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  1. Effects of central imidazolinergic and alpha2-adrenergic activation on water intake

    Directory of Open Access Journals (Sweden)

    Sugawara A.M.

    2001-01-01

    Full Text Available Non-adrenergic ligands that bind to imidazoline receptors (I-R, a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol, mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol and UK 14304 (20 nmol inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol. The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand and imidazole-4-acetic acid (80 nmol, imidazoline ligand did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.

  2. [Antiviral activity of recombinant interferon-alpha-2b in combination with certain antioxidant].

    Science.gov (United States)

    Vasil'ev, A N; Deriabin, P G; Galegov, G A

    2011-01-01

    In vitro activity of interferon-alpha-2b in combination with various antioxidants against the influenza virus and Herpes simplex was studied. The standard strains and a clinical strain of Herpes simplex isolated from a patient with resistance to acyclovir were used. The in vitro studie showed that antioxidants, such as alpho-tocoferol acetate (vitamin E), Unithiol and ascorbic acid had a significant antiinfluenzae and antiherpetic action on the influenza virus A/H5N1 and Herpes simplex variants. They protected up to 100% of the cell monolayer from the virus cytopathic effect. The taurin solutions had no antiviral activity irrespective of the infection dose. Combinations of interferon-alpha-2b with alpha-tocopherol acetate (vitamin E), Unithiol or ascorbic acid showed a significant synergistic effect: the antiviral activity of interferon increased several times. The antiinfluenza activity of interferon-a-2b in the presence of various concentrations of taurin did not change.

  3. Alpha1 and Alpha2 Integrins Mediate Invasive Activity of Mouse Mammary Carcinoma Cells through Regulation of Stromelysin-1 Expression

    Energy Technology Data Exchange (ETDEWEB)

    Lochter, Andre; Navre, Marc; Werb, Zena; Bissell, Mina J

    1998-06-29

    Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits {alpha}6 and {beta}1, but not against {alpha}1 and {alpha}2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against {beta}1, but not against a6 or {alpha}2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against {alpha}1 integrins impaired only cell adhesion to type IV collagen. Antibodies against {alpha}1, {alpha}2, {alpha}6, and {beta}1, but not {alpha}5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins {alpha}1 and {alpha}2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against {alpha}1 and {alpha}2, but not {alpha}6 and {beta}1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-1. Inhibition of tumor cell invasion by antibodies against {alpha}1 and {alpha}2 was reversed by addition of recombinant stromelysin-1. In contrast, stromelysin-1 could not rescue invasion inhibited by anti-{alpha}6 antibodies. Our data indicate that {alpha}1 and {alpha}2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas {alpha}6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.

  4. Expression of biologically active human interferon alpha 2 in aloe vera

    Science.gov (United States)

    We have developed a system for transgenic expression of proteins in Aloe Vera. Using this approach we have generated plants expressing the human gene interferon alpha 2, IFNa2. IFNa2 is a small secreted cytokine that plays a vital role in regulating the body’s immune response to viral infections a...

  5. The effect of alpha2-adrenergic drugs on the activity of neurons in the rat nucleus raphe magnus in vitro.

    Science.gov (United States)

    Kanda, T; Ohta, Y; Kida, A; Kemmotsu, O

    1999-02-01

    The nucleus raphe magnus (NRM) is an important descending inhibitory system for pain transmission. We tested whether clonidine, an alpha2-adrenergic agonist, and yohimbine, an alpha2-adrenergic antagonist, modulate the activity of NRM neurons using extracellular recording in a rat brainstem slice preparation. Clonidine 1-20 microM increased firing frequencies (FF) in 22 (37%) and decreased FF in 6 (10%) spontaneously active neurons. Correlation between the concentrations of clonidine and FF changes was unremarkable. Eight spontaneously active neurons (13%) showed increases followed by decreases in FF with increasing doses of clonidine. The remaining 24 neurons (40%) showed no change in FF. Yohimbine 1 microM decreased FF in 38 spontaneously active neurons (58%), whereas the remaining 27 neurons (42%) showed no change in FF. In some neurons, yohimbine antagonized the increase or decrease in FF by application of clonidine. In three silent neurons (25%), clonidine (5 or 10 microM) induced firing activity, which stopped or decreased with the increasing doses of clonidine. In the remaining nine neurons (75%), clonidine did not induce firing activity. We conclude that activation and inhibition of alpha2-adrenergic receptors of NRM neurons augments and suppresses output of the descending inhibitory pain pathway. The nucleus raphe magnus is implicated in descending control of the nociceptive processes. We found that clonidine and yohimbine increased and decreased, respectively, the firing activity of a substantial number of nucleus raphe magnus neurons. Clonidine and may facilitate and yohimbine may reduce the outflow of the descending inhibitory pathway.

  6. Active MMPs captured by alpha2Macroglobulin as a marker of disease activity in rheumatoid arthritis

    NARCIS (Netherlands)

    Tchetverikov, I.; Verzijl, N.; Huizinga, T.W.J.; TeKoppele, J.M.; Hanemaaijer, R.; Groot, J. de

    2003-01-01

    Objective. The aim of the present study was to analyze α2Macroglobulin/MMP (α2M/MMP) complex formation and to investigate whether MMP activity in α2M/MMP complexes in serum can be used as a disease marker in rheumatoid arthritis (RA). Methods. High and low molecular weight (H/LMW) substrates and

  7. Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha

    DEFF Research Database (Denmark)

    Bergmeier, W; Bouvard, D; Eble, J A

    2001-01-01

    Although alpha(2)beta(1) integrin (glycoprotein Ia/IIa) has been established as a platelet collagen receptor, its role in collagen-induced platelet activation has been controversial. Recently, it has been demonstrated that rhodocytin (also termed aggretin), a snake venom toxin purified from...... the venom of Calloselasma rhodostoma, induces platelet activation that can be blocked by monoclonal antibodies against alpha(2)beta(1) integrin. This finding suggested that clustering of alpha(2)beta(1) integrin by rhodocytin is sufficient to induce platelet activation and led to the hypothesis...

  8. Adhesion and activation of human platelets induced by convulxin involve glycoprotein VI and integrin alpha2beta1.

    Science.gov (United States)

    Jandrot-Perrus, M; Lagrue, A H; Okuma, M; Bon, C

    1997-10-24

    We analyzed the interaction of convulxin (Cvx), a 72-kDa protein isolated from the venom of Crotalus durissus terrificus, with human platelets. Cvx is a potent platelet agonist that induces an increase in the intracellular Ca2+ concentration ([Ca2+]i), granule exocytosis and aggregation. 125I-Labeled Cvx binds specifically and rapidly to platelets at binding sites of high and moderate affinity. Platelets adhere to immobilized Cvx in a time-dependent but cation-independent manner. Platelet exocytosis and aggregation induced by Cvx were inhibited by an anti-integrin alpha2beta1 monoclonal antibody (6F1) and by the Fab fragments of a polyclonal anti-glycoprotein VI (GPVI) antibody. Both the adhesion of platelets to Cvx and the Cvx-induced increase in [Ca2+]i were inhibited by anti-GPVI Fab fragments but not by 6F1. Ligand blotting assay showed that 125I-Cvx binds to a 57-kDa platelet protein with an electrophoretic mobility identical to that of GPVI. In addition, we observed the following: (i) 125I-Cvx binds to GPVI immunoprecipitated by the anti-GPVI antibody from a platelet lysate, and (ii) Cvx inhibits the binding of anti-GPVI IgG to GPVI. Taken together, these results demonstrate that GPVI behaves as a Cvx receptor and that the alpha2beta1 integrin appears to be involved in the later stages of Cvx-induced platelet activation, i.e. exocytosis and aggregation.

  9. Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist.

    Science.gov (United States)

    Bagheri, H; Chale, J J; Guyen, L N; Tran, M A; Berlan, M; Montastruc, J L

    1995-01-01

    Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mg.kg-1, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mg.kg-1, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1 mg.kg-1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle

    DEFF Research Database (Denmark)

    Birk, Jesper Bratz; Wojtaszewski, Jørgen

    2006-01-01

    -Thr-172 AMPK phosphorylation (r2 = 0.84, P important actor in exercise-regulated AMPK signalling in human skeletal muscle, probably mediating phosphorylation of ACCß.......5'AMP-activated protein kinase (AMPK) is a key regulator of cellular metabolism and is regulated in muscle during exercise. We have previously established that only three of 12 possible AMPK a/ß/¿-heterotrimers are present in human skeletal muscle. Previous studies describe discrepancies between...... total AMPK activity and regulation of its target acetyl-CoA-carboxylase (ACC)ß. Also, exercise training decreases expression of the regulatory ¿3 AMPK subunit and attenuates a2 AMPK activity during exercise. We hypothesize that these observations reflect a differential regulation of the AMPK...

  11. Expression and functional importance of collagen-binding integrins, alpha 1 beta 1 and alpha 2 beta 1, on virus-activated T cells

    DEFF Research Database (Denmark)

    Andreasen, Susanne Ø; Thomsen, Allan R; Koteliansky, Victor E

    2003-01-01

    decreased responses were seen upon transfer of alpha(1)-deficient activated/memory T cells. Thus, expression of alpha(1)beta(1) and alpha(2)beta(1) integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect......Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, alpha(1)beta(1) and alpha(2)beta(1), on activated and memory T cells. Using...... this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of alpha(1)beta(1) and alpha(2)beta(1) can be rapidly induced on acutely activated T cells, that expression of alpha(1)beta(1) remains elevated on memory T cells, and that expression of alpha(1...

  12. The Na,K-ATPase alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice.

    Science.gov (United States)

    Moseley, Amy E; Lieske, Steve P; Wetzel, Randall K; James, Paul F; He, Suiwen; Shelly, Daniel A; Paul, Richard J; Boivin, Gregory P; Witte, David P; Ramirez, Jan Marino; Sweadner, Kathleen J; Lingrel, Jerry B

    2003-02-14

    Na,K-ATPase is an ion transporter that impacts neural and glial physiology by direct electrogenic activity and the modulation of ion gradients. Its three isoforms in brain have cell-type and development-specific expression patterns. Interestingly, our studies demonstrate that in late gestation, the alpha2 isoform is widely expressed in neurons, unlike in the adult brain, in which alpha2 has been shown to be expressed primarily in astrocytes. This unexpected distribution of alpha2 isoform expression in neurons is interesting in light of our examination of mice lacking the alpha2 isoform which fail to survive after birth. These animals showed no movement; however, defects in gross brain development, muscle contractility, neuromuscular transmission, and lung development were ruled out. Akinesia suggests a primary neuronal defect and electrophysiological recordings in the pre-Bötzinger complex, the brainstem breathing center, showed reduction of respiratory rhythm activity, with less regular and smaller population bursts. These data demonstrate that the Na,K-ATPase alpha2 isoform could be important in the modulation of neuronal activity in the neonate.

  13. Whole blood assay for NK activity in splenectomized and non-splenectomized hairy cell leukemia patients during IFN-alpha-2b treatment

    DEFF Research Database (Denmark)

    Nielsen, B; Hokland, P; Ellegaard, J

    1989-01-01

    Natural killer cell (NK) activity in peripheral blood (PB) was followed longitudinally for up to 2 yr after initiation of low-dose IFN-alpha-2b therapy in nine hairy cell leukemia (HCL) patients. A whole blood NK (WB-NK) assay was employed in order to measure the NK activity per unit blood. The p...

  14. Imidazoline2 (I2) receptor- and alpha2-adrenoceptor-mediated modulation of hypothalamic-pituitary-adrenal axis activity in control and acute restraint stressed rats.

    Science.gov (United States)

    Finn, David P; Hudson, Alan L; Kinoshita, Hiroshi; Coventry, Toni L; Jessop, David S; Nutt, David J; Harbuz, Michael S

    2004-03-01

    Central noradrenaline regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. alpha2-adrenoceptors and imidazoline2 (I2) receptors modulate the activity of the central noradrenergic system. The present set of experiments investigated the role of alpha2-adrenoceptors and I2 receptors in the regulation of HPA axis activity under basal conditions and during exposure to the acute psychological stress of restraint. Three separate experiments were carried out in which rats were given an i.p. injection of either saline vehicle, the combined alpha2-adrenoceptor antagonist and I2 receptor ligand idazoxan (10 mg/kg), the selective I2 receptor ligand BU224 (2.5 or 10 mg/kg) or the selective alpha2-adrenoceptor antagonist RX821002 (2.5 mg/kg) with or without restraint stress. Drugs were administered immediately prior to restraint of 60 min duration. Blood was sampled pre-injection, 30, 60 and 240 min post-injection and plasma corticosterone was measured by radioimmunoassay. In experiment 1, idazoxan increased plasma corticosterone levels in naive animals and potentiated the corticosterone response to acute restraint stress. In experiment 2, BU224 administration increased plasma corticosterone levels in a dose-related manner in naive rats. The results of experiment 3 indicated that RX821002 also elevated plasma corticosterone levels in naive rats, however, only BU224 potentiated the corticosterone response to restraint stress. These studies suggest that both alpha2-adrenoceptors and I2 receptors play a role in modulating basal HPA axis activity and that I2 receptors may play a more important role than alpha2-adrenoceptors in modulating the HPA axis response to the acute psychological stress of restraint.

  15. Alpha-2 adrenergic activity of bromocriptine and quinpirole in chicken pineal gland. Effects on melatonin synthesis and [3H]rauwolscine binding

    International Nuclear Information System (INIS)

    Zawilska, J.; Iuvone, P.M.

    1990-01-01

    In the pineal gland and retina of chickens, serotonin N-acetyl-transferase (NAT) activity and melatonin content are modulated by different receptors, alpha-2 adrenergic receptors in pineal gland and D2-dopamine receptors in retina. The effect of two D2-dopamine receptor agonists, bromocriptine and quinpirole (LY 171555), on melatonin synthesis in these tissues was investigated. Systemic administrations of bromocriptine and quinpirole decreased nocturnal NAT activity and melatonin content of both pineal gland and retina. Bromocriptine was equipotent in the two tissues, whereas quinpirole was approximately 100-fold more potent in retina than in pineal gland. In pineal gland, the suppressive effects of bromocriptine and quinpirole on NAT activity were blocked by yohimbine, a selective alpha-2 adrenergic receptor antagonist, but not by spiperone, a D2-dopamine receptor antagonist. In contrast, bromocriptine- and quinpirole-induced decreases of the enzyme activity in retina were antagonized by spiperone, and not affected by yohimbine. The nocturnal increase of NAT activity of pineal glands in vitro was inhibited with an order of potency clonidine greater than bromocriptine greater than quinpirole. Additionally, bromocriptine and quinpirole displaced the specific binding of [3H]rauwolscine, an alpha-2 adrenergic receptor antagonist, to membranes from chicken pineal gland, with potencies comparable to those observed for inhibition of NAT activity in vitro. It is suggested that bromocriptine and quinpirole, in addition to their D2-dopaminergic activity, can stimulate alpha-2 adrenergic receptors in pineal gland of chicken

  16. New ALPHA-2 magnet

    CERN Multimedia

    Anaïs Schaeffer

    2012-01-01

    On 21 June, members of the ALPHA collaboration celebrated the handover of the first solenoid designed for the ALPHA-2 experiment. The magnet has since been successfully installed and is working well.   Khalid Mansoor, Sumera Yamin and Jeffrey Hangst in front of the new ALPHA-2 solenoid. “This was the first of three identical solenoids that will be installed between now and September, as the rest of the ALPHA-2 device is installed and commissioned,” explains ALPHA spokesperson Jeffrey Hangst. “These magnets are designed to allow us to transfer particles - antiprotons, electrons and positrons - between various parts of the new ALPHA-2 device by controlling the transverse size of the particle bunch that is being transferred.” Sumera Yamin and Khalid Mansoor, two Pakistani scientists from the National Centre for Physics in Islamabad, came to CERN in February specifically to design and manufacture these magnets. “We had the chance to work on act...

  17. Chemical stimulation of the ST36 acupoint reduces both formalin-induced nociceptive behaviors and spinal astrocyte activation via spinal alpha-2 adrenoceptors.

    Science.gov (United States)

    Kang, Suk-Yun; Kim, Chi-Young; Roh, Dae-Hyun; Yoon, Seo-Yeon; Park, Ji-Ho; Lee, Hye-Jung; Beitz, Alvin J; Lee, Jang-Hern

    2011-11-25

    Spinal astrocytes have emerged as important mechanistic contributors to pathological and chronic pain. Recently, we have demonstrated that injection of diluted bee venom (DBV) into the Zusanli (ST36) acupoint produces a potent anti-nociceptive effect via the activation of spinal alpha-2 adrenoceptors. However, it is unclear if this anti-nociceptive effect is associated with alterations in spinal astrocytes. Thus, the present study was designed to determine: (1) whether DBV's anti-nociceptive effect in the formalin test involves suppression of spinal astrocyte activation; (2) whether DBV-induced astrocyte inhibition is mediated by spinal alpha-2 adrenoceptors; and (3) whether this glial modulation is potentiated by intrathecal administration of the glial metabolic inhibitor, fluorocitrate (FC) in combination with DBV injection. DBV was injected directly into the ST36 acupoint, and spinal expression of the astrocytic marker, glial fibrillary acidic protein (GFAP), was assessed together with effects on formalin-induced nociception. DBV treatment reduced pain responses in the late phase of the formalin test and significantly blocked the formalin-evoked increase in spinal GFAP expression. These effects of DBV were prevented by intrathecal pretreatment with selective alpha-2A and alpha-2C adrenoceptor antagonists. Moreover, low dose intrathecal injection of FC in conjunction with low dose DBV injection into the ST36 acupoint synergistically suppressed pain responses and GFAP expression. These results demonstrate that DBV stimulation of the ST36 acupoint inhibits the formalin-induced activation of spinal astrocytes and nociceptive behaviors in this inflammatory pain model and this inhibition is associated with the activation of spinal alpha-2 adrenoceptors. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. ALPHA-2: the sequel

    CERN Multimedia

    Katarina Anthony

    2012-01-01

    While many experiments are methodically planning for intense works over the long shutdown, there is one experiment that is already working at full steam: ALPHA-2. Its final components arrived last month and will completely replace the previous ALPHA set-up. Unlike its predecessor, this next generation experiment has been specifically designed to measure the properties of antimatter.   The ALPHA team lower the new superconducting solenoid magnet into place. The ALPHA collaboration is working at full speed to complete the ALPHA-2 set-up for mid-November – this will give them a few weeks of running before the AD shutdown on 17 December. “We really want to get some experience with this device this year so that, if we need to make any changes, we will have time during the long shutdown in which to make them,” says Jeffrey Hangst, ALPHA spokesperson. “Rather than starting the 2014 run in the commissioning stage, we will be up and running from the get go.&...

  19. The alpha(2)-adrenoceptors do not modify the activity of tyrosine hydroxylase, corticoliberine, and neuropeptide Y producing hypothalamic magnocellular neurons ion the Long Evans and Brattleboro rats

    DEFF Research Database (Denmark)

    Bundzikova, J; Pirnik, Z; Zelena, D

    2010-01-01

    The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei are activated by body salt-fluid variations. Stimulation of alpha(2)-adrenoceptors by an agonist-xylazine (XYL) activates oxytocinergic but not vasopressinergic magnocellular neurons. In this study, tyrosine hydroxylase (TH...... sections of 30 mum thickness double immunolabeled with Fos/neuropeptide were evaluated under light microscope. Under basal conditions, di/di in comparison with control Long Evans rats, displayed significantly higher number of TH, CRH, and NPY immunoreactive neurons in the SON and PVN (except NPY cells...

  20. A telecare programme for self-management of COPD exacerbations and promotion of an active lifestyle

    NARCIS (Netherlands)

    Tabak, Monique; Brusse-Keizer, Marjolein; Ommeren, Clara; Kotte, Hayke; Weltevreden, Paul; Hermens, Hermanus J.; Vollenbroek-Hutten, Miriam Marie Rosé

    2013-01-01

    Objective: The Condition Coach (CoCo) is a technology-supported care programme for self-management of COPD exacerbations and for promotion of an active lifestyle. The objective is to investigate the added value of the telecare programme in terms of clinical changes compared to usual care, and in

  1. Computer-Assisted Determination of Minimum Energy Conformations. 7. A pharmacophore Model of the Active Region of the Alpha2-Adrenoceptor.

    Science.gov (United States)

    1992-09-01

    helpful discussions on the adrenergic system; Fu-Lian Hsu, Research Directorate, CRDEC, for his advice on synthesis and chemical interactions; Duane...Miller and Yoshiya Amomiya, Ohio State University, Columbus, OH, for their assistance in the synthesis of suggested alpha2- adrenergic compounds...Preferred Conformations of Ephedrine Isomers and the Nature of the Alpha Adrenergic Receptor," J. Pharmacol. Exp. Ther. Vol. 164 (1), pp 75-81 (1968). 24

  2. Role of alpha1- and alpha2-adrenoceptors in the regulation of locomotion and spatial behavior in the active place avoidance task: A dose–response study

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš; Valeš, Karel

    2008-01-01

    Roč. 433, č. 3 (2008), s. 235-240 ISSN 0304-3940 R&D Projects: GA ČR(CZ) GA309/07/0341; GA MZd(CZ) NR9178; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : alpha1- alpha2 adrenoceptors * avoidance * memory Subject RIV: FH - Neurology Impact factor: 2.200, year: 2008

  3. Alternaria-derived serine protease activity drives IL-33–mediated asthma exacerbations

    Science.gov (United States)

    Snelgrove, Robert J.; Gregory, Lisa G.; Peiró, Teresa; Akthar, Samia; Campbell, Gaynor A.; Walker, Simone A.; Lloyd, Clare M.

    2014-01-01

    Background The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear. Objective We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation. Methods IL-33 levels were quantified in wild-type and ST2−/− mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later. Results Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease–IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model. Conclusion Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease. PMID:24636086

  4. Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations.

    Science.gov (United States)

    Snelgrove, Robert J; Gregory, Lisa G; Peiró, Teresa; Akthar, Samia; Campbell, Gaynor A; Walker, Simone A; Lloyd, Clare M

    2014-09-01

    The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear. We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation. IL-33 levels were quantified in wild-type and ST2(-/-) mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later. Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease-IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model. Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria.

    Science.gov (United States)

    Morissette, Mathieu C; Shen, Pamela; Thayaparan, Danya; Stämpfli, Martin R

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)γ activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARγ may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection. Copyright ©ERS 2015.

  6. The interplay between neuroendocrine activity and psychological stress-induced exacerbation of allergic asthma.

    Science.gov (United States)

    Miyasaka, Tomomitsu; Dobashi-Okuyama, Kaori; Takahashi, Tomoko; Takayanagi, Motoaki; Ohno, Isao

    2018-01-01

    Psychological stress is recognized as a key factor in the exacerbation of allergic asthma, whereby brain responses to stress act as immunomodulators for asthma. In particular, stress-induced enhanced type 2 T-helper (Th2)-type lung inflammation is strongly associated with asthma pathogenesis. Psychological stress leads to eosinophilic airway inflammation through activation of the hypothalamic-pituitary-adrenal pathway and autonomic nervous system. This is followed by the secretion of stress hormones into the blood, including glucocorticoids, epinephrine, and norepinephrine, which enhance Th2 and type 17 T-helper (Th17)-type asthma profiles in humans and rodents. Recent evidence has shown that a defect of the μ-opioid receptor in the brain along with a defect of the peripheral glucocorticoid receptor signaling completely disrupted stress-induced airway inflammation in mice. This suggests that the stress response facilitates events in the central nervous and endocrine systems, thus exacerbating asthma. In this review, we outline the recent findings on the interplay between stress and neuroendocrine activities followed by stress-induced enhanced Th2 and Th17 immune responses and attenuated regulatory T (Treg) cell responses that are closely linked with asthma exacerbation. We will place a special focus on our own data that has emphasized the continuity from central sensing of psychological stress to enhanced eosinophilic airway inflammation. The mechanism that modulates psychological stress-induced exacerbation of allergic asthma through neuroendocrine activities is thought to involve a series of consecutive pathological events from the brain to the lung, which implies there to be a "neuropsychiatry phenotype" in asthma. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  7. Elevated levels of serum alpha(2) macroglobulin in wild black bears during hibernation.

    Science.gov (United States)

    Sheikh, Ashfaq M; Chauhan, Ved; Tsiouris, John A; Mehta, Pankaj D; Burguess, Kelcey; Fenko, Michael D; Spivack, Warren; Vaughan, Michael; Malik, Mazhar

    2003-10-01

    Bear serum alpha(2) macroglobulin (alpha(2)M) was purified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and partially characterized by tryptic digestion of alpha(2)M and analysis of the peptides by peptide mass fingerprinting. The molecular weight of bear serum alpha(2)M was 181 kDa, same as for human serum alpha(2)M, on SDS-PAGE. However, the MALDI mass spectrum of the tryptic digested bear serum alpha(2)M showed that it is different from human alpha(2)M or other data bank proteins. Liquid chromatography (LC)/mass spectrometry (MS)/MS of the proteolytic products of bear serum alpha(2)M showed eight peptides that had similarities to human alpha(2)M suggesting that the protein of interest was indeed alpha(2)M of bear. The polyclonal antibody against bear serum alpha(2)M recognized only one protein from the western blot of bear serum proteins. It also recognized human alpha(2)M. The levels of serum alpha(2)M were significantly increased during hibernating state as compared to active state of bears indicating its protective role from the consequences of the metabolic depression during hibernation.

  8. Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity

    International Nuclear Information System (INIS)

    Qin Xujun; Hudson, Laurie G.; Liu Wenlan; Timmins, Graham S.; Liu Kejian

    2008-01-01

    Epidemiological studies have associated arsenic exposure with many types of human cancers. Arsenic has also been shown to act as a co-carcinogen even at low concentrations. However, the precise mechanism of its co-carcinogenic action is unknown. Recent studies indicate that arsenic can interfere with DNA-repair processes. Poly(ADP-ribose) polymerase (PARP)-1 is a zinc-finger DNA-repair protein, which can promptly sense DNA strand breaks and initiate DNA-repair pathways. In the present study, we tested the hypothesis that low concentrations of arsenic could inhibit PAPR-1 activity and so exacerbate levels of ultraviolet radiation (UVR)-induced DNA strand breaks. HaCat cells were treated with arsenite and/or UVR, and then DNA strand breaks were assessed by comet assay. Low concentrations of arsenite (≤ 2 μM) alone did not induce significant DNA strand breaks, but greatly enhanced the DNA strand breaks induced by UVR. Further studies showed that 2 μM arsenite effectively inhibited PARP-1 activity. Zinc supplementation of arsenite-treated cells restored PARP-1 activity and significantly diminished the exacerbating effect of arsenite on UVR-induced DNA strand breaks. Importantly, neither arsenite treatment, nor zinc supplementation changed UVR-triggered reactive oxygen species (ROS) formation, suggesting that their effects upon UVR-induced DNA strand breaks are not through a direct free radical mechanism. Combination treatments of arsenite with PARP-1 inhibitor 3-aminobenzamide or PARP-1 siRNA demonstrate that PARP-1 is the target of arsenite. Together, these findings show that arsenite at low concentration exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity, which may represent an important mechanism underlying the co-carcinogenicity of arsenic

  9. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

    Directory of Open Access Journals (Sweden)

    Jeffrey B Eells

    Full Text Available Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%, genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/- mice and wild-type (+/+ mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  10. Noradrenergic lesion of the locus coeruleus increases the firing activity of the medial prefrontal cortex pyramidal neurons and the role of alpha2-adrenoceptors in normal and medial forebrain bundle lesioned rats.

    Science.gov (United States)

    Wang, Yong; Zhang, Qiao Jun; Liu, Jian; Ali, Umar; Gui, Zhen Hua; Hui, Yan Ping; Wang, Tao; Chen, Li; Li, Qiang

    2010-04-09

    Degeneration of noradrenergic neurons in the locus coeruleus (LC) and dysfunction of the prefrontal cortex were regarded as playing a specific role in the occurrence of non-motor symptoms in Parkinson's disease. The present study examined the spontaneous firing rate and firing pattern of medial prefrontal cortex (mPFC) pyramidal neurons, and effects of alpha(2)-adrenoceptor agonist UK-14,304 and antagonist yohimbine on the neuronal activity in rats with 6-hydroxydopamine lesions of the LC, medial forebrain bundle (MFB) and with combined MFB and LC lesions. The firing rate of mPFC pyramidal neurons in rats with lesions of the LC and with combine LC and MFB lesions is significantly higher than that of normal and MFB-lesioned rats and the firing pattern of these neurons in rats with lesions of the LC and with combine LC and MFB lesions also changed significantly towards more regular compared with normal and MFB-lesioned rats. The local administration of UK-14,304 in the mPFC inhibited the firing activity of the pyramidal neurons in normal rats and rats with lesions of the LC, MFB and with combined LC and MFB lesions, while yohimbine increased the firing activity of the pyramidal neurons. These results indicate that the lesions of the LC lead to hyperactivity of mPFC pyramidal neurons in normal and MFB-lesioned rats, and the postsynaptic alpha(2)-adrenoceptors may partially mediate the inhibitory effects of LC-noradrenergic system on the firing activity of pyramidal neurons in the mPFC, suggesting that LC-noradrenergic system plays an important role in the functional disorders of mPFC in Parkinson's disease. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  11. Higher skeletal muscle alpha2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise

    DEFF Research Database (Denmark)

    Roepstorff, Carsten; Thiele, Maja; Hillig, Thore

    2006-01-01

    5'AMP-activated protein kinase (AMPK) is an energy sensor activated by perturbed cellular energy status such as during muscle contraction. Activated AMPK is thought to regulate several key metabolic pathways. We used sex comparison to investigate whether AMPK signalling in skeletal muscle regulat...... fat oxidation during exercise....

  12. Biological activity of rainbow trout Ea4-peptide of the pro-insulin-like growth factor (pro-IGF)-I on promoting attachment of breast cancer cells (MDA-MB-231) via alpha2- and beta1-integrin.

    Science.gov (United States)

    Siri, Sineenat; Chen, Maria J; Chen, Thomas T

    2006-12-15

    E-peptide of pro-IGF-I was considered as biologically inactive. We have demonstrated that rainbow trout (rt) Ea4-peptide exerted biological activities in several established tumor cell lines [Chen et al., 2002; Kuo and Chen, 2002]. Here we report the activity of rtEa4-peptide in promoting attachment of human breast cancer cells (MDA-MB-231). While rtEa2-, rtEa3-, and rtEa4-peptides enhanced the attachment of MDA-MB-231 cells in a dose dependent manner, rtEa4-peptide possessed the highest activity. Antibodies specific to alpha2 and beta1 integrins significantly inhibited the attachment of cells to rtEa4-peptide coated-plates by 40%. In addition, rtEa4-peptide induced the expression of fibronectin 1 and laminin receptor genes in MDA-MB-231 cells. Blocking new protein synthesis by cycloheximide significantly reduced the attachment of MDA-MB-231 cells to rtEa4-peptide coated wells by 50%. These results suggest that rtEa4-peptide may promote cell attachment by interacting with alpha2/beta1 integrin receptors at the cell surface and by inducing the expression of fibronectin 1 and laminin receptor genes. Expression of fibronectin 1 gene induced by rtEa4-peptide in MDA-MB-231 cells was abolished by inhibitors of PI3K, PKC, Mek1/2, JNK1/2, and p38 MAPK signaling transduction molecules. These results suggested that induction of fibronectin 1 gene expression in MDA-MB-231 cells by rtEa4-peptide may be mediated via PI3K, PKC, Mek1/2, JNK1/2, and p38 MAPK signal transduction molecules. (c) 2006 Wiley-Liss, Inc.

  13. Decreased spontaneous activity in AMPK alpha 2 muscle specific kinase dead mice is not caused by changes in brain dopamine metabolism

    DEFF Research Database (Denmark)

    Møller, Lisbeth Liliendal Valbjørn; Sylow, Lykke; Gøtzsche, Casper René

    2016-01-01

    It is well known that physical activity has several health benefits, yet many people do not exercise. Dopamine levels in the striatum of the brain are thought to be important for the motivation to exercise. Conversely, we hypothesized that muscle quality can affect the motivation to exercise...... DOPAC and HVA were also similar between genotypes. These findings show that decreased AMPK activity in muscle leads to decreased voluntary activity which is not due to secondary abnormalities in dopamine levels in the ventral striatum or sensitivity to cocaine. Thus, decreased voluntary activity in AMPK...

  14. Fast form alpha-2-macroglobulin

    DEFF Research Database (Denmark)

    Biltoft, Daniel; Gram, Jørgen Brodersen; Larsen, Anette

    2017-01-01

    in vitro. Methods: A F-α2M specific monoclonal antibody was generated and applied in an ELISA setup. Using the F-α2M ELISA, we investigated activation of calcium dependent and in-dependent proteases by polyvinylchloride (n=10), polytetrafluoroethylene (n=10) and silicone (n=10) tubings as well as glass...

  15. Fast form alpha-2-macroglobulin

    DEFF Research Database (Denmark)

    Biltoft, Daniel; Gram, Jørgen Brodersen; Larsen, Anette

    2017-01-01

    . In this study, we investigated whether an enzyme-linked immunosorbent assay (ELISA), that specifically measures the electrophoretic "fast form" of α2-macroglobulin (F-α2M), could be a sensitive and global marker for activation of calcium dependent and in-dependent proteases in plasma exposed to biomaterials...

  16. Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.

    Science.gov (United States)

    Hill, Timothy M; Gilchuk, Pavlo; Cicek, Basak B; Osina, Maria A; Boyd, Kelli L; Durrant, Douglas M; Metzger, Dennis W; Khanna, Kamal M; Joyce, Sebastian

    2015-06-01

    The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.

  17. NMDAR-Mediated Hippocampal Neuronal Death is Exacerbated by Activities of ASIC1a

    Science.gov (United States)

    Gao, Su; Yu, Yang; Ma, Zhi-Yuan; Sun, Hui; Zhang, Yong-Li; Wang, Xing-Tao; Wang, Chaoyun; Fan, Wei-Ming; Zheng, Qing-Yin

    2015-01-01

    NMDARs and ASIC1a both exist in central synapses and mediate important physiological and pathological conditions, but the functional relationship between them is unclear. Here we report several novel findings that may shed light on the functional relationship between these two ion channels in the excitatory postsynaptic membrane of mouse hippocampus. Firstly, NMDAR activation induced by either NMDA or OGD led to increased [Ca2+]i and greater apoptotic and necrotic cell deaths in cultured hippocampal neurons; these cell deaths were prevented by application of NMDAR antagonists. Secondly, ASIC1a activation induced by pH 6.0 extracellular solution (ECS) showed similar increases in apoptotic and necrotic cell deaths; these cell deaths were prevented by ASIC1a antagonists, and also by NMDAR antagonists. Since increased [Ca2+]i leads to increased cell deaths and since NMDAR exhibits much greater calcium permeability than ASIC1a, these data suggest that ASIC1a-induced neuronal death is mediated through activation of NMDARs. Thirdly, treatment of hippocampal cultures with both NMDA and acidic ECS induced greater degrees of cell deaths than either NMDA or acidic ECS treatment alone. These results suggest that ASIC1a activation up-regulates NMDAR function. Additional data supporting the functional relationship between ASIC1a and NMDAR are found in our electrophysiology experiments in hippocampal slices, where stimulation of ASIC1a induced a marked increase in NMDAR EPSC amplitude, and inhibition of ASIC1a resulted in a decrease in NMDAR EPSC amplitude. In summary, we present evidence that ASIC1a activity facilitates NMDAR function and exacerbates NMDAR-mediated neuronal death in pathological conditions. These findings are invaluable to the search for novel therapeutic targets in the treatment of brain ischemia. PMID:25947342

  18. Activation of TRPV1-dependent calcium oscillation exacerbates seawater inhalation-induced acute lung injury.

    Science.gov (United States)

    Li, Congcong; Bo, Liyan; Liu, Qingqing; Liu, Wei; Chen, Xiangjun; Xu, Dunquan; Jin, Faguang

    2016-03-01

    Calcium is an important second messenger and it is widely recognized that acute lung injury (ALI) is often caused by oscillations of cytosolic free Ca2+. Previous studies have indicated that the activation of transient receptor potential‑vanilloid (TRPV) channels and subsequent Ca2+ entry initiates an acute calcium‑dependent permeability increase during ALI. However, whether seawater exposure induces such an effect through the activation of TRPV channels remains unknown. In the current study, the effect of calcium, a component of seawater, on the inflammatory reactions that occur during seawater drowning‑induced ALI, was examined. The results demonstrated that a high concentration of calcium ions in seawater increased lung tissue myeloperoxidase activity and the secretion of inflammatory mediators, such as tumor necrosis factor‑α (TNF‑α) and interleukin (IL)‑1β and IL‑6. Further study demonstrated that the seawater challenge elevated cytosolic Ca2+ concentration, indicated by [Ca2+]c, by inducing calcium influx from the extracellular medium via TRPV1 channels. The elevated [Ca2+c] may have resulted in the increased release of TNF‑α and IL‑1β via increased phosphorylation of nuclear factor‑κB (NF‑κB). It was concluded that a high concentration of calcium in seawater exacerbated lung injury, and TRPV1 channels were notable mediators of the calcium increase initiated by the seawater challenge. Calcium influx through TRPV1 may have led to greater phosphorylation of NF‑κB and increased release of TNF‑α and IL‑1β.

  19. PSA-alpha-2-macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones.

    Science.gov (United States)

    Kostova, Maya B; Brennen, William Nathaniel; Lopez, David; Anthony, Lizamma; Wang, Hao; Platz, Elizabeth; Denmeade, Samuel R

    2018-04-16

    Prostate cancer cells produce high levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the tumor microenvironment but is presumed to be enzymatically inactive in the blood due to complex formation with serum protease inhibitors α-1-antichymotrypsin and α-2-macroglobulin (A2M). PSA-A2M complexes cannot be measured by standard ELISA assays and are also rapidly cleared from the circulation. Thus the exact magnitude of PSA production by prostate cancer cells is not easily measured. The PSA complexed to A2M is unable to cleave proteins but maintains the ability to cleave small peptide substrates. Thus, in advanced prostate cancer, sufficient PSA-A2M may be in circulation to effect total A2M levels, levels of cytokines bound to A2M and hydrolyze small circulating peptide hormones. Total A2M levels in men with advanced prostate cancer and PSA levels above 1000 ng/mL were measured by ELISA and compared to controls. Additional ELISA assays were used to measure levels of IL-6 and TGF-beta which can bind to A2M. The ability of PSA-A2M complexes to hydrolyze protein and peptide substrates was analyzed ± PSA inhibitor. Enzymatic activity of PSA-A2M in serum of men with high PSA levels was also assayed. Serum A2M levels are inversely correlated with PSA levels in men with advanced prostate cancer. Il-6 Levels are significantly elevated in men with PSA >1000 ng/mL compared to controls with PSA PSA-A2M complex in serum of men with PSA levels >1000 ng/mL can hydrolyze small fluorescently labeled peptide substrates but not large proteins that are PSA substrates. PSA can hydrolyze small peptide hormones like PTHrP and osteocalcin. PSA complexed to A2M retains the ability to degrade PTHrP. In advanced prostate cancer with PSA levels >1000 ng/mL, sufficient PSA-A2M is present in circulation to produce enzymatic activity against circulating small peptide hormones. Sufficient PSA is produced in advanced prostate cancer to alter

  20. Primary structure of human alpha 2-macroglobulin. V. The complete structure

    DEFF Research Database (Denmark)

    Sottrup-Jensen, Lars; Stepanik, Terrence M; Kristensen, Torsten

    1984-01-01

    in the activation cleavage area (the "bait" region) are located in the sequence: -Arg681-Val-Gly-Phe-Tyr-Glu-. The molecular weight of the unmodified alpha 2-macroglobulin subunit is 160,837 and approximately 179,000, including the carbohydrate groups. The presence of possible internal homologies within the alpha 2......-macroglobulin subunit is discussed. A comparison of stretches of sequences from alpha 2-macroglobulin with partial sequence data for complement components C3 and C4 indicates that these proteins are evolutionary related. The properties of alpha 2-macroglobulin are discussed within the context of proteolytically...

  1. Field production and functional evaluation of chloroplast-derived interferon-alpha2b.

    Science.gov (United States)

    Arlen, Philip A; Falconer, Regina; Cherukumilli, Sri; Cole, Amy; Cole, Alexander M; Oishi, Karen K; Daniell, Henry

    2007-07-01

    Type I interferons (IFNs) inhibit viral replication and cell growth and enhance the immune response, and therefore have many clinical applications. IFN-alpha2b ranks third in world market use for a biopharmaceutical, behind only insulin and erythropoietin. The average annual cost of IFN-alpha2b for the treatment of hepatitis C infection is $26,000, and is therefore unavailable to the majority of patients in developing countries. Therefore, we expressed IFN-alpha2b in tobacco chloroplasts, and transgenic lines were grown in the field after obtaining United States Department of Agriculture Animal and Plant Health Inspection Service (USDA-APHIS) approval. Stable, site-specific integration of transgenes into chloroplast genomes and homoplasmy through several generations were confirmed. IFN-alpha2b levels reached up to 20% of total soluble protein, or 3 mg per gram of leaf (fresh weight). Transgenic IFN-alpha2b had similar in vitro biological activity to commercially produced PEG-Introntrade mark when tested for its ability to protect cells against cytopathic viral replication in the vesicular stomatitis virus cytopathic effect (VSV CPE) assay and to inhibit early-stage human immunodeficiency virus (HIV) infection. The antitumour and immunomodulating properties of IFN-alpha2b were also seen in vivo. Chloroplast-derived IFN-alpha2b increased the expression of major histocompatibility complex class I (MHC I) on splenocytes and the total number of natural killer (NK) cells. Finally, IFN-alpha2b purified from chloroplast transgenic lines (cpIFN-alpha2b) protected mice from a highly metastatic tumour line. This demonstration of high levels of expression of IFN-alpha2b, transgene containment and biological activity akin to that of commercial preparations of IFN-alpha2b facilitated the first field production of a plant-derived human blood protein, a critical step towards human clinical trials and commercialization.

  2. Pharmacologic specificity of alpha-2 adrenergic receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Petrash, A.; Bylund, D.

    1986-03-01

    The authors have defined alpha-2 adrenergic receptor subtypes in human and rat tissues using prazosin as a subtype selective drug. Prazosin has a lower affinity (250 nM) at alpha-2A receptor and a higher affinity (5 nM) at alpha-2B receptors. In order to determine if other adrenergic drugs are selective for one or the other subtypes, the authors performed (/sup 3/H)yohimbine inhibition experiments with various adrenergic drugs in tissues containing alpha-2A, alpha-2B or both subtypes. Oxymetazoline, WB4101 and yohimbine were found to be 80-, 20- and 10-fold more potent at alpha-2A receptors than at alpha-2B receptors. Phentolamine, adazoxan, (+)- and (-)-mianserin, clonidine, (+)-butaclamol, (-)- and (+)-norepinephrine, epinephrine, dopamine and thioridazine were found to have equal affinities for the two subtypes. These results further validate the subdivision of alpha-2 adrenergic receptors into alpha-2A and alpha-2B subtypes.

  3. Soluble urokinase-type plasminogen activator receptor is a novel biomarker predicting acute exacerbation in COPD

    Directory of Open Access Journals (Sweden)

    Gumus A

    2015-02-01

    Full Text Available Aziz Gumus,1 Nejat Altintas,2 Halit Cinarka,1 Aynur Kirbas,3 Muge Haziroglu,1 Mevlut Karatas,1 Unal Sahin1 1Department of Pulmonary Medicine, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey; 2Department of Pulmonary Medicine, School of Medicine, Namik Kemal University, Tekirdag, Turkey; 3Department of Clinical Biochemistry, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey Background: Chronic obstructive pulmonary disease (COPD is a chronic inflammatory condition, and progresses with acute exacerbations. (AE. During AE, levels of acute phase reactants such as C-reactive protein (CRP and inflammatory cells in the circulation increase. Soluble urokinase-type plasminogen activator receptor (suPAR levels increase in acute viral and bacterial infections and in diseases involving chronic inflammation. The purpose of this study was to investigate the effectiveness of suPAR in predicting diagnosis of AE of COPD (AE-COPD and response to treatment. Methods: The study population consisted of 43 patients diagnosed with AE-COPD and 30 healthy controls. suPAR, CRP, and fibrinogen levels were measured on the first day of hospitalization and on the seventh day of treatment. Results: We found that fibrinogen (P<0.001, CRP (P<0.001, and suPAR (P<0.001 were significantly higher in patients with AE-COPD than in healthy controls. Fibrinogen (P<0.001, CRP (P=0.001, and suPAR (P<0.001 were significantly decreased by the seventh day of treatment. However, the area under receiver operator characteristic curve showed that suPAR is superior to CRP and fibrinogen in distinguishing AE-COPD. There was a correlation between fibrinogen, CRP, and suPAR. However, only fibrinogen was a powerful predictor of suPAR in multiple linear regression. In multiple logistic regression, only suPAR and fibrinogen were strong predictors of AE-COPD (P=0.002 and P=0.014, respectively. Serum suPAR was negatively correlated with forced expiratory volume in 1

  4. Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes

    Directory of Open Access Journals (Sweden)

    Mabel B. Esteves

    2005-06-01

    Full Text Available Lymphocytes activated by mitogenic lectins display changes in transmembrane potential, an elevation in the cytoplasmic Ca2+ concentrations, proliferation and/or activation induced cell death. Low concentrations of ouabain (an inhibitor of Na+,K+-ATPase suppress mitogen-induced proliferation and increases cell death. To understand the mechanisms involved, a number of parameters were analyzed using fluorescent probes and flow cytometry. The addition of 100nM ouabain to cultures of peripheral blood lymphocytes activated with 5µg/ml phytohemagglutinin (PHA did not modify the increased expression of the Fas receptor or its ligand FasL induced by the mitogen. However, treatment with ouabain potentiated apoptosis induced by an anti-Fas agonist antibody. A synergy between ouabain and PHA was also observed with regard to plasma membrane depolarization. PHA per se did not induce dissipation of mitochondrial membrane potential but when cells were also exposed to ouabain a marked depolarization could be observed, and this was a late event. It is possible that the inhibitory effect of ouabain on activated peripheral blood lymphocytes involves the potentiation of some of the steps of the apoptotic process and reflects an exacerbation of the mechanism of activation-induced cell death.Quando linfócitos são ativados por lectinas mitogênicas apresentam mudanças do potencial de membrana, elevação das concentrações citoplasmáticas de cálcio, proliferação e/ou morte celular induzida por ativação (AICD. Concentrações baixas de ouabaína (um inibidor da Na,K-ATPase suprimem a proliferação induzida por mitógenos e aumentam a morte celular. Para entender os mecanismos envolvidos, uma série de parâmetros foram avaliados usando sondas fluorescentes e citometria de fluxo. A adição de 100nM de ouabaína para culturas de linfócitos de sangue periférico ativadas por fitohemaglutinina (PHA não modificou o aumento de expressão do receptor Fas ou de

  5. Activation of amygdala opioid receptors by electroacupuncture of Feng-Chi (GB20) acupoints exacerbates focal epilepsy.

    Science.gov (United States)

    Yi, Pei-Lu; Lu, Chin-Yu; Cheng, Chiung-Hsiang; Tsai, Yi-Fong; Lin, Chung-Tien; Chang, Fang-Chia

    2013-10-29

    The effect of seizure suppression by acupuncture of Feng-Chi (GB20) acupoints has been documented in the ancient Chinese literature, Lingshu Jing (Classic of the Miraculous Pivot), however, there is a lack of scientific evidence to prove it. This current study was designed to elucidate the effect of electroacupuncture (EA) stimulation of bilateral Feng-Chi (GB20) acupoints on the epileptic activity by employing an animal model of focal epilepsy. Administration of pilocarpine into the left central nucleus of amygdala (CeA) induced the focal epilepsy in rats. Rats received a 30-min 100 Hz EA stimulation of bilateral Feng-Chi acupoints per day, beginning at 30 minutes before the dark period and performing in three consecutive days. The broad-spectrum opioid receptor antagonist (naloxone), μ-receptor antagonist (naloxonazine), δ-receptor antagonist (naltrindole) and κ-receptor antagonist (nor-binaltorphimine) were administered directly into the CeA to elucidate the involvement of CeA opioid receptors in the EA effect. High-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints did not suppress the pilocarpine-induced epileptiform electroencephalograms (EEGs), whereas it further increased the duration of epileptiform EEGs. We also observed that epilepsy occurred while 100 Hz EA stimulation of Feng-Chi acupoints was delivered into naïve rats. EA-induced augmentation of epileptic activity was blocked by microinjection of naloxone, μ- (naloxonazine), κ- (nor-binaltorphimine) or δ-receptor antagonists (natrindole) into the CeA, suggesting that activation of opioid receptors in the CeA mediates EA-exacerbated epilepsy. The present study suggests that high-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints has no effect to protect against pilocarpine-induced focal epilepsy; in contrast, EA further exacerbated focal epilepsy induced by pilocarpine. Opioid receptors in the CeA mediated EA-induced exacerbation of focal epilepsy.

  6. Alpha-2-Macroglobulin Is Acutely Sensitive to Freezing and Lyophilization: Implications for Structural and Functional Studies.

    Directory of Open Access Journals (Sweden)

    Amy R Wyatt

    Full Text Available Alpha-2-macroglobulin is an abundant secreted protein that is of particular interest because of its diverse ligand binding profile and multifunctional nature, which includes roles as a protease inhibitor and as a molecular chaperone. The activities of alpha-2-macroglobulin are typically dependent on whether its conformation is native or transformed (i.e. adopts a more compact conformation after interactions with proteases or small nucleophiles, and are also influenced by dissociation of the native alpha-2-macroglobulin tetramer into stable dimers. Alpha-2-macroglobulin is predominately present as the native tetramer in vivo; once purified from human blood plasma, however, alpha-2-macroglobulin can undergo a number of conformational changes during storage, including transformation, aggregation or dissociation. We demonstrate that, particularly in the presence of sodium chloride or amine containing compounds, freezing and/or lyophilization of alpha-2-macroglobulin induces conformational changes with functional consequences. These conformational changes in alpha-2-macroglobulin are not always detected by standard native polyacrylamide gel electrophoresis, but can be measured using bisANS fluorescence assays. Increased surface hydrophobicity of alpha-2-macroglobulin, as assessed by bisANS fluorescence measurements, is accompanied by (i reduced trypsin binding activity, (ii increased chaperone activity, and (iii increased binding to the surfaces of SH-SY5Y neurons, in part, via lipoprotein receptors. We show that sucrose (but not glycine effectively protects native alpha-2-macroglobulin from denaturation during freezing and/or lyophilization, thereby providing a reproducible method for the handling and long-term storage of this protein.

  7. Receptor-mediated antigen delivery into macrophages. Complexing antigen to alpha 2-macroglobulin enhances presentation to T cells.

    Science.gov (United States)

    Chu, C T; Pizzo, S V

    1993-01-01

    Macrophages secrete alpha 2-macroglobulin (alpha 2M), a protein that may facilitate early Ag handling. alpha 2M is able to entrap and form covalent linkages with diverse proteins during a transient proteinase-activated state. The resulting complexes are rapidly endocytosed after binding to high affinity receptors. Such a system could be capable of efficiently delivering a multitude of proteins to macrophages. We have used T hybridoma clones that respond only to hen egg lysozyme, in a MHC-restricted manner, to probe the effect of complex formation on Ag uptake and processing by murine macrophages. Radiolabeled lysozyme was internalized more rapidly and to a greater extent when bound to alpha 2M than when unbound. Macrophages pulsed with lysozyme-alpha 2M-elastase complexes required 200 to 250 times less Ag than those pulsed with free lysozyme to achieve effective presentation to T cells. Adding equimolar amounts of alpha 2M-elastase complexes, or of alpha 2M-methylamine, to free lysozyme had no effect on basal lysozyme presentation. Receptor-recognized forms of alpha 2M, but not lysozyme or BSA, competed effectively for both uptake and presentation of lysozyme-alpha 2M-elastase complexes. These results indicate that proteinase-activated alpha 2M can enhance Ag processing by carrying Ag into macrophages through a receptor-mediated process.

  8. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group.

    Science.gov (United States)

    Glue, P; Fang, J W; Rouzier-Panis, R; Raffanel, C; Sabo, R; Gupta, S K; Salfi, M; Jacobs, S

    2000-11-01

    The objectives of this study were to assess the safety, pharmacokinetic and pharmacodynamic profiles, and antiviral efficacy of pegylated interferon-alpha2b monotherapy in patients with chronic hepatitis C. Fifty-eight patients (38 men, 20 women; age range, 25 to 65 years) with compensated chronic hepatitis C were enrolled in this open-label, randomized, active controlled study. Patients received 0.035 to 2.0 microg/kg pegylated interferon-alpha2b subcutaneously weekly or the active control, interferon-alpha2b 3 million IU subcutaneously three times/week, for 24 weeks. Safety and antiviral efficacy assessments were performed during treatment and in a subsequent 4-week follow-up period. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. Pegylated interferon-alpha2b produced dose-related reductions in white blood cells, neutrophils, and platelets, and dose-related increases in oral temperature, serum neopterin, and serum 2'5'-oligoadenylate synthetase activity, which were qualitatively similar to those produced by nonpegylated interferon-alpha2b. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in pegylated interferon-alpha2b- and nonpegylated interferon-alpha2b-treated groups. Dose-related antiviral activity, as measured by loss of detectable serum hepatitis C virus RNA (safety and pharmacodynamic profiles were comparable. Pegylated interferon-alpha2b demonstrated delayed clearance compared with nonpegylated interferon-alpha2b, consistent with once-weekly administration.

  9. Sepsis causes presynaptic histamine H3 and alpha2-adrenergic dysfunction in canine myocardium.

    Science.gov (United States)

    Cheng, Zao-Qin; Bose, Deepak; Jacobs, Han; Light, R Bruce; Mink, Steven N

    2002-11-01

    Histamine H3 receptors and alpha2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system. We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) [J. Appl. Physiol. 85 (1998) 1693-1701] H3-receptors and alpha2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels. There may also be interaction between H3-receptors and alpha2-receptors on AR that may occur either at the receptor or a more downstream level. In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR. We determined whether there was interaction between H(3)-receptors and alpha2-adrenoceptors and tested whether H3 activation would attenuate the alpha2-agonist and alpha2-antagonist effects of clonidine and yohimbine, respectively. We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect. We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein. H3 activation also attenuated the alpha2-agonist and alpha2-antagonist effects on adrenergic activation as compared with nonseptic plasma. We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.

  10. Potential antisecretory antidiarrheals. 1. Alpha 2-adrenergic aromatic aminoguanidine hydrazones.

    Science.gov (United States)

    Pitzele, B S; Moormann, A E; Gullikson, G W; Albin, D; Bianchi, R G; Palicharla, P; Sanguinetti, E L; Walters, D E

    1988-01-01

    Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).

  11. Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C

    DEFF Research Database (Denmark)

    Hauser, Goran; Awad, Tahany; Thorlund, Kristian

    2014-01-01

    : We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until October 2013. We also searched conference abstracts, journals, and grey...... compared peginterferon alpha-2a plus ribavirin versus peginterferon alpha-2b plus ribavirin in 5847 patients. All trials had a high risk of bias. Very few trials reported data on very few patients for the patient-relevant outcomes all-cause mortality, liver-related morbidity, serious adverse events......, and quality of life. Accordingly, we were unable to conduct meta-analyses on all-cause mortality, liver-related morbidity, and quality of life. Twelve trials reported on adverse events leading to discontinuation of treatment without clear evidence of a difference between the two peginterferons (197/2171 (9...

  12. Functional labeling of insulin receptor subunits in live cells. Alpha 2 beta 2 species is the major autophosphorylated form

    International Nuclear Information System (INIS)

    Le Marchand-Brustel, Y.; Ballotti, R.; Gremeaux, T.; Tanti, J.F.; Brandenburg, D.; Van Obberghen, E.

    1989-01-01

    Both receptor subunits were functionally labeled in order to provide methods allowing, in live cells and in broken cell systems, concomitant evaluation of the insulin receptor dual function, hormone binding, and kinase activity. In cell-free systems, insulin receptors were labeled on their alpha-subunit with 125I-photoreactive insulin, and on their beta-subunit by autophosphorylation. Thereafter, phosphorylated receptors were separated from the complete set of receptors by means of anti-phosphotyrosine antibodies. Using this approach, a subpopulation of receptors was found which had bound insulin, but which were not phosphorylated. Under nonreducing conditions, receptors appeared in three oligomeric species identified as alpha 2 beta 2, alpha 2 beta, and alpha 2. Mainly the alpha 2 beta 2 receptor species was found to be phosphorylated while insulin was bound to alpha 2 beta 2, alpha 2 beta, and alpha 2 forms. In live cells, biosynthetic labeling of insulin receptors was used. Receptors were first labeled with [35S]methionine. Subsequently, the addition of insulin led to receptor autophosphorylation by virtue of the endogenous ATP pool. The total amount of [35S]methionine-labeled receptors was precipitated with antireceptor antibodies, whereas with anti-phosphotyrosine antibodies, only the phosphorylated receptors were isolated. Using this approach we made the two following key findings: (1) Both receptor species, alpha 2 beta 2 and alpha 2 beta, are present in live cells and in comparable amounts. This indicates that the alpha 2 beta form is not a degradation product of the alpha 2 beta 2 form artificially generated during receptor preparation. (2) The alpha 2 beta 2 species is the prevalently autophosphorylated form

  13. Differences in clinical outcomes among hepatitis C genotype 1-infected patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin: a meta-analysis

    Directory of Open Access Journals (Sweden)

    O'Regan C

    2012-02-01

    Full Text Available Eric Druyts1, Edward J Mills1,2, Jean Nachega3, Christopher O'Regan4, Curtis L Cooper51Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada; 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; 3Centre for Infectious Diseases, Stellenbosch University, Stellenbosch, South Africa; 4Division of Outcomes Research, Merck, Shire and Dohme, Hoddesdon, UK; 5Division of Infectious Diseases, University of Ottawa at The Ottawa Hospital, Ottawa, ON, CanadaBackground: With the development of new direct acting antiviral (DAA therapy for hepatitis C, the backbone peginterferon alpha used may be of importance in maximizing treatment outcomes. To this end, the rates of sustained virologic response (SVR, relapse, and treatment discontinuation among hepatitis C genotype 1-infected patients given peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin were determined using a meta-analysis.Methods: Randomized trials examining peginterferon alpha-2a or peginterferon alpha-2b co-administered with ribavirin for 48 weeks were included. Data were extracted on SVR, relapse, and treatment discontinuations for treatment-naïve and treatment-experienced patients. Pooled proportions using fixed and random effects meta-analysis were calculated.Results: Twenty-six trials provided data on patients treated with peginterferon alpha-2a plus ribavirin, and 19 trials provided data on patients treated with peginterferon alpha-2b plus ribavirin. Five trials were direct head-to-head evaluations. In the subset of trials that included head-to-head evaluations, no significant differences were observed between the two treatments for treatment-naïve (relative risk [RR]: 1.07, 95% confidence intervals [CI]: 0.97–1.18 and treatment-experienced patients (RR: 1.27, 95% CI: 0.58–2.77. Using only active trial arms, a larger proportion of the treatment-naïve patients who were provided peginterferon alpha-2a

  14. Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes

    OpenAIRE

    Esteves Mabel B.; Marques-Santos Luis F.; Affonso-Mitidieri Ottília R.; Rumjanek Vivian M.

    2005-01-01

    Lymphocytes activated by mitogenic lectins display changes in transmembrane potential, an elevation in the cytoplasmic Ca2+ concentrations, proliferation and/or activation induced cell death. Low concentrations of ouabain (an inhibitor of Na+,K+-ATPase) suppress mitogen-induced proliferation and increases cell death. To understand the mechanisms involved, a number of parameters were analyzed using fluorescent probes and flow cytometry. The addition of 100nM ouabain to cultures of peripheral b...

  15. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Satwiko, Muhammad Gahan [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Ikeda, Koji [Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan); Nakayama, Kazuhiko [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Yagi, Keiko [Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan); Hocher, Berthold [Institute for Nutritional Science, University of Potsdam, Potsdam (Germany); Hirata, Ken-ichi [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Emoto, Noriaki, E-mail: emoto@med.kobe-u.ac.jp [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan)

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. - Highlights: • Role of endothelin-1 in pulmonary arterial hypertension (PAH) was investigated. • The endothelin-1 transgenic (ETTG) and wild type (WT) mice were analyzed. • ETTG mice spontaneously developed PAH under normoxia conditions. • SU5416 further aggravated PAH in ETTG mice. • Enhanced endothelin system activity could be a causative factor in

  16. Dark chocolate exacerbates acne.

    Science.gov (United States)

    Vongraviopap, Saivaree; Asawanonda, Pravit

    2016-05-01

    The effects of chocolate on acne exacerbations have recently been reevaluated. For so many years, it was thought that it had no role in worsening acne. To investigate whether 99% dark chocolate, when consumed in regular daily amounts, would cause acne to worsen in acne-prone male subjects, twenty-five acne prone male subjects were asked to consume 25 g of 99% dark chocolate daily for 4 weeks. Assessments which included Leeds revised acne scores as well as lesion counts took place weekly. Food frequency questionnaire was used, and daily activities were recorded. Statistically significant changes of acne scores and numbers of comedones and inflammatory papules were detected as early as 2 weeks into the study. At 4 weeks, the changes remained statistically significant compared to baseline. Dark chocolate when consumed in normal amounts for 4 weeks can exacerbate acne in male subjects with acne-prone skin. © 2015 The International Society of Dermatology.

  17. Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat

    Science.gov (United States)

    Hanlon, Lauren A.; Huh, Jimmy W.

    2016-01-01

    Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury. PMID:26825312

  18. (ALPHA)2(BETA)1 Integrin-Induced Breast Cancer Differentiation

    National Research Council Canada - National Science Library

    Kamata, Tetsuji

    1998-01-01

    .... The integrin alpha 2 beta 1 functions as a collagen and/or laminin receptor. Previous reports suggest that alpha 2 beta 1 plays a critical role in normal mammary cell differentiation as well as in the pathogenesis of breast cancer...

  19. PKA activity exacerbates hypoxia-induced ROS formation and hypoxic injury in PC-12 cells.

    Science.gov (United States)

    Gozal, Evelyne; Metz, Cynthia J; Dematteis, Maurice; Sachleben, Leroy R; Schurr, Avital; Rane, Madhavi J

    2017-09-05

    Hypoxia is a primary factor in many pathological conditions. Hypoxic cell death is commonly attributed to metabolic failure and oxidative injury. cAMP-dependent protein kinase A (PKA) is activated in hypoxia and regulates multiple enzymes of the mitochondrial electron transport chain, thus may be implicated in cellular energy depletion and hypoxia-induced cell death. Wild type (WT) PC-12 cells and PKA activity-deficient 123.7 PC-12 cells were exposed to 3, 6, 12 and 24h hypoxia (0.1% or 5% O 2 ). Hypoxia, at 24h 0.1% O 2 , induced cell death and increased reactive oxygen species (ROS) in WT PC-12 cells. Despite lower ATP levels in normoxic 123.7 cells than in WT cells, hypoxia only decreased ATP levels in WT cells. However, menadione-induced oxidative stress similarly affected both cell types. While mitochondrial COX IV expression remained consistently higher in 123.7 cells, hypoxia decreased COX IV expression in both cell types. N-acetyl cysteine antioxidant treatment blocked hypoxia-induced WT cell death without preventing ATP depletion. Transient PKA catα expression in 123.7 cells partially restored hypoxia-induced ROS but did not alter ATP levels or COX IV expression. We conclude that PKA signaling contributes to hypoxic injury, by regulating oxidative stress rather than by depleting ATP levels. Therapeutic strategies targeting PKA signaling may improve cellular adaptation and recovery in hypoxic pathologies. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Amoxicillin concentrations in relation to beta-lactamase activity in sputum during exacerbations of chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    Brusse-Keizer, Marjolein; VanderValk, Paul; van der Zanden, Rogier W.; Nijdam, Lars; van der Palen, Job; Hendrix, Ron; Movig, Kris

    2015-01-01

    Background: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are often treated with antibiotics. Theoretically, to be maximally effective, the antibiotic concentration at sites of infection should exceed the minimum inhibitory concentration at which 90% of the growth of potential

  1. Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries.

    Science.gov (United States)

    Eid, A H; Maiti, K; Mitra, S; Chotani, M A; Flavahan, S; Bailey, S R; Thompson-Torgerson, C S; Flavahan, N A

    2007-09-01

    Raynaud's phenomenon, which is characterized by intense cold-induced constriction of cutaneous arteries, is more common in women compared with men. Cold-induced constriction is mediated in part by enhanced activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) located on vascular smooth muscle cells (VSMs). Experiments were therefore performed to determine whether 17beta-estradiol regulates alpha(2C)-AR expression and function in cutaneous VSMs. 17beta-Estradiol (0.01-10 nmol/l) increased expression of the alpha(2C)-AR protein and the activity of the alpha(2C)-AR gene promoter in human cultured dermal VSMs, which was assessed following transient transfection of the cells with a promoter-reporter construct. The effect of 17beta-estradiol was associated with increased accumulation of cAMP and activation of the cAMP-responsive Rap2 GTP-binding protein. Transient transfection of VSMs with a dominant-negative mutant of Rap2 inhibited the 17beta-estradiol-induced activation of the alpha(2C)-AR gene promoter, whereas a constitutively active mutant of Rap2 increased alpha(2C)-AR promoter activity. The effects of 17beta-estradiol were inhibited by the estrogen receptor (ER) antagonist, ICI-182780 (1 micromol/l), and were mimicked by a cell-impermeable form of the hormone (estrogen:BSA) or by the selective ER-alpha receptor agonist 4,4',4'''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl)tris-phenol (PPT; 10 nmol/l) or the selective ER-beta receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nmol/l). Therefore, 17beta-estradiol increased expression of alpha(2C)-ARs by interacting with cell surface receptors to cause a cAMP/Rap2-dependent increase in alpha(2C)-AR transcription. In mouse tail arteries, 17beta-estradiol (10 nmol/l) increased alpha(2C)-AR expression and selectively increased the cold-induced amplification of alpha(2)-AR constriction, which is mediated by alpha(2C)-ARs. An estrogen-dependent increase in expression of cold-sensitive alpha(2C)-ARs may contribute

  2. Unique presynaptic alpha 2-receptor selectivity and specificity of the antihypertensive agent moxonidine.

    Science.gov (United States)

    Armah, B I

    1988-10-01

    The characteristics of the alpha-receptor activating property of the new antihypertensive agent moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methyl-2-methyl-5-pyrimidinamine, BDF 5895) was studied using peripheral vasculature and brain membranes of various animals. Moxonidine exerted a full agonist effect in elevating diastolic blood pressure in the pithed rat. Activation of postsynaptic alpha 1- and alpha 2-receptors contribute to the vasoconstrictory effect in rats. In the vasculature of the rabbit, moxonidine was a full agonist at presynaptic alpha 2-receptors in inhibiting transmitter release induced by electrical stimulation of pulmonary artery strips. At postsynaptic sites, exogenously applied moxonidine was a full agonist at alpha 1-receptors in the isolated aorta, pulmonary artery and vena cava of the rabbit. Selectivity for alpha 2-receptors in the pulmonary artery was 106-fold. In rat brain membranes, moxonidine showed 288-fold greater selectivity for alpha 2-receptors, when the displacement of [3H]-rauwolscine was compared with the displacement of [3H]-prazosin. On the whole, clonidine exhibited greater potency than moxonidine on both alpha-receptor subtypes, but moxonidine consistently showed greater alpha 2-receptor selectivity than clonidine. In the guinea pig myocardium, moxonidine caused neither bradycardia nor tachycardia in the isolated right atrium and produced a negligible positive inotropic effect at 100 mumol/l in the isolated papillary muscle.

  3. The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1.

    Science.gov (United States)

    Li, Tao; Qin, Juan-Juan; Yang, Xia; Ji, Yan-Xiao; Guo, Fangliang; Cheng, Wen-Lin; Wu, Xiaolin; Gong, Fu-Han; Hong, Ying; Zhu, Xue-Yong; Gong, Jun; Wang, Zhihua; Huang, Zan; She, Zhi-Gang; Li, Hongliang

    2017-12-13

    Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury. SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting

  4. Identification of alpha 2-adrenergic receptors in chicken pineal gland using (/sup 3/H)rauwolscine

    Energy Technology Data Exchange (ETDEWEB)

    Bylund, D.B.; Rudeen, P.K.; Petterborg, L.J.; Ray-Prenger, C.

    1988-07-01

    The norepinephrine-induced inhibition of avian pineal N-acetyltransferase activity appears to be mediated by alpha 2-adrenergic receptors. In this study, alpha 2-adrenergic receptors in the chicken pineal gland were directly identified by radioligand binding. Membrane preparations of pineal glands from chickens from 1 to 6 weeks of age were examined using (/sup 3/H)rauwolscine, a selective alpha 2-adrenergic receptor antagonist, to characterize the binding sites. The results indicate no ontological change in either the affinity (KD) or density of receptor binding sites (Bmax) during the time span examined. The binding was saturable and of high affinity with a mean KD of 0.27 +/- 0.01 nM and a mean Bmax of 242 +/- 12 fmol/mg protein. Further characterization of these binding sites indicated that the alpha 2-adrenergic receptor is of the alpha 2A subtype, since prazosin and ARC-239 bound with low affinities and oxymetazoline bound with high affinity.

  5. Alpha 2-adrenergic receptor turnover in adipose tissue and kidney: irreversible blockade of alpha 2-adrenergic receptors by benextramine

    Energy Technology Data Exchange (ETDEWEB)

    Taouis, M.; Berlan, M.; Lafontan, M.

    1987-01-01

    The recovery of post- and extrasynaptic alpha 2-adrenergic receptor-binding sites was studied in vivo in male golden hamsters after treatment with an irreversible alpha-adrenoceptor antagonist benextramine, a tetramine disulfide that possesses a high affinity for alpha 2-binding sites. The kidney alpha 2-adrenergic receptor number was measured with (/sup 3/H)yohimbine, whereas (/sup 3/H)clonidine was used for fat cell and brain membrane alpha 2-binding site identification. Benextramine treatment of fat cell, kidney, and brain membranes reduced or completely suppressed, in an irreversible manner, (/sup 3/H) clonidine and (/sup 3/H)yohimbine binding without modifying adenosine (A1-receptor) and beta-adrenergic receptor sites. This irreversible binding was also found 1 and 2 hr after intraperitoneal administration of benextramine to the hamsters. Although it bound irreversibly to peripheral and central alpha 2-adrenergic receptors on isolated membranes, benextramine was unable to cross the blood-brain barrier of the hamster at the concentrations used (10-20 mg/kg). After the irreversible blockade, alpha 2-binding sites reappeared in kidney and adipose tissue following a monoexponential time course. Recovery of binding sites was more rapid in kidney than in adipose tissue; the half-lives of the receptor were 31 and 46 hr, respectively in the tissues. The rates of receptor production were 1.5 and 1.8 fmol/mg of protein/hr in kidney and adipose tissue. Reappearance of alpha 2-binding sites was associated with a rapid recovery of function (antilipolytic potencies of alpha 2-agonists) in fat cells inasmuch as occupancy of 15% of (/sup 3/H)clonidine-binding sites was sufficient to promote 40% inhibition of lipolysis. Benextramine is a useful tool to estimate turnover of alpha 2-adrenergic receptors under normal and pathological situations.

  6. A discrepancy between platelet alpha 2-receptor density and functional circulatory changes in hypertensives

    International Nuclear Information System (INIS)

    Mores, N.; Martire, M.; Pistritto, G.; Cardillo, C.; Folli, G.

    1990-01-01

    To investigate whether differences exist in peripheral alpha 2-adrenoceptors between normotensive and hypertensive subjects, we determined platelet alpha 2-adrenoceptor density in 10 (7 males) untreated essential hypertensives (mean age of 51.1 years, range of 44-59 years) and in 10 age- and sex-matched normotensive controls. Moreover, in hypertensive patients, we examined the relationship between receptor density and cardiovascular reactivity to mental arithmetic, static handgrip, and bicycle exercise, to verify the hypothesis that alpha 2-adrenoceptors might play a role in modulation of hemodynamic response to sympathetic stimuli. alpha 2-Adrenoceptor density, as calculated by binding of [3H]yohimbine to platelets, was significantly higher in essential hypertensives (314.8 +/- 38.7 fmol/mg) than in normotensive subjects (213.6 +/- 34.7 fmol/mg) (p less than 0.05), whereas receptor affinity was similar in both groups (4.0 +/- 0.5 nM hypertensives, 4.3 +/- 0.5 nM normotensives; p greater than 0.05). Mental arithmetic increased mean arterial pressure (MAP) by 21.5% from basal values and heart rate (HR) by 13.2%. During isometric exercise, MAP increased by 38.1% and HR by 24.7%, while during bicycle ergometry, mean increases in MAP and HR from baseline were of 27.2 and 54.3%, respectively. No correlation was found between platelet alpha 2-adrenoceptor density and percent changes in MAP induced by all tests, or between adrenoceptors and absolute basal and peak MAP values. Our findings suggest that in hypertensive patients, peripheral alpha 2-adrenoceptors are increased with respect to matched normotensives, but these receptors seem not to be involved in the modulation of cardiovascular adaptation to enhanced sympathetic activity

  7. Interaction of alpha-2-macroglobulin and HSV-1 during infection of neuronal cells.

    Science.gov (United States)

    Alonso, M; Dimitrijevic, A; Recuero, M; Serrano, E; Valdivieso, F; López-Guerrero, J A

    2001-12-01

    We describe the effect of pretreatment with alpha-2-macroglobulin (A2M) on the susceptibility of the human neuroblastoma SKNMC cell line to infection by herpes virus type 1 (HSV-1). ELISA and co-immunoprecipitation experiments confirmed the A2M-HSV-1 interaction in vitro. Indirect immunofluorescence shows that A2M exacerbated the cytopathic effect induced after HSV-1 infection. However, A2M-pretreated SKNMC cells notably produced fewer HSV-1 particles than did the untreated cells, suggesting that A2M could induce a restrictive infection. Furthermore, high levels of HSV-1 and A2M induced the production of nitric oxide (NO) in SKNMC. Preliminary results suggest that A2M might induce apoptosis in HSV-1-infected cells. These findings affirm the conclusion that A2M may interact directly with HSV-1 and modulate the course of the infection in SKNMC human neuroblastoma cells.

  8. CYP24A1 exacerbated activity during diabetes contributes to kidney tubular apoptosis via caspase-3 increased expression and activation.

    Directory of Open Access Journals (Sweden)

    Alexandre Tourigny

    Full Text Available Decreases in circulating 25,hydroxyl-vitamin D3 (25 OH D3 and 1,25,dihydroxyl-vitamin D3 (1,25 (OH2 D3 have been extensively documented in patients with type 2 diabetes. Nevertheless, the molecular reasons behind this drop, and whether it is a cause or an effect of disease progression is still poorly understood. With the skin and the liver, the kidney is one of the most important sites for vitamin D metabolism. Previous studies have also shown that CYP24A1 (an enzyme implicated in vitamin D metabolism, might play an important role in furthering the progression of kidney lesions during diabetic nephropathy. In this study we show a link between CYP24A1 increase and senescence followed by apoptosis induction in the renal proximal tubules of diabetic kidneys. We show that CYP24A1 expression was increased during diabetic nephropathy progression. This increase derived from protein kinase C activation and increased H(2O(2 cellular production. CYP24A1 increase had a major impact on cellular phenotype, by pushing cells into senescence, and later into apoptosis. Our data suggest that control of CYP24A1 increase during diabetes has a beneficial effect on senescence induction and caspase-3 increased expression. We concluded that diabetes induces an increase in CYP24A1 expression, destabilizing vitamin D metabolism in the renal proximal tubules, leading to cellular instability and apoptosis, and thereby accelerating tubular injury progression during diabetic nephropathy.

  9. Molecular characterization of alpha 1- and alpha 2-adrenoceptors.

    Science.gov (United States)

    Harrison, J K; Pearson, W R; Lynch, K R

    1991-02-01

    Three 'alpha 1-adrenoceptors' and three 'alpha 2-adrenoceptors' have now been cloned. How closely do these receptors match the native receptors that have been identified pharmacologically? What are the properties of these receptors, and how do they relate to other members of the cationic amine receptor family? Kevin Lynch and his colleagues discuss these questions in this review.

  10. Zinc alpha-2 glycoprotein is overproduced in Cushing's syndrome.

    Science.gov (United States)

    Escoté, Xavier; Aranda, Gloria B; Mora, Mireia; Casals, Gregori; Enseñat, Joaquim; Vidal, Oscar; Esteban, Yaiza; Halperin, Irene; Hanzu, Felicia A

    2017-01-01

    Cushing syndrome (CS), an endogenous hypercortisolemic condition with increased cardiometabolic morbidity, leads to development of abdominal obesity, insulin resistance, diabetes and proatherogenic dyslipidemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized lipolytic adipokine implicated in regulation of adipose tissue metabolism and fat distribution. In vitro and animal studies suggest that glucocorticoids interact with ZAG secretion and action. To assess the relationship between ZAG and glucocorticoids in a human model of hypercortisolism, circulating ZAG levels were tested in patients with CS and its counterpart controls. An observational, cross-sectional study on 39 women, 13 with active CS and 26 controls matched by age and body mass index. Plasma ZAG levels (μg/ml) were measured by ELISA and correlated with hypercortisolism, metabolic, and phenotypic parameters. Plasma ZAG levels were significantly higher in patients with CS compared to controls (64.3±16.6 vs. 44.0±16.1, p=0.002). In a univariate analysis, ZAG levels positively correlated to 24-h urinary free cortisol (p=0.001), body mass index (p=0.02), non-esterified fatty acids (p=0.05), glucose (p=0.003), LDL-C (p=0.028), and type 2 diabetes mellitus (p=0.016), and were inversely related to total adiponectin levels (p=0.035). In a multivariate analysis, after adjusting for CS, ZAG levels only correlated with body mass index (p=0.012), type 2 diabetes mellitus (p=0.004), and glucose (p<0.001). This study provides initial evidence that plasma ZAG levels are higher in patients with CS as compared to controls. The close relationship of ZAG with metabolic and phenotypic changes in CS suggests that ZAG may play a significant role in adipose tissue changes in hypercortisolism. Copyright © 2017 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Prevention of COPD exacerbations

    DEFF Research Database (Denmark)

    Vestbo, Jørgen; Lange, Peter

    2015-01-01

    Exacerbations have significant impact on the morbidity and mortality of patients with chronic obstructive pulmonary disease. Most guidelines emphasise prevention of exacerbations by treatment with long-acting bronchodilators and/or anti-inflammatory drugs. Whereas most of this treatment is evidence......-based, it is clear that patients differ regarding the nature of exacerbations and are likely to benefit differently from different types of treatment. In this short review, we wish to highlight this, suggest a first step in differentiating pharmacological exacerbation prevention and call for more studies...... in this area. Finally, we wish to highlight that there are perhaps easier ways of achieving similar success in exacerbation prevention using nonpharmacological tools....

  12. Individual levels of plasma alpha 2-antiplasmin and alpha 2-macroglobulin during the normal menstrual cycle and in women on oral contraceptives low in oestrogen

    DEFF Research Database (Denmark)

    Jespersen, J; Sidelmann, Johannes Jakobsen

    1983-01-01

    Determinations of alpha 2-antiplasmin and alpha 2-macroglobulin were made in plasma samples collected during one normal or hormone induced cycle in 15 normal women and 11 women using oral contraceptives containing 30 micrograms ethinyl oestradiol and 150 micrograms levo-norgestrel. The immediate...... plasmin inhibition test for determination of alpha 2-antiplasmin was modified for application on a centrifugal analyser using the chromogenic peptide substrate Chromozym PL. alpha 2-Macroglobulin concentration was determined by radial-immunodiffusion. There were no differences between the two groups...... in the mean concentrations of alpha 2-antiplasmin and alpha 2-macroglobulin, but during the cycle a slight, and statistically significant fall occurred in the alpha 2-antiplasmin concentration in both groups, while the fluctuations of alpha 2-macroglobulin were small and insignificant. Distinctly individual...

  13. Blood Coagulation and Asthma Exacerbation in Children.

    Science.gov (United States)

    Manuyakorn, Wiparat; Mairiang, Dara; Sirachainan, Nongnuch; Kadegasem, Praguywan; Kamchaisatian, Wasu; Benjaponpitak, Suwat; Chuansumrit, Ampaiwan

    2016-01-01

    Recent studies have demonstrated the activation of coagulation pathways in asthmatic airways. This study aimed to determine systemic blood coagulation during asthma exacerbation compared with the stable state in children. Pediatric patients (aged between 5 and 15 years) suffering from asthma exacerbation were enrolled. von Willebrand factor (vWF), plasminogen activator inhibitor type-1 (PAI-1), protein C, D-dimer, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), and C-reactive protein (CRP) levels were measured during asthma exacerbation and stable state. A total of 22 patients were enrolled. The median vWF, PAI-1, and CRP during asthma exacerbation were significantly higher than those of the stable state: 147.5% (interquartile range, IQR: 111.05-196.57) versus 94% (IQR: 69.72-109.62, p coagulation in asthma exacerbation. © 2016 S. Karger AG, Basel.

  14. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Baatrup Gunnar

    2005-09-01

    Full Text Available Abstract Background Ulcerative colitis (UC and Crohn's disease (CD are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment. Methods Plasma from patients with exacerbations of UC (n = 18 or CD (n = 18 were collected before and during high dose prednisolone treatment (1 mg/kg body weight and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used Results Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p Conclusion Our findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation.

  15. Acute exacerbation of COPD.

    Science.gov (United States)

    Ko, Fanny W; Chan, Ka Pang; Hui, David S; Goddard, John R; Shaw, Janet G; Reid, David W; Yang, Ian A

    2016-10-01

    The literature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is fast expanding. This review focuses on several aspects of acute exacerbation of COPD (AECOPD) including epidemiology, diagnosis and management. COPD poses a major health and economic burden in the Asia-Pacific region, as it does worldwide. Triggering factors of AECOPD include infectious (bacteria and viruses) and environmental (air pollution and meteorological effect) factors. Disruption in the dynamic balance between the 'pathogens' (viral and bacterial) and the normal bacterial communities that constitute the lung microbiome likely contributes to the risk of exacerbations. The diagnostic approach to AECOPD varies based on the clinical setting and severity of the exacerbation. After history and examination, a number of investigations may be useful, including oximetry, sputum culture, chest X-ray and blood tests for inflammatory markers. Arterial blood gases should be considered in severe exacerbations, to characterize respiratory failure. Depending on the severity, the acute management of AECOPD involves use of bronchodilators, steroids, antibiotics, oxygen and noninvasive ventilation. Hospitalization may be required, for severe exacerbations. Nonpharmacological interventions including disease-specific self-management, pulmonary rehabilitation, early medical follow-up, home visits by respiratory health workers, integrated programmes and telehealth-assisted hospital at home have been studied during hospitalization and shortly after discharge in patients who have had a recent AECOPD. Pharmacological approaches to reducing risk of future exacerbations include long-acting bronchodilators, inhaled steroids, mucolytics, vaccinations and long-term macrolides. Further studies are needed to assess the cost-effectiveness of these interventions in preventing COPD exacerbations. © 2016 Asian Pacific Society of Respirology.

  16. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis

    DEFF Research Database (Denmark)

    Zimmermann-Nielsen, Erik; Grønbaek, Henning; Dahlerup, Jens Frederik

    2005-01-01

    BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity...... and prednisolone treatment. METHODS: Plasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used...... RESULTS: Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p UC patients (p

  17. Synthesis and evaluation of alpha-(((2-haloethyl)amino)methyl)-2- nitro-1H-imidazole-1-ethanols as prodrugs of alpha-((1-aziridinyl)methyl)-2- nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins

    Energy Technology Data Exchange (ETDEWEB)

    Jenkins, T.C.; Naylor, M.A.; O' Neill, P.; Threadgill, M.D.; Cole, S.; Stratford, I.J.; Adams, G.E.; Fielden, E.M.; Suto, M.J.; Stier, M.A. (Medical Research Council Radiobiology Unit, Didcot, Oxfordshire (England))

    1990-09-01

    alpha-((1-Aziridinyl)methyl)-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, where Im = 2-nitroimidazole and R1, R2, R3, R4 = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo. Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-, where R1, R2, R3, R4 = H, Me, and X = F, Cl, Br, I. These 2-haloethylamines were evaluated as prodrugs of the parent aziridines. The rates of ring closure in aqueous solution at pH approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-(2-hyroxy-3-(2-nitro-1H-imidazol-1-yl)propyl)-2-oxazolidinone. The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. alpha-(((2-Bromoethyl)amino)methyl)-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-((1-aziridinyl)methyl)-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions.

  18. TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Song Min

    2011-08-01

    Full Text Available Abstract Background Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD, are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs, a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Aβ deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Aβ deposits start. Methods Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aβ were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aβ-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze. Results While no difference was found in cerebral Aβ load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg was less than that in a TLR4 wild-type AD model (TLR4W Tg. At 9 months, TLR4M Tg mice had increased Aβ deposition and soluble Aβ42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1β, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aβ-induced IL-1β, CCL3, and CCL4 expression in monocytes. Conclusion This is the first demonstration of TLR4

  19. Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver.

    Science.gov (United States)

    Zhang, Meiyuan; Sun, Weilan; Qian, Jin; Tang, Yan

    2018-02-01

    Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Prevention of Asthma Exacerbation in a Mouse Model by Simultaneous Inhibition of NF-κB and STAT6 Activation Using a Chimeric Decoy Strategy

    Directory of Open Access Journals (Sweden)

    Tetsuo Miyake

    2018-03-01

    Full Text Available Transactivation of inflammatory and immune mediators in asthma is tightly regulated by nuclear factor κB (NF-κB and signal transducer and activator of transcription 6 (STAT6. Therefore, we investigated the efficacy of simultaneous inhibition of NF-κB and STAT6 using a chimeric decoy strategy to prevent asthma exacerbation. The effects of decoy oligodeoxynucleotides were evaluated using an ovalbumin-induced mouse asthma model. Ovalbumin-sensitized mice received intratracheal administration of decoy oligodeoxynucleotides 3 days before ovalbumin challenge. Fluorescent-dye-labeled decoy oligodeoxynucleotides could be detected in lymphocytes and macrophages in the lung, and activation of NF-κB and STAT6 was inhibited by chimeric decoy oligodeoxynucleotide transfer. Consequently, treatment with chimeric or NF-κB decoy oligodeoxynucleotides protected against methacholine-induced airway hyperresponsiveness, whereas the effect of chimeric decoy oligodeoxynucleotides was significantly greater than that of NF-κB decoy oligodeoxynucleotides. Treatment with chimeric decoy oligodeoxynucleotides suppressed airway inflammation through inhibition of overexpression of interleukin-4 (IL-4, IL-5, and IL-13 and inflammatory infiltrates. Histamine levels in the lung were reduced via suppression of mast cell accumulation. A significant reduction in mucin secretion was observed due to suppression of MUC5AC gene expression. Interestingly, the inhibitory effects on IL-5, IL-13, and histamine secretion were achieved by transfer of chimeric decoy oligodeoxynucleotides only. This novel therapeutic approach could be useful to treat patients with various types of asthma.

  1. Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway

    Directory of Open Access Journals (Sweden)

    Simões Ana

    2012-08-01

    Full Text Available Abstract Background and purpose Blockade of adenosine A2A receptors (A2AR affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL-1β. We investigated whether A2AR controls the signaling of IL-1β and its deleterious effects in cultured hippocampal neurons. Methods Hippocampal neuronal cultures were treated with IL-1β and/or glutamate in the presence or absence of the selective A2AR antagonist, SCH58261 (50 nmol/l. The effect of SCH58261 on the IL-1β-induced phosphorylation of the mitogen-activated protein kinases (MAPKs c-Jun N-terminal kinase (JNK and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1β was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A2AR blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1β, was studied using single-cell calcium imaging. Results IL-1β (10 to 100 ng/ml enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 μg/ml, in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1β failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 μmol/l glutamate for 25 minutes (evaluated after 24 hours. It is likely that this resulted from the ability of IL-1β to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1β alone. The selective A2AR antagonist, SCH58261 (50 nmol

  2. Suppressor of Cytokine Signaling 3 in Macrophages Prevents Exacerbated Interleukin-6-Dependent Arginase-1 Activity and Early Permissiveness to Experimental Tuberculosis

    Directory of Open Access Journals (Sweden)

    Erik Schmok

    2017-11-01

    Full Text Available Suppressor of cytokine signaling 3 (SOCS3 is a feedback inhibitor of interleukin (IL-6 signaling in macrophages. In the absence of this molecule, macrophages become extremely prone to an IL-6-dependent expression of arginase-1 (Arg1 and nitric oxide synthase (NOS2, the prototype markers for alternative or classical macrophage activation, respectively. Because both enzymes are antipodean macrophage effector molecules in Mycobacterium tuberculosis (Mtb infection, we assessed the relevance of SOCS3 for macrophage activation during experimental tuberculosis using macrophage-specific SOCS3-deficient (LysMcreSOCS3loxP/loxP mice. Aerosol infection of LysMcreSOCS3loxP/loxP mice resulted in remarkably higher bacterial loads in infected lungs and exacerbated pulmonary inflammation. This increased susceptibility to Mtb infection was accompanied by enhanced levels of both classical and alternative macrophage activation. However, high Arg1 expression preceded the increased induction of NOS2 and at early time points of infection mycobacteria were mostly found in cells positive for Arg1. This sequential activation of Arg1 and NOS2 expression in LysMcreSOCS3loxP/loxP mice appears to favor the initial replication of Mtb particularly in Arg1-positive cells. Neutralization of IL-6 in Mtb-infected LysMcreSOCS3loxP/loxP mice reduced arginase activity and restored control of mycobacterial replication in LysMcreSOCS3loxP/loxP mice. Our data reveal an unexpected role of SOCS3 during experimental TB: macrophage SOCS3 restrains early expression of Arg1 and helps limit Mtb replication in resident lung macrophages, thereby limiting the growth of mycobacteria. Together, SOCS3 keeps IL-6-dependent divergent macrophage responses such as Nos2 and Arg1 expression under control and safeguard protective macrophage effector mechanisms.

  3. Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure.

    Science.gov (United States)

    Lobo, Denise M L; Trevizan, Patricia F; Toschi-Dias, Edgar; Oliveira, Patricia A; Piveta, Rafael B; Almeida, Dirceu R; Mady, Charles; Bocchi, Edimar A; Lorenzi-Filho, Geraldo; Middlekauff, Holly R; Negrão, Carlos E

    2016-11-01

    Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), and hypoxia and hypercapnia episodes activate chemoreceptors stimulating autonomic reflex responses. We tested the hypothesis that muscle vasoconstriction and muscle sympathetic nerve activity (MSNA) in response to hypoxia and hypercapnia would be more pronounced in patients with HF and SDB than in patients with HF without SDB (NoSBD). Ninety consecutive patients with HF, New York Heart Association functional class II-III, and left ventricular ejection fraction ≤40% were screened for the study. Forty-one patients were enrolled: NoSDB (n=13, 46 [39-53] years) and SDB (n=28, 57 [54-61] years). SDB was characterized by apnea-hypopnea index ≥15 events per hour (polysomnography). Peripheral (10% O 2 and 90% N 2 , with CO 2 titrated) and central (7% CO 2 and 93% O 2 ) chemoreceptors were stimulated for 3 minutes. Forearm and calf blood flow were evaluated by venous occlusion plethysmography, MSNA by microneurography, and blood pressure by beat-to-beat noninvasive technique. Baseline forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance were similar between groups. MSNA was higher in the SDB group. During hypoxia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (Phypoxia (P=0.024) and tended to be higher to hypercapnia (P=0.066) in the SDB group. Patients with HF and SDB have more severe muscle vasoconstriction during hypoxia and hypercapnia than HF patients without SDB, which seems to be associated with endothelial dysfunction and, in part, increased MSNA response. © 2016 American Heart Association, Inc.

  4. Exacerbation of experimental autoimmune encephalomyelitis in P2X7R-/- mice: evidence for loss of apoptotic activity in lymphocytes.

    Science.gov (United States)

    Chen, Lanfen; Brosnan, Celia F

    2006-03-01

    The purinergic receptor P2X7R is a nucleotide-gated ion channel that has been proposed to function as a major regulator of inflammation. In this study we examined the role of this receptor in regulating inflammation in the CNS by determining the effects of the loss of this receptor (P2X7R-/-) on experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We show here that P2X7R-/- mice developed more severe clinical and pathological expression of EAE than wild type (WT) controls and that spleen and lymph node cells from P2X7R-/- mice proliferated more vigorously to Ag in vitro. Bone marrow (BM) radiation chimeras revealed that enhanced susceptibility to EAE was detected in chimeric mice of WT host engrafted with P2X7R-/- BM cells, indicating that the genotype of the BM cells regulated disease susceptibility. Coculture of P2X7R-/- macrophages with WT lymphocytes and vice versa showed that enhanced proliferative activity resided within the P2X7R-/- lymphocyte population and correlated with reduced levels of IFN-gamma and NO and apoptosis of lymphocytes. mRNA and protein for IFN-gamma were also significantly reduced in the CNS of P2X7R-/- mice with EAE. FACS analysis of cells isolated from the CNS showed significantly fewer annexin V/propidium iodide-positive lymphocytes in the CNS of P2X7R-/- mice early in the disease, and TUNEL staining of inflamed CNS tissues supported this result. From these data we conclude that enhanced susceptibility of P2X7R-/- mice to EAE reflects a loss of apoptotic activity in lymphocytes, supporting an important role for this receptor in lymphocyte homeostasis.

  5. p-( sup 125 I)iodoclonidine is a partial agonist at the alpha 2-adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Gerhardt, M.A.; Wade, S.M.; Neubig, R.R. (Univ. of Michigan Medical School, Ann Arbor (USA))

    1990-08-01

    The binding properties of p-(125I)iodoclonidine (( 125I)PIC) to human platelet membranes and the functional characteristics of PIC are reported. (125I)PIC bound rapidly and reversibly to platelet membranes, with a first-order association rate constant (kon) at room temperature of 8.0 +/- 2.7 x 10(6) M-1 sec-1 and a dissociation rate constant (koff) of 2.0 +/- 0.8 x 10(-3) sec-1. Scatchard plots of specific (125I)PIC binding (0.1-5 nM) were linear, with a Kd of 1.2 +/- 0.1 nM. (125I)PIC bound to the same number of high affinity sites as the alpha 2-adrenergic receptor (alpha 2-AR) full agonist (3H) bromoxidine (UK14,304), which represented approximately 40% of the sites bound by the antagonist (3H)yohimbine. Guanosine 5'-(beta, gamma-imido)triphosphate greatly reduced the amount of (125I)PIC bound (greater than 80%), without changing the Kd of the residual binding. In competition experiments, the alpha 2-AR-selective ligands yohimbine, bromoxidine, oxymetazoline, clonidine, p-aminoclonidine, (-)-epinephrine, and idazoxan all had Ki values in the low nanomolar range, whereas prazosin, propranolol, and serotonin yielded Ki values in the micromolar range. Epinephrine competition for (125I)PIC binding was stereoselective. Competition for (3H)bromoxidine binding by PIC gave a Ki of 1.0 nM (nH = 1.0), whereas competition for (3H)yohimbine could be resolved into high and low affinity components, with Ki values of 3.7 and 84 nM, respectively. PIC had minimal agonist activity in inhibiting adenylate cyclase in platelet membranes, but it potentiated platelet aggregation induced by ADP with an EC50 of 1.5 microM. PIC also inhibited epinephrine-induced aggregation, with an IC50 of 5.1 microM. Thus, PIC behaves as a partial agonist in a human platelet aggregation assay. (125I)PIC binds to the alpha 2B-AR in NG-10815 cell membranes with a Kd of 0.5 +/- 0.1 nM.

  6. alpha2 adrenoceptors are involved in the regulation of the gripping-induced immobility episodes in taiep rats.

    Science.gov (United States)

    Eguibar, José R; Cortés, Ma Del Carmen; Valencia, Jaime; Arias-Montaño, José A

    2006-10-01

    In 1989 Holmgren et al. (Holmgren et al. 1989 Lab Anim Sci 39:226-228) described a new mutant rat that developed a progressive motor disturbance during its lifespan. The syndrome is characterized by a tremor in the hind limbs followed by ataxia, episodes of tonic immobility, epilepsy, and paralysis. The acronym of these symptoms (taiep) became the name of this autosomic, recessive mutant rat. The taiep rats are neurological mutant animals with a hypomyelination, followed by a progressive demyelination process. At 7-8 months of age, taiep rats develop immobility episodes (IEs) characterized by a cortical desynchronization, associated with the theta rhythm in the hippocampus and changes of the nucal electromyogram (EMG), whose pattern is like rapid-eye-movement (REM) sleep. These rats also show an altered sleep pattern with an equal REM sleep distribution. This study analyzed therole of alpha(2) adrenoceptors in the expression of gripping-induced IEs in 8-month-old male taiep rats. The alpha(2) adrenoceptor agonists clonidine and xylacine increased the frequency of gripping-induced IEs whereas the alpha(2) antagonists yohimbine and idazoxandecreased or prevented such episodes. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which alpha(2) adrenergic mechanisms are involved in the modulation of cataplexy. Unexpectedly, the repetitive administration of clonidine resulted in jumping behavior, indicative of phasic activation of extensor musculature. Taken together, our results show that alpha(2) adrenoceptors are involved in the modulation in gripping-induced IEs and after the administration of several doses of clonidine produced phasic motor activation.

  7. Effects of the pesticide amitraz and its metabolite BTS 27271 on insulin and glucagon secretion from the perfused rat pancreas: involvement of alpha2D-adrenergic receptors.

    Science.gov (United States)

    Abu-Basha, E A; Yibchok-Anun, S; Hopper, D L; Hsu, W H

    1999-11-01

    The study purpose was to investigate the direct effect of amitraz, a formamidine insecticide/acaricide, and its active metabolite BTS 27271 on insulin and glucagon secretion from the perfused rat pancreas. Amitraz and BTS 27271 (0.01, 0.1, 1, and 10 micromol/L) inhibited insulin secretion in a concentration-dependent manner. Amitraz increased glucagon secretion at 10 micromol/L, whereas BTS 27271 increased glucagon secretion at 1 and 10 micromol/L. Amitraz- and BTS 27271-induced decreases in insulin secretion and increases in glucagon secretion were not abolished during the 10-minute washout period. During the arginine treatment, both amitraz and BTS 27271 groups (0.1, 1, and 10 micromol/L) had lower insulin secretion and higher glucagon secretion than the control group. Idazoxan, an alpha2A/2D-adrenergic receptor (AR) antagonist, prevented the inhibitory effect of amitraz on insulin secretion in a concentration-dependent manner, but prazosin, an alpha1- and alpha2B/2C-AR antagonist, failed to antagonize the effect of amitraz. These results demonstrate that (1) amitraz and BTS 27271 inhibit insulin and stimulate glucagon secretion from the perfused rat pancreas, (2) amitraz inhibits insulin secretion by activation of alpha2D-ARs, since rats have alpha2D- but not alpha2A-ARs, and (3) amitraz and BTS 27271 may have a high binding affinity to the alpha2D-ARs of pancreatic islets.

  8. d-Limonene-induced male rat-specific nephrotoxicity: Evaluation of the association between d-limonene and alpha 2u-globulin

    International Nuclear Information System (INIS)

    Lehman-McKeeman, L.D.; Rodriguez, P.A.; Takigiku, R.; Caudill, D.; Fey, M.L.

    1989-01-01

    d-Limonene is a naturally occurring monoterpene, which when dosed orally, causes a male rat-specific nephrotoxicity manifested acutely as the exacerbation of protein droplets in proximal tubule cells. Experiments were conducted to examine the retention of [ 14 C]d-limonene in male and female rat kidney, to determine whether d-limonene or one or more of its metabolites associates with the male rat-specific protein, alpha 2u-globulin, and if so, to identify the bound material. The results indicated that, 24 hr after oral administration of 3 mmol d-limonene/kg, the renal concentration of d-limonene equivalents was approximately 2.5 times higher in male rats than in female rats. Equilibrium dialysis in the presence or absence of sodium dodecyl sulfate indicated that approximately 40% of the d-limonene equivalents in male rat kidney associated with proteins in a reversible manner, whereas no significant association was observed between d-limonene equivalents and female rat kidney proteins. Association between d-limonene and male rat kidney proteins was characterized by high-performance gel filtration and reverse-phase chromatography. Gel filtration HPLC indicated that d-limonene in male rat kidney is associated with a protein fraction having a molecular weight of approximately 20,000. Separation of alpha 2u-globulin from other kidney proteins by reverse-phase HPLC indicated that d-limonene associated with a protein present only in male rat kidney which was definitively identified as alpha 2u-globulin by amino acid sequencing. The major metabolite associated with alpha 2u-globulin was d-limonene-1,2-oxide. Parent d-limonene was also identified as a minor component in the alpha 2u-globulin fraction

  9. CD16+ monocyte subset was enriched and functionally exacerbated in driving T-cell activation and B-cell response in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Huaqun Zhu

    2016-11-01

    Full Text Available Background: The roles that CD16+ monocyte subset plays in T-cell activation and B-cell response have not been well studied in systemic lupus erythematosus (SLE. Objective: The present study aimed to investigate the distribution of CD16+ monocyte subsets in SLE and explore their possible roles in T-cell activation and B-cell differentiation. Methods: The frequencies of monocyte subsets in the peripheral blood of healthy controls (HCs and patients with SLE were determined by flow cytometry. Monocyte subsets were sorted and co-cultured with CD4+ T cells and CD19+ B cells. Then, T and B cells were collected for different subset detection, while the supernatants were collected for immunoglobulin G (IgG, IgA, and IgM or interferon (IFN-γ and interleukin (IL-17A detection by enzyme-linked immunosorbent assay. Results: Our results showed that CD16+ monocytes exhibited a pro-inflammatory phenotype with elevated CD80, CD86, HLA-DR, and CX3CR1 expression on the cell surface. It’s further demonstrated that CD16+ monocytes from patients and HCs shared different cell-surface marker profiles. The CD16+ subset was enriched in SLE and had an exacerbated capacity to promote CD4+ T cell polarization into a Th17 phenotype. Also, CD16+ monocytes had enhanced impacts on CD19+ B cells to differentiate into plasma B cells and regulatory B cells with more Ig production. Conclusions: This study demonstrated that CD16+ monocytes, characterized by different cell-surface marker profiles, were enriched and played a critical role in driving the pathogenic T- and B-cell responses in patients with SLE.

  10. COPD exacerbation: Lost in translation

    Directory of Open Access Journals (Sweden)

    Bouros Demosthenes

    2009-01-01

    Full Text Available Abstract The introduction and acceptance of a standard definition for exacerbations of COPD can be helpful in prompt diagnosis and management of these events. The latest GOLD executive committee recognised this necessity and it has now included a definition of exacerbation in the guidelines for COPD which is an important step forward in the management of the disease. This definition is pragmatic and compromises the different approaches for exacerbation. However, the inclusion of the "healthcare utilisation" approach (".. may warrant a change in regular medication" in the definition may introduce in the diagnosis of exacerbation factors related to the access to health care services which may not be related to the underlying pathophysiologal process which characterizes exacerbations. It should be also noted that the aetiology of COPD exacerbations has not yet been included in the current definition. In this respect, the definition does not acknowledge the fact that many patients with COPD may suffer from additional conditions (i.e. congestive cardiac failure or pulmonary embolism that can masquerade as exacerbations but they should not be considered as causes of them. The authors therefore suggest that an inclusion of the etiologic factors of COPD exacerbations in the definition. Moreover, COPD exacerbations are characterized by increased airway and systemic inflammation and significant deterioration in lung fuction. These fundamental aspects should be accounted in diagnosis/definition of exacerbations. This could be done by the introduction of a "laboratory" marker in the diagnosis of these acute events. The authors acknowledge that the use of a test or a biomarker in the diagnosis of exacerbations meets certain difficulties related to performing lung function tests or to sampling during exacerbations. However, the introduction of a test that reflects airway or systemic inflammation in the diagnosis of exacerbations might be another step forward

  11. Asthma induction in mice leads to appearance of alpha2-3- and alpha2-6-linked sialic acid residues in respiratory goblet-like cells

    DEFF Research Database (Denmark)

    Kirkeby, Svend; Jensen, Niels-Erik Viby; Mandel, Ulla

    2008-01-01

    incubation with the sialic acid detecting agents, while the goblet-like cells expressed both alpha2-3- and alpha2-6-linked sialic acid residues in the asthmatic animals. The lectins but not the antibodies reacted with intestinal goblet cells. Instead, an antibody recognizing a disialoganglioside, stained......Allergic asthmatic inflammation in mice was induced by sensitization with ovalbumin and lipopolysaccharide from Escherichia coli and visualized in the airways of asthmatic mice by spatial and temporal changes of carbohydrates containing sialic acid residues. Immunohistochemistry was used...... to demonstrate binding of lectins and antibodies that detect alpha2-3- and alpha2-6-linked sialic acid residues. After sensitization and challenge, the histology of the lung changed markedly, and goblet-like cells appeared, most likely caused by Clara cell metaplasia. Normal Clara cells showed no reaction after...

  12. Extract of Polygala tenuifolia Alleviates Stress-Exacerbated Atopy-Like Skin Dermatitis through the Modulation of Protein Kinase A and p38 Mitogen-Activated Protein Kinase Signaling Pathway.

    Science.gov (United States)

    Sur, Bongjun; Lee, Bombi; Yoon, Ye Seul; Lim, Pooreum; Hong, Riwon; Yeom, Mijung; Lee, Hyang Sook; Park, Hijoon; Shim, Insop; Lee, Hyejung; Jang, Young Pyo; Hahm, Dae-Hyun

    2017-01-18

    Atopic dermatitis (AD) and stress create a vicious cycle: stress exacerbates atopic symptoms, and atopic disease elicits stress and anxiety. Targeting multiple pathways including stress and allergic inflammation is, therefore, important for treating AD. In this study, we investigated the remedial value of Polygala tenuifolia Willd. (PTW) for treating immobilization (IMO) stress-exacerbated atopy-like skin dermatitis and its underlying mechanism. Trimellitic anhydride (TMA) was applied to dorsal skin for sensitization and subsequently both ears for eliciting T-cell-dependent contact hypersensitivity in mice, which underwent 2 h-IMO stress and PTW administration for the latter 6 and 9 days in the ear exposure period of TMA, respectively. To elicit in vitro degranulation of human mast cell line-1 (HMC-1), 10 µM substance P (SP) and 200 nM corticotrophin-releasing factor (CRF) were sequentially added with 48 h-interval. PTW extract (500 µg/mL) was added 30 min before CRF treatment. IMO stress exacerbated TMA-induced scratching behavior by 252%, and increased their blood corticosterone levels by two-fold. Treatment with 250 mg/kg PTW significantly restored IMO stress-exacerbated scratching behavior and other indicators such as skin inflammation and water content, lymph node weights, and serum histamine and immunoglobulin E (lgE) levels. Furthermore, it also reversed TMA-stimulated expression of tumor necrosis factor (TNF)-α and interleukin (IL)-4 mRNAs in ear tissues. PTW significantly inhibited SP/CRF-stimulated degranulation of HMC-1 cells, subsequent tryptase secretion, and protein kinase A (PKA) activity. PTW also selectively inhibited p38 mitogen-activated protein kinase (MAPK) phosphorylation in SP/CRF-treated HMC-1 cells. PTW significantly inhibited HMC-1 cell degranulation and alleviated IMO stress-exacerbated atopic dermatitis symptoms by modulating the PKA/p38 MAPK signaling pathway.

  13. Extract of Polygala tenuifolia Alleviates Stress-Exacerbated Atopy-Like Skin Dermatitis through the Modulation of Protein Kinase A and p38 Mitogen-Activated Protein Kinase Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Bongjun Sur

    2017-01-01

    Full Text Available Atopic dermatitis (AD and stress create a vicious cycle: stress exacerbates atopic symptoms, and atopic disease elicits stress and anxiety. Targeting multiple pathways including stress and allergic inflammation is, therefore, important for treating AD. In this study, we investigated the remedial value of Polygala tenuifolia Willd. (PTW for treating immobilization (IMO stress-exacerbated atopy-like skin dermatitis and its underlying mechanism. Trimellitic anhydride (TMA was applied to dorsal skin for sensitization and subsequently both ears for eliciting T-cell-dependent contact hypersensitivity in mice, which underwent 2 h-IMO stress and PTW administration for the latter 6 and 9 days in the ear exposure period of TMA, respectively. To elicit in vitro degranulation of human mast cell line-1 (HMC-1, 10 µM substance P (SP and 200 nM corticotrophin-releasing factor (CRF were sequentially added with 48 h-interval. PTW extract (500 µg/mL was added 30 min before CRF treatment. IMO stress exacerbated TMA-induced scratching behavior by 252%, and increased their blood corticosterone levels by two-fold. Treatment with 250 mg/kg PTW significantly restored IMO stress-exacerbated scratching behavior and other indicators such as skin inflammation and water content, lymph node weights, and serum histamine and immunoglobulin E (lgE levels. Furthermore, it also reversed TMA-stimulated expression of tumor necrosis factor (TNF-α and interleukin (IL-4 mRNAs in ear tissues. PTW significantly inhibited SP/CRF-stimulated degranulation of HMC-1 cells, subsequent tryptase secretion, and protein kinase A (PKA activity. PTW also selectively inhibited p38 mitogen-activated protein kinase (MAPK phosphorylation in SP/CRF-treated HMC-1 cells. PTW significantly inhibited HMC-1 cell degranulation and alleviated IMO stress-exacerbated atopic dermatitis symptoms by modulating the PKA/p38 MAPK signaling pathway.

  14. Hepatic histomorphological and biochemical changes following highly active antiretroviral therapy in an experimental animal model: Does Hypoxis hemerocallidea exacerbate hepatic injury?

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    Onyemaechi Okpara Azu

    Full Text Available As the roll-out of antiretroviral therapy continues to drive downwards morbidity and mortality in people living with HIV/AIDS (PLWHAs, organ toxicities (especially the liver are frequently becoming a major concern for researchers, scientists and healthcare planners.This study was conducted to investigate the possible protective effect of Hypoxis hemerocallidea (AP against highly active antiretroviral therapy (HAART-induced hepatotoxicity. A total of 63 pathogen-free adult male Sprague-Dawley rats were divided into 9 groups and treated according to protocols.While no mortality was reported, animals treated with adjuvant HAART and AP recorded least% body weight gain. Significant derangements in serum lipid profiles were exacerbated by treatment of with AP as LDL (increased p < 0.03, triglycerides (increased p < 0.03 with no change in total cholesterol levels. Adjuvant AP with HAART caused reduction in LDL (p < 0.05 and 0.03, increased HDL (p < 0.05 and TG (p < 0.05 and 0.001 for AP100 and AP200 doses respectively. Markers of liver injury assayed showed significant increase (p < 0.003, 0.001 in AST in AP alone as well as HAART+ vitamins C and E groups respectively. Adjuvant HAART and AP and vitamins C and E also caused significant declines in ALT and ALP levels. Serum GGT was not markedly altered. Disturbances in histopathology ranged from severe hepatocellular distortions, necrosis and massive fibrosis following co-treatment of HAART with vitamins C and E as well as HAART alone. These results warrant caution on the adjuvant use of AP with HAART by PLWHAs as implications for hepatocellular injuries are suspect with untoward cardiometabolic changes. Keywords: Liver morphology, HAART, Cytotoxicity, Stains, Biochemistry, Lipid profile

  15. The adrenergic alpha2 receptor and sexual incentive motivation in male rats.

    Science.gov (United States)

    Viitamaa, Timo; Haapalinna, Antti; Agmo, Anders

    2006-03-01

    The purpose of the present series of experiments was to determine whether drugs acting at the alpha2-adrenoceptor modify unconditioned sexual incentive motivation in the male rat. To that end a highly specific agonist, dexmedetomidine, a corresponding antagonist, atipamezole, and a less specific antagonist, yohimbine, were administered to groups of sexually inexperienced male rats. The subjects were tested in a large rectangular arena, where a sexually receptive female and an intact male were employed as incentives. The incentive animals were confined behind a wire mesh in opposite corners of the arena. The animals could see, hear and smell each other, but no sexual interaction was possible. Approach to the incentives constituted the measure of incentive motivation. In addition, the test provided data on ambulatory activity and general arousal. Dexmedetomidine, at a dose of 8 microg/kg, produced a slight reduction of sexual incentive motivation. Ambulatory activity and general arousal were also inhibited. Atipamezole, in doses of 0.1 and 0.3mg/kg enhanced the positive incentive properties of the receptive female. A high dose of 1mg/kg did not have any significant effect. Ambulatory activity was slightly reduced by the two larger doses of atipamezole. Yohimbine had a slight stimulatory effect on sexual incentive motivation at a dose (4 mg/kg) that also reduced ambulatory activity and general arousal. It is concluded that blockade of the adrenergic alpha2 receptor stimulates sexual incentive motivation in the male rat whereas stimulation of it has the opposite effect. At present it is not clear if these drug effects are caused by pre- or postsynaptic actions of the drugs, and the importance of secondary changes in other neurotransmitter systems remains unknown.

  16. Alpha 2-adrenergic receptor stimulation of phospholipase A2 and of adenylate cyclase in transfected Chinese hamster ovary cells is mediated by different mechanisms

    International Nuclear Information System (INIS)

    Jones, S.B.; Halenda, S.P.; Bylund, D.B.

    1991-01-01

    The effect of alpha 2-adrenergic receptor activation on adenylate cyclase activity in Chinese hamster ovary cells stably transfected with the alpha 2A-adrenergic receptor gene is biphasic. At lower concentrations of epinephrine forskolin-stimulated cyclic AMP production is inhibited, but at higher concentrations the inhibition is reversed. Both of these effects are blocked by the alpha 2 antagonist yohimbine but not by the alpha 1 antagonist prazosin. Pretreatment with pertussis toxin attenuates inhibition at lower concentrations of epinephrine and greatly potentiates forskolin-stimulated cyclic AMP production at higher concentrations of epinephrine. alpha 2-Adrenergic receptor stimulation also causes arachidonic acid mobilization, presumably via phospholipase A2. This effect is blocked by yohimbine, quinacrine, removal of extracellular Ca2+, and pretreatment with pertussis toxin. Quinacrine and removal of extracellular Ca2+, in contrast, have no effect on the enhanced forskolin-stimulated cyclic AMP production. Thus, it appears that the alpha 2-adrenergic receptor in these cells can simultaneously activate distinct signal transduction systems; inhibition of adenylate cyclase and stimulation of phospholipase A2, both via G1, and potentiation of cyclic AMP production by a different (pertussis toxin-insensitive) mechanism

  17. Alpha 2-adrenergic receptor stimulation of phospholipase A2 and of adenylate cyclase in transfected Chinese hamster ovary cells is mediated by different mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Jones, S.B.; Halenda, S.P.; Bylund, D.B. (Univ. of Missouri-Columbia (USA))

    1991-02-01

    The effect of alpha 2-adrenergic receptor activation on adenylate cyclase activity in Chinese hamster ovary cells stably transfected with the alpha 2A-adrenergic receptor gene is biphasic. At lower concentrations of epinephrine forskolin-stimulated cyclic AMP production is inhibited, but at higher concentrations the inhibition is reversed. Both of these effects are blocked by the alpha 2 antagonist yohimbine but not by the alpha 1 antagonist prazosin. Pretreatment with pertussis toxin attenuates inhibition at lower concentrations of epinephrine and greatly potentiates forskolin-stimulated cyclic AMP production at higher concentrations of epinephrine. alpha 2-Adrenergic receptor stimulation also causes arachidonic acid mobilization, presumably via phospholipase A2. This effect is blocked by yohimbine, quinacrine, removal of extracellular Ca2+, and pretreatment with pertussis toxin. Quinacrine and removal of extracellular Ca2+, in contrast, have no effect on the enhanced forskolin-stimulated cyclic AMP production. Thus, it appears that the alpha 2-adrenergic receptor in these cells can simultaneously activate distinct signal transduction systems; inhibition of adenylate cyclase and stimulation of phospholipase A2, both via G1, and potentiation of cyclic AMP production by a different (pertussis toxin-insensitive) mechanism.

  18. 25-hydroxyvitamin D deficiency, exacerbation frequency and human rhinovirus exacerbations in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Quint Jennifer K

    2012-06-01

    Full Text Available Abstract Background 25-hydroxyvitamin D deficiency is associated with COPD and increased susceptibility to infection in the general population. Methods We investigated whether COPD patients deficient in 25-hydroxyvitamin D were more likely to be frequent exacerbators, had reduced outdoor activity and were more susceptible to human rhinovirus (HRV exacerbations than those with insufficient and normal levels. We also investigated whether the frequency of FokI, BsmI and TaqIα 25-hydroxyvitamin D receptor (VDR polymorphisms differed between frequent and infrequent exacerbators. Results There was no difference in 25-hydroxyvitamin D levels between frequent and infrequent exacerbators in the summer; medians 44.1nmol/L (29.1 – 68.0 and 39.4nmol/L (22.3 – 59.2 or winter; medians 24.9nmol/L (14.3 – 43.1 and 27.1nmol/L (19.9 – 37.6. Patients who spent less time outdoors in the 14 days prior to sampling had lower 25-hydroxyvitamin D levels (p = 0.02. Day length was independently associated with 25-hydroxyvitamin D levels (p = 0.02. There was no difference in 25-hydroxyvitamin D levels between baseline and exacerbation; medians 36.2nmol/L (IQR 22.4-59.4 and 33.3nmol/L (23.0-49.7; p = 0.43. HRV positive exacerbations were not associated with lower 25-hydroxyvitamin D levels at exacerbation than exacerbations that did not test positive for HRV; medians 30.0nmol/L (20.4 – 57.8 and 30.6nmol/L (19.4 – 48.7. There was no relationship between exacerbation frequency and any VDR polymorphisms (all p > 0.05. Conclusions Low 25-hydroxyvitamin D levels in COPD are not associated with frequent exacerbations and do not increase susceptibility to HRV exacerbations. Independent of day length, patients who spend less time outdoors have lower 25-hydroxyvitamin D concentration.

  19. Mannan-binding protein forms complexes with alpha-2-macroglobulin. A protein model for the interaction

    DEFF Research Database (Denmark)

    Storgaard, P; Holm Nielsen, E; Skriver, E

    1995-01-01

    We report that alpha-2-macroglobulin (alpha 2M) can form complexes with a high molecular weight porcine mannan-binding protein (pMBP-28). The alpha 2M/pMBP-28 complexes was isolated by PEG-precipitation and affinity chromatography on mannan-Sepharose, protein A-Sepharose and anti-IgM Sepharose......-PAGE, which reacted with antibodies against alpha 2M and pMBP-28, respectively, in Western blotting. Furthermore, alpha 2M/pMBP-28 complexes were demonstrated by electron microscopy. Fractionation of pMBP-containing D-mannose eluate from mannan-Sepharose on Superose 6 showed two protein peaks which reacted...

  20. Exacerbations of asthma during pregnancy

    DEFF Research Database (Denmark)

    Ali, Z; Hansen, A V; Ulrik, C S

    2016-01-01

    Asthma is common among pregnant women, and the incidence of asthma exacerbations during pregnancy is high. This literature review provides an overview of the impact of exacerbations of asthma during pregnancy on pregnancy-related complications. The majority of published retrospective studies reveal...... that asthma exacerbations during pregnancy increase the risk of pre-eclampsia, gestational diabetes, placental abruption and placenta praevia. Furthermore, these women also have higher risk for breech presentation, haemorrhage, pulmonary embolism, caesarean delivery, maternal admission to the intensive care...... to these outcomes. In conclusion, asthma exacerbations during pregnancy are associated with complications of pregnancy, labour and delivery. Prevention of exacerbations is essential to reduce the risk of complications and poor outcome....

  1. Aspirin-Exacerbated Asthma

    Directory of Open Access Journals (Sweden)

    Varghese Mathew

    2008-06-01

    Full Text Available This review focuses on aspirin-exacerbated asthma (AEA. The review includes historical perspective of aspirin, prevalence, pathogenesis, clinical features and treatment of AEA. The pathogenesis of AEA involves the cyclooxygenase and lipooxygenase pathway. Aspirin affects both of these pathways by inhibiting the enzyme cycooxygenase-1 (COX-1. Inhibition of COX-1 leads to a decrease in prostaglandin E2 (PGE2. The decrease in PGE2 results in an increase in cysteinyl leukotrienes by the lipooxygenase pathway involving the enzyme 5-lipooxygenase (5-LO. Leukotriene C4 (LTC4 synthase is the enzyme responsible for the production of leukotriene C4, the chief cysteinyl leukotriene responsible for AEA. There have been familial occurences of AEA. An allele of the LTC4 synthase gene in AEA is known as allele C. Allele C has a higher frequency in AEA. Clinical presentation includes a history of asthma after ingestion of aspirin, nasal congestion, watery rhinorrhea and nasal polyposis. Treatment includes leukotriene receptor antagonists, leukotriene inhibitors, aspirin desinsitaztion and surgery. AEA is the most well-defined phenotype of asthma. Although AEA affects adults and children with physician-diagnosed asthma, in some cases there is no history of asthma and AEA often goes unrecognized and underdiagnosed.

  2. Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice

    DEFF Research Database (Denmark)

    Guo, L T; Zhang, X U; Kuang, W

    2003-01-01

    Deficiency of laminin alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal...... the human laminin alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in laminin alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated laminin alpha......2, lacking domain VI. Interestingly, all mutants lack laminin alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human laminin alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific creatine kinase promoter...

  3. Binding of alpha2ML1 to the low density lipoprotein receptor-related protein 1 (LRP1 reveals a new role for LRP1 in the human epidermis.

    Directory of Open Access Journals (Sweden)

    Marie-Florence Galliano

    Full Text Available BACKGROUND: The multifunctional receptor LRP1 has been shown to bind and internalize a large number of protein ligands with biological importance such as the pan-protease inhibitor alpha2-macroglobulin (alpha2M. We recently identified Alpha2ML1, a new member of the alpha2M gene family, expressed in epidermis. alpha2ML1 might contribute to the regulation of desquamation through its inhibitory activity towards proteases of the chymotrypsin family, notably KLK7. The expression of LRP1 in epidermis as well as its ability to internalize alpha2ML1 was investigated. METHODS AND PRINCIPAL FINDINGS: In human epidermis, LRP1 is mainly expressed within the granular layer of the epidermis, which gathers the most differentiated keratinocytes, as shown by immunohistochemistry and immunofluorescence using two different antibodies. By using various experimental approaches, we show that the receptor binding domain of alpha2ML1 (RBDl is specifically internalized into the macrophage-like cell line RAW and colocalizes with LRP1 upon internalization. Coimmunoprecipitation assays demonstrate that RBDl binds LRP1 at the cell surface. Addition of RAP, a universal inhibitor of ligand binding to LRP1, prevents RBDl binding at the cell surface as well as internalization into RAW cells. Silencing Lrp1 expression with specific siRNA strongly reduces RBDl internalization. CONCLUSIONS AND SIGNIFICANCE: Keratinocytes of the upper differentiated layers of epidermis express LRP1 as well as alpha2ML1. Our study also reveals that alpha2ML1 is a new ligand for LRP1. Our findings are consistent with endocytosis by LRP1 of complexes formed between alpha2ML1 and proteases. LRP1 may thus control desquamation by regulating the biodisponibility of extracellular proteases.

  4. Mannan-binding protein forms complexes with alpha-2-macroglobulin. A protein model for the interaction

    DEFF Research Database (Denmark)

    Storgaard, P; Holm Nielsen, E; Skriver, E

    1995-01-01

    . The occurrence of alpha 2M/pMBP-28 complexes was further indicated by crossed immunoelectrophoresis and by use of an anti-alpha 2M affinity column and chelating Sepharose loaded with Zn2+. The eluates from these affinity columns showed alpha 2M subunits (94 and 180 kDa) and pMBP subunits (28kDa) in SDS-PAGE...... with anti-C1 s antibodies in ELISA, one of about 650-800 kDa, which in addition contained pMBP-28 and anti-alpha 2M reactive material, the other with an M(r) of 100-150 kDa. The latter peak revealed rhomboid molecules (7 x 15 nm) in the electron microscope and a 67 kDa band in SDS-PAGE under reducing...

  5. Dietary Salt Exacerbates Experimental Colitis.

    Science.gov (United States)

    Tubbs, Alan L; Liu, Bo; Rogers, Troy D; Sartor, R Balfour; Miao, Edward A

    2017-08-01

    The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10-deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD. Copyright © 2017 by The American Association of Immunologists, Inc.

  6. Expression and ligand binding of alpha 2 beta 1 integrin on breast carcinoma cells.

    Science.gov (United States)

    Maemura, M; Akiyama, S K; Woods, V L; Dickson, R B

    1995-07-01

    We examined the expression and ligand specificity of the alpha 2 beta 1 integrin on human mammary epithelial cells (HMEC) and a panel of breast carcinoma cell lines in vitro. We found that the alpha 2 beta 1 integrin was universally, but quite variably expressed on these cells by FACS analysis. No significant correlation was observed between its expression and other known cellular phenotypes. Substrate attachment assays using blocking antibodies demonstrated that alpha 2 beta 1 integrin served as a receptor for collagen on HMEC and almost all breast carcinoma cells. However, its contribution to laminin binding of these cells appeared to be related to cellular differentiation as evaluated by sex steroid receptor status and by markers of epithelial-mesenchymal transition, i.e. loss of E-cadherin and expression of vimentin. Two different populations of non-malignant immortalized HMEC (184A1N4 and MCF-10A) contained cells capable of using alpha 2 beta 1 integrin as a laminin receptor. Breast cancer cell lines positive for estrogen receptor (ER) and E-cadherin (MCF-7, T47D, ZR75-1) could also use alpha 2 beta 1 integrin as a laminin receptor. Conversely, alpha 2 beta 1 integrin appeared to be incapable of binding to laminin or to be a very minor receptor for laminin on metastatic ER-negative breast carcinoma cells that expressed vimentin (MDA-MB 231, MDA-MB 435, and MDA-MB 436). These findings suggest that the ligand specificity of alpha 2 beta 1 integrin, i.e. its function as a laminin receptor, may be regulated during the malignant progression of breast carcinoma cells. A reduced contribution of alpha 2 beta 1 integrin to the cellular laminin binding appears to be associated with an increased malignant phenotype and with an epithelial-mesenchymal transition of breast carcinoma cells.

  7. Serum eosinophil cationic protein levels can be useful for predicting acute exacerbation of asthma

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Kamimura

    1998-01-01

    Full Text Available We report on a case in which five consecutive exacerbations of asthma were monitored by following serum eosinophil cationic protein (ECP levels. The serum ECP level correlated well with each exacerbation and tended to increase even before the exacerbations of asthma became apparent. This case shows that serum levels of ECP can be useful markers of disease activity and may also be predictive markers for acute exacerbation.

  8. Subclassification of release-regulating alpha 2-autoreceptors in human brain cortex.

    Science.gov (United States)

    Raiteri, M.; Bonanno, G.; Maura, G.; Pende, M.; Andrioli, G. C.; Ruelle, A.

    1992-01-01

    1. Release-regulating alpha 2-autoreceptors in human brain were characterized pharmacologically in cortical slices from patients undergoing neurosurgery to remove subcortical tumours; the slices were prelabelled with [3H]-noradrenaline ([3H]-NA) and stimulated electrically (3 Hz, 2 ms, 24 mA) under superfusion conditions. 2. The stimulus-evoked tritium overflow was almost totally Ca(2+)-dependent and tetrodotoxin-sensitive. 3. Clonidine and oxymetazoline 0.01 to 1 microM inhibited in a concentration-dependent manner the evoked overflow of tritium. The two drugs were equipotent (EC50 = 0.03 microM) and their maximal effect was approx. 45%. Phenylephrine and methoxamine, up to 1 microM, did not affect tritium overflow. 4. Yohimbine (0.01-0.1 microM) shifted the concentration-response curve of clonidine to the right. The calculated pA2 value was 8.29. 5. Prazosin and 2-[2-[4-(o-methoxyphenyl)piperazine-1-yl]ethyl]-4,4- dimethyl-1,3(2H,4H)-isoquinolinedione (AR-C 239), tested at 0.3 microM, did not modify the concentration-response curve of clonidine. 6. The effect of clonidine was antagonized by (+)-mianserin (pA2 = 7.74), but not by up to 0.3 microM of the (-)-enantiomer. The concentration-response curve of clonidine was shifted to the right by the novel alpha 2-adrenoceptor antagonist, 5-chloro-4-(1-butyl-1,2,5,6-tetrahydropyridin-3-yl)-thiazole-2-ami ne (Z)-2-butenedioate (1:1) salt (ORG 20350) (pA2 = 7.55). 7. Yohimbine, (+)-mianserin and ORG 20350, but not prazosin and (-)-mianserin, increased the electrically-evoked tritium overflow, suggesting that autoreceptors may be tonically activated by endogenous NA. 8. Desipramine (1 microM) increased evoked tritium overflow from human cortex slices.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1361400

  9. Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response.

    Science.gov (United States)

    Federici Canova, Donata; Pavlov, Anton M; Norling, Lucy V; Gobbetti, Thomas; Brunelleschi, Sandra; Le Fauder, Pauline; Cenac, Nicolas; Sukhorukov, Gleb B; Perretti, Mauro

    2015-11-10

    Synthetic microstructures can be engineered to deliver bioactive compounds impacting on their pharmacokinetics and pharmacodynamics. Herein, we applied dextran-based layer-by-layer (LbL) microcapsules to deliver alpha-2-macroglobulin (α2MG), a protein with modulatory properties in inflammation. Extending recent observations made with dextran-microcapsules loaded with α2MG in experimental sepsis, we focused on the physical and chemical characteristics of these microstructures and determined their biology on rodent and human cells. We report an efficient encapsulation of α2MG into microcapsules, which enhanced i) human leukocyte recruitment to inflamed endothelium and ii) human macrophage phagocytosis: in both settings microcapsules were more effective than soluble α2MG or empty microcapsules (devoid of active protein). Translation of these findings revealed that intravenous administration of α2MG-microcapsules (but not empty microcapsules) promoted neutrophil migration into peritoneal exudates and augmented macrophage phagocytic functions, the latter response being associated with alteration of bioactive lipid mediators as assessed by mass spectrometry. The present study indicates that microencapsulation can be an effective strategy to harness the complex biology of α2MG with enhancing outcomes on fundamental processes of the innate immune response paving the way to potential future development in the control of sepsis. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Alpha-2 adrenergic stimulation triggers Achilles tenocyte hypercellularity: Comparison between two model systems.

    Science.gov (United States)

    Backman, L J; Andersson, G; Fong, G; Alfredson, H; Scott, A; Danielson, P

    2013-12-01

    The histopathology of tendons with painful tendinopathy is often tendinosis, a fibrosis-like condition of unclear pathogenesis characterized by tissue changes including hypercellularity. The primary tendon cells (tenocytes) have been shown to express adrenoreceptors (mainly alpha-2A) as well as markers of catecholamine production, particularly in tendinosis. It is known that adrenergic stimulation can induce proliferation in other cells. The present study investigated the effects of an exogenously administered alpha-2 adrenergic agonist in an established in vivo Achilles tendinosis model (rabbit) and also in an in vitro human tendon cell culture model. The catecholamine producing enzyme tyrosine hydroxylase and the alpha-2A-adrenoreceptor (α2A AR) were expressed by tenocytes, and alpha-2 adrenergic stimulation had a proliferative effect on these cells, in both models. The proliferation was inhibited by administration of an α2A AR antagonist, and the in vitro model further showed that the proliferative alpha-2A effect was mediated via a mitogenic cell signaling pathway involving phosphorylation of extracellular-signal-regulated kinases 1 and 2. The results indicate that catecholamines produced by tenocytes in tendinosis might contribute to the proliferative nature of the pathology through stimulation of the α2A AR, pointing to a novel target for future therapies. The study furthermore shows that animal models are not necessarily required for all aspects of this research. © 2013 The Authors. Scand J Med Sci Sports published by John Wiley & Sons Ltd.

  11. Accelerated extracellular matrix turnover during exacerbations of COPD.

    Science.gov (United States)

    Sand, Jannie M B; Knox, Alan J; Lange, Peter; Sun, Shu; Kristensen, Jacob H; Leeming, Diana J; Karsdal, Morten A; Bolton, Charlotte E; Johnson, Simon R

    2015-06-11

    Exacerbations of chronic obstructive pulmonary disease (COPD) contribute significantly to disease progression. However, the effect on tissue structure and turnover is not well described. There is an urgent clinical need for biomarkers of disease activity associated with disease progression. Extracellular matrix (ECM) turnover reflects activity in tissues and consequently assessment of ECM turnover may serve as biomarkers of disease activity. We hypothesized that the turnover of lung ECM proteins were altered during exacerbations of COPD. 69 patients with COPD hospitalised for an exacerbation were recruited at admission and returned for a 4 weeks follow-up. Competitive ELISAs measuring circulating protein fragments in serum or plasma assessed the formation and degradation of collagen types III (Pro-C3 and C3M, respectively), IV (P4NP 7S and C4M, respectively), and VI (Pro-C6 and C6M, respectively), and degradation of elastin (ELM7 and EL-NE) and versican (VCANM). Circulating levels of C3M, C4M, C6M, ELM7, and EL-NE were elevated during an exacerbation of COPD as compared to follow-up (all P <0.0001), while VCANM levels were decreased (P <0.0001). Pro-C6 levels were decreased and P4NP 7S levels were elevated during exacerbation (P <0.0001). Pro-C3 levels were unchanged. At time of exacerbation, degradation/formation ratios were increased for collagen types III and VI and decreased for collagen type IV. Exacerbations of COPD resulted in elevated levels of circulating fragments of structural proteins, which may serve as markers of disease activity. This suggests that patients with COPD have accelerated ECM turnover during exacerbations which may be related to disease progression.

  12. COPD exacerbations, inflammation and treatment

    NARCIS (Netherlands)

    Bathoorn, Derk

    2007-01-01

    This thesis describes investigations into the inflammation in COPD, and its treatment. Inflammation in COPD is a central factor in the onset of the disease and its progression. During acute deteriorations of the disease, exacerbations, the inflammation is more severe, and depending on the cause of

  13. Reactive protoplasmic and fibrous astrocytes contain high levels of calpain-cleaved alpha 2 spectrin.

    Science.gov (United States)

    Kim, Jung H; Kwon, Soojung J; Stankewich, Michael C; Huh, Gi-Yeong; Glantz, Susan B; Morrow, Jon S

    2016-02-01

    Calpain, a family of calcium-dependent neutral proteases, plays important roles in neurophysiology and pathology through the proteolytic modification of cytoskeletal proteins, receptors and kinases. Alpha 2 spectrin (αII spectrin) is a major substrate for this protease family, and the presence of the αII spectrin breakdown product (αΙΙ spectrin BDP) in a cell is evidence of calpain activity triggered by enhanced intracytoplasmic Ca(2+) concentrations. Astrocytes, the most dynamic CNS cells, respond to micro-environmental changes or noxious stimuli by elevating intracytoplasmic Ca(2+) concentration to become activated. As one measure of whether calpains are involved with reactive glial transformation, we examined paraffin sections of the human cerebral cortex and white matter by immunohistochemistry with an antibody specific for the calpain-mediated αΙΙ spectrin BDP. We also performed conventional double immunohistochemistry as well as immunofluorescent studies utilizing antibodies against αΙΙ spectrin BDP as well as glial fibrillary acidic protein (GFAP). We found strong immunopositivity in selected protoplasmic and fibrous astrocytes, and in transitional forms that raise the possibility of some of fibrous astrocytes emerging from protoplasmic astrocytes. Immunoreactive astrocytes were numerous in brain sections from cases with severe cardiac and/or respiratory diseases in the current study as opposed to our previous study of cases without significant clinical conditions that failed to reveal such remarkable immunohistochemical alterations. Our study suggests that astrocytes become αΙΙ spectrin BDP immunopositive in various stages of activation, and that spectrin cleavage product persists even in fully reactive astrocytes. Immunohistochemistry for αΙΙ spectrin BDP thus marks reactive astrocytes, and highlights the likelihood that calpains and their proteolytic processing of spectrin participate in the morphologic and physiologic transition from

  14. IMMUNOMODULATING THERAPY BY RECOMBINANT ALPHA-2B INTERFERON AMONG CHILDREN WITH TIMOMEGALIA

    Directory of Open Access Journals (Sweden)

    L.A. Nikulin

    2007-01-01

    Full Text Available The study of the enlarged thymus gland syndrome is extremely important for understanding of the immune system formation and functioning mechanisms. the purpose of this study is to conduct clinical and immunological analysis of the children, suffering from the syndrome of the enlarged thymus gland II and III degrees, who received recombinant alpha2b interferon (in suppositories. The revealed changes in the immune sys tem during timomegalia are complex and conducive to the development of the infectious and inflammatory diseases among infants, thus, determining the necessity for the adequate immune correction. The application of the recombinant alpha 2b interferon among such children allows one to uncover the immunomodulating effects, normalizing the imbalances in the immune system of children with timomegalia.Key words: timomegalia, alpha 2b interferon, immunity, immune correction, children.

  15. Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

    LENUS (Irish Health Repository)

    Enudi, W

    2009-08-01

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

  16. Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

    LENUS (Irish Health Repository)

    Enudi, W

    2012-02-01

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

  17. Inactivation of gating currents of L-type calcium channels. Specific role of the alpha 2 delta subunit.

    Science.gov (United States)

    Shirokov, R; Ferreira, G; Yi, J; Ríos, E

    1998-06-01

    In studies of gating currents of rabbit cardiac Ca channels expressed as alpha 1C/beta 2a or alpha 1C/beta 2a/alpha 2 delta subunit combinations in tsA201 cells, we found that long-lasting depolarization shifted the distribution of mobile charge to very negative potentials. The phenomenon has been termed charge interconversion in native skeletal muscle (Brum, G., and E. Ríos. 1987. J. Physiol. (Camb.). 387:489-517) and cardiac Ca channels (Shirokov, R., R. Levis, N. Shirokova, and E. Ríos. 1992. J. Gen. Physiol. 99:863-895). Charge 1 (voltage of half-maximal transfer, V1/2 approximately 0 mV) gates noninactivated channels, while charge 2 (V1/2 approximately -90 mV) is generated in inactivated channels. In alpha 1C/beta 2a cells, the available charge 1 decreased upon inactivating depolarization with a time constant tau approximately 8, while the available charge 2 decreased upon recovery from inactivation (at -200 mV) with tau approximately 0.3 s. These processes therefore are much slower than charge movement, which takes charge movement and that of changes in their availability, which was even wider in the presence of alpha 2 delta, implies that charges 1 and 2 originate from separate channel modes. Because clear modal separation characterizes slow (C-type) inactivation of Na and K channels, this observation establishes the nature of voltage-dependent inactivation of L-type Ca channels as slow or C-type. The presence of the alpha 2 delta subunit did not change the V1/2 of charge 2, but sped up the reduction of charge 1 upon inactivation at 40 mV (to tau approximately 2 s), while slowing the reduction of charge 2 upon recovery (tau approximately 2 s). The observations were well simulated with a model that describes activation as continuous electrodiffusion (Levitt, D. 1989. Biophys. J. 55:489-498) and inactivation as discrete modal change. The effects of alpha 2 delta are reproduced assuming that the subunit lowers the free energy of the inactivated mode.

  18. A model for the stepwise radiation inactivation of the alpha 2-dimer of Na,K-ATPase

    Energy Technology Data Exchange (ETDEWEB)

    Norby, J.G.; Jensen, J. (Univ. of Aarhus (Denmark))

    1989-11-25

    This study is a direct continuation of Jensen, J., and Norby. A new model in which we propose that the in situ organization of the Na,K-ATPase alpha-subunit is an alpha 2-dimer and which describes the stepwise degradation by radiation inactivation of this assembly is presented on the basis of the following findings. Radiation inactivation size for alpha-peptide integrity, normal nucleotide, vanadate and ouabain binding, and K-pNPPase activity is close to m(alpha) = 112 kDa; for Na-ATPase activity it is 135 kDa and for Na,K-ATPase activity it increases from 140 to about 195 kDa with increasing assay ATP concentration (equal to increasing average turnover). Normal Tl+ occlusion had the same radiation inactivation size as Vmax for Na,K-ATPase, i.e. about 195 kDa. The binding experiments disclosed radiation-produced molecules with active binding sites but with a lower than normal affinity. Radiation inactivation size for the total binding capacity of ADP and ouabain was therefore smaller than the size of an alpha-peptide, namely about 70 kDa, and for total Tl+ occlusion it was down to 40 kDa. We can explain all these observations by using a new approach to target size analysis and by assuming a dimeric organization of the alpha-subunit. Each alpha-peptide is degraded stepwise by first destruction of either a 42- or a 70-kDa domain, and the partly damaged peptide may retain biochemical activity. We conclude that there is no role for the beta-subunit in catalysis and that the alpha-peptide is organized as an alpha 2-dimer in the membrane with each alpha-subunit being able to perform complete catalytic cycles (and probably also active transport), provided that it is stabilized by an adjacent alpha-peptide or a sufficiently large fragment thereof.

  19. A model for the stepwise radiation inactivation of the alpha 2-dimer of Na,K-ATPase

    International Nuclear Information System (INIS)

    Norby, J.G.; Jensen, J.

    1989-01-01

    This study is a direct continuation of Jensen, J., and Norby. A new model in which we propose that the in situ organization of the Na,K-ATPase alpha-subunit is an alpha 2-dimer and which describes the stepwise degradation by radiation inactivation of this assembly is presented on the basis of the following findings. Radiation inactivation size for alpha-peptide integrity, normal nucleotide, vanadate and ouabain binding, and K-pNPPase activity is close to m(alpha) = 112 kDa; for Na-ATPase activity it is 135 kDa and for Na,K-ATPase activity it increases from 140 to about 195 kDa with increasing assay ATP concentration (equal to increasing average turnover). Normal Tl+ occlusion had the same radiation inactivation size as Vmax for Na,K-ATPase, i.e. about 195 kDa. The binding experiments disclosed radiation-produced molecules with active binding sites but with a lower than normal affinity. Radiation inactivation size for the total binding capacity of ADP and ouabain was therefore smaller than the size of an alpha-peptide, namely about 70 kDa, and for total Tl+ occlusion it was down to 40 kDa. We can explain all these observations by using a new approach to target size analysis and by assuming a dimeric organization of the alpha-subunit. Each alpha-peptide is degraded stepwise by first destruction of either a 42- or a 70-kDa domain, and the partly damaged peptide may retain biochemical activity. We conclude that there is no role for the beta-subunit in catalysis and that the alpha-peptide is organized as an alpha 2-dimer in the membrane with each alpha-subunit being able to perform complete catalytic cycles (and probably also active transport), provided that it is stabilized by an adjacent alpha-peptide or a sufficiently large fragment thereof

  20. Evidence of an alpha 2-macroglobulin-like molecule in plasma of Salamandra salamandra. Structural and functional similarity with human alpha 2-macroglobulin.

    Science.gov (United States)

    Sallenave, J M; Bellot, R

    1987-07-13

    A high-Mr (Mr 750,000) alpha 1-macroglobulin, obtained from Salamandra salamandra, is described. Salamander alpha 1-macroglobulin is composed of two monomers of equal Mr, which are composed of two polypeptide chains, each of Mr 180,000, linked by disulfide bonds. The molecular parameters of this protein, its binding to trypsin and inactivation by methylamine suggest that salamander alpha 1-macroglobulin is closely related to human alpha 2-macroglobulin and to other related proteins described in the animal kingdom.

  1. Inhibition of K+ permeability diminishes alpha 2-adrenoceptor mediated effects on norepinephrine release

    International Nuclear Information System (INIS)

    Zimanyi, I.; Folly, G.; Vizi, E.S.

    1988-01-01

    The effect of two different potassium channel blockers, 4-aminopyridine (4-AP) and quinine, on the alpha 2-adrenoceptor mediated modulation of norepinephrine (NE) release was investigated. Pairs of mouse vasa deferentia were loaded with 3 H-norepinephrine ( 3 H-NE), superfused continuously, and stimulated electrically. 4-AP (5.3 x 10(-4) M), and quinine (10(-5) M) enhanced the stimulation-evoked release of tritium significantly. The electrically induced release of radioactivity was reduced by alpha 2-adrenoceptor agonists (1-NE and xylazine) and enhanced by the alpha 2-adrenoceptor antagonist yohimbine. Both effects were affected markedly by 4-AP or quinine: the depressant action of 1-NA and xylazine was partially antagonized and the facilitatory effect of yohimbine was completely abolished during the blockade of the potassium channels. It is suggested that the blockade of the potassium permeability counteracts negative feedback modulation; therefore, it seems likely that the stimulation of alpha 2-adrenoceptors leads to an enhanced potassium permeability and hyperpolarization of varicose axon terminals

  2. Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene

    DEFF Research Database (Denmark)

    Xu, H; Wu, X R; Wewer, U M

    1994-01-01

    The classic murine muscular dystrophy strain, dy, was first described almost 40 years ago. We have identified the molecular basis of an allele of dy, called dy2J, by detecting a mutation in the laminin alpha 2 chain gene--the first identified mutation in laminin-2. The G to A mutation in a splice...

  3. Differential transcription of alpha-2-macroglobulin in carp (Cyprinus carpio) infected with parasites

    NARCIS (Netherlands)

    Onara, D.F.; Forlenza, M.; Gonzalez, S.F.; Rakus, K.L.; Pilarczyk, A.; Irnazarow, I.; Wiegertjes, G.F.

    2008-01-01

    Alpha-2-macroglobulin (a2M) is a non-specific protease inhibitor involved in host defense mechanisms, inhibiting both endogenous and exogenous proteases. It is unique among the plasma anti-proteases with respect to the diversity of proteases that it can inactivate. Carp a2M consists of an alpha and

  4. Loss of platelet alpha 2-adrenergic receptors during simulated extracorporeal circulation: prevention with prostaglandin E1

    Energy Technology Data Exchange (ETDEWEB)

    Wachtogel, Y.T.; Musial, J.; Jenkin, B.; Niewiarowski, S.; Edmunds, L.H. Jr.; Colman, R.W.

    1985-05-01

    Cardiopulmonary bypass prolongs bleeding time and increases postoperative blood loss. During in vitro recirculation in an extracorporeal circuit containing a membrane oxygenator and primed with fresh heparinized human blood, the authors previously observed thrombocytopenia, impaired platelet aggregation, and depletion of granular contents, all of which were prevented with prostaglandin E1 (PGE1). To investigate these changes further, they studied the number and affinity of platelet alpha 2-adrenergic receptors by measuring the binding of /sup 3/H-yohimbine. Before recirculation, they found 235 alpha 2-adrenergic receptors per platelet, a Kd of 3.37 nmol/L, complete aggregation with 1.04 mumol/L epinephrine, and a platelet count of 281,000 microliters/sup -1/. After 2 minutes of recirculation, 9.44 mumol/L epinephrine was required to produce complete aggregation, and the platelet count was 104,000 microliters-1 (44% of control). After 2 hours of recirculation, the platelet count had increased to 123,000 microliters/sup -1/. However, epinephrine did not induce platelet aggregation even at 100 mumol/L. Moreover, alpha 2-adrenergic binding sites were not detectable, and affinity for yohimbine could not be calculated. Two minutes after PGE1 0.3 mumol/L was added to the circuit, platelet numbers, response to epinephrine, alpha 2-adrenergic binding sites per platelet, and affinity for yohimbine were not significantly different from control values. At 2 hours, the number of alpha 2-adrenergic sites was not significantly changed from control, but the affinity of yohimbine for platelets was significantly decreased 2.5-fold.

  5. Loss of platelet alpha 2-adrenergic receptors during simulated extracorporeal circulation: prevention with prostaglandin E1

    International Nuclear Information System (INIS)

    Wachtogel, Y.T.; Musial, J.; Jenkin, B.; Niewiarowski, S.; Edmunds, L.H. Jr.; Colman, R.W.

    1985-01-01

    Cardiopulmonary bypass prolongs bleeding time and increases postoperative blood loss. During in vitro recirculation in an extracorporeal circuit containing a membrane oxygenator and primed with fresh heparinized human blood, the authors previously observed thrombocytopenia, impaired platelet aggregation, and depletion of granular contents, all of which were prevented with prostaglandin E1 (PGE1). To investigate these changes further, they studied the number and affinity of platelet alpha 2-adrenergic receptors by measuring the binding of 3 H-yohimbine. Before recirculation, they found 235 alpha 2-adrenergic receptors per platelet, a Kd of 3.37 nmol/L, complete aggregation with 1.04 mumol/L epinephrine, and a platelet count of 281,000 microliters -1 . After 2 minutes of recirculation, 9.44 mumol/L epinephrine was required to produce complete aggregation, and the platelet count was 104,000 microliters-1 (44% of control). After 2 hours of recirculation, the platelet count had increased to 123,000 microliters -1 . However, epinephrine did not induce platelet aggregation even at 100 mumol/L. Moreover, alpha 2-adrenergic binding sites were not detectable, and affinity for yohimbine could not be calculated. Two minutes after PGE1 0.3 mumol/L was added to the circuit, platelet numbers, response to epinephrine, alpha 2-adrenergic binding sites per platelet, and affinity for yohimbine were not significantly different from control values. At 2 hours, the number of alpha 2-adrenergic sites was not significantly changed from control, but the affinity of yohimbine for platelets was significantly decreased 2.5-fold

  6. Platelet alpha 2-adrenergic receptors in major depressive disorder. Binding of tritiated clonidine before and after tricyclic antidepressant drug treatment

    International Nuclear Information System (INIS)

    Garcia-Sevilla, J.A.; Zis, A.P.; Hollingsworth, P.J.; Greden, J.F.; Smith, C.B.

    1981-01-01

    The specific binding of tritiated (3H)-clonidine, an alpha 2-adrenergic receptor agonist, to platelet membranes was measured in normal subjects and in patients with major depressive disorder. The number of platelet alpha 2-adrenergic receptors from the depressed group was significantly higher than that found in platelets obtained from the control population. Treatment with tricyclic antidepressant drugs led to significant decreases in the number of platelet alpha 2-adrenergic receptors. These results support the hypothesis that the depressive syndrome is related to an alpha 2-adrenergic receptor supersensitivity and that the clinical effectiveness of tricyclic antidepressant drugs is associated with a decrease in the number of these receptors

  7. Identification of alpha 2-adrenergic receptor sites in human retinoblastoma (Y-79) and neuroblastoma (SH-SY5Y) cells

    Energy Technology Data Exchange (ETDEWEB)

    Kazmi, S.M.; Mishra, R.K.

    1989-02-15

    The existence of specific alpha 2-adrenergic receptor sites has been shown in human retinoblastoma (Y-79) and neuroblastoma (SH-SH5Y) cells using direct radioligand binding. (/sup 3/H)Rauwolscine, a selective alpha 2-adrenergic receptor antagonist, exhibited high affinity, saturable binding to both Y-79 and SH-SY5Y cell membranes. The binding of alpha 1 specific antagonist, (/sup 3/H)Prazocine, was not detectable in either cell type. Competition studies with antagonists yielded pharmacological characteristics typical of alpha 2-adrenergic receptors: rauwolscine greater than yohimbine greater than phentolamine greater than prazocine. Based on the affinity constants of prazocine and oxymetazoline, it appears that Y-79 cells contain alpha 2A receptor, whereas SH-SY5Y cells probably represent a mixture of alpha 2A and alpha 2B receptors. alpha 2-agonists clonidine and (-)epinephrine inhibition curves yielded high and low affinity states of the receptor in SH-SY5Y cells. Gpp(NH)p and sodium ions reduced the proportion of high affinity sites of alpha 2 receptors. These two neuronal cell lines of human origin would prove useful in elucidating the action and regulation of human alpha 2-adrenergic receptors and their interaction with other receptor systems.

  8. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients.

    Science.gov (United States)

    Chen, Ken; Lu, Zhijun; Xin, Yi Chun; Cai, Yong; Chen, Yi; Pan, Shu Ming

    2015-01-06

    Sedation reduces patient levels of anxiety and stress, facilitates the delivery of care and ensures safety. Alpha-2 agonists have a range of effects including sedation, analgesia and antianxiety. They sedate, but allow staff to interact with patients and do not suppress respiration. They are attractive alternatives for long-term sedation during mechanical ventilation in critically ill patients. To assess the safety and efficacy of alpha-2 agonists for sedation of more than 24 hours, compared with traditional sedatives, in mechanically-ventilated critically ill patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 10, 2014), MEDLINE (1946 to 9 October 2014), EMBASE (1980 to 9 October 2014), CINAHL (1982 to 9 October 2014), Latin American and Caribbean Health Sciences Literature (1982 to 9 October 2014), ISI Web of Science (1987 to 9 October 2014), Chinese Biological Medical Database (1978 to 9 October 2014) and China National Knowledge Infrastructure (1979 to 9 October 2014), the World Health Organization international clinical trials registry platform (to 9 October 2014), Current Controlled Trials metaRegister of controlled trials active registers (to 9 October 2014), the ClinicalTrials.gov database (to 9 October 2014), the conference proceedings citation index (to 9 October 2014) and the reference lists of included studies and previously published meta-analyses and systematic reviews for relevant studies. We imposed no language restriction. We included all randomized and quasi-randomized controlled trials comparing alpha-2 agonists (clonidine or dexmedetomidine) versus alternative sedatives for long-term sedation (more than 24 hours) during mechanical ventilation in critically ill patients. Two review authors independently assessed study quality and extracted data. We contacted study authors for additional information. We performed meta-analyses when more than three studies were included, and selected a random-effects model due

  9. Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model.

    Science.gov (United States)

    Philippens, Ingrid H C H M; Joosen, Marloes J A; Ahnaou, Abdellah; Andres, Ignacio; Drinkenburg, Wilhelmus Pim H I M

    2014-08-01

    Current dopamine replacement therapies, in Parkinson's disease (PD), result in aversive side effects and rapid drug dose escalation over time. Therefore, a non-dopaminergic treatment would be an advantageous supplement to lower the dose of dopamine replacement treatment postponing the occurrence of side effects. The noradrenergic system plays an important role in the facilitation or maintenance of the activity of the nigrostriatal dopamine pathways. Here the putative anti-Parkinson effects of the oral selective alpha2C-adrenoceptor antagonist (JNJ27063699 0.1-10mg/kg p.o.) and of vehicle (fruit syrup) were evaluated in the MPTP-marmoset model. Dose-related anti-Parkinson effects were assessed by means of a behavioural rating scale covering parkinsonian symptoms, body weight and body temperature, and two test systems assessing locomotor activity and complex motor skills of hand-eye coordination for controlled movements in MPTP- or saline-pretreated marmosets. JNJ27063699, at the middle and higher doses, consistently improved locomotor activity and hand-eye coordination capabilities, which indicates an improvement in the coordination of motor control -or movements- in MPTP-pretreated monkeys. No additional effects on the parkinsonian symptoms or side effects were observed on other test systems. Overall, the findings link deficit in motor coordination with dysfunctional adrenergic signalling and it suggest that selective alpha2C adrenergic antagonism may contribute to behavioural improvement in the MPTP-monkey model of PD. In multi-drug medication JNJ27063699 might have potential in the treatment of motor deficit in PD. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Embryo implantation in mouse: fetomaternal coordination in the pattern of expression of uPA, uPAR, PAI-1 and alpha 2MR/LRP genes.

    Science.gov (United States)

    Teesalu, T; Blasi, F; Talarico, D

    1996-05-01

    During the process of embryo implantation, trophoblast cells invade deep into uterine stroma and play a key role in establishing fetomaternal exchange of molecules. We have studied the in vivo expression patterns of the molecules of the urokinase system, during the process of mouse embryo implantation and early placentation. The sites of synthesis of urokinase-type plasminogen activator (uPA), uPA-receptor (uPAR), plasminogen activator inhibitor type 1 (PAI-1) and alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) transcripts were determined by in situ hybridization. These genes were found to be expressed in a finely regulated pattern. High levels of uPA mRNA were found in invasive trophoblast cells, while the same cells did not appear to synthesize PAI-1. Starting from day 6.5, endothelial cells of newly forming vessels also transcribed uPA gene. uPAR and alpha 2MR/LRP were in all stages expressed by decidual tissue, and their expression domains overlapped in large areas. Immunohistochemistry with uPA and PAI-1 antibodies revealed areas of co-localization of these secreted proteins with the expression domains of uPAR and alpha 2MR/LRP, which is of great interest in view of the role of these two receptors in clearing uPA-PAI-1 complexes. In situ zymography demonstrated the presence of active uPA in the ectoplacental cone region at 7.5 and 8.5 days. Our studies outline the expression of a set of functionally related genes that is well coordinated between fetal and maternal tissues. This coordination may model other physiological and pathological invasive processes.

  11. Alpha2B-adrenoceptors couple to Ca2+ increase in both endogenous and recombinant expression systems

    NARCIS (Netherlands)

    Holmberg, C. I.; Kukkonen, J. P.; Bischoff, A.; Näsman, J.; Courtney, M. J.; Michel, M. C.; Akerman, K. E.

    1998-01-01

    The ability of cloned human alpha2B-adrenoceptors heterologously expressed in Sf9 cells and endogenous alpha2B-adrenoceptors in NG 108-15 neuroblastoma x glioma cells to couple to increase of intracellular Ca2+ was studied. Ca2+ increases in NG 108-15 cells were detectable but slight, whereas those

  12. Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice.

    Science.gov (United States)

    Caglayan, Berrak; Caglayan, Ahmet B; Beker, Mustafa C; Yalcin, Esra; Beker, Merve; Kelestemur, Taha; Sertel, Elif; Ozturk, Gürkan; Kilic, Ulkan; Sahin, Fikrettin; Kilic, Ertugrul

    2017-10-01

    Conflicting data in the literature about the function of P2X7R in survival following ischemia necessitates the conductance of in-depth studies. To investigate the impacts of activation vs inhibition of the receptor on neuronal survival as well as the downstream signaling cascades, in addition to optic nerve transection (ONT), 30min and 90min of middle cerebral artery occlusion (MCAo) models were performed in mice. Intracellular calcium levels were assessed in primary cortical neuron cultures. Here, we show that P2X7R antagonist Brilliant Blue G (BBG) decreased DNA fragmentation, infarct volume, brain swelling, neurological deficit scores and activation of microglial cells after focal cerebral ischemia. BBG also significantly increased the number of surviving retinal ganglion cells (RGCs) after ONT and the number of surviving neurons following MCAo. Importantly, receptor agonist BzATP resulted in increased activation of microglial cells and induced phosphorylation of ERK, AKT and JNK. These results indicated that inhibition of P2X7R with BBG promoted neuronal survival, not through the activation of survival kinase pathways, but possibly by improved intracellular Ca 2+ overload and decreased the levels of Caspase 1, IL-1β and Bax proteins. On the other hand, BzATP-mediated increased number of activated microglia and increased survival kinase levels in addition to increased caspase-1 and IL-1β levels indicate the complex nature of the P2X7 receptor-mediated signaling in neuronal injury. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Stereoselective synthesis of phosphoramidate alpha(2-6)sialyltransferase transition-state analogue inhibitors.

    Science.gov (United States)

    Skropeta, Danielle; Schwörer, Ralf; Schmidt, Richard R

    2003-10-06

    The asymmetric synthesis of novel, potent phosphoramidate alpha(2-6)sialyltransferase transition-state analogue inhibitors such as (R)-9 (K(i)=68 microM) is described, via condensation of cytidine phosphitamide 6 with key chiral, non-racemic alpha-aminophosphonates, prepared in >98% ee by Mitsunobu azidation followed by Staudinger reduction of the corresponding chiral, non-racemic alpha-hydroxyphosphonates.

  14. Developmental Activation of the AHR Increases Effector CD4+ T Cells and Exacerbates Symptoms in Autoimmune Disease-Prone Gnaq+/- Mice.

    Science.gov (United States)

    Boule, Lisbeth A; Burke, Catherine G; Fenton, Bruce M; Thevenet-Morrison, Kelly; Jusko, Todd A; Lawrence, B Paige

    2015-12-01

    Perinatal environmental exposures are potentially important contributors to the increase in autoimmune diseases. Yet, the mechanisms by which these exposures increase self-reactive immune responses later in life are poorly understood. Autoimmune diseases require CD4(+) T cells for initiation, progression, and/or clinical symptoms; thus, developmental exposures that cause durable changes in CD4(+) T cells may play a role. Early life activation of the aryl hydrocarbon receptor (AHR) causes persistent changes in the response of CD4(+) T cells to infection later in life but whether CD4(+) T cells are affected by developmental exposure in the context of an autoimmune disease is unknown. Gnaq(+/-) mice develop symptoms of autoimmune disease similar to those measured clinically, and therefore can be used to evaluate gene-environment interactions during development on disease progression. Herein, we examined the effect of AHR activation in utero and via lactation, or solely via lactation, on disease onset and severity in adult Gnaq(+/-) offspring. Developmental activation of the AHR-accelerated disease in Gnaq(+/-) mice, and this correlates with increases in effector CD4(+) T-cell populations. Increased symptom onset and cellular changes due to early life AHR activation were more evident in female Gnaq(+/-) mice compared with males. These observations suggest that developmental AHR activation by pollutants, and other exogenous ligands, may increase the likelihood that genetically predisposed individuals will develop clinical symptoms of autoimmune disease later in life. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm.

    Science.gov (United States)

    Miyagawa, Kotaro; Ogata, Takehiro; Ueyama, Tomomi; Kasahara, Takeru; Nakanishi, Naohiko; Naito, Daisuke; Taniguchi, Takuya; Hamaoka, Tetsuro; Maruyama, Naoki; Nishi, Masahiro; Kimura, Taizo; Yamada, Hiroyuki; Aoki, Hiroki; Matoba, Satoaki

    2017-06-03

    Abdominal aortic aneurysm (AAA) is relatively common in elderly patients with atherosclerosis. MURC (muscle-restricted coiled-coil protein)/Cavin-4 modulating the caveolae function of muscle cells is expressed in cardiomyocytes, skeletal muscle cells and smooth muscle cells. Here, we show a novel functional role of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and AAA development. Both wild-type (WT) and MURC/Cavin-4 knockout (MURC -/- ) mice subjected to periaortic application of CaCl 2 developed AAAs. Six weeks after CaCl 2 treatment, internal and external aortic diameters were significantly increased in MURC -/- AAAs compared with WT AAAs, which were accompanied by advanced fibrosis in the tunica media of MURC -/- AAAs. The activity of JNK and matrix metalloproteinase (MMP) -2 and -9 were increased in MURC -/- AAAs compared with WT AAAs at 5 days after CaCl 2 treatment. At 6 weeks after CaCl 2 treatment, MURC -/- AAAs exhibited attenuated JNK activity compared with WT AAAs. There was no difference in the activity of MMP-2 or -9 between saline and CaCl 2 treatments. In MURC/Cavin-4-knockdown VSMCs, TNFα-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, MURC -/- , apolipoprotein E -/- (ApoE -/- ), and MURC/Cavin-4 and ApoE double-knockout (MURC -/- ApoE -/- ) mice were subjected to angiotensin II (Ang II) infusion. In both ApoE -/- and MURC -/- ApoE -/- mice infused for 4 weeks with Ang II, AAAs were promoted. The internal aortic diameter was significantly increased in Ang II-infused MURC -/- ApoE -/- mice compared with Ang II-infused ApoE -/- mice. In MURC/Cavin-4-knockdown VSMCs, Ang II-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Our results suggest that MURC/Cavin-4 in VSMCs modulates AAA progression at the early stage via the activation of JNK and MMP-9. MURC/Cavin-4 is a potential therapeutic target against AAA progression. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. p-( sup 125 I)iodoclonidine, a novel radiolabeled agonist for studying central alpha 2-adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Baron, B.M.; Siegel, B.W. (Merrell Dow Research Institute, Cincinnati, OH (USA))

    1990-09-01

    Unlabeled p-iodoclonidine was efficacious in attenuating forskolin-stimulated cAMP accumulation in SK-N-SH neuroblastoma cells. Maximal attenuation was 76 +/- 3%, with an EC50 of 347 +/- 60 nM. Comparable values of epinephrine were 72 +/- 3% and 122 +/- 22 nM. Responses to both agonists were abolished by 10 microM phentolamine. Therefore, p-iodoclonidine is an agonist in a cell culture model system of the neuronal alpha 2-adrenergic receptor. p-(125I)Iodoclonidine binding to membranes were measured using various regions of the rat brain. The agonist labeled a single population of sites present on cerebral cortical membranes, which was saturable (Bmax = 230 fmol/mg of protein) and possessed high affinity for the ligand (Kd = 0.6 nM). Binding was largely specific (93% at 0.6 nM). A variety of alpha 2-adrenergic agonists and antagonists were shown to compete for the binding of the radioligand. The binding of p-(125I)iodoclonidine was much less sensitive to agents that interact with alpha 1-adrenergic, serotonergic, and dopaminergic receptors. Approximately 65% of the binding was sensitive to guanine nucleotides. Association kinetics using 0.4 nM radioligand were biphasic (37% associate rapidly, with kobs = 0.96 min-1, with the remainder binding more slowly, with kobs = 0.031 min-1) and reached a plateau by 90 min at 25 degrees. Dissociation kinetics were also biphasic, with 30% of the binding dissociating rapidly (k1 = 0.32 min-1) and the remainder dissociating 50-fold more slowly (k2 = 0.006 min-1). Agonist binding is, therefore, uniquely complex and probably reflects the conformational changes that accompany receptor activation.

  17. Kleptomania and Potential Exacerbating Factors

    Science.gov (United States)

    2011-01-01

    Kleptomania is an impulse control disorder that can cause significant impairment and serious consequences. Often, the condition is kept secret by the patient, and usually help is sought only when confronted by the legal consequences of the impulsive behaviors. Historically, kleptomania has been viewed from a psychodynamic perspective, and the mainstay of treatment has been psychotherapy. Recently, attempts to explain kleptomania within a neuropsychiatric paradigm have highlighted the possible links between mood disorders, addictive behaviors, and brain injury with kleptomania. These associations with kleptomania can be extrapolated to pharmacological strategies that can potentially help in treating kleptomania. A case of kleptomania, which was potentially exacerbated by multiple factors, will be reviewed. Treatment modalities used in this case, including the use of the Yale-Brown Obsessive Compulsive Scale as a surrogate marker to gauge response to treatment, will be discussed. PMID:22132369

  18. Asthma exacerbation prediction: recent insights.

    Science.gov (United States)

    Fleming, Louise

    2018-04-01

    Asthma attacks are frequent in children with asthma and can lead to significant adverse outcomes including time off school, hospital admission and death. Identifying children at risk of an asthma attack affords the opportunity to prevent attacks and improve outcomes. Clinical features, patient behaviours and characteristics, physiological factors, environmental data and biomarkers are all associated with asthma attacks and can be used in asthma exacerbation prediction models. Recent studies have better characterized children at risk of an attack: history of a severe exacerbation in the previous 12 months, poor adherence and current poor control are important features which should alert healthcare professionals to the need for remedial action. There is increasing interest in the use of biomarkers. A number of novel biomarkers, including patterns of volatile organic compounds in exhaled breath, show promise. Biomarkers are likely to be of greatest utility if measured frequently and combined with other measures. To date, most prediction models are based on epidemiological data and population-based risk. The use of digital technology affords the opportunity to collect large amounts of real-time data, including clinical and physiological measurements and combine these with environmental data to develop personal risk scores. These developments need to be matched by changes in clinical guidelines away from a focus on current asthma control and stepwise escalation in drug therapy towards inclusion of personal risk scores and tailored management strategies including nonpharmacological approaches. There have been significant steps towards personalized prediction models of asthma attacks. The utility of such models needs to be tested in the ability not only to predict attacks but also to reduce them.

  19. Pertussis toxin-sensitive G-protein mediates the alpha 2-adrenergic receptor inhibition of melatonin release in photoreceptive chick pineal cell cultures

    International Nuclear Information System (INIS)

    Pratt, B.L.; Takahashi, J.S.

    1988-01-01

    The avian pineal gland is a photoreceptive organ that has been shown to contain postjunctional alpha 2-adrenoceptors that inhibit melatonin synthesis and/or release upon receptor activation. Physiological response and [32P]ADP ribosylation experiments were performed to investigate whether pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins) were involved in the transduction of the alpha 2-adrenergic signal. For physiological response studies, the effects of pertussis toxin on melatonin release in dissociated cell cultures exposed to norepinephrine were assessed. Pertussis toxin blocked alpha 2-adrenergic receptor-mediated inhibition in a dose-dependent manner. Pertussis toxin-induced blockade appeared to be noncompetitive. One and 10 ng/ml doses of pertussis toxin partially blocked and a 100 ng/ml dose completely blocked norepinephrine-induced inhibition. Pertussis toxin-catalyzed [32P]ADP ribosylation of G-proteins in chick pineal cell membranes was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Membranes were prepared from cells that had been pretreated with 0, 1, 10, or 100 ng/ml pertussis toxin. In the absence of pertussis toxin pretreatment, two major proteins of 40K and 41K mol wt (Mr) were labeled by [32P]NAD. Pertussis toxin pretreatment of pineal cells abolished [32P] radiolabeling of the 40K Mr G-protein in a dose-dependent manner. The norepinephrine-induced inhibition of both cAMP efflux and melatonin release, as assessed by RIA of medium samples collected before membrane preparation, was also blocked in a dose-dependent manner by pertussis toxin. Collectively, these results suggest that a pertussis toxin-sensitive 40K Mr G-protein labeled by [32P]NAD may be functionally associated with alpha 2-adrenergic signal transduction in chick pineal cells

  20. Murinoglobulin, a novel protease inhibitor from murine plasma. Isolation, characterization, and comparison with murine alpha-macroglobulin and human alpha-2-macroglobulin.

    Science.gov (United States)

    Saito, A; Sinohara, H

    1985-01-25

    Two glycoproteins having trypsin-protein esterase activity were purified to apparent homogeneity from murine plasma. One was alpha-macroglobulin, a homologue of human alpha-2-macroglobulin, while the other, tentatively named murinoglobulin, did not correspond to any of the known plasma protease inhibitors that have been well characterized in men or other mammals. Murinoglobulin contained about 7.6% carbohydrate and was composed of a single-polypeptide chain of Mr = 180,000 as judged by the equilibrium sedimentation analysis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. Murinoglobulin did not cross-react immunologically with mouse alpha-macroglobulin nor with human alpha-2-macroglobulin. Protease-inhibiting properties of murinoglobulin were compared with those of mouse alpha-macroglobulin and human alpha-2-macroglobulin. All the three proteins inhibited trypsin, papain, and thermolysin, although they differed considerably in both the degree of inhibition and the binding stoichiometry of protease-inhibitor complexes. The two macroglobulins inhibited pepsin at pH 5.5, whereas murinoglobulin was inactivated at this pH. Murinoglobulin was more sensitive to methylamine than the two macroglobulins. No protein corresponding to murinoglobulin was detected in human plasma.

  1. [Effects of recombinant human alpha-2b and gamma interferons on bone marrow megakaryocyte progenitors (CFU-Meg) from patients with chronic myelocytic leukemia].

    Science.gov (United States)

    Tanabe, Y; Dan, K; Kuriya, S; Nomura, T

    1989-10-01

    The effects of recombinant human interferon (IFN) alpha-2b and gamma on the bone marrow megakaryocyte progenitors (CFU-Meg) were compared between eight patients in the chronic phase of Ph1-positive chronic myelocytic leukemia (CML) and five hematologically normal patients. CFU-Meg was assayed in plasma clot culture added with phytohemagglutinin-stimulated leukocyte-conditioned medium as a source of colony stimulating activity. The average count of CFU-Meg colonies formed from the bone marrow of CML patients was 5.5 times that of normal controls. Spontaneous CFU-Meg colonies were grown in seven of eight CML patients, but in none of five controls. Colony formation by CFU-Meg in CML as well as normal bone marrow was suppressed by the two preparations of IFN in a dose dependent fashion. Their suppressive influence on colonies from CFU-Meg was comparable between CML and normal bone marrow at lower concentrations, but was less marked for CML than normal bone marrow at higher concentrations. The formation of CFU-Meg colonies from CML bone marrow was more severely suppressed by IFN-gamma than IFN-alpha-2b. Depletion of either T lymphocytes or adherent cells from the CML bone marrow cells diminished the suppressive effects of IFN-gamma, but had no influence on the effects of IFN-alpha-2b.

  2. NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases.

    Science.gov (United States)

    Sadegh, Leila; Chen, Peter W; Brown, Joseph R; Han, Zhiqiang; Niederkorn, Jerry Y

    2015-09-01

    Uveal melanoma (UM) is the most common intraocular tumor in adults and liver metastasis is the leading cause of death in UM patients. We have previously shown that NKT cell-deficient mice develop significantly fewer liver metastases from intraocular melanomas than do wild-type (WT) mice. Here, we examine the interplay between liver NKT cells and NK cells in resistance to liver metastases from intraocular melanomas. NKT cell-deficient CD1d(-/-) mice and WT C57BL/6 mice treated with anti-CD1d antibody developed significantly fewer liver metastases than WT mice following either intraocular or intrasplenic injection of B16LS9 melanoma cells. The increased number of metastases in WT mice was associated with reduced liver NK cytotoxicity and decreased production of IFN-γ. However, liver NK cell-mediated cytotoxic activity was identical in non-tumor bearing NKT cell-deficient mice and WT mice, indicating that liver metastases were crucial for the suppression of liver NK cells. Depressed liver NK cytotoxicity in WT mice was associated with production of IL-10 by bone marrow-derived liver cells that were neither Kupffer cells nor myeloid-derived suppressor cells and by increased IL-10 receptor expression on liver NK cells. IL-10(-/-) mice had significantly fewer liver metastases than WT mice, but were not significantly different from NKT cell-deficient mice. Thus, development of melanoma liver metastases is associated with upregulation of IL-10 in the liver and an elevated expression of IL-10 receptor on liver NK cells. This impairment of liver NK activity is NKT cell-dependent and only occurs in hosts with melanoma liver metastases. © 2015 UICC.

  3. Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses, while Reducing Cholesterol Efflux from Human Macrophages.

    Directory of Open Access Journals (Sweden)

    Mirko Lanuti

    Full Text Available The G protein-coupled receptor GPR55 has been proposed as a new cannabinoid receptor associated with bone remodelling, nervous system excitability, vascular homeostasis as well as in several pathophysiological conditions including obesity and cancer. However, its physiological role and underlying mechanism remain unclear. In the present work, we demonstrate for the first time its presence in human macrophages and its increased expression in ox-LDL-induced foam cells. In addition, pharmacological activation of GPR55 by its selective agonist O-1602 increased CD36- and SRB-I-mediated lipid accumulation and blocked cholesterol efflux by downregulating ATP-binding cassette (ABC transporters ABCA1 and ABCG1, as well as enhanced cytokine- and pro-metalloprotease-9 (pro-MMP-9-induced proinflammatory responses in foam cells. Treatment with cannabidiol, a selective antagonist of GPR55, counteracted these pro-atherogenic and proinflammatory O-1602-mediated effects. Our data suggest that GPR55 could play deleterious role in ox-LDL-induced foam cells and could be a novel pharmacological target to manage atherosclerosis and other related cardiovascular diseases.

  4. TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Hou, Jiwei; Ma, Tan; Cao, Honghui; Chen, Yabing; Wang, Cong; Chen, Xiang; Xiang, Zou; Han, Xiaodong

    2018-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-α (TNF-α) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-α in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-α and the transcription factor nuclear factor kappa B (NF-κB) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-α promotes myofibroblast differentiation of LR-MSCs through activating NF-κB signaling. Interestingly, we also found that TNF-α promotes the expression of β-catenin. Moreover, we demonstrated that suppression of the NF-κB signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of β-catenin. Our data implicates that inhibition of the NF-κB signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches. © 2017 Wiley Periodicals, Inc.

  5. Treatment-emergent depression and anxiety between peginterferon alpha-2a versus alpha-2b plus ribavirin for chronic hepatitis C.

    Science.gov (United States)

    Wang, Liang-Jen; Chen, Shuo-Wei; Chen, Chih-Ken; Yen, Cho-Li; Chang, Jia-Jang; Lee, Tsung-Shih; Liu, Ching-Jung; Chen, Li-Wei; Chien, Rong-Nan

    2016-11-25

    This study investigates differences in depression and anxiety between patients with chronic hepatitis C who are treated with peginterferon alpha-2a (PegIFN-α-2a) plus ribavirin and those who are treated with peginterferon alpha-2b (PegIFN-α-2b) plus ribavirin. In this 24 week, non-randomized, observational, prospective study, 55 patients with chronic hepatitis C were treated with PegIFN-α-2a plus ribavirin (Group 1), and 26 patients were treated with PegIFN-α-2b plus ribavirin (Group 2). All patients underwent assessment using the Hospital Anxiety and Depression Scale (HADS) at the baseline and at weeks 4, 12 and 24. Patients with depression scores (HADS-D) ≥ 8 and anxiety scores (HADS-A) ≥ 8 were defined as having depression and anxiety, respectively. The factors that were associated with depression and anxiety during the 24 week antiviral treatment were determined. During the 24 week antiviral treatment, the proportion of patients with depression significantly increased over time in both groups (Group 1: p = 0.048; Group 2: p = 0.044). The proportion of patients with anxiety did not significantly change during the follow-up period in either group. Incidences of depression or anxiety did not differ significantly between Group 1 and Group 2. A history of alcohol use disorder was an independent predictor of depression at week 12 (p anxiety at week 12 (p = 0.038). This study did not identify significant differences in depression or anxiety between in patients with chronic hepatitis C who underwent a 24 week antiviral treatment regimen with PegIFN-α-2a plus ribavirin and those who underwent a regiment with PegIFN-α-2b plus ribavirin. Future research with larger samples and a randomized, controlled design are required to verify the findings in this study. This clinical study has been registered at ClinicalTrials.gov. (Trial registration: NCT02943330 ).

  6. Long-term motor improvement after stroke is enhanced by short-term treatment with the alpha-2 antagonist, atipamezole.

    Science.gov (United States)

    Beltran, Erik J; Papadopoulos, Catherine M; Tsai, Shih-Yen; Kartje, Gwendolyn L; Wolf, William A

    2010-07-30

    Drugs that increase central noradrenergic activity have been shown to enhance the rate of recovery of motor function in pre-clinical models of brain damage. Less is known about whether noradrenergic agents can improve the extent of motor recovery and whether such improvement can be sustained over time. This study was designed to determine if increasing central noradrenergic tone using atipamezole, an alpha-2 adrenoceptor antagonist, could induce a long-term improvement in motor performance in rats subjected to ischemic brain damage caused by permanent middle cerebral artery occlusion. The importance of pairing physical "rehabilitation" with enhanced noradrenergic activity was also investigated. Atipamezole (1 mg/kg, s.c.) or vehicle (sterile saline) was administered once daily on Days 2-8 post-operatively. Half of each drug group was housed under enriched environment conditions supplemented with daily focused activity sessions while the other half received standard housing with no focused activity. Skilled motor performance in forelimb reaching and ladder rung walking was assessed for 8 weeks post-operatively. Animals receiving atipamezole plus rehabilitation exhibited significantly greater motor improvement in both behavioral tests as compared to vehicle-treated animals receiving rehabilitation. Interestingly, animals receiving atipamezole without rehabilitation exhibited a significant motor improvement in the ladder rung walk test but not the forelimb reaching test. These results suggest that a short-term increase in noradrenergic activity can lead to sustained motor improvement following stroke, especially when paired with rehabilitation. Published by Elsevier B.V.

  7. Cortical effect of oxaliplatin associated with sustained neuropathic pain: exacerbation of cortical activity and down-regulation of potassium channel expression in somatosensory cortex.

    Science.gov (United States)

    Thibault, Karine; Calvino, Bernard; Dubacq, Sophie; Roualle-de-Rouville, Marie; Sordoillet, Vallier; Rivals, Isabelle; Pezet, Sophie

    2012-08-01

    Oxaliplatin is a third-generation platinum-based chemotherapy drug that has gained importance in the treatment of advanced metastatic colorectal cancer. Its dose-limiting side effect is the production of chronic peripheral neuropathy. Using a modified model of oxaliplatin-induced sensory neuropathy, we investigated plastic changes at the cortical level as possible mechanisms underlying the chronicity of pain sensation in this model. Changes in gene expression were studied using DNA microarray which revealed that when oxaliplatin-treated animals displayed clinical neuropathic pain symptoms, including mechanical and thermal hypersensitivity, approximately 900 were down-regulated in the somatosensory cortex. Because of the known role of potassium channels in neuronal excitability, the study further focussed on the down-regulation of these channels as the possible molecular origin of cortical hyperexcitability. Quantification of the magnitude of neuronal extracellular signal-regulated kinase (ERK) phosphorylation in cortical neurons as a marker of neuronal activity revealed a 10-fold increase induced by oxaliplatin treatment, suggesting that neurons of cortical areas involved in transmission of painful stimuli undergo a chronic cortical excitability. We further demonstrated, using cortical injection of lentiviral vector shRNA against Kv2.2, that down-regulation of this potassium channel in naive animals induced a sustained thermal and mechanical hypersensitivity. In conclusion, although the detailed mechanisms leading to this cortical excitability are still unknown, our study demonstrated that a cortical down regulation of potassium channels could underlie pain chronicity in this model of chemotherapy-induced neuropathic pain. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  8. The impact of interferon-alpha2 on HLA genes in patients with polycythemia vera and related neoplasms

    DEFF Research Database (Denmark)

    Skov, Vibe; Riley, Caroline Hasselbalch; Thomassen, Mads

    2017-01-01

    and II genes used by tumor cells to escape antitumor T-cell-mediated immune responses. Several genes encoding human leukocyte antigen (HLA) class I and II molecules have been shown to be significantly downregulated. Upregulation of HLA genes is considered one of the mechanisms of action of interferon...... (IFN)-alpha2, but regulation of these genes during IFN-alpha2 treatment in MPNs has never been studied. Our findings show a significant upregulation of several HLA genes of importance for tumor immune surveillance by IFN-alpha2 treatment in MPNs. This mechanism might enhance the cytotoxic potential...

  9. Assessment of Aerobic Exercise Adverse Effects during COPD Exacerbation Hospitalization.

    Science.gov (United States)

    Knaut, Caroline; Mesquita, Carolina Bonfanti; Caram, Laura M O; Ferrari, Renata; Dourado, Victor Zuniga; de Godoy, Irma; Tanni, Suzana Erico

    2017-01-01

    Introduction. Aerobic exercise performed after hospital discharge for exacerbated COPD patients is already recommended to improve respiratory and skeletal muscle strength, increase tolerance to activity, and reduce the sensation of dyspnea. Previous studies have shown that anaerobic activity can clinically benefit patients hospitalized with exacerbated COPD. However, there is little information on the feasibility and safety of aerobic physical activity performed by patients with exacerbated COPD during hospitalization. Objective. To evaluate the effects of aerobic exercise on vital signs in hospitalized patients with exacerbated COPD. Patients and Methods. Eleven COPD patients (63% female, FEV1: 34.2 ± 13.9% and age: 65 ± 11 years) agreed to participate. Aerobic exercise was initiated 72 hours after admission on a treadmill; speed was obtained from the distance covered in a 6-minute walk test (6MWT). Vital signs were assessed before and after exercise. Results. During the activity systolic blood pressure increased from 125.2 ± 13.6 to 135.8 ± 15.0 mmHg ( p = 0.004) and respiratory rate from 20.9 ± 4.4 to 24.2 ± 4.5 rpm ( p = 0.008) and pulse oximetry (SpO 2 ) decreased from 93.8 ± 2.3 to 88.5 ± 5.7% ( p Aerobic activity was considered intense, heart rate ranged from 99.2 ± 11.5 to 119.1 ± 11.1 bpm at the end of exercise ( p = 0.092), and patients reached on average 76% of maximum heart rate. Conclusion. Aerobic exercise conducted after 72 hours of hospitalization in patients with exacerbated COPD appears to be safe.

  10. Evidence that two stereochemically different alpha-2 adrenoceptors modulate norepinephrine release in rat cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Harsing, L.G. Jr.; Vizi, E.S. (Institute of Experimental Medicine, Budapest (Hungary))

    1991-01-01

    Cerebral cortex slices from the rat were loaded with (3H)norepinephrine ((3H)NE) and superfused in order to measure the release of radioactivity at rest and in response to electrical stimulation. The (-)-isomer and the (+)-isomer of CH-38083 (7,8-(methylenedioxy)-14- alpha-hydroxyalloberbane HCl), a selective alpha-2-adrenoceptor antagonist with an alloberbane skeleton, increased the electrically induced release of (3H)NE in a concentration-dependent manner, and a similar effect was observed with racemic CH-38083 and idazoxan. The stereoisomers of CH-38083 applied in a concentration range of 10(-8) to 10(-6) mol/l were equipotent in facilitating stimulation-evoked (3H)NE release: concentrations needed to enhance tritium outflow by 50% were 1.3 X 10(-7) mol/l for (-)-CH-38083 and 1.4 X 10(-7) mol/l for (+)-CH-38083. Exogenous NE decreased the electrically stimulated release of (3H)NE, and the stereoisomers of CH-38083 antagonized this inhibition with different potencies: the dissociation constant (KB) values for (-)-isomer and for (+)-isomer of CH-38083 were 14.29 and 97.18 nmol/l. These data indicate that presynaptic alpha-2 adrenoceptors that are available for NE released from axon terminals do not show stereospecificity toward enantiomers of CH-38083, whereas those that are occupied by exogenous NE are much more sensitive toward (-)-CH-38083. The alpha-1 adrenoceptor antagonist prazosin also differentiated between the alpha-2 adrenoceptor subtypes: prazosin (10(-6) mol/l) did not alter the increase of electrically induced (3H)NE release evoked by (-)- and (+)-CH-38083; however, in its presence, the stereoisomers of CH-38083 failed to antagonize the inhibitory effect of exogenous NE on its own release.

  11. Sustained major molecular response on interferon alpha-2b in two patients with polycythemia vera

    DEFF Research Database (Denmark)

    Larsen, Thomas Stauffer; Bjerrum, O W; Pallisgaard, N

    2008-01-01

    Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia...... chromosome negative chronic myeloproliferative disorders. Reductions in the JAK2 V617F allele burden in patients treated with pegylated interferon alpha-2a (Peg-IFN-2a) have been demonstrated, although follow-up was relatively short. We report here the first profound and sustained molecular responses...

  12. Minimal residual disease after long-term interferon-alpha2 treatment

    DEFF Research Database (Denmark)

    Utke Rank, Cecilie; Weis Bjerrum, Ole; Larsen, Thomas Stauffer

    2016-01-01

    burden by a highly sensitive quantitative PCR (qPCR) assay appears to be a useful tool for monitoring minimal residual disease (MRD) and evaluating treatment efficacy. This report expands and substantiates existing data, showing that IFN-alpha2 is a highly potent immunomodulating agent capable...... of inducing MRD with low-burden JAK2 V617F, major molecular response (MMR), complete hematological remission (CHR) and complete histomorphological normalization of the bone marrow in a sub-set of patients with ET and PV after long-term treatment (≥ 3.5 years). Furthermore, long-lasting hematological...

  13. Clinical characteristics of eosinophilic asthma exacerbations

    DEFF Research Database (Denmark)

    Bjerregaard, Asger; Laing, Ingrid A; Backer, Vibeke

    2017-01-01

    BACKGROUND AND OBJECTIVE: Airway eosinophilia is associated with an increased risk of asthma exacerbations; however, the impact on the severity of exacerbations is largely unknown. We describe the sputum inflammatory phenotype during asthma exacerbation and correlate it with severity and treatment...... response. METHODS: Patients presenting to hospital with an asthma exacerbation were recruited during a 12-month period and followed up after 4 weeks. Induced sputum was collected at both visits. Patients underwent spirometry, arterial blood gas analysis, fractional exhaled nitric oxide analysis, white...... with a sensitivity of 86% and a specificity of 70%. CONCLUSION: Our findings suggest that eosinophilic asthma exacerbations may be clinically more severe than NEEs, supporting the identification of these higher risk patients for specific interventions....

  14. Determination of the Crystal Structure of Human Zn-Alpha 2-Gylcoprotein, A Protein Implicated in Breast Cancer

    National Research Council Canada - National Science Library

    Bjorkman, Pamela

    2000-01-01

    Zn-alpha 2-glycoprotein (ZAG) is a 41 kDa soluble protein whose sequence and domain organization are surprisingly similar to those of the membrane glycoproteins of the major histocompatibility complex (MHC...

  15. DYSFUNCTIONAL PRESYNAPTIC ALPHA-2-ADRENOCEPTORS EXPOSE FACILITATORY BETA-2-ADRENOCEPTORS IN THE VASCULATURE OF SPONTANEOUSLY HYPERTENSIVE RATS

    NARCIS (Netherlands)

    REMIE, R; VANROSSUM, JXM; COPPES, RP; ZAAGSMA, J

    1992-01-01

    Previous studies on spontaneously hypertensive rats (SHR) have yielded inconsistent information about functional aberrations of the presynaptic alpha(2)- and beta(2)-adrenoceptor-mediated modulation of sympathetic neurotransmitter release. In the present investigation we studied the capacity of

  16. Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia.

    Science.gov (United States)

    Lewis, Sharon R; Nicholson, Amanda; Smith, Andrew F; Alderson, Phil

    2015-08-10

    Shivering after general anaesthesia is common. It is unpleasant but can also have adverse physiological effects. Alpha-2 (α-2) adrenergic agonist receptors, which can lead to reduced sympathetic activity and central regulation of vasoconstrictor tone, are a group of drugs that have been used to try to prevent postoperative shivering. To assess the following: the effects of α-2 agonists on the prevention of shivering and subsequent complications after general anaesthesia in people undergoing surgery; the effects of α-2 agonists on the risk of inadvertent perioperative hypothermia; and whether any adverse effects are associated with these interventions. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE on 13 June 2014. Our search terms were relevant to the review question and limited to studies that assessed shivering or hypothermia. We also carried out searches of clinical trials registers, and forward and backward citation tracking. We considered all randomized controlled trials, quasi-randomized studies, and cluster-randomized studies with adult participants undergoing surgery with general anaesthesia in which an α-2 agonist was compared with another α-2 agonist or a placebo for the prevention of shivering. Two review authors independently assessed trial quality and extracted data, consulting a third review author in the case of disagreements. We used standard Cochrane methodological procedures, including an assessment of risk of bias and use of GRADEpro software to interpret findings. We included 20 studies with 1401 surgical participants comparing an α-2 agonist against a control. Thirteen studies compared clonidine with a control, whilst seven compared dexmedetomidine with a control. The doses, methods, and time of administration varied between studies: three studies gave the drug orally or as an intravenous bolus preoperatively and nine intraoperatively; one study gave the drug as an infusion starting

  17. SERUM PROLACTIN IN MELANOMA PATIENTS WITH INTERFERON ALPHA2B TREATMENT.

    Science.gov (United States)

    Ene, Corina-Daniela; Nicolae, Ilinca

    2015-01-01

    The authors' interest was focused on prolactin status in patients with melanocytic lesions and on changes induced by interferon treatment in melanoma patients. The study lasted 5 years and included 128 melanoma patients, 48 dysplastic nevi patients and 48 healthy volunteers. Sixty melanoma cases were selected after surgical removal of tumor and divided into 2 groups: 30 patients with 10 MUmp(-1) interferon alpha2b treatment, three times a week, one year and 30 patients without interferon treatment. Prolactin assessment was made at inclusion in the study, after surgical removal of tumor, when patients started the treatment, after 1, 6, 12 months of treatment and 6 months after treatment end. In melanoma patients, high values of prolactin (10.55 ± 5.94 ng/ml) were detected when compared with dysplastic nevi group (5.94 ± 2.87 ng/ml) and control group (5.74 ± 3.66 ng.ml). Prolactin levels decreased after surgical removal of melanoma, significantly increased during interferon treatment and returned to baseline few months after the immunomodulatory treatment. The treatment with interferon alpha2b stimulated reversible and non-cumulative prolactin production. Evaluating prolactin in melanoma patients could become necessary in the future, both for finding a possible pituitary disorder, but also for a new pharmacological intervention.

  18. Evaluation of equine electroretinographic responses by using two different electrodes and four different Alpha-2 agonist sedatives

    Directory of Open Access Journals (Sweden)

    Maurílio Rosa

    2014-12-01

    Full Text Available ABSTRACT. Rosa M., Botteon P.T.L., Pereira J.S., Brooks D.E. & Rosa M.V.D. Evaluation of equine electroretinographic responses by using two different electrodes and four different Alpha-2 agonist sedatives. [Avaliação da resposta eletroretinográfica de equinos utilizando dois tipos de eletrodos quatro sedativos Alfa-2 agonistas diferentes.] Revista Brasileira de Medicina Veterinária, 36(4:367-374, 2014. Centro de Pesquisa em Oftalmologia Veterinária (CEPOV, Avenida das Américas, 700, Bloco 8, Loja 103J, Barra da Tijuca, Rio de Janeiro, RJ 22640-100, Brasil. E-mail: marcmax@globo.com The aim of this study was the evaluation and comparison of field electroretinographic responses in standing horses using two different active electrodes (DTL- plus™ and ERG-jet®, and four different alpha-2 agonist drugs Xylazine, Romifidine, Detomidine, Medetomidine. Forty healthy horses were evaluated by full field ERG. Horses were randomly allocated into eight groups according four sedative drugs and two electrodes types. In all groups a- and b- wave amplitudes and implicit times were investigated and compared for both eyes. Quality and costs of sedation drugs were estimated. This research leaded to the conclusion that there were no significant differences of a- and b-wave complex results between ERG-jet® and DTL-plus™ electrodes with any sedative type. The ERG-jet® lens proved to be more practical during the examination than the DTL-plus™ electrode. The use of a single dose of xylazine, romifidine, detomidine or medetomidine was sufficient to provide a good level of sedation and muscle relaxation during the ERG examination, although detomidine and medetomidine gave slightly superior results when compared with the otherdrugs in this study. The sedation with xylazine was the least when compared with the other drugs and it was also the cheapest to use. Any of the sedatives and either active electrode tested in this study should permit a good full field

  19. Lung microbiology and exacerbations in COPD

    Directory of Open Access Journals (Sweden)

    Beasley V

    2012-08-01

    Full Text Available Victoria Beasley,2 Priya V Joshi,2 Aran Singanayagam,1,2 Philip L Molyneaux,1,2 Sebastian L Johnston,1,2 Patrick Mallia,1,21National Heart and Lung Institute, Imperial College London, London, UK; 2Imperial College Healthcare NHS Trust, London, UKAbstract: Chronic obstructive pulmonary disease (COPD is the most common chronic respiratory condition in adults and is characterized by progressive airflow limitation that is not fully reversible. The main etiological agents linked with COPD are cigarette smoking and biomass exposure but respiratory infection is believed to play a major role in the pathogenesis of both stable COPD and in acute exacerbations. Acute exacerbations are associated with more rapid decline in lung function and impaired quality of life and are the major causes of morbidity and mortality in COPD. Preventing exacerbations is a major therapeutic goal but currently available treatments for exacerbations are not very effective. Historically, bacteria were considered the main infective cause of exacerbations but with the development of new diagnostic techniques, respiratory viruses are also frequently detected in COPD exacerbations. This article aims to provide a state-of-the art review of current knowledge regarding the role of infection in COPD, highlight the areas of ongoing debate and controversy, and outline emerging technologies and therapies that will influence future diagnostic and therapeutic pathways in COPD.Keywords: COPD, exacerbations, bacteria, viruses

  20. Single base mutation in the pro. alpha. 2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in-frame pro. alpha. 2(I) chain

    Energy Technology Data Exchange (ETDEWEB)

    Tromp, G.; Prockop, D.J. (Thomas Jefferson Univ., Philadelphia, PA (USA))

    1988-07-01

    Previous observations demonstrated that a lethal variant of osteogenesis imperfecta had two altered alleles for pro{alpha}2(I) chains of type I procollagen. One mutation produced a nonfunctioning allele in that there was synthesis of mRNA but no detectable synthesis of pro{alpha}2(I) chains from the allele. The mutation in the other allele caused synthesis of shortened pro{alpha}2(I) chains that lacked most or all of the 18 amino acids encoded by exon 28. Subclones of the pro{alpha}2(I) gene were prepared from the proband's DNA and the DNA sequence was determined for a 582-base-pair (bp) region that extended from the last 30 bp of intervening sequence 26 to the first 26 bp of intervening sequence 29. Data from six independent subclones demonstrated that all had the same sequence as a previously isolated normal clone for the pro{alpha}2(I) gene except that four subclones had a single base mutation at the 3{prime} end of intervening sequence 27. The mutation was a substitution of guanine for adenine that changed the universal consensus sequence for the 3{prime} splicing site of RNA from -AG- to -GG-. S1 nuclease experiments demonstrated that about half the pro{alpha}2(I) mRNA in the proband's fibroblasts was abnormally spliced and that the major species of abnormal pro{alpha}2(I) mRNA was completely spliced from the last codon of exon 27 to the first codon of exon 29. The mutation is apparently unique among RNA splicing mutations of mammalian systems in producing a shortened polypeptide chain that is in-frame in terms of coding sequences, that is used in the subunit assembly of a protein, and that contributes to a lethal phenotype.

  1. Thiazolidinediones are associated with a reduced risk of COPD exacerbations

    Directory of Open Access Journals (Sweden)

    Rinne ST

    2015-08-01

    Full Text Available Seppo T Rinne,1,2 Chuan-Fen Liu,3,4 Laura C Feemster,3,5 Bridget F Collins,3,5 Christopher L Bryson,3,6 Thomas G O’Riordan,7 David H Au3,4 1Department of Veterans Affairs, VA Connecticut Healthcare System, West Haven, 2Division of Pulmonary and Critical Care, Yale University, New Haven, CT, USA; 3VA Puget Sound Health Care System, Department of Veterans Affairs, 4Department of Health Services, University of Washington, 5Division of Pulmonary and Critical Care, University of Washington, 6Division of General Internal Medicine, University of Washington, 7Gilead Sciences, Inc., Seattle, WA, USA Background: Thiazolidinediones (TZDs are oral antihyperglycemic medications that are selective agonists to peroxisome proliferator-activated receptor gamma and have been shown to have potent anti-inflammatory effects in the lung.Objective: The purpose of this study was to assess whether exposure to TZDs is associated with a decreased risk of chronic obstructive pulmonary disease (COPD exacerbation.Methods: A cohort study was performed by collecting data on all US veterans with diabetes and COPD who were prescribed oral antihyperglycemic medications during from period of October 1, 2005 to September 30, 2007. Patients who had two or more prescriptions for TZDs were compared with patients who had two or more prescriptions for an alternative oral antihyperglycemic medication. Multivariable negative binomial regression was performed with adjustment for potential confounding factors. The primary outcome was COPD exacerbations, including both inpatient and outpatient exacerbations.Results: We identified 7,887 veterans who were exposed to TZD and 42,347 veterans who were exposed to non-TZD oral diabetes medications. COPD exacerbations occurred in 1,258 (16% of the TZD group and 7,789 (18% of the non-TZD group. In multivariable negative binomial regression, there was a significant reduction in the expected number of COPD exacerbations among patients who were

  2. The alpha(2)-adrenoceptor agonist dexmedetomidine suppresses memory formation only at doses attenuating the perception of sensory input.

    Science.gov (United States)

    van Oostrom, Hugo; Stienen, Peter J; Doornenbal, Arie; Hellebrekers, Ludo J

    2010-03-10

    It was investigated whether continuous rate infusion of the alpha(2)-adrenoceptor agonist dexmedetomidine can suppress memory formation by mechanisms other than reducing perception of sensory input in a fear-conditioning paradigm. Different groups of rats infused with either saline or dexmedetomidine (2.0, 4.0 or 10.0microg/kg bolus, followed by 2.0, 4.0 or 10.0microg/kg/h continuous rate infusion respectively), were subjected to a somatosensory-evoked potential (SEP) fear-conditioning paradigm. This paradigm combined the pairing of an innoxious conditioned stimulus (CS) and a noxious unconditioned stimulus (US), of which the latter was used to generate the SEPs (training phase).The following day, the perception of the US during the training phase was assessed by presenting the CS only and subsequently scoring the resulting duration of freezing behaviour (testing phase). Freezing behaviour was reduced only in those groups which demonstrated reduced SEPs. Based on these findings, it is concluded that dexmedetomidine suppresses memory formation only at doses reducing central nervous system activity in response to sensory input. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  3. Susceptibility to exacerbation in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Hurst, John R; Vestbo, Jørgen; Anzueto, Antonio

    2010-01-01

    to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS: Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year......, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could...... by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)...

  4. Characteristics of Endotoxin-Altering Fractions Derived from Normal Serum III. Isolation and Properties of Horse Serum alpha(2)-Macroglobulin.

    Science.gov (United States)

    Yoshioka, M; Konno, S

    1970-05-01

    The endotoxin-altering activity of fractions isolated from normal horse serum was examined by incubation of Salmonella typhosa strain 0-901 endotoxin (Boivin) in a solution of the fraction, and subsequent quantitation of any diminution in the capacity of endotoxin to be precipitated by specific anti-endotoxin antiserum. The horse serum fraction isolated by precipitation with ammonium sulfate at a concentration between 1.6 and 2.7 m was incubated with Pronase PA and then with trypsin. When this partly digested fraction was passed twice through a Sephadex G-200 column and eluted with 0.2 m tris(hydroxymethyl)aminomethane buffer, most of the endotoxinaltering activity was found in the first protein peak designated F-1a. F-1a was found to be homogeneous and corresponded to an alpha(2)-macroglobulin by the techniques of electrophoresis, immunodiffusion, and ultracentrifugation. Approximately 100-fold more F-1a than endotoxin was needed to reduce the antigenicity of the endotoxin by one-half. Alteration was increased when F-1a was incubated with the endotoxin at acid pH or at 45 C rather than at 37 C and was lost after heating F-1a at 56 C for 30 min. N-ethylmaleimide increased the endotoxin-altering activity of horse serum, F-1a, and human plasma fraction III(0), whereas p-chloromercuribenzoate did not. On the other hand, diazonium-1-H-tetrazole, iodoacetic acid, and benzylchloride suppressed the activity of F-1a. When the interaction of endotoxin and F-1a was examined by immunodiffusion techniques, depolymerization of the endotoxin molecule was indicated. The endotoxin-altering factor of horse serum is discussed in relation to the mechanisms of other known reagents, such as deoxycholate and sodium lauryl sulfate.

  5. Prion protein paralog doppel protein interacts with alpha-2-macroglobulin: a plausible mechanism for doppel-mediated neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Stefano Benvegnù

    2009-06-01

    Full Text Available Doppel protein (Dpl is a paralog of the cellular form of the prion protein (PrP(C, together sharing common structural and biochemical properties. Unlike PrP(C, which is abundantly expressed throughout the central nervous system (CNS, Dpl protein expression is not detectable in the CNS. Interestingly, its ectopic expression in the brain elicits neurodegeneration in transgenic mice. Here, by combining native isoelectric focusing plus non-denaturing polyacrylamide gel electrophoresis and mass spectrometry analysis, we identified two Dpl binding partners: rat alpha-1-inhibitor-3 (alpha(1I(3 and, by sequence homology, alpha-2-macroglobulin (alpha(2M, two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP(C with either alpha(1I(3 or alpha(2M. Nevertheless, enzyme-linked immunosorbent assays and surface plasmon resonance experiments revealed a high affinity binding occurring between PrP(C and Dpl. In light of these findings, we suggest a mechanism for Dpl-induced neurodegeneration in mice expressing Dpl ectopically in the brain, linked to a withdrawal of natural inhibitors of metalloproteinase such as alpha(2M. Interestingly, alpha(2M has been proven to be a susceptibility factor in Alzheimer's disease, and as our findings imply, it may also play a relevant role in other neurodegenerative disorders, including prion diseases.

  6. Prion protein paralog doppel protein interacts with alpha-2-macroglobulin: a plausible mechanism for doppel-mediated neurodegeneration.

    Science.gov (United States)

    Benvegnù, Stefano; Franciotta, Diego; Sussman, Josh; Bachi, Angela; Zardini, Elisabetta; Torreri, Paola; Govaerts, Cedric; Pizzo, Salvatore; Legname, Giuseppe

    2009-06-18

    Doppel protein (Dpl) is a paralog of the cellular form of the prion protein (PrP(C)), together sharing common structural and biochemical properties. Unlike PrP(C), which is abundantly expressed throughout the central nervous system (CNS), Dpl protein expression is not detectable in the CNS. Interestingly, its ectopic expression in the brain elicits neurodegeneration in transgenic mice. Here, by combining native isoelectric focusing plus non-denaturing polyacrylamide gel electrophoresis and mass spectrometry analysis, we identified two Dpl binding partners: rat alpha-1-inhibitor-3 (alpha(1)I(3)) and, by sequence homology, alpha-2-macroglobulin (alpha(2)M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP(C) with either alpha(1)I(3) or alpha(2)M. Nevertheless, enzyme-linked immunosorbent assays and surface plasmon resonance experiments revealed a high affinity binding occurring between PrP(C) and Dpl. In light of these findings, we suggest a mechanism for Dpl-induced neurodegeneration in mice expressing Dpl ectopically in the brain, linked to a withdrawal of natural inhibitors of metalloproteinase such as alpha(2)M. Interestingly, alpha(2)M has been proven to be a susceptibility factor in Alzheimer's disease, and as our findings imply, it may also play a relevant role in other neurodegenerative disorders, including prion diseases.

  7. Can we predict fall asthma exacerbations? Validation of the seasonal asthma exacerbation index.

    Science.gov (United States)

    Hoch, Heather E; Calatroni, Agustin; West, Joseph B; Liu, Andrew H; Gergen, Peter J; Gruchalla, Rebecca S; Khurana Hershey, Gurjit K; Kercsmar, Carolyn M; Kim, Haejin; Lamm, Carin I; Makhija, Melanie M; Mitchell, Herman E; Teach, Stephen J; Wildfire, Jeremy J; Busse, William W; Szefler, Stanley J

    2017-10-01

    A Seasonal Asthma Exacerbation Predictive Index (saEPI) was previously reported based on 2 prior National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium trials. This study sought to validate the saEPI in a separate trial designed to prevent fall exacerbations with omalizumab therapy. The saEPI and its components were analyzed to characterize those who had an asthma exacerbation during the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study. We characterized those inner-city children with and without asthma exacerbations in the fall period treated with guidelines-based therapy (GBT) in the absence and presence of omalizumab. A higher saEPI was associated with an exacerbation in both the GBT alone (P children treated with GBT with or without omalizumab was associated with a higher saEPI along with higher markers of allergic inflammation, treatment step, and a recent exacerbation. Those that exacerbated on omalizumab had similar features with the exception of some markers of allergic sensitization, indicating a need to develop better markers to predict poor response to omalizumab therapy and alternative treatment strategies for children with these risk factors. The saEPI was able to reliably predict those children unlikely to have an asthma exacerbation in both groups. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  8. Self-management behaviors to reduce exacerbation impact in COPD patients: a Delphi study.

    Science.gov (United States)

    Korpershoek, Yvonne Jg; Bruins Slot, Joyce C; Effing, Tanja W; Schuurmans, Marieke J; Trappenburg, Jaap Ca

    2017-01-01

    Little is known about which self-management behaviors have the highest potential to influence exacerbation impact in COPD patients. We aimed to reach expert consensus on the most relevant set of self-management behaviors that can be targeted and influenced to maximize reduction of exacerbation impact. A 2-round Delphi study was performed using online surveys to rate the relevance and feasibility of predetermined self-management behaviors identified by literature and expert opinion. Descriptive statistics and qualitative analyses were used. An international expert panel reached consensus on 17 self-management behaviors focusing on: stable phase (n=5): pharmacotherapy, vaccination, physical activity, avoiding stimuli and smoking cessation; periods of symptom deterioration (n=1): early detection; during an exacerbation (n=5): early detection, health care contact, self-treatment, managing stress/anxiety and physical activity; during recovery (n=4): completing treatment, managing stress/anxiety, physical activity and exercise training; and after recovery (n=2): awareness for recurrent exacerbations and restart of pulmonary rehabilitation. This study has provided insight into expert opinion on the most relevant and feasible self-management behaviors that can be targeted and influenced before, during and after an exacerbation to exert the highest magnitude of influence on the impact of exacerbations. Future research should focus at developing more comprehensive patient-tailored interventions supporting patients in these exacerbation-related self-management behaviors.

  9. Discovery, structural characterization and functional analysis of alpha-2-macroglobulin, a novel immune-related molecule from Holothuria atra.

    Science.gov (United States)

    Qian, Jing; Ren, Chunhua; Xia, Jianjun; Chen, Ting; Yu, Zonghe; Hu, Chaoqun

    2016-07-10

    The non-specific protease inhibitor alpha-2-macroglobulin (A2M) is a key macromolecular glycoprotein that involved in host immune defense against pathogens in vertebrates and invertebrates. However, no research regarding A2M has been developed in echinoderms to date. In this study, the full-length cDNA of A2M was cloned from the sea cucumber (Holothuria atra), which is a tropical species widely distributed along the coasts of the South China Sea and designated HaA2M. HaA2M possesses all three conserved functional domains of known A2M proteins, including the bait region domain, thioester domain and receptor-binding domain. Compared to fish and shrimp A2Ms, the histidine residue from the catalytical regions is well conserved in HaA2M. HaA2M mRNA was predominantly expressed in coelomocytes and, to a lesser extent, in the body wall, intestine and respiratory tree. A2M activity was detected in the coelomic fluids of H. atra. The mRNA expression and activity levels were investigated in the major immune tissues and coelomic fluids of H. atra after challenge with inactivated Vibrio alginolyticus or polyriboinosinic polyribocytidylic acid [Poly (I: C)]. RNA interference (RNAi)-mediated knockdown of HaA2M resulted in a significant reduction of HaA2M gene transcript level (86%). RNAi-mediated silencing of HaA2M gene significantly decreased the A2M activity (38%) and increased the number of viable bacteria (2.8-fold) in the coelomic fluids of H. atra infected by V. alginolyticus. Our study, as a whole, supplied the evidences for HaA2M as an immune-relevant molecule and it might have multiple functions in the innate immune system of H. atra. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Effects of local alpha2-adrenergic receptor blockade on adipose tissue lipolysis during prolonged systemic adrenaline infusion in normal man

    DEFF Research Database (Denmark)

    Simonsen, Lene; Enevoldsen, Lotte H; Stallknecht, Bente

    2008-01-01

    During prolonged adrenaline infusion, lipolysis peaks within 30 min and thereafter tends to decline, and we hypothesized that the stimulation of local adipose tissue alpha2-adrenergic receptors accounts for this decline. The lipolytic effect of a prolonged intravenous adrenaline infusion combined....... Regional adipose tissue blood flow was measured by the (133)Xe clearance technique. Regional glycerol output (lipolytic rate) was calculated from these measurements and simultaneous measurements of arterial glycerol concentrations. Adrenaline infusion increased lipolysis in all three depots (data...... circulating adrenaline concentrations, and the decrease in lipolysis in subcutaneous adipose tissue under prolonged adrenaline stimulation is thus not attributed to alpha2-adrenergic receptor inhibition of lipolysis. However, in the preperitoneal adipose tissue depot, alpha2-adrenergic receptor tone plays...

  11. Mepolizumab and exacerbations of refractory eosinophilic asthma.

    Science.gov (United States)

    Haldar, Pranabashis; Brightling, Christopher E; Hargadon, Beverley; Gupta, Sumit; Monteiro, William; Sousa, Ana; Marshall, Richard P; Bradding, Peter; Green, Ruth H; Wardlaw, Andrew J; Pavord, Ian D

    2009-03-05

    Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients

  12. MR imaging of hepatic hemangiomas of infancy and changes seen with interferon alpha-2a treatment

    International Nuclear Information System (INIS)

    Chung, T.; Hoffer, F.A.; Burrows, P.E.; Paltiel, H.J.

    1996-01-01

    The purpose of this study was to describe the appearance on magnetic resonance (MR) imaging of hepatic hemangioma, and how the appearance changes in infants who have received interferon alpha-2a (IFN) treatment. We retrospectively studied 16 MR examinations in seven infants (mean age 3.2 months; range 5 days to 13 months) who were symptomatic with hepatic hemangiomas. Five of these seven patients had MR examinations both before and after treatment with IFN. In six of the seven patients, the hepatic hemangiomas were multicentric; they were usually discrete, well-defined nodules, best seen on T2-weighted images as high intensity lesions. One patient had a large solitary heterogeneous lesion. They all exhibited fast flow (seen as flow voids on spin-echo images and high signal intensity structures on gradient-recalled echo images) and enlarged hepatic arteries and veins. There was enlargement of the proximal abdominal aorta with distal tapering. Treatment was followed by accelerated regression of the hemangiomas in size and number and variable shrinkage of the enlarged vessels. As the tumor nodules regressed, they were replaced by normal-appearing hepatic parenchyma; neither fat nor fibrosis was detected by MR imaging. (orig.). With 4 figs., 1 tab

  13. Association between alpha-2a-adrenergic receptor gene and ADHD inattentive type.

    Science.gov (United States)

    Schmitz, Marcelo; Denardin, Daniel; Silva, Tatiana Laufer; Pianca, Thiago; Roman, Tatiana; Hutz, Mara Helena; Faraone, Stephen V; Rohde, Luis Augusto

    2006-11-15

    Previous investigations have demonstrated that an MspI polymorphism at the adrenergic alpha2A receptor gene (ADRA2A) is associated with severity of attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms in clinical samples composed mainly of subjects with ADHD, combined type. This study aimed to investigate the association between this ADRA2A polymorphism and attention-deficit/hyperactivity disorder-inattentive type (ADHD-I) in a nonreferred sample. In a case-control study, we assessed a sample of 100 children and adolescents with ADHD-I and 100 non-ADHD controls. Cases and controls were matched by gender and age and were screened by using teacher reports in a revised version of the Swanson, Nolan, and Pelham rating scale at 12 schools. Psychiatric diagnoses were derived through structured diagnostic interviews. Homozygous subjects for the G allele at the ADRA2A had significantly higher odds ratio (OR) for ADHD-I than did those with other genotypes (CC + CG genotypes), even after adjusting for potential confounders (p = .02; OR = 3.78; 95% confidence interval = 1.23-11.62). In family-based analyses, no significant associations were detected. Our results suggest that the ADRA2A may be associated with ADHD-I, replicating previous findings from clinical samples that have suggested the importance of this gene for the dimension of inattention. In addition, these results support the role of the noradrenergic system in ADHD.

  14. Human Interferon Alpha2a as Anti Hepatitis B and C

    Directory of Open Access Journals (Sweden)

    Ratih A. Ningrum

    2017-12-01

    Full Text Available Hepatitis is an inflammation of the liver mainly caused by hepatitis viruses. There are 5 different types of hepatitis based on the infecting virus; A, B, C, D and E. Hepatitis B and C are chronic diseases that potentially develop into hepatocarcinoma and cirrhosis on unappropriate treatments. World Health Organization (WHO stated that currently 350 million people worldwide are living with chronic hepatitis B and 150 million people are living with Hepatitis C. The mortality rate in the world due to hepatitis is about 1.5 million people per year. The human interferon alpha2a (hIFNα2a is a therapeutic protein used as therapeutic protein for hepatitis B and C. This review discusses the hepatitis B (HBV and C (HCV viruses, mechanisms of hIFNα2a as antivirus through signal transduction pathway and improvement of hIFNα2a properties by protein modification. The application of recombinant hIFNα2a (rhIFNα2a in the treatment of hepatitis B and C that recommended by European Association for The Study of Liver (EASL and the viral resistance mechanism are also included. The status of hepatitis B and C and the development of rhIFNα2a is also described as well.

  15. Recombinant human interferon alpha 2b prevents and reverses experimental pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Eileen M Bauer

    Full Text Available Pulmonary hypertension (PH is a progressive and fatal disease with no cure. Vascular remodeling in PH involves intraluminal growth of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Cell growth in these lesions is quasi-neoplastic, with evidence of monoclonality, apoptosis resistance and cancer-like metabolic derangements. Herein we tested the effect of human interferon alpha 2b (IFNα, a pleiotropic cytokine and anti-cancer therapeutic, on the development and progression of PH in the rat SU5416/hypoxia (SUH model and mouse hypoxia model of the disease. In both models IFNα attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFNα was dependent on the type I interferon receptor (IFNAR since mice lacking a subunit of the IFNAR were not protected by IFNα. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFNα inhibited pulmonary vascular remodeling in both models and that IFNα reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFNα decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFNα inhibited proliferation of human pulmonary artery smooth muscle cells and as well as human pulmonary artery endothelial cell proliferation and apoptosis. Together these findings demonstrate that IFNα reverses established experimental PH and provide a rationale for further exploration of the use of IFNα and other immunotherpies in PH.

  16. NADPH oxidase 1 controls the persistence of directed cell migration by a Rho-dependent switch of alpha2/alpha3 integrins.

    Science.gov (United States)

    Sadok, Amine; Pierres, Anne; Dahan, Laetitia; Prévôt, Charles; Lehmann, Maxime; Kovacic, Hervé

    2009-07-01

    NADPH oxidase 1 (Nox1) is expressed mainly in colon epithelial cells and produces superoxide ions as a primary function. We showed that Nox1 knockdown inhibits directional persistence of migration on collagen I. This paper dissects the mechanism by which Nox1 affects the direction of colonic epithelial cell migration in a two-dimensional model. Transient activation of Nox1 during cell spreading on collagen 1 temporarily inactivated RhoA and led to efficient exportation of alpha2beta1 integrin to the cell surface, which supported persistent directed migration. Nox1 knockdown led to a loss of directional migration which takes place through a RhoA-dependent alpha2/alpha3 integrin switch. Transient RhoA overactivation upon Nox1 inhibition led to transient cytoskeletal reorganization and increased cell-matrix contact associated with a stable increase in alpha3 integrin cell surface expression. Blocking of alpha3 integrin completely reversed the loss of directional persistence of migration. In this model, Nox1 would represent a switch between random and directional migration through RhoA-dependent integrin cell surface expression modulation.

  17. [3H]idazoxan and some other alpha 2-adrenergic drugs also bind with high affinity to a nonadrenergic site

    NARCIS (Netherlands)

    Michel, M. C.; Brodde, O. E.; Schnepel, B.; Behrendt, J.; Tschada, R.; Motulsky, H. J.; Insel, P. A.

    1989-01-01

    We compared the pharmacological properties of the alpha 2-adrenergic radioligand [3H]idazoxan with those of [3H]rauwolscine in rat and [3H]yohimbine in human renal cortical membranes. The density of "specific" [3H]idazoxan binding sites (defined by 100 microM tolazoline) was twice as high as that of

  18. Diverse functional consequences of mutations in the Na+/K+-ATPase alpha2-subunit causing familial hemiplegic migraine type 2.

    NARCIS (Netherlands)

    Tavraz, N.N.; Friedrich, T.; Durr, K.L.; Koenderink, J.B.; Bamberg, E.; Freilinger, T.; Dichgans, M.

    2008-01-01

    Mutations in ATP1A2, the gene coding for the Na(+)/K(+)-ATPase alpha(2)-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic

  19. Comparative therapeutic response to pegylated interferon plus ribavirin versus interferon alpha-2b in chronic hepatitis C patients

    International Nuclear Information System (INIS)

    Ali, S.; Nazir, G.; Khan, S.A.; Fatima, F.; Iram, S.

    2010-01-01

    Background: Hepatitis C is an epidemic worldwide since discovery in 1989. Conventional interferon alpha-2b plus Ribavirin therapy was started in 1998 but over all sustained viral response (SVR) rates are much below the desired rates to eradicate the diseases and stopping its epidemic. This study was conducted to access the therapeutic and cost-effectiveness of long acting pegylated interferon alpha-2b plus Ribavirin therapy verses conventional interferon alpha-2b plus Ribavirin. Methods: This comparative study was done at PAF Hospital Shorkot Cantt from July 2005 to July 2008. One hundred anti-HCV positive patients were selected randomly for the study according to willingness due to cost afford ability of the patients for conventional interferon. Group-A was labelled as pegylated interferon alpha-2b plus Ribavirin group, and Group-B interferon alpha-2b plus Ribavirin group. Both groups were given treatment for 24 weeks. Early virological response (EVR) was accessed at 12 weeks of the treatment. Sustained virological response (SVR) in both the groups was done at 24 week during the treatment and 6 monthly after treatment for 2 years. Initially non-responders and relapsed patients within 2 years of treatment were re-treated for 24 weeks with the same treatment. In both groups non-responders and relapsed patients were labelled as resistant patients. Both groups were followed with same protocol for 2 years. Results: Out of 100 patients included in the study, 34% were females and 66% were males. Group-A patients over all showed 94% SVR as compare to 80% in Group-B in 2 year follow-up. Group-A showed 6% resistant patients as compare to Group-B (20%). Conventional interferons were better tolerated. Higher incidence of side-effects was seen in Group-A. Conclusion: Pegylated interferon plus Ribavirin showed 94% SVR in 2 years. Pegylated interferon plus Ribavirin is the treatment of choice.

  20. Quetiapine reverse paclitaxel-induced neuropathic pain in mice: Role of Alpha2- adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Alireza Abed

    2017-11-01

    Full Text Available Objective(s: Paclitaxel-induced peripheral neuropathy is a common adverse effect of cancer chemo -therapy. This neuropathy has a profound impact on quality of life and patient’s survival. Preventing and treating paclitaxel-induced peripheral neuropathy is a major concern. First- and second-generation antipsychotics have shown analgesic effects both in humans and animals. Quetiapine is a novel atypical antipsychotic with low propensity to induce extrapyramidal or hyperprolactinemia side effects. The present study was designed to investigate the effects of quetiapine on the development and expression of neuropathic pain induced by paclitaxel in mice and the role of α2-adrenoceptors on its antinociception. Materials and Methods: Paclitaxel (2 mg/kg IP was injected for five consecutive days which resulted in thermal hyperalgesia and mechanical and cold allodynia. Results: Early administration of quetiapine from the 1st day until the 5th day (5, 10, and 15 mg/kg PO did not affect thermal, mechanical, and cold stimuli and could not prevent the development of neuropathic pain. In contrast, when quetiapine (10 and 15 mg/kg PO administration was started on the 6th day after the first paclitaxel injections, once the model had been established, and given daily until the 10th day, heat hyperalgesia and mechanical and cold allodynia were significantly attenuated. Also, the effect of quetiapine on heat hyperalgesia was reversed by pretreatment with yohimbine, as an alpha-2 adrenergic receptor antagonist. Conclusion: These results indicate that quetiapine, when administered after nerve injury can reverse the expression of neuropathic pain. Also, we conclude that α2-adrenoceptors participate in the antinociceptive effects of quetiapine.

  1. Prevention of Acute Exacerbations of COPD

    Science.gov (United States)

    Bourbeau, Jean; Diekemper, Rebecca L.; Ouellette, Daniel R.; Goodridge, Donna; Hernandez, Paul; Curren, Kristen; Balter, Meyer S.; Bhutani, Mohit; Camp, Pat G.; Celli, Bartolome R.; Dechman, Gail; Dransfield, Mark T.; Fiel, Stanley B.; Foreman, Marilyn G.; Hanania, Nicola A.; Ireland, Belinda K.; Marchetti, Nathaniel; Marciniuk, Darcy D.; Mularski, Richard A.; Ornelas, Joseph; Stickland, Michael K.

    2015-01-01

    BACKGROUND: COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations. METHODS: In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion. RESULTS: The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in

  2. Frequency of self-reported COPD exacerbation and airflow obstruction in five Latin American cities: the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar (PLATINO) study.

    Science.gov (United States)

    Montes de Oca, Maria; Tálamo, Carlos; Halbert, Ronald J; Perez-Padilla, Rogelio; Lopez, Maria Victorina; Muiño, Adriana; Jardim, José Roberto B; Valdivia, Gonzalo; Pertuzé, Julio; Moreno, Dolores; Menezes, Ana Maria B

    2009-07-01

    Recurrent exacerbations are common in COPD patients. Limited information exists regarding exacerbation frequency in COPD patients from epidemiologic studies. We examined the frequency of self-reported exacerbations and the factors influencing exacerbation frequency among COPD patients in a population-based study conducted in Latin America. We used a post-bronchodilator FEV(1)/FVC ratio of < 0.70 to define COPD. Exacerbation was self-reported and defined by symptoms (deterioration of breathing symptoms that affected usual daily activities or caused missed work). Spirometry was performed in 5,314 subjects. There were 759 subjects with airflow limitation; of these, 18.2% reported ever having had an exacerbation, 7.9% reported having an exacerbation, and 6.2% reported having an exacerbation requiring at least a doctor visit within the past year. The proportion of individuals with an exacerbation significantly increased by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, from 4.2% in stage 1 to 28.9% in stages 3 and 4. The self-reported exacerbation rate was 0.58 exacerbations per year. The rate of exacerbations requiring at least a doctor visit and length of stay in hospital due to exacerbations also increased as COPD severity progressed. The factors associated with having an exacerbation in the past year were dyspnea, prior asthma diagnosis, receiving any respiratory therapy, and disease severity of GOLD stages 3 and 4. The proportion of individuals with airflow limitation and self-reported exacerbation increases as the disease severity progresses. Dyspnea, prior asthma diagnosis, receiving any respiratory therapy, and more severe obstruction were significantly associated with having an exacerbation in the past year.

  3. [Digital action plan for asthma exacerbations (PANAME)].

    Science.gov (United States)

    Beydon, N; Delclaux, C

    2017-11-01

    A written action plan (WAP) reduces emergency visits for asthma exacerbations. However, a WAP is underused and often focused on asthma control. The innovation is an AppWeb that includes an expert software aimed at diagnosing the level of severity of asthma exacerbations and delivering a personalized digital action plan (DAP) when patients are in urgent need of medical advice. Symptoms describing the level of severity of asthma exacerbations and the consequent treatments have been established by working groups of the French Respiratory Societies (SPLF and SP2A for adults and children, respectively). The main objective of the study is to evaluate the effect of the DAP on the frequency of urgent medical attendance. Secondary objectives are to evaluate adherence to the DAP compared to a WAP and the qualitative satisfaction of patients using the DAP. A randomized, prospective, comparative, multicenter study on two parallel groups, conducted in private practice and in hospitals. In both arms, asthmatic patients (240 children aged 6 to 12 years and 270 adults aged 18 to 50 years) with severe asthma exacerbation(s) during the previous year and an Internet connection via a smartphone or a tablet computer, will have at their disposal a WAP and one arm will have, in addition, the DAP. Included patients will be followed up every three months for one year. A decrease in the number of urgent medical attendances and better adherence in the WAP+DAP group compared to the WAP group. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  4. Haemophilus influenzae from Patients with Chronic Obstructive Pulmonary Disease Exacerbation Induce More Inflammation than Colonizers

    Science.gov (United States)

    Chin, Cecilia L.; Manzel, Lori J.; Lehman, Erin E.; Humlicek, Alicia L.; Shi, Lei; Starner, Timothy D.; Denning, Gerene M.; Murphy, Timothy F.; Sethi, Sanjay; Look, Dwight C.

    2005-01-01

    Rationale: Airway infection with Haemophilus influenzae causes airway inflammation, and isolation of new strains of this bacteria is associated with increased risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine whether strains of H. influenzae associated with exacerbations cause more inflammation than strains that colonize the airways of patients with COPD. Methods: Exacerbation strains of H. influenzae were isolated from patients during exacerbation of clinical symptoms with subsequent development of a homologous serum antibody response and were compared with colonization strains that were not associated with symptom worsening or an antibody response. Bacterial strains were compared using an in vivo mouse model of airway infection and in vitro cell culture model of bacterial adherence and defense gene and signaling pathway activation in primary human airway epithelial cells. Results: H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in the mouse model of airway bacterial infection. Furthermore, exacerbation strains adhered to epithelial cells in significantly higher numbers and induced more interleukin-8 release after interaction with airway epithelial cells. This effect was likely mediated by increased activation of the nuclear factor-κB and p38 mitogen-activated protein kinase signaling pathways. Conclusions: The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function. PMID:15805181

  5. Early investigational antibiotics for the treatment of acute exacerbations of chronic bronchitis.

    Science.gov (United States)

    Falagas, Matthew E; Georgiou, Maria

    2017-03-01

    Acute exacerbations in patients with chronic bronchitis are a leading cause of hospitalizations and death. Bacteria contribute significantly to such exacerbations. The aim of this review was to explore the potential role of investigational antibiotics in the treatment of these episodes. Areas covered: The available literature in PubMed database, in websites related to investigational drugs and in websites of the producing companies has been searched. The in vitro activity against pathogens involved in acute exacerbations of chronic bronchitis and the pharmacokinetic profile of antibiotics currently under development were taken into consideration for inclusion in the review. Expert opinion: Several novel antimicrobial agents have completed preclinical and Phase I studies and were well-tolerated. Further investigation is mandatory in order to evaluate their future in treatment of chronic bronchitis exacerbations and discover potential advantages compared to already approved antimicrobials.

  6. Different roles of alpha2-adrenoceptor subtypes in non-pregnant and late-pregnant uterine contractility in vitro in the rat.

    Science.gov (United States)

    Gáspár, Róbert; Gál, Adrienn; Gálik, Márta; Ducza, Eszter; Minorics, Renáta; Kolarovszki-Sipiczki, Zoltán; Klukovits, Anna; Falkay, George

    2007-10-01

    The roles of the alpha2-adrenoceptor (alpha2-AR) subtypes (alpha2A-, alpha2B- and alpha2C-AR) in uterine contractility have not been investigated. The aims of this study were to identify these receptors in the non-pregnant and the late-pregnant rat myometrium and to determine their roles in contractions. We found that the myometrial alpha2-AR subtypes are involved differently in the control of late-pregnant contractions, while they have no influence on the contractions of the non-pregnant myometrium. The myometrial expressions of the alpha2-AR subtypes were determined by RT-PCR and Western blotting techniques. In vitro contractions were stimulated with noradrenaline, and its effect was modified with the selective antagonists BRL 44408 (alpha2A), ARC 239 (alpha2B/C) and spiroxatrine (alpha2C). cAMP production was followed by noradrenaline stimulation in the presence of isobutylmethylxanthine and forskolin, and alterations induced in it by the antagonists were determined with an Enzyme Immunoassay Kit. The most effective antagonist was tested on labour-induced uteri in vitro. All the alpha2-AR subtypes were identified in both non-pregnant and pregnant uteri. Noradrenaline was not able to contract the non-pregnant tissue in the presence of propranolol and doxazosin, while its contracting effect in the pregnant uteri was enhanced by BRL 44408, spiroxatrine and the combination BRL 44408+spiroxatrine. ARC 239 exerted a strong inhibitory effect on noradrenaline-stimulated contractions. The increasing and the decreasing effects of the compounds were confirmed by the changes in the intracellular cAMP levels. The effect of ARC 239 on the labour-induced myometrium was similar to that on the 22-day-pregnant myometrium. The stimulation of alpha2-ARs does not evoke contractions in the non-pregnant uterus. The alpha2A- and alpha2C-ARs mediate decreases, while the alpha2B-AR mediates an increase in the contractions in the 22-day-pregnant myometrium. These differences may offer new

  7. Treatment profile of hepatitis C patients - a comparison of interferon alpha 2a and 2b treatment regimes

    International Nuclear Information System (INIS)

    Aziz, S.; Rajper, J.; Nafay, S.; Imran, K.; Khan, M.H.

    2010-01-01

    To compare the side effects, cost, end treatment response (ETR) and Sustained viral response (SVR) with combination therapy of either interferon alpha 2a or 2b in combination with Ribavarin. Study Design: Randomized Control Clinical Trial (RCCT). Place and Duration of Study: The study was conducted at Sarwar Zuberi Liver Centre (SZLC), Civil Hospital Karachi (CHK), from May 2004 to July 2009. Methodology: Patients positive for qualitative HCV ribonucleic acid (RNA) by Polymerase chain reaction (PCR) and genotype 3 were included. Patients with decompensated cirrhosis, severe depressive illness, autoimmune hepatitis, hyperthyroidism, pregnancy, heart failure, uncontrolled diabetes, obstructive pulmonary disease, children less than three years and patients who had previously received treatment were excluded. Single blind randomization using computerized randomization list was done and patients divided into groups A and B, those requiring treatment were given injection Interferon 3 million units (MU) subcutaneously (SC) three times/week and Ribavarin 1000 mg per day (weight greater or equal to 75kg) and 1200 mg/day (weight > 75kg) orally with either interferon alpha 2a (group A; FDA approved products) or alpha 2b (group B; non FDA approved product). Demographics, side effects, ETR and SVR were noted. ETR was defined as absence of virus at the end of treatment and SVR was taken as absence of HCV RNA at 6 months after completion of treatment. Results: There were a total 310 patients with mean age of 34.07 +- 9.38 years including 52.4% males, (n=162). Majority of the patients were from North Pakistan. There were 155 patients each in group A and group B respectively. The cost of treatment for interferon alpha for a single patient for 6 months was Rs 60,000, while for Interferon alpha 2b was Rs 30,000. Side effects (fever initially, followed by fatigue, headache, musculoskeletal pain, depression, alopecia, insomnia, and anorexia) were more prominent in group B when compared

  8. Low-dose intravenous alpha-2 agonists as adjuvants to spinal levobupivacaine: A randomized study

    Directory of Open Access Journals (Sweden)

    Pranav Jetley

    2017-01-01

    Full Text Available Background: Alpha-2 agonists have been used with spinal anesthesia for anxiolysis, analgesia, and hypnosis and for postoperative pain relief. These beneficial effects may, however, be offset by their propensity to prolong the duration of motor block and adversely affect hemodynamics when used in higher doses. This study compares the effects of low-dose premedication with intravenous (IV dexmedetomidine and IV clonidine with placebo, on spinal blockade duration, analgesia, and sedation with intrathecal levobupivacaine. Materials and Methods: In this prospective, randomized, double-blinded, placebo-controlled study, ninety American Society of Anesthesiologists Status I and II patients were randomly allocated into three groups: Group A (control received 10 ml normal saline IV, Group B received IV dexmedetomidine 0.6 μg/kg, and Group C received IV clonidine 1.2 μg/kg over 10 min, before spinal anesthesia with 0.5% levobupivacaine. Hemodynamics, total duration of analgesia, onset and duration of sensory and motor block, visual analog scale score, and sedation score were assessed. Complications, if any, were noted. Results: The level of sensory block achieved was higher with dexmedetomidine (T4.2 ± 0.8 and clonidine (T4.4 ± 0.7 as compared to control (T5.1 ± 0.7; P< 0.001. Time to two segment regression was greater with dexmedetomidine (146.5 ± 12.5 min and clonidine (138.9 ± 17.4 min compared to control (90.1 ± 9.4; P< 0.001. Dexmedetomidine maximally prolonged the duration to first patient request for analgesia (245.2 ± 26.8 min, followed by clonidine (175.3 ± 20.1 min, P< 0.001 and control (121.3 ± 16.1 min, P< 0.001. The duration of motor block was similar in all three groups. Incidence of bradycardia was significantly greater with both dexmedetomidine and clonidine compared to saline (P < 0.05. Conclusion: Premedication with low-dose IV dexmedetomidine and clonidine prolonged sensory blockade and analgesic duration and provided

  9. Bothrops asper metalloproteinase BaP1 is inhibited by alpha(2)-macroglobulin and mouse serum and does not induce systemic hemorrhage or coagulopathy.

    Science.gov (United States)

    Escalante, Teresa; Rucavado, Alexandra; Kamiguti, Aura S; Theakston, R David G; Gutiérrez, José María

    2004-02-01

    The ability of the P-I metalloproteinase BaP1, isolated from the venom of the snake Bothrops asper, to induce systemic bleeding, thrombocytopenia and defibrinogenation was assessed in an experimental mouse model. Intravenous administration of BaP1 caused neither systemic bleeding nor any evidence of pathology in lungs, kidneys, liver, heart and brain. Moreover, there were no alterations in the whole blood clotting time or in platelet numbers. In addition, BaP1 did not inhibit collagen-induced platelet aggregation in vitro. Proteolytic and hemorrhagic activities of BaP1 were readily inhibited by the plasma proteinase inhibitor, alpha(2)-macroglobulin, and normal mouse serum also inhibited hemorrhage. Such inhibition may explain why BaP1 induces multiple local tissue-damaging effects, but is largely devoid of systemic toxicity.

  10. Effect of acute exacerbations on circulating endothelial, clotting and fibrinolytic markers in COPD patients.

    Science.gov (United States)

    Polosa, Riccardo; Malerba, Mario; Cacciola, Rossella R; Morjaria, Jaymin B; Maugeri, Cinzia; Prosperini, Gaetano; Gullo, Raimondo; Spicuzza, Lucia; Radaeli, Alessandro; Di Maria, Giuseppe U

    2013-10-01

    Patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inflammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial-coagulative system during acute exacerbations. The aim was to investigate whether the activation of the endothelial-coagulative system occurs in association with the acute inflammatory response of COPD exacerbation. We monitored the blood levels of surrogate markers of inflammation: interleukin-6 (IL-6); endothelium damage: von Willebrand's factor (vWF); clotting activation: D-dimer (D-D), and prothrombin fragment 1+2 (F1+2); fibrinolytic response: plasminogen activator inhibitor 1 (PAI-1), in COPD subjects, during hospital admission and after clinical resolution. In 30 COPD subjects, IL-6, vWF, D-D and F1+2 levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p = 0.005; vWF, p < 0.001; D-D, p < 0.001; F1+2, p < 0.001). PAI-1 levels did not change at exacerbation compared to clinically stable situations. Positive correlations were observed between several of the markers measured. Elevation of IL-6, vWF, D-D and F1+2 levels during COPD exacerbations implies a strict association between acute inflammation, endothelial activation and clotting initiation. This was not associated with a change in PAI-1, implying an increase in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations sustained by enhanced clotting activation appears to be mitigated by excessive fibrinolysis.

  11. 40 CFR 721.5356 - Ethanol, 2,2′2″-nitrilotris-, compound with alpha-2,4,6-tris (1-phenylethyl)phenyl]-omega...

    Science.gov (United States)

    2010-07-01

    ...-, compound with alpha-2,4,6-tris (1-phenylethyl)phenyl]-omega-hydroxypoly (oxy-1,2-ethanediyl) phosphate. 721...]-omega-hydroxypoly (oxy-1,2-ethanediyl) phosphate. (a) Chemical substance and significant new uses... alpha-[2,4,6-tris(1-phenylethyl)phenyl]-omega-hydroxypoly (oxy-1,2-ethanediyl) phosphate (PMN P-98-185...

  12. Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain

    DEFF Research Database (Denmark)

    Smith, Donald F; Dyve, Suzan; Minuzzi, Luciano

    2006-01-01

    Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain......Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain...

  13. Origin and effect of Acetobacteraceae Alpha 2.2 in honey bee larvae and description of Parasaccharibacter apium, gen. nov., sp. nov

    Science.gov (United States)

    The honey bee hive environment contains a rich microbial community that differs according to niche. Acetobacteraceae Alpha 2.2 (Alpha 2.2) are present in the food stores, the forager crop, and larvae but at negligible levels in the remainder (non-crop portion) of the nurse and forager gut. We first ...

  14. The inhibitory effect of newer calcium antagonists (nimodipine and PY-108-068) on vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors

    NARCIS (Netherlands)

    Van Meel, J. C. A.; Wilffert, B; De Zoeten, K; Timmermans, P B; Van Zwieten, P A

    1982-01-01

    In the pithed rat, stimulation of postsynaptic alpha 1 as well as alpha 2-adrenoceptors is known to cause vasoconstriction. The two newer nifedipine-related calcium antagonistic agents nimodipine and PY-108-068 proved potent inhibitors of pressor responses induced by the selective alpha 2-receptor

  15. IFN-alpha antibodies in patients with age-related macular degeneration treated with recombinant human IFN-alpha2a

    DEFF Research Database (Denmark)

    Ross, Christian; Engler, Claus Bødker; Sander, Birgit

    2002-01-01

    We tested for development of binding and neutralizing antibodies to interferon-alpha (IFN-alpha) during IFN-alpha2a therapy of patients with age-related macular degeneration (AMD) of the eyes. Antibodies were investigated retrospectively in sera of 34 patients treated with 3 x 10(6) IU IFN-alpha2a...

  16. Pneumonic vs nonpneumonic acute exacerbations of COPD.

    Science.gov (United States)

    Lieberman, David; Lieberman, Devora; Gelfer, Yevgenia; Varshavsky, Raiesa; Dvoskin, Bella; Leinonen, Maija; Friedman, Maureen G

    2002-10-01

    To describe and compare the background, clinical manifestations, disease course, and infectious etiologies of pneumonic acute exacerbations (PNAE) vs nonpneumonic acute exacerbations (NPAE) of COPD. A prospective, observational study. A tertiary university medical center in southern Israel. Twenty-three hospitalizations for PNAE and 217 hospitalizations for NPAE were included in the study. Paired sera were obtained for each of the hospitalizations and were tested serologically for 12 pathogens. Only a significant change in antibody titers or levels was considered diagnostic. No significant differences were found between the two groups for any of the parameters related to COPD or comorbidity. The clinical type of the exacerbation was not significantly different between the groups. Compared to NPAE, patients with PNAE had lower PO(2) values at hospital admission (p = 0.004) but higher rates of abrupt onset (p = 0.005), ICU admissions (p = 0.006), invasive mechanical ventilation (p = 0.01), mortality (p = 0.007), and longer hospital stay (p = 0.001). In 22 PNAE hospitalizations (96%) and in 153 NPAE hospitalizations (71%), at least one infectious etiology was identified (p = 0.001). Mixed infection was found in 13 patients with PNAE (59%) and in 59 patients with NPAE (39%; not significant [NS]). Viral etiology was identified in 18 patients with PNAE (78%) compared with 99 patients with NPAE (46%; p = 0.003). Pneumococcal etiology was found in 10 patients with PNAE (43%) and in 38 patients with NPAE (18%; p = 0.006). An atypical etiology was identified in 8 patients with PNAE (35%) and 64 patients with NPAE (30%; NS). Community-acquired pneumonia is common among patients hospitalized for an acute exacerbation of COPD and is generally manifested by more severe clinical and laboratory parameters. In PNAE, compared to NPAE, viral and pneumococcal etiologies are more common, but the rate of atypical pathogens is similar. The therapeutic significance of these findings

  17. Airways inflammation and treatment during acute exacerbations of COPD

    NARCIS (Netherlands)

    Bathoorn, Erik; Kerstjens, Huib; Postma, Dirkje; Timens, Wim; MacNee, William

    2008-01-01

    INTRODUCTION: Inflammation is a core feature of acute chronic obstructive pulmonary disease (COPD) exacerbations. It is important to focus on inflammation since it gives insight into the pathological changes causing an exacerbation, thereby possibly providing directions for future therapies which

  18. Glycosylation of alpha(2)delta(1) subunit: a sweet talk with Ca(v)1.2 channels

    Czech Academy of Sciences Publication Activity Database

    Lazniewska, Joanna; Weiss, Norbert

    2016-01-01

    Roč. 35, č. 3 (2016), s. 239-242 ISSN 0231-5882 R&D Projects: GA ČR GA15-13556S; GA MŠk 7AMB15FR015 Institutional support: RVO:61388963 Keywords : calcium channel * Ca(v)1.2 channel * ancillary subunit * alpha(2)delta(1) subunit * glycosylation * trafficking Subject RIV: CE - Biochemistry Impact factor: 1.170, year: 2016

  19. Functional characterization of neuronal pre and postsynaptic alpha 2-adrenoceptor subtypes in guinea-pig submucosal plexus.

    Science.gov (United States)

    Shen, K. Z.; Barajas-Lopez, C.; Surprenant, A.

    1990-01-01

    1. The alpha 2-adrenoceptors on cell bodies of submucosal neurones, on presynaptic cholinergic nerve terminals innervating submucosal neurones, and on presynaptic sympathetic fibres innervating submucosal arterioles were characterized in functional studies by use of subtype selective ligands. 2. Both membrane hyperpolarization and presynaptic inhibition of nicotinic excitatory synaptic potentials (e.p.s.ps) produced by UK 14304 were similarly antagonized by idazoxan, yohimbine. SKF 104078, WB 4101 and ARC-239. Antagonism was competitive and dissociation equilibrium constants were the same for both effects. 3. Vasoconstriction of submucosal arterioles in response to stimulation of the sympathetic nerves (20 Hz for 2 s) was inhibited by UK 14304 and clonidine: concentrations producing half-maximum responses were 6 nm and 10 nM respectively. Idazoxan, yohimbine, WB 4101 and SKF 104078 antagonized this action, with dissociation constants similar to those for antagonism of the postsynaptic membrane hyperpolarization and presynaptic inhibition of nicotinic e.p.s.ps. 4. Oxymetazoline was a partial agonist when membrane hyperpolarization or presynaptic inhibition of nicotinic e.p.s.ps were measured but a full agonist when presynaptic inhibition of sympathetically-mediated arteriolar vasoconstriction was measured. As an agonist, oxymetazoline produced half maximum responses at 80-120 nM; the dissociation constant for oxymetazoline as an antagonist was 130 nM. 5. Neither prazosin nor chlorpromazine (up to 30 microM) altered any of the three responses to alpha 2-adrenoceptor agonists. 6. It is concluded that alpha 2-adrenoceptors present on submucosal neuronal cell bodies, on presynaptic cholinergic nerve terminals and on presynaptic sympathetic nerve terminals are the alpha 2A subtype. However, functional characterization of this subtype differs from that provided by ligand binding studies. PMID:1982232

  20. Myasthenia gravis exacerbation and diarrhea associated with erythromycin treatment

    Directory of Open Access Journals (Sweden)

    Sora Yasr

    2017-02-01

    Full Text Available An important problem in management of the case with myasthenia gravis (MG is the control of exacerbation. There are several possible causes of exacerbation of MG including the use of drug. Here, the authors report a case of MG exacerbation and diarrhea associated with erythromycin treatment.

  1. Asthma Exacerbations and Unconventional Natural Gas Development in the Marcellus Shale

    Science.gov (United States)

    Rasmussen, Sara G.; Ogburn, Elizabeth L.; McCormack, Meredith; Casey, Joan A.; Bandeen-Roche, Karen; Mercer, Dione G.; Schwartz, Brian S.

    2017-01-01

    Importance Asthma is common and can be exacerbated by air pollution and stress. Unconventional natural gas development (UNGD) has community and environmental impacts. In Pennsylvania, development began in 2005 and by 2012, 6,253 wells were drilled. There are no prior studies of UNGD and objective respiratory outcomes. Objective To evaluate associations between UNGD and asthma exacerbations. Design A nested case-control study comparing asthma patients with exacerbations to asthma patients without exacerbations from 2005–12. Setting The Geisinger Clinic, which provides primary care services to over 400,000 patients in Pennsylvania. Participants Asthma patients aged 5–90 years (n = 35,508) were identified in electronic health records; those with exacerbations were frequency-matched on age, sex, and year of event to those without. Exposure(s) On the day before each patient’s index date (cases: date of event or medication order; controls: contact date), we estimated UNGD activity metrics for four phases (pad preparation, drilling, stimulation [“fracking”], and production) using distance from the patient’s home to the well, well characteristics, and the dates and durations of phases. Main Outcome(s) and Measure(s) We identified mild, moderate, and severe asthma exacerbations (new oral corticosteroid medication order, emergency department encounter, and hospitalization, respectively). Results We identified 20,749 mild, 1,870 moderate, and 4,782 severe asthma exacerbations, and frequency-matched these to 18,693, 9,350, and 14,104 control index dates, respectively. In three-level adjusted models, there was an association between the highest group of the activity metric for each UNGD phase compared to the lowest group for 11 out of 12 UNGD-outcome pairs (odds ratios [95% CI] ranged from 1.5 [1.2–1.7] for the association of the pad metric with severe exacerbations to 4.4 [3.8–5.2] for the association of the production metric with mild exacerbations). Six of

  2. alpha2-Adrenoceptor antagonists reverse the 5-HT2 receptor antagonist suppression of head-twitch behavior in mice.

    Science.gov (United States)

    Matsumoto, K; Mizowaki, M; Thongpraditchote, S; Murakami, Y; Watanabe, H

    1997-03-01

    The alpha2-adrenoceptor agonist clonidine, as well as 5-HT2 receptor antagonists, reportedly suppress 5-HT2 receptor-mediated head-twitch behavior. We investigated the effect of alpha2-adrenoceptor antagonists on the suppressive action of 5-HT2 receptor antagonists in mice pretreated with the noradrenaline toxin 6-hydroxydopamine (6-OHDA) or the 5-HT synthesis inhibitor p-chlorophenylalanine (p-CPA). In normal mice, idazoxan (0.08-0.2 mg/kg, IP) or yohimbine (0.2-2.0 mg/kg, IP), both alpha2-adrenoceptor antagonists, had no effect on the head-twitch response caused by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 16 mg/kg, IP), but idazoxan significantly enhanced the response at 0.5 mg/kg. On the other hand, these alpha2-adrenoceptor antagonists, at doses that had no effect on the basal number of head-twitches (idazoxan 0.2 mg/kg and yohimbine 0.5 mg/kg), significantly attenuated not only the suppressive effect of clonidine (0.01 mg/kg, IP) on head-twitch response but also that of the 5-HT2 receptor antagonist ritanserin (0.03 mg/kg, IP). Moreover, idazoxan (0.2 mg/kg) also significantly reversed the inhibition by 0.01 mg/kg (IP) ketanserin, a selective 5-HT2 receptor antagonist. Pretreatment with 6-OHDA plus nomifensine but not with p-CPA significantly attenuated the effect of idazoxan (0.2-0.5 mg/kg) on the ritanserin inhibition of the head-twitch response. Prazosin, an alpha1-adrenoceptor antagonist, dose-dependently suppressed the response, and the effect of prazosin (1.25 mg/kg) was significantly attenuated by 0.5 mg/kg idazoxan. These results indicate that endogenous noradrenaline is involved in the apparent antagonistic interaction between selective alpha2-adrenoceptor antagonists and 5-HT2 receptor antagonists in the head-twitch response, and suggest that noradrenaline stimulation of alpha1-adrenoceptors may be involved in this apparent antagonism.

  3. Use of recombinant alpha-2b-interferon in combination with antioxidants in the form of rectal suppositories (viferon) in children with chronic hepatitides B and C.

    Science.gov (United States)

    Uchaikin, V; Cherednichenko, T; Malinovskaya, V; Orlova, T; Kovalev, O; Kharlamova, F; Chaplygina, G; Konev, V; Voronina, F; Delenian, N

    2000-04-01

    A new antiviral and immunomodulating preparation Viferon, produced as rectal suppositories containing recombinant alpha-2b-interferon (IFN) and antioxidants, was used in complex therapy of viral chronic hepatitides B and C (ChHB and ChHC) in children. Results of our investigation showed a high efficiency of Viferon. Viferon was found to suppress replication of hepatotropic viruses and to decrease activity of the pathologic process in the liver of children with ChHB and ChHC. After a Viferon treatment with daily doses of (1-2) x 10(6) IU of IFN (3.0 x 10(6) IU/m2) primary remission was registered in 78% of patients with ChHB and in 44% of patients with ChHC, while lasting remission was found in 82% of ChHB and in 33% of ChHC patients. Thus, a more marked effect was observed with ChHB, in which 3.0 x 10(6) IU/m2 was the optimal daily dose for children. Increasing the dose to 5.0 x 10(6) IU/m2 did not result in rise of the percentage of the remissions. Side effects, which are characteristic for injection of IFN preparations, were never found even after a longterm treatment. Absence of induction of neutralizing antibodies was observed after administration of alpha-2b-IFN, an integral part of Viferon. In pediatrics, the method of rectal administration has advantages over parenteral delivery due to its convenience, non-traumatic character and possibility of use for prolonged periods.

  4. Pharmacokinetic and pharmacodynamic characterization of a novel formulation containing co-formulated interferons alpha-2b and gamma in healthy male volunteers.

    Science.gov (United States)

    García-García, Idrian; Hernández-González, Ignacio; Díaz-Machado, Alina; González-Delgado, Carlos A; Pérez-Rodríguez, Sonia; García-Vega, Yanelda; Campos-Mojena, Rosario; Tuero-Iglesias, Ángela D; Valenzuela-Silva, Carmen M; Cruz-Ramírez, Alieski; Martín-Trujillo, Alis; Santana-Milián, Héctor; López-Saura, Pedro A; Bello-Rivero, Iraldo

    2016-12-07

    More potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be achieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics and pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and gamma (CIGB-128-A). A group of nine healthy male subjects received intramuscularly 24.5 × 10 6 IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (β 2 M) and 2'-5' oligoadenylate synthetase (2'-5' OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme immunoassay and body temperature was used as pharmacodynamic variable as well. Concerning pharmacokinetics, serum IFNs' profiles were better fitted to a mono-compartmental model with consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous administered IFNs were observed in their typical similar systemic profiles. Neopterin and β 2 M time profiles showed a delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin level was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time, mean serum β 2 M peaked around the double from baseline. Serum concentrations of the enzyme 2'-5' OAS was still elevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever, headache, arthralgia and lymphopenia, mostly mild. The administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies. Cuban Public Registry of Clinical Trials RPCEC00000118 , May 24, 2011.

  5. Preventing Severe Asthma Exacerbations in Children. A Randomized Trial of Mite-Impermeable Bedcovers.

    Science.gov (United States)

    Murray, Clare S; Foden, Philip; Sumner, Helen; Shepley, Elizabeth; Custovic, Adnan; Simpson, Angela

    2017-07-15

    Allergen exposure in sensitized individuals with asthma interacts with viruses to increase the risk of asthma exacerbation. To evaluate the use of house dust mite-impermeable bedding and its impact on severe asthma exacerbations in children. We randomized mite-sensitized children with asthma (ages 3-17 yr) after an emergency hospital attendance with an asthma exacerbation to receive mite-impermeable (active group) or control (placebo group) bed encasings. Over a 12-month intervention period, the occurrence of severe asthma exacerbations was investigated. Of 434 children with asthma who consented, 286 (mean age, 7.7 yr; male sex, 65.8%) were mite sensitized, and 284 were randomized (146 to the active group and 138 to the placebo group). At 12 months, significantly fewer children in the active group than in the placebo group had attended the hospital with an exacerbation (36 [29.3%] of 123 vs. 49 [41.5%] of 118; P = 0.047). In the multivariable analysis, the risk of emergency hospital attendance was 45% lower in the active group (hazard ratio, 0.55; 95% confidence interval [CI], 0.36-0.85; P = 0.006) than in the placebo group. The annual rate of emergency hospital attendance with exacerbations was 27% lower in the active group than in the placebo group, but this did not reach significance (estimated marginal mean [95% CI], active, 0.38 [0.26-0.56] vs. placebo, 0.52 [0.35-0.76]; P = 0.18). No difference between the groups in the risk of prednisolone use for exacerbation was found (hazard ratio, 0.82; 95% CI, 0.58-1.17; P = 0.28). Mite-impermeable encasings are effective in reducing the number of mite-sensitized children with asthma attending the hospital with asthma exacerbations but not the number requiring oral prednisolone. This simple measure may reduce the health care burden of asthma exacerbations in children. Clinical trial registered with www.isrctn.com (ISRCTN 69543196).

  6. Origin and Effect of Alpha 2.2 Acetobacteraceae in Honey Bee Larvae and Description of Parasaccharibacter apium gen. nov., sp. nov.

    OpenAIRE

    Corby-Harris, Vanessa; Snyder, Lucy A.; Schwan, Melissa R.; Maes, Patrick; McFrederick, Quinn S.; Anderson, Kirk E.

    2014-01-01

    The honey bee hive environment contains a rich microbial community that differs according to niche. Acetobacteraceae Alpha 2.2 (Alpha 2.2) bacteria are present in the food stores, the forager crop, and larvae but at negligible levels in the nurse and forager midgut and hindgut. We first sought to determine the source of Alpha 2.2 in young larvae by assaying the diversity of microbes in nurse crops, hypopharyngeal glands (HGs), and royal jelly (RJ). Amplicon-based pyrosequencing showed that Al...

  7. Chronic Hepatitis B with Spontaneous Severe Acute Exacerbation

    Directory of Open Access Journals (Sweden)

    Wei-Lun Tsai

    2015-11-01

    Full Text Available Chronic hepatitis B virus (HBV infection is a major global health problem with an estimated 400 million HBV carriers worldwide. In the natural history of chronic hepatitis B (CHB, spontaneous acute exacerbation (AE is not uncommon, with a cumulative incidence of 10%–30% every year. While exacerbations can be mild, some patients may develop hepatic decompensation and even die. The underlying pathogenesis is possibly related to the activation of cytotoxic T lymphocyte-mediated immune response against HBV. An upsurge of serum HBV DNA usually precedes the rise of alanine aminotransferase (ALT and bilirubin. Whether antiviral treatment can benefit CHB with severe AE remains controversial, but early nucleos(tide analogues treatment seemed to be associated with an improved outcome. There has been no randomized study that compared the effects of different nucleos(tide analogues (NA in the setting of CHB with severe AE. However, potent NAs with good resistance profiles are recommended. In this review, we summarized current knowledge regarding the natural history, pathogenetic mechanisms, and therapeutic options of CHB with severe AE.

  8. 5-Fluorouracil-induced exacerbation of rosacea.

    Science.gov (United States)

    Haddock, Ellen S; Cohen, Philip R

    2016-11-15

    Background Topical 5-fluorouracil (5-FU) is an antineoplastic antimetabolite used for the treatment of actinic keratosis.Purpose A 66-year-old man with erythematotelangiectatic rosacea and biopsy-confirmed actinic keratoses who experienced a rosacea exacerbation after initiating topical 5-FU treatment of his actinic keratoses is described and this adverse event associated with 5-FU is reviewed.Materials and methods Using PubMed.gov the following terms were searched and relevant citations were assessed: rosacea and 5-fluorouracil. 5-FU drug label information and data sheets also were reviewed.ResultsErythematous facial papules developed within a week of starting topical treatment of his actinic keratoses with 5-FU. The lesions resolved within two weeks of discontinuing the medication. Albeit rarely, exacerbation of rosacea by topical 5-FU treatment has been described when 5-FU was introduced as a topical treatment for actinic keratosis.Conclusion Topical 5-FU has been associated with several adverse cutaneous events, including accentuation of rosacea. Although rosacea flares due to topical 5-FU may be uncommon, the incidence may be greater than reflected in the literature. Physicians should be aware of this potential adverse effect in patients in whom they plan to initiate 5-FU therapy.

  9. Efficacy and safety of peginterferon alpha-2a (40KD) in HBeAg-positive chronic hepatitis B patients.

    Science.gov (United States)

    Caruntu, Florin Alexandru; Streinu-Cercel, Adrian; Gheorghe, Liliana Simona; Grigorescu, Mircea; Sporea, Ioan; Stanciu, Carol; Andronescu, Dan; Voinea, Florea; Diculescu, Mircea; Oproiu, Alexandru; Voiosu, Radu

    2009-12-01

    The study was designed to evaluate the efficacy and safety of peginterferon alpha-2a in HBeAg-positive chronic hepatitis B patients, nonresponders or relapsers after previous lamivudine or standard interferon therapy. This prospective, national, multicentric, open label, not randomized trial enrolled 43 HBeAg-positive chronic hepatitis B patients with detectable HBsAg for at least 6 months prior to screening, positive HBeAg and negative anti-HBe, serum HBV DNA levels of at least 500,000 copies/mL by PCR assay, elevated ALT up to 10 x ULN, no response or relapse after previous lamivudine or standard interferon therapy. All eligible patients received pegIFN alpha-2a 180 micrograms weekly for 48 weeks with 24 weeks treatment free follow-up. There were two main efficacy assessments: HBeAg seroconversion and viral supression below 100,000 copies/mL. HBeAg seroconversion rate at the end-of-treatment was 4.65% (n=2; p less than 0.05) increasing to 11.62% 24 weeks after end of therapy (n=5; p less than 0.05). The rate of viral supression at levels below 100,000 copies/mL was 23.25% (n=10; p less than 0.05) at end-of-treatment, and 16.3% (n=7; p less than 0.05) at end of follow-up. ALT normalization was obtained in 20.9% (p less than 0.05) of patients at end-of-treatment, the percentage being significantly higher - 37.2% (p less than 0.05) at the end of follow-up. Even in a difficult-to-treat patient population with HBeAg-positive chronic hepatitis B, peginterferon alpha 2a proved to be efficient in a defined proportion of patients. The increase in HBeAg seroconversion rate from end-of-treatment (4.65%) to the end of follow-up period (11.62%) also proves the benefits of prolonged immunological effect of pegIFN alpha 2a.

  10. A rare case of ulcerative colitis exacerbated by VZV infection.

    Science.gov (United States)

    Nishimura, Satoshi; Yoshino, Takuya; Fujikawa, Yoshiki; Watanabe, Masaki; Yazumi, Shujiro

    2015-12-01

    A 16-years old man with severe ulcerative colitis (UC) was admitted to our hospital. After initiating treatment with corticosteroid for UC, chicken pox appeared. At the same time of appearance of chicken pox, the disease activity of UC was exacerbated. After initiating the treatment with acyclovir, both chicken pox and UC improved. Because colonoscopic findings revealed the remaining of moderately active UC, initiating the treatment with infliximab could induce clinical remission of UC without relapse of varicella-zoster virus (VZV) infection. This is a very rare case of UC with concomitant VZV infection. According to our report, the vaccination for VZV prior to immunosuppressive treatments would be necessary for VZV naïve patients with UC.

  11. Seasonal Risk Factors for Asthma Exacerbations among Inner City Children

    Science.gov (United States)

    Teach, Stephen J.; Gergen, Peter J.; Szefler, Stanley J.; Mitchell, Herman E.; Calatroni, Agustin; Wildfire, Jeremy; Bloomberg, Gordon; Kercsmar, Carolyn; Liu, Andrew H.; Makhija, Melanie; Matsui, Elizabeth; Morgan, Wayne; O'Connor, George; Busse, William W.

    2015-01-01

    Background Exacerbations of asthma remain common even in children and adolescents despite optimal medical management. Identification of host risk factors for exacerbations is incomplete, particularly for seasonal episodes. Objective Define host risk factors for asthma exacerbations unique to their season of occurrence. Methods This is a retrospective analysis of patients aged 6-20 years who comprised the control groups of the Asthma Control Evaluation trial and the Inner City Anti-IgE Therapy for Asthma trial. Univariate and multivariate models were constructed to determine if patient demographic and historical factors, allergic sensitization, fractional exhaled nitric oxide, spirometric measurements, asthma control, and treatment requirements were associated with seasonal exacerbations. Results The analysis included 400 patients (54.5% male; 59.0% African American; median age 13 years). Exacerbations occurred in 37.5% of participants over the periods of observation and were most common in the fall (28.8% of participants). In univariate analysis, impaired pulmonary function was significantly associated with greater odds of exacerbations for all seasons, as was an exacerbation in the previous season for all seasons except spring. In multivariate analysis, exacerbation in the previous season was the strongest predictor in fall and winter while a higher requirement for inhaled corticosteroids was the strongest predictor in spring and summer. The multivariate models had the best predictive power for fall exacerbations (30.5% variance attributed). Conclusions Among a large cohort of inner city children with asthma, patient risk factors for exacerbations vary by season. Thus, individual patient information may be beneficial in strategies to prevent these seasonal events. Clinical Implications Inner city children remain at risk for asthma exacerbations despite appropriate therapy. Because their risk factors vary by season, strategies to prevent them may need to differ as

  12. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Höglund, A Urban

    2004-01-01

    Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinal acetylcholine. The cholinergic receptor system interacts with several other receptor types, such as alpha2-adrenergic receptors. To fully understand these interactions, the effects of ...

  13. Regions involved in binding of urokinase-type-1 inhibitor complex and pro-urokinase to the endocytic alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Evidence that the urokinase receptor protects pro-urokinase against binding to the endocytic receptor.

    Science.gov (United States)

    Nykjaer, A; Kjøller, L; Cohen, R L; Lawrence, D A; Garni-Wagner, B A; Todd, R F; van Zonneveld, A J; Gliemann, J; Andreasen, P A

    1994-10-14

    The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) binds several ligands, including complex between the two chain urokinase-type plasminogen activator (uPA) and type-1 plasminogen activator inhibitor (PAI-1), and the single chain zymogen pro-urokinase (pro-uPA). We have used truncated variants of uPA and PAI-1 as well as Fab fragments of monoclonal antibodies with known epitopes to identify regions in the uPA.PAI-1 complex and in pro-uPA involved in binding to alpha 2MR/LRP.uPA.PAI-1 complex bound with high affinity (EC50 about 0.4 nM) via contacts in the PAI-1 moiety as well as the uPA serine proteinase domain and the uPAA chain. Pro-uPA bound with lower affinity (EC50 about 10 nM), and efficient binding to alpha 2MR/LRP was dependent on contact with both the A chain and the serine proteinase domain. We analyzed the effect of complex formation with the urokinase receptor since this is the primary target for binding of uPA.PAI-1 and pro-uPA at the cell surface, and since it has been demonstrated that urokinase receptor-bound uPA.PAI-1 complex is internalized following interaction with alpha 2 MR/LRP (Nykjaer, A., Petersen, C. M., Møller, B., Jensen, P.H., Moestrup, S.K., Holtet, T.L., Etzerodt M., Thøgersen, H.C., Munch, M., Andreasen, P.A., and Gliemann, J. (1992) J. Biol. Chem. 267, 14543-14546). Soluble recombinant urokinase receptor blocked the binding of pro-uPA to alpha 2MR/LRP but caused only a slight reduction in the affinity for binding of uPA.PAI-1. Moreover, pro-uPA bound to the urokinase receptor at the cell surface was not internalized and degraded unless activated to uPA and complexed with PAI-1. We conclude that pro-uPA is protected against degradation via alpha 2MR/LRP when bound to uPAR due to shielding of a binding contact in the A chain, whereas the affinity of uPAR-bound uPA.PAI-1 complex for binding to alpha 2MR/LRP remains sufficient to allow rapid internalization and degradation.

  14. Origin and effect of Alpha 2.2 Acetobacteraceae in honey bee larvae and description of Parasaccharibacter apium gen. nov., sp. nov.

    Science.gov (United States)

    Corby-Harris, Vanessa; Snyder, Lucy A; Schwan, Melissa R; Maes, Patrick; McFrederick, Quinn S; Anderson, Kirk E

    2014-12-01

    The honey bee hive environment contains a rich microbial community that differs according to niche. Acetobacteraceae Alpha 2.2 (Alpha 2.2) bacteria are present in the food stores, the forager crop, and larvae but at negligible levels in the nurse and forager midgut and hindgut. We first sought to determine the source of Alpha 2.2 in young larvae by assaying the diversity of microbes in nurse crops, hypopharyngeal glands (HGs), and royal jelly (RJ). Amplicon-based pyrosequencing showed that Alpha 2.2 bacteria occupy each of these environments along with a variety of other bacteria, including Lactobacillus kunkeei. RJ and the crop contained fewer bacteria than the HGs, suggesting that these tissues are rather selective environments. Phylogenetic analyses showed that honey bee-derived Alpha 2.2 bacteria are specific to bees that "nurse" the hive's developing brood with HG secretions and are distinct from the Saccharibacter-type bacteria found in bees that provision their young differently, such as with a pollen ball coated in crop-derived contents. Acetobacteraceae can form symbiotic relationships with insects, so we next tested whether Alpha 2.2 increased larval fitness. We cultured 44 Alpha 2.2 strains from young larvae that grouped into nine distinct clades. Three isolates from these nine clades flourished in royal jelly, and one isolate increased larval survival in vitro. We conclude that Alpha 2.2 bacteria are not gut bacteria but are prolific in the crop-HG-RJ-larva niche, passed to the developing brood through nurse worker feeding behavior. We propose the name Parasaccharibacter apium for this bacterial symbiont of bees in the genus Apis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  15. Pulmonary rehabilitation and severe exacerbations of COPD: solution or white elephant?

    Directory of Open Access Journals (Sweden)

    William D-C. Man

    2015-10-01

    Full Text Available Hospitalisations for severe exacerbations of chronic obstructive pulmonary disease are associated with significant physical and psychological consequences including an increase in symptom severity, severe reductions in physical activity, a deleterious effect on skeletal muscle, impaired exercise tolerance/ability to self-care, decline in quality of life, and increased anxiety and depression. As these consequences are potentially amenable to exercise training, there is a clear rationale for pulmonary rehabilitation in the peri/post-exacerbation setting. Although a 2011 Cochrane review was overwhelmingly positive, subsequent trials have shown less benefit and real-life observational studies have revealed poor acceptability. Qualitative studies have demonstrated that the patient experience is a determining factor while the presence of comorbidities may influence referral, adherence and response to pulmonary rehabilitation. Systematic reviews of less supervised interventions, such as self-management, have shown limited benefits in the post-exacerbation setting. The recent update of the Cochrane review of peri-exacerbation pulmonary rehabilitation showed that benefits were associated with the “comprehensive” nature of the intervention (the number of sessions received, the intensity of exercise training and education delivered, and the degree of supervision but implementation is demanding. The challenge is to develop interventions that are deliverable and acceptable around the time of an acute exacerbation but also deliver the desired clinical impact.

  16. Stability of the frequent COPD exacerbator in the general population

    DEFF Research Database (Denmark)

    Reilev, Mette; Lykkegaard, Jesper; Halling, Anders

    2017-01-01

    Exacerbation frequency is central in treatment strategies for chronic obstructive pulmonary disease. However, whether chronic obstructive pulmonary disease patients from the general population with frequent exacerbations continue to have frequent exacerbations over an extended period of time...... is currently unknown. In this study, we aimed to investigate the stability of the frequent exacerbator in a population-based setting. To this end, we conducted a nationwide register-based descriptive study with a 10-year follow-up period of chronic obstructive pulmonary disease patients with at least one...... no additional years as frequent exacerbators, while the minority (6%) remained in this category each year. In conclusion, the rate of exacerbations shows considerable variation over time among chronic obstructive pulmonary disease patients in the general population. This might hold implications for chronic...

  17. Determinants of low risk of asthma exacerbation during pregnancy

    DEFF Research Database (Denmark)

    Ali, Zarqa; Nilas, Lisbeth; Ulrik, Charlotte Suppli

    2017-01-01

    of Asthma during Pregnancy (MAP) program at Hvidovre Hospital since 2007. Assessment of asthma control, adjustment of treatment, spirometry and measurement of exhaled nitric oxide (FE NO) were performed, and baseline characteristics and exacerbation history was collected at enrolment. Determinants of low......-exacerbation risk pregnancies were identified by logistic regression analysis (stepwise backward elimination). RESULTS: In 1,283 pregnancies, 107 exacerbations were observed. Multiple regression analysis revealed that no history of pre-pregnancy exacerbations (p...: Clinically stable asthma at enrolment, together with no history of previous exacerbations and no prescribed controller medication, are determinants of low risk of an asthma exacerbation during pregnancy, which may guide clinicians in individualising surveillance of asthma during pregnancy. This article...

  18. [Treatment of multiple sclerosis symptoms and exacerbations].

    Science.gov (United States)

    Prieto González, José María

    2014-12-01

    In the last few years, there has been an explosion of new drugs acting on the clinical course of multiple sclerosis (MS) but less attention has been paid to better knowledge of the symptoms of this disease and their pathogenesis and treatment, which is essential to improve patients' quality of life. Because many patients have numerous concurrent symptoms during their clinical course, their management is complex and consequently it is important to know which symptoms are a direct result of the degenerative lesions of MS. The present article describes all the therapeutic options available for spasticity and its associated pain, paroxystic symptoms, fatigue, genitourinary disorders and sexual dysfunction, tremor, ataxia, gait disorder and cognitive impairment, with special emphasis on novel treatments. The article also defines exacerbations, how to recognize them and the available treatments, mainly oral administration of high-dose methylprednisolone and plasmapheresis. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  19. Beta Blockers for the Prevention of Acute Exacerbations of COPD

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0705 TITLE: Beta Blockers for the Prevention of Acute Exacerbations of COPD PRINCIPAL INVESTIGATOR: Mark T...SUBTITLE 5a. CONTRACT NUMBER Beta Blockers for the Prevention of Acute Exacerbations of COPD 5b. GRANT NUMBER W81XWH-15-1-0705 5c. PROGRAM ELEMENT...period the following article was published: β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD

  20. Fibrinogen and alpha(1)-antitrypsin in COPD exacerbations

    DEFF Research Database (Denmark)

    Sylvan Ingebrigtsen, Truls; Marott, J. L.; Rode, L.

    2015-01-01

    Background We tested the hypotheses that fibrinogen and alpha(1)-antitrypsin are observationally and genetically associated with exacerbations in COPD. Methods We studied 13 591 individuals with COPD from the Copenhagen General Population Study (2003-2013), of whom 6857 were genotyped for FGB -455...... and exacerbations in instrumental variable analyses. Results Elevated fibrinogen and alpha(1)-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p...

  1. Overweight/obesity and risk of seasonal asthma exacerbations.

    Science.gov (United States)

    Schatz, Michael; Zeiger, Robert S; Zhang, Feng; Chen, Wansu; Yang, Su-Jau; Camargo, Carlos A

    2013-01-01

    Obesity is associated with an increased risk for asthma exacerbations, but whether this risk is related to the season of exacerbation is not known. To determine the relationship of increased body mass index (BMI) to the season of asthma exacerbation. Study subjects were adult (aged 18-65 years) and children (aged 5-17 years) health plan members with persistent asthma in 2008 for whom a BMI measurement was available. BMI categories were normal (fall, or winter of 2009. The cohort included 17,316 adults and 10,700 children. There was a significant (P children with exacerbations during fall and winter. Relationships of overweight or obesity (vs normal weight) to fall and winter exacerbations remained significant in both adults and children after adjustment for sex and education. In a generalized estimating equation model, both BMI status and season (spring, fall, and winter) were related to exacerbations. Moreover, we noted a significant interaction in adults (P = .03) but not children (P = .97) of the BMI-exacerbation association by season (fall-winter vs spring-summer). Higher BMI values increased the risk for asthma exacerbations in adults and children with persistent asthma, particularly for fall-winter exacerbations in adults. Potential mechanisms for these findings, including vitamin D status, viral infections, and corticosteroid responsiveness, merit further study. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  2. Erdosteine reduces inflammation and time to first exacerbation postdischarge in hospitalized patients with AECOPD

    Directory of Open Access Journals (Sweden)

    Moretti M

    2015-10-01

    Full Text Available Maurizio Moretti,1 Stefano Fagnani2 1Respiratory Unit, Massa-Carrara Hospital and University of Pisa, Pisa, Italy; 2Medical Department, Edmond Pharma Srl, Paderno Dugnano, Milan, Italy Purpose: Mucolytics can improve disease outcome in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD. The objectives of this study were to investigate the effects of erdosteine (ER, a mucolytic agent with antioxidant activity, on systemic inflammation, symptoms, recurrence of exacerbation, and time to first exacerbation postdischarge in hospitalized patients with AECOPD. Patients and methods: Patients admitted to hospital with AECOPD were randomized to receive either ER 900 mg daily (n=20 or a matching control (n=20. Treatment was continued for 10 days until discharge. Patients also received standard treatment with steroids, nebulized bronchodilators, and antibiotics as appropriate. Serum C-reactive protein levels, lung function, and breathlessness–cough–sputum scale were measured on hospital admission and thereafter at days 10 and 30 posttreatment. Recurrence of AECOPD-requiring antibiotics and/or oral steroids and time to first exacerbation in the 2 months (days 30 and 60 postdischarge were also assessed. Results: Mean serum C-reactive protein levels were lower in both groups at days 10 and 30, compared with those on admission, with significantly lower levels in the ER group at day 10. Improvements in symptom score and forced expiratory volume in 1 second were greater in the ER than the control group, which reached statistical significance on day 10. ER was associated with a 39% lower risk of exacerbations and a significant delay in time to first exacerbation (log-rank test P=0.009 and 0.075 at days 30 and 60, respectively compared with controls. Conclusion: Results confirm that the addition of ER (900 mg/d to standard treatment improves outcomes in patients with AECOPD. ER significantly reduced airway inflammation, improved

  3. Vitamin E antagonizes ozone-induced asthma exacerbation in Balb/c mice through the Nrf2 pathway.

    Science.gov (United States)

    Duan, Liju; Li, Jinquan; Ma, Ping; Yang, Xu; Xu, Shunqing

    2017-09-01

    Millions of people are regularly exposed to ozone, a gas known to contribute significantly to worsening the symptoms of patients with asthma. However, the mechanisms underlying these ozone exacerbation effects are not fully understood. In this study, we examined the exacerbation effect of ozone in OVA-induced asthma mice and tried to demonstrate the protective mechanism of vitamin E (VE). An asthma mouse model was established, and used to identify the exacerbating effects of ozone by assessing cytokine and serum immunoglobulin concentrations, airway leukocyte infiltration, histopathological changes in lung tissues, and airway hyper-responsiveness. We then determined the amount of reactive oxygen species (ROS) accumulated, the extent to which VE induced ROS elimination, and examined the antagonistic effects of VE on the ozone-induced exacerbating effects. This study showed that 1-ppm ozone exposure could exacerbate OVA-induced asthma in mice. More importantly we found that ozone induced oxidative stress in asthmatic airways may lead to the inhibition of Nuclear factor-erythroid 2-related factor 2 (Nrf2), and may subsequently induce even more exaggerated oxidative stress associated with asthma exacerbation. Through VE induced Nrf2 activation and the subsequent increase in Nrf2 target protein expression, this study suggests a novel mechanism for alleviating ozone exacerbated asthma symptoms. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen

    DEFF Research Database (Denmark)

    Nieswandt, B; Brakebusch, C; Bergmeier, W

    2001-01-01

    subsequent interactions with the activating platelet collagen receptor, glycoprotein VI (GPVI). Here we show that Cre/loxP-mediated loss of beta1 integrin on platelets has no significant effect on the bleeding time in mice. Aggregation of beta1-null platelets to native fibrillar collagen is delayed...

  5. Rural Residence and COPD Exacerbations: Analysis of the SPIROMICS Cohort.

    Science.gov (United States)

    Burkes, Robert M; Gassett, Amanda J; Ceppe, Agathe S; Anderson, Wayne; O'Neal, Wanda K; Woodruff, Prescott G; Krishnan, Jerry A; Barr, R Graham; Han, MeiLan K; Martinez, Fernando J; Comellas, Alejandro P; Lambert, Allison A; Kaufman, Joel D; Dransfield, Mark T; Wells, J Michael; Kanner, Richard E; Paine, Robert; Bleecker, Eugene R; Paulin, Laura M; Hansel, Nadia N; Drummond, M Bradley

    2018-03-27

    Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear. To determine the independent association between rural residence and COPD-related outcomes including COPD exacerbations, airflow obstruction and symptom burden. A total of 1684 Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) participants with FEV1/FVCresidence status determined (N=204 rural and N=1480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of home address to the block level at time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures.The primary outcome measures were exacerbations determined over the one-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. Odds ratio and incidence rate of exacerbations that required treatment with medications including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates. Rural residence was independently associated with 70% increase in odds of total exacerbations [OR 1.70 (95% CI 1.13-2.56); p=0.012] and 46% higher incidence rate of total exacerbations [IRR 1.46 (95% CI 1.02-2.10); p=0.039]. There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation to analysis attenuated the association between rural residence and odds and

  6. Exacerbation of diabetic renal alterations in mice lacking vasohibin-1.

    Directory of Open Access Journals (Sweden)

    Norikazu Hinamoto

    Full Text Available Vasohibin-1 (VASH1 is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1(+/- or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1(+/- mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickening and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1(+/- mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31(+ endothelial area was also increased in the diabetic VASH1(+/- mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1(+/- mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may

  7. Prevalence and pattern of asthma exacerbation in children seen at ...

    African Journals Online (AJOL)

    Background: Acute exacerbation is a major cause of morbidity in asthmatic children. It can occur even in well controlled asthma. Aim: To determine the prevalence and pattern of acute exacerbation of asthma in children seen at the emergency room of the University of Nigeria Teaching Hospital (UNTH), Enugu. Materials ...

  8. Susceptibility to exacerbation in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Hurst, John R; Vestbo, Jørgen; Anzueto, Antonio

    2010-01-01

    BACKGROUND: Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype...

  9. Factors associated with change in exacerbation frequency in COPD

    DEFF Research Database (Denmark)

    Donaldson, Gavin C; Müllerova, Hanna; Locantore, Nicholas

    2013-01-01

    Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to y...

  10. Detection of rhinovirus-associated asthma exacerbations using ...

    African Journals Online (AJOL)

    Ehab

    INTRODUCTION. Acute asthma exacerbation is a cause of strong concern among children and parents and represents a challenge for pediatric healthcare providers1. Studies reported the issue of “virus-induced exacerbation in asthma and chronic obstructive pulmonary disease” and evidence of viral infection is found in ...

  11. Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis.

    LENUS (Irish Health Repository)

    Judge, Eoin P

    2012-07-01

    The aim of this study was to evaluate the risk factors for and outcomes of acute exacerbations in patients with advanced idiopathic pulmonary fibrosis (IPF), and to examine the relationship between disease severity and neovascularisation in explanted IPF lung tissue. 55 IPF patients assessed for lung transplantation were divided into acute (n=27) and non-acute exacerbation (n=28) groups. Haemodynamic data was collected at baseline, at the time of acute exacerbation and at lung transplantation. Histological analysis and CD31 immunostaining to quantify microvessel density (MVD) was performed on the explanted lung tissue of 13 transplanted patients. Acute exacerbations were associated with increased mortality (p=0.0015). Pulmonary hypertension (PH) at baseline and acute exacerbations were associated with poor survival (p<0.01). PH at baseline was associated with a significant risk of acute exacerbations (HR 2.217, p=0.041). Neovascularisation (MVD) was significantly increased in areas of cellular fibrosis and significantly decreased in areas of honeycombing. There was a significant inverse correlation between mean pulmonary artery pressure and MVD in areas of honeycombing. Acute exacerbations were associated with significantly increased mortality in patients with advanced IPF. PH was associated with the subsequent development of an acute exacerbation and with poor survival. Neovascularisation was significantly decreased in areas of honeycombing, and was significantly inversely correlated with mean pulmonary arterial pressure in areas of honeycombing.

  12. Effects of written action plan adherence on COPD exacerbation recovery

    NARCIS (Netherlands)

    Bischoff, E.W.M.A.; Hamd, D.H.; Sedeno, M.; Benedetti, A.; Schermer, T.R.J.; Bernard, S.; Maltais, F.; Bourbeau, J.

    2011-01-01

    BACKGROUND: The effects of written action plans on recovery from exacerbations of chronic obstructive pulmonary disease (COPD) have not been well studied. The aims of this study were to assess the effects of adherence to a written action plan on exacerbation recovery time and unscheduled healthcare

  13. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Thomsen, Mette; Ingebrigtsen, Truls Sylvan; Marott, Jacob Louis

    2013-01-01

    Exacerbations of respiratory symptoms in chronic obstructive pulmonary disease (COPD) have profound and long-lasting adverse effects on patients.......Exacerbations of respiratory symptoms in chronic obstructive pulmonary disease (COPD) have profound and long-lasting adverse effects on patients....

  14. Blood Eosinophils and Exacerbations in Chronic Obstructive Pulmonary Disease

    DEFF Research Database (Denmark)

    Vedel-Krogh, Signe; Nielsen, Sune F; Lange, Peter

    2016-01-01

    RATIONALE: Whether high blood eosinophils are associated with COPD exacerbations among individuals with COPD in the general population is largely unknown. OBJECTIVES: To test the hypothesis that high blood eosinophils predict COPD exacerbations. METHODS: Among 81,668 individuals from the Copenhag...

  15. Incidence and risk factors for exacerbations of asthma during pregnancy

    DEFF Research Database (Denmark)

    Ali, Zarqa; Ulrik, Charlotte Suppli

    2013-01-01

    Asthma is one of the most common chronic diseases among pregnant women. Acute exacerbations of asthma during pregnancy have an unfavorable impact on pregnancy outcome. This review provides an overview of current knowledge of incidence, mechanisms, and risk factors for acute exacerbations of asthma...

  16. Exacerbation of Acute Traumatic Brain Injury by Circulating Extracellular Vesicles.

    Science.gov (United States)

    Hazelton, Isla; Yates, Abi; Dale, Ashley; Roodselaar, Jay; Akbar, Naveed; Ruitenberg, Marc J; Anthony, Daniel C; Couch, Yvonne

    2018-02-15

    Inflammatory lesions in the brain activate a systemic acute-phase response (APR), which is dependent on the release of extracellular vesicles (EVs) into the circulation. The resulting APR is responsible for regulating leukocyte mobilization and subsequent recruitment to the brain. Factors that either exacerbate or inhibit the APR will also exacerbate or inhibit central nervous system (CNS) inflammation as a consequence and have the potential to influence ongoing secondary damage. Here, we were interested to discover how the circulating EV population changes after traumatic brain injury (TBI) and how manipulation of the circulating EV pool impacts on the outcome of TBI. We found the number of circulating EVs increased rapidly post-TBI, and this was accompanied by an increase in CNS and hepatic leukocyte recruitment. In an adoptive transfer study, we then evaluated the outcomes of TBI after administering EVs derived from either in vitro macrophage or endothelial cell lines stimulated with lipopolysaccharide (LPS), or from murine plasma from an LPS challenge using the air-pouch model. By manipulating the circulating EV population, we were able to demonstrate that each population of transferred EVs increased the APR. However, the characteristics of the response were dependent on the nature of the EVs; specifically, it was significantly increased when animals were challenged with macrophage-derived EVs, suggesting that the cellular origins of EVs may determine their function. Selectively targeting EVs from macrophage/monocyte populations is likely to be of value in reducing the impact of the systemic inflammatory response on the outcome of traumatic CNS injury.

  17. A pilot study to monitor changes in spirometry and lung volume, following an exacerbation of Chronic Obstructive Pulmonary Disease (COPD), as part of a supported discharge program.

    Science.gov (United States)

    Cushen, Breda; McCormack, Niamh; Hennigan, Kerrie; Sulaiman, Imran; Costello, Richard W; Deering, Brenda

    2016-10-01

    One-third of patients with an exacerbation of Chronic Obstructive Pulmonary Disease(COPD) are re-hospitalised at 90 days. Exacerbation recovery is associated with reductions in lung hyperinflation and improvements in symptoms and physical activity. We assessed the feasibility of monitoring these clinical parameters in the home. We hypothesised that the degree of change in spirometry and lung volumes differs between those who had an uneventful recovery and those who experienced a further exacerbation. Hospitalised patients with an acute exacerbation of COPD referred for a supported discharge program participated in the study. Spirometry and Inspiratory Vital Capacity(IVC) were measured in the home at Days 1, 14 and 42 post-discharge. Patients also completed Medical Research Council(MRC), Borg and COPD Assessment Test(CAT) scores and were provided with a tri-axial accelerometer. Any new exacerbation events were recorded. Sixty-five patients with 72 exacerbation episodes were recruited. Fifty percent experienced a second exacerbation. Adequate IVC measurements were achieved by 90%, while only 70% completed spirometry. Uneventful recovery was accompanied by significant improvements in physiological measurements at day14, improved symptom scores and step count, p spirometry, lung volumes, symptoms and step count following a COPD exacerbation may help to identify patients at risk of re-exacerbation. It is feasible to carry out these assessments in the home as part of a supported discharge programme. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Relationship of Buckling and Knee Injury to Pain Exacerbation in Knee Osteoarthritis: A Web-Based Case-Crossover Study.

    Science.gov (United States)

    Zobel, Isabelle; Erfani, Tahereh; Bennell, Kim L; Makovey, Joanna; Metcalf, Ben; Chen, Jian Sheng; March, Lyn; Zhang, Yuqing; Eckstein, Felix; Hunter, David J

    2016-06-24

    pain exacerbation (OR 4.0, 95% CI 2.6, 6.2) compared with no buckling and the association increased with a greater number of buckling events (for ≥ 6 buckling events, OR 20.1, 95% CI 3.7, 110). Knee injury and buckling are associated with knee pain exacerbation. Reducing the likelihood of these mechanical events through avoidance of particular activities and/or appropriate rehabilitation programs may decrease the risk of pain exacerbation.

  19. Medically treated exacerbations in COPD by GOLD 1-4

    DEFF Research Database (Denmark)

    Ingebrigtsen, Truls S.; Marott, Jacob L.; Lange, Peter

    2015-01-01

    AIM: We hypothesized that medically treated exacerbations in COPD defined as treatments with oral corticosteroids alone or in combination with antibiotics by register linkage with a nationwide prescription registry is a valid, robust and low-biased measure of exacerbations. METHODS: A total of 13......,591 individuals with COPD in the Copenhagen General Population Study (2003-2013) were linked to the Danish prescription registry. Exacerbations were defined as dispensing of oral corticosteroids alone or in combination with antibiotics, dispensed less than four weeks apart during three years of follow......-up. Construct validity of this definition of medically treated exacerbations was assessed by studying baseline determinants as well as by studying the association between GOLD 1 through 4 grades and time to first exacerbation during follow-up. RESULTS: Among individuals with COPD, 964 individuals (7.1%) had...

  20. Predicting asthma exacerbations using artificial intelligence.

    Science.gov (United States)

    Finkelstein, Joseph; Wood, Jeffrey

    2013-01-01

    Modern telemonitoring systems identify a serious patient deterioration when it already occurred. It would be much more beneficial if the upcoming clinical deterioration were identified ahead of time even before a patient actually experiences it. The goal of this study was to assess artificial intelligence approaches which potentially can be used in telemonitoring systems for advance prediction of changes in disease severity before they actually occur. The study dataset was based on daily self-reports submitted by 26 adult asthma patients during home telemonitoring consisting of 7001 records. Two classification algorithms were employed for building predictive models: naïve Bayesian classifier and support vector machines. Using a 7-day window, a support vector machine was able to predict asthma exacerbation to occur on the day 8 with the accuracy of 0.80, sensitivity of 0.84 and specificity of 0.80. Our study showed that methods of artificial intelligence have significant potential in developing individualized decision support for chronic disease telemonitoring systems.

  1. Early life persistent vitamin D deficiency exacerbates ...

    Science.gov (United States)

    Epidemiological and animal data have conclusively linked adverse cardiovascular outcomes to air pollution exposure. As such, cardiovascular function is maintained by adequate levels of certain essential micronutrients like vitamin D. Unfortunately, vitamin D deficiency (VDD) has become highly prevalent in the United States, as well as in the world, even affecting otherwise healthy individuals. My initial studies showed that VDD alters cardiac function, increases cardiac arrhythmia and HRV (i.e. indirect measure of autonomic tone) in mice; this response is further exacerbated after smog exposure. VDD has been shown to alter the responsiveness of transient receptor potential A1 (TRPA1) channels, which we have previously shown to be involved in cardiopulmonary dysfunction to acrolein, which is a ubiquitous air pollutant and potent TRPA1 agonist. The effect of VDD on TRPA1-induced air pollution responses is not known and is the purpose of this study. 3-week old mice were placed on a VDD or normal diet (ND) for 19 weeks and then implanted with radiotelemeters for the measurement of heart rate, electrocardiogram and HRV. Mice were exposed to filtered air then acrolein for 3 hours each on separate days. During exposure, ventilatory function and ECG were simultaneously recorded. Acrolein increased parasympathetic tone in ND mice, but not VDD mice during exposure. However, acrolein caused cardiac arrhythmias only in VDD mice during exposure. Similar to previous studies,

  2. Spectroscopic and thermodynamic studies on ferulic acid - Alpha-2-macroglobulin interaction

    Science.gov (United States)

    Rehman, Ahmed Abdur; Sarwar, Tarique; Arif, Hussain; Ali, Syed Saqib; Ahsan, Haseeb; Tabish, Mohammad; Khan, Fahim Halim

    2017-09-01

    Ferulic acid is a major phenolic acid found in numerous plant species in conjugated form. It binds to enzymes and oligomeric proteins and modifies their structure and function. This study was designed to examine the interaction of ferulic acid, an active ingredient of some important medicines, with α2M, a key serum proteinase, under physiological conditions. The mechanism of interaction was studied by spectroscopic techniques such as, UV-visible absorption, fluorescence spectroscopy, circular dichroism along with isothermal titration calorimetry. Fluorescence quenching of α2M by ferulic acid demonstrated the formation of α2M-ferulic acid complex by static quenching mechanism. Binding parameters calculated by Stern-Volmer method showed that ferulic acid binds to α2M with moderate affinity of the order of ∼104 M-1. The thermodynamic signatures reveal that binding was enthalpy driven and hydrogen bonding played a major role in ferulic acid-α2M binding. CD spectra analysis suggests very little conformational changes in α2M on ferulic acid binding.

  3. Differential Levels of Alpha-2-Macroglobulin, Haptoglobin and Sero-Transferrin as Adjunct Markers for TB Diagnosis and Disease Progression in the Malnourished Tribal Population of Melghat, India.

    Science.gov (United States)

    Bapat, Prachi R; Satav, Ashish R; Husain, Aliabbas A; Shekhawat, Seema D; Kawle, Anuja P; Chu, Justin J; Purohit, Hemant J; Daginawala, Hatim F; Taori, Girdhar M; Kashyap, Rajpal S

    2015-01-01

    Lack of diagnostic capacity has been a crucial barrier preventing an effective response to the challenges of malnutrition and tuberculosis (TB). Point-of-care diagnostic tests for TB in immuno-incompetent, malnourished population are thus needed to ensure rapid and accurate detection. The aim of the study was to identify potential biomarkers specific for TB infection and progression to overt disease in the malnourished population of Melghat. A prospective cohort study was conducted in the year 2009 through 2011 in six villages of the Melghat region. 275 participants consisting of malnourished cases with a) active TB (n = 32), b) latent TB infection (n = 90), c) with no clinical or bacteriological signs of active or latent TB (n = 130) and healthy control subjects (n = 23) were recruited for the study. The proteome changes of the host serum in response to Mycobacterium tuberculosis (M.tb) infection were investigated using one dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Three most differentially expressed proteins; alpha-2-macroglobulin (A-2-M), sero-transferrin and haptoglobin were identified by MALDI-TOF MS analysis, which were up-regulated in the malnourished patients with active TB and down-regulated in the malnourished patients compared with the healthy controls. Additionally, follow-up studies indicated that the expression of these proteins increased to nearly two folds in patients who developed active disease from latent state. Our preliminary results suggest that A-2-M, sero-transferrin and haptoglobin may be clinically relevant host biomarkers for TB diagnosis and disease progression in the malnourished population. This study provides preliminary framework for an in-depth analysis of the biomarkers in larger well-characterized cohorts. Evaluation of these biomarkers in follow-up cases may further aid in improving TB diagnosis.

  4. A novel function of N-linked glycoproteins, alpha-2-HS-glycoprotein and hemopexin: Implications for small molecule compound-mediated neuroprotection.

    Directory of Open Access Journals (Sweden)

    Takuya Kanno

    Full Text Available Therapeutic agents to the central nervous system (CNS need to be efficiently delivered to the target site of action at appropriate therapeutic levels. However, a limited number of effective drugs for the treatment of neurological diseases has been developed thus far. Further, the pharmacological mechanisms by which such therapeutic agents can protect neurons from cell death have not been fully understood. We have previously reported the novel small-molecule compound, 2-[mesityl(methylamino]-N-[4-(pyridin-2-yl-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316, as a unique neuroprotectant against oxidative injury and a highly promising remedy for the treatment of amyotrophic lateral sclerosis (ALS. One of the remarkable characteristics of WN1316 is that its efficacious doses in ALS mouse models are much less than those against oxidative injury in cultured human neuronal cells. It is also noted that the WN1316 cytoprotective activity observed in cultured cells is totally dependent upon the addition of fetal bovine serum in culture medium. These findings led us to postulate some serum factors being tightly linked to the WN1316 efficacy. In this study, we sieved through fetal bovine serum proteins and identified two N-linked glycoproteins, alpha-2-HS-glycoprotein (AHSG and hemopexin (HPX, requisites to exert the WN1316 cytoprotective activity against oxidative injury in neuronal cells in vitro. Notably, the removal of glycan chains from these molecules did not affect the WN1316 cytoprotective activity. Thus, two glycoproteins, AHSG and HPX, represent a pivotal glycoprotein of the cytoprotective activity for WN1316, showing a concrete evidence for the novel glycan-independent function of serum glycoproteins in neuroprotective drug efficacy.

  5. Exacerbation of lupus erythematodes visceralis as a result of UV irradiation - a hypothesis

    International Nuclear Information System (INIS)

    Diezel, W.; Meffert, H.; Guenther, W.; Huse, K.; Soennichsen, N.

    1979-01-01

    In the culture medium of human fibroblasts a proteolytic activity is evident after UV irradiation (290 - 320 nm). The effect of this proteolytic activity on human serum results in an electrophoretic mobility towards the anode of the C3 component of complement, which thus proves to be activated. In discussing recent and former results, a hypothesis on the exacerbation of lupus erythematodes visceralis is presented: UV irradiation causes peroxydation of lipids resulting in the release of proteolytic enzymes from lysosomal membranes and activation of the complemental system. Thus the reactivity of the immune system is increased and the disease becomes exacerbated. Further the following hypothetic aspects are discussed: porphyrins cause enhanced peroxydation of lipids, increased synthesis rate of porphyrins by drugs, decrease of lipid peroxydation by antioxidants, e.g. vitamin E, in relation to possible therapeutic effects

  6. Headache Exacerbates Pain Characteristics in Temporomandibular Disorders.

    Science.gov (United States)

    Costa, Yuri Martins; Alves da Costa, Dayse Regina; de Lima Ferreira, Ana Paula; Porporatti, André Luís; Svensson, Peter; Rodrigues Conti, Paulo César; Bonjardim, Leonardo Rigoldi

    2017-01-01

    To evaluate the impact of headache in adults with masticatory myofascial pain (MMP) on the outcome variables clinical pain (ie, self-reported pain intensity and pressure pain sensitivity), sleep quality, and pain catastrophizing. A total of 97 patients with MMP were diagnosed with co-existing headache (MMPH group, n = 50) or without headache (MMP group, n = 47) according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The outcome parameters were the Pittsburgh Sleep Quality Index (PSQI); the Catastrophizing Thoughts subscale of the Pain-Related Self-Statement Scale (PRSS-C); pressure pain thresholds (PPTs) of the masseter and anterior temporalis muscles; and self-reported facial pain intensity measured on a 0- to 10-cm visual analog scale (VAS). Student t test for independent samples (α = 1.2%) and factorial analysis of variance (ANOVA) (α = 5%) were used to analyze the data. The MMPH group showed significantly impaired sleep quality (mean ± standard deviation [SD] PSQI score 9.1 ± 3.5) compared with the MMP group (7.2 ± 3.4; P = .008). Subscale scores on the PRSS-C were significantly higher in the MMPH (2.1 ± 1.2) than in the MMP group (1.6 ± 1.4, uncorrected P = .048). Also, the PPTs (kgf/cm²) of the masseter and anterior temporalis muscles were significantly lower in the MMPH group (1.52 ± 0.53; 1.29 ± 0.43, respectively) than in the MMP group (2.09 ± 0.73; 1.70 ± 0.68, respectively; P headache patients had lower PPTs in the anterior temporalis muscle (P = .041) in comparison with non-headache patients. Co-existence of headache further exacerbates clinical characteristics in patients with painful TMD, which implies involvement of common mechanisms and pathways of vulnerability in these patients.

  7. Virus-induced exacerbations in asthma and COPD

    Directory of Open Access Journals (Sweden)

    Daisuke eKurai

    2013-10-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is characterized by chronic airway inflammation and/or airflow limitation due to pulmonary emphysema. Chronic bronchitis, pulmonary emphysema, and bronchial asthma may all be associated with airflow limitation; therefore, exacerbation of asthma may be associated with the pathophysiology of COPD. Furthermore, recent studies have suggested that the exacerbation of asthma, namely virus-induced asthma, may be associated with a wide variety of respiratory viruses.COPD and asthma have different underlying pathophysiological processes and thus require individual therapies. Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality. Similar pathogens, including human rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus and coronavirus, are also frequently detected during exacerbation of asthma and/or COPD. Immune response to respiratory viral infections, which may be related to the severity of exacerbation in each disease, varies in patients with both COPD and asthma. In this regard, it is crucial to recognize and understand both the similarities and differences of clinical features in patients with COPD and/or asthma associated with respiratory viral infections, especially in the exacerbative stage.In relation to definition, epidemiology, and pathophysiology, this review aims to summarize current knowledge concerning exacerbation of both COPD and asthma by focusing on the clinical significance of associated respiratory virus infections.

  8. Identification of human platelet alpha 2-adrenoceptors with a new antagonist [3H]-RX821002, a 2-methoxy derivative of idazoxan.

    Science.gov (United States)

    Galitzky, J.; Senard, J. M.; Lafontan, M.; Stillings, M.; Montastruc, J. L.; Berlan, M.

    1990-01-01

    1. The binding of a new alpha 2-adrenoceptor antagonist, [3H]-RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), was investigated in human platelet membranes and compared with [3H]-yohimbine binding parameters. 2. Analysis of kinetic data revealed association and dissociation time courses consistent with a simple biomolecular reaction. Saturation isotherms showed that [3H]-RX821002 labelled a higher total number of alpha 2-binding sites (224 +/- 31 vs 168 +/- 24 fmol mg-1 protein) than [3H]-yohimbine and with higher affinity (Kd: 0.92 +/- 0.06 vs 1.51 +/- 0.08 nM). Moreover [3H]-RX821002 exhibited a lower percentage of nonspecific binding 3. The difference in total binding is due to a better labelling of the alpha 2-adrenoceptors in the low affinity state by [3H]-RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands. 4. [3H]-RX821002 binding displayed a specificity similar to that obtained with [3H]-yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine greater than oxymetazoline greater than UK14304 greater than (-)-adrenaline greater than prazosin greater than or equal to (+)-adrenaline greater than isoprenaline. This order of potency is classical for an alpha 2A-adrenoceptor. 5. RX821002 is a more potent alpha 2-adrenoceptor antagonist than yohimbine on adrenaline-induced platelet aggregation. 6. These results indicate that [3H]-RX821002 is a suitable ligand for the identification of human platelet alpha 2-adrenoceptors. PMID:1976403

  9. Acute kidney injury in stable COPD and at exacerbation

    Directory of Open Access Journals (Sweden)

    Barakat MF

    2015-09-01

    Full Text Available MF Barakat,1 HI McDonald,1 TJ Collier,1 L Smeeth,1 D Nitsch,1 JK Quint1,2 1Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, 2Department of Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UK Background: While acute kidney injury (AKI alone is associated with increased mortality, the incidence of hospital admission with AKI among stable and exacerbating COPD patients and the effect of concurrent AKI at COPD exacerbation on mortality is not known.Methods: A total of 189,561 individuals with COPD were identified from the Clinical Practice Research Datalink. Using Poisson and logistic regressions, we explored which factors predicted admission for AKI (identified in Hospital Episode Statistics in this COPD cohort and concomitant AKI at a hospitalization for COPD exacerbation. Using survival analysis, we investigated the effect of concurrent AKI at exacerbation on mortality (n=36,107 and identified confounding factors.Results: The incidence of AKI in the total COPD cohort was 128/100,000 person-years. The prevalence of concomitant AKI at exacerbation was 1.9%, and the mortality rate in patients with AKI at exacerbation was 521/1,000 person-years. Male sex, older age, and lower glomerular filtration rate predicted higher risk of AKI or death. There was a 1.80 fold (95% confidence interval: 1.61, 2.03 increase in adjusted mortality within the first 6 months post COPD exacerbation in patients suffering from AKI and COPD exacerbation compared to those who were AKI free.Conclusion: In comparison to previous studies on general populations and hospitalizations, the incidence and prevalence of AKI is relatively high in COPD patients. Coexisting AKI at exacerbation is prognostic of poor outcome. Keywords: acute renal failure, mortality, emphysema, chronic bronchitis, prognosis

  10. Clinically Promising Biomarkers in Cystic Fibrosis Pulmonary Exacerbations.

    Science.gov (United States)

    Scott, L Keith; Toner, Robert

    2017-08-01

    Cystic fibrosis is a complex genetic disease hallmarked by repetitive infectious exacerbations that leads to destruction of airway architecture, acute on chronic inflammatory changes, and deterioration in lung function. Predicting an exacerbation may help preempt some of these changes by the initiation of swift antibiotic and anti-inflammatory therapy. A search for biomarkers that could predict exacerbations or help guide duration of antibiotic therapy is being aggressively sought. In this review, we discuss the most recent and promising biomarkers that hopefully will assist in the future management of the CF patient.

  11. Viral-associated exacerbations of asthma and COPD.

    Science.gov (United States)

    Traves, Suzanne L; Proud, David

    2007-06-01

    Exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the healthcare system, and contribute significantly to the mortality and morbidity associated with these diseases. Upper respiratory viral infections are associated with the majority of such disease exacerbations. The past few years have seen advances in the mechanisms by which viral infections induce pro-inflammatory chemokine production, and in our understanding of host antiviral and anti-inflammatory defence pathways that might regulate responses to infection. A more comprehensive understanding of the molecular basis of these processes could elucidate new therapeutic approaches to reduce the devastating impact that these exacerbations have on quality of life and healthcare costs.

  12. Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial

    Science.gov (United States)

    2014-01-01

    Background Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation. Methods/Design A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients’ perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion. Discussion Ways to minimise potential problems regarding the execution of this study will be discussed. Trial registration The Netherlands National Trial Register NTR1972. PMID:24767519

  13. alpha2- to beta3-Adrenoceptor switch in 3T3-L1 preadipocytes and adipocytes: modulation by testosterone, 17beta-estradiol, and progesterone.

    Science.gov (United States)

    Monjo, Marta; Pujol, Esperanza; Roca, Pilar

    2005-07-01

    Sex steroid hormones are important factors in the determination of fat distribution and accumulation. The aim of this study was to investigate the effect of testosterone (T), 17beta-estradiol (17betaE), and progesterone (P) on adrenergic receptor (AR) gene expression in 3T3-L1 preadipocytes and adipocytes and their relation to the proliferation and differentiation processes. Our data clearly show that alpha(2A)-AR was the highest AR subtype expressed in preadipocytes, whereas in mature adipocytes was by far beta(3)-AR. In the differentiation process to adipocytes, alpha(2A)-AR expression was decreased to 0.3-fold (P distribution.

  14. Developmental regulation of expression of the alpha 1 and alpha 2 subunits mRNAs of the voltage-dependent calcium channel in a differentiating myogenic cell line.

    Science.gov (United States)

    Varadi, G; Orlowski, J; Schwartz, A

    1989-07-03

    The voltage-dependent calcium channel (VDCC) in skeletal muscle probably plays a key role in transducing membrane charge movement to the calcium release channel. We report here that the expression of VDCC alpha 1 and alpha 2 mRNAs is developmentally regulated in differentiating C2C12 myogenic cells. The alpha 1 mRNA is not detectable in the myoblast form of C2C12 cells while its expression is induced 20-fold in differentiated myotubes. In contrast, the alpha 2 mRNA is weakly expressed in myoblasts but is also induced upon myogenic differentiation.

  15. Pharmacodynamics of PEG-IFN-alpha-2a in HIV/HCV co-infected patients: implications for treatment outcomes.

    Science.gov (United States)

    Dahari, Harel; Affonso de Araujo, Evaldo S; Haagmans, Bart L; Layden, Thomas J; Cotler, Scott J; Barone, Antonio A; Neumann, Avidan U

    2010-09-01

    The pharmacokinetics and pharmacodynamics of pegylated-interferon-alpha-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 microg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p=0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (delta), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p=0.013], 0.27 vs. 0.11 day(-1) [p=0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p=0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p=0.114). Genotype 1 had a significantly lower delta compared to genotype 3 (median 0.14 vs. 0.23 day(-1) [p=0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC(50)) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p=0.034]). Both the HCV-infected cell loss rate (delta) and the maximum effectiveness of the first dose of PEG-IFN-alpha-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV. Copyright 2010

  16. The inflammasome pathway in stable COPD and acute exacerbations

    Directory of Open Access Journals (Sweden)

    Rosa Faner

    2016-07-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD. The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear. We investigated the NLRP3 inflammasome status in: 1 lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2 sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery. We observed that: 1 in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL-1β mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2 during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1β, IL-18 were significantly increased in sputum compared with clinical recovery. The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD.

  17. [Possibility of exacerbation of allergy by lunar regolith].

    Science.gov (United States)

    Horie, Masanori; Kambara, Tatsunori; Kuroda, Etsushi; Miki, Takeo; Honma, Yoshiyuki; Aoki, Shigeru; Morimoto, Yasuo

    2012-09-01

    Japan, U.S.A. and other foreign space agencies have plans for the construction of a lunar base and long-term stay of astronauts on the moon. The surface of the moon is covered by a thick layer of soil that includes fine particles called "lunar regolith", which is formed by meteorite impact and space weathering. Risk assessment of particulate matter on the moon is important for astronauts working in microgravity on the moon. However, there are few investigations about the biological influences of lunar regolith. Especially, there is no investigation about allergic activity to lunar regolith. The main chemical components of lunar regolith are SiO2, Al2O3, CaO, FeO, etc. Of particular interest, approximately 50% of lunar regolith consists of SiO2. There is a report that the astronauts felt hay fever-like symptoms from the inhalation of the lunar regolith. Yellow sand, whose chemical components are similar to lunar regolith, enhances allergenic reactions, suggesting the possibility that lunar regolith has an adjuvant-like activity. Although intraperitoneal administration of lunar regolith with ovalbumin to mouse did not show enhancement of allergenic reactions, further evaluation of lunar regolith's potential to exacerbate the effects of allergies is essential for development of the moon.

  18. Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI

    Directory of Open Access Journals (Sweden)

    Lee Jing-Ying

    2010-07-01

    Full Text Available Abstract Background The gold standard of assessing liver fibrosis is liver biopsy, which is invasive and not without risk. Therefore, searching for noninvasive serologic biomarkers for liver fibrosis is an importantly clinical issue. Methods A total of 16 healthy volunteers and 45 patients with chronic hepatitis C virus (HCV were enrolled (F0: n = 16, F1: n = 7, F2: n = 17, F3: n = 8 and F4: n = 13, according to the METAVIR classification. Three serum samples of each fibrotic stage were analyzed by two-dimension difference gel electrophoresis (2D-DIGE. The differential proteins were identified by the cooperation of MALDI-TOF/TOF and MASCOT; then western blotting and Bio-Plex Suspension Array were used to quantify the protein levels. Results Three prominent candidate biomarkers were identified: alpha 2 macroglobulin (A2M is up regulated; vitamin D binding protein (VDBP and apolipoprotein AI (ApoAI are down regulated. The serum concentration of A2M was significantly different among normal, mild (F1/F2 and advanced fibrosis (F3/F4 (p p Conclusions This study not only reveals three putative biomarkers of liver fibrosis (A2M, VDBP and ApoAI but also proves the differential expressions of those markers in different stages of fibrosis. We expect that combination of these novel biomarkers could be applied clinically to predict the stage of liver fibrosis without the need of liver biopsy.

  19. Aversive stimuli exacerbate defensive motor behaviour in motor conversion disorder.

    Science.gov (United States)

    Blakemore, Rebekah L; Sinanaj, Indrit; Galli, Silvio; Aybek, Selma; Vuilleumier, Patrik

    2016-12-01

    Conversion disorder or functional neurological symptom disorder (FND) can affect the voluntary motor system, without an organic cause. Functional symptoms are thought to be generated unconsciously, arising from underlying psychological stressors. However, attempts to demonstrate a direct relationship between the limbic system and disrupted motor function in FND are lacking. We tested whether negative affect would exacerbate alterations of motor control and corresponding brain activations in individuals with FND. Ten patients and ten healthy controls produced an isometric precision-grip contraction at 10% of maximum force while either viewing visual feedback of their force output, or unpleasant or pleasant emotional images (without feedback). Force magnitude was continuously recorded together with change in brain activity using fMRI. For controls, force output decayed from the target level while viewing pleasant and unpleasant images. Patients however, maintained force at the target level without decay while viewing unpleasant images, indicating a pronounced effect of negative affect on force output in FND. This emotional modulation of force control was associated with different brain activation patterns between groups. Contrasting the unpleasant with the pleasant condition, controls showed increased activity in the inferior frontal cortex and pre-supplementary motor area, whereas patients had greater activity in the cerebellum (vermis), posterior cingulate cortex, and hippocampus. Engagement of a cerebellar-limbic network in patients is consistent with heightened processing of emotional salience, and supports the role of the cerebellum in freezing responses in the presence of aversive events. These data highlight a possible neural circuit through which psychological stressors elicit defensive behaviour and modulate motor function in FND. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Phenytoin induced Stevens-Johnson syndrome exacerbated by cefepime

    OpenAIRE

    Prabhu, Varsha A.; Doddapaneni, Sahiti; Thunga, Girish; Thiyagu, Rajakannan; Prabhu, M. Mukyaprana; Naha, Kushal

    2013-01-01

    Steven Johnson syndrome (SJS) is a rare drug induced mucocutaneous reaction. Here, we present an elaborate report of a 28-year-old female patient who developed Phenytoin induced SJS, which was exacerbated by cefepime.

  1. Phenytoin induced Stevens-Johnson syndrome exacerbated by cefepime.

    Science.gov (United States)

    Prabhu, Varsha A; Doddapaneni, Sahiti; Thunga, Girish; Thiyagu, Rajakannan; Prabhu, M Mukyaprana; Naha, Kushal

    2013-10-01

    Steven Johnson syndrome (SJS) is a rare drug induced mucocutaneous reaction. Here, we present an elaborate report of a 28-year-old female patient who developed Phenytoin induced SJS, which was exacerbated by cefepime.

  2. Childhood obesity in relation to poor asthma control and exacerbations

    NARCIS (Netherlands)

    Ahmadizar, Fariba; Vijverberg, Susanne; Arets, Hubertus; De Boer, Anthonius; Lang, Jason; Kattan, Meyer; Palmer, Colin; Mukhopadhyay, Somnath; Turner, Steve; Van Der Zee, Anke-Hilse Maitland

    2016-01-01

    Background: The relationship between obesity and asthma severity in children is inconsistent across studies. Objectives: To estimate the association between obesity and poor asthma control/ risk of exacerbations in asthmatic children and adolescents, and to assess whether these associations are

  3. Age-Specific Characteristics of Inpatients with Severe Asthma Exacerbation

    Directory of Open Access Journals (Sweden)

    Kiyoshi Sekiya

    2013-01-01

    Conclusions: The characteristics of inpatients with severe asthma vary depending on age. We need to establish countermeasures for asthma exacerbation according to the characteristics of patients depending on age.

  4. Postpartum airway responsiveness and exacerbation of asthma during pregnancy

    DEFF Research Database (Denmark)

    Ali, Zarqa; Nilas, Lisbeth; Ulrik, Charlotte Suppli

    2017-01-01

    BACKGROUND: Airway responsiveness and inflammation are associated with the clinical manifestations of asthma and the response to pharmacological therapy. OBJECTIVE: To investigate if airway responsiveness and inflammatory characteristics are related to asthma exacerbations during pregnancy....... MATERIALS AND METHODS: In women with asthma who were prescribed controller medication and monitored closely during pregnancy, the risk of exacerbations was analyzed in relation to postpartum measures of fractional exhaled nitric oxide (FENO), skin prick test reactivity, static and dynamic lung volumes...

  5. A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation.

    Science.gov (United States)

    Yamaguchi, Masahiko; Matsui, Masakazu; Higa, Ryoko; Yamazaki, Yasuhiro; Ikari, Akira; Miyake, Masaki; Miwa, Masao; Ishii, Satoshi; Sugatani, Junko; Shimizu, Takao

    2015-02-15

    Platelet-activating factor (PAF) is a well-known phospholipid that mediates acute inflammatory responses. In the present study, we investigated whether PAF/PAF receptor signaling contributed to chronic inflammation in the white adipose tissue (WAT) of PAF receptor-knockout (PAFR-KO) mice. Body and epididymal WAT weights were higher in PAFR-KO mice fed a high-fat diet (HFD) than in wild-type (WT) mice. TNF-α mRNA expression levels in epididymal WAT and the infiltration of CD11c-positive macrophages into epididymal WAT, which led to chronic inflammation, were also elevated in HFD-fed PAFR-KO mice. HFD-fed PAFR-KO mice had higher levels of fasting serum glucose than HFD-fed WT mice as well as impaired glucose tolerance. Although PAF receptor signaling up-regulated the expression of TNF-α and lipopolysaccharide induced the expression of acyl-CoA:lysophosphatidylcholine acyltransferase 2 (LPCAT2) mRNA in bone marrow-derived macrophages, no significant differences were observed in the expression of LPCAT2 mRNA and PAF levels in epididymal WAT between HFD-fed mice and normal diet-fed mice. In addition to our previous finding in which energy expenditure in PAF receptor (PAFR)-deficient mice was low due to impaired brown adipose tissue function, the present study demonstrated that PAF/PAF receptor signaling up-regulated the expression of Ucp1 mRNA, which is essential for cellular thermogenesis, in 3T3-L1 adipocytes. We concluded that the marked accumulation of abdominal fat due to HFD feeding led to more severe chronic inflammation in WAT, which is associated with glucose metabolism disorders, in PAFR-KO mice than in WT mice, and PAF/PAF receptor signaling may regulate energy expenditure and adiposity. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Exacerbation rate, health status and mortality in COPD – a review of potential interventions

    Directory of Open Access Journals (Sweden)

    Terence AR Seemungal

    2009-05-01

    Full Text Available Terence AR Seemungal1, John R Hurst2, Jadwiga A Wedzicha21Department of Clinical Medical Sciences, University of the West Indies, St. Augustine Campus, Trinidad and Tobago; 2Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, University College London, UKAbstract: COPD is prevalent in Western society and its incidence is rising in the developing world. Acute exacerbations of COPD, about 50% of which are unreported, lead to deterioration in quality of life and contribute significantly to disease burden. Quality of life deteriorates with time; thus, most of the health burden occurs in more severe disease. COPD severity and frequent and more severe exacerbations are all related to an increased risk of mortality. Inhaled corticosteroids (ICS have similar effects on quality of life but ICS/long-acting bronchodilator combinations and the long-acting antimuscarinic tiotropium all improve health status and exacerbation rates and are likely to have an effect on mortality but perhaps only with prolonged use. Erythromycin has been shown to decrease the rate of COPD exacerbations. Pulmonary rehabilitation and regular physical activity are indicated in all severities of COPD and improve quality of life. Noninvasive ventilation is associated with improved quality of life. Long-term oxygen therapy improves mortality but only in hypoxic COPD patients. The choice of an inhaler device is a key component of COPD therapy and this requires more attention from physicians than perhaps we are aware of. Disease management programs, characterized as they are by patient centeredness, improve quality of life and decrease hospitalization rates. Most outcomes in COPD can be modified by interventions and these are well tolerated and have acceptable safety profiles.Keywords: COPD, exacerbation, health burden, mortality, inhaled steroids, long-acting bronchodilators, long-acting antimuscarinic agents, macrolide, disease management program

  7. Metabolomics of pulmonary exacerbations reveals the personalized nature of cystic fibrosis disease

    Directory of Open Access Journals (Sweden)

    Robert A. Quinn

    2016-08-01

    Full Text Available Background. Cystic fibrosis (CF is a genetic disease that results in chronic infections of the lungs. CF patients experience intermittent pulmonary exacerbations (CFPE that are associated with poor clinical outcomes. CFPE involves an increase in disease symptoms requiring more aggressive therapy. Methods. Longitudinal sputum samples were collected from 11 patients (n = 44 samples to assess the effect of exacerbations on the sputum metabolome using liquid chromatography-tandem mass spectrometry (LC-MS/MS. The data was analyzed with MS/MS molecular networking and multivariate statistics. Results. The individual patient source had a larger influence on the metabolome of sputum than the clinical state (exacerbation, treatment, post-treatment, or stable. Of the 4,369 metabolites detected, 12% were unique to CFPE samples; however, the only known metabolites significantly elevated at exacerbation across the dataset were platelet activating factor (PAF and a related monacylglycerophosphocholine lipid. Due to the personalized nature of the sputum metabolome, a single patient was followed for 4.2 years (capturing four separate exacerbation events as a case study for the detection of personalized biomarkers with metabolomics. PAF and related lipids were significantly elevated during CFPEs of this patient and ceramide was elevated during CFPE treatment. Correlating the abundance of bacterial 16S rRNA gene amplicons to metabolomics data from the same samples during a CFPE demonstrated that antibiotics were positively correlated to Stenotrophomonas and Pseudomonas, while ceramides and other lipids were correlated with Streptococcus, Rothia, and anaerobes. Conclusions. This study identified PAF and other inflammatory lipids as potential biomarkers of CFPE, but overall, the metabolome of CF sputum was patient specific, supporting a personalized approach to molecular detection of CFPE onset.

  8. [Risk factors for acute exacerbation in patients with bronchiectasis].

    Science.gov (United States)

    Jiao, Rui; Liu, Shuang

    2015-01-27

    To evaluate the risk factors for patients with an acute exacerbation of bronchiectasis. Retrospective analyses were conducted for 228 patients diagnosed with acute exacerbation of bronchiectasis at Affiliated Beijing Anzhen Hospital, Capital Medical University from January 2008 to December 2012. Depending on whether there were recurrences with exacerbation within one year after discharge, they were divided into two groups. Their basic profiles, clinical symptoms and signs, blood tests, sputum culture, dyspnea score (mMRC) and imaging data were analyzed. There were 110 males and 118 females with an average age of (64.5+14.5) years. The incidence of the recurrence of acute exacerbation was 55.7% (127/228) within one year after discharge. Multivariate Logistic regression analysis showed that age ≥ 60 years (OR = 2.583, 95%CI: 1.188-5.613), body mass index (BMI)resolution computed tomography (CT) displayed bronchiectasis involving ≥ 3 lobes (OR = 3.179, 95%CI: 1.449-6.976) and staying in intensive care unit (ICU) (OR = 2.499, 95%CI: 1.301-4.801) were associated with the acute exacerbation of bronchiectasis (all P < 0.05). There are multiple risk factors of acute exacerbation in patients with bronchiectasis. And their proper identification and management shall improve the prognosis of bronchiectasis patients.

  9. The causes and consequences of seasonal variation in COPD exacerbations

    Directory of Open Access Journals (Sweden)

    Donaldson GC

    2014-10-01

    Full Text Available Gavin C Donaldson, Jadwiga A Wedzicha Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Abstract: The time of year when patients experience exacerbations of chronic obstructive pulmonary disease is a much-overlooked feature of the disease. The higher incidence of exacerbations in winter has important consequences for patients in terms of increased morbidity and mortality. The seasonality also imposes a considerable burden on already-overloaded health care services, with both primary care consultations and hospital admissions increasing in number. The seasonality of exacerbations varies with latitude, and is greater in more temperate climates, where there may be less protection from outdoor and indoor cold exposure. The precise causes of the seasonality are unknown, but thought to be partly due to the increased prevalence of respiratory viral infections circulating in cold, damp conditions. Increased susceptibility to viral infection may also be a mechanism mediated through increased airway inflammation or possibly reduced vitamin D levels. The seasonality of exacerbations informs us about the triggers of exacerbations and suggests possible strategies to reduce their number. Keywords: exacerbations of COPD, seasonality, winter mortality, winter morbidity

  10. Randomized study on hydroxyurea alone versus hydroxyurea combined with low-dose interferon-alpha 2b for chronic myeloid leukemia

    NARCIS (Netherlands)

    Kluin-Nelemans, JC; Delannoy, A; Louwagie, A; Le Cessie, S; Hermans, J; van der Burgh, JF; Hagemeijer, AM; Van den Berghe, H

    1998-01-01

    Interferon-alpha (IFN-alpha) is considered the standard therapy for chronic myeloid leukemia (CML) patients not suitable for allogeneic stem cell transplantation. From 1987 through 1992, 195 patients in the Benelux with recent untreated CML were randomized between low-dose IFN-alpha 2b (3 MIU, 5

  11. Proteomic analysis of coronary sinus serum reveals leucine-rich alpha2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.

    LENUS (Irish Health Repository)

    Watson, Chris J

    2012-02-01

    BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF. METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich alpha2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P<\\/=0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-alpha (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-betaR1 (P<0.001) and alpha-smooth muscle actin (P=0.025) expression. CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, beta-blocker therapy, and BNP.

  12. Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies.

    Science.gov (United States)

    Meilleur, Katherine G; Jain, Minal S; Hynan, Linda S; Shieh, Ching-Yi; Kim, Eunice; Waite, Melissa; McGuire, Michelle; Fiorini, Courtney; Glanzman, Allan M; Main, Marion; Rose, Kristy; Duong, Tina; Bendixen, Roxanna; Linton, Melody M; Arveson, Irene C; Nichols, Carmel; Yang, Kelly; Fischbeck, Kenneth H; Wagner, Kathryn R; North, Kathryn; Mankodi, Ami; Grunseich, Christopher; Hartnett, Elizabeth J; Smith, Michaele; Donkervoort, Sandra; Schindler, Alice; Kokkinis, Angela; Leach, Meganne; Foley, A Reghan; Collins, James; Muntoni, Francesco; Rutkowski, Anne; Bönnemann, Carsten G

    2015-01-01

    Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes. Published by Elsevier B.V.

  13. Adiponectin deficiency exacerbates age-related hearing impairment

    Science.gov (United States)

    Tanigawa, T; Shibata, R; Ouchi, N; Kondo, K; Ishii, M; Katahira, N; Kambara, T; Inoue, Y; Takahashi, R; Ikeda, N; Kihara, S; Ueda, H; Murohara, T

    2014-01-01

    Obesity-related disorders are closely associated with the development of age-related hearing impairment (ARHI). Adiponectin (APN) exerts protective effects against obesity-related conditions including endothelial dysfunction and atherosclerosis. Here, we investigated the impact of APN on ARHI. APN-knockout (APN-KO) mice developed exacerbation of hearing impairment, particularly in the high frequency range, compared with wild-type (WT) mice. Supplementation with APN prevented the hearing impairment in APN-KO mice. At 2 months of age, the cochlear blood flow and capillary density of the stria vascularis (SV) were significantly reduced in APN-KO mice as compared with WT mice. APN-KO mice also showed a significant increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells in the organ of Corti in the cochlea at 2 months of age. At the age of 6 months, hair cells were lost at the organ of Corti in APN-KO mice. In cultured auditory HEI-OC1 cells, APN reduced apoptotic activity under hypoxic conditions. Clinically, plasma APN levels were significantly lower in humans with ARHI. Multiple logistic regression analysis identified APN as a significant and independent predictor of ARHI. Our observations indicate that APN has an important role in preventing ARHI. PMID:24763046

  14. Clinical diaries in COPD: compliance and utility in predicting acute exacerbations

    Directory of Open Access Journals (Sweden)

    Walters EH

    2012-07-01

    Full Text Available E Haydn Walters,1 Julia Walters,1 Karen E Wills,1 Andrew Robinson,2 Richard Wood-Baker11Menzies Research Institute Tasmania, University of Tasmania, Hobart; 2School of Nursing and Midwifery, University of Tasmania, Hobart, AustraliaBackground: Daily diaries are often used to collect data on disease activity, but are burdensome and compliance may be poor. Their use in chronic obstructive pulmonary disease (COPD and impact on the prevention and treatment of exacerbations is poorly researched.Methods: We investigated diary-keeping in COPD and ascertained items that best predicted emergency attendances for exacerbations. Participants in the active limb of a clinical trial in COPD kept daily diaries rating breathlessness, cough, sputum, physical activity, and use of reliever medication.Results: Data on 55 participants, 67% of whom were female, showed that overall compliance with diary-keeping was 62%. Participants educated to primary school level only had lower compliance (P = 0.05. Twenty patients had at least one emergency attendance, in whom the relative risk of an acute exacerbation for an increase in item score rose from six days prior to hospitalization, most sharply in the last two days. Even for optimal combinations of items, the positive predictive value was poor, the best combination being cough, activity level, and inhaler use.Conclusion: Good compliance can be achieved using daily diaries in COPD, although this is worse in those with a poor educational level. Diary-keeping is not accurate in predicting acute exacerbations, but could be substantially simplified without loss of efficiency.Keywords: chronic obstructive pulmonary disease, daily diary, secondary prevention

  15. Markers of exacerbation severity in chronic obstructive pulmonary disease

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    Walker Michael J

    2006-05-01

    Full Text Available Abstract Background Patients with chronic obstructive pulmonary disease (COPD can experience 'exacerbations' of their conditions. An exacerbation is an event defined in terms of subjective descriptors or symptoms, namely dyspnoea, cough and sputum that worsen sufficiently to warrant a change in medical management. There is a need for reliable markers that reflect the pathological mechanisms that underlie exacerbation severity and that can be used as a surrogate to assess treatment effects in clinical studies. Little is known as to how existing study variables and suggested markers change in both the stable and exacerbation phases of COPD. In an attempt to find the best surrogates for exacerbations, we have reviewed the literature to identify which of these markers change in a consistent manner with the severity of the exacerbation event. Methods We have searched standard databases between 1966 to July 2004 using major keywords and terms. Studies that provided demographics, spirometry, potential markers, and clear eligibility criteria were included in this study. Central tendencies and dispersions for all the variables and markers reported and collected by us were first tabulated according to sample size and ATS/ERS 2004 Exacerbation Severity Levels I to III criteria. Due to the possible similarity of patients in Levels II and III, the data was also redefined into categories of exacerbations, namely out-patient (Level I and in-patient (Levels II & III combined. For both approaches, we performed a fixed effect meta-analysis on each of the reported variables. Results We included a total of 268 studies reported between 1979 to July 2004. These studies investigated 142,407 patients with COPD. Arterial carbon dioxide tension and breathing rate were statistically different between all levels of exacerbation severity and between in out- and in-patient settings. Most other measures showed weak relationships with either level or setting, or they had

  16. Visualization of transepithelial passage of the immunogenic 33-residue peptide from alpha-2 gliadin in gluten-sensitive macaques.

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    Kaushiki Mazumdar

    Full Text Available BACKGROUND: Based on clinical, histopathological and serological similarities to human celiac disease (CD, we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2 antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from alpha(2-gliadin in the distal duodenum of gluten-sensitive macaques. METHODOLOGY/PRINCIPAL FINDINGS: Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD and again after remission by gluten-free diet (GFD. Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with "leaky" duodenum, the peptide penetrated beneath the epithelium into the lamina propria. CONCLUSIONS/SIGNIFICANCE: The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.

  17. Synthesis and evaluation of radioiodinated (S,S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Kanegawa, Naoki; Kimura, Hiroyuki; Sugita, Taku; Kajiyama, Satomi; Kuge, Yuji; Saji, Hideo [Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Sakyo-ku, Kyoto (Japan); Kiyono, Yasushi [Kyoto University, Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Sakyo-ku, Kyoto (Japan); Kawashima, Hidekazu [Kyoto University, Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Ueda, Masashi [Kyoto Prefectural University of Medicine, Radioisotope Laboratory, Sakyo-ku, Kyoto (Japan)

    2006-06-15

    Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. (S,S)-{sup 123/125}I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of {sup 3}H-nisoxetine and (S,S)-{sup 125}I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-{sup 125}I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-{sup 123}I-IPBM were carried out in the common marmoset. (S,S)-{sup 125}I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-{sup 125}I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-{sup 125}I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-{sup 123}I-IPBM allowed brain NET imaging in the common marmoset with SPECT. These results suggest that (S,S)-{sup 123}I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET. (orig.)

  18. Comparative effectiveness and adverse effects of interferon alpha-2b plus ribavirin therapy in hepatitis 'C' for 26 weeks

    International Nuclear Information System (INIS)

    Ali, S.

    2009-01-01

    Hepatitis C is major emerging challenge for pathologists and treating physicians all over the world. Already 10 million Pakistani population has become anti-HCV positive. It is not only affecting hepatobiliary system but with passage of time research is revealing that Hepatitis C is going to involve almost every organ of the body. With timely diagnosis and treatment, millions of patients can be saved from morbidity and mortality. The nation has to sacrifice initial economic allocations to avoid later millions of mortalities and greater economic losses on affected patients and to support their families. The objective of this study was to evaluate effectiveness of combine therapy of Hepatitis C in local population of Pakistan. This case series study was done at CMH Okara, Kohat, Abbottabad, and PAF Hospital, Shorkot from August 2000 to August 2009. All 1,000 patients from 10 to 60 years of age, confirmed anti-HCV Positive by ELISA and PCR Positive for HCV RNA, were subjected to Interferon alpha-2b and Ribavirin therapy for similar period of time. Response and adverse affects were observed by clinical examination, blood complete picture including platelet count and ALT fortnightly. PCR for HCV RNA and ultrasound abdomen (hepatobiliary system) was done quarterly during treatment and 6 monthly for 2 years after treatment to review the sustained response and relapse. Over all cure rate after 2 years was 855 (85.5%) excluding the 50 (5%) of initial resistant to one year treatment and 95 (9.5%) re-treated relapse cases. One hundred and forty-five (14.5%) patients were found to be resistant to treatment. Hepatitis C must be treated timely after proper diagnosis. Interferon and Ribavirin combination have shown high 'cure' rate in Hepatitis C. In spite of high cure rate of 85.5% with timely and proper treatment, low socio-economic status is a major problem for poor individuals to get treatment. Preventive aspect must be strictly followed and implemented. (author)

  19. Loss of protein kinase 2 subunit alpha 2 (CK2α') effect ram sperm function after freezing and thawing process.

    Science.gov (United States)

    He, Yuxuan; Li, Hongyan; Wang, Ke; Zhang, Yong; Zhao, Xingxu

    2017-06-01

    Protein kinase 2 subunit alpha 2 (CK2α'), a serine/threonine-selective protein kinase, is associated with sperm apoptosis. However, the presence of CK2α' in ram sperm during the freezing-thawing process has not been previously reported. Thus, this study was conducted to determine the effect of cryopreservation on the association between CK2α' and ram sperm function. Sperm variables, including sperm motility, DNA damage and acrosome integrity, were measured in fresh (F), cooled (CO) and freeze-thawed (FT) sperm. Sperm proteins and total mRNA were extracted form cells of each group, and subjected to western blot and real-time PCR analysis for detection of CK2α' proteins and relative abundance of mRNA. The distribution pattern of CK2α' protein in ram sperm was also monitored in each group using an immunofluorescence technique. The results provided evidence that the freeze-thaw process has an impact on ram sperm variables, and the normalized CK2α' protein and relative abundance of CK2α' mRNA were both significantly less in FT than F sperm. The amount of CK2α' in FT extended seminal plasma was increased as compared with F samples. Furthermore, immunofluorescence revealed that CK2α' was distributed throughout the acrosome of ram sperm. The association of CK2α' with DNA damage and acrosome integrity was confirmed using Pearson's linear correlation. In conclusion, the understanding the molecular effects of cryopreservation on CK2α' in ram sperm could provide insight into methods for improving fertility associated with frozen-thawed ram sperm. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Cannabis exacerbates depressive symptoms in rat model induced by reserpine.

    Science.gov (United States)

    Khadrawy, Yasser A; Sawie, Hussein G; Abdel-Salam, Omar M E; Hosny, Eman N

    2017-05-01

    Cannabis sativa is one of the most widely recreational drugs and its use is more prevalent among depressed patients. Some studies reported that Cannabis has antidepressant effects while others showed increased depressive symptoms in Cannabis users. Therefore, the present study aims to investigate the effect of Cannabis extract on the depressive-like rats. Twenty four rats were divided into: control, rat model of depression induced by reserpine and depressive-like rats treated with Cannabis sativa extract (10mg/kg expressed as Δ9-tetrahydrocannabinol). The depressive-like rats showed a severe decrease in motor activity as assessed by open field test (OFT). This was accompanied by a decrease in monoamine levels and a significant increase in acetylcholinesterase activity in the cortex and hippocampus. Na + ,K + -ATPase activity increased in the cortex and decreased in the hippocampus of rat model. In addition, a state of oxidative stress was evident in the two brain regions. This was indicated from the significant increase in the levels of lipid peroxidation and nitric oxide. No signs of improvement were observed in the behavioral and neurochemical analyses in the depressive-like rats treated with Cannabis extract. Furthermore, Cannabis extract exacerbated the lipid peroxidation in the cortex and hippocampus. According to the present findings, it could be concluded that Cannabis sativa aggravates the motor deficits and neurochemical changes induced in the cortex and hippocampus of rat model of depression. Therefore, the obtained results could explain the reported increase in the depressive symptoms and memory impairment among Cannabis users. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Analysis of Alpha-2 Macroglobulin from the Long-Lived and Cancer-Resistant Naked Mole-Rat and Human Plasma.

    Science.gov (United States)

    Thieme, René; Kurz, Susanne; Kolb, Marlen; Debebe, Tewodros; Holtze, Susanne; Morhart, Michaela; Huse, Klaus; Szafranski, Karol; Platzer, Matthias; Hildebrandt, Thomas B; Birkenmeier, Gerd

    2015-01-01

    The naked mole-rat (NMR) is a long-lived and cancer resistant species. Identification of potential anti-cancer and age related mechanisms is of great interest and makes this species eminent to investigate anti-cancer strategies and understand aging mechanisms. Since it is known that the NMR expresses higher liver mRNA-levels of alpha 2-macroglobulin than mice, nothing is known about its structure, functionality or expression level in the NMR compared to the human A2M. Here we show a comprehensive analysis of NMR- and human plasma-A2M, showing a different prediction in glycosylation of NMR-A2M, which results in a higher molecular weight compared to human A2M. Additionally, we found a higher concentration of A2M (8.3±0.44 mg/mL vs. and 4.4±0.20 mg/mL) and a lower total plasma protein content (38.7±1.79 mg/mL vs. 61.7±3.20 mg/mL) in NMR compared to human. NMR-A2M can be transformed by methylamine and trypsin resulting in a conformational change similar to human A2M. NMR-A2M is detectable by a polyclonal antibody against human A2M. Determination of tryptic and anti-tryptic activity of NMR and human plasma revealed a higher anti-tryptic activity of the NMR plasma. On the other hand, less proteolytic activity was found in NMR plasma compared to human plasma. We found transformed NMR-A2M binding to its specific receptor LRP1. We could demonstrate lower protein expression of LRP1 in the NMR liver tissue compared to human but higher expression of A2M. This was accompanied by a higher EpCAM protein expression as central adhesion molecule in cancer progression. NMR-plasma was capable to increase the adhesion in human fibroblast in vitro most probably by increasing CD29 protein expression. This is the first report, demonstrating similarities as well as distinct differences between A2M in NMR and human plasma. This might be directly linked to the intriguing phenotype of the NMR and suggests that A2M might probably play an important role in anti-cancer and the anti

  2. Analysis of Alpha-2 Macroglobulin from the Long-Lived and Cancer-Resistant Naked Mole-Rat and Human Plasma.

    Directory of Open Access Journals (Sweden)

    René Thieme

    Full Text Available The naked mole-rat (NMR is a long-lived and cancer resistant species. Identification of potential anti-cancer and age related mechanisms is of great interest and makes this species eminent to investigate anti-cancer strategies and understand aging mechanisms. Since it is known that the NMR expresses higher liver mRNA-levels of alpha 2-macroglobulin than mice, nothing is known about its structure, functionality or expression level in the NMR compared to the human A2M.Here we show a comprehensive analysis of NMR- and human plasma-A2M, showing a different prediction in glycosylation of NMR-A2M, which results in a higher molecular weight compared to human A2M. Additionally, we found a higher concentration of A2M (8.3±0.44 mg/mL vs. and 4.4±0.20 mg/mL and a lower total plasma protein content (38.7±1.79 mg/mL vs. 61.7±3.20 mg/mL in NMR compared to human. NMR-A2M can be transformed by methylamine and trypsin resulting in a conformational change similar to human A2M. NMR-A2M is detectable by a polyclonal antibody against human A2M. Determination of tryptic and anti-tryptic activity of NMR and human plasma revealed a higher anti-tryptic activity of the NMR plasma. On the other hand, less proteolytic activity was found in NMR plasma compared to human plasma.We found transformed NMR-A2M binding to its specific receptor LRP1. We could demonstrate lower protein expression of LRP1 in the NMR liver tissue compared to human but higher expression of A2M. This was accompanied by a higher EpCAM protein expression as central adhesion molecule in cancer progression. NMR-plasma was capable to increase the adhesion in human fibroblast in vitro most probably by increasing CD29 protein expression. This is the first report, demonstrating similarities as well as distinct differences between A2M in NMR and human plasma. This might be directly linked to the intriguing phenotype of the NMR and suggests that A2M might probably play an important role in anti-cancer and the

  3. Reduction of Oxidative Stress Attenuates Lipoapoptosis Exacerbated by Hypoxia in Human Hepatocytes

    Directory of Open Access Journals (Sweden)

    Sang Youn Hwang

    2015-02-01

    Full Text Available Chronic intermittent hypoxia, a characteristic of obstructive sleep apnea (OSA, is associated with the progression of simple hepatic steatosis to necroinflammatory hepatitis. We determined whether inhibition of a hypoxia-induced signaling pathway could attenuate hypoxia-exacerbated lipoapoptosis in human hepatocytes. The human hepatocellular carcinoma cell line (HepG2 was used in this study. Palmitic acid (PA-treated groups were used for two environmental conditions: Hypoxia (1% O2 and normoxia (20% O2. Following the treatment, the cell viability was determined by the 3,4-(5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium salt (MTS assay, and the mechanism of lipoapoptosis was evaluated by Western blotting. Hypoxia exacerbated the suppression of hepatocyte growth induced by palmitic acid via activation of mitochondrial apoptotic pathways as a result of endoplasmic reticulum (ER and oxidative stresses. Ammonium pyrrolidine dithiocarbamate, a scavenger of reactive oxygen species, attenuated the hypoxia-exacerbated lipoapoptosis in hepatocytes, whereas glycerol, which reduces ER stress, did not. This may have been because inhibition of oxidative stress decreases the expression of pro-apoptotic proteins, such as caspase 9 and cytochrome c. These results suggested that modulation of apoptotic signaling pathways activated by oxidative stress can aid in identifying novel therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH with OSA. Further in vivo studies are necessary to understand the pathophysiologic mechanism of NASH with OSA and to prove the therapeutic effect of the modulation of the signaling pathways.

  4. Efficacy of a self-management plan in exacerbations for patients with advanced COPD

    Directory of Open Access Journals (Sweden)

    Sánchez-Nieto JM

    2016-08-01

    Full Text Available Juan Miguel Sánchez-Nieto,1,2 Rubén Andújar-Espinosa,3 Roberto Bernabeu-Mora,1,2 Chunshao Hu,1 Beatriz Gálvez-Martínez,1 Andrés Carrillo-Alcaraz,1 Carlos Federico Álvarez-Miranda,3 Olga Meca-Birlanga,1 Eva Abad-Corpa4 1Division of Pneumology, Hospital Morales Meseguer, 2University of Murcia, 3Division of Pneumology, Hospital Arrixaca, Murcia, 4Department of Professional Development Unit, Murcia, Spain Background: Self-management interventions improve different outcome variables in various chronic diseases. Their role in COPD has not been clearly established. We assessed the efficacy of an intervention called the self-management program on the need for hospital care due to disease exacerbation in patients with advanced COPD.Methods: Multicenter, randomized study in two hospitals with follow-up of 1 year. All the patients had severe or very severe COPD, and had gone to either an accident and emergency (A&E department or had been admitted to a hospital at least once in the previous year due to exacerbation of COPD. The intervention consisted of a group education session on the main characteristics of the disease, an individual training session on inhalation techniques, at the start and during the 3rd month, and a written action plan containing instructions for physical activity and treatment for stable phases and exacerbations. We determined the combined number of COPD-related hospitalizations and emergency visits per patient per year. Secondary endpoints were number of patients with visits to A&E and the number of patients hospitalized because of exacerbations, use of antibiotics and corticosteroids, length of hospital stay, and all-cause mortality.Results: After 1 year, the rate of COPD exacerbations with visits to A&E or hospitalization had decreased from 1.37 to 0.89 (P=0.04 and the number of exacerbations dropped from 52 to 42 in the group of patients who received the intervention. The numbers of patients hospitalized, at 19 (40

  5. Molecular identification and expression profiling of a novel alpha2-macroglobulin gene in giant freshwater prawn (Macrobrachium rosenbergii, De Man

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    Wirot Likittrakulwong

    2017-02-01

    Full Text Available A full-length cDNA encoding a novel alpha-2 macroglobulin (Mr-2α2M gene in giant freshwater prawn was cloned and sequenced using rapid amplification cDNA end techniques. The Mr-2α2M was 5194 bp and comprised a 4560-bp open reading frame (ORF encoding 1519 amino acid residues. The mature Mr-2α2M protein had a calculated molecular mass of 168.8 kDa and an estimated pI of 5.14. Mr-2α2M contained significantly functional domains, including a bait region, a thiol ester motif and a receptor-binding domain, similar to the α2Ms of other species. Amino acid sequence analysis of α2Ms indicated that Mr-2α2M was most similar to the Chinese white shrimp (Fenneropenaeus chinensis α2M isoform 2 (Fc-A2M-2, with an identity of 58.8%, and the previously identified giant freshwater prawn Mr-1α2M protein, with an identity of 43.5%. Phylogenetic analysis revealed that Mr-2α2M was more closely related to Fc-A2M-2 than Mr-1α2M, which was placed in a different subminor group. Quantitative real-time reverse-transcription polymerase chain reaction assay illustrated that Mr-2α2M mRNA transcripts were strongly detected in the subcuticular epithelium, heart, midgut and muscle but marginally detected in the hemocytes of normal prawns. Immune response analysis in prawns stimulated with Aeromonas hydrophila clearly indicated that Mr-2α2M was quickly up-regulated to high levels in hemocytes and hepatopancreas after 12 h, in contrast to the expression pattern of Mr-1α2M. This novel α2M gene may have unique, important roles in giant freshwater prawn immune systems that differ significantly from those of the previously identified Mr-1α2M gene.

  6. Job strain and the risk of severe asthma exacerbations

    DEFF Research Database (Denmark)

    Heikkilä, K; Madsen, I E H; Nyberg, S T

    2014-01-01

    in working-age European men and women. METHODS: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe......BACKGROUND: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations...... asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. RESULTS: During a median follow-up of 10 years...

  7. Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

    Science.gov (United States)

    Jackson, Daniel J; Bacharier, Leonard B; Mauger, David T; Boehmer, Susan; Beigelman, Avraham; Chmiel, James F; Fitzpatrick, Anne M; Gaffin, Jonathan M; Morgan, Wayne J; Peters, Stephen P; Phipatanakul, Wanda; Sheehan, William J; Cabana, Michael D; Holguin, Fernando; Martinez, Fernando D; Pongracic, Jacqueline A; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Covar, Ronina; Gentile, Deborah A; Israel, Elliot; Krishnan, Jerry A; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Long, Dayna; Ly, Ngoc; Marbin, Jyothi; Moy, James N; Myers, Ross E; Olin, J Tod; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Lemanske, Robert F

    2018-03-08

    Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma

  8. Can resistive breathing injure the lung? Implications for COPD exacerbations

    Directory of Open Access Journals (Sweden)

    Vassilakopoulos T

    2016-09-01

    Full Text Available Theodoros Vassilakopoulos, Dimitrios Toumpanakis Pulmonary and Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Greece Abstract: In obstructive lung diseases, airway inflammation leads to bronchospasm and thus resistive breathing, especially during exacerbations. This commentary discusses experimental evidence that resistive breathing per se (the mechanical stimulus in the absence of underlying airway inflammation leads to lung injury and inflammation (mechanotransduction. The potential implications of resistive breathing-induced mechanotrasduction in COPD exacerbations are presented along with the available clinical evidence. Keywords: resistive breathing, COPD, mechanotransduction, bronchoconstriction, inflammation

  9. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Cardiovascular Links

    Science.gov (United States)

    Laratta, Cheryl R.; van Eeden, Stephan

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease resulting from exposure to cigarette smoke, noxious gases, particulate matter, and air pollutants. COPD is exacerbated by acute inflammatory insults such as lung infections (viral and bacterial) and air pollutants which further accelerate the steady decline in lung function. The chronic inflammatory process in the lung contributes to the extrapulmonary manifestations of COPD which are predominantly cardiovascular in nature. Here we review the significant burden of cardiovascular disease in COPD and discuss the clinical and pathological links between acute exacerbations of COPD and cardiovascular disease. PMID:24724085

  10. Peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials

    DEFF Research Database (Denmark)

    Awad, Tahany; Thorlund, Kristian; Hauser, Goran

    2010-01-01

    ) is most effective. We performed a systematic review of head-to-head randomized trials to assess the benefits and harms of the two treatments. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. Using standardized forms, two reviewers independently...... extracted data from each eligible trial report. We statistically combined data using a random effects meta-analysis according to the intention-to-treat principle. We identified 12 randomized clinical trials, including 5,008 patients, that compared peginterferon alpha-2a plus ribavirin versus peginterferon...... alfa-2b plus ribavirin. Overall, peginterferon alpha-2a significantly increased the number of patients who achieved a sustained virological response (SVR) versus peginterferon alfa-2b (47% versus 41%; risk ratio 1.11, 95% confidence interval 1.04-1.19; P = 0.004 [eight trials]). Subgroup analyses...

  11. Commentary: Are alpha-2 agonist really effective in children with tics with comorbid ADHD? A commentary on Whittington et al. (2016).

    Science.gov (United States)

    Bloch, Michael H

    2016-09-01

    In this issue, Whittington et al. (2016) present a systematic review that reports the efficacy of three primary treatments for children with Tourette syndrome (TS) - (a) α2-adrenergic receptor agonists; (b) antipsychotic medications; and (c) habit reversal training/comprehensive behavioral intervention. In this commentary, we highlight the large degree of heterogeneity observed in the meta-analysis of trials involving alpha-2 agonist medications and present possible explanations for the observed heterogeneity. Among these possible explanations is the possibility that presence of comorbid ADHD may moderate the efficacy of alpha-2 agonists in the treatment of tic disorder with the medications being more effective in patients with both conditions. The commentary reviews the evidence supporting this possible moderating effect of ADHD and discusses the implications for such a relationship. © 2016 Association for Child and Adolescent Mental Health.

  12. Kinetics of the urea-induced dissociation of human plasma alpha-2-macroglobulin as measured by small-angle neutron scattering

    DEFF Research Database (Denmark)

    Sjöberg, B.; Pap, S.; Järnberg, S.-E.

    1991-01-01

    that there is a pronounced kinetic isotope effect, i.e. the dissociation is 4 times faster in the H-1-containing medium as compared with the H-2-containing medium at the same molar concentration of urea. From the angular dependence of the neutron scattering it can be concluded that the dissociation is associated......The kinetics of the urea-induced dissociation of human plasma alpha-2-macroglobulin into two half-molecular fragments was investigated at 21.0-degrees-C by using small-angle neutron scattering. The relative change in molecular mass that occurs upon dissociation was monitored by recording...... the forward scattering of neutrons as a function of time. All these kinetic data can be explained by a reaction that is first-order with respect to the concentration of undissociated alpha-2-macroglobulin. The velocity constant is a function of urea concentration and it varies within wide limits. For instance...

  13. Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis.

    Science.gov (United States)

    Oba, Yuji; Lone, Nazir A

    2014-01-01

    A combination therapy with inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations. Currently, there are five ICS/LABA combination products available on the market. The purpose of this study was to systematically review the efficacy of various ICS/LABA combinations with a network meta-analysis. Several databases and manufacturer's websites were searched for relevant clinical trials. Randomized control trials, at least 12 weeks duration, comparing an ICS/LABA combination with active control or placebo were included. Moderate and severe exacerbations were chosen as the outcome assessment criteria. The primary analyses were conducted with a Bayesian Markov chain Monte Carlo method. Most of the ICS/LABA combinations reduced moderate-to-severe exacerbations as compared with placebo and LABA, but none of them reduced severe exacerbations. However, many studies excluded patients receiving long-term oxygen therapy. Moderate-dose ICS was as effective as high-dose ICS in reducing exacerbations when combined with LABA. ICS/LABA combinations had a class effect with regard to the prevention of COPD exacerbations. Moderate-dose ICS/LABA combination therapy would be sufficient for COPD patients when indicated. The efficacy of ICS/LABA combination therapy appeared modest and had no impact in reducing severe exacerbations. Further studies are needed to evaluate the efficacy of ICS/LABA combination therapy in severely affected COPD patients requiring long-term oxygen therapy.

  14. Three complement-like repeats compose the complete alpha2-macroglobulin binding site in the second ligand binding cluster of the low density lipoprotein receptor-related protein.

    Science.gov (United States)

    Dolmer, Klavs; Gettins, Peter G W

    2006-11-10

    Given the importance of the low density lipoprotein receptor-related protein (LRP) as an essential endocytosis and signaling receptor for many protein ligands, and of alpha2-macroglobulin (alpha2M)-proteinase complexes as one such set of ligands, an understanding of the specificity of their interaction with LRP is an important goal. A starting point is the known role of the 138-residue receptor binding domain (RBD) in binding to LRP. Previous studies have localized high affinity alpha2M binding to the eight complement repeat (CR)-containing cluster 2 of LRP. In the present study we have identified the minimum CR domains that constitute the full binding site for RBD and, hence, for alpha2M on LRP. We report on the ability of the triple construct of CR3-4-5 to bind RBD with an affinity (Kd = 130 nM) the same as for isolated RBD to intact LRP. This Kd is 30-fold smaller than for RBD to CR5-6-7, demonstrating the specificity of the interaction with CR3-4-5. Binding requires previously identified critical lysine residues but is almost pH-independent within the range of pH values encountered between extracellular and internal compartments, consistent with an earlier proposed model of intracellular ligand displacement by intramolecular YWTD domains. The present findings suggest a model to explain the ability of LRP to bind a wide range of structurally unrelated ligands in which a nonspecific ligand interaction with the acidic region present in most CR domains is augmented by interactions with other CR surface residues that are unique to a particular CR cluster.

  15. The influence of nifedipine and pertussis toxin (PTX) on vascular responsiveness to alpha1- and alpha2-adrenergic stimulation of isolated femoral arteries

    Czech Academy of Sciences Publication Activity Database

    Líšková, Silvia; Kuneš, Jaroslav; Paulis, Ĺudovít; Zicha, Josef

    2006-01-01

    Roč. 48, č. 4 (2006), s. 769-769 ISSN 0194-911X. [Annual Meeting of the European Council for Cardiovascular Research (ECCR) /11./. 29.09.2006-01.10.2006, La Colle sur Loup] R&D Projects: GA MZd NR7786 Institutional research plan: CEZ:AV0Z50110509 Keywords : nifedipine * pertussis toxin * vascular responsiveness * alpha1- and alpha2-adrenergic stimulation * femorel arteria Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  16. Kinetics of the urea-induced dissociation of human plasma alpha-2-macroglobulin as measured by small-angle neutron scattering

    DEFF Research Database (Denmark)

    Sjöberg, B.; Pap, S.; Järnberg, S.-E.

    1991-01-01

    The kinetics of the urea-induced dissociation of human plasma alpha-2-macroglobulin into two half-molecular fragments was investigated at 21.0-degrees-C by using small-angle neutron scattering. The relative change in molecular mass that occurs upon dissociation was monitored by recording the forw......The kinetics of the urea-induced dissociation of human plasma alpha-2-macroglobulin into two half-molecular fragments was investigated at 21.0-degrees-C by using small-angle neutron scattering. The relative change in molecular mass that occurs upon dissociation was monitored by recording...... the forward scattering of neutrons as a function of time. All these kinetic data can be explained by a reaction that is first-order with respect to the concentration of undissociated alpha-2-macroglobulin. The velocity constant is a function of urea concentration and it varies within wide limits. For instance...... that there is a pronounced kinetic isotope effect, i.e. the dissociation is 4 times faster in the H-1-containing medium as compared with the H-2-containing medium at the same molar concentration of urea. From the angular dependence of the neutron scattering it can be concluded that the dissociation is associated...

  17. Pharmacodynamics of PEG-IFN alpha-2a and HCV response as a function of IL28B polymorphism in HIV/HCV co-infected patients

    Science.gov (United States)

    de Araújo, Evaldo Stanislau Affonso; Dahari, Harel; Cotler, Scott J; Layden, Thomas J; Neumann, Avidan U; Melo, Carlos Eduardo; Barone, Antonio Alci

    2011-01-01

    We examined the association between IL28B single-nucleotide-polymorphism rs12979860, hepatitis C virus (HCV) kinetic and pegylated-interferon-alpha-2a pharmacodynamic parameters in HIV/HCV-co-infected patients from South America. Twenty-six subjects received PEG-IFN-alpha-2a+ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12-weeks of therapy and analyzed using mathematical models. African Americans and Whites had a similar distribution of IL28B genotypes (p=0.5). The CC genotype was overrepresented (p=0.015) in patients infected with HCV genotype-3 compared to genotype-1. In both genotype-1 and genotype-3, the first-phase-viral decline and the average PEG-IFN-alpha-2a effectiveness during the first week of therapy were larger (trend P≤0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second-slower phase of viral decline (days 2–29) and infected-cells-loss rate, δ, were larger (p=0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients. PMID:21157362

  18. Pharmacodynamics of PEG-IFN-[alpha]-2a and HCV response as a function of IL28B polymorphism in HIV/HCV-coinfected patients.

    Science.gov (United States)

    de Araujo, Evaldo Stanislau Affonso; Dahari, Harel; Cotler, Scott J; Layden, Thomas J; Neumann, Avidan U; Melo, Carlos Eduardo; Barone, Antonio Alci

    2011-02-01

    We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P <= 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, [delta], were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.

  19. [Precipitating factors of mortality in chronic obstructive pulmonary disease patients with frequent exacerbations].

    Science.gov (United States)

    Cervera, M Palop; Damiá, A de Diego; Fábregas, M León; Gutiérrez, F J Bravo; Torrego, L Compte

    2010-01-01

    To identify the main characteristics in patients with COPD exacerbation, capables to predict the short-term COPD mortality. This is a case-control retrospective study of admitted patients with COPD to identify risk factors of mortality. The control group was constituted by alive patients after 6 months. The variables studied were clinical antecedents, comorbility, health and nutritional status, basal dyspnea, dependency, exacerbations, physical examination, pulmonary function, radiology, ECG, microbiology and treatment. Both groups were compared with the Chi-square and the T tests. The predictive capacity was analyzed with logistic regression for which the dependent variable was mortality. 125 patients were enrolled (44 exitus and 81 alive) (10 females and 115 males) with mean age of 74+10 years. No significant differences were found between groups in age, sex and disease severity. On the other hand, we found statistically significant differences in basal dyspnea (pphysic activity (p<0,036), accessory muscles use (p<0,007), positive microbiological culture (p<0,013) and treatment with anticholinergic agents (p<0,029) and digoxin (p<0,039). However, none of these variables was able to predict mortality in the logistic regression analysis. The usual data managed in the follow-up of COPD patients are not useful to identify short-term mortality predictors (6 months) during a hospital admittance. Only some variables that would represent a higher chronic inflammation and a lower exercise tolerance showed a statistical tendence in the dead patients group in a exacerbation of COPD.

  20. Clinical Insights into Pulmonary Exacerbations in Cystic Fibrosis from the Microbiome. What Are We Missing?

    Science.gov (United States)

    Whelan, Fiona J; Surette, Michael G

    2015-11-01

    Pulmonary exacerbations account for much of the decrease in lung function and consequently most of the morbidity and mortality in patients with cystic fibrosis. These events are driven by an acute inflammatory response to infection. Recent technological advancements in molecular profiling techniques have allowed for a proliferation of microbiome studies of the lower airways of patients with cystic fibrosis. But these methods may not provide a comprehensive and unbiased measure of the lung microbiota in these patients and molecular profiles do not always translate to quantitative microbiology. Furthermore, these studies have not yet been able to provide much in the way of mechanistic insights into exacerbations or to guide patient therapy. We propose a model in which pulmonary exacerbations may be driven by an active subpopulation of the lung microbiota, which may represent only a small portion of the microbiota measured in a clinical sample. Methodology should be focused on the ultimate goal, which is to use the best available approaches to provide accurate quantitative measures of the microbiome to inform clinical decisions and provide rapid assessment of treatment efficacy. These strategies would be relevant to other chronic lung diseases such as chronic obstructive pulmonary disease and neutrophilic asthma.

  1. Benefits of whole body vibration training in patients hospitalised for COPD exacerbations - a randomized clinical trial.

    Science.gov (United States)

    Greulich, Timm; Nell, Christoph; Koepke, Janine; Fechtel, Juliane; Franke, Maja; Schmeck, Bernd; Haid, Daniel; Apelt, Sandra; Filipovic, Silke; Kenn, Klaus; Janciauskiene, Sabina; Vogelmeier, Claus; Koczulla, Andreas Rembert

    2014-04-11

    Patients with stable COPD show improvements in exercise capacity and muscular function after the application of whole body vibration. We aimed to evaluate whether this modality added to conventional physiotherapy in exacerbated hospitalised COPD patients would be safe and would improve exercise capacity and quality of life. 49 hospitalised exacerbated COPD patients were randomized (1:1) to undergo physiotherapy alone or physiotherapy with the addition of whole body vibration. The primary endpoint was the between-group difference of the 6-minute walking test (day of discharge - day of admission). Secondary assessments included chair rising test, quality of life, and serum marker analysis. Whole body vibration did not cause procedure-related adverse events. Compared to physiotherapy alone, it led to significantly stronger improvements in 6-minute walking test (95.55 ± 76.29 m vs. 6.13 ± 81.65 m; p = 0.007) and St. Georges Respiratory Questionnaire (-6.43 ± 14.25 vs. 5.59 ± 19.15, p = 0.049). Whole body vibration increased the expression of the transcription factor peroxisome proliferator receptor gamma coactivator-1-α and serum levels of irisin, while it decreased serum interleukin-8. Whole body vibration during hospitalised exacerbations did not cause procedure-related adverse events and induced clinically significant benefits regarding exercise capacity and health-related quality of life that were associated with increased serum levels of irisin, a marker of muscle activity. German Clinical Trials Register DRKS00005979. Registered 17 March 2014.

  2. Seasonal Exacerbation of Asthma Is Frequently Associated with Recurrent Episodes of Acute Urticaria.

    Science.gov (United States)

    Vadasz, Zahava; Kessel, Aharon; Hershko, Alon Y; Maurer, Marcus; Toubi, Elias

    2016-01-01

    Asthma and urticaria are both partially mediated by an increased release of histamine from highly activated mast cells. They are pathophysiologically different, as mast cell degranulation in these 2 disorders results from different mechanisms. To assess the incidence of urticaria in patients with asthma, and of asthma in patients with chronic spontaneous urticaria (CSU). Over 1 year of follow-up, asthma patients (n = 110) were assessed for the incidence and characteristics of urticaria, and a link, if it existed, to seasonal exacerbations and the severity of asthma was traced. We also prospectively assessed CSU patients (n = 95) during the same period of time for the incidence of asthma. Healthy individuals (n = 100), serving as a control group, were also assessed. Episodes of urticaria occurred in 26/110 asthma patients (23.6%), but in only 2/100 healthy control subjects (2%) (p urticaria were significantly more frequent in asthma patients with positive skin-prick test reactions (mainly seasonal pollens), and consequently occurred mostly during seasonal asthma exacerbation, i.e. during acute episodes of urticaria. The incidence of asthma in CSU patients was recorded in 10.5% of the group, similar to that in the healthy control population. Our study demonstrates, for the first time, that asthma patients frequently develop acute urticaria, mainly during seasonal exacerbations. In contrast, CSU patients do not show an increased incidence of asthma. © 2016 S. Karger AG, Basel.

  3. Tic exacerbation and precipitation during atomoxetine treatment in two children with attention-deficit hyperactivity disorder.

    Science.gov (United States)

    Párraga, Humberto C; Párraga, Marianela I; Harris, David K

    2007-01-01

    Stimulants have been the mainstay of treatment for children with Attention-deficit/hyperactivity Disorder (ADHD). However, stimulants have been controversially purported to precipitate and exacerbate tics. Atomoxetine, a selective norepinephrine inhibitor, was introduced as a safe non-stimulant alternative treatment for ADHD children with comorbid tics or TS. We are presenting two children with ADHD, in which atomoxetine, at relatively low doses, exacerbated and precipitated tics. The diagnoses of ADHD and tic disorder were based on clinical observations and standardized rating scales. Case 1, an 8-year-old boy, had history of stimulant-induced tics. This child was placed on atomoxetine reported to be safe for patients with tics. This patient's tic control was adequate prior to atomoxetine treatment. However, while on atomoxetine, the patient promptly experienced tic exacerbation. Case 2, a 6-year-old boy, had no previous history of stimulant therapy and was receiving citalopram due to a comorbid anxiety disorder. Atomoxetine was initiated for the treatment of ADHD with improvement in the ADHD symptoms. But, upon a mild dose increase, the patient presented tic precipitation consisting primarily of neck twitches. Both cases experienced a decrease in tic activity when atomoxetine was discontinued, but tics did not fully resolve, causing psychosocial disturbance. Atypical neuroleptics were used with good results. Periodic assessments of the need for continued neuroleptic treatment were emphasized. These two children exemplify atomoxetine's potential to exacerbate and precipitate tics in children with ADHD. Independent controlled studies are needed to determine if atomoxetine should be used in children with ADHD and comorbid tic disorders or TS.

  4. hospitalised due to exacerbation of the disease

    Directory of Open Access Journals (Sweden)

    Dominika Anna Szalewska

    2016-12-01

    Full Text Available Background . Coronary artery disease (CAD is a common cause of hospitalisation in cardiac wards, while chronic pancreatitis (CP is in gastroenterology wards. Both diseases are chronic and the clinical picture is dominated by pain. Objectives . The objective was to describe the psychological characteristics of patients hospitalised for the worsening of CAD and CP. Material and methods. The sample comprised 30 patients with CAD and 30 with CP. Participants completed personal questionnaires, the Eysenck Personality Questionnaire-Revised, STAI , Beck Depression Inventory and Scale A-Framingham. Results . Mild depression occurred in 20% of patients with CAD and 30% with CP. A severe degree of depression was found in 20% of patients with CAD and in 15% with CP while the highest levels of anxiety (9–10 sten were found in 30% of patients with CP and in 20% of patients with CAD . In relation to introversion-extraversion personality dimension, 74% of patients with CAD and 53% of patients with CP were classified as ambivert or introvert. In both groups, most patients had moderate emotional balance as follows: 47% patients with CAD and 43% with CP. Conclusions . Compared to patients with CAD , patients with CP presented more severe depression symptoms and anxiety. The subjects with high intensification of neurotic traits more often presented high levels of anxiety and depression wherein more than half of these patients had severe anxiety and depression. Patients with low physical activity had significantly higher levels of anxiety than patients who were active daily or several times per week.

  5. Risk factors for asthma exacerbation in patients presenting to an ...

    African Journals Online (AJOL)

    Background: Asthma exacerbations are caused by a variety of risk factors. Reducing exposure to these risk factors improves the control of asthma and reduces medication needs. Knowledge of the particular risk factors is essential in formulating controlling and treatment protocols. This study set out to determine the risk ...

  6. Risk factors for asthma exacerbation in patients presenting to an ...

    African Journals Online (AJOL)

    Abstract. Background: Asthma exacerbations are caused by a variety of risk factors. Reducing exposure to these risk factors improves the control of asthma and reduces medication needs. Knowledge of the particular risk factors is essential in formulating controlling and treatment protocols. This study set out to determine the ...

  7. Prevalence and pattern of asthma exacerbation in children seen at ...

    African Journals Online (AJOL)

    2016-01-15

    Jan 15, 2016 ... morbidity in asthmatic children. It can occur even in well controlled asthma. Aim: To determine the prevalence and pattern of acute exacerbation of asthma in children seen at the emergency room of the University of Nigeria Teaching Hospital. (UNTH), Enugu. Materials and methods: This was a descriptive ...

  8. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

    Magnussen, Helgo; Disse, Bernd; Rodriguez-Roisin, Roberto

    2014-01-01

    exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT...

  9. Risk factors precipitating exacerbations in adult asthma patients ...

    African Journals Online (AJOL)

    adult asthma patients presenting at Kalafong. Hospital, Pretoria a Geyser MM, BSc, DipPEC(SA), ... patients with exacerbations presenting at Kalafong Hospital's emergency unit were chosen as cases. Controls were stable asthma patients recruited .... Self-diagnosed asthma. • Newly diagnosed asthma. • Pulmonary ...

  10. How Clinical Diagnosis Might Exacerbate the Stigma of Mental Illness

    Science.gov (United States)

    Corrigan, Patrick W.

    2007-01-01

    Stigma can greatly exacerbate the experience of mental illness. Diagnostic classification frequently used by clinical social workers may intensify this stigma by enhancing the public's sense of "groupness" and "differentness" when perceiving people with mental illness. The homogeneity assumed by stereotypes may lead mental health professionals and…

  11. Oxygen therapy in acute exacerbations of chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Ringbaek, T.; Lange, P.; Mogensen, T.

    2008-01-01

    Acute exacerbation of COPD is a major cause of hospitalisation in Denmark. Most of the patients require supplemental oxygen in the acute phase and some patients continue oxygen therapy at home after discharge. In this paper we discuss the physiological mechanisms of respiratory failure seen in ac...

  12. PRODUCTION OF PROINFLAMMATORY CYTOKINES AND ALPHA-2-MACROGLOBULIN BY PERIPHERAL BLOOD CELLS IN THE PATIENTS WITH COLORECTAL CANCER

    Directory of Open Access Journals (Sweden)

    V. N. Zorina

    2016-01-01

    Full Text Available Colorectal cancer (CRC is the third most common cancer worldwide, being quite complicated, with respect to diagnostics and postoperative prognosis. Proinflammatory cytokines are shown to be involved into CRC pathogenesis. However, the changes in alpha-2-macroglobulin (α2-MG, a known regulator of cytokine production, still remain unclear. The aim of this work was to compare contents and production of a2-MG and several pro-inflammatory cytokines in blood serum and supernates from short-term blood cell cultures. The samples were taken from the patients with CRC at initial terms and after surgical removal of the tumor.Studies of cytokines and a2-MG concentrations in serum and supernates of 24-h blood cell cultures from the patients with verified CRC (stages T2-3N0-1M0 and T4N0-1M0 have shown some sufficient differences from healthy volunteers (control group. Pre-surgery IL-6 and TNFα contents in blood of CRC patients was significantly increased agains healthy controls (respectively, 29.9±5.4 and 3.4±1.5 pg/mL versus control group (1.0±0.3 and 0 pg/mL, respectively. Following surgical treatment, the cytokine levels were decreased by 40- 60% after the operation, however, without significant differences from initial values.The supernates of blood cultures stimulated with polyclonal mitogens exhibited significant reduction of IFNγ levels prior to surgery (273±123 pg/ml versus 804±154 pg/mL, and elevated IL-6 levels (14412±2570 pg/mL versus 1970±457 pg/mL. The mean α2-MG concentrations before CRC surgery comprised 1.96±0.11 g/L for blood serum, 0.0304±0.0047 g/L, for non-stimulated blood cell cultures, and 0.0300±0.0052 g/L in mitogen-induced cultures. These parameters did not significantly differ from control values (2.21±0.17 g/L, 0.0328±0.0018 g/L, and 0.0314±0.0019 g/L, respectively. Similar results have been yielded with the samples obtained after surgical treatment of the CRC patients.The obtained data indicate that surgical

  13. Presynaptic alpha2-adrenoceptor-mediated modulation of adenosine 5' triphosphate and noradrenaline corelease: differences in canine mesenteric artery and vein.

    Science.gov (United States)

    Bobalova, J; Mutafova-Yambolieva, V N

    2001-02-01

    1. The modulatory effects of agonists and antagonists of prejunctional alpha2-adrenoceptors on the electrical field stimulation (EFS, 0.3 ms, 12 V)-induced release of endogenous noradrenaline (NA) and the cotransmitter adenosine 5' triphosphate (ATP) were measured in endothelium-denuded segments of canine inferior mesenteric artery and compared with effects in mesenteric vein. The overflow of NA and ATP was evoked by long-duration (2 min) EFS at low frequency (4 Hz) and high frequency (16 Hz) of stimulation and was analysed using HPLC techniques with electrochemical detection and fluorescence detection, respectively. 2. The EFS-evoked overflow of both NA and ATP was significantly reduced by tetrodotoxin (1 microM) and guanethidine (10 microM) in the artery and vein. Desipramine (10 microM), a blocker of neuronal uptake of NA, increased the EFS (4 and 16 Hz)-evoked overflow of NA in both artery and vein. EFS-evoked overflow of NA in vein exceeded the NA overflow in artery at both 4 and 16 Hz in control preparations as well as in the presence of desipramine. However, the EFS-evoked overflow of ATP was equal in the artery and vein. 3. Stimulation of alpha2-adrenoceptors with clonidine (0.1 microM) and oxymethazoline (0.3 microM) reduced the EFS evoked overflow of NA in both artery and vein at 4 Hz, whereas the NA overflow at 16 Hz remained unchanged in both blood vessels. The overflow of ATP as well as of ADP (and hence ATP:ADP ratio) was unaffected by the alpha2-adrenoceptor agonists in the artery and vein. 4. In artery, blockade of alpha2-adrenoceptors with yohimbine at a concentration of 0.1 microM caused no effect on the NA overflow neither at 4 Hz nor at 16 Hz of EFS. Yohimbine at a concentration of 1 microM increased the overflow of NA at 4 Hz but not 16 Hz of EFS. In vein, however, yohimbine (0.1 and 1 microM) increased NA overflow at both 4 and 16 Hz of stimulation. Idazoxan (1 microM) increased the NA overflow in artery only at 4 Hz, whereas in vein idazoxan

  14. A biallelic RFLP of the human. alpha. 2-C4 adrenergic receptor gene (ADRA2RL2) localized on the short arm of chromosome 4 and encoding the putative. alpha. 2B receptor is identified with Bsu 36 L using a 1. 5 kb probe (p ADRA2RL2)

    Energy Technology Data Exchange (ETDEWEB)

    Hoeche, M.R.; Berrettini, W.H. (Clinical Neurogenetics Branch, Bethesda, MD (USA)); Regan, J.W. (Duke Univ. Medical Center, Durham, NC (USA))

    1989-12-11

    A 1.5 kb Eco RI cDNA fragment representing the human alpha2-C4 adrenergic receptor (AR) gene encoding the putative alpha2B-AR, containing approximately 1270 bp of the coding and 240 bp of the 3{prime}flanking region, inserted into pSP65, was used as a probe (p ADRA2RL2). This clone was obtained by screening a human kidney lambda GT10 cDNA library with the 0.95 kb Pst I restriction fragment derived from the coding block of the gene for the human platelet alpha2-AR. Hybridization of human genomic DNA digested with Bsu 36 I identifies a two allele polymorphism with bands at 12 kb and 5.8 kb. 20 unrelated North American caucasian subjects were evaluated with frequencies of: A allele, 0.45; B allele, 0.55, heterozygosity (obs), 0.5. This alpha2-AR gene has been mapped in a separation effort in 59 CEPH reference pedigrees to the tip of the short arm of chromosome 4 just proximal to GB (4p 16.3) reported to be linked to the Huntingston's disease gene. Codominant inheritance was observed in seven families with two and three generations, respectively. The number of meioses scored was 95.

  15. Management of acute exacerbations of chronic obstructive pulmonary disease (COPD). Guidelines from the Société de pneumologie de langue française (summary).

    Science.gov (United States)

    Jouneau, S; Dres, M; Guerder, A; Bele, N; Bellocq, A; Bernady, A; Berne, G; Bourdin, A; Brinchault, G; Burgel, P R; Carlier, N; Chabot, F; Chavaillon, J M; Cittee, J; Claessens, Y E; Delclaux, B; Deslée, G; Ferré, A; Gacouin, A; Girault, C; Ghasarossian, C; Gouilly, P; Gut-Gobert, C; Gonzalez-Bermejo, J; Jebrak, G; Le Guillou, F; Léveiller, G; Lorenzo, A; Mal, H; Molinari, N; Morel, H; Morel, V; Noel, F; Pégliasco, H; Perotin, J M; Piquet, J; Pontier, S; Rabbat, A; Revest, M; Reychler, G; Stelianides, S; Surpas, P; Tattevin, P; Roche, N

    2017-04-01

    Chronic obstructive pulmonary disease (COPD) is the chronic respiratory disease with the most important burden on public health in terms of morbidity, mortality and health costs. For patients, COPD is a major source of disability because of dyspnea, restriction in daily activities, exacerbation, risk of chronic respiratory failure and extra-respiratory systemic organ disorders. The previous French Language Respiratory Society (SPLF) guidelines on COPD exacerbations were published in 2003. Using the GRADE methodology, the present document reviews the current knowledge on COPD exacerbation through 4 specific outlines: (1) epidemiology, (2) clinical evaluation, (3) therapeutic management and (4) prevention. Specific aspects of outpatients and inpatients care are discussed, especially regarding assessment of exacerbation severity and pharmacological approach. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  16. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD.

    Science.gov (United States)

    Baumeler, Luzia; Papakonstantinou, Eleni; Milenkovic, Branislava; Lacoma, Alicia; Louis, Renaud; Aerts, Joachim G; Welte, Tobias; Kostikas, Konstantinos; Blasi, Francesco; Boersma, Wim; Torres, Antoni; Rohde, Gernot G U; Boeck, Lucas; Rakic, Janko; Scherr, Andreas; Tamm, Michael; Stolz, Daiana

    2016-07-01

    Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD. A total of 638 patients with stable COPD for ≥6 weeks, ≥10 pack-years of smoking and Global Initiative for Chronic Obstructive Lung Disease II-IV seeking care in tertiary hospitals in eight European countries in the Predicting Outcome using Systemic Markers in Severe Exacerbations-COPD cohort was prospectively evaluated by us. Comorbidities including associated medical treatment were assessed at baseline, at exacerbation and at biannual visits. Median observation time was 24 months. The primary study outcomes were exacerbation and/or death. A total of 85 (13.3%) of COPD patients were on anti-GERD therapy. These patients had higher annual and higher severe exacerbation rates (P = 0.009 and P = 0.002), decreased quality of life (SF-36: activity score P = 0.004, St. George's Respiratory Questionnaire: physical functioning P = 0.013 and social functioning P = 0.007), higher body mass airflow obstruction, dyspnea and exercise capacity index (P = 0.033) and Modified Medical Research Council scores (P = 0.002), shorter 6-min walking distance (P = 0.0004) and a higher adjusted Charlson score (P GERD therapy was associated with a shorter time to severe exacerbation (HR 2.05 95% CI 1.37-3.08). Using three multivariable Cox-regression models, this association was independent of the following: (i) adjusted Charlson score and FEV1% predicted (HR 1.91 95% CI 1.26-2.90); (ii) adjusted Charlson score, body mass, airflow obstruction, dyspnea and exercise capacity index and Modified Medical Research Council (HR 1.62 95% CI 1.04-2.54); and (iii) adjusted Charlson score, FEV1% predicted and nine classes of medication for comorbidities (HR 1.63 95% CI 1.04-2.53). These findings

  17. Characterization and regional distribution of alpha 2-adrenoceptors in postmortem human brain using the full agonist (/sup 3/H)UK 14304

    Energy Technology Data Exchange (ETDEWEB)

    Meana, J.J.; Barturen, F.; Garcia-Sevilla, J.A.

    1989-04-01

    The full agonist (3H)UK 14304 (5-bromo-6-(2-imidazolin-2-yl-amino)-quinoxaline) was used to characterize alpha 2-adrenoceptors in postmortem human brain. The binding at 25 degrees C was rapid (t1/2, 4.6 min) and reversible (t1/2, 14.1 min), and the KD determined from the kinetic studies was 0.48 nM. In frontal cortex, the rank order of potency of adrenergic drugs competing with (3H)UK 14304 or (3H)clonidine showed the specificity for an alpha 2A-adrenoceptor: UK 14304 approximately equal to yohimbine approximately equal to oxymetazoline approximately equal to clonidine greater than phentolamine approximately equal to (-)-adrenaline greater than idazoxan approximately equal to (-)-noradrenaline greater than phenylephrine greater than (+/-)-adrenaline much greater than corynanthine greater than prazosin much greater than (+/-)-propranolol. GTP induced a threefold decrease in the affinity of (3H)UK 14304, with no alteration in the maximum number of binding sites, suggesting that the radioligand labelled the high-affinity state of the alpha 2-adrenoceptor. In the frontal cortex, analyses of saturation curves indicated the existence of a single population of noninteracting sites for (3H)UK 14304 (KD = 0.35 +/- 0.13 nM; Bmax = 74 +/- 9 fmol/mg of protein). In other brain regions (hypothalamus, hippocampus, cerebellum, brainstem, caudate nucleus, and amygdala) the Bmax ranged from 68 +/- 7 to 28 +/- 4 fmol/mg of protein. No significant changes in the KD values were found in the different regions examined. The binding of (3H)UK 14304 was not affected by age, sex or postmortem delay.

  18. Functional expression of the GABAA receptor alpha2 and alpha3 subunits at synapses between intercalated medial paracapsular neurons of mouse amygdala

    Directory of Open Access Journals (Sweden)

    Raffaella eGeracitano

    2012-05-01

    Full Text Available In the amygdala, GABAergic neurons in the intercalated medial paracapsular cluster (Imp have been suggested to play a key role in fear learning and extinction. These neurons project to the central amygdaloid nucleus and to other areas within and outside the amygdala. In addition, they give rise to local collaterals that innervate other neurons in the Imp. Several drugs, including benzodiazepines, are allosteric modulators of GABA-A receptors. Benzodiazepines have both anxiolytic and sedative actions, which are mediated through GABA-A receptors containing alpha2/3 and alpha1 subunits, respectively. To establish whether alpha1 or alpha2/3 subunits are expressed at Imp cell synapses, we used paired recordings of anatomically-identified Imp neurons and high resolution immunocytochemistry in the mouse. We observed that a selective alpha3 subunit agonist, TP003 (100 nM, significantly increased the decay time constant of the unitary IPSCs. A similar effect was also induced by zolpidem (10 microM or by diazepam (1 microM. In contrast, lower doses of zolpidem (0.1-1 microM did not significantly alter the kinetics of the unitary IPSCs. Accordingly, immunocytochemical experiments established that the alpha2 and alpha3, but not the alpha1 subunits of the GABA-A receptors, were present at Imp cell synapses of the mouse amygdala. These results define, for the first time, some of the functional GABA-A receptor subunits expressed at synapses of Imp cells. The data also provide an additional rationale to prompt the search of GABA-A receptor alpha3 selective ligands as improved anxiolytic drugs.

  19. Preliminary results of treatment with pegylated interferon alpha 2A for chronic hepatitis C virus in kidney transplant candidates on hemodialysis.

    Science.gov (United States)

    Casanovas-Taltavull, T; Baliellas, C; Llobet, M; Cruzado, J M; Castellote, J; Casanova, A; Niubó, J; Valls, C; Serrano, T

    2007-09-01

    At present, there is little published information on the outcome of treatment with pegylated interferon (Peg-IF alpha 2a) in hepatitis C virus (HCV)-infected hemodialysis patients awaiting renal transplantation. The objective of this study was to assess the efficacy and tolerance of Peg-IF alpha 2a in this population. Twelve noncirrhotic HCV-infected patients (10 men, 50 +/- 8 years of age, genotype 1b 84%), were prescribed Peg-IF alpha 2a, at 135 microg/wk for 48 weeks. Liver biopsy was performed in 11 of 12 cases. Six patients completed 48 weeks of treatment, with one end of treatment response (ETR), two sustained viral responses (SVRs), and three HCV relapses. Treatment was shorter in the six remaining patients: two cases 24 weeks (one due to medical reasons with relapse, one due to nonresponse), one patient chose to discontinue at 14 weeks (with relapse), one patient died of stroke at 10 weeks, and in two additional patients interferon was withdrawn at 18 weeks because of severe anemia (SVR) and at 26 weeks due to prolonged fever (relapse). Other secondary treatment-related events included anemia (requiring transfusion in two patients and major erythropoietin administration in six), and fever in four patients. Peg-IF had limited efficacy in this group, with ETR in 83%, SVR in only 25%, and recurrence in 50%. Tolerance was moderate, with 4/12 (33%) discontinuing treatment due to adverse events, personal decision, or death. Large randomized controlled studies are needed to determine the role of Peg-IF treatment in this population.

  20. Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema

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    Atsushi Suzuki

    Full Text Available Acute exacerbation (AE is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF. In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF. Keywords: Idiopathic pulmonary fibrosis, Acute exacerbation, AE-IPF, Triggered AE, Aspergillus infection

  1. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.

    Science.gov (United States)

    Green, Ruth H; Brightling, Christopher E; McKenna, Susan; Hargadon, Beverley; Parker, Debbie; Bradding, Peter; Wardlaw, Andrew J; Pavord, Ian D

    2002-11-30

    Treatment decisions in asthma are based on assessments of symptoms and simple measures of lung function, which do not relate closely to underlying eosinophilic airway inflammation. We aimed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a standard management strategy. We recruited 74 patients with moderate to severe asthma from hospital clinics and randomly allocated them to management either by standard British Thoracic Society asthma guidelines (BTS management group) or by normalisation of the induced sputum eosinophil count and reduction of symptoms (sputum management group). We assessed patients nine times over 12 months. The results were used to manage those in the sputum management group, but were not disclosed in the BTS group. The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation, measured by induced sputum eosinophil count. Analyses were by intention to treat. The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002). Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group (35 vs 109; p=0.01) and significantly fewer patients were admitted to hospital with asthma (one vs six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not differ between the two groups. A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.

  2. Reduced volume and increased training intensity elevate muscle Na+/K+ pump {alpha}2-subunit expression as well as short- and long-term work capacity in humans

    DEFF Research Database (Denmark)

    Bangsbo, Jens; Gunnarsson, Thomas Petursson; Wendell, Jesper

    2009-01-01

    was unaltered, but the 3-K (3,000 m) time was reduced (Pexpression and performance remained unaltered in CON. The present data suggest that both short- and long-term......% reduction in the amount of training but including speed endurance training consisting of 6-12 30-s sprint runs 3-4 times a week (SET, n=12) or a control group (CON, n=5), which continued the endurance training (about 55 km(.)wk(-1)). For SET the expression of the muscle Na(+)/K(+) pump alpha2-subunit was 68...

  3. Study design considerations in a large COPD trial comparing effects of tiotropium with salmeterol on exacerbations

    NARCIS (Netherlands)

    K-M. Beeh (Kai-Michael); B. Hederer (Bettina); T. Glaab (Thomas); A. Müller (Achim); M.P.M.H. Rutten-van Mölken (Maureen); S. Kesten (Steven); C. Vogelmeier (Claus)

    2009-01-01

    textabstractAbstract Currently available long-acting inhaled bronchodilators (tiotropium, salmeterol, formoterol) have demonstrated beneficial effects on exacerbations in placebo-controlled trials. However, there have been no direct comparisons of these drugs with exacerbations as the primary

  4. T cells exacerbate Lyme borreliosis in TLR2-deficient mice

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    Carrie E. Lasky

    2016-11-01

    Full Text Available Infection of humans with the spirochete, Borrelia burgdorferi, causes Lyme borreliosis and can lead to clinical manifestations such as, arthritis, carditis and neurological conditions. Experimental infection of mice recapitulates many of these symptoms and serves as a model system for the investigation of disease pathogenesis and immunity. Innate immunity is known to drive the development of Lyme arthritis and carditis, but the mechanisms driving this response remain unclear. Innate immune cells recognize B. burgdorferi surface lipoproteins primarily via Toll-like receptor (TLR2; however, previous work has demonstrated TLR2-/- mice had exacerbated disease and increased bacterial burden. We demonstrate increased CD4 and CD8 T cell infiltrates in B. burgdorferi-infected joints and hearts of C3H TLR2-/- mice. In vivo depletion of either CD4 or CD8 T cells reduced Borrelia-induced joint swelling and lowered tissue spirochete burden, while depletion of CD8 T cells alone reduced disease severity scores. Exacerbation of Lyme arthritis correlated with increased production of CXCL9 by synoviocytes and this was reduced with CD8 T cell depletion. These results demonstrate T cells can exacerbate Lyme disease pathogenesis and prolong disease resolution possibly through dysregulation of inflammatory responses and inhibition of bacterial clearance.

  5. Cerebral ischemia is exacerbated by extracellular nicotinamide phosphoribosyltransferase via a non-enzymatic mechanism.

    Directory of Open Access Journals (Sweden)

    Bing Zhao

    Full Text Available Intracellular nicotinamide phosphoribosyltransferase (iNAMPT in neuron has been known as a protective factor against cerebral ischemia through its enzymatic activity, but the role of central extracellular NAMPT (eNAMPT is not clear. Here we show that eNAMPT protein level was elevated in the ischemic rat brain after middle-cerebral-artery occlusion (MCAO and reperfusion, which can be traced to at least in part from blood circulation. Administration of recombinant NAMPT protein exacerbated MCAO-induced neuronal injury in rat brain, while exacerbated oxygen-glucose-deprivation (OGD induced neuronal injury only in neuron-glial mixed culture, but not in neuron culture. In the mixed culture, NAMPT protein promoted TNF-α release in a time- and concentration-dependent fashion, while TNF-α neutralizing antibody protected OGD-induced, NAMPT-enhanced neuronal injury. Importantly, H247A mutant of NAMPT with essentially no enzymatic activity exerted similar effects on ischemic neuronal injury and TNF-α release as the wild type protein. Thus, eNAMPT is an injurious and inflammatory factor in cerebral ischemia and aggravates ischemic neuronal injury by triggering TNF-α release from glia cells, via a mechanism not related to NAMPT enzymatic activity.

  6. Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis.

    Science.gov (United States)

    Hurley, Matthew N; Prayle, Andrew P; Flume, Patrick

    2015-07-30

    Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. To establish if intravenous antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short- and long-term clinical outcomes. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers.Date of last search of Cochrane trials register: 27 July 2015. Randomised controlled trials and the first treatment cycle of cross-over studies comparing intravenous antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. The authors assessed studies for eligibility and risk of bias and extracted data. We included 40 studies involving 1717 participants. The quality of the included studies was largely poor and, with a few exceptions, these comprised of mainly small, inadequately reported studies.When comparing treatment with a single antibiotic to a combined antibiotic regimen, those participants receiving a combination of antibiotics experienced a greater improvement in lung function when considered as a whole group across a number of different measurements of lung function, but with very low quality evidence. When limited to the four placebo-controlled studies (n = 214), no difference was observed, again with very low quality evidence. With regard to the review's remaining primary outcomes, there was no effect upon time to next exacerbation and

  7. Factors influencing exacerbation-related self-management in patients with COPD : A qualitative study

    NARCIS (Netherlands)

    Korpershoek, Y. J G; Vervoort, S. C J M|info:eu-repo/dai/nl/202634957; Nijssen, L. I T; Trappenburg, J. C A|info:eu-repo/dai/nl/31144556X; Schuurmans, M. J.|info:eu-repo/dai/nl/127722386

    2016-01-01

    Background: In patients with COPD, self-management skills are important to reduce the impact of exacerbations. However, both detection and adequate response to exacerbations appear to be difficult for some patients. Little is known about the underlying process of exacerbation-related

  8. The protease inhibitor alpha-2-macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic pemphigus autoantibodies in human.

    Directory of Open Access Journals (Sweden)

    Isabelle Schepens

    Full Text Available BACKGROUND: Paraneoplastic pemphigus (PNP is a devastating autoimmune blistering disease, involving mucocutaneous and internal organs, and associated with underlying neoplasms. PNP is characterized by the production of autoantibodies targeting proteins of the plakin and cadherin families involved in maintenance of cell architecture and tissue cohesion. Nevertheless, the identity of an antigen of Mr 170,000 (p170, thought to be critical in PNP pathogenesis, has remained unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using an immunoprecipitation and mass spectrometry based approach, we identified p170 as alpha-2-macroglobuline-like-1, a broad range protease inhibitor expressed in stratified epithelia and other tissues damaged in the PNP disease course. We demonstrate that 10 PNP sera recognize alpha-2-macroglobuline-like-1 (A2ML1, while none of the control sera obtained from patients with bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus and normal subjects does. CONCLUSIONS/SIGNIFICANCE: Our study unravels a broad range protease inhibitor as a new class of target antigens in a paraneoplastic autoimmune multiorgan syndrome and opens a new challenging investigation avenue for a better understanding of PNP pathogenesis.

  9. A randomised trial of a pre-synaptic stimulator of DA2-dopaminergic and alpha2-adrenergic receptors on morbidity and mortality in patients with heart failure

    DEFF Research Database (Denmark)

    Torp-Pedersen, Christian; Køber, Lars; Carlsen, Jan E

    2008-01-01

    Background: By pre-synaptic stimulation of DA(2)-dopaminergic and alpha(2)-adrenergic receptors, nolomirole inhibits norepinephrine secretion from sympathetic nerve endings. We performed a clinical study with nolomirole in patients with heart failure (HF). Methods: The study was designed as a mul.......i.d. of nolomirole was not beneficial (or harmful) in patients with heart failure. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved Udgivelsesdato: 2008/1......Background: By pre-synaptic stimulation of DA(2)-dopaminergic and alpha(2)-adrenergic receptors, nolomirole inhibits norepinephrine secretion from sympathetic nerve endings. We performed a clinical study with nolomirole in patients with heart failure (HF). Methods: The study was designed...... as a multicentre, double blind, parallel group trial of 5 mg b.i.d. of nolomirole (n=501) versus placebo (n=499) in patients with severe left ventricular systolic dysfunction, recently in New York Heart Association (NYHA) class III/IV. The primary endpoint was time to all cause death or hospitalisation for HF...

  10. Gemifloxacin use in the treatment of acute bacterial exacerbation of chronic bronchitis

    Directory of Open Access Journals (Sweden)

    Cristian Jivcu

    2009-07-01

    Full Text Available Cristian Jivcu1, Mark Gotfried21Department of Internal Medicine, Banner Good Samaritan Medical Center, Phoenix, AZ, USA; 2Department of Medicine, University of Arizona, Phoenix, AZ, USAAbstract: The newest generation of fluoroquinolones have proven efficacy against bacterial organisms associated with acute exacerbation of chronic bronchitis (AECB. Gemifloxacin, as one of the quinolones in this class, exhibits many of the pharmacokinetic and pharmacodynamic characteristics of the class with a few notable differences. Against Streptococccus pneumoniae it has a lower minimal inhibitory concentration (MIC than the other respiratory fluoroquinolones and it has activity against both bacterial DNA gyrase and topoisomerase IV. The increased activity of gemifloxacin against both enzymes may be associated with decreased rates of resistance. Clinically, gemifloxacin has been shown to have positive effects on length of hospitalization and increased success at long-term follow-up in AECB patients. These associations were observed in noninferiority comparison studies. Although an advantage with the use of gemifloxacin in AECB is suggested, there are no comparison data is available to conclude that gemifloxacin is superior to the other respiratory fluoroquinolones. Gemifloxacin is generally well tolerated, but is associated with a characteristic rash and gastrointestinal upset as its most common observed side effects.Keywords: gemifloxacin, respiratory fluoroquinolones, acute exacerbation of chronic bronchitis

  11. Does granulocyte colony-stimulating factor exacerbate radiation-induced acute lung injury in rats?

    International Nuclear Information System (INIS)

    Miura, Gouji; Awaya, Hitomi; Matsumoto, Tsuneo; Tanaka, Nobuyuki; Matsunaga, Naofumi

    2000-01-01

    Radiation pneumonitis (RP) frequently occurs as a complication of thoracic irradiation. However, the mechanism of RP is not well known. Activated neutrophils are a possible pathogenesis of RP. Neutrophil activation induced by granulocyte colony-stimulating factor (G-CSF) may exacerbate RP. We studied the effects of recombinant human G-CSF on acute lung injury induced by thoracic irradiation using rats. Animals were divided into three groups: sham irradiation with saline control, irradiation alone, and irradiation with G-CSF. Actual irradiation was given as a single fraction of 16 Gy delivered to the right hemithorax. G-CSF at a dose of 12 μg/body was administered subcutaneously once a day from 14 to 18 days after actual irradiation. Lung injury was evaluated 21 days after irradiation by bronchoalveolar lavage (BAL) fluid findings and the lung wet/dry weight (W/D) ratio. Neutrophil and lymphocyte counts in BAL fluid and the W/D ratio were significantly increased in the irradiation alone and the irradiation with G-CSF groups compared with those of the sham irradiation+saline control group. However, there was no significant difference observed between the irradiation alone and irradiation with G-CSF groups. In conclusion, this study suggests that postradiation administration of G-CSF does not exacerbate acute lung injury induced by thoracic irradiation in rats. (author)

  12. Predictors of Change in Dyspnea Level in Acute Exacerbations of COPD.

    Science.gov (United States)

    Garcia-Gutierrez, Susana; Quintana, José M; Unzurrunzaga, Anette; Esteban, Cristóbal; Baré, Marisa; Fernández de Larrea, Nerea; Pulido, Esther; Rivas, Paco; -Copd Group, Iryss

    2016-06-01

    The aim of this study was to identify factors related to changes in dyspnoea level in the acute and short-term periods after acute exacerbation of chronic obstructive pulmonary disease. This was a prospective cohort study of patients with symptoms of acute chronic obstructive pulmonary disease exacerbation who attended one of 17 hospitals in Spain between June 2008 and September 2010. Clinical data and patient reported measures (dyspnoea level, health-related quality of life, anxiety and depression levels, capacity to perform physical activity) were collected from arrival to the emergency department up to a week after the visit in discharged patients and to discharge in admitted patients (short term). Main outcomes were time course of dyspnoea over the acute (first 24 hours) and short-term periods, mortality and readmission within 2 months of the index episode. Changes in dyspnoea in both periods were related capacity to perform physical activity as well as clinical variables. Short-term changes in dyspnoea were also related to dyspnoea at 24 hours after the ED visit, and anxiety and depression levels. Dyspnoea worsening or failing to improve over the studied periods was associated with poor clinical outcomes. Patient-reported measures are predictive of changes in dyspnoea level.

  13. Does granulocyte colony-stimulating factor exacerbate radiation-induced acute lung injury in rats?

    Energy Technology Data Exchange (ETDEWEB)

    Miura, Gouji; Awaya, Hitomi; Matsumoto, Tsuneo; Tanaka, Nobuyuki; Matsunaga, Naofumi [Yamaguchi Univ., Ube (Japan). School of Medicine

    2000-08-01

    Radiation pneumonitis (RP) frequently occurs as a complication of thoracic irradiation. However, the mechanism of RP is not well known. Activated neutrophils are a possible pathogenesis of RP. Neutrophil activation induced by granulocyte colony-stimulating factor (G-CSF) may exacerbate RP. We studied the effects of recombinant human G-CSF on acute lung injury induced by thoracic irradiation using rats. Animals were divided into three groups: sham irradiation with saline control, irradiation alone, and irradiation with G-CSF. Actual irradiation was given as a single fraction of 16 Gy delivered to the right hemithorax. G-CSF at a dose of 12 {mu}g/body was administered subcutaneously once a day from 14 to 18 days after actual irradiation. Lung injury was evaluated 21 days after irradiation by bronchoalveolar lavage (BAL) fluid findings and the lung wet/dry weight (W/D) ratio. Neutrophil and lymphocyte counts in BAL fluid and the W/D ratio were significantly increased in the irradiation alone and the irradiation with G-CSF groups compared with those of the sham irradiation+saline control group. However, there was no significant difference observed between the irradiation alone and irradiation with G-CSF groups. In conclusion, this study suggests that postradiation administration of G-CSF does not exacerbate acute lung injury induced by thoracic irradiation in rats. (author)

  14. Hemostasis and Lipoprotein Indices Signify Exacerbated Lung Injury in TB With Diabetes Comorbidity.

    Science.gov (United States)

    Dong, Zhengwei; Shi, Jingyun; Dorhoi, Anca; Zhang, Jie; Soodeen-Lalloo, Adiilah K; Tan, WenLing; Yin, Hongyun; Sha, Wei; Li, Weitong; Zheng, Ruijuan; Liu, Zhonghua; Yang, Hua; Qin, Lianhua; Wang, Jie; Huang, Xiaochen; Wu, Chunyan; Kaufmann, Stefan H E; Feng, Yonghong

    2017-12-07

    Exacerbated immunopathology is a frequent consequence of TB that is complicated by diabetes mellitus (DM); however, the underlying mechanisms are still poorly defined. In the two groups of age- and sex-matched patients with TB and DM (DM-TB) and with TB and without DM, we microscopically evaluated the areas of caseous necrosis and graded the extent of perinecrotic fibrosis in lung biopsies from the sputum smear-negative (SN) patients. We scored acid-fast bacilli in sputum smear-positive (SP) patients and compiled CT scan data from both the SN and SP patients. We compared inflammatory biomarkers and routine hematologic and biochemical parameters. Binary logistic regression analyses were applied to define the indices associated with the extent of lung injury. Enlarged caseous necrotic areas with exacerbated fibrotic encapsulations were found in SN patients with DM-TB, consistent with the higher ratio of thick-walled cavities and more bacilli in the sputum from SP patients with DM-TB. Larger necrotic foci were detected in men compared with women within the SN TB groups. Significantly higher fibrinogen and lower high-density lipoprotein cholesterol (HDL-C) were observed in SN patients with DM-TB. Regression analyses revealed that diabetes, activation of the coagulation pathway (shown by increased platelet distribution width, decreased mean platelet volume, and shortened prothrombin time), and dyslipidemia (shown by decreased low-density lipoprotein cholesterol, HDL-C, and apolipoprotein A) are risk factors for severe lung lesions in both SN and SP patients with TB. Hemostasis and dyslipidemia are associated with granuloma necrosis and fibroplasia leading to exacerbated lung damage in TB, especially in patients with DM-TB. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  15. Non-diabetic hyperglycemia exacerbates disease severity in Mycobacterium tuberculosis infected guinea pigs.

    Directory of Open Access Journals (Sweden)

    Brendan K Podell

    Full Text Available Hyperglycemia, the diagnostic feature of diabetes also occurs in non-diabetics associated with chronic inflammation and systemic insulin resistance. Since the increased risk of active TB in diabetics has been linked to the severity and duration of hyperglycemia, we investigated what effect diet-induced hyperglycemia had on the severity of Mycobacterium tuberculosis (Mtb infection in non-diabetic guinea pigs. Post-prandial hyperglycemia was induced in guinea pigs on normal chow by feeding a 40% sucrose solution daily or water as a carrier control. Sucrose feeding was initiated on the day of aerosol exposure to the H37Rv strain of Mtb and continued for 30 or 60 days of infection. Despite more severe hyperglycemia in sucrose-fed animals on day 30, there was no significant difference in lung bacterial or lesion burden until day 60. However the higher spleen and lymph node bacterial and lesion burden at day 30 indicated earlier and more severe extrapulmonary TB in sucrose-fed animals. In both sucrose- and water-fed animals, serum free fatty acids, important mediators of insulin resistance, were increased by day 30 and remained elevated until day 60 of infection. Hyperglycemia mediated by Mtb infection resulted in accumulation of advanced glycation end products (AGEs in lung granulomas, which was exacerbated by sucrose feeding. However, tissue and serum AGEs were elevated in both sucrose and water-fed guinea pigs by day 60. These data indicate that Mtb infection alone induces insulin resistance and chronic hyperglycemia, which is exacerbated by sucrose feeding. Moreover, Mtb infection alone resulted in the accumulation tissue and serum AGEs, which are also central to the pathogenesis of diabetes and diabetic complications. The exacerbation of insulin resistance and hyperglycemia by Mtb infection alone may explain why TB is more severe in diabetics with poorly controlled hyperglycemia compared to non-diabetics and patients with properly controlled

  16. Physical symptoms of chronic fatigue syndrome are exacerbated by the stress of Hurricane Andrew.

    Science.gov (United States)

    Lutgendorf, S K; Antoni, M H; Ironson, G; Fletcher, M A; Penedo, F; Baum, A; Schneiderman, N; Klimas, N

    1995-01-01

    This study examined the effects of Hurricane Andrew on physical symptoms and functional impairments in a sample of chronic fatigue syndrome (CFS) patients residing in South Florida. In the months after Hurricane Andrew (September 15-December 31, 1992), 49 CFS patients were assessed for psychosocial and physical functioning with questionnaires, interviews, and physical examinations. This sample was made up of 25 CFS patients living in Dade county, a high impact area, and 24 patients in Broward and Palm Beach counties, areas less affected by the hurricane. Based on our model for stress-related effects on CFS, we tested the hypothesis that the patients who had the greatest exposure to this natural disaster would show the greatest exacerbation in CFS symptoms and related impairments in activities of daily living (illness burden). In support of this hypothesis, we found that the Dade county patients showed significant increases in physician-rated clinical relapses and exacerbations in frequency of several categories of self-reported CFS physical symptoms as compared to the Broward/Palm Beach county patients. Illness burden, as measured on the Sickness Impact Profile, also showed a significant increase in the Dade county patients. Although extent of disruption due to the storm was a significant factor in predicting relapse, the patient's posthurricane distress response was the single strongest predictor of the likelihood and severity of relapse and functional impairment. Additionally, optimism and social support were significantly associated with lower illness burden after the hurricane, above and beyond storm-related disruption and distress responses. These findings provide information on the impact of environmental stressors and psychosocial factors in the exacerbation of CFS symptoms.

  17. Acute exacerbated COPD: room for improvement in key elements of care

    Directory of Open Access Journals (Sweden)

    Markun S

    2017-10-01

    Full Text Available Stefan Markun,1,* Daniel P Franzen,2,* Kaba Dalla Lana,1 Swantje Beyer,3 Stephan Wieser,4 Thomas Hess,3 Malcolm Kohler,2 Thomas Rosemann,1 Oliver Senn,1 Claudia Steurer-Stey1,5 1Institute of Primary Care, 2Department of Pneumology, University Hospital Zurich, University of Zurich, Zurich, 3Department of Pneumology, Cantonal Hospital of Winterthur, Winterthur, 4Department of Pneumology, City Hospital Waid, 5MediX Group Practice Ltd, Zurich, Switzerland *These authors contributed equally to this work Introduction: Hospitalizations because of acute exacerbated COPD (AECOPD are a major burden to patients and the health care system. Interventions during acute and post-acute hospital care exist not only to improve short-term outcomes but also to prevent future exacerbations and disease progression. We aimed at measuring the implementation rates of acute and post-acute hospital care interventions for AECOPD.Methods: We performed 24 months (January 1, 2012, to December 31, 2013 retrospective medical chart review of consecutive cases hospitalized to one of three public hospitals in the canton of Zurich due to AECOPD. Implementation rates of five acute care and seven post-acute care interventions were assessed.Results: Data from 263 hospitalizations (61% male, mean age 68.5 years, 47% active smokers were analyzed. The median length of stay was 9 days (interquartile range [IQR] 6–12 days. In all, 32% of hospitalizations were caused by individuals with previous hospitalizations because of AECOPD. Implementation rates of four acute care interventions were >75% (lowest was appropriate antibiotic therapy with 56%. Compared to this, implementation rates of five post-acute care interventions were <25% (lowest was patient education and self-management advice with 2%.Conclusion: The results of this audit revealed room for improvement mainly in post-acute care interventions for AECOPD. Keywords: audit, COPD, exacerbation, guideline adherence, hospital

  18. The calcineurin inhibitor Sarah (Nebula exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Soojin Lee

    2016-03-01

    Full Text Available Expression of the Down syndrome critical region 1 (DSCR1 protein, an inhibitor of the Ca2+-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS or Alzheimer's disease (AD. Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula, a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi, exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  19. Predicting an asthma exacerbation in children 2 to 5 years of age

    DEFF Research Database (Denmark)

    Swern, A.S.; Tozzi, C.A.; Knorr, B.

    2008-01-01

    BACKGROUND: Asthma exacerbations in young children are prevalent. Identification of symptoms or other factors that are precursors of asthma exacerbations would be useful for early treatment and prevention. OBJECTIVES: To determine whether diary symptoms and beta2-agonist use before an exacerbation...... could predict an asthma exacerbation in children 2 to 5 years of age. METHODS: Post hoc analyses were conducted on data collected in a study of 689 patients 2 to 5 years of age with asthma symptoms, randomly assigned to montelukast, 4 mg, or placebo daily for 12 weeks. During the study, 196 patients had...... of an exacerbation. These methods predicted 149 (66.8%) of the exacerbations with a very low false-positive rate of 14.2%. CONCLUSIONS: No individual symptom was predictive of an imminent asthma exacerbation, but a combination of increased daytime cough, daytime wheeze, and nighttime beta2-agonist use 1 day before...

  20. Will climate change exacerbate water stress in Central Asia?

    DEFF Research Database (Denmark)

    Siegfried, Tobias; Bernauer, Thomas; Guiennet, Renaud

    2012-01-01

    Millions of people in the geopolitically important region of Central Asia depend on water from snow- and glacier-melt driven international rivers, most of all the Syr Darya and Amu Darya. The riparian countries of these rivers have experienced recurring water allocation conflicts ever since...... the Soviet Union collapsed. Will climate change exacerbate water stress and thus conflicts? We have developed a coupled climate, land-ice and rainfall-runoff model for the Syr Darya to quantify impacts and show that climatic changes are likely to have consequences on runoff seasonality due to earlier snow-melt...

  1. [Vaccinoprophylaxis of chronic somatic diseases exacerbations in groups of risk].

    Science.gov (United States)

    Semenov, B F; Zverev, V V

    2010-01-01

    Modem version of I. Mechnikov's hypothesis on association of somatic diseases with infectious agents is presented. List of bacteria and viruses associated with various types of cardiomyopathies, atherosclerosis, gastritis, gastric and duodenal ulcerative disease, type 1 diabetes mellitus. Literature data showing that influenza vaccination reduces number of fatal myocardial infarctions and strokes during winter seasons as well as number of hospitalizations due to exacerbations of chronic cardiovascular and cerebrovascular diseases are summarized. Data on probability of coincidence of influenza vaccination and sudden death in elderly persons are reviewed.

  2. The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Patel NR

    2018-03-01

    Full Text Available Naimish R Patel,1,2 Danen M Cunoosamy,1 Malin Fagerås,1 Ziad Taib,1 Sara Asimus,1 Tove Hegelund-Myrbäck,1 Sofia Lundin,1 Katerina Pardali,1 Nisha Kurian,1 Eva Ersdal,1 Cecilia Kristensson,1 Katarina Korsback,1 Robert Palmér,1 Mary N Brown,3 Steven Greenaway,4 Leonard Siew,4 Graham W Clarke,4,5 Stephen I Rennard,6,7 Barry J Make,8 Robert A Wise,9 Paul Jansson11Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA, 3Innovative Medicines and Early Development, AstraZeneca, Boston, MA, USA; 4Quintiles Drug Research Unit at Guy’s Hospital, London, 5Department of Cardiothoracic Pharmacology, NHLI, Imperial College London, London, UK; 6Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska, Omaha, NE, USA; 7Clinical Discovery Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK; 8Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, 9Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USABackground: p38 mitogen-activated protein kinase (MAPK plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls

  3. Incidence and outcomes of patients hospitalized with COPD exacerbation with and without pneumonia

    Directory of Open Access Journals (Sweden)

    Søgaard M

    2016-03-01

    Full Text Available Mette Søgaard,1 Morten Madsen,1 Anders Løkke,2 Ole Hilberg,2 Henrik Toft Sørensen,1 Reimar W Thomsen1 1Department of Clinical Epidemiology, 2Department of Respiratory Medicine, Aarhus University Hospital, Aarhus C, Denmark Background: Pneumonia may be a major contributor to hospitalizations for chronic obstructive pulmonary disease (COPD exacerbation and influence their outcomes.Methods: We examined hospitalization rates, health resource utilization, 30-day mortality, and risk of subsequent hospitalizations for COPD exacerbations with and without pneumonia in Denmark during 2006–2012.Results: We identified 179,759 hospitalizations for COPD exacerbations, including 52,520 first-time hospitalizations (29.2%. Pneumonia was frequent in first-time exacerbations (36.1%, but declined in successive exacerbations to 25.6% by the seventh or greater exacerbation. Pneumonic COPD exacerbations increased 20% from 0.92 per 1,000 population in 2006 to 1.10 per 1,000 population in 2012. Nonpneumonic exacerbations decreased by 6% from 1.74 per 1,000 population to 1.63 per 1,000 population during the same period. A number of markers of health resource utilization were more prevalent in pneumonic exacerbations than in nonpneumonic exacerbations: length of stay (median 7 vs 4 days, intensive care unit admission (7.7% vs 12.5%, and several acute procedures. Thirty-day mortality was 12.1% in first-time pneumonic COPD exacerbations versus 8.3% in first-time nonpneumonic cases (adjusted HR [aHR] 1.20, 95% confidence interval [CI] 1.17–1.24. Pneumonia also predicted increased mortality associated with a second exacerbation (aHR 1.14, 95% CI 1.11–1.18, and up to a seventh or greater exacerbation (aHR 1.10, 95% CI 1.07–1.13. In contrast, the aHR of a subsequent exacerbation was 8%–13% lower for patients with pneumonic exacerbations.Conclusions: Pneumonia is frequent among patients hospitalized for COPD exacerbations and is associated with increased health care

  4. Experiencia con las reacciones adversas asociadas con el interferón alfa 2b recombinante en hematología Experience with the adverse reactions associated with recombinant alpha 2b interferon in hematology

    Directory of Open Access Journals (Sweden)

    Idalmis Brito Pascual

    2005-08-01

    Full Text Available El interferón alfa 2b es una citoquina con actividad antiviral, antiproliferativa e inmunomoduladora que ha demostrado ser eficaz para el tratamiento de enfermedades virales y neoplásicas. El presente trabajo se realizó con el propósito de describir la frecuencia de las reacciones adversas asociada con la administración de Heberon alfa R (interferón alfa 2b recombinante en enfermedades hematológicas. Se analizaron las características de base de los pacientes, así como la frecuencia, intensidad y relación de causalidad de los eventos reportados. Los eventos adversos más frecuentes fueron las manifestaciones del síndrome gripal que incluyó fiebre, escalofrío, astenia, mialgias, anorexia y cefalea. Estas manifestaciones son transitorias y responden al tratamiento con antiinflamatorios no esteroideos. La mayoría de los eventos fueron de intensidad leve a moderada y no requirieron la suspensión del tratamiento. En conclusión, el Heberon alfa R es un fármaco relativamente seguro para el tratamiento de trastornos hematológicosAlpha 2b interferon is a cytokine with antiviral, antiproliferative and immunomodulator activity that has proved to be efficient for the treatment of viral and neoplastic diseases, This paper is aimed at describing the frequency of adverse reactions associated with the administration of alpha R Heberon (recombinant alpha 2b interferon in hematological diseases. The basic characteristics of the patients, as well as the frequency, intensity and causality relation of the reported events were analyzed. The most common adverse effects were the manifestations of the gripal syndrome that included fever, chills, astenia, myalgia, anorexia and headache. These manifestations are transitory and respond to the treatment with non-steroideal antiinflammatory drugs. Most of the events were from mild to moderate intensity and did not require the suspension of the treatment. To conclude, alpha R Heberon is a relatively safe drug

  5. Microangiopathy triggers, and inducible nitric oxide synthase exacerbates dextran sulfate sodium-induced colitis.

    Science.gov (United States)

    Saijo, Hiroki; Tatsumi, Norifumi; Arihiro, Seiji; Kato, Tomohiro; Okabe, Masataka; Tajiri, Hisao; Hashimoto, Hisashi

    2015-07-01

    Ulcerative colitis (UC) is a representative clinical manifestation of inflammatory bowel disease that causes chronic gastrointestinal tract inflammation. Dextran sulfate sodium (DSS)-induced colitis mice have been used to investigate UC pathogenesis, and in this UC model, disturbance and impairment of the mucosal epithelium have been reported to cause colitis. However, how DSS sporadically breaks down the epithelium remains unclear. In this study, we focused on the colonic microcirculation and myenteric neurons of DSS-induced colitis. Moreover, we examined the potential of myenteric neurons as a target to prevent exacerbation of colitis. Fluorescent angiographic and histopathological studies revealed that DSS administration elicited blood vessel disruption before epithelial disorders appeared. Ischemic conditions in the lamina propria induced inducible nitric oxide synthase (iNOS) expression in myenteric neurons as colitis aggravated. When neuronal activity was inhibited with butylscopolamine, neuronal iNOS expression decreased, and the exacerbation of colitis was prevented. These results suggested that DSS-induced colitis was triggered by microcirculatory disturbance in the mucosa, and that excessive neuronal excitation aggravated colitis. During remission periods of human UC, endoscopic inspection of the colonic microcirculation may enable the early detection of disease recurrence, and inhibition of neuronal iNOS expression may prevent the disease from worsening.

  6. 5-Aminosalicylate intolerance causing exacerbation in pediatric ulcerative colitis.

    Science.gov (United States)

    Shimizu, Hirotaka; Arai, Katsuhiro; Tang, Julian; Hosoi, Kenji; Funayama, Rie

    2017-05-01

    5-Aminosalicylate (5-ASA) is widely used as the first-line drug for ulcerative colitis (UC). 5-ASA is mostly a safe and effective drug, but it can bring about exacerbation due to 5-ASA intolerance. 5-ASA intolerance can be confusing and it can mislead physicians into considering unnecessary treatment escalation, including corticosteroid (CS), biologics, or even surgery. In spite of the clinical importance of 5-ASA intolerance, there have been few studies on its incidence, clinical features, and diagnosis. In order to evaluate the incidence, characteristic symptoms, disease course, and laboratory data of children with 5-ASA intolerance, we retrospectively reviewed the medical records of 80 children with UC. Eleven of 80 children (13.8%) with UC were diagnosed with 5-ASA intolerance. The median time between the initiation of 5-ASA and the onset of 5-ASA intolerance was 10 days (range, 4-20 days) in patients not receiving CS. Drug-induced lymphocyte stimulation test (DLST) was performed in 10 patients, and was positive in eight. C-reactive protein (CRP) increased significantly when exacerbation of colitis symptoms occurred. The incidence of 5-ASA intolerance was relatively high. Besides the challenge test, elevation of CRP and positive DLST appeared to support the diagnosis of 5-ASA intolerance. © 2017 Japan Pediatric Society.

  7. Acute exacerbation in chronic hepatitis B virus infection

    Directory of Open Access Journals (Sweden)

    Marcio Vieira Santos

    1996-06-01

    Full Text Available A case of an acute exacerbation of liver injury in a chronic HBV infected young male is reported. The correlation between the severe symptomatic hepatitis is done with the histopathologic findings of extense areas of bridging necrosis on the Iwer biopsy. The serological pattern for markers of HBV (HBsAg +, anti HBs g -, HBeAg -, anti HBe +, anti HBcIgG + and IgM - confirm a chronic infection, ana the authors propose that the episode of severe hepatitis relates to the recent spontaneous seroconvertion of HBe Ag to anti HBe. Other causes of hepatitis were excluded, and the control liver biopsy (6 months later showed normalization of hepatic architecture and absence of markers of viral replication in tissue and serum. A review of literature is done in an attempt to elucidate the diagnostic possibilities in this case, with emphasis on new immunoassays useful in differentiating between acute hepatitis B and acute exacerbation of a chronic hepatitis by the same virus.

  8. Tic Exacerbation in Adults with Tourette Syndrome: A Case Series

    Directory of Open Access Journals (Sweden)

    Sara M. Schaefer

    2017-03-01

    Full Text Available Background: Tourette syndrome (TS has been described as peaking in adolescence with subsequent regression. We report patients who were diagnosed with TS during childhood who experienced a latent period (significant reduction in or absence of tics followed by tic re-emergence in adulthood.Methods: We performed a retrospective chart review of outpatients over age 21 seen at the Yale neurology clinic between January 2012 and July 2016 who were diagnosed with childhood-onset tics, and who experienced a latent period of greater than 1 year followed by an exacerbation.Results: Sixteen patients were identified. The mean latent period was 16 years. Ten patients (62.5% identified an exacerbation trigger, most commonly changes in substance use (five patients. Seven patients (43.8% reported worsening of tics since childhood. Six patients (37.5% had received pharmacological intervention for tics as children, and 15 patients (93.8% as adults. Six of 15 patients (40.0% had an effective response from those pharmacological intervention(s.Discussion: Our study demonstrates that the decline in symptoms as patients age may represent temporary improvement. The latent period lasted years in our patients, different from the more rapid waxing and waning in children. A change in substance use was an important trigger. Requests for pharmacological intervention were not necessarily correlated with worsening tic severity. 

  9. Tic Exacerbation in Adults with Tourette Syndrome: A Case Series.

    Science.gov (United States)

    Schaefer, Sara M; Chow, Christopher A; Louis, Elan D; Robakis, Daphne

    2017-01-01

    Tourette syndrome (TS) has been described as peaking in adolescence with subsequent regression. We report patients who were diagnosed with TS during childhood who experienced a latent period (significant reduction in or absence of tics) followed by tic re-emergence in adulthood. We performed a retrospective chart review of outpatients over age 21 seen at the Yale neurology clinic between January 2012 and July 2016 who were diagnosed with childhood-onset tics, and who experienced a latent period of greater than 1 year followed by an exacerbation. Sixteen patients were identified. The mean latent period was 16 years. Ten patients (62.5%) identified an exacerbation trigger, most commonly changes in substance use (five patients). Seven patients (43.8%) reported worsening of tics since childhood. Six patients (37.5%) had received pharmacological intervention for tics as children, and 15 patients (93.8%) as adults. Six of 15 patients (40.0%) had an effective response from those pharmacological intervention(s). Our study demonstrates that the decline in symptoms as patients age may represent temporary improvement. The latent period lasted years in our patients, different from the more rapid waxing and waning in children. A change in substance use was an important trigger. Requests for pharmacological intervention were not necessarily correlated with worsening tic severity.

  10. Exacerbation of bronchiectasis by Pseudomonas monteilii: a case report.

    Science.gov (United States)

    Aditi; Shariff, Malini; Beri, Kiran

    2017-07-24

    Pseudomonas spp are important opportunistic and nosocomial pathogens. One such species is Pseudomonas monteilii (P. monteilii). It has been described as an environmental contaminant and potential pathogen. We identified this organism as the causative agent of an exacerbation of bronchiectasis and an environmental contaminant in our hospital on two separate occasions. P. monteilii was the cause of an exacerbation of bronchiectasis in a 30-year-old HIV negative male. Patient presented with cough with sputum production and exertional dyspnea. The isolate was recovered from a sputum sample in significant counts and definitively identified by Matrix-Assisted Laser Desorption/Ionisation- Time of Flight Mass Spectrometry (MALDI-TOF MS). He was treated with piperacillin-tazobactam and recovered clinically and microbiologically. Another two isolates of the organism were contaminants from the hospital environment. The three isolates were susceptible to all tested antibiotics. Typing by Random amplification of polymorphic DNA (RAPD) found no clonal relationship between them. Less common species of Pseudomonas need to be identified accurately. This organism is identified by commonly used phenotypic systems as P. putida which may have contributed to a lower reported prevalence. P. monteilii is a known environmental contaminant and must also be considered as a potential pathogen, particularly in patients with chronic lung disease.

  11. POSSIBILITY TO APPLY LIPOSOMAL ALPHA-2B INTERFERON FOR THE PREVENTION OF FLU AND OTHER ACUTE RESPIRATORY INFECTIONS

    Directory of Open Access Journals (Sweden)

    M.K. Erofeeva

    2007-01-01

    Full Text Available Within recent years, a special attention has been paid to the nonspecific prevention of the acute respiratory disease related to the increase of the activity of the natural mechanisms for antiviral protection. The application of the liposomal forms of the different medications contributes to the directed transportation of the biodegraded protein substances. A special interest is aroused by the opportunity to orally apply protein medications, as their injection forms quickly degrade in the stomach. New Russian liposomal recombinant alphac2b interferon has antiviral, immuno-modulating and interferonogenic activity. The work demonstrates experience of the oral application form of the liposomal medication of recombinant alphac2b interferon — reaferoncesclipint for the extra prevention of flu and other acute respiratory infections among children. The application of this medication to prevent flu and acute respiratory infections in the dose of 250,000 Ме twice a week for the 4 weeks' period proved to be efficient within the group of the preschool children (aged between 7–10 years old and manifested itself in the reduction of the flu and acute respiratory infections recurrence.Key words: flu, prevention, efficiency index, interferon.

  12. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Höglund, A Urban

    2004-01-01

    in the rat. Spinal microdialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or without nicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptors were investigated. It was found that clonidine...... and rilmenidine increased, while yohimbine decreased spinal acetylcholine release. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade attenuated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand......, all ligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curve and rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested alpha2-adrenergic receptor ligands affect intraspinal acetylcholine...

  13. MicroRNA Expression Profiling by Bead Array Technology in Human Tumor Cell Lines Treated with Interferon-Alpha-2a

    Directory of Open Access Journals (Sweden)

    Siegrist Fredy

    2009-01-01

    Full Text Available Abstract MicroRNAs are positive and negative regulators of eukaryotic gene expression that modulate transcript abundance by specific binding to sequence motifs located prevalently in the 3' untranslated regions of target messenger RNAs (mRNA. Interferon-alpha-2a (IFNα induces a large set of protein coding genes mediating antiproliferative and antiviral responses. Here we use a global microarray-based microRNA detection platform to identify genes that are induced by IFNα in hepatoma- or melanoma-derived human tumor cell lines. Despite the enormous differences in expression levels between these models, we were able to identify microRNAs that are upregulated by IFNα in both lines suggesting the possibility that interferon-regulated microRNAs are involved in the transcriptional repression of mRNA relevant to cytokine responses.

  14. INDUCTION OF PROTEIN DROPLET (ALPHA(2-MU)-GLOBULIN) NEPHROPATHY IN MALE-RATS AFTER SHORT-TERM DOSAGE WITH 1,8-CINEOLE AND L-LIMONENE

    DEFF Research Database (Denmark)

    Kristiansen, E.; Madsen, Charlotte Bernhard

    1995-01-01

    As part of a series of short-term studies on peppermint oil constituents for their possible induction of the encephalopathy found with peppermint oil, 1,8-cineole and l-limonene were studied. Groups of 10 male Wistar rats were given 0, 500, or 1000 mg 1,8-cineole/kg body wt./day or 0, 800, or 1600...... mg l-limonene/kg body wt./day for 2& days. 1,8-Cineole and l-limonene both induced accumulation of protein droplets containing alpha(2 mu)-globulin in proximal tubular epithelial cells in male rats. These results suggest that both 1,8-cineole and I-limonene possibly belong to the group of chemicals...

  15. Genetic impairment of AMPK{alpha}2 signaling does not reduce muscle glucose uptake during treadmill exercise in mice

    DEFF Research Database (Denmark)

    Maarbjerg, Stine Just; Jørgensen, Sebastian Beck; Rose, Adam John

    2009-01-01

    Some studies suggest that the 5'-AMP-activated protein kinase (AMPK) is important in regulating muscle glucose uptake in response to intense electrically stimulated contractions. However, it is unknown if AMPK regulates muscle glucose uptake during in vivo exercise. We studied this in male and fe...... signaling is not essential in regulating glucose uptake in mouse skeletal muscle during treadmill exercise and that other unknown mechanisms play a central role. Key words: exercise, glucose uptake, AMPK.......-KD mouse. Muscle glucose clearance was measured using [3H]-2-deoxy-glucose as tracer. In wildtype mice glucose clearance was increased at 30% and 70% of maximal running speed by 40% and 350% in the quadriceps muscle, and by 120% and 380% in gastrocnemius muscle, respectively. Glucose clearance...

  16. Factors influencing exacerbation-related self-management in patients with COPD: a qualitative study.

    Science.gov (United States)

    Korpershoek, Yjg; Vervoort, Scjm; Nijssen, Lit; Trappenburg, Jca; Schuurmans, M J

    2016-01-01

    In patients with COPD, self-management skills are important to reduce the impact of exacerbations. However, both detection and adequate response to exacerbations appear to be difficult for some patients. Little is known about the underlying process of exacerbation-related self-management. Therefore, the objective of this study was to identify and explain the underlying process of exacerbation-related self-management behavior. A qualitative study using semi-structured in-depth interviews was performed according to the grounded theory approach, following a cyclic process in which data collection and data analysis alternated. Fifteen patients (male n=8; age range 59-88 years) with mild to very severe COPD were recruited from primary and secondary care settings in the Netherlands, in 2015. Several patterns in exacerbation-related self-management behavior were identified, and a conceptual model describing factors influencing exacerbation-related self-management was developed. Acceptance, knowledge, experiences with exacerbations, perceived severity of symptoms and social support were important factors influencing exacerbation-related self-management. Specific factors influencing recognition of exacerbations were heterogeneity of exacerbations and habituation to symptoms. Feelings of fear, perceived influence on exacerbation course, patient beliefs, ambivalence toward treatment, trust in health care providers and self-empowerment were identified as specific factors influencing self-management actions. This study provided insight into factors influencing exacerbation-related self-management behavior in COPD patients. The conceptual model can be used as a framework for health care professionals providing self-management support. In the development of future self-management interventions, factors influencing the process of exacerbation-related self-management should be taken into account.

  17. The role of pneumococcal infection in development of exacerbations in children with bronchial asthma and obstructive bronchitis

    Directory of Open Access Journals (Sweden)

    N.V. Kukhtinova

    2011-01-01

    Full Text Available Pneumococcal infection remains the key cause of severe diseases of lower airways and deaths in children. The objective: to study the role of pneumococcal infection in pathogenesis of exacerbations of recurrent obstructive pulmonary diseases. Methods: etiological structure of lower airways infections was evaluated in 125 patients 1–15 years old with bronchial asthma or recurrent bronchitis. Results: etiologic role of Streptococcus pneumoniae in development of low airways infections was detected in 48% of patients with atopic asthma, 85% — with asthma without atopy, 97% — with recurrent bronchitis. Repeated microbiological examination confirmed chronic carriage of S. рneumoniae in nasopharinx in 31% of patients. Conclusion: early active prophylaxis with vaccine against pneumococcal infection including conjugated vaccines is able to prevent further progression of a disease.Key words: children, bronchial asthma, obstructive bronchitis, exacerbation, pneumococcal infection.

  18. Cingulate Alpha-2A Adrenoceptors Mediate the Effects of Clonidine on Spontaneous Pain Induced by Peripheral Nerve Injury

    Directory of Open Access Journals (Sweden)

    Yong-Jie Wang

    2017-09-01

    Full Text Available The anterior cingulate cortex (ACC is an important brain area for the regulation of neuropathic pain. The α2A adrenoceptor is a good target for pain management. However, the role of cingulate α2A adrenoceptors in the regulation of neuropathic pain has been less studied. In this study, we investigated the involvement of cingulate α2A adrenoceptors in the regulation of neuropathic pain at different time points after peripheral nerve injury in mice. The application of clonidine, either systemically (0.5 mg/kg intraperitoneally or specifically to the ACC, increased paw withdrawal thresholds (PWTs and induced conditioned place preference (CPP at day 7 after nerve injury, suggesting that cingulate α2 adrenoceptors are involved in the regulation of pain-like behaviors. Quantitative real-time PCR data showed that α2A adrenoceptors are the dominant α2 adrenoceptors in the ACC. Furthermore, the expression of cingulate α2A adrenoceptors was increased at day 3 and day 7 after nerve injury, but decreased at day 14, while no change was detected in the concentration of adrenaline or noradrenaline. BRL-44408 maleate, a selective antagonist of α2A adrenoceptors, was microinfused into the ACC. This blocking of cingulate α2A adrenoceptors activity abolished the CPP induced by clonidine (0.5 mg/kg intraperitoneally but not the effects on PWTs at day 7. However, clonidine applied systemically or specifically to the ACC at day 14 increased the PWTs but failed to induce CPP; this negative effect was reversed by the overexpression of cingulate α2A adrenoceptors. These results suggest that cingulate α2A adrenoceptors are necessary for the analgesic effects of clonidine on spontaneous pain.

  19. Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injury

    Directory of Open Access Journals (Sweden)

    Nagai Atsushi

    2011-06-01

    Full Text Available Abstract Background Genotoxic stress, such as by exposure to bromodeoxyuridine (BrdU and cigarette smoke, induces premature cell senescence. Recent evidence indicates that cellular senescence of various types of cells is accelerated in COPD patients. However, whether the senescence of airway epithelial cells contributes to the development of airway diseases is unknown. The present study was designed to test the hypothesis that premature senescence of airway epithelial cells (Clara cells impairs repair processes and exacerbates inflammation after airway injury. Methods C57/BL6J mice were injected with the Clara-cell-specific toxicant naphthalene (NA on days 0, 7, and 14, and each NA injection was followed by a daily dose of BrdU on each of the following 3 days, during which regenerating cells were allowed to incorporate BrdU into their DNA and to senesce. The p38 MAPK inhibitor SB202190 was injected 30 minutes before each BrdU dose. Mice were sacrificed at different times until day 28 and lungs of mice were obtained to investigate whether Clara cell senescence impairs airway epithelial regeneration and exacerbates airway inflammation. NCI-H441 cells were induced to senesce by exposure to BrdU or the telomerase inhibitor MST-312. Human lung tissue samples were obtained from COPD patients, asymptomatic smokers, and nonsmokers to investigate whether Clara cell senescence is accelerated in the airways of COPD patients, and if so, whether it is accompanied by p38 MAPK activation. Results BrdU did not alter the intensity of the airway epithelial injury or inflammation after a single NA exposure. However, after repeated NA exposure, BrdU induced epithelial cell (Clara cell senescence, as demonstrated by a DNA damage response, p21 overexpression, increased senescence-associated β-galactosidase activity, and growth arrest, which resulted in impaired epithelial regeneration. The epithelial senescence was accompanied by p38 MAPK-dependent airway

  20. Prediction of exacerbation chronic bronchopulmonary diseases in children with influenza

    Directory of Open Access Journals (Sweden)

    O. I. Afanaseva

    2015-01-01

    Full Text Available The objective: To develop a method for predicting exacerbation of chronic illness in children with asthma and cystic fibrosis, patients with influenza, based on the study of the dynamics of cytokines. Materials and methods: Were examined 52 patients with bronchial asthma and 45 children with cystic fibrosis at the age from 1 year to 12 years, located in infectious pulmonary Department at the planned treatment of underlying pathology, in which influenza was in-hospital infection. Control group observations included 40 patients with the flu, without concomitant pulmonary disease. The etiology of viral infection was established by detection of viral RNA in nasopharyngeal swabs by PCR. Among the influenza viruses were identified influenza АH1N1, АH3N2, influenza B, and in 2009–2010 the predominant antigen was the pandemic influenza virus АH1N1pdm09. Determination of the concentration of serum interleukins IL-1β, IL-4, IL-8, IL-10, ТNF-α, IFN-γ was performed in the 1st and 3rd day of hospitalization cytokines by the solid-phase immune-enzyme assay. Analysis of the results performed using statistical package SPSS 17.0 EN for Windows. Results: The flu caused the aggravation associated bronchopulmonary pathology in 2/3 of children, as MV patients, and patients with BA (65,4%-66,7%, respectively. With an increase of the ratio of IL-4 / IFN-γ and IL-10/IFN-γ, at least 5-6 times, influenza can be considered a trigger of exacerbation of chronic bronchopulmonary pathologies that require amplification of the therapy of bronchial asthma and of сystic fibrosis. The growth of prognostic coefficients in 2-3 times allows using for treatment of influenza in these patients only antiviral agents. Conclusion: The study has shown a method for predicting exacerbation of bronchial asthma and cystic fibrosis in children at an early stage of influenza by calculating the ratio of IL-4/IFN-γ and IL-10/IFN-γ in children aged from 1 year to 12 years. 

  1. The effect of transcutaneous electrical nerve stimulation in patients with acute exacerbation of chronic obstructive pulmonary disease: randomised controlled trial.

    Science.gov (United States)

    Öncü, Emine; Zincir, Handan

    2017-07-01

    The aim of the present study was to assess the efficacy of transcutaneous electrical nerve stimulation in patients with acute exacerbation of chronic obstructive pulmonary disease. In patients with stable chronic obstructive pulmonary disease, transcutaneous electrical nerve stimulation has been known to attain improvement in forced expiratory volume in 1 seconds, physical activity, and quality of life. However, information about the effects of transcutaneous electrical nerve stimulation on acute exacerbation of chronic obstructive pulmonary disease is quite limited. A single-blind, randomised controlled trial. Data were collected between August 2013-May 2014. Eighty-two patients who were hospitalised with a diagnosis of acute exacerbation of chronic obstructive pulmonary disease were randomly assigned to a transcutaneous electrical nerve stimulation group receiving transcutaneous electrical nerve stimulation treatment for 20 seance over the acupuncture points with pharmacotherapy or placebo group receiving the same treatment without electrical current output from the transcutaneous electrical nerve stimulation device. Pulmonary functional test, six-minute walking distance, dyspnoea and fatigue scale, and St. George's Respiratory Questionnaire scores were assessed pre- and postprogram. The program started at the hospital by the researcher was sustained in the patient's home by the caregiver. All patients were able to complete the program, despite the exacerbation. The 20 seance transcutaneous electrical nerve stimulation program provided clinically significant improvement in forced expiratory volume in 1 seconds 21 ml, 19·51% but when compared with the placebo group, the difference was insignificant (p > 0·05). The six-minute walking distance increased by 48·10 m more in the placebo group (p  0·05). Adding transcutaneous electrical nerve stimulation therapy to pharmacotherapy in patients with acute exacerbation of chronic obstructive pulmonary disease

  2. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.

    Science.gov (United States)

    Han, MeiLan K; Quibrera, Pedro M; Carretta, Elizabeth E; Barr, R Graham; Bleecker, Eugene R; Bowler, Russell P; Cooper, Christopher B; Comellas, Alejandro; Couper, David J; Curtis, Jeffrey L; Criner, Gerard; Dransfield, Mark T; Hansel, Nadia N; Hoffman, Eric A; Kanner, Richard E; Krishnan, Jerry A; Martinez, Carlos H; Pirozzi, Cheryl B; O'Neal, Wanda K; Rennard, Stephen; Tashkin, Donald P; Wedzicha, Jadwiga A; Woodruff, Prescott; Paine, Robert; Martinez, Fernando J

    2017-08-01

    Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV 1 . Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas

  3. [Features of Autonomic Response in Children with Bronchial Asthma in the Period of Exacerbation].

    Science.gov (United States)

    Lebedenko, A A; Semernik, O E

    2015-01-01

    Asthma is one of the urgent problems of modern pediatrics, but neuroregulation mechanisms underlying this disease have not been fully disclosed so far. The autonomic interaction assessment in patients with bronchial asthma is important to understand the pathogenesis and prognosis of the disease. The aim of this study was to investigate features of autonomic response in children with asthma in the period of exacerbation. The autonomic nervous system ANS) of 82 children aged 6 to 18 years old with asthma in the period of exacerbation were investigated. The spectral analysis of the heart rate variability and the correlation rhythmography method (skaterography) were used to assess the ANS state. Investigations were carried out at rest and after clinoorthostatic test. Non-respiratory (slow) waves reflecting (be degree of activity of humoral and neural canals of heart rate central regulation were dominated at the spectrogram of 72 (87.80%) children experiencing asthma attack; more than half of patients (58.53%) had predominantly very low-frequency component (VLF%) in the range of fluctuation rate that indicated (the influence of neurohumoral regulation. A significant increase in vagosympathetic balance coefficient (LE/HF) was recorded after clinoorthostatic test indicating the activation of the sympathetic nervous system. According to the correlation rhytlimnography data, a considerable scattering of scattergraphy points was detected in patients in (the baseline state that indicated the predominant influence of parasympathetic nervous system. After the clinoorthostatic test, on the contrary, we observed the of the scattergraphy cloud that could indicate sympathicotonia. The imbalance of the autonomic nervous system in the form of activation of the sympathetic amid neurohumoral regulation department was found in children with asthma.

  4. Fine particulate matter in acute exacerbation of COPD

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    Lei eNi

    2015-10-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is a common airway disorder. In particular, acute exacerbations of COPD (AECOPD can significantly reduce pulmonary function. The majority of AECOPD episodes are attributed to infections, although environmental stress also plays a role. Increasing urbanization and associated air pollution, especially in developing countries, have been shown to contribute to COPD pathogenesis. Elevated levels of particulate matter (PM in polluted air are strongly correlated with the onset and development of various respiratory diseases. In this review, we have conducted an extensive literature search of recent studies of the role of PM2.5 (fine PM in AECOPD. PM2.5 leads to AECOPD via inflammation, oxidative stress, immune dysfunction, and altered airway epithelial structure and microbiome. Reducing PM2.5 levels is a viable approach to lower AECOPD incidence, attenuate COPD progression and decrease the associated healthcare burden.

  5. A case of chronic urticaria exacerbating with menstrual cycles

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    Goknur Kalkan

    2013-09-01

    menstrual cycle, pregnancy, menopause and hormonal contraceptives or hormone replacement therapy. Chronic urticaria is approximately twice more frequent in women than in men. Hypersensitivity reactions to endogenous or exogenous female sex hormones have been implicated in the pathogenesis of urticarial lesions. Progesterone or estrogen-depended urticaria should be suspected in women showing eruption in cyclic interval with each menses or chronic urticarial lesions with periodic variations at different times. Here we would like to present a case of 36-year-old woman that decribes and has urticarial lesions exacerbating in menstrual periods for 12 years and remind this issue which may not take into consideration in daily practice in the pathogenesis of urticaria. Consequently, the influence of fluctuations in the hormonal milieu and altered sex hormone expression on the triggering-off, maintenance or aggravation of urticaria should be taken into account. [J Contemp Med 2013; 3(3.000: 200-202

  6. Suppression of autophagy exacerbates Mefloquine-mediated cell death.

    Science.gov (United States)

    Shin, Ji Hyun; Park, So Jung; Jo, Yoon Kyung; Kim, Eun Sung; Kang, Hee; Park, Ji-Ho; Lee, Eunjoo H; Cho, Dong-Hyung

    2012-05-02

    Mefloquine is an effective treatment drug for malaria. However, it can cause several adverse side effects, and the precise mechanism associated with the adverse neurological effects of Mefloquine is not clearly understood. In this study, we investigated the effect of Mefloquine on autophagy in neuroblastoma cells. Mefloquine treatment highly induced the formation of autophagosomes and the conversion of LC3I into LC3II. Moreover, Mefloquine-induced autophagy was efficiently suppressed by an autophagy inhibitor and by down regulation of ATG6. The autophagy was also completely blocked in ATG5 deficient mouse embryonic fibroblast cells. Moreover, suppression of autophagy significantly intensified Mefloquine-mediated cytotoxicity in SH-SY5Y cells. Our findings suggest that suppression of autophagy may exacerbate Mefloquine toxicity in neuroblastoma cells. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  7. [Etiological and exacerbation factors for COPD. Body weight loss].

    Science.gov (United States)

    Yokoyama, Akihito

    2016-05-01

    Hunger or malnutrition is not only a historical issue but also a current problem worldwide. Biological responses to hunger are evolutionary prepared in our body, including energy generation by degradation of body proteins. Extreme weight loss (malnutrition) can cause air space enlargement in human and rodents. However, the changes in rodents could be reversible, since refeeding could repair the pathology. On the other hand, weight loss is a common feature in patients with more severe COPD. Complex factors, such as increased energy consumption, decreased food uptake by low grade inflammation, socio-economic factors and so on, are involved in weight loss. Weight loss in patients with COPD also increases the risk of exacerbation, hospitalization, and death.

  8. EXACERBATION OF ANKYLOSING SPONDYLITIS AFTER LOW-DOSE METHOTREXATE THERAPY

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    A. V. Orlov-Morozov

    2014-01-01

    Full Text Available Background: Efficacy of methotrexate in ankylosing spondylitis (AS is disputable. Nevertheless, methotrexate is still used for disease-modifying therapy of AS. Aim: To assess efficacy and safety of methotrexate in AS patients. Materials and methods: It was an open comparative study of efficacy of methotrexate (n=12 versus standard therapy (n=12 in AS patients. Results: Negative results of methotrexate therapy were obtained. In the majority of patients methotrexate therapy was associated with increased joint pain, swelling and morning stiffness as well as elevation of erythrocyte sedimentation rate, fever and visceritis. Worsening of symptoms was regarded as exacerbation of inflammatory process. The study was terminated prematurely. Conclusion: Methotrexate demonstrated no therapeutic effect in AS patients. In AS, methotrexate should be administrated under close physician control in order to ensure treatment safety

  9. Potential Biomarkers for NSAID-Exacerbated Respiratory Disease

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    Hanki Park

    2017-01-01

    Full Text Available Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD is one such endotype characterized by asthma, chronic rhinosinusitis (CRS with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin-tolerant asthma. We also provided an overview of the different NERD subgroups.

  10. Delusional Disorder, Erotomanic Type, Exacerbated by Social Media Use

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    Justin Faden

    2017-01-01

    Full Text Available Erotomania is an uncommon form of delusional disorder in which an individual has an unfounded belief that another is in love with him. Previous case reports have shown that social media networks may play a role in worsening delusional beliefs. We report the case of a 24-year-old male college student that utilized social media to stalk a female college student, resulting in his suspension from school and hospitalization. The student was diagnosed with delusional disorder, erotomanic type, and started on risperidone. He showed little improvement and was transferred to another facility. This is the first identified case of social media triggering or exacerbating delusional disorder. We recommend increasing education on the ramifications of sharing personal information on social media.

  11. Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

    International Nuclear Information System (INIS)

    Schneider, Brent C.; Constant, Stephanie L.; Patierno, Steven R.; Jurjus, Rosalyn A.; Ceryak, Susan M.

    2012-01-01

    Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr

  12. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.

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    Edith T Zemanick

    Full Text Available Pulmonary exacerbations (PEx, frequently associated with airway infection and inflammation, are the leading cause of morbidity in cystic fibrosis (CF. Molecular microbiologic approaches detect complex microbiota from CF airway samples taken during PEx. The relationship between airway microbiota, inflammation, and lung function during CF PEx is not well understood.To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx.Expectorated sputum and blood were collected and lung function testing performed in CF subjects during early (0-3d. and late treatment (>7d. for PEx. Sputum was analyzed by culture, pyrosequencing of 16S rRNA amplicons, and quantitative PCR for total and specific bacteria. Sputum IL-8 and neutrophil elastase (NE; and circulating C-reactive protein (CRP were measured.Thirty-seven sputum samples were collected from 21 CF subjects. At early treatment, lower diversity was associated with high relative abundance (RA of Pseudomonas (r = -0.67, p<0.001, decreased FEV(1% predicted (r = 0.49, p = 0.03 and increased CRP (r = -0.58, p = 0.01. In contrast to Pseudomonas, obligate and facultative anaerobic genera were associated with less inflammation and higher FEV₁. With treatment, Pseudomonas RA and P. aeruginosa by qPCR decreased while anaerobic genera showed marked variability in response. Change in RA of Prevotella was associated with more variability in FEV₁ response to treatment than Pseudomonas or Staphylococcus.Anaerobes identified from sputum by sequencing are associated with less inflammation and higher lung function compared to Pseudomonas at early exacerbation. CF PEx treatment results in variable changes of anaerobic genera suggesting the need for larger studies particularly of patients without traditional CF pathogens.

  13. The Christmas Season as a Risk Factor for Chronic Obstructive Pulmonary Disease Exacerbations

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    Neil W Johnston

    2010-01-01

    Full Text Available BACKGROUND: Epidemics of hospitalization for chronic obstructive pulmonary disease (COPD occur annually during the Christmas holidays, and COPD exacerbations commonly coincide with respiratory viral infections.

  14. Clinical and laboratory aspects of diagnosis and treatment of chronic obstructive pulmonary disease infectious exacerbations in seniors of the Ministry of Defense of Ukraine

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    N. V. Popenko

    2018-02-01

    . The protected aminopenicillins and the III generation cephalosporins have remained high activity against the main pathogens of COPD exacerbation. In patients of the first group with microbiological sputum examination the number of days spent in the hospital (7.5 ± 0.36 was significantly less than in patients of the second group (11.3 ± 0.46 and the normalization of clinical and laboratory parameters after treatment was faster.

  15. Alcohol use Exacerbates Acculturative Stress Among Recently Immigrated, Young Adult Latinas.

    Science.gov (United States)

    Ertl, Melissa M; Dillon, Frank R; Martin, Jessica L; Babino, Rosa; De La Rosa, Mario

    2017-04-19

    Associations between theorized sociocultural factors and acculturative stress were examined among Latina immigrants (aged 18-23 years) during their initial months in the US. Participants' quantity of alcohol use was hypothesized to be linked with more acculturative stress. Using respondent-driven sampling, 530 Latinas who recently immigrated to Miami-Dade County, Florida, were recruited from community activities, Latino health fairs, advertisements at community agencies, and online postings. A path analysis revealed associations between acculturative stress and more time in the US and greater commitment to ethnic identity. Marianismo gender role beliefs differentially related with acculturative stress. Quantity of alcohol use moderated the positive association between time in US and acculturative stress, such that women in the US for less time who drank more alcohol experienced higher levels of acculturative stress than their peers. Findings suggest quantity of alcohol use may exacerbate acculturative stress during some Latina young adult immigrants' initial months in the US.

  16. Pegylated interferon alpha-2a combined with ribavirin for chronic hepatitis C: a clinical analysis of 160 patients of Uygur nationality or Han nationality

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    LIN Wei

    2015-11-01

    Full Text Available ObjectiveTo investigate the influencing factors for achieving sustained virological response (SVR to pegylated interferon alpha-2a combined with ribavirin in Uygur and Han patients with chronic hepatitis C, and to provide a reference for predicting the treatment of chronic hepatitis C in Uygur and Han patients. MethodsA retrospective analysis was performed on the clinical data of 160 patients (80 cases of Uygur nationality and 80 cases of Han nationality with chronic hepatitis C who received pegylated interferon alpha-2a combined with ribavirin in the Infectious Disease Hospital in Hetian from January 2012 to March 2014. All patients were followed up for 24 weeks after 48 weeks of treatment. The two groups were compared in terms of the ratios of rapid virological response (RVR, early virological response (EVR, end treated virus response (ETVR, SVR, and no response (NR. The factors which might influence achieving SVR to interferon therapy in the two groups were subjected to univariate analysis and multivariate analysis (conditional logistic regression. For normally distributed continuous data, the comparison was made by t test, and Wilcoxon rank-sum test was made for abnormally distributed continuous data. The comparison of categorical data was made by chi-square test. And univariate analysis and multivariate analysis (conditional logistic regression were carried out. ResultsThere were no significant differences in the rates of RVR (48.8% vs 60.0%, P>0.05, EVR (53.8% vs 63.8%, P>0.05, ETVR (72.5% vs 78.7%, P>0.05, SVR (63.8% vs 72.5%, P>0.05, and NR (27.5% vs 213%, P>0.05 between Uygur group and Han group. The univariate analysis showed that age and age>40 years were the influencing factors for all patients′ SVR (P<0.05. Age>40 years and HCV RNA level>1×106 copies/ml were the influencing factors for Uygur patients′ SVR (P<0.05. Male sex, age, and age>50 years were the influencing factors for Han patients′ SVR (P

  17. Blocking rpS6 Phosphorylation Exacerbates Tsc1 Deletion–Induced Kidney Growth

    Science.gov (United States)

    Wu, Huijuan; Chen, Jianchun; Xu, Jinxian; Dong, Zheng; Meyuhas, Oded

    2016-01-01

    The molecular mechanisms underlying renal growth and renal growth–induced nephron damage remain poorly understood. Here, we report that in murine models, deletion of the tuberous sclerosis complex protein 1 (Tsc1) in renal proximal tubules induced strikingly enlarged kidneys, with minimal cystogenesis and occasional microscopic tumorigenesis. Signaling studies revealed hyperphosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and increased phosphorylation of ribosomal protein S6 (rpS6) in activated renal tubules. Notably, knockin of a nonphosphorylatable rpS6 in these Tsc1-mutant mice exacerbated cystogenesis and caused drastic nephron damage and renal fibrosis, leading to kidney failure and a premature death rate of 67% by 9 weeks of age. In contrast, Tsc1 single-mutant mice were all alive and had far fewer renal cysts at this age. Mechanistic studies revealed persistent activation of mammalian target of rapamycin complex 1 (mTORC1) signaling causing hyperphosphorylation and consequent accumulation of 4E-BP1, along with greater cell proliferation, in the renal tubules of Tsc1 and rpS6 double-mutant mice. Furthermore, pharmacologic treatment of Tsc1 single-mutant mice with rapamycin reduced hyperphosphorylation and accumulation of 4E-BP1 but also inhibited phosphorylation of rpS6. Rapamycin also exacerbated cystic and fibrotic lesions and impaired kidney function in these mice, consequently leading to a premature death rate of 40% within 2 weeks of treatment, despite destroying tumors and decreasing kidney size. These findings indicate that Tsc1 prevents aberrant renal growth and tumorigenesis by inhibiting mTORC1 signaling, whereas phosphorylated rpS6 suppresses cystogenesis and fibrosis in Tsc1-deleted kidneys. PMID:26296742

  18. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy.

    Science.gov (United States)

    Black, Sarah Wurts; Morairty, Stephen R; Fisher, Simon P; Chen, Tsui-Ming; Warrier, Deepti R; Kilduff, Thomas S

    2013-03-01

    Humans with narcolepsy and orexin/ataxin-3 transgenic (TG) mice exhibit extensive, but incomplete, degeneration of hypo-cretin (Hcrt) neurons. Partial Hcrt cell loss also occurs in Parkinson disease and other neurologic conditions. Whether Hcrt antagonists such as almorexant (ALM) can exert an effect on the Hcrt that remains after Hcrt neurodegeneration has not yet been determined. The current study was designed to evaluate the hypnotic and cataplexy-inducing efficacy of a Hcrt antagonist in an animal model with low Hcrt tone and compare the ALM efficacy profile in the disease model to that produced in wild-type (WT) control animals. Counterbalanced crossover study. Home cage. Nine TG mice and 10 WT mice. ALM (30, 100, 300 mg/kg), vehicle and positive control injections, dark/active phase onset. During the 12-h dark period after dosing, ALM exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/ kg) paradoxically induced a transient increase in active wakefulness. Core body temperature (Tb) decreased after acute Hcrt receptor blockade, but the reduction in Tb that normally accompanies the wake-to-sleep transition was blunted in TG mice. These complex dose- and genotype-dependent interactions underscore the importance of effector mechanisms downstream from Hcrt receptors that regulate arousal state. Cataplexy promotion by ALM warrants cautious use of Hcrt antagonists in patient populations with Hcrt neurodegeneration, but may also facilitate the discovery of anticataplectic medications. Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336.

  19. No association between exacerbation frequency and stroke in patients with COPD

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    Windsor C

    2016-02-01

    Full Text Available Claire Windsor,1 Emily Herrett,1 Liam Smeeth,1 Jennifer Kathleen Quint1,2 1Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK; 2Department of Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UK Background: Patients with chronic obstructive pulmonary disease (COPD have a higher risk of stroke than the general population. Chronic inflammation associated with COPD is thought to contribute to this risk. Exacerbations of COPD are associated with a rise in inflammation, suggesting that there may be an association between exacerbation frequency and the risk of stroke. This study examined that association.Methods: Using the UK Clinical Practice Research Datalink, COPD patients with a first stroke between January 2004 and December 2013 were identified as cases and matched on age, sex, and general practice to controls with COPD but without a stroke (6,441 cases and 19,323 controls. Frequent exacerbators (FEs were defined as COPD patients with ≥2 exacerbations, and infrequent exacerbators (IEs have ≤1 exacerbation in the year prior to their stroke. Conditional logistic regression was used to estimate the association between exacerbation frequency and stroke overall, and by stroke subtype (hemorrhagic, ischemic, or transient ischemic attack. Exacerbations were also categorized into 0, 1, 2, or ≥3 exacerbations in the year prior to stroke.Results: There was no evidence that FE had an increased odds of stroke compared to IE (OR [odds ratio] =0.95, 95% CI [confidence interval] =0.89–1.01. There was strong evidence that the risk of stroke decreased with each exacerbation of COPD experienced per year (Ptrend =0.003. In the subgroup analysis investigating stroke subtype, FE had 33% lower odds of hemorrhagic stroke than IE (OR =0.67, 95% CI =0.51–0.88, P=0.003. No association was found within other stroke types

  20. Adverse Effects of AMP-Activated Protein Kinase alpha 2-Subunit Deletion and High-Fat Diet on Heart Function and Ischemic Tolerance in Aged Female Mice

    Czech Academy of Sciences Publication Activity Database

    Slámová, Kristýna; Papoušek, František; Janovská, Petra; Kopecký, Jan; Kolář, František

    2016-01-01

    Roč. 65, č. 1 (2016), s. 33-42 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GB14-36804G Institutional support: RVO:67985823 Keywords : AMP kinase * ischemia/reperfusion * myocardial infarction * aging * high-fat diet Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.461, year: 2016

  1. Aspirin induces IL-4 production: augmented IL-4 production in aspirin-exacerbated respiratory disease

    Science.gov (United States)

    Kong, Su-Kang; Soo Kim, Byung; Gi Uhm, Tae; Soo Chang, Hun; Sook Park, Jong; Woo Park, Sung; Park, Choon-Sik; Chung, Il Yup

    2016-01-01

    Aspirin hypersensitivity is a hallmark of aspirin-exacerbated respiratory disease (AERD), a clinical syndrome characterized by the severe inflammation of the respiratory tract after ingestion of cyclooxygenase-1 inhibitors. We investigated the capacity of aspirin to induce interleukin-4 (IL-4) production in inflammatory cells relevant to AERD pathogenesis and examined the associated biochemical and molecular pathways. We also compared IL-4 production in peripheral blood mononuclear cells (PBMCs) from patients with AERD vs aspirin-tolerant asthma (ATA) upon exposure to aspirin. Aspirin induced IL-4 expression and activated the IL-4 promoter in a report assay. The capacity of aspirin to induce IL-4 expression correlated with its activity to activate mitogen-activated protein kinases, to form DNA–protein complexes on P elements in the IL-4 promoter and to synthesize nuclear factor of activated T cells, critical transcription factors for IL-4 transcription. Of clinical importance, aspirin upregulated IL-4 production twice as much in PBMCs from patients with AERD compared with PBMCs from patients with ATA. Our results suggest that IL-4 is an inflammatory component mediating intolerance reactions to aspirin, and thus is crucial for AERD pathogenesis. PMID:27534531

  2. Alfa-2-glicoproteína rica en leucina urinaria en pacientes con apendicitis aguda (Urinary leucine-rich alpha-2-glycoprotein in patients with acute appendicitis

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    Heberto Machado-Montero

    2015-04-01

    Full Text Available The objective of research was to determine diagnostic efficacy of urinary concentrations of leucine-rich alpha-2-glycoprotein (A2GRL in patients with acute appendicitis. There were included patients with high suspicion of acute appendicitis (group A; cases, n = 30. In group B (controls, n = 30 were included patients with non-surgical abdominal pain who attended to Hospital Central “Dr. Urquinaona”, Maracaibo, Zulia. General characteristics, urinary concentrations of A2GRL and diagnostic efficacy of assay were evaluated. Mean age of patients in group A was 36.3 +/- 8.8 years-old and in group B was 35.8 +/- 9.6 years-old (p = ns. There were not found significant differences in sex distribution, weight and height between groups (p = ns. Urinary concentrations of A2GRL were significantly higher in group A (1543.8 +/- 762.7 ng/mL compared with mean value in patients of group B (774.1 +/- 356.1 ng/mL; p < 0.0001. A2GRL presented a value below curve 0.81. A cut-off value of 1000 ng/mL, showed sensivity 73.3%, specificity 70.9%, positive predictive value 72.4% and negative predictive value 72.4%. It is concluded that urinary concentrations of A2GRL have a high diagnostic efficacy in patients with acute appendicitis

  3. Clinico-pathogenetic substantiation and experience of the use of interferon alpha 2b in children with acute respiratory viral infections

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    Marushko Yu.V.

    2016-03-01

    Full Text Available Objective. To evaluate the efficacy and safety of interferon preparations in children under three years with acute respiratory viral infections. Patients and methods. A total of 97 observed children with a diagnosis ARVI has been consulted by doctor at 152 days after the onset of the disease. In the main group in the complex treatment additionally was prescribed nasal interferon alpha 2b «Nazoferon» in the age dosages. Children of the control group had received conventional treatment only. Results. Due to the application of Nazoferon was observed a decrease in the duration as of the main symptoms of the disease (catarrhal phenomena and temperature reaction, so the effects of intoxication. On the fifth day of treatment the difference between clinical parameters was more pronounced. It is found that Nazoferon well tolerated, does not cause discomfort on the part of the respiratory system. Conclusions. The good clinical efficacy and lack of adverse reactions allow recommending Nazoferon for use in pediatric patients. Application of Nazoferon is important to start from the early 152 days of the disease. Allow it to use as a prophylactic measure.

  4. Lectin-based protein microarray analysis of differences in serum alpha-2-macroglobulin glycosylation between patients with colorectal cancer and persons without cancer.

    Science.gov (United States)

    Šunderić, Miloš; Šedivá, Alena; Robajac, Dragana; Miljuš, Goran; Gemeiner, Peter; Nedić, Olgica; Katrlík, Jaroslav

    2016-07-01

    Glycosylation is co- and posttranslational modifications affecting proteins. The glycopattern changes are associated with changes in biological function and are involved in many diseases including cancer. We present the lectin-based protein microarray method enabling determination of differences in protein glycosylation. The method involves isolation of targeted protein from samples by immunoprecipitation, spotting of protein from multiple samples into arrays on a microarray slide, incubation with set of biotinylated lectins, the reaction with fluorescent conjugate of streptavidin, and detection of fluorescent intensities by microarray scanner. Lectin-based protein microarray was applied in investigation of differences in alpha-2-macroglobulin (α2M) glycosylation isolated from sera samples of healthy persons and patients with colorectal cancer (CC). From 14 lectins used in analysis, statistically significant differences (Student's t-test, P microarray developed and described can serve as a suitable analytical technique for sensitive, simple, fast, and high-throughput determination of differences in protein glycosylation isolated from serum or other samples. © 2015 International Union of Biochemistry and Molecular Biology, Inc.

  5. Binding diversity of monoclonal antibodies to alpha(2-->8) polysialic acid conjugated to outer membrane vesicle via adipic acid dihydrazide.

    Science.gov (United States)

    Devi, S J; Karpas, A B; Frasch, C E

    1996-07-01

    Murine monoclonal antibodies (mAbs) were generated using group B Neisseria meningitidis and Escherichia coli K1 polysaccharides (PSs) conjugated to outer membrane vesicle (OMV) via adipic acid dihydrazide, and were used to identify the immunodeterminants expressed on these capsular PSs. Ten mAbs representative of IgM and all subclasses of IgG were obtained which recognized diverse immunodeterminants on alpha(2-->8) polysialic acid (PSA). The specificity of mAbs to different antigenic determinants was assessed by their differential binding to PSA attached to a solid phase by different methods and confirmed by absorption studies. Two mAbs from the E. coli K1 fusion were directed to the O-acetyl epitope and the rest reacted with both the PSs only when attached to a solid phase by certain means. The methods by which PSA was coated on the solid phase had an impact on the epitope expression and binding pattern. At the concentrations used, the O-acetyl-specific mAbs, IgG1 and IgG3 mAbs were not bactericidal against group B N. meningitidis, whereas other mAbs were. The conjugates B and K1 PSs present to the murine immune system different antigenic determinants, some of which elicit bactericidal antibodies.

  6. Acute exacerbation in chronic hepatitis B virus infection

    Directory of Open Access Journals (Sweden)

    Marcio Vieira Santos

    1996-06-01

    Full Text Available A case of an acute exacerbation of liver injury in a chronic HBV infected young male is reported. The correlation between the severe symptomatic hepatitis is done with the histopathologic findings of extense areas of bridging necrosis on the Iwer biopsy. The serological pattern for markers of HBV (HBsAg +, anti HBs g -, HBeAg -, anti HBe +, anti HBcIgG + and IgM - confirm a chronic infection, ana the authors propose that the episode of severe hepatitis relates to the recent spontaneous seroconvertion of HBe Ag to anti HBe. Other causes of hepatitis were excluded, and the control liver biopsy (6 months later showed normalization of hepatic architecture and absence of markers of viral replication in tissue and serum. A review of literature is done in an attempt to elucidate the diagnostic possibilities in this case, with emphasis on new immunoassays useful in differentiating between acute hepatitis B and acute exacerbation of a chronic hepatitis by the same virus.Descreve-se um caso de exacerbação aguda sintomática em um paciente cronicamente infectado pelo VHB, mostrando-se correlação entre o quadro clínico grave (com insuficiência hepática transitória e os achados histopatológicos de hepatite severa com extensas áreas de necrose em ponte. O perfil sorológico para marcadores do VHB (Ag HB S +, anti HB S Ag HBe -, anti HBe +, anti HB C IgG + IgM - confirmou infecção crônica, e os autores levantam a hipótese de que a hepatite tenha se coiTelacionado â recente soroconversão Ag HBe para anti-HBe. Outras etiologias possíveis foram descartadas e se contou com biópsia controle 6 meses depois, mostrando normalização da arquitetura hepática e ausência de marcadores de replicação viral no tecido e no soro. Revisa-se a literatura sobre o diagnóstico diferencial cabível nesta situação, dando ênfase a novos ensaios sorológicos úteis na diferenciação entre infecção aguda pelo VHB e exacerbação aguda de uma hepatite cr

  7. Clinical predictors of bacterial involvement in exacerbations of chronic obstructive pulmonary disease.

    NARCIS (Netherlands)

    Valk, P.D.L.P.M. van der; Monninkhof, E.M.; Palen, J.A.M. van der; Zielhuis, G.A.; Herwaarden, C.L.A. van; Hendrix, R.G.

    2004-01-01

    BACKGROUND: The wide use of antibiotics for treatment of exacerbations of chronic obstructive pulmonary disease (COPD) lacks evidence. The efficacy is debatable, and bacterial involvement in exacerbation is difficult to verify. The aim of this prospective study was to identify factors that can help

  8. How Do Dual Long-acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

    DEFF Research Database (Denmark)

    Beeh, Kai M; Burgel, Pierre-Regis; Franssen, Frits M E

    2017-01-01

    Decreasing the frequency and severity of exacerbations is one of the main goals of treatment for patients with chronic obstructive pulmonary disease (COPD). Several studies have documented that long-acting bronchodilators (LABDs) can reduce exacerbation rate and/or severity, and others have shown...

  9. Psychological Factors and Pain Exacerbation in Knee Osteoarthritis : A Web Based Case-Crossover Study

    NARCIS (Netherlands)

    Erfani, Tahereh; Keefe, Francis; Bennell, Kim; Chen, J; Makovey, J; Metcalf, B; Williams, A.D.; Zhang, Y; Hunter, David

    2015-01-01

    OBJECTIVES: The pain experienced by osteoarthritis (OA) patients is neither constant nor unchanging and patients experience episodes of pain exacerbations. Using an innovative web based case-crossover design, we evaluated whether psychological factors are risk factors for pain exacerbations in

  10. Low-intensity noninvasive ventilation: Lower pressure, more exacerbations of chronic respiratory failure

    Directory of Open Access Journals (Sweden)

    Toru Kadowaki

    2016-01-01

    Conclusions: Attention should be paid to CRF patients who are initially administered LI-NPPV; they should be carefully observed because they can develop more exacerbations of CRF than patients undergoing C-NPPV. If possible, higher initial PS should be administered to prevent CRF exacerbations.

  11. Relation of sputum colour to bacterial load in acute exacerbations of COPD

    NARCIS (Netherlands)

    Brusse-Keizer, M. G. J.; Grotenhuis, A. J.; Kerstjens, H. A. M.; Telgen, M. C.; van der Palen, J.; Hendrix, M. G. R.; van der Valk, P. D. L. P. M.

    Background: When COPI) patients present with an exacerbation, one cannot verify a bacterial. cause of an exacerbation without time-consuming laboratory analyses. This makes it difficult to decide up front if antibiotic treatment is needed. Therefore, in clinical, practice sputum colour and purulence

  12. Relation of sputum colour to bacterial load in acute exacerbations of COPD

    NARCIS (Netherlands)

    Brusse-Keizer, M.G.J.; Grotenhuis, A.J.; Kerstjens, H.A.M.; Telgen, M.C.; van der Palen, Jacobus Adrianus Maria; Hendrix, M.G.R.; van der Valk, P.D.L.P.M.

    2009-01-01

    Background: When COPD patients present with an exacerbation, one cannot verify a bacterial cause of an exacerbation without time-consuming laboratory analyses. This makes it difficult to decide up front if antibiotic treatment is needed. Therefore, in clinical practice sputum colour and purulence

  13. COPD exacerbation: anthropometric characteristics of patients and the frequency of hospital admissions

    Directory of Open Access Journals (Sweden)

    Gashynova K.Y.

    2014-11-01

    Full Text Available Exceptional importance of exacerbations for COPD course prognosing was reflected in the GOLD, 2011, where the number of exacerbations during the past year has been recognized as one of the main criteria of the future risks for patients. The aim of study was to determine the anthropometric indicators that increase the risk of re-hospitalization due to acute exacerbation of COPD. A retrospective analysis of medical records of inpatients who were hospitalized with COPD exacerbation to therapeutic department of CI "Dnipropetrovs’k sixth municipal clinical hospital" of Dnipropetrovsk regional council" during three years was done. It was established that neither sex, nor height, nor weight affect the rate of hospitalization due to COPD exacerbations. Older age is not a factor that increases the risk of hospitalization due to COPD exacerbation (despite the fact that the majority of hospitalized patients were elderly patients, 37% of them were persons of potentially working age. Severe exacerbation of COPD may occur in any patients with, even one year, experience of the disease. Among anthropometric indices, the most important predictor of re-hospitalization due to exacerbation of COPD is BMI<18.5, so its calculation is advisable in long-term observation of patients.

  14. Case-fatality of COPD exacerbations: a meta-analysis and statistical modeling approach

    DEFF Research Database (Denmark)

    Hoogendoorn, M; Hoogenveen, R T; Rutten-van Mölken, M P

    2010-01-01

    Objective of the study was to estimate the case-fatality of a severe exacerbation from long-term survival data presented in the literature. A literature search identified studies reporting at least 1.5 year survival after a severe COPD exacerbation resulting in hospitalization. Each study's survi...

  15. Altered gene expression in blood and sputum in COPD frequent exacerbators in the ECLIPSE cohort.

    Directory of Open Access Journals (Sweden)

    Dave Singh

    Full Text Available Patients with chronic obstructive pulmonary disease (COPD who are defined as frequent exacerbators suffer with 2 or more exacerbations every year. The molecular mechanisms responsible for this phenotype are poorly understood. We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort. Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR testing. Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01 between frequent compared to non-exacerbators. In sputum cells, only 6 genes were differentially expressed. The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes. Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10. The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively. There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations.

  16. Sodium chloride-enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice.

    Science.gov (United States)

    Monteleone, Ivan; Marafini, Irene; Dinallo, Vincenzo; Di Fusco, Davide; Troncone, Edoardo; Zorzi, Francesca; Laudisi, Federica; Monteleone, Giovanni

    2017-02-01

    Environmental factors are supposed to play a decisive role in the pathogenesis of inflammatory bowel diseases [IBDs]. Increased dietary salt intake has been linked with the development of autoimmune diseases, but the impact of a salt-enriched diet on the course of IBD remains unknown. In this study, we examined whether high salt intake alters mucosal cytokine production and exacerbates colitis. Normal intestinal lamina propria mononuclear cells [LPMCs] were activated with anti-CD3/CD28 in the presence or absence of increasing concentrations of sodium chloride [NaCl] and/or SB202190, a specific inhibitor of p38/MAP Kinase. For in vivo experiments, a high dose of NaCl was administered to mice 15 days before induction of trinitrobenzene-sulfonic acid [TNBS]-colitis or dextran sulfate sodium [DSS]-colitis. In parallel, mice were given SB202190 before induction of TNBS-colitis. Transcription factors and effector cytokines were evaluated by flow-cytometry and real-time PCR. IL-17A, IL-23R, TNF-α, and Ror-γT were significantly increased in human LPMCs following NaCl exposure, while there was no significant change in IFN-γ, T-bet or Foxp3. Pharmacologic inhibition of p38/MAPK abrogated the NaCl-inducing effect on LPMC-derived cytokines. Mice receiving the high-salt diet developed a more severe colitis than control mice, and this effect was preventable by SB202190. Our data indicated that exposure of intestinal mononuclear cells to a high-NaCl diet enhanced effector cytokine production and contributed to the exacerbation of experimental colitis in mice. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. Treatment of exacerbations as a predictor of subsequent outcomes in patients with COPD

    Directory of Open Access Journals (Sweden)

    Calverley PMA

    2018-04-01

    Full Text Available Peter MA Calverley,1 Antonio R Anzueto,2 Daniel Dusser,3 Achim Mueller,4 Norbert Metzdorf,5 Robert A Wise6 1Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; 2Pulmonary/Critical Care, University of Texas and South Texas Veterans Health Care System, San Antonio, TX, USA; 3Department of Pneumology, Hôpital Cochin, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 4Biostatistics and Data Sciences Europe, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 5Respiratory Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Rationale: Exacerbations of COPD are managed differently, but whether treatment of one exacerbation predicts the likelihood of subsequent events is unknown. Objective: We examined whether the treatment given for exacerbations predicted subsequent outcomes. Methods: This was a post-hoc analysis of 17,135 patients with COPD from TIOtropium Safety and Performance In Respimat® (TIOSPIR®. Patients treated with tiotropium with one or more moderate to severe exacerbations on study were analyzed using descriptive statistics, logistic and Cox regression analysis, and Kaplan–Meier plots. Results: Of 8,061 patients with moderate to severe exacerbation(s, demographics were similar across patients with exacerbations treated with antibiotics and/or steroids or hospitalization. Exacerbations treated with systemic corticosteroids alone or in combination with antibiotics had the highest risk of subsequent exacerbation (HR: 1.21, P=0.0004 and HR: 1.33, P<0.0001, respectively, and a greater risk of having a hospitalized (severe exacerbation (HR: 1.59 and 1.63, P<0.0001, respectively or death (HR: 1.50, P=0.0059 and HR: 1.47, P=0.0002, respectively compared with exacerbations treated

  18. Defining moderate asthma exacerbations in clinical trials based on ATS/ERS joint statement

    DEFF Research Database (Denmark)

    Virchow, J Christian; Backer, Vibeke; de Blay, Frédéric

    2015-01-01

    BACKGROUND: Exacerbations are a key outcome in clinical research, providing patient-relevant information about symptomatic control, health state and disease progression. Generally considered as an episode of (sub)acute deterioration of respiratory symptoms, a precise, clinically useful definition...... is needed for use in clinical trials. AIM AND METHODS: Focussing on moderate exacerbations, this opinion piece reviews landmark trials and current guidelines to provide a practical definition of a moderate exacerbation. Specifically, we adapt the ATS/ERS consensus statement of terminology Reddel et al....... (2009) [1] which provides a conceptual (or 'theoretical') definition for moderate exacerbations, to an operational (or 'practical') criterion suitable for use in clinical research. RESULTS: The proposed definition for a moderate exacerbation requires ≥1 of the following criteria combined with a change...

  19. Effect of long-acting beta2 agonists on exacerbation rates of asthma in children

    DEFF Research Database (Denmark)

    Bisgaard, Hans

    2003-01-01

    The purpose of this analysis was to examine the effect of long-acting beta(2)-adrenoceptor agonists (LABAs) on the asthma exacerbation rate in pediatric patients. Randomized controlled trials (RCT) that included the use of LABAs to treat symptoms of pediatric asthma in children on inhaled...... corticosteroids, that reported asthma exacerbation rates, and that were published as full papers in peer-reviewed journals were retrieved from a search of the medical literature. Eight studies were identified that fulfilled these criteria. An exacerbation was defined as deterioration in a patient's asthma...... requiring a change in prescribed medication or not defined but reported as an asthma exacerbation or an asthma-related hospitalization. Analysis of data from the eight studies revealed no apparent protection from an asthma exacerbation among children on a LABA compared to patients on comparator treatment...

  20. Statin use and exacerbations in individuals with chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Ingebrigtsen, Truls S; Marott, Jacob L; Nordestgaard, Børge G

    2015-01-01

    BACKGROUND: We tested the hypothesis that statin use in individuals with COPD is associated with a reduced risk of exacerbations. METHODS: We identified 5794 individuals with COPD and a measurement of C reactive protein (CRP) in the Copenhagen General Population Study (2003-2008). During 3 years...... of follow-up we recorded exacerbations with hospital admissions or oral corticosteroid treatment. In a nested case-control design, matching on age, gender, smoking, COPD severity and comorbidity, we estimated the association between statin use and exacerbations. In addition, we examined the association...... between statin use and high CRP (>3 mg/L), and the association between high CRP and exacerbations during follow-up. RESULTS: Statin use was associated with reduced odds of exacerbations in crude analysis, OR=0.68 (95% CI 0.51 to 0.91, p=0.01), as well as in multivariable conditional logistic regression...

  1. Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice.

    Directory of Open Access Journals (Sweden)

    Min Ao

    Full Text Available BACKGROUND: A number of studies have revealed a link between chronic periodontitis and cardiovascular disease in obese patients. However, there is little information about the influence of periodontitis-associated bacteria, Porphyromonas gingivalis (Pg, on pathogenesis of atherosclerosis in obesity. METHODS: In vivo experiment: C57BL/6J mice were fed with a high-fat diet (HFD or normal chow diet (CD, as a control. Pg was infected from the pulp chamber. At 6 weeks post-infection, histological and immunohistochemical analysis of aortal tissues was performed. In vitro experiment: hTERT-immortalized human umbilical vein endothelial cells (HuhT1 were used to assess the effect of Pg/Pg-LPS on free fatty acid (FFA induced endothelial cells apoptosis and regulation of cytokine gene expression. RESULTS: Weaker staining of CD31 and increased numbers of TUNEL positive cells in aortal tissue of HFD mice indicated endothelial injury. Pg infection exacerbated the endothelial injury. Immunohistochemically, Pg was detected deep in the smooth muscle of the aorta, and the number of Pg cells in the aortal wall was higher in HFD mice than in CD mice. Moreover, in vitro, FFA treatment induced apoptosis in HuhT1 cells and exposure to Pg-LPS increased this effect. In addition, Pg and Pg-LPS both attenuated cytokine production in HuhT1 cells stimulated by palmitate. CONCLUSIONS: Dental infection of Pg may contribute to pathogenesis of atherosclerosis by accelerating FFA-induced endothelial injury.

  2. Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease

    Directory of Open Access Journals (Sweden)

    Nami Shrestha Palikhe

    2012-01-01

    Full Text Available Aspirin-exacerbated respiratory disease (AERD refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.

  3. RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Lingjun, E-mail: menglingjun@nibs.ac.cn [College of Biological Sciences, China Agricultural University, Beijing 100094 (China); National Institute of Biological Sciences, Beijing 102206 (China); Jin, Wei [Institute for Immunology, Tsinghua University, Beijing 100084 (China); Wang, Yuhui [Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100191 (China); Huang, Huanwei; Li, Jia; Zhang, Cai [National Institute of Biological Sciences, Beijing 102206 (China)

    2016-04-29

    Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

  4. Influence of Pseudomonas aeruginosa on exacerbation in patients with bronchiectasis

    Directory of Open Access Journals (Sweden)

    Kiran Chawla

    2015-01-01

    Full Text Available Background: A majority of the studies done on the western population have shown that Pseudomonas aeruginosa causes many severe infections in patients with bronchiectasis as compared to other pathogens. There is scarcity of similar data from the Asian population. Materials and Methods: A prospective study was undertaken to identify the various pathogens isolated from the respiratory samples of 117 patients with bronchiectasis from south India and to compare the clinicomicrobiological profile of infections caused by P. aeruginosa and other respiratory pathogens. Results: The respiratory pathogens were isolated from 63 (53.8% patients. P. aeruginosa was the most common isolate (46.0% followed by Klebsiella pneumoniae (14.3% and other pathogenic bacteria. Patients included in the P. aeruginosa group had a higher number of exacerbations (p: 0.008, greater number of hospital admissions (p: 0.007, a prolonged hospital stay (p: 0.03, and poor lung function, compared to the patients infected with the non-Pseudomonas group. Conclusion: It is necessary to investigate the etiology of respiratory tract infections among bronchiectasis patients followed by the prompt management of cases diagnosed with P. aeruginosa infections, so as to lower the morbidity and have a better prognosis.

  5. Stress Cardiomyopathy in the Setting of COPD Exacerbation

    Directory of Open Access Journals (Sweden)

    Kevin Landefeld

    2015-10-01

    Full Text Available Introduction. Stress cardiomyopathy, or takotsubo cardiomyopathy, is an acute, reversible left ventricular dysfunction usually initiated by a psychological or physical stress. We report this case of stress cardiomyopathy following a chronic obstructive pulmonary disease exacerbation and the subsequent treatment. Case Description. A 49-year-old white female with a history of chronic obstructive pulmonary disease presented to the emergency room via emergency medical services with worsening severe shortness of breath and productive cough for 2 weeks but denied any chest pain on arrival. On presentation, she was noted to be tachypneic, using her accessory muscles and with bilateral coarse expiratory wheezing on lung auscultation. Initial electrocardiogram demonstrated sinus tachycardia. She was treated with multiple albuterol treatments. Soon afterwards, the course was complicated by hypoxic respiratory failure eventually requiring intubation. Her repeat electrocardiogram showed acute changes consistent with myocardial infarction, and an echocardiograph demonstrated apical akinesia with an ejection fraction of 25% to 30%. The patient was urgently taken for cardiac catheterization, which showed no angiographic evidence of coronary artery disease. Three days after initial presentation, a repeat transthoracic echocardiogram showed overall left ventricular systolic function improvement. Discussion. This case provided a unique look at the difficulty of balancing catecholamines in a patient with bronchospasm and stress cardiomyopathy.

  6. [Acute bacterial exacerbation of chronic obstructive pulmonary disease and biofilm].

    Science.gov (United States)

    Legnani, Delfino

    2009-07-01

    The lower respiratory tract of patients affected by COPD is constantly colonized by pathogenic microrganisms such as H. influenzae, M. catarrhalis and S. pneumoniae. Role of bacterial colonization of big and small airways in patients affected by COPD is still unclear but it is likely to play a role in directly or indirectly maintaining the vicious circle of infection/inflammation. Colonizer pathogens are capable to stimulate mucus production, to alter the ciliary function by inducing dyskinesia and stasis; in addition, they represent a strong stimulus for neutrophils to come in the airways, which release elastase that, in turn, inhibit the mucus-ciliary function. The same pathogens are responsible for epithelial damage and chronic inflammation, by releasing neutrophilic elastase, leading to the damage progression and obstruction. Recent studies have also shown that infection sustained by H. influenzae is not limited to bronchial mucosa, i.e. surface epithelial cells, but that the pathogen is capable to penetrate cells, so spreading the infection in sub-epithelial cellular layers. In addition, the ability to produce biofilm is another possible defence mechanism which allows them to grow and colonise. Such a mechanism could in part explain the lack of response to antimicrobials and contribute to stimulation of parenchymal inflammatory response, the cause of pathological-anatomic damage which occurs in COPD. The impossibility to eradicate chronic infection and bacterial exacerbations of COPD are likely the elements that promt and worsen obstruction, so determining the disease's progression.

  7. COPD Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry.

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    Full Text Available Acute exacerbations of chronic obstructive pulmonary disease (AECOPD result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD.We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72. Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate 1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109 using leave-pair-out cross-validation methods.Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001. The receiver operating characteristic cross-validation area under the curve (CV-AUC statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C.A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.

  8. Alpha- and beta-adrenoceptors in hypertension. II. Platelet alpha 2- and lymphocyte beta 2-adrenoceptors in children of parents with essential hypertension. A model for the pathogenesis of the genetically determined hypertension

    NARCIS (Netherlands)

    Michel, M. C.; Galal, O.; Stoermer, J.; Bock, K. D.; Brodde, O. E.

    1989-01-01

    To study whether changes in alpha- and beta-adrenoceptors in human essential hypertension (EHT) might be genetically determined, we assessed platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children of normotensive parents (NT) and in 41 normotensive children with one

  9. Post-Training Intrahippocampal Injection of Synthetic Poly-Alpha-2,8-Sialic Acid-Neural Cell Adhesion Molecule Mimetic Peptide Improves Spatial Long-Term Performance in Mice

    Science.gov (United States)

    Florian, Cedrick; Foltz, Jane; Norreel, Jean-Chretien; Rougon, Genevieve; Roullet, Pascal

    2006-01-01

    Several data have shown that the neural cell adhesion molecule (NCAM) is necessary for long-term memory formation and might play a role in the structural reorganization of synapses. The NCAM, encoded by a single gene, is represented by several isoforms that differ with regard to their content of alpha-2,8-linked sialic acid residues (PSA) on their…

  10. Altered expression of the voltage-gated calcium channel subunit alpha(2)delta-1: A comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain

    Czech Academy of Sciences Publication Activity Database

    Nieto-Rostro, M.; Sandhu, G.; Bauer, C. S.; Jiruška, Přemysl; Jefferys, J. G. R.; Dolphin, A. C.

    2014-01-01

    Roč. 283, Dec (2014), s. 124-137 ISSN 0306-4522 R&D Projects: GA MZd(CZ) NT14489 Institutional support: RVO:67985823 Keywords : calcium channel * dorsal root ganglion (DRG) * alpha2delta subunit * epilepsy * neuropathic pain * reactive gliosis Subject RIV: FH - Neurology Impact factor: 3.357, year: 2014

  11. Seasonal risk factors for asthma exacerbations among inner-city children.

    Science.gov (United States)

    Teach, Stephen J; Gergen, Peter J; Szefler, Stanley J; Mitchell, Herman E; Calatroni, Agustin; Wildfire, Jeremy; Bloomberg, Gordon R; Kercsmar, Carolyn M; Liu, Andrew H; Makhija, Melanie M; Matsui, Elizabeth; Morgan, Wayne; O'Connor, George; Busse, William W

    2015-06-01

    Asthma exacerbations remain common, even in children and adolescents, despite optimal medical management. Identification of host risk factors for exacerbations is incomplete, particularly for seasonal episodes. We sought to define host risk factors for asthma exacerbations unique to their season of occurrence. This is a retrospective analysis of patients aged 6 to 20 years who comprised the control groups of the Asthma Control Evaluation study and the Inner City Anti-IgE Therapy for Asthma study. Univariate and multivariate models were constructed to determine whether patients' demographic and historical factors, allergic sensitization, fraction of exhaled nitric oxide values, spirometric measurements, asthma control, and treatment requirements were associated with seasonal exacerbations. The analysis included 400 patients (54.5% male; 59.0% African American; median age, 13 years). Exacerbations occurred in 37.5% of participants over the periods of observation and were most common in the fall (28.8% of participants). In univariate analysis impaired pulmonary function was significantly associated with greater odds of exacerbations for all seasons, as was an exacerbation in the previous season for all seasons except spring. In multivariate analysis exacerbation in the previous season was the strongest predictor in fall and winter, whereas a higher requirement for inhaled corticosteroids was the strongest predictor in spring and summer. The multivariate models had the best predictive power for fall exacerbations (30.5% variance attributed). Among a large cohort of inner-city children with asthma, patients' risk factors for exacerbation vary by season. Thus information on individual patients might be beneficial in strategies to prevent these seasonal events. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  12. Inflammatory Responses, Spirometry, and Quality of Life in Subjects With Bronchiectasis Exacerbations.

    Science.gov (United States)

    Guan, Wei-Jie; Gao, Yong-Hua; Xu, Gang; Lin, Zhi-Ya; Tang, Yan; Li, Hui-Min; Lin, Zhi-Min; Jiang, Mei; Zheng, Jin-Ping; Chen, Rong-Chang; Zhong, Nan-Shan

    2015-08-01

    Bronchiectasis exacerbations are critical events characterized by worsened symptoms and signs (ie, cough frequency, sputum volume, malaise). Our goal was to examine variations in airway and systemic inflammation, spirometry, and quality of life during steady state, bronchiectasis exacerbations, and convalescence (1 week following a 2-week antibiotic treatment) to determine whether potentially pathogenic microorganisms, including Pseudomonas aeruginosa, were associated with poorer conditions during bronchiectasis exacerbations. Peripheral blood and sputum were sampled to detect inflammatory mediators and bacterial densities. Spirometry and quality of life (St George Respiratory Questionnaire [SGRQ]) were assessed during the 3 stages. Forty-eight subjects with bronchiectasis (43.2 ± 14.2 y of age) were analyzed. No notable differences in species and density of potentially pathogenic microorganisms were found during bronchiectasis exacerbations. Except for CXCL8 and tumor necrosis factor alpha (TNF-α), serum inflammation was heightened during bronchiectasis exacerbations and recovered during convalescence. Even though sputum TNF-α was markedly higher during bronchiectasis exacerbations and remained heightened during convalescence, the variations in miscellaneous sputum markers were unremarkable. Bronchiectasis exacerbations were associated with notably higher SGRQ symptom and total scores, which recovered during convalescence. FVC, FEV1, and maximum mid-expiratory flow worsened during bronchiectasis exacerbations (median change from baseline of -2.2%, -0.8%, and -1.3%) and recovered during convalescence (median change from baseline of 0.6%, 0.7%, and -0.7%). Compared with no bacterial isolation, potentially pathogenic microorganism or P. aeruginosa isolation at baseline did not result in poorer clinical condition during bronchiectasis exacerbations. Bronchiectasis exacerbations are characterized by heightened inflammatory responses and poorer quality of life and

  13. Impact and prevention of severe exacerbations of COPD: a review of the evidence

    Directory of Open Access Journals (Sweden)

    Halpin DMG

    2017-10-01

    Full Text Available David MG Halpin,1 Marc Miravitlles,2 Norbert Metzdorf,3 Bartolomé Celli4 1Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, UK; 2Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES, Barcelona, Spain; 3Respiratory Medicine, Boehringer Ingelheim Pharma GmBH & Co KG, Ingelheim am Rhein, Germany; 4Pulmonary Division, Brigham and Women’s Hospital, Boston, MA, USA Abstract: Severe exacerbations of COPD, ie, those leading to hospitalization, have profound clinical implications for patients and significant economic consequences for society. The prevalence and burden of severe COPD exacerbations remain high, despite recognition of the importance of exacerbation prevention and the availability of new treatment options. Severe COPD exacerbations are associated with high mortality, have negative impact on quality of life, are linked to cardiovascular complications, and are a significant burden on the health-care system. This review identified risk factors that contribute to the development of severe exacerbations, treatment options (bronchodilators, antibiotics, corticosteroids [CSs], oxygen therapy, and ventilator support to manage severe exacerbations, and strategies to prevent readmission to hospital. Risk factors that are amenable to change have been highlighted. A number of bronchodilators have demonstrated successful reduction in risk of severe exacerbations, including long-acting muscarinic antagonist or long-acting β2-agonist mono- or combination therapies, in addition to vaccination, mucolytic and antibiotic therapy, and nonpharmacological interventions, such as pulmonary rehabilitation. Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD. Evidence-based approaches to prevent and manage severe exacerbations should be implemented as part of targeted strategies for disease management. Keywords

  14. Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD.

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    Brian N McCullagh

    Full Text Available Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8, specific antibody deficiency (20, and selective IgA deficiency (1. Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies

  15. Serum CCL-18 level is a risk factor for COPD exacerbations requiring hospitalization

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    Dilektasli AG

    2017-01-01

    Full Text Available Asli Gorek Dilektasli,1 Ezgi Demirdogen Cetinoglu,1 Esra Uzaslan,1 Ferah Budak,2 Funda Coskun,1 Ahmet Ursavas,1 Ilker Ercan,3 Ercument Ege1 1Department of Pulmonary Disesaes, 2Department of Immunology, 3Department of Biostatistics, Uludag University Faculty of Medicine, Bursa, Turkey Introduction: Chemokine (C-C motif ligand 18 (CCL-18 has been shown to be elevated in chronic obstructive pulmonary disease (COPD patients. This study primarily aimed to evaluate whether the serum CCL-18 level differentiates the frequent exacerbator COPD phenotype from infrequent exacerbators. The secondary aim was to investigate whether serum CCL-18 level is a risk factor for exacerbations requiring hospitalization. Materials and methods: Clinically stable COPD patients and participants with smoking history but normal spirometry (NSp were recruited for the study. Modified Medical Research Council Dyspnea Scale, COPD Assessment Test, spirometry, and 6-min walking test were performed. Serum CCL-18 levels were measured with a commercial ELISA Kit. Results: Sixty COPD patients and 20 NSp patients were recruited. Serum CCL-18 levels were higher in COPD patients than those in NSp patients (169 vs 94 ng/mL, P<0.0001. CCL-18 level was significantly correlated with the number of exacerbations (r=0.30, P=0.026, although a difference in CCL-18 values between infrequent and frequent exacerbator COPD (168 vs 196 ng/mL subgroups did not achieve statistical significance (P=0.09. Serum CCL-18 levels were significantly higher in COPD patients who had experienced at least one exacerbation during the previous 12 months. Overall, ROC analysis revealed that a serum CCL-18 level of 181.71 ng/mL could differentiate COPD patients with hospitalized exacerbations from those who were not hospitalized with a 88% sensitivity and 88.2% specificity (area under curve: 0.92. Serum CCL-18 level had a strong correlation with the frequency of exacerbations requiring hospitalization (r=0.68, P<0

  16. Preventing and managing exacerbations in COPD – critical appraisal of the role of tiotropium

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    Donald P Tashkin

    2010-02-01

    Full Text Available Donald P TashkinDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA,Los Angeles, CA, USAAbstract: The course of COPD is punctuated by acute exacerbations that are associated with an increase in the morbidity and mortality related to this chronic disease and may contribute to its rate of progression. Therefore, preventing and treating exacerbations are major goals of COPD management. The role of tiotropium in the prevention of exacerbations has been investigated in several placebo-controlled randomized clinical trials varying in duration from 3 months to 4 years in patients with moderate to very severe COPD. In all of these trials, tiotropium has uniformly reduced the proportion of patients experiencing at least one exacerbation and delayed the time to the first exacerbation compared with placebo. In the longer trials (≥6 months’ duration tiotropium has also reduced the exposure-adjusted incidence rate of exacerbations. In trials of at least 1 year in duration, tiotropium either significantly reduced the risk of hospitalization for an exacerbation and/or the proportion of patients with an exacerbation-related hospitalization. In a meta-analysis that included 15 trials of tiotropium vs either placebo (n = 13 and/or a longacting beta-agonist (LABA; n = 4, tiotropium significantly reduced the odds of experiencing an exacerbation compared to placebo as well as a LABA. The potential additive benefits of tiotropium to those of a LABA and/or inhaled corticosteroid in reducing exacerbations require further investigation. The mechanism whereby tiotropium reduces exacerbations is not due to an anti-inflammatory effect but more likely relates to its property of causing a sustained increase in airway patency and reduction in hyperinflation, thereby counteracting the tendency for respiratory insults to worsen airflow obstruction and hyperinflation. For the management of acute exacerbations, an

  17. Upregulation of calcium channel alpha-2-delta-1 subunit in dorsal horn contributes to spinal cord injury-induced tactile allodynia.

    Science.gov (United States)

    Kusuyama, Kazuki; Tachibana, Toshiya; Yamanaka, Hiroki; Okubo, Masamichi; Yoshiya, Shinichi; Noguchi, Koichi

    2018-01-31

    Spinal cord injury (SCI) commonly results not only in motor paralysis but also in the emergence of neuropathic pain (NeuP), both of which can impair the quality of life for patients with SCI. In the clinical field, it is well known that pregabalin, which binds to the voltage-gated calcium channel alpha-2-delta-1 (α 2 δ-1) subunit has therapeutic effects on NeuP after SCI. A previous study has demonstrated that SCI increased α 2 δ-1 in the L4-L6 dorsal spinal cord of SCI rats by Western blot analysis and that the increase of α 2 δ-1 was correlated with tactile allodynia of the hind paw. However, the detailed feature of an increase in α 2 δ-1 protein in the spinal dorsal horn and the mechanism of pregabalin effect on SCI-induced NeuP have not been fully examined. This study aimed to examine the detailed distribution of α 2 δ-1 expression in the lumbar spinal cord after thoracic SCI in rats and the correlation of the therapeutic effect of pregabalin in SCI rats. Male Sprague-Dawley rats underwent thoracic (T10) spinal cord contusion injury using the IH impactor device. Spinal cord injury rats received pregabalin (30 mg/kg) once a day for 2 weeks over a 4-week period after SCI. The mechanical threshold in the rat hind paw was measured over 4 weeks. Alpha-2-delta-1 expression in the lumbar spinal cord and in the dorsal root ganglion (DRG) was analyzed using immunohistochemistry and in situ hybridization histochemistry. A significant reduction of the withdrawal threshold of mechanical stimuli to the hind paw was observed for 2 weeks and continued at least 4 weeks after SCI. In the control rats, expression of α 2 δ-1 immunoreactivity was detected mainly in laminae I and II in the lumbar dorsal horn. Thoracic SCI significantly increased α 2 δ-1 immunoreactivity in laminae I and II in the lumbar dorsal horn 4 weeks after SCI; however, thoracic SCI did not affect the expression of α 2 δ-1 mRNA in the L4 and L5 DRGs. Meanwhile, the signal intensity of α 2

  18. Weight-based combination therapy with peginterferon alpha-2b and ribavirin for Naïve, relapser and non-responder patients with chronic hepatitis C

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    Fernando Lopes Gonçales Jr.

    Full Text Available Combination therapy with pegylated interferon and ribavirin is considered the new standard therapy for naïve patients with chronic hepatitis C. We evaluated the efficacy and safety of treatment with weight-based peginterferon alpha-2b (1.5 mg/kg per week plus ribavirin (800-1,200 mg/day for 48 weeks in naïve, relapser and non-responder (to previous treatment with interferon plus ribavirin patients with chronic hepatitis C. Sixty-seven naïve, 26 relapser and 40 non-responder patients were enrolled. The overall sustained virological response (SVR for the intention-to-treat population was 54% for naïve, 62% for relapser and 38% for non-responder patients. In the naïve subgroup, SVR was significantly higher in patients with the non-1 genotype (67% compared to those with genotype 1 (45%. In relapsers and non-responders, SVR was, respectively, 69% and 24% in patients with genotype 1 and 43% and 73% in those with genotype non-1. There were no significant differences in SVR rates among the three body weight ranges ( 85 kg in any of the subgroups. Early virological response (EVR was reached by 78%, 81% and 58% of naïve, relapser and non-responder patients, respectively, and among those with EVR, 63%, 67% and 61%, respectively, subsequently achieved SVR. All of the non-responder patients who did not have EVR reached SVR. Treatment was discontinued in 13% of the patients, due to loss to follow-up, hematological abnormalities or depression.

  19. The effect of the alpha 2-adrenergic agonist, guanfacin, on the energy metabolism of steers fed on low-quality-roughage diets.

    Science.gov (United States)

    Hunter, R A

    1992-05-01

    The effect of the alpha 2-adrenergic agonist, guanfacin, on the energy metabolism, feed intake and live weight (LW) change of steers was studied in three experiments. In the first, the metabolic rate of twelve steers was measured after a 72 h fast. The next day, after a 96 h fast, six steers were injected intramuscularly with 15 mg guanfacin in sterile saline (9 g sodium chloride/l) and six with sterile saline alone, and metabolic rate was measured again. Treatment significantly (P less than 0.01) lowered metabolic rate by approximately 20% (53.9 v. 66.8 kJ/kg per d). In the second experiment twelve steers were fed on long-chopped, low-quality roughage (Pangola grass (Digitaria decumbens) hay) ad lib. for 6 weeks. Six steers were continuously infused through a jugular catheter with 15 mg guanfacin/d (about 40 micrograms/kg LW) in sterile saline. The other six served as controls. There was no significant effect of treatment on feed intake (g dry matter (DM)/kg LW) or the rate of LW loss. Treatment significantly (P less than 0.05) increased the retention time of fluid (17.9 v. 22.1 h) in the alimentary tract. In the final experiment twenty-three steers were divided into four treatment groups and fed on long-chopped, low-quality roughage (Pangola hay). Treated animals were continuously infused with guanfacin at the rate of 20, 40 or 80 micrograms/kg LW per d. Control steers were not infused. At the end of the 6-week feeding period metabolic rate was measured after a 72 h fast. Regardless of dose, guanfacin significantly (P less than 0.01) lowered metabolic rate.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. A Phase 3 Placebo-Controlled, Double Blind, Multi-Site Trial of the alpha-2-adrenergic Agonist, Lofexidine, for Opioid Withdrawal

    Science.gov (United States)

    Yu, Elmer; Miotto, Karen; Akerele, Evaristo; Montgomery, Ann; Elkashef, Ahmed; Walsh, Robert; Montoya, Ivan; Fischman, Marian W.; Collins, Joseph; McSherry, Frances; Boardman, Kathy; Davies, David K.; O’Brien, Charles P.; Ling, Walter; Kleber, Herbert; Herman, Barbara H.

    2008-01-01

    Context Lofexidine is an alpha-2-A noradrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. Objective To demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally-defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. Design An inpatient, Phase 3, placebo-controlled, double blind, randomized multi-site trial with three phases: (1) Opioid Agonist Stabilization Phase (days 1–3), (2) Detoxification/Medication or Placebo Phase (days 4–8), and (3) Post Detoxification/Medication Phase (days 9–11). Subjects Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. Main Outcome Measure Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (2nd opioid detoxification treatment day). Results Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (Least squares means 19.5 ± 2.1 versus 30.9 ± 2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). Conclusions Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification. Trial Registration trial registry name A Phase 3 Placebo-Controlled, Double-Blind Multi-Site Trial of Lofexidine for Opiate Withdrawal, registration number NCT00032942, URL for the registry http://clinicaltrials.gov/ct/show/NCT00032942?order=4. PMID:18508207

  1. Evaluation of Zinc-alpha-2-Glycoprotein and Proteasome Subunit beta-Type 6 Expression in Prostate Cancer Using Tissue Microarray Technology.

    LENUS (Irish Health Repository)

    2010-07-23

    Prostate cancer (CaP) is a significant cause of illness and death in males. Current detection strategies do not reliably detect the disease at an early stage and cannot distinguish aggressive versus nonaggressive CaP leading to potential overtreatment of the disease and associated morbidity. Zinc-alpha-2-glycoprotein (ZAG) and proteasome subunit beta-Type 6 (PSMB-6) were found to be up-regulated in the serum of CaP patients with higher grade tumors after 2-dimensional difference gel electrophoresis analysis. The aim of this study was to investigate if ZAG and PSMB-6 were also overexpressed in prostatic tumor tissue of CaP patients. Immunohistochemical analysis was performed on CaP tissue microarrays with samples from 199 patients. Confirmatory gene expression profiling for ZAG and PSMB-6 were performed on 4 cases using Laser Capture Microdissection and TaqMan real-time polymerase chain reaction. ZAG expression in CaP epithelial cells was inversely associated with Gleason grade (benign prostatic hyperplasia>G3>G4\\/G5). PSMB-6 was not expressed in either tumor or benign epithelium. However, strong PSMB-6 expression was noted in stromal and inflammatory cells. Our results indicate ZAG as a possible predictive marker of Gleason grade. The inverse association between grade and tissue expression with a rising serum protein level is similar to that seen with prostate-specific antigen. In addition, the results for both ZAG and PSMB-6 highlight the challenges in trying to associate the protein levels in serum with tissue expression.

  2. Evaluation of minimal residual disease in patients with chronic myeloid leukaemia on IFN-alpha 2b therapy using conventional cytogenetics and fluorescence in situ hybridization.

    Science.gov (United States)

    Talwar, Rashmi; Choudhry, V P; Jobanputra, Vaidehi; Kucheria, Kiran

    2002-01-01

    Chronic myeloid leukaemia (CML) is a haematopoietic malignancy characterized by the presence of the Philadelphia (Ph) chromosome that results from balanced reciprocal translocation between chromosomes 9 and 22 leading to the formation of the bcr/abl fusion gene. Studies have shown that interferon-alpha (IFN-alpha) therapy induces both cytogenetic (reduction in Ph+ cells) and molecular response (reduction in the bcr/abl positive cells) in a large proportion of patients, thereby improving their prognosis and survival. There are no reports available from India on the clinical management of CML patients using IFN-alpha therapy and molecular methods for the evaluation of residual disease. We evaluated the efficacy of IFN-alpha 2b therapy bysequential cytogenetic and molecularanalysis. Karyotypingwas done from G-banded metaphases obtained from 24-hour culture of bone marrow aspirates of 45 patients. Cytogenetic analysis was repeated at intervals of 4-6 months during the course of IFN-alpha therapy. Dual-colour fluorescence in situ hybridization (FISH) analysis using specific probes for bcr and abl genes was done to assess the molecular response. Eight patients achieved complete cytogenetic response with no Ph+ cells. Using FISH analysis, 4 of these patients were negative for the fusion gene implying a complete response, while the remaining 4 patients showed bcr/abl fusion signals that represent residual disease. Our study emphasizes the need for sequential cytogenetic and molecular analysis in the management of patients with CML and for the evaluation of minimal residual disease in patients on IFN-alpha therapy.

  3. Overproduction, purification and characterization of human interferon alpha2a-human serum albumin fusion protein produced in methilotropic yeast Pichia pastoris

    Science.gov (United States)

    Ningrum, R. A.; Santoso, A.; Herawati, N.

    2017-05-01

    Human interferon alpha2a (hIFNα2a) is a therapeutic protein that used in cancer and hepatitis B/C therapy. The main problem of using hIFNα-2a is its short elimination half life due to its low molecular weight. Development of higher molecular weight protein by albumin fusion technology is a rational strategy to solve the problem. In our previous research we constructed an open reading frame (ORF) encoding hIFNα2a-human serum albumin (HSA) fusion protein that expressed in Pichia pastoris (P. pastoris) protease deficient strain SMD1168. This research was performed to overproduce, purify and characterize the fusion protein. To overproduce the protein, cultivation was performed in buffered complex medium containing glyserol (BMGY) for 24 h and protein overproduction was applied in buffered complex medium containing methanol (BMMY) for 48 hours at 30°C. The fusion protein was purified by blue sepharose affinity chromatography. Molecular weight characterization by SDS PAGE corresponds with its theoretical size, 85 kDa. Western blot analysis demonstrated that the fusion protein was recognized by anti hIFNα2 and anti HSA monoclonal antibody as well. Amino acid sequence of the fusion protein was determined by LC MS/MS2 mass spectrometry with trypsin as proteolitic enzyme. There were three fragments that identified as hIFNα2a and seven fragments that identified as HSA. Total identified amino acids were 150 residues with 20% coverage from total residues. To conclude, hIFNα2a-HSA fusion protein was overproduced, purified and characterized. Characterization based on molecular weight, antibody recognition and amino acid sequence confirmed that the fusion protein has correct identity as theoretically thought.

  4. Heterogeneity of alpha 2-adrenoceptors in rat cortex but not human platelets can be defined by 8-OH-DPAT, RU 24969 and methysergide.

    Science.gov (United States)

    Brown, C. M.; MacKinnon, A. C.; McGrath, J. C.; Spedding, M.; Kilpatrick, A. T.

    1990-01-01

    1. Saturation experiments indicated that [3H]-yohimbine binding was specific, saturable and labelled a single population of sites in rat cerebral cortex (Kd 5.3 +/- 0.9 nM, Bmax 121 +/- 10 fmol mg-1 protein) and human platelets (Kd 0.7 +/- 0.1 nM, Bmax 152 +/- 10 fmol mg-1 protein). 2. The alpha 2-adrenoceptor antagonists, yohimbine, rauwolscine, WY 26703, idazoxan and BDF 6143 displaced [3H]-yohimbine binding to each tissue in a simple manner, with high affinity and Hill slopes close to unity. 3. The alpha 1-adrenoceptor agonist, oxymetazoline and the antagonist prazosin inhibited the binding of [3H]-yohimbine to rat in a complex manner consistent with an interaction at more than one site. However, indoramin and WB 4101 only appeared to interact with one site. In contrast, in human platelets, all antagonists gave rise to monophasic displacement curves with Hill slopes close to unity suggesting a single site of interaction. 4. The 5-hydroxytryptamine (5-HT) receptor ligands, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), RU 24969, and methysergide inhibited the binding of [3H]-yohimbine to rat cortex with high and low affinity, consistent with an interaction with two populations of binding sites. However, inhibition of [3H]-yohimbine binding to human platelets suggested a single site of interaction. The low affinity of 5-HT, 5-carboxyamidotryptamine (5-CT) and dipropyl-5-CT indicated that [3H]-yohimbine was not labelling a 5-HT1-like site in rat cortex.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1970497

  5. Exonic variants associated with development of aspirin exacerbated respiratory diseases.

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    Seung-Woo Shin

    Full Text Available Aspirin-exacerbated respiratory disease (AERD is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA, and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1 were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC of the receiver operating characteristic (ROC curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10-8 in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954 showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21, with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be "probably damaging" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

  6. The Food Contaminant Deoxynivalenol Exacerbates the Genotoxicity of Gut Microbiota

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    Delphine Payros

    2017-03-01

    Full Text Available An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON is the most prevalent mycotoxin that contaminates staple food—especially cereal products—in Europe and North America. This study investigates the effect of the food contaminant DON on the genotoxicity of the E. coli strains producing colibactin. In vitro, intestinal epithelial cells were coexposed to DON and E. coli producing colibactin. In vivo, newborn rats colonized at birth with E. coli producing colibactin were fed a DON-contaminated diet. Intestinal DNA damage was estimated by the phosphorylation of histone H2AX. DON exacerbates the genotoxicity of the E. coli producing colibactin in a time- and dose-dependent manner in vitro. Although DON had no effect on the composition of the gut microbiota, and especially on the number of E. coli, a significant increase in DNA damage was observed in intestinal epithelial cells of animals colonized by E. coli strains producing colibactin and coexposed to DON compared to animals colonized with E. coli strains unable to produce colibactin or animals exposed only to DON. In conclusion, our data demonstrate that the genotoxicity of E. coli strains producing colibactin, increasingly present in the microbiota of asymptomatic human beings, is modulated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis.

  7. Right ventricular function during acute exacerbation of severe equine asthma.

    Science.gov (United States)

    Decloedt, A; Borowicz, H; Slowikowska, M; Chiers, K; van Loon, G; Niedzwiedz, A

    2017-09-01

    Pulmonary hypertension has been described in horses with severe equine asthma, but its effect on the right ventricle has not been fully elucidated. To evaluate right ventricular structure and function after a 1-week period of pulmonary hypertension secondary to acute exacerbation of severe equine asthma. Prospective study. A clinical episode of severe equine asthma was induced experimentally in six susceptible horses. Examinations in remission and on day 7 of the clinical episode included a physical examination with clinical scoring, echocardiography, arterial blood gas measurements, venous blood sampling for cardiac biomarkers, intracardiac pressure measurements, right ventricular and right atrial myocardial biopsies, airway endoscopy and bronchoalveolar lavage. After 1 month of recovery, physical examination, echocardiography and cardiac biomarker analysis were repeated. Echocardiographic and pressure measurements were compared with those in 10 healthy control horses. All horses developed clinical signs of acute pulmonary obstruction. Right heart pressures increased significantly. Altered right ventricular function could be detected by tissue Doppler and speckle tracking echocardiography. Cardiac troponin concentrations did not increase significantly, but were highly elevated in one horse which exercised in the paddock prior to sampling. Focal neutrophil infiltration was present in two myocardial samples. Even in remission, asthmatic horses showed a thicker right ventricular wall, an increased left ventricular end-systolic eccentricity index at chordal level and decreased right ventricular longitudinal strain compared with controls. The induced clinical episode was rather mild and the number of horses was limited because of the invasive nature of the study. Pulmonary obstruction in asthmatic horses induces pulmonary hypertension with right ventricular structural and functional changes. © 2017 EVJ Ltd.

  8. Analysis of acutely exacerbated chronic tinnitus by the Tinnitus Handicap Inventory.

    Science.gov (United States)

    Zeng, X; Li, P; Li, Z; Cen, J; Li, Y; Zhang, G

    2016-01-01

    To examine factors potentially contributing to acutely exacerbated chronic tinnitus initiation using the Tinnitus Handicap Inventory. Sixty acutely exacerbated chronic tinnitus out-patients were divided into two groups depending on whether hearing loss was aggravated or stable during tinnitus exacerbation. Total Tinnitus Handicap Inventory scores and scores for the three subscales (assessing functional limitations, emotional attitudes and catastrophic thoughts) were analysed. Total Tinnitus Handicap Inventory scores did not differ between groups. In patients with acutely exacerbated chronic tinnitus and aggravated hearing loss, functional subscale scores were significantly higher after acutely exacerbated chronic tinnitus than at baseline, but catastrophic and emotional subscale scores did not change. In patients with acutely exacerbated chronic tinnitus and stable hearing loss, emotional subscale scores were significantly higher after acutely exacerbated chronic tinnitus than at baseline, but catastrophic and functional subscale scores did not change. Elevated Tinnitus Handicap Inventory functional subscale scores might indicate further hearing loss, whereas elevated emotional subscale scores might be associated with negative life or work events.

  9. Monitoring of Physiological Parameters to Predict Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

    Science.gov (United States)

    Al Rajeh, Ahmed M.; Hurst, John R.

    2016-01-01

    Introduction: The value of monitoring physiological parameters to predict chronic obstructive pulmonary disease (COPD) exacerbations is controversial. A few studies have suggested benefit from domiciliary monitoring of vital signs, and/or lung function but there is no existing systematic review. Objectives: To conduct a systematic review of the effectiveness of monitoring physiological parameters to predict COPD exacerbation. Methods: An electronic systematic search compliant with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. The search was updated to April 6, 2016. Five databases were examined: Medical Literature Analysis and Retrieval System Online, or MEDLARS Online (Medline), Excerpta Medica dataBASE (Embase), Allied and Complementary Medicine Database (AMED), Cumulative Index of Nursing and Allied Health Literature (CINAHL) and the Cochrane clinical trials database. Results: Sixteen articles met the pre-specified inclusion criteria. Fifteen of these articules reported positive results in predicting COPD exacerbation via monitoring of physiological parameters. Nine studies showed a reduction in peripheral oxygen saturation (SpO2%) prior to exacerbation onset. Three studies for peak flow, and two studies for respiratory rate reported a significant variation prior to or at exacerbation onset. A particular challenge is accounting for baseline heterogeneity in parameters between patients. Conclusion: There is currently insufficient information on how physiological parameters vary prior to exacerbation to support routine domiciliary monitoring for the prediction of exacerbations in COPD. However, the method remains promising. PMID:27897995

  10. Clinical and Functional Lung Parameters Associated With Frequent Exacerbator Phenotype in Subjects With Severe COPD.

    Science.gov (United States)

    Capozzolo, Alberto; Carratù, Pierluigi; Dragonieri, Silvano; Falcone, Vito Antonio; Quaranta, Vitaliano Nicola; Liotino, Vito; D'Alba, Giuseppina; Castellana, Giorgio; Resta, Onofrio

    2017-05-01

    COPD is currently recognized as a syndrome associated with a high prevalence of comorbidities and various phenotypes. Exacerbations are very important events in the clinical history of COPD because they drive the decline in lung function. In the present study, we aim to identify whether there are any clinical and functional specific features of frequent exacerbators in a population of patients with severe COPD. We conducted a cross-sectional, case control study. All subjects had Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3 or 4 COPD (FEV 1 lower inspiratory capacity percentage predicted. The Motley index (residual volume/total lung capacity percentage) was significantly increased in frequent exacerbators. Infrequent exacerbators had lower Modified Medical Research Council dyspnea scale and BODE index than frequent exacerbators. In the multivariate model, a reduced inspiratory capacity percentage predicted and an increase of residual volume/total lung capacity percentage, BODE index and Modified Medical Research Council dyspnea scale were associated with the frequent exacerbation phenotype. Static hyperinflation and respiratory disability, measured by Motley index and Modified Medical Research Council dyspnea scale, respectively, in the same way as the multidimensional BODE index staging system, were independently associated with frequent exacerbation status in subjects with severe COPD. Copyright © 2017 by Daedalus Enterprises.

  11. [Behavior of predictive variables of exacerbations of the COPD in the neumological hospital of Cuba.

    Science.gov (United States)

    León Valdivies, Yusbiel José; Sánchez de la Osa, Reinaldo B; Garcia Silvera, Eberto; Machado Molina, Delfina; Oses Herrera, Liliana

    2017-01-01

    The use of predictive variables of exacerbations of the COPD is not a practice generalized in our environment, for what we cannot characterize the exacerbating patient neither to design strategies for its integral handling. There was carried out a prospective descriptive study to correlate in patient with diagnosis of COPD from the Neumologic Hospital of Cuba, with the objective of determining the association between clinical, functional variables and imagenological and the exacerbations frequency a year. The population was constituted for patients with clinical diagnosis of COPD and the sample for those patients with confirmed diagnosis that they completed the inclusion approaches. The correlation among the variables was carried out by means of the Coefficient of Correlation of Pearson with an interval of Trust of 95% and the test t student with a significance level (p) smaller than 0.05. 81.82% of the very serious patients are exacerbating with emphysema. 75% of the patients with index of the lung artery / aorta have more than two exacerbations a year. 84.61% of the patient exacerbating presented degree four of the dyspnea. The half pressure of the lung artery next to the VEF1 constituted the best exacerbations predictors in the group of studied patients.

  12. Trauma-Focused Treatment in PTSD Patients With Psychosis: Symptom Exacerbation, Adverse Events, and Revictimization.

    Science.gov (United States)

    van den Berg, David P G; de Bont, Paul A J M; van der Vleugel, Berber M; de Roos, Carlijn; de Jongh, Ad; van Minnen, Agnes; van der Gaag, Mark

    2016-05-01

    Most clinicians refrain from trauma treatment for patients with psychosis because they fear symptom exacerbation and relapse. This study examined the negative side effects of trauma-focused (TF) treatment in patients with psychosis and posttraumatic stress disorder (PTSD). Analyses were conducted on data from a single-blind randomized controlled trial comparing TF treatment (N = 108; 8 sessions prolonged exposure or eye movement desensitization) and waiting list (WL; N = 47) among patients with a lifetime psychotic disorder and current chronic PTSD. Symptom exacerbation, adverse events, and revictimization were assessed posttreatment and at 6-month follow-up. Also investigated were symptom exacerbation after initiation of TF treatment and the relationship between symptom exacerbation and dropout. Any symptom exacerbation (PTSD, paranoia, or depression) tended to occur more frequently in the WL condition. After the first TF treatment session, PTSD symptom exacerbation was uncommon. There was no increase of hallucinations, dissociation, or suicidality during the first 2 sessions. Paranoia decreased significantly during this period. Dropout was not associated with symptom exacerbation. Compared with the WL condition, fewer persons in the TF treatment condition reported an adverse event (OR = 0.48, P = .032). Surprisingly, participants receiving TF treatment were significantly less likely to be revictimized (OR = 0.40, P = .035). In these participants, TF treatment did not result in symptom exacerbation or adverse events. Moreover, TF treatment was associated with significantly less exacerbation, less adverse events, and reduced revictimization compared with the WL condition. This suggests that conventional TF treatment protocols can be safely used in patients with psychosis without negative side effects. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email

  13. Association between respiratory impedance measured by forced oscillation technique and exacerbations in patients with COPD

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    Yamagami H

    2017-12-01

    Full Text Available Hitomi Yamagami, Akihiko Tanaka, Yasunari Kishino, Hatsuko Mikuni, Tomoko Kawahara, Shin Ohta, Mayumi Yamamoto, Shintaro Suzuki, Tsukasa Ohnishi, Hironori Sagara Division of Respiratory Medicine and Allergology, Department of Medicine, School of Medicine, Showa University, Tokyo, Japan Background: It is well known that increased airflow limitation as measured by spirometry is associated with the risk of exacerbation in patients with COPD. The forced oscillation technique (FOT is a noninvasive method used to assess respiratory impedance (resistance and reactance with minimal patient cooperation required. The clinical utility of the FOT in assessing the risk of exacerbations of COPD is yet to be determined. We examined the relationship between respiratory impedance as measured by FOT and exacerbations in patients with COPD. Materials and methods: Among 310 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stages I–IV who presented at the outpatient clinic of the Showa University Hospital from September 2014 through January 2015, 119 were collected and assigned into 2 groups according to their history of exacerbation: exacerbators and nonexacerbators. Respiratory resistance components and respiratory reactance components, as measured by FOT, were compared between the two groups. Results: Exacerbators were significantly older and had a higher white blood cell count than nonexacerbators. Resistance at 20 Hz, reactance at 5 Hz (X5, resonant frequency (Fres, and area of low reactance (ALX differed significantly between the two groups. In addition, among patients with stage II COPD, there were significant differences in X5, Fres, and ALX between the two groups despite no significant differences in respiratory function as assessed by spirometry. Finally, receiver operating characteristic curve analysis revealed that the reactance components rather than the resistance components were associated with the risk of exacerbation

  14. Plasma sCD14 as a biomarker to predict pulmonary exacerbations in cystic fibrosis.

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    Bradley S Quon

    Full Text Available BACKGROUND: One in four cystic fibrosis (CF patients diagnosed with a pulmonary exacerbation will not recover their baseline lung function despite standard treatment. This highlights the importance of preventing such events. Clinical decision-making can be improved through a simple blood test that predicts individuals at elevated short-term risk of an exacerbation. METHODS: We obtained plasma samples from 30 stable CF patients from the St. Paul's Hospital Adult CF Clinic (Vancouver, Canada. For 15 patients, an additional plasma sample was obtained during an exacerbation. Soluble CD14 (sCD14 and C-reactive protein (CRP were quantified using ELISA kits. Myeloperoxidase (MPO, interleukin(IL-6, IL-1β, monocyte chemoattractant protein-1 (MCP-1, vascular endothelial growth factor (VEGF, and granulocyte colony-stimulating factor (G-CSF were quantified using Luminex™ immunoassays. Stable state biomarker levels were examined in their ability to predict individuals that would experience a pulmonary exacerbation requiring intravenous (IV antibiotics within 4 months. Paired stable and exacerbation plasma biomarker levels were also compared. RESULTS: sCD14 levels were significantly higher in patients that experienced a pulmonary exacerbation requiring IV antibiotics within 4 months (p = 0.001. sCD14 cut-off value of 1450 ng/mL was associated with an area under the curve of 0.91 (95% CI 0.83-0.99 for predicting an exacerbation within 4 months of a stable visit, with a sensitivity of 100% and specificity of 82%. Plasma sCD14 levels were significantly higher during exacerbations than during periods of clinical stability (p = 0.03. CONCLUSIONS: Plasma sCD14 is a promising biomarker for identifying CF patients who will exacerbate within 4 months of a stable visit but requires further study in larger, independent cohorts.

  15. Exacerbations of chronic obstructive pulmonary disease: when are antibiotics indicated? A systematic review

    Directory of Open Access Journals (Sweden)

    Steurer Johann

    2007-04-01

    Full Text Available Abstract Background For decades, there is an unresolved debate about adequate prescription of antibiotics for patients suffering from exacerbations of chronic obstructive pulmonary disease (COPD. The aim of this systematic review was to analyse randomised controlled trials investigating the clinical benefit of antibiotics for COPD exacerbations. Methods We conducted a systematic review of randomised, placebo-controlled trials assessing the effects of antibiotics on clinically relevant outcomes in patients with an exacerbation. We searched bibliographic databases, scrutinized reference lists and conference proceedings and asked the pharmaceutical industry for unpublished data. We used fixed-effects models to pool results. The primary outcome was treatment failure of COPD exacerbation treatment. Results We included 13 trials (1557 patients of moderate to good quality. For the effects of antibiotics on treatment failure there was much heterogeneity across all trials (I2 = 82%. Meta-regression revealed severity of exacerbation as significant explanation for this heterogeneity (p = 0.016: Antibiotics did not reduce treatment failures in outpatients with mild to moderate exacerbations (pooled odds ratio 1.09, 95% CI 0.75–1.59, I2 = 18%. Inpatients with severe exacerbations had a substantial benefit on treatment failure rates (pooled odds ratio of 0.25, 95% CI 0.16–0.39, I2 = 0%; number-needed to treat of 4, 95% CI 3–5 and on mortality (pooled odds ratio of 0.20, 95% CI 0.06–0.62, I2 = 0%; number-needed to treat of 14, 95% CI 12–30. Conclusion Antibiotics effectively reduce treatment failure and mortality rates in COPD patients with severe exacerbations. For patients with mild to moderate exacerbations, antibiotics may not be generally indicated and further research is needed to guide antibiotic prescription in these patients.

  16. Consumption of Diet Containing Free Amino Acids Exacerbates Colitis in Mice

    Directory of Open Access Journals (Sweden)

    Adna Luciana Souza

    2017-11-01

    Full Text Available Dietary proteins can influence the maturation of the immune system, particularly the gut-associated lymphoid tissue, when consumed from weaning to adulthood. Moreover, replacement of dietary proteins by amino acids at weaning has been shown to impair the generation of regulatory T cells in the gut as well as immune activities such as protective response to infection, induction of oral and nasal tolerance as well as allergic responses. Polymeric and elemental diets are used in the clinical practice, but the specific role of intact proteins and free amino acids during the intestinal inflammation are not known. It is plausible that these two dietary nitrogen sources would yield distinct immunological outcomes since proteins are recognized by the immune system as antigens and amino acids do not bind to antigen-recognition receptors but instead to intracellular receptors such as mammalian target of rapamycin (mTOR. In this study, our aim was to evaluate the effects of consumption of an amino acid-containing diet (AA diet versus a control protein-containing diet in adult mice at steady state and during colitis development. We showed that consumption of a AA diet by adult mature mice lead to various immunological changes including decrease in the production of serum IgG as well as increase in the levels of IL-6, IL-17A, TGF-β, and IL-10 in the small and large intestines. It also led to changes in the intestinal morphology, to increase in intestinal permeability, in the number of total and activated CD4+ T cells in the small intestine as well as in the frequency of proliferating cells in the colon. Moreover, consumption of AA diet during and prior to development of dextran sodium sulfate-induced colitis exacerbated gut inflammation. Administration of rapamycin during AA diet consumption prevented colitis exacerbation suggesting that mTOR activation was involved in the effects triggered by the AA diet. Therefore, our study suggests that different

  17. Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly.

    Science.gov (United States)

    Taylor, Stephanie Parks; Sellers, Eric; Taylor, Brice T

    2015-12-01

    Long-term azithromycin therapy has been shown to reduce exacerbations of chronic obstructive pulmonary disease (COPD), and is recommended by recent society guidelines for use in COPD patients who are at risk for recurrent exacerbations. However, concerns about adverse effects have limited its widespread adoption. Physicians deciding whether to use long-term azithromycin therapy must weigh each patient's individual risk of cardiovascular complications and both the individual and population impact of macrolide resistance against the expected benefit. This review will summarize evidence on the effectiveness and safety of chronic azithromycin for the prevention of COPD exacerbations. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

    Science.gov (United States)

    Wells, J. Michael; Farris, Roopan F.; Gosdin, Taylor A.; Dransfield, Mark T.; Wood, Michelle E.; Bell, Scott C.; Rowe, Steven M.

    2017-01-01

    Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:Apulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF. PMID:27298019

  19. Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock

    Energy Technology Data Exchange (ETDEWEB)

    Li, L.L.; Zhang, C.H.; Liu, J.C.; Yang, L.N.; Niu, C.Y.; Zhao, Z.G. [Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei, China, Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei (China)

    2014-04-15

    The intestinal lymph pathway plays an important role in the pathogenesis of organ injury following superior mesenteric artery occlusion (SMAO) shock. We hypothesized that mesenteric lymph reperfusion (MLR) is a major cause of spleen injury after SMAO shock. To test this hypothesis, SMAO shock was induced in Wistar rats by clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h. Similarly, MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h, followed by reperfusion for 2 h. In the MLR+SMAO group rats, both the SMA and MLD were clamped and then released for reperfusion for 2 h. SMAO shock alone elicited: 1) splenic structure injury, 2) increased levels of malondialdehyde, nitric oxide (NO), intercellular adhesion molecule-1, endotoxin, lipopolysaccharide receptor (CD14), lipopolysaccharide-binding protein, and tumor necrosis factor-α, 3) enhanced activities of NO synthase and myeloperoxidase, and 4) decreased activities of superoxide dismutase and ATPase. MLR following SMAO shock further aggravated these deleterious effects. We conclude that MLR exacerbates spleen injury caused by SMAO shock, which itself is associated with oxidative stress, excessive release of NO, recruitment of polymorphonuclear neutrophils, endotoxin translocation, and enhanced inflammatory responses.

  20. Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock.

    Science.gov (United States)

    Li, L L; Zhang, C H; Liu, J C; Yang, L N; Niu, C Y; Zhao, Z G

    2014-05-01

    The intestinal lymph pathway plays an important role in the pathogenesis of organ injury following superior mesenteric artery occlusion (SMAO) shock. We hypothesized that mesenteric lymph reperfusion (MLR) is a major cause of spleen injury after SMAO shock. To test this hypothesis, SMAO shock was induced in Wistar rats by clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h. Similarly, MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h, followed by reperfusion for 2 h. In the MLR+SMAO group rats, both the SMA and MLD were clamped and then released for reperfusion for 2 h. SMAO shock alone elicited: 1) splenic structure injury, 2) increased levels of malondialdehyde, nitric oxide (NO), intercellular adhesion molecule-1, endotoxin, lipopolysaccharide receptor (CD14), lipopolysaccharide-binding protein, and tumor necrosis factor-α, 3) enhanced activities of NO synthase and myeloperoxidase, and 4) decreased activities of superoxide dismutase and ATPase. MLR following SMAO shock further aggravated these deleterious effects. We conclude that MLR exacerbates spleen injury caused by SMAO shock, which itself is associated with oxidative stress, excessive release of NO, recruitment of polymorphonuclear neutrophils, endotoxin translocation, and enhanced inflammatory responses.

  1. Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states.

    Science.gov (United States)

    Boroujerdi, Amin; Zeng, Jun; Sharp, Kelli; Kim, Donghyun; Steward, Oswald; Luo, Z David

    2011-03-01

    Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca(v)α2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca(v)α2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca(v)α2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca(v)α2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca(v)α2δ-1 protein upregulation by intrathecal Ca(v)α2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca(v)α2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients. Spinal cord contusion injury caused increased calcium channel Ca(v)α2δ-1 subunit expression in dorsal spinal cord that contributes to neuropathic pain states. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  2. Alpha-2 Heremans Schmid Glycoprotein (AHSG) Modulates Signaling Pathways in Head and Neck Squamous Cell Carcinoma Cell Line SQ20B

    International Nuclear Information System (INIS)

    Thompson, Pamela D.; Sakwe, Amos; Koumangoye, Rainelli; Yarbrough, Wendell G.; Ochieng, Josiah; Marshall, Dana R.

    2014-01-01

    This study was performed to identify the potential role of Alpha-2 Heremans Schmid Glycoprotein (AHSG) in Head and Neck Squamous Cell Carcinoma (HNSCC) tumorigenesis using an HNSCC cell line model. HNSCC cell lines are unique among cancer cell lines, in that they produce endogenous AHSG and do not rely, solely, on AHSG derived from serum. To produce our model, we performed a stable transfection to down-regulate AHSG in the HNSCC cell line SQ20B, resulting in three SQ20B sublines, AH50 with 50% AHSG production, AH20 with 20% AHSG production and EV which is the empty vector control expressing wild-type levels of AHSG. Utilizing these sublines, we examined the effect of AHSG depletion on cellular adhesion, proliferation, migration and invasion in a serum-free environment. We demonstrated that sublines EV and AH50 adhered to plastic and laminin significantly faster than the AH20 cell line, supporting the previously reported role of exogenous AHSG in cell adhesion. As for proliferative potential, EV had the greatest amount of proliferation with AH50 proliferation significantly diminished. AH20 cells did not proliferate at all. Depletion of AHSG also diminished cellular migration and invasion. TGF-β was examined to determine whether levels of the TGF-β binding AHSG influenced the effect of TGF-β on cell signaling and proliferation. Whereas higher levels of AHSG blunted TGF-β influenced SMAD and ERK signaling, it did not clearly affect proliferation, suggesting that AHSG influences on adhesion, proliferation, invasion and migration are primarily due to its role in adhesion and cell spreading. The previously reported role of AHSG in potentiating metastasis via protecting MMP-9 from autolysis was also supported in this cell line based model system of endogenous AHSG production in HNSCC. Together, these data show that endogenously produced AHSG in an HNSCC cell line, promotes in vitro cellular properties identified as having a role in tumorigenesis. Highlights: • Head

  3. Alpha-2 Heremans Schmid Glycoprotein (AHSG) Modulates Signaling Pathways in Head and Neck Squamous Cell Carcinoma Cell Line SQ20B

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Pamela D.; Sakwe, Amos [Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208 (United States); Koumangoye, Rainelli [Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Yarbrough, Wendell G. [Division of Otolaryngology, Departments of Surgery and Pathology and Yale Cancer Center, Yale University, New Haven, CT 06520 (United States); Ochieng, Josiah [Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208 (United States); Marshall, Dana R., E-mail: dmarshall@mmc.edu [Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, Nashville, TN 37208 (United States)

    2014-02-15

    This study was performed to identify the potential role of Alpha-2 Heremans Schmid Glycoprotein (AHSG) in Head and Neck Squamous Cell Carcinoma (HNSCC) tumorigenesis using an HNSCC cell line model. HNSCC cell lines are unique among cancer cell lines, in that they produce endogenous AHSG and do not rely, solely, on AHSG derived from serum. To produce our model, we performed a stable transfection to down-regulate AHSG in the HNSCC cell line SQ20B, resulting in three SQ20B sublines, AH50 with 50% AHSG production, AH20 with 20% AHSG production and EV which is the empty vector control expressing wild-type levels of AHSG. Utilizing these sublines, we examined the effect of AHSG depletion on cellular adhesion, proliferation, migration and invasion in a serum-free environment. We demonstrated that sublines EV and AH50 adhered to plastic and laminin significantly faster than the AH20 cell line, supporting the previously reported role of exogenous AHSG in cell adhesion. As for proliferative potential, EV had the greatest amount of proliferation with AH50 proliferation significantly diminished. AH20 cells did not proliferate at all. Depletion of AHSG also diminished cellular migration and invasion. TGF-β was examined to determine whether levels of the TGF-β binding AHSG influenced the effect of TGF-β on cell signaling and proliferation. Whereas higher levels of AHSG blunted TGF-β influenced SMAD and ERK signaling, it did not clearly affect proliferation, suggesting that AHSG influences on adhesion, proliferation, invasion and migration are primarily due to its role in adhesion and cell spreading. The previously reported role of AHSG in potentiating metastasis via protecting MMP-9 from autolysis was also supported in this cell line based model system of endogenous AHSG production in HNSCC. Together, these data show that endogenously produced AHSG in an HNSCC cell line, promotes in vitro cellular properties identified as having a role in tumorigenesis. Highlights: • Head

  4. Evaluation of radioiodinated (2S,{alpha}S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine as a radioligand for imaging of norepinephrine transporter in the heart

    Energy Technology Data Exchange (ETDEWEB)

    Kiyono, Yasushi [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan)], E-mail: ykiyono@u-fukui.ac.jp; Sugita, Taku [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Ueda, Masashi [Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Kawashima, Hidekazu [Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Kanegawa, Naoki; Kuge, Yuji [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Fujibayashi, Yasuhisa [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Saji, Hideo [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2008-02-15

    Introduction: The norepinephrine transporter (NET) is located presynaptically on noradrenergic nerve terminals and plays a critical role in the regulation of the synaptic norepinephrine (NE) concentration via the reuptake of NE. Changes in NET have been recently reported in several cardiac failures. Therefore, a NET-specific radioligand is useful for in vivo assessment of changes in NET density in various cardiac disorders. Recently, we developed a radioiodinated reboxetine analogue, (2S,{alpha}S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine ((S,S)-IPBM), for NET imaging. In the current study, we assessed the applicability of radioiodinated (S,S)-IPBM to NET imaging in the heart. Methods: The NET affinity and selectivity were measured from the ability to displace specific [{sup 3}H]nisoxetine and (S,S)-[{sup 125}I]IPBM binding to rat heart membrane, respectively. To evaluate the distribution of (S,S)-[{sup 125}I]IPBM in vivo, biodistribution experiment was performed in rats. With the use of several monoamine transporter binding agents, pharmacological blocking experiments were performed in rats. Results: In vitro binding assays showed that the affinity of (S,S)-IPBM to NET was similar to those of the well-known NET-specific binding agents, nisoxetine and desipramine. Furthermore, (S,S)-[{sup 125}I]IPBM binding was inhibited by nisoxetine and desipramine, but not by dopamine or serotonin transporter binding agents. These data indicated that (S,S)-IPBM had high affinity and selectivity for NET in vitro. Biodistribution studies in rats showed rapid and high uptake of (S,S)-[{sup 125}I]IPBM by the heart and rapid clearance from the blood. The heart-to-blood ratio was 31.9 at 180 min after the injection. The administration of nisoxetine and desipramine decreased (S,S)-[{sup 125}I]IPBM accumulation in the heart, but injection of fluoxetine and GBR12909 had little influence. Conclusions: Radioiodinated (S,S)-IPBM is a potential radioligand for NET imaging in the heart.

  5. Basic Research on Virus-Induced Asthma Exacerbation: Inhibition of Inflammatory Chemokine Expression by Fluticasone Propionate

    Science.gov (United States)

    Matsukura, Satoshi; Kurokawa, Masatsugu; Homma, Tetsuya; Watanabe, Shin; Suzuki, Shintaro; Ieki, Koushi; Takeuchi, Hiroko; Notomi, Kyoko; Schleimer, Robert P.; Kawaguchi, Mio; Kokubu, Fumio

    2016-01-01

    Background Viral infection can exacerbate asthma by inducing the accumulation of inflammatory cells in the airway. We have previously reported that double-stranded RNA (dsRNA), a viral product and ligand of the Toll-like receptor-3 (TLR3), activates the transcription factors NF-κB and IRF-3 and upregulates the expression of inflammatory chemokines in airway epithelial cells. Here, we examined the effects of the glucocorticoid fluticasone propionate (FP) on the expression of the inflammatory chemokines CCL5, CXCL8 and CXCL10. Methods The airway epithelial cell line BEAS-2B was used for this study. Expression of CCL5, CXCL8 and CXCL10 mRNA and protein was quantified by real-time PCR and ELISA assay, respectively. To examine the association of FP with the physiology of chemokine production, we included several methods. Nuclear translocation of transcription factors was determined by performing Western blot analysis. Histone deacetylase (HDAC) activity in nuclear extracts was measured using a colorimetric assay. Stability of the chemokine mRNAs was examined in cells incubated with actinomycin D. The activities of the CCL5 promoter and the transcription factors NF-κB and IRF-3 were assessed using luciferase reporter assays. Results Treatment of BEAS-2B cells with FP significantly and dose-dependently (10−9 to 10−6 M) inhibited dsRNA-induced expression of CCL5, CXCL8 and CXCL10 protein and mRNA, but did not affect mRNA stability. FP also significantly inhibited dsRNA-stimulated CCL5 promoter activity. However, FP had no effect on the activity of HDAC or the nuclear translocation of NF-κB and IRF-3. Conclusions FP inhibits the dsRNA-stimulated expression of inflammatory chemokines in airway epithelial cells. FP may act by inhibiting chemokine transcription through an as yet Unidentified mechanism. PMID:23711858

  6. Viruses and bacteria in acute asthma exacerbations - A GA(2) LEN-DARE* systematic review

    DEFF Research Database (Denmark)

    Papadopoulos, N G; Christodoulou, I; Rohde, G

    2011-01-01

    less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable...... and bacteria in acute asthma exacerbations - A GA(2) LEN-DARE systematic review. Allergy 2010; DOI: 10.1111/j.1398-9995.2010.02505.x. ABSTRACT: A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections....... Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate...

  7. The effect of COPD severity and study duration on exacerbation outcome in randomized controlled trials

    NARCIS (Netherlands)

    Eriksson, Goran; Calverley, Peter M.; Jenkins, Christine R.; Anzueto, Antonio R.; Make, Barry J.; Lindberg, Magnus; Fageras, Malin; Postma, Dirkje S.

    2017-01-01

    Background: When discontinuation in COPD randomized controlled trials (RCTs) is unevenly distributed between treatments (differential dropout), the capacity to demonstrate treatment effects may be reduced. We investigated the impact of the time of differential dropout on exacerbation outcomes in

  8. The Relationship Between 24-Hour Symptoms and COPD Exacerbations and Healthcare Resource Use

    DEFF Research Database (Denmark)

    Miravitlles, Marc; Worth, Heinrich; Soler-Cataluña, Juan José

    2016-01-01

    and healthcare resource use. 727 patients were eligible (65.8% male, mean age: 67.2 years, % predicted forced expiratory volume in 1 second: 52.8%); 698 patients (96.0%) provided information after 6 months. Symptoms in any part of the day were associated with a prior history of exacerbations (all p ...This observational study assessed the relationship between nighttime, early-morning and daytime chronic obstructive pulmonary disease (COPD) symptoms and exacerbations and healthcare resource use. COPD symptoms were assessed at baseline in patients with stable COPD using a standardised...... questionnaire during routine clinical visits. Information was recorded on exacerbations and healthcare resource use during the year before baseline and during a 6-month follow-up period. The main objective of the analysis was to determine the predictive nature of current symptoms for future exacerbations...

  9. Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients

    Directory of Open Access Journals (Sweden)

    Christini Takemi Emori

    2014-11-01

    Conclusions: Acute exacerbation was a frequent and severe event in HBV-infected renal transplant patients. Prophylactic/preemptive therapy with antiviral drugs should be indicated for all HBsAg-positive renal transplant patients.

  10. Management and prevention of chronic obstructive pulmonary disease exacerbations: a state of the art review

    Directory of Open Access Journals (Sweden)

    Wedzicha Jadwiga A

    2009-08-01

    Full Text Available Abstract Exacerbations of chronic obstructive pulmonary disease (COPD are important events in the natural history of this prevalent and devastating condition. This review provides a concise, state of the art summary on prevention and management of exacerbations. Considerable new data underpins evidence in support of many preventative interventions, pharmacological and non-pharmacological, that are now available. Challenges remain in developing new approaches, and delivering those that already exist to the right patient at the right time. Management of an exacerbation remains stepwise according to clinical severity, but there is now additional focus on addressing comorbidities and taking the opportunity at acute events to optimise preventative strategies for the future. Ultimately, exacerbations are heterogeneous events in a heterogeneous disease, and an individualised approach is paramount.

  11. Induction of Thymic Stromal Lymphopoietin Production by Nonanoic Acid and Exacerbation of Allergic Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Saori Yamashita

    2013-01-01

    Conclusions: Nonanoic acid and certain fatty acids induced TSLP production, resulting in the exacerbation of allergic inflammation. We propose that TSLP-inducing chemical compounds such as nonanoic acid be recognized as chemical allergo-accelerators.

  12. Necessity of amoxicillin clavulanic acid in addition to prednisolone in mild-to-moderate COPD exacerbations

    NARCIS (Netherlands)

    Brusse-Keizer, Marjolein; van der Valk, Paul; Hendrix, Ron; Kerstjens, Huib A.M.; van der Palen, Jacobus Adrianus Maria

    2014-01-01

    Background: The effectiveness of antibiotics in chronic obstructive pulmonary disease (COPD) exacerbations is still a matter of debate, especially in outpatients with an intermediate probability of bacterial infection. Methods: In this study, 35 COPD outpatients diagnosed by their chest physician

  13. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study

    DEFF Research Database (Denmark)

    Jenkins, C R; Celli, B; Anderson, J A

    2012-01-01

    We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1))...

  14. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma

    DEFF Research Database (Denmark)

    Bisgaard, Hans; Zielen, Stefen; Garcia-Garcia, María Luz

    2005-01-01

    The PREVIA study was designed to investigate the role of montelukast, a leukotriene receptor antagonist, in the prevention of viral-induced asthma exacerbations in children aged 2 to 5 years with a history of intermittent asthma symptoms. The study was a 12-month multicenter, double-blind, parallel......-group study of patients with asthma exacerbations associated with respiratory infections and minimal symptoms between episodes. Patients were randomized to receive oral montelukast 4 or 5 mg (depending on age) (n = 278) or placebo (n = 271) once per day for 12 months. Caregivers recorded children's symptoms......, beta-agonist use, and health care resource use in a diary card. Over 12 months of therapy, montelukast significantly reduced the rate of asthma exacerbations by 31.9% compared with placebo. The average rate of exacerbation episodes per patient was 1.60 episodes per year on montelukast compared with 2...

  15. The Use of Noninvasive Mechanical Ventilation for the Treatment of Acute Exacerbations of Copd in Canada

    Directory of Open Access Journals (Sweden)

    Jennifer Drummond

    2005-01-01

    Full Text Available BACKGROUND: Noninvasive mechanical ventilation (NIMV is accepted as a life-saving treatment for patients presenting to the emergency department and other acute care settings with severe exacerbations of chronic obstructive pulmonary disease (COPD.

  16. Study of plasma orexin-A level in COPD patients during acute exacerbation

    Directory of Open Access Journals (Sweden)

    Magdy M. Omar

    2017-10-01

    Conclusion: Patients with COPD during acute exacerbation had higher values of plasma orexin-A when compared with normal subjects and plasma orexin-A correlated positively with BMI and BFP in these patients.

  17. A score to predict short-term risk of COPD exacerbations (SCOPEX

    Directory of Open Access Journals (Sweden)

    Make BJ

    2015-01-01

    Full Text Available Barry J Make,1 Göran Eriksson,2 Peter M Calverley,3 Christine R Jenkins,4 Dirkje S Postma,5 Stefan Peterson,6 Ollie Östlund,7 Antonio Anzueto8 1Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado Denver School of Medicine, Denver, CO, USA; 2Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 3Pulmonary and Rehabilitation Research Group, University Hospital Aintree, Liverpool, UK; 4George Institute for Global Health, The University of Sydney and Concord Clinical School, Woolcock Institute of Medical Research, Sydney, NSW, Australia; 5Department of Pulmonology, University of Groningen and GRIAC Research Institute, University Medical Center Groningen, Groningen, The Netherlands; 6StatMind AB, Lund, Sweden; 7Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; 8Department of Pulmonary/Critical Care, University of Texas Health Sciences Center and South Texas Veterans Healthcare System, San Antonio, TX, USA Background: There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year. Methods: Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC curves and the corresponding C-index were used to investigate the discriminatory

  18. Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model.

    Science.gov (United States)

    Ressler, Ilana B; Grayson, Bernadette E; Ulrich-Lai, Yvonne M; Seeley, Randy J

    2015-06-15

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Although a comorbidity of PCOS is obesity, many are lean. We hypothesized that increased saturated fat consumption and obesity would exacerbate metabolic and stress indices in a rodent model of PCOS. Female rats were implanted with the nonaromatizable androgen dihydrotestosterone (DHT) or placebo pellets prior to puberty. Half of each group was maintained ad libitum on either a high-fat diet (HFD; 40% butter fat calories) or nutrient-matched low-fat diet (LFD). Irrespective of diet, DHT-treated animals gained more body weight, had irregular cycles, and were glucose intolerant compared with controls on both diets. HFD/DHT animals had the highest levels of fat mass and insulin resistance. DHT animals demonstrated increased anxiety-related behavior in the elevated plus maze by decreased distance traveled and time in the open arms. HFD consumption increased immobility during the forced-swim test. DHT treatment suppressed diurnal corticosterone measurements in both diet groups. In parallel, DHT treatment significantly dampened stress responsivity to a mild stressor. Brains of DHT animals showed attenuated c-Fos activation in the ventromedial hypothalamus and arcuate nucleus; irrespective of DHT-treatment, however, all HFD animals had elevated hypothalamic paraventricular nucleus c-Fos activation. Whereas hyperandrogenism drives overall body weight gain, glucose intolerance, anxiety behaviors, and stress responsivity, HFD consumption exacerbates the effect of androgens on adiposity, insulin resistance, and depressive behaviors. Copyright © 2015 the American Physiological Society.

  19. Stress exacerbates neuron loss and microglia proliferation in a rat model of excitotoxic lower motor neuron injury.

    Science.gov (United States)

    Puga, Denise A; Tovar, C Amy; Guan, Zhen; Gensel, John C; Lyman, Matthew S; McTigue, Dana M; Popovich, Phillip G

    2015-10-01

    All individuals experience stress and hormones (e.g., glucocorticoids/GCs) released during stressful events can affect the structure and function of neurons. These effects of stress are best characterized for brain neurons; however, the mechanisms controlling the expression and binding affinity of glucocorticoid receptors in the spinal cord are different than those in the brain. Accordingly, whether stress exerts unique effects on spinal cord neurons, especially in the context of pathology, is unknown. Using a controlled model of focal excitotoxic lower motor neuron injury in rats, we examined the effects of acute or chronic variable stress on spinal cord motor neuron survival and glial activation. New data indicate that stress exacerbates excitotoxic spinal cord motor neuron loss and associated activation of microglia. In contrast, hypertrophy and hyperplasia of astrocytes and NG2+ glia were unaffected or were modestly suppressed by stress. Although excitotoxic lesions cause significant motor neuron loss and stress exacerbates this pathology, overt functional impairment did not develop in the relevant forelimb up to one week post-lesion. These data indicate that stress is a disease-modifying factor capable of altering neuron and glial responses to pathological challenges in the spinal cord. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Effect of esomeprazole versus placebo on pulmonary exacerbations in cystic fibrosis

    Science.gov (United States)

    2014-01-01

    Background Gastro esophageal reflux (GER) is common in cystic fibrosis (CF) and may contribute to lung disease. Approximately 50% of patients with cystic fibrosis are being treated with proton pump inhibitors (PPIs). Methods In a randomized controlled study in adults, we compared treatment with esomeprazole 40 mg twice daily versus placebo in patients with CF and frequent respiratory exacerbations over a thirty-six week treatment period to determine effect on time to first exacerbation and other health related outcomes. Results 17 patients without symptoms of GER were randomized and 15 completed the study. 13 subjects underwent 24 hour ambulatory pH probe monitoring; 62% had pH probe evidence of GER. Forty one percent of subjects had a pulmonary exacerbation during the study. There was no significant difference in time to first pulmonary exacerbation (log rank test p = 0.3169). Five of nine subjects in the esomeprazole group compared with 2 of eight subjects in the placebo group experienced exacerbations (esomeprazole vs. placebo: odds ratio = 3.455, 95% CI = (0.337, 54.294), Fisher’s exact test: p = 0.334). There was no change in Forced Expiratory Volume in one second, Gastroesophageal Symptom Assessment Score or CF Quality of Life score between the two treatment groups. Conclusions There was a trend to earlier exacerbation and more frequent exacerbations in subjects randomized to esomeprazole compared with placebo. The effect of proton pump inhibitors on pulmonary exacerbations in CF warrants further investigation. Clinical trials registration Clinicaltrials.gov, NCT01983774 PMID:24528942

  1. Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients.

    Science.gov (United States)

    Emori, Christini Takemi; Perez, Renata Melo; Matos, Carla Adriana Loureiro de; Uehara, Silvia Naomi Oliveira; Pereira, Patricia da Silva Fucuta; Feldner, Ana Cristina Amaral; Carvalho-Filho, Roberto José de; Silva, Ivonete Sandra de Souza e; Silva, Antonio Eduardo Benedito; Ferraz, Maria Lucia Gomes

    2014-01-01

    There is scarce information regarding clinical evolution of HBV infection in renal transplant patients. To evaluate the prevalence of acute exacerbation in HBV-infected renal transplant patients and its association with the time after transplantation, presence of viral replication, clinical evolution, and use of antiviral prophylaxis. HBV infected renal transplant patients who underwent r