fus) and Tu (EF-Tu) (tuf). This kirromycin producer contains three tuf or tuf-like genes; tuf1 encodes the regular EF-Tu and is located immediately downstream of fus. In vivo and in vitro transcription analysis revealed a transcription start site directly upstream of S. ramocissimus tuf1, in addition to the operon promoter rpsLp. Transcription from these promoters appeared to be growth phase dependent, diminishing drastically upon entry into stationary phase and at the onset of production of the EF-Tu-targeted antibiotic kirromycin. In surface-grown cultures, a second round of tuf1 transcription, coinciding with aerial mycelium formation and kirromycin production, was observed. The tuf1-specific promoter (tuf1p) was located in the intercistronic region between fus and tuf1 by high-resolution S1 mapping, in vitro transcription, and in vivo promoter probing. During logarithmic growth, the tuf1p and rpsLp transcripts are present at comparable levels. In contrast to Escherichia coli, which has two almost identical tuf genes, the gram-positive S. ramocissimus contains only tuf1 for its regular EF-Tu. High levels of EF-Tu may therefore be achieved by the compensatory activity of tuf1p. PMID:9171408

  2. [The significance of the epigenetics modifying gene mutations in acute myeloid leukemia].

    PubMed

    Wakita, Satoshi; Yamaguchi, Hiroki

    2014-06-01

    In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation, and in histone modifications have been reported in myeloid malignancies. Large clinical correlative studies are beginning to clear the clinical importance, prevalence, and potential prognostic significance of these epigenetics modifying gene mutations. Additionally, recent studies shedding light on the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. In this review, we summarize the current understanding of the epigenetics modifying gene mutation, discuss how contribute to its pathogenesis and clinical feature in AML.

  3. Detection of Mutant NPM1 mRNA in Acute Myeloid Leukemia Using Custom Gene Expression Arrays

    PubMed Central

    van Vliet, Martin H.; Dumee, Belinda; Simons, Erik; Bullinger, Lars; Döhner, Konstanze; Döhner, Hartmut; Viëtor, Henk; Löwenberg, Bob; Valk, Peter J.M.

    2013-01-01

    Mutations in the gene encoding nucleophosmin (NPM1) carry a prognostic value for patients with acute myeloid leukemia (AML). Various techniques are currently being used to detect these mutations in routine molecular diagnostics. Incorporation of accurate NPM1 mutation detection on a gene expression platform would enable simultaneous detection with various other expression biomarkers. Here we present an array-based mutation detection using custom probes for NPM1 WT mRNA and NPM1 type A, B, and D mutant mRNA. This method was 100% accurate on a training cohort of 505 newly diagnosed unselected AML cases. Validation on an independent cohort of 143 normal-karyotype AML cases revealed no false-negative results, and one false positive (sensitivity 100.0% and specificity 98.7%). Based on this, we conclude that this method provides a reliable method for NPM1 mutation detection. The method can be applied to other genes/mutations as long as the mutant alleles are sufficiently highly expressed. PMID:23530539

  4. Lack of Association between Genetic Polymorphisms of JAK-STAT Signaling Pathway Genes and Acute Anterior Uveitis in Han Chinese

    PubMed Central

    2016-01-01

    Purpose. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) of JAK-STAT signaling pathway genes and acute anterior uveitis (AAU) with or without ankylosing spondylitis (AS) in the Han Chinese population. Methods. Eleven SNPs of the JAK1, JAK2, STAT1, IRF1, and NOS2 genes were analyzed in 443 AAU patients with AS, 486 AAU patients without AS, and 714 healthy controls. Genotyping was performed by PCR-RFLP assay or TaqMan® probe assay. The Chi-squared (χ2) test and multivariate logistic regression analysis were used to compare the distributions of alleles and genotypes between patients and controls. P values were adjusted using Bonferroni correction. Results. We did not observe significant differences in the genotype and allele frequencies of any SNP between AAU patients with or without AS and healthy controls. Stratification analyses by gender and HLA-B27 status showed a boundary significant association between two SNPs (rs10975003 and rs10758669) in JAK2 and AAU (P = 0.052 and P = 0.053, resp.). Conclusions. Our results indicated that genetic polymorphisms of the JAK-STAT signaling pathway genes may not be associated with AAU in the Han Chinese population. PMID:27965977

  5. A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL)

    PubMed Central

    Mavrakis, Konstantinos J; Van Der Meulen, Joni; Wolfe, Andrew L; Liu, Xiaoping; Mets, Evelien; Taghon, Tom; Khan, Aly A; Setty, Manu; Rondou, Pieter; Vandenberghe, Peter; Delabesse, Eric; Benoit, Yves; Socci, Nicholas B; Leslie, Christina S; Van Vlierberghe, Pieter; Speleman, Frank; Wendel, Hans-Guido

    2014-01-01

    The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer. PMID:21642990

  6. Prediction of relapse in paediatric pre-B acute lymphoblastic leukaemia using a three-gene risk index.

    PubMed

    Hoffmann, Katrin; Firth, Martin J; Beesley, Alex H; Freitas, Joseph R; Ford, Jette; Senanayake, Saranga; de Klerk, Nicholas H; Baker, David L; Kees, Ursula R

    2008-03-01

    Despite high cure rates 25% of children with acute lymphoblastic leukaemia (ALL) relapse and have dismal outcome. Crucially, many are currently stratified as standard risk (SR) and additional markers to improve patient stratification are required. Here we have used diagnostic bone marrow specimens from 101 children with pre-B ALL to examine the use of gene expression profiles (GEP) as predictors of long-term clinical outcome. Patients were divided into two cohorts for model development and validation based on availability of specimen material. Initially, GEP from 55 patients with sufficient material were analysed using HG-U133A microarrays, identifying an 18-gene classifier (GC) that was more predictive of outcome than conventional prognostic parameters. After feature selection and validation of expression levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR), a three-gene qRT-PCR risk index [glutamine synthetase (GLUL), ornithine decarboxylase antizyme inhibitor (AZIN), immunoglobulin J chain (IGJ)] was developed that predicted outcome with an accuracy of 89% in the array cohort and 87% in the independent validation cohort. The data demonstrate the feasibility of using GEP to improve risk stratification in childhood ALL. This is particularly important for the identification of patients destined to relapse despite their current stratification as SR, as more intensive front-line treatment options for these individuals are already available.

  7. Phase 1 Multicenter Study of Vincristine Sulfate Liposomes Injection and Dexamethasone in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia

    PubMed Central

    Thomas, Deborah A.; Kantarjian, Hagop M.; Stock, Wendy; Heffner, Leonard T.; Faderl, Stefan; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Wierda, William; Pierce, Sherry; Lu, Biao; Deitcher, Steven R.; O’Brien, Susan

    2015-01-01

    BACKGROUND Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity. METHODS A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m2, 1.825 mg/m2, 2.0 mg/m2, 2.25 mg/m2, or 2.4 mg/m2 was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose-escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4-week cycle. RESULTS Thirty-six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m2 dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent-to-treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission. CONCLUSIONS In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single-agent VSLI as second salvage therapy for patients with previously treated ALL is underway. PMID:19708032

  8. Exacerbated skeletal muscle inflammation and calcification in the acute phase of infection by Mexican Trypanosoma cruzi DTUI strain.

    PubMed

    Vizcaíno-Castillo, Andrea; Jiménez-Marín, Andrea; Espinoza, Bertha

    2014-01-01

    A murine model was used to study the histopathological aspects and cytokine expression levels in skeletal muscle provoked by the infection with Mexican TcI strains. BALB/c mice were inoculated with the virulent Querétaro strain and the nonvirulent Ninoa strain. Parasite numbers were counted in blood and skeletal muscle at different times post-infection, and real time-PCR expression levels of the cytokines IL-12, IL-4, IL-10, IFN- γ , and TNF- α were evaluated. In the acute phase of infection, a high parasitic load, both in blood and skeletal muscle, was detected. The histopathological analyses showed an exacerbated inflammation and granulomatous-like infiltrate with the Querétaro strain. Interestingly, extensive calcification areas were observed in the skeletal muscle surrounded by inflammatory infiltrates. TNF- α and IL-10 expression exhibited a significant increase at the peak of infection. In summary, Querétaro strain, a Mexican TcI strain, is virulent enough to induce high inflammation and calcification in skeletal muscle of the hind limbs, which could be related to high expression levels of TNF- α .

  9. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia.

    PubMed

    Fehniger, Todd A; Uy, Geoffrey L; Trinkaus, Kathryn; Nelson, Alissa D; Demland, Jeffery; Abboud, Camille N; Cashen, Amanda F; Stockerl-Goldstein, Keith E; Westervelt, Peter; DiPersio, John F; Vij, Ravi

    2011-02-10

    Older patients with acute myeloid leukemia (AML) have limited treatment options and a poor prognosis, thereby warranting novel therapeutic strategies. We evaluated the efficacy of lenalidomide as front-line therapy for older AML patients. In this phase 2 study, patients 60 years of age or older with untreated AML received high-dose (HD) lenalidomide at 50 mg daily for up to 2 28-day cycles. If patients achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) or did not progress after 2 cycles of HD lenalidomide, they received low-dose lenalidomide (10 mg daily) until disease progression, an unacceptable adverse event, or completion of 12 cycles. Thirty-three AML patients (median age, 71 years) were enrolled with intermediate (55%), unfavorable (39%), or unknown (6%) cytogenetic risk. Overall CR/CRi rate was 30%, and 53% in patients completing HD lenalidomide. The CR/CRi rate was significantly higher in patients presenting with a low (< 1000/μL) circulating blast count (50%, P = .01). The median time to CR/CRi was 30 days, and duration of CR/CRi was 10 months (range, 1- ≥ 17 months). The most common grades ≥ 3 toxicities were thrombocytopenia, anemia, infection, and neutropenia. HD lenalidomide has evidence of clinical activity as initial therapy for older AML patients, and further study of lenalidomide in AML and MDS is warranted. This study is registered at www.clinicaltrials.gov as #NCT00546897.

  10. The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications.

    PubMed

    Dumnicka, Paulina; Maduzia, Dawid; Ceranowicz, Piotr; Olszanecki, Rafał; Drożdż, Ryszard; Kuśnierz-Cabala, Beata

    2017-02-08

    Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients.

  11. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia

    PubMed Central

    Eghtedar, Alireza; Verstovsek, Srdan; Estrov, Zeev; Burger, Jan; Cortes, Jorge; Bivins, Carol; Faderl, Stefan; Ferrajoli, Alessandra; Borthakur, Gautam; George, Solly; Scherle, Peggy A.; Newton, Robert C.; Kantarjian, Hagop M.

    2012-01-01

    We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479. PMID:22422826

  12. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia

    PubMed Central

    Fehniger, Todd A.; Uy, Geoffrey L.; Trinkaus, Kathryn; Nelson, Alissa D.; Demland, Jeffery; Abboud, Camille N.; Cashen, Amanda F.; Stockerl-Goldstein, Keith E.; Westervelt, Peter; DiPersio, John F.

    2011-01-01

    Older patients with acute myeloid leukemia (AML) have limited treatment options and a poor prognosis, thereby warranting novel therapeutic strategies. We evaluated the efficacy of lenalidomide as front-line therapy for older AML patients. In this phase 2 study, patients 60 years of age or older with untreated AML received high-dose (HD) lenalidomide at 50 mg daily for up to 2 28-day cycles. If patients achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) or did not progress after 2 cycles of HD lenalidomide, they received low-dose lenalidomide (10 mg daily) until disease progression, an unacceptable adverse event, or completion of 12 cycles. Thirty-three AML patients (median age, 71 years) were enrolled with intermediate (55%), unfavorable (39%), or unknown (6%) cytogenetic risk. Overall CR/CRi rate was 30%, and 53% in patients completing HD lenalidomide. The CR/CRi rate was significantly higher in patients presenting with a low (< 1000/μL) circulating blast count (50%, P = .01). The median time to CR/CRi was 30 days, and duration of CR/CRi was 10 months (range, 1- ≥ 17 months). The most common grades ≥ 3 toxicities were thrombocytopenia, anemia, infection, and neutropenia. HD lenalidomide has evidence of clinical activity as initial therapy for older AML patients, and further study of lenalidomide in AML and MDS is warranted. This study is registered at www.clinicaltrials.gov as #NCT00546897. PMID:21051557

  13. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia.

    PubMed

    Harousseau, Jean-Luc; Lancet, Jeffrey E; Reiffers, Josy; Lowenberg, Bob; Thomas, Xavier; Huguet, Francoise; Fenaux, Pierre; Zhang, Steven; Rackoff, Wayne; De Porre, Peter; Stone, Richard

    2007-06-15

    This phase 2 study evaluated the efficacy and safety of the oral farnesyltransferase inhibitor tipifarnib in adults with refractory or relapsed acute myeloid leukemia (AML). Patients (n=252) received tipifarnib 600 mg twice a day for 21 days in 28-day cycles. Median age was 62 years; 99 (39%) patients were 65 years or older. Eleven (4%) of 252 patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp; 9 CR and 2 CRp). Nineteen patients (8%), including those who achieved CR/CRp, achieved a reduction in bone marrow blasts to less than 5% blasts. Bone marrow blasts were reduced more than 50% in an additional 8 patients (total = 27; 11%). Median survival was 369 days for patients who achieved CR/CRp. Myelosuppression was the most common adverse event. The most common nonhematologic toxicities were fever, nausea, and hypokalemia. Single-agent treatment with tipifarnib induced durable CR/CRp, which was associated with prolonged survival, in some patients with refractory or relapsed AML. The response rate observed in this heavily pretreated group of patients suggests the requirement to enhance the response rate either by combining tipifarnib with other active agents or determining factors that are predictive of response.

  14. Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia

    PubMed Central

    Vey, Norbert; Delaunay, Jacques; Martinelli, Giovanni; Fiedler, Walter; Raffoux, Emmanuel; Prebet, Thomas; Gomez-Roca, Carlos; Papayannidis, Cristina; Kebenko, Maxim; Paschka, Peter; Christen, Randolph; Guarin, Ernesto; Bröske, Ann-Marie; Baehner, Monika; Brewster, Michael; Walz, Antje-Christine; Michielin, Francesca; Runza, Valeria; Meresse, Valerie; Recher, Christian

    2016-01-01

    RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML). Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg. Forty-four patients (median age, 69 years) were enrolled. One dose-limiting toxicity occurred (grade 3 hemolysis exacerbation) after one 1200 mg dose (twice-weekly cohort). The majority of adverse events were mild/moderate. Infusion-related reactions occurred in 64% of patients mainly during cycle 1. Two patients experienced grade 3 drug-induced aseptic meningitis. Pharmacokinetics increased supraproportionally, suggesting a target-mediated drug disposition (TMDD) at ≥ 1200 mg. Two patients achieved complete response with incomplete platelet recovery or partial response, respectively. One patient had stable disease with hematologic improvement. RG7356 was generally safe and well tolerated. Maximum tolerated dose was not reached, but saturation of TMDD was achieved. The recommended dose for future AML evaluations is 2400 mg every other week. PMID:27081038

  15. Acute-phase proteins, oxidative stress biomarkers, proinflammatory cytokines, and cardiac troponin in Arabian mares affected with pyometra.

    PubMed

    El-Bahr, S M; El-Deeb, W M

    2016-09-01

    New biomarkers are essential for diagnosis of pyometra in mares. In this context, 12 subfertile Arabian mares suffered from pyometra were admitted to the Veterinary Teaching Hospital. The basis for diagnosis of pyometra was positive findings of clinical examination and rectal palpation. Blood samples were collected from diseased animals and from five Arabian healthy mares, which were considered as control group. Acute-phase proteins (APP), oxidative stress biomarkers, proinflammatory cytokines, and cardiac troponin I were estimated in the harvested sera of both groups. Clinical examination revealed purulent yellowish fluid discharged from vagina of affected animals and rectal palpation of the reproductive tract revealed uterine distention. The biochemical analysis of the serum revealed significant increase in cardiac troponin I, creatin kinase, alkaline phosphatase, malondialdehyde, tumor necrosis factor α, interleukins 6, prostaglandin F2α, haptoglobin, and serum amyloid A and significant decrease in reduced glutathione, superoxide dismutase (SOD), total antioxidant capacity, and nitric oxide (NO) of mares affected with pyometra compare to control. Cardiac troponin I was positively correlated with aspartate aminotransferase, creatin kinase, malondialdehyde, alkaline phosphatase, tumor necrosis factor α, interleukins 6, prostaglandin F2α, haptoglobin and serum amyloid A and negatively correlated with glutathione, superoxide dismutase, total antioxidant capacity and nitric oxide in serum of mares affected with pyometra. Moreover, there was high positive correlation between proinflammatory cytokines and APP in serum of mares affected with pyometra. The present study suggests cardiac troponin I together with APP, proinflammatory cytokines, and oxidative stress parameters as biomarkers for pyometra in Arabian mares.

  16. Antibiotics Increase Gut Metabolism and Antioxidant Proteins and Decrease Acute Phase Response and Necrotizing Enterocolitis in Preterm Neonates

    PubMed Central

    Jiang, Pingping; Jensen, Michael Ladegaard; Cilieborg, Malene Skovsted; Thymann, Thomas; Wan, Jennifer Man-Fan; Sit, Wai-Hung; Tipoe, George L.; Sangild, Per Torp

    2012-01-01

    Background The appropriate use of antibiotics for preterm infants, which are highly susceptible to develop necrotizing enterocolitis (NEC), is not clear. While antibiotic therapy is commonly used in neonates with NEC symptoms and sepsis, it remains unknown how antibiotics may affect the intestine and NEC sensitivity. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms. Methodology/Principal Findings Preterm pigs were treated with antibiotics for 5 d (oral and systemic doses of gentamycin, ampicillin and metrodinazole; AB group) and compared with untreated pigs. Only the untreated pigs showed evidence of NEC lesions and reduced digestive function, as indicated by lowered villus height and activity of brush border enzymes. In addition, 53 intestinal and 22 plasma proteins differed in expression between AB and untreated pigs. AB treatment increased the abundance of intestinal proteins related to carbohydrate and protein metabolism, actin filaments, iron homeostasis and antioxidants. Further, heat shock proteins and the complement system were affected suggesting that all these proteins were involved in the colonization-dependent early onset of NEC. In plasma, acute phase proteins (haptoglobin, complement proteins) decreased, while albumin, cleaved C3, ficolin and transferrin increased. Conclusions/Significance Depressed bacterial colonization following AB treatment increases mucosal integrity and reduces bacteria-associated inflammatory responses in preterm neonates. The plasma proteins C3, ficolin, and transferrin are potential biomarkers of the colonization-dependent NEC progression in preterm neonates. PMID:23028687

  17. In vitro culture and drug sensitivity assay of Plasmodium falciparum with nonserum substitute and acute-phase sera.

    PubMed

    Ringwald, P; Meche, F S; Bickii, J; Basco, L K

    1999-03-01

    The short-term in vitro growth of Plasmodium falciparum parasites in the asexual erythrocytic stage and the in vitro activities of eight standard antimalarial drugs were assessed and compared by using RPMI 1640 medium supplemented with 10% nonimmune human serum, 10% autologous or homologous acute-phase serum, or 0.5% Albumax I (lipid-enriched bovine serum albumin). In general, parasite growth was maximal with autologous (or homologous) serum, followed by Albumax I and nonimmune serum. The 50% inhibitory concentrations (IC50s) varied widely, depending on the serum or serum substitute. The comparison of IC50s between assays with autologous and nonimmune sera showed that monodesethylamodiaquine, halofantrine, pyrimethamine, and cycloguanil had similar IC50s. Although the IC50s of chloroquine, monodesethylamodiaquine, and dihydroartemisinin were similar with Albumax I and autologous sera, the IC50s of all test compounds obtained with Albumax I differed considerably from the corresponding values obtained with nonimmune serum. Our results suggest that Albumax I and autologous and homologous sera from symptomatic, malaria-infected patients may be useful alternative sources of serum for in vitro culture of P. falciparum isolates in the field. However, autologous sera and Albumax I do not seem to be suitable for the standardization of isotopic in vitro assays for all antimalarial drugs.

  18. Effect of Calendula officinalis Flower Extract on Acute Phase Proteins, Antioxidant Defense Mechanism and Granuloma Formation During Thermal Burns

    PubMed Central

    Chandran, Preethi K.; Kuttan, Ramadasan

    2008-01-01

    Effect of Calendula officinalis flower extract was investigated against experimentally induced thermal burns in rats. Burn injury was made on the shaven back of the rats under anesthesia and the animals were treated orally with different doses of the flower extract (20 mg, 100 mg and 200 mg/kg body weight). The animals treated with the extract showed significant improvement in healing when compared with the control untreated animals. The indicators of the wound healing such as collagen-hydroxyproline and hexosamine contents were significantly increased in the treated group indicating accelerated wound healing in the treated animals. The acute phase proteins—haptoglobin and orosomucoid which were increased due to burn injury were found to be decreased significantly in 200 mg/kg body weight extract treated animals. The antioxidant defense mechanism, which was decreased in the liver during burn injury, was found to be enhanced in treated animals. The lipid peroxidation was significantly lowered in the treated group when compared to control animals. Tissue damage marker enzymes- alkaline phosphatase, alanine and aspartate transaminases were significantly lowered in the treated groups in a dose dependant manner. The histopathological analyses of skin tissue also give the evidence of the increased healing potential of the extract after burn injury. PMID:18818737

  19. The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

    PubMed Central

    Dumnicka, Paulina; Maduzia, Dawid; Ceranowicz, Piotr; Olszanecki, Rafał; Drożdż, Ryszard; Kuśnierz-Cabala, Beata

    2017-01-01

    Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients. PMID:28208708

  20. Acute phase proteins increase with sarcoptic mange status and severity in Iberian ibex (Capra pyrenaica, Schinz 1838).

    PubMed

    Ráez-Bravo, Arián; Granados, José Enrique; Cerón, José Joaquín; Cano-Manuel, Francisco Javier; Fandos, Paulino; Pérez, Jesús María; Espinosa, José; Soriguer, Ramón Casimiro; López-Olvera, Jorge Ramón

    2015-11-01

    Sarcoptic mange is a contagious skin disease caused by Sarcoptes scabiei, affecting both domestic and wild mammals, including the Iberian ibex (Capra pyrenaica), a medium-sized mountain ungulate almost endemic to the Iberian Peninsula. Acute phase proteins (APPs) could be an indicator of sarcoptic mange disease and severity in Iberian ibex. Serum samples from 131 healthy and sarcoptic mange-affected Iberian ibexes were collected from 2005 to 2012 in Sierra Nevada Natural Space in southern Spain. Serum alpha-1-acid glycoprotein (AGP), serum amyloid A (SAA) and haptoglobin (Hp) concentrations were quantified, and statistically significant differences according to sarcoptic mange disease and severity were assessed. Both AGP and SAA were significantly higher in the sarcoptic mange-affected ibexes than in the healthy ones as well as in the severely affected ibexes as compared to those with less than 50 % of the body surface affected. For the first time, changes in APP are reported in relation to sarcoptic mange in Iberian ibex. It is also reported for the first time that the intensity of APP increase depends on the severity of sarcoptic mange, which could be related with the pathological secondary amyloidosis, leading to organ dysfunction in severely mange-affected animals. Species and population differences in the increase of APP in response to sarcoptic mange could indicate individual and population differences in the immune capability of each population to deal with mange, population prevalence and mortality being the last indicators of such sensitivity.

  1. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia.

    PubMed

    Konopleva, Marina; Pollyea, Daniel A; Potluri, Jalaja; Chyla, Brenda; Hogdal, Leah; Busman, Todd; McKeegan, Evelyn; Salem, Ahmed Hamed; Zhu, Ming; Ricker, Justin L; Blum, William; DiNardo, Courtney D; Kadia, Tapan; Dunbar, Martin; Kirby, Rachel; Falotico, Nancy; Leverson, Joel; Humerickhouse, Rod; Mabry, Mack; Stone, Richard; Kantarjian, Hagop; Letai, Anthony

    2016-10-01

    We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.

  2. A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure.

    PubMed

    Thepot, Sylvain; Boehrer, Simone; Seegers, Valérie; Prebet, Thomas; Beyne-Rauzy, Odile; Wattel, Eric; Delaunay, Jacques; Raffoux, Emmanuel; Hunault, Mathilde; Jourdan, Eric; Chermat, Fatiha; Sebert, Marie; Kroemer, Guido; Fenaux, Pierre; Adès, Lionel

    2014-12-01

    Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

  3. Challenge with lipopolysaccharides or Freund's adjuvant? What is the best option to trigger acute phase protein production in broilers?

    PubMed

    Koppenol, A; Everaert, N; Buyse, J; Delezie, E

    2015-04-01

    Broilers were injected at 10 days of age with either Escherichia coli lipopolysaccharides (LPS) or with Freund's adjuvants (FA) to investigate its triggering effect on the acute phase reaction (APR). First the kinetics of certain APP was studied by sampling blood 4 h, 8 h, 12 h and 24 h post injection with LPS. Ovotransferrin (OVT) and α-1 acid glycoprotein (AGP) concentration increased with time post injection (PI) with LPS to reach a plateau at 12 and 24 h PI. Caeruloplasmin (CP) did not increase with time PI. Compared to injection with phosphate buffered saline, OVT concentrations were higher when injecting chicks with LPS at all time points PI. At 24 h PI, LPS injection resulted in higher OVT and AGP concentration compared to injection with FA. It is recommended to use LPS instead of FA to trigger the APR. The best time point to sample blood for APP determination is 24 h PI.

  4. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia.

    PubMed

    Eghtedar, Alireza; Verstovsek, Srdan; Estrov, Zeev; Burger, Jan; Cortes, Jorge; Bivins, Carol; Faderl, Stefan; Ferrajoli, Alessandra; Borthakur, Gautam; George, Solly; Scherle, Peggy A; Newton, Robert C; Kantarjian, Hagop M; Ravandi, Farhad

    2012-05-17

    We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479.

  5. Ras gene product expression in blood and marrow smears of patients with acute leukemia: importance of fixation.

    PubMed

    Needleman, S W; Gutheil, J C; Kapil, V; Cimino, E F; Chana, G; Mane, S M

    1990-04-01

    Activation of ras protooncogenes by any of several possible mutations in codons 12, 13 or 61 has been demonstrated in a variety of human malignancies, including acute non-lymphoblastic leukemia (ANLL). In situ staining for the ras gene product, p21, has been demonstrated in carcinomas of several sites. High levels of p21 expression have been associated with histologic anaplasia in prostate cancer and regional lymph node metastasis in breast cancer. We examined 16 marrow aspirates and blood smears from patients with acute leukemia, predominantly ANLL, and eight controls. Marrow aspirates or blood were smeared on glass slides and fixed immediately in 10% buffered formalin. p21 was examined with avidin-biotin linked immunoperoxidase visualization. Particular attention must be paid to antibody selection and fixation protocol to demonstrate p21, owing to its rapid degradation ex vivo. Three of 16 patients exhibited occasional high p21 expression primarily in leukemic blasts, but in no case were more than 10% of blast cells positive. Normal reticuloendothelial and myeloid cells occasionally exhibited mild to moderately heavy staining, but megakaryocytes, erythroid precursors, lymphocytes and plasma cells were consistently negative. Most patients, 5 normal volunteers and 3 patients with non-malignant disease, exhibited no reactivity, or only a faint blush. These data suggest that while point mutation and concomitant activation of c-N-ras occurs regularly in ANLL, high levels of ras p21 expression are rarely found with this technique.

  6. Are Results of Targeted Gene Sequencing Ready to Be Used for Clinical Decision Making for Patients with Acute Myelogenous Leukemia?

    PubMed Central

    Rao, Arati V.; Smith, B. Douglas

    2013-01-01

    Acute Myeloid Leukemia (AML) is the most common acute leukemia in the US, which despite recent advances, continues to have a high mortality rate. It is a biologically active disease characterized by numerous cytogenetic abnormalities and multiple genetic mutations. Next-generation sequencing will perhaps not reveal all the factors that make AML a complex disease, but does have the potential to impact the diagnosis and risk-stratification of AML patients and allow for more personalized therapy. AML cells are easy to access from the patient and samples are only minimally contaminated with normal cells, which makes it an attractive cancer to study. Several studies have now demonstrated that the majority of AML patients are cytogenetically normal and the genome of these patients may contain fewer mutations than cancer genomes that are highly aneuploidy, suggesting that mutations in diploid genomes are more likely to be pathogenetically relevant. Whole-genome, exome, transcriptome, and targeted gene sequencing studies have been conducted successfully in AML and have provided us with valuable information. The challenges for the future include: reducing the cost of sequencing, understanding epigenetic changes, managing data across various platforms, separating the driver mutations from the sea of passenger mutations and finally, educating future generations to allow a better understanding and easy availability of these complex methodologies. PMID:23595294

  7. The acute impact of polyphenols from Hibiscus sabdariffa in metabolic homeostasis: an approach combining metabolomics and gene-expression analyses.

    PubMed

    Beltrán-Debón, Raúl; Rodríguez-Gallego, Esther; Fernández-Arroyo, Salvador; Senan-Campos, Oriol; Massucci, Francesco A; Hernández-Aguilera, Anna; Sales-Pardo, Marta; Guimerà, Roger; Camps, Jordi; Menendez, Javier A; Joven, Jorge

    2015-09-01

    We explored the acute multifunctional effects of polyphenols from Hibiscus sabdariffa in humans to assess possible consequences on the host's health. The expected dynamic response was studied using a combination of transcriptomics and metabolomics to integrate specific functional pathways through network-based methods and to generate hypotheses established by acute metabolic effects and/or modifications in the expression of relevant genes. Data were obtained from healthy male volunteers after 3 hours of ingestion of an aqueous Hibiscus sabdariffa extract. The data were compared with data obtained prior to the ingestion, and the overall findings suggest that these particular polyphenols had a simultaneous role in mitochondrial function, energy homeostasis and protection of the cardiovascular system. These findings suggest beneficial actions in inflammation, endothelial dysfunction, and oxidation, which are interrelated mechanisms. Among other effects, the activation of the heme oxygenase-biliverdin reductase axis, the systemic inhibition of the renin-angiotensin system, the inhibition of the angiotensin-converting enzyme, and several actions mirroring those of the peroxisome proliferator-activated receptor agonists further support this notion. We also found concordant findings in the serum of the participants, which include a decrease in cortisol levels and a significant increase in the active vasodilator metabolite of bradykinin (des-Arg(9)-bradykinin). Therefore, our data support the view that polyphenols from Hibiscus sabdariffa play a regulatory role in metabolic health and in the maintenance of blood pressure, thus implying a multi-faceted impact in metabolic and cardiovascular diseases.

  8. 16S rRNA gene-targeted TTGE in determining diversity of gut microbiota during acute diarrhoea and convalescence.

    PubMed

    Monira, Shirajum; Shabnam, Syeda Antara; Alam, Nur Haque; Endtz, Hubert Ph; Cravioto, Alejandro; Alam, Munirul

    2012-09-01

    The human gut microbiota play a vital role in health and nutrition but are greatly modified during severe diarrhoea due to purging and pathogenic colonization. To understand the extent of loss during and after diarrhoea, faecal samples collected from children (n=21) suffering from acute diarrhoea and from their healthy siblings (n=9) were analyzed by 16S rRNA gene-targeted universal primer polymerase chain reaction (PCR), followed by temporal temperature gradient gel electrophoresis (TTGE). The gut microbiota decreased significantly as indicated by the number of TTGE bands at day 0 of acute diarrhoea [patients vs healthy siblings: 11±0.9 vs 21.8±1.1 (mean ± standard error), p<0.01]. The number of bands showed a steady increase from day 1 to day 7; however, it remained significantly less than that in healthy siblings (15±0.9, p<0.01). These results suggest that appropriate therapeutic and post-diarrhoeal nutritional intervention might be beneficial for the early microbial restoration and recovery.

  9. 16S rRNA Gene-targeted TTGE in Determining Diversity of Gut Microbiota during Acute Diarrhoea and Convalescence

    PubMed Central

    Monira, Shirajum; Shabnam, Syeda Antara; Alam, Nur Haque; Endtz, Hubert Ph.; Cravioto, Alejandro

    2012-01-01

    The human gut microbiota play a vital role in health and nutrition but are greatly modified during severe diarrhoea due to purging and pathogenic colonization. To understand the extent of loss during and after diarrhoea, faecal samples collected from children (n=21) suffering from acute diarrhoea and from their healthy siblings (n=9) were analyzed by 16S rRNA gene-targeted universal primer polymerase chain reaction (PCR), followed by temporal temperature gradient gel electrophoresis (TTGE). The gut microbiota decreased significantly as indicated by the number of TTGE bands at day 0 of acute diarrhoea [patients vs healthy siblings: 11±0.9 vs 21.8±1.1 (mean±standard error), p<0.01]. The number of bands showed a steady increase from day 1 to day 7; however, it remained significantly less than that in healthy siblings (15±0.9, p<0.01). These results suggest that appropriate therapeutic and post-diarrhoeal nutritional intervention might be beneficial for the early microbial restoration and recovery. PMID:23082626

  10. Inflammatory Cytokine Gene Expression in Mesenteric Adipose Tissue during Acute Experimental Colitis

    PubMed Central

    Mustain, W. Conan; Starr, Marlene E.; Valentino, Joseph D.; Cohen, Donald A.; Okamura, Daiki; Wang, Chi; Evers, B. Mark; Saito, Hiroshi

    2013-01-01

    Background Production of inflammatory cytokines by mesenteric adipose tissue (MAT) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Animal models of colitis have demonstrated inflammatory changes within MAT, but it is unclear if these changes occur in isolation or as part of a systemic adipose tissue response. It is also unknown what cell types are responsible for cytokine production within MAT. The present study was designed to determine whether cytokine production by MAT during experimental colitis is depot-specific, and also to identify the source of cytokine production within MAT. Methods Experimental colitis was induced in 6-month-old C57BL/6 mice by administration of dextran sulfate sodium (2% in drinking water) for up to 5 days. The induction of cytokine mRNA within various adipose tissues, including mesenteric, epididymal, and subcutaneous, was analyzed by qRT-PCR. These adipose tissues were also examined for histological evidence of inflammation. The level of cytokine mRNA during acute colitis was compared between mature mesenteric adipocytes, mesenteric stromal vascular fraction (SVF), and mesenteric lymph nodes. Results During acute colitis, MAT exhibited an increased presence of infiltrating mononuclear cells and fibrotic structures, as well as decreased adipocyte size. The mRNA levels of TNF-α, IL-1β, and IL-6 were significantly increased in MAT but not other adipose tissue depots. Within the MAT, induction of these cytokines was observed mainly in the SVF. Conclusions Acute experimental colitis causes a strong site-specific inflammatory response within MAT, which is mediated by cells of the SVF, rather than mature adipocytes or mesenteric lymph nodes. PMID:24386254

  11. The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse.

    PubMed

    Ang, Abel D; Rivers-Auty, Jack; Hegde, Akhil; Ishii, Isao; Bhatia, Madhav

    2013-11-15

    Hydrogen sulfide (H2S) has been reported to be involved in the signaling of the inflammatory response; however, there are differing views as to whether it is pro- or anti-inflammatory. In this study, we sought to determine whether endogenously synthesized H2S via cystathionine-γ-lyase (CSE) plays a pro- or anti-inflammatory role in caerulein-induced pancreatitis. To investigate this, we used mice genetically deficient in CSE to elucidate the function of CSE in caerulein-induced acute pancreatitis. We compared the inflammatory response and tissue damage of wild-type (WT) and CSE knockout (KO) mice following 10 hourly administrations of 50 μg/kg caerulein or saline control. From this, we found that the CSE KO mice showed significantly less local pancreatic damage as well as acute pancreatitis-associated lung injury compared with the WT mice. There were also lower levels of pancreatic eicosanoid and cytokines, as well as reduced acinar cell NF-κB activation in the CSE KO mice compared with WT mice. Additionally, in WT mice, there was a greater level of pancreatic CSE expression and sulfide-synthesizing activity in caerulein-induced pancreatitis compared with the saline control. When comparing the two saline-treated control groups, we noted that the CSE KO mice showed significantly less pancreatic H2S-synthesizing activity relative to the WT mice. These results indicate that endogenous H2S generated by CSE plays a key proinflammatory role via NF-κB activation in caerulein-induced pancreatitis, and its genetic deletion affords significant protection against acute pancreatitis and associated lung injury.

  12. Genome-wide association study for acute otitis media in children identifies FNDC1 as disease contributing gene

    PubMed Central

    van Ingen, Gijs; Li, Jin; Goedegebure, André; Pandey, Rahul; Li, Yun Rose; March, Michael E.; Jaddoe, Vincent W. V.; Bakay, Marina; Mentch, Frank D.; Thomas, Kelly; Wei, Zhi; Chang, Xiao; Hain, Heather S.; Uitterlinden, André G.; Moll, Henriette A.; van Duijn, Cornelia M.; Rivadeneira, Fernando; Raat, Hein; Baatenburg de Jong, Robert J.; Sleiman, Patrick M.; van der Schroeff, Marc P.; Hakonarson, Hakon

    2016-01-01

    Acute otitis media (AOM) is among the most common pediatric diseases, and the most frequent reason for antibiotic treatment in children. Risk of AOM is dependent on environmental and host factors, as well as a significant genetic component. We identify genome-wide significance at a locus on 6q25.3 (rs2932989, Pmeta=2.15 × 10−09), and show that the associated variants are correlated with the methylation status of the FNDC1 gene (cg05678571, P=1.43 × 10−06), and further show it is an eQTL for FNDC1 (P=9.3 × 10−05). The mouse homologue, Fndc1, is expressed in middle ear tissue and its expression is upregulated upon lipopolysaccharide treatment. In this first GWAS of AOM and the largest OM genetic study to date, we identify the first genome-wide significant locus associated with AOM. PMID:27677580

  13. Hypomethylation of the CTGF gene locus is a common feature of paediatric pre-B acute lymphoblastic leukaemia.

    PubMed

    Welch, Mathew D; Greene, Wayne K; Kees, Ursula R

    2013-08-01

    The connective tissue growth factor gene (CTGF) is aberrantly expressed in 75% of precursor B-cell acute lymphoblastic leukaemias (pre-B ALL) and is associated with poor outcome. We identified consistent hypomethylation of the CTGF locus in primary pre-B ALL specimens regardless of CTGF expression. By contrast, primary T-cell ALL specimens, which do not express CTGF, exhibited distinctive patterns of hypermethylation. Furthermore, we confirmed that global changes in DNA methylation and histone acetylation can both functionally modulate CTGF expression in pre-B ALL cell lines. These data suggest that hypomethylation of the CTGF locus is an essential prerequisite for aberrant CTGF expression in pre-B ALL.

  14. Phase I Metabolic Genes and Risk of Lung Cancer: Multiple Polymorphisms and mRNA Expression

    PubMed Central

    Rotunno, Melissa; Yu, Kai; Lubin, Jay H.; Consonni, Dario; Pesatori, Angela C.; Goldstein, Alisa M.; Goldin, Lynn R.; Wacholder, Sholom; Burdette, Laurie; Chanock, Stephen J.; Bertazzi, Pier Alberto; Tucker, Margaret A.; Caporaso, Neil E.; Chatterjee, Nilanjan; Bergen, Andrew W.; Landi, Maria Teresa

    2009-01-01

    Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underling dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and

  15. Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia

    SciTech Connect

    Tholouli, Eleni; MacDermott, Sarah; Hoyland, Judith; Yin, John Liu; Byers, Richard

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Development of a quantitative high throughput in situ expression profiling method. Black-Right-Pointing-Pointer Application to a tissue microarray of 242 AML bone marrow samples. Black-Right-Pointing-Pointer Identification of HOXA4, HOXA9, Meis1 and DNMT3A as prognostic markers in AML. -- Abstract: Measurement and validation of microarray gene signatures in routine clinical samples is problematic and a rate limiting step in translational research. In order to facilitate measurement of microarray identified gene signatures in routine clinical tissue a novel method combining quantum dot based oligonucleotide in situ hybridisation (QD-ISH) and post-hybridisation spectral image analysis was used for multiplex in-situ transcript detection in archival bone marrow trephine samples from patients with acute myeloid leukaemia (AML). Tissue-microarrays were prepared into which white cell pellets were spiked as a standard. Tissue microarrays were made using routinely processed bone marrow trephines from 242 patients with AML. QD-ISH was performed for six candidate prognostic genes using triplex QD-ISH for DNMT1, DNMT3A, DNMT3B, and for HOXA4, HOXA9, Meis1. Scrambled oligonucleotides were used to correct for background staining followed by normalisation of expression against the expression values for the white cell pellet standard. Survival analysis demonstrated that low expression of HOXA4 was associated with poorer overall survival (p = 0.009), whilst high expression of HOXA9 (p < 0.0001), Meis1 (p = 0.005) and DNMT3A (p = 0.04) were associated with early treatment failure. These results demonstrate application of a standardised, quantitative multiplex QD-ISH method for identification of prognostic markers in formalin-fixed paraffin-embedded clinical samples, facilitating measurement of gene expression signatures in routine clinical samples.

  16. A Phase 1 Study of AMG 900, an Orally Administered Pan-Aurora Kinase Inhibitor, in Adult Patients With Acute Myeloid Leukemia.

    PubMed

    Kantarjian, Hagop M; Schuster, Michael W; Jain, Nitin; Advani, Anjali; Jabbour, Elias; Gamelin, Erick; Rasmussen, Erik; Juan, Gloria; Anderson, Abraham; Chow, Vincent F; Friberg, Greg; Vogl, Florian D; Sekeres, Mikkael A

    2017-03-28

    Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML. Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3+3 design were used: AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents. This article is protected by copyright. All rights reserved.

  17. An Acute-phase Protein as a Regulator of Sperm Survival in the Bovine Oviduct: Alpha 1-acid-glycoprotein Impairs Neutrophil Phagocytosis of Sperm In Vitro

    PubMed Central

    LIU, Jinghui; MAREY, Mohamed A.; KOWSAR, Rasoul; HAMBRUCH, Nina; SHIMIZU, Takashi; HANEDA, Shingo; MATSUI, Motozumi; SASAKI, Motoki; HAYAKAWA, Hiroyuki; PFARRER, Christiane; MIYAMOTO, Akio

    2014-01-01

    We have previously shown that polymorphonuclear neutrophils (PMNs) are present in bovine oviduct fluid under physiological conditions, and that the oviduct provides a microenvironment that protects sperm from phagocytosis by PMNs. Alpha 1-acid glycoprotein (AGP) is a major acute-phase protein produced mainly in the liver that has immunomodulatory functions. AGP mRNA is expressed in extrahepatic organs, such as the lung, kidney, spleen, lymph node, uterus, and ovary. Therefore, in this study, we investigated, 1) the local production of AGP in the bovine oviduct, 2) the effect of AGP on the phagocytic activity of PMNs for sperm and superoxide production and 3) the impact of AGP desialylation on the PMN phagocytosis of sperm. The AGP gene was expressed in cultured bovine oviduct epithelial cells (BOECs) and AGP protein was detected in oviduct fluid. Preexposure of PMNs to AGP at physiological levels impaired PMN phagocytosis for sperm and superoxide generation. The desialylation of AGP eliminated these suppressive effects of AGP on PMN. Scanning electron microscopy revealed that AGP drastically reduced the formation of DNA-based neutrophil extracellular traps (NETs) for sperm entanglement. Additionally, AGP dose-dependently stimulated BOECs to produce prostaglandin E2 (PGE2) which has been shown to partially contribute to the regulation of sperm phagocytosis in the bovine oviduct. AGP and PGE2 at concentrations detected in the oviducts additively suppressed sperm phagocytosis by PMNs. These results provide evidence that locally produced AGP may be involved in protecting sperm from phagocytosis by PMNs in the bovine oviduct. PMID:24931131

  18. The effect of acute dose charge particle radiation on expression of DNA repair genes in mice.

    PubMed

    Tariq, Muhammad Akram; Soedipe, Ayodotun; Ramesh, Govindarajan; Wu, Honglu; Zhang, Ye; Shishodia, Shishir; Gridley, Daila S; Pourmand, Nader; Jejelowo, Olufisayo

    2011-03-01

    The space radiation environment consists of trapped particle radiation, solar particle radiation, and galactic cosmic radiation (GCR), in which protons are the most abundant particle type. During missions to the moon or to Mars, the constant exposure to GCR and occasional exposure to particles emitted from solar particle events (SPE) are major health concerns for astronauts. Therefore, in order to determine health risks during space missions, an understanding of cellular responses to proton exposure is of primary importance. The expression of DNA repair genes in response to ionizing radiation (X-rays and gamma rays) has been studied, but data on DNA repair in response to protons is lacking. Using qPCR analysis, we investigated changes in gene expression induced by positively charged particles (protons) in four categories (0, 0.1, 1.0, and 2.0 Gy) in nine different DNA repair genes isolated from the testes of irradiated mice. DNA repair genes were selected on the basis of their known functions. These genes include ERCC1 (5' incision subunit, DNA strand break repair), ERCC2/NER (opening DNA around the damage, Nucleotide Excision Repair), XRCC1 (5' incision subunit, DNA strand break repair), XRCC3 (DNA break and cross-link repair), XPA (binds damaged DNA in preincision complex), XPC (damage recognition), ATA or ATM (activates checkpoint signaling upon double strand breaks), MLH1 (post-replicative DNA mismatch repair), and PARP1 (base excision repair). Our results demonstrate that ERCC1, PARP1, and XPA genes showed no change at 0.1 Gy radiation, up-regulation at 1.0 Gy radiation (1.09 fold, 7.32 fold, 0.75 fold, respectively), and a remarkable increase in gene expression at 2.0 Gy radiation (4.83 fold, 57.58 fold and 87.58 fold, respectively). Expression of other genes, including ATM and XRCC3, was unchanged at 0.1 and 1.0 Gy radiation but showed up-regulation at 2.0 Gy radiation (2.64 fold and 2.86 fold, respectively). We were unable to detect gene expression for the

  19. Association Between Cytokines and Their Receptor Antagonist Gene Polymorphisms and Clinical Risk Factors and Acute Rejection Following Renal Transplantation

    PubMed Central

    Ding, Siqing; Xie, Jianfei; Wan, Qiquan

    2016-01-01

    Background Acute rejection (AR) after renal transplantation affects both patient and graft survival. There is growing evidence of the genetic association between cytokine or its receptor antagonist and AR in solid organ transplantation. The objectives of this study were to investigate the role of recipient TNF β, IL-10, IL-1β, and IL-1 receptor antagonist (ra) gene polymorphism, as well as traditional clinical variables such as panel-reactive antibody (PRA) levels, donor type, and HLA mismatches in AR following renal transplantation. Material/Methods TNF β (+252A/G), IL-10 (−592A/C), IL-1β (−511C/T) and IL-1ra (86 bp VNTR) gene polymorphisms were determined in 195 renal allograft recipients with and without AR, using PCR. Both these genotypic variants and clinical risk factors were investigated for correlation with AR within the first year after renal transplantation. Results Patients with increased pre-transplant PRA levels (P<0.001) and donor type (P=0.012) were prone to the development of AR. After adjusting for all variables of P<0.2, a PRA level >10% (OR=4.515, 95% confidence intervals=1.738–11.727, P=0.002) and the receipt of a graft from a donation after cardiac death (DCD) donor (OR=2.437, 95% confidence intervals=1.047–5.673, P=0.039) remained significantly associated with AR in a multivariate logistic regression analysis. No correlation could be found between recipients