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  1. Binding of receptor-recognized forms of alpha2-macroglobulin to the alpha2-macroglobulin signaling receptor activates phosphatidylinositol 3-kinase.

    Science.gov (United States)

    Misra, U K; Pizzo, S V

    1998-05-29

    Ligation of the alpha2-macroglobulin (alpha2M) signaling receptor by receptor-recognized forms of alpha2M (alpha2M*) initiates mitogenesis secondary to increased intracellular Ca2+. We report here that ligation of the alpha2M signaling receptor also causes a 1. 5-2.5-fold increase in wortmannin-sensitive phosphatidylinositol 3-kinase (PI3K) activity as measured by the quantitation of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 formation was alpha2M* concentration-dependent with a maximal response at approximately 50 pM ligand concentration. The peak formation of PIP3 occurred at 10 min of incubation. The alpha2M receptor binding fragment mutant K1370R which binds to the alpha2M signaling receptor activating the signaling cascade, increased PIP3 formation by 2-fold. The mutant K1374A, which binds very poorly to the alpha2M signaling receptor, did not cause any increase in PIP3 formation. alpha2M*-induced DNA synthesis was inhibited by wortmannin. 1, 2Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acetoxymethylester a chelator of intracellular Ca2+, drastically reduced alpha2M*-induced increases in PIP3 formation. We conclude that PI3K is involved in alpha2M*-induced mitogenesis in macrophages and intracellular Ca2+ plays a role in PI3K activation. PMID:9593670

  2. 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.

  3. Perineural alpha(2A)-adrenoceptor activation inhibits spinal cord neuroplasticity and tactile allodynia after nerve injury.

    OpenAIRE

    Lavand'homme, Patricia; Ma, Weiya; Kock, Marc De; Eisenach, James C.

    2002-01-01

    BACKGROUND: Nerve injury in animals increases alpha(2)-adrenoceptor expression in dorsal root ganglion cells and results in novel excitatory responses to their activation, perhaps leading to the phenomenon of sympathetically maintained pain. In contrast to this notion, peripheral alpha(2)-adrenoceptor stimulation fails to induce pain in patients with chronic pain. We hypothesized that alpha(2) adrenoceptors at the site of nerve injury play an inhibitory, not excitatory role. METHODS: Partial ...

  4. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of alpha-2 and beta receptor activation.

    Science.gov (United States)

    Buffalari, Deanne M; Grace, Anthony A

    2007-11-01

    Substantial data exists demonstrating the importance of the amygdala and the locus ceruleus (LC) in responding to stress, aversive memory formation, and the development of stress-related disorders; however, little is known about the effects of norepinephrine (NE) on amygdala neuronal activity in vivo. The basolateral nucleus of the amygdala (BLA) receives dense NE projections from the LC, NE increases in the BLA in response to stress, and the BLA can also modulate the LC via reciprocal projections. These experiments examined the effects of noradrenergic agents on spontaneous and evoked responses of BLA neurons. NE iontophoresis inhibited spontaneous firing and decreased the responsiveness of BLA neurons to electrical stimulation of entorhinal cortex and sensory association cortex (Te3). Confirmed BLA projection neurons exhibited exclusively inhibitory responses to NE. Systemic administration of propranolol, a beta-receptor antagonist, decreased the spontaneous firing rate and potentiated the NE-evoked inhibition of BLA neurons. In addition, iontophoresis of the alpha-2 agonist clonidine, footshock administration, and LC stimulation mimicked the effects of NE iontophoresis on spontaneous activity. Furthermore, the effects of LC stimulation were partially blocked by systemic administration of alpha 2 and beta receptor antagonists. This is the first study to demonstrate the actions of directly applied and stimulus-evoked NE in the BLA in vivo, and provides a mechanism by which beta receptors can mediate the important behavioral consequences of NE within the BLA. The interaction between these two structures is particularly relevant with regard to their known involvement in stress responses and stress-related disorders. PMID:17989300

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

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    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.

  6. The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells.

    Science.gov (United States)

    Zhang, J C; Sakthivel, R; Kniss, D; Graham, C H; Strickland, D K; McCrae, K R

    1998-11-27

    The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor (LRP/alpha2MR) mediates the internalization of numerous ligands, including prourokinase (pro-UK) and complexes between two-chain urokinase (tc-u-PA) and plasminogen activator inhibitor type-1 (PAI-1). It has been suggested that through its ability to internalize these ligands, LRP/alpha2MR may regulate the expression of plasminogen activator activity on cell surfaces; this hypothesis, however, has not been experimentally confirmed. To address this issue, we assessed the ability of LRP/alpha2MR to regulate plasminogen activator activity on human trophoblast cells, which express both LRP/alpha2MR and the urokinase receptor (uPAR). Trophoblasts internalized and degraded exogenous 125I-pro-UK (primarily following its conversion to tc-u-PA and incorporation into tc-u-PA.PAI complexes) in an LRP/alpha2MR-dependent manner, which was inhibited by the LRP/alpha2MR receptor-associated protein. Receptor-associated protein also caused a approximately 50% reduction in cell surface plasminogen activator activity and delayed the regeneration of unoccupied uPAR by cells on which uPAR were initially saturated with pro-UK. Identical effects were caused by anti-LRP/alpha2MR antibodies. These results demonstrate that LRP/alpha2MR promotes the expression of cell surface plasminogen activator activity on trophoblasts by facilitating the clearance of tc-u-PA.PAI complexes and regeneration of unoccupied cell surface uPAR. PMID:9822706

  7. 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...

  8. [Antiviral activity of extracts of transgenic cichory and lettuce plants with the human interferon alpha-2b gene].

    Science.gov (United States)

    Matveeva, N A; Kudriavets, Iu I; Likhova, A A; Shakhovskiĭ, A M; Bezdenezhnykh, N A; Kvasko, E Iu

    2012-01-01

    Biological activity of protein extracts from transgenic plants of chicory Cichorium intybus L. and lettuce Lactuca sativa L. with human interferon alpha2b gene was investigated against vesicular stomatitis virus. It was shown that the extracts from the hairy roots of chicory and lettuce transformed by A. rhizogenes possess the antiviral activity 1620...5400 IU/g weight, and the extracts from leaves of the plants transformed by A. tumefaciens--till 9375 IU/g weight. Dependence of plant extract biological activity on the transformation vector was shown. PMID:23342646

  9. An alpha2,6-sialyltransferase cloned from Photobacterium leiognathi strain JT-SHIZ-119 shows both sialyltransferase and neuraminidase activity.

    Science.gov (United States)

    Mine, Toshiki; Katayama, Sakurako; Kajiwara, Hitomi; Tsunashima, Masako; Tsukamoto, Hiroshi; Takakura, Yoshimitsu; Yamamoto, Takeshi

    2010-02-01

    We cloned, expressed, and characterized a novel beta-galactoside alpha2,6-sialyltransferase from Photobacterium leiognathi strain JT-SHIZ-119. The protein showed 56-96% identity to the marine bacterial alpha2,6-sialyltransferases classified into glycosyltransferase family 80. The sialyltransferase activity of the N-terminal truncated form of the recombinant enzyme was 1477 U/L of Escherichia coli culture. The truncated recombinant enzyme was purified as a single band by sodium dodecyl sulfate polyacrylamide gel electrophoresis through 3 column chromatography steps. The enzyme had distinct activity compared with known marine bacterial alpha2,6-sialyltransferases. Although alpha2,6-sialyltransferases cloned from marine bacteria, such as Photobacterium damselae strain JT0160, P. leiognathi strain JT-SHIZ-145, and Photobacterium sp. strain JT-ISH-224, show only alpha2,6-sialyltransferase activity, the recombinant enzyme cloned from P. leiognathi strain JT-SHIZ-119 showed both alpha2,6-sialyltransferase and alpha2,6-linkage-specific neuraminidase activity. Our results provide important information toward a comprehensive understanding of the bacterial sialyltransferases belonging to the group 80 glycosyltransferase family in the CAZy database. PMID:19797322

  10. Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Jonas Christian Schupp

    Full Text Available Acute exacerbation (AE of idiopathic pulmonary fibrosis (IPF is a common cause of disease acceleration in IPF and has a major impact on mortality. The role of macrophage activation in AE of IPF has never been addressed before.We evaluated BAL cell cytokine profiles and BAL differential cell counts in 71 IPF patients w/wo AE and in 20 healthy volunteers. Twelve patients suffered from AE at initial diagnosis while sixteen patients developed AE in the 24 months of follow-up. The levels of IL-1ra, CCL2, CCL17, CCL18, CCL22, TNF-α, IL-1β, CXCL1 and IL-8 spontaneously produced by BAL-cells were analysed by ELISA.In patients with AE, the percentage of BAL neutrophils was significantly increased compared to stable patients. We found an increase in the production rate of the pro-inflammatory cytokines CXCL1 and IL-8 combined with an increase in all tested M2 cytokines by BAL-cells. An increase in CCL18 levels and neutrophil counts during AE was observed in BAL cells from patients from whom serial lavages were obtained. Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE.BAL cell cytokine production levels at acute exacerbation show up-regulation of pro-inflammatory as well as anti-inflammatory/ M2 cytokines. Our data suggest that AE in IPF is not an incidental event but rather driven by cellular mechanisms including M2 macrophage activation.

  11. Up-Regulation of Hepatic Alpha-2-HS-Glycoprotein Transcription by Testosterone via Androgen Receptor Activation

    Directory of Open Access Journals (Sweden)

    Jakob Voelkl

    2014-06-01

    Full Text Available Background/Aims: Fetuin-A (alpha-2-HS-glycoprotein, AHSG, a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone. Methods: HepG2 cells were treated with testosterone and androgen receptor antagonist flutamide, and were silenced with androgen receptor siRNA. To test the in vivo relevance, male mice were subjected to androgen deprivation therapy (ADT for 7 weeks. AHSG mRNA levels were determined by quantitative RT-PCR and fetuin-A protein abundance by Western blotting. Results: In HepG2 cells, AHSG mRNA expression and fetuin-A protein abundance were both up-regulated following testosterone treatment. The human alpha-2-HS-glycoprotein gene harbors putative androgen receptor response elements in the proximal 5 kb promoter sequence relative to TSS. The effect of testosterone on AHSG mRNA levels was abrogated by silencing of the androgen receptor in HepG2 cells. Moreover, treatment of HepG2 cells with the androgen receptor antagonist flutamide in presence of endogenous ligands in the medium significantly down-regulated AHSG mRNA expression and fetuin-A protein abundance. In addition, ADT of male mice was followed by a significant decrease of hepatic Ahsg mRNA expression and fetuin-A protein levels. Conclusions: Testosterone participates in the regulation of hepatic fetuin-A expression, an effect mediated, at least partially, by androgen receptor activation.

  12. 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

    collagen may activate platelets by a similar mechanism. In contrast to these findings, we provided evidence that rhodocytin does not bind to alpha(2)beta(1) integrin. Here we show that the Cre/loxP-mediated loss of beta(1) integrin on mouse platelets has no effect on rhodocytin-induced platelet activation......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......, excluding an essential role of alpha(2)beta(1) integrin in this process. Furthermore, proteolytic cleavage of the 45-kDa N-terminal domain of glycoprotein (GP) Ibalpha either on normal or on beta(1)-null platelets had no significant effect on rhodocytin-induced platelet activation. Moreover, mouse platelets...

  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. 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)

    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

  15. Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high-fat diet on heart function and ischemic tolerance in aged female mice.

    Science.gov (United States)

    Slámová, K; Papoušek, F; Janovská, P; Kopecký, J; Kolář, F

    2016-03-14

    AMP-activated protein kinase (AMPK) plays a role in metabolic regulation under stress conditions, and inadequate AMPK signaling may be also involved in aging process. The aim was to find out whether AMPK alpha2-subunit deletion affects heart function and ischemic tolerance of adult and aged mice. AMPK alpha2(-/-) (KO) and wild type (WT) female mice were compared at the age of 6 and 18 months. KO mice exhibited subtle myocardial AMPK alpha2-subunit protein level, but no difference in AMPK alpha1-subunit was detected between the strains. Both alpha1- and alpha2-subunits of AMPK and their phosphorylation decreased with advanced age. Left ventricular fractional shortening was lower in KO than in WT mice of both age groups and this difference was maintained after high-fat feeding. Infarct size induced by global ischemia/reperfusion of isolated hearts was similar in both strains at 6 months of age. Aged WT but not KO mice exhibited improved ischemic tolerance compared with the younger group. High-fat feeding for 6 months during aging abolished the infarct size-reduction in WT without affecting KO animals; nevertheless, the extent of injury remained larger in KO mice. The results demonstrate that adverse effects of AMPK alpha2-subunit deletion and high-fat feeding on heart function and myocardial ischemic tolerance in aged female mice are not additive. PMID:26596312

  16. Stress Exacerbates Neuropathic Pain via Glucocorticoid and NMDA Receptor Activation

    OpenAIRE

    Alexander, Jessica K.; DeVries, A. Courtney; KIGERL, KRISTINA A.; Dahlman, Jason M.; G.Popovich, Phillip

    2009-01-01

    There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g. corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, ...

  17. 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...

  18. Neu1 desialylation of sialyl alpha-2,3-linked beta-galactosyl residues of TOLL-like receptor 4 is essential for receptor activation and cellular signaling.

    Science.gov (United States)

    Amith, Schammim Ray; Jayanth, Preethi; Franchuk, Susan; Finlay, Trisha; Seyrantepe, Volkan; Beyaert, Rudi; Pshezhetsky, Alexey V; Szewczuk, Myron R

    2010-02-01

    The ectodomain of TOLL-like receptors (TLR) is highly glycosylated with several N-linked gylcosylation sites located in the inner concave surface. The precise role of these sugar N-glycans in TLR receptor activation is unknown. Recently, we have shown that Neu1 sialidase and not Neu2, -3 and -4 forms a complex with TLR-2, -3 and -4 receptors on the cell-surface membrane of naïve and activated macrophage cells (Glycoconj J DOI 10.1007/s10719-009-9239-8). Activation of Neu1 is induced by TLR ligands binding to their respective receptors. Here, we show that endotoxin lipopolysaccharide (LPS)-induced MyD88/TLR4 complex formation and subsequent NFkappaB activation is dependent on the removal of alpha-2,3-sialyl residue linked to beta-galactoside of TLR4 by the Neu1 activity associated with LPS-stimulated live primary macrophage cells, macrophage and dendritic cell lines but not with primary Neu1-deficient macrophage cells. Exogenous alpha-2,3 sialyl specific neuraminidase (Streptoccocus pneumoniae) and wild-type T. cruzi trans-sialidase (TS) but not the catalytically inactive mutant TSAsp98-Glu mediate TLR4 dimerization to facilitate MyD88/TLR4 complex formation and NFkappaB activation similar to those responses seen with LPS. These same TLR ligand-induced NFkappaB responses are not observed in TLR deficient HEK293 cells, but are re-established in HEK293 cells stably transfected with TLR4/MD2, and are significantly inhibited by alpha-2,3-sialyl specific Maackia amurensis (MAL-2) lectin, alpha-2,3-sialyl specific galectin-1 and neuraminidase inhibitor Tamiflu but not by alpha-2,6-sialyl specific Sambucus nigra lectin (SNA). Taken together, the findings suggest that Neu1 desialylation of alpha-2,3-sialyl residues of TLR receptors enables in removing a steric hinderance to receptor association for TLR activation and cellular signaling. PMID:19796680

  19. 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; Novobrantseva, Tatiana I; Sprague, Andrew G; de Fougerolles, Antonin R; Christensen, Jan P

    2003-01-01

    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)beta(1) parallels that of viral-specific effector CD8(+) T cells (defined by tetramer and IFN-gamma staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar...

  20. Functional properties of the CaV1.2 calcium channel activated by calmodulin in the absence of alpha2delta subunits.

    Science.gov (United States)

    Ravindran, Arippa; Kobrinsky, Evgeny; Lao, Qi Zong; Soldatov, Nikolai M

    2009-01-01

    Voltage-activated CaV1.2 calcium channels require association of the pore-forming alpha1C subunit with accessory CaVbeta and alpha2delta subunits. Binding of a single calmodulin (CaM) to alpha1C supports Ca2+-dependent inactivation (CDI). The human CaV1.2 channel is silent in the absence of CaVbeta and/or alpha2delta. Recently, we found that coexpression of exogenous CaM (CaMex) supports plasma membrane targeting, gating facilitation and CDI of the channel in the absence of CaVbeta. Here we discovered that CaMex and its Ca2+-insensitive mutant (CaM1234) rendered active alpha1C/CaVbeta channel in the absence of alpha2delta. Coexpression of CaMex with alpha1C and beta2d in calcium-channel-free COS-1 cells recovered gating of the channel and supported CDI. Voltage-dependence of activation was shifted by approximately +40 mV to depolarization potentials. The calcium current reached maximum at +40 mV (20 mM Ca2+) and exhibited approximately 3 times slower activation and 5 times slower inactivation kinetics compared to the wild-type channel. Furthermore, both CaMex and CaM1234 accelerated recovery from inactivation and induced facilitation of the calcium current by strong depolarization prepulse, the properties absent from the human vascular/neuronal CaV1.2 channel. The data suggest a previously unknown action of CaM that in the presence of CaVbeta; translates into activation of the alpha2delta-deficient calcium channel and alteration of its properties. PMID:19106618

  1. Physical activity and exercise capacity in patients with moderate COPD exacerbations.

    Science.gov (United States)

    Alahmari, Ayedh D; Kowlessar, Beverly S; Patel, Anant R C; Mackay, Alex J; Allinson, James P; Wedzicha, Jadwiga A; Donaldson, Gavin C

    2016-08-01

    Little is known about changes in physical activity during moderate (out-patient managed) exacerbations.6-min walking distance (6MWD) was measured during 50 exacerbations when the patients were stable, and at 3 and 7 days post-exacerbation presentation. At similar time points, quadriceps maximum voluntary contraction (QMVC) was measured during 47 different exacerbations. Physical activity (SenseWear; Bodymedia Inc., Pittsburgh, PA, USA) was recorded over 2 consecutive-week periods post-presentation.6MWD fell from a median 422 m when stable to 373 m on day 3 (p=0.001). Similarly, QMVC fell from 32.6 versus 29.7 kg (p=0.026). Falls in 6MWD were associated with a rise in C-reactive protein (r= -0.364; p=0.041) and increased Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) (r= -0.44; p=0.013). Light physical activity was 2.18 h·day(-1) during the first week post-exacerbation and was less over week 2 (1.98 h·day(-1); p=0.009). Patients who had attended pulmonary rehabilitation had smaller changes in 6MWD than those who had not attended (-35.0 versus -114.9 m; p=0.013). Falls in physical activity were correlated with higher depression scores (rho= -0.51; p=0.006).These findings indicate that exercise capacity and muscle strength fall at exacerbation in chronic obstructive pulmonary disease patients who are treated at home and are free to maintain normal activity. PMID:27126688

  2. NOX Activity in Brain Aging: Exacerbation by High Fat Diet

    OpenAIRE

    Bruce-Keller, Annadora J.; White, Christy L.; Gupta, Sunita; Knight, Alecia G.; Pistell, Paul J.; Ingram, Donald K.; Morrison, Christopher D.; Keller, Jeffrey N.

    2010-01-01

    This study describes how age and high fat diet affect the profile of NADPH oxidase (NOX). Specifically, NOX activity and subunit expression were evaluated in the frontal cerebral cortex of 7-, 16-, and 24-month old mice following a 4-month exposure to either Western diet (WD, 41% calories from fat) or very high fat lard diet (VHFD, 60% calories from fat). Data reveal a significant effect of age in on NOX activity, and show that NOX activity was only increased by VHFD, and only in 24-month old...

  3. 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, Hermie; Vollenbroek-Hutten, Miriam

    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 add

  4. Evidence that adiponectin receptor 1 activation exacerbates ischemic neuronal death

    Directory of Open Access Journals (Sweden)

    Thundyil John

    2010-08-01

    Full Text Available Abstract Background- Adiponectin is a hormone produced in and released from adipose cells, which has been shown to have anti-diabetic and anti-inflammatory actions in peripheral cells. Two cell surface adiponectin receptors (ADRs mediate the majority of the known biological actions of adiponectin. Thus far, ADR expression in the brain has been demonstrated in the arcuate and the paraventricular nucleus of hypothalamus, where its activation affects food intake. Recent findings suggest that levels of circulating adiponectin increase after an ischemic stroke, but the role of adiponectin receptor activation in stroke pathogenesis and its functional outcome is unclear. Methods- Ischemic stroke was induced in C57BL/6 mice by middle cerebral artery occlusion (MCAO for 1 h, followed by reperfusion. Primary cortical neuronal cultures were established from individual embryonic neocortex. For glucose deprivation (GD, cultured neurons were incubated in glucose-free Locke's medium for 6, 12 or 24 h. For combined oxygen and glucose deprivation (OGD, neurons were incubated in glucose-free Locke's medium in an oxygen-free chamber with 95% N2/5% CO2 atmosphere for either 3, 6, 9, 12 or 24 h. Primary neurons and brain tissues were analysed for Adiponectin and ADRs using reverse transcriptase polymerase chain reaction (RT-PCR, immunoblot and immunochemistry methods. Results- Cortical neurons express ADR1 and ADR2, and that the levels of ADR1 are increased in neurons in response to in vitro or in vivo ischemic conditions. Neurons treated with either globular or trimeric adiponectin exhibited increased vulnerability to oxygen and glucose deprivation which was associated with increased activation of a pro-apoptotic signaling cascade involving p38 mitogen-activated protein kinase (p38MAPK and AMP-activated protein kinase (AMPK. Conclusions- This study reveals a novel pathogenic role for adiponectin and adiponectin receptor activation in ischemic stroke. We show that

  5. 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.&...

  6. Removing a Cystein Group On Interferon Alpha 2b at Position 2 and 99 does Not Diminish Antitumor Activity of the Protein, Even Better.

    Science.gov (United States)

    Rachmawati, Heni; Jessica, Adhitya; Sumirtaputra, Yeyet Cahyati; Retnoningrum, Debbie Sofie; Adlia, Amirah; Ningrum, Ratih Asmana

    2016-01-01

    Interferon alpha 2b is the only standard therapeutic protein for hepatitis virus infections. Further study demonstrated that this protein also posseses antitumor activity in several cancerous organs. One main pathway of this antitumor activity is mediated through antiproliferation as well as proapoptotic effects. Previously, we have successfully developed recombinant human interferon alpha 2b (rhIFNα2b) by using a synthetic gene. In addition, two mutein forms of rhIFNα2b were generated to improve the characteristics of this protein. Two point mutations showed better pharmacokinetic profiles than one point mutation as well as the native form. In the present study, this mutein form was studied for ist antitumor effect in vitro using HepG2 cells. As a comparison, the native form as well as a commercial rIFNα2b were used. Several parameters were investigated including the MTT assay, cell viability test, cell cycle using flow cytometric analysis, and the genes and protein expressions involved in cell growth. The latest was observed to study the mechanism of rhIFNα2b. There was no significant difference in the MTT assay and cell viability after cells were treated with both forms of rhIFNα2b. However, the mutein rhIFNα2b tended to show better proapoptotic activity reflected by flow cytometric data, protein expression of pSTAT1, and DNA expression of caspase 3. PMID:27110503

  7. Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation.

    Directory of Open Access Journals (Sweden)

    Isa Mambetsariev

    Full Text Available Acute lung injury (ALI is accompanied by decreased lung compliance. However, a role of tissue mechanics in modulation of inflammation remains unclear. We hypothesized that bacterial lipopolysacharide (LPS stimulates extracellular matrix (ECM production and vascular stiffening leading to stiffness-dependent exacerbation of endothelial cell (EC inflammatory activation and lung barrier dysfunction. Expression of GEF-H1, ICAM-1, VCAM-1, ECM proteins fibronectin and collagen, lysyl oxidase (LOX activity, interleukin-8 and activation of Rho signaling were analyzed in lung samples and pulmonary EC grown on soft (1.5 or 2.8 kPa and stiff (40 kPa substrates. LPS induced EC inflammatory activation accompanied by expression of ECM proteins, increase in LOX activity, and activation of Rho signaling. These effects were augmented in EC grown on stiff substrate. Stiffness-dependent enhancement of inflammation was associated with increased expression of Rho activator, GEF-H1. Inhibition of ECM crosslinking and stiffening by LOX suppression reduced EC inflammatory activation and GEF-H1 expression in response to LPS. In vivo, LOX inhibition attenuated LPS-induced expression of GEF-H1 and lung dysfunction. These findings present a novel mechanism of stiffness-dependent exacerbation of vascular inflammation and escalation of ALI via stimulation of GEF-H1-Rho pathway. This pathway represents a fundamental mechanism of positive feedback regulation of inflammation.

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

    International Nuclear Information System (INIS)

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

    Science.gov (United States)

    Qin, Xu-Jun; Hudson, Laurie G; Liu, Wenlan; Timmins, Graham S; Liu, Ke Jian

    2008-10-01

    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 (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. PMID:18619636

  10. 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.

  11. Human fat cell alpha-2 adrenoceptors. I. Functional exploration and pharmacological definition with selected alpha-2 agonists and antagonists

    International Nuclear Information System (INIS)

    This study was undertaken to investigate more fully the pharmacological characteristics of the human fat cell alpha-2 adrenoceptor. Biological assays were performed on intact isolated fat cells while radioligand binding studies were carried out with [3H]yohimbine in membranes. These pharmacological studies brought: (1) a critical definition of the limits of the experimental conditions required for the exploration of alpha-2 adrenergic responsiveness on human fat cells and membranes; (2) an improvement in the pharmacological definition of the human fat cell postsynaptic alpha-2 adrenoceptor. Among alpha-2 agonists, UK-14,304 was the most potent and the relative order of potency was: UK-14,304 greater than p-aminoclonidine greater than clonidine = B-HT 920 greater than rilmenidine. For alpha-2 antagonists, the potency order was: yohimbine greater than idazoxan greater than SK ampersand F-86,466 much greater than benextramine; (3) a description of the impact of benextramine (irreversible alpha-1/alpha-2 antagonist) on human fat cell alpha-2 adrenergic receptors and on human fat cell function; the drug inactivates the alpha-2 adrenergic receptors with a minor impact on beta adrenergic receptors and without noticeable alterations of fat cell function as assessed by preservation of beta adrenergic and Al-adenosine receptor-mediated lipolytic responses; and (4) a definition of the relationship existing between alpha-2 adrenergic receptor occupancy, inhibition of adenylate cyclase activity and antilipolysis with full and partial agonists. The existence of a receptor reserve must be taken into account when evaluating alpha-2 adrenergic receptor distribution and regulation of human fat cells

  12. [Obtaining and characteristics of domestic preparation interferon alpha-2b with prolonged effect].

    Science.gov (United States)

    Pokholenko, Ia A; Porubleva, L V; Dubeĭ, I Ia; Rebriev, A V; Sutugina, L P; Gromovoĭ, T Iu; Pokrovskiĭ, V A; Obolenskaia, M Iu; Chernykh, S I

    2008-01-01

    Pegylated interferon alpha-2b (PEG-IFN alpha-2b) is a domestic preparation of a modified recombinant interferon alpha-2b with prolonged effect. The preparation was obtained by N-terminal pegylation of IFN alpha-2b with polyethylene glycol (PEG). This paper presents the method of PEG-IFN alpha-2b synthesis and characteristics of the obtained product. PAAG electrophoresis, Western blot analysis and MALDI-TOF mass-spectrometry confirm that the preparation is an N-terminal pegylated IFN alpha-2b that contains no more than 10% of dipegylated IFN alpha-2b. The comparison of PEG-IFN alpha-2b with its foreign analogue has revealed the similarity of their biological activity and pharmacokinetic parameters. PMID:19351063

  13. 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

  14. 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

  15. Allergic Conjunctivitis Exacerbates Corneal Allograft Rejection by Activating Th1 and Th2 Alloimmune Responses

    OpenAIRE

    Niederkorn, Jerry Y.; Chen, Peter W.; Mellon, Jessamee; Stevens, Christina; Mayhew, Elizabeth

    2010-01-01

    Allergic conjunctivitis (AC) and airway hyperreactivity exacerbate corneal allograft rejection. Because AC and airway hyperreactivity are allergic diseases of mucosal tissues, we determined whether an allergic disease of a nonmucosal tissue would affect corneal allograft rejection and whether Th2 cells alone accounted for accelerated graft rejection in allergic mice. Hosts sensitized cutaneously with short ragweed pollen developed cutaneous immediate hypersensitivity but rejected corneal allo...

  16. DAMPs-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury

    Science.gov (United States)

    Huang, Hai; Tohme, Samer; Al-Khafaji, Ahmed B; Tai, Sheng; Loughran, Patricia; Chen, Li; Wang, Shu; Kim, Jiyun; Billiar, Timothy; Wang, Yanming; Tsung, Allan

    2015-01-01

    Innate immunity plays a crucial role in the response to sterile inflammation such as liver ischemia/reperfusion (I/R) injury. The initiation of liver I/R injury results in the release of damage associated molecular patterns (DAMPs), which trigger innate immune and inflammatory cascade via pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to the organ damage, innate immune and inflammatory responses. Formation of neutrophil extracellular trap (NET) has been recently found in response to various stimuli. However, the role of NETs during liver I/R injury remains unknown. We show that NETs form in the sinusoids of ischemic liver lobes in vivo. This was associated with increased NET markers, serum level of myeloperoxidase (MPO)-DNA complexes and tissue level of citrullinated-histone H3 compared to control mice. Treatment with peptidyl-arginine-deiminase (PAD) 4 inhibitor or DNase I significantly protected hepatocytes and reduced inflammation after liver I/R as evidenced by inhibition of NET formation, indicating the pathophysiological role of NETs in liver I/R injury. In vitro, NETs increase hepatocyte death and induce Kupffer cells to release proinflammatory cytokines. DAMPs, such as HMGB1 and histones, released by injured hepatocytes stimulate NET formation through Toll-like receptor (TLR4)- and TLR9-MyD88 signaling pathways. After neutrophil depletion in mice, the adoptive transfer of TLR4 knockout (KO) or TLR9 KO neutrophils confers significant protection from liver I/R injury with significant decrease in NET formation. In addition, we found inhibition of NET formation by PAD4 inhibitor or DNase I reduces HMGB1 and histone-mediated liver I/R injury. Conclusion DAMPs released during liver I/R promotes NET formation through TLRs signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R. PMID:25855125

  17. Guinea-pig ileum as ex vivo model useful to characterize ligands displaying Imidazoline I2 and Adrenergic alpha2 mixed activity: a preliminary study

    Directory of Open Access Journals (Sweden)

    Marialessandra Contino

    2013-01-01

    Full Text Available The lack of an effective analgesic treatment makes pain a clinical challenge and the need of a novel approach to identify new agents is urgent. In this scenario I2-ligands can be considered an alternative strategy in pain therapy. The development of an ex vivo model useful for the evaluation of functional activities at both a2 and I2-IBs (imidazoline binding sites is an important task in pharmacological sciences since several I2 ligands display activity also towards a receptors. The present study aims to develop an ex vivo model for estimating the activity of I2-IBs ligands in a biological sample where a1 and a2 adrenergic receptors are present. For this purpose the imidalzoline endogenous ligand, harmane, reference compounds, 2BFI and BU224, and imidazoline derivatives 1-3 have been selected taking into account their in vitro activity towards IBs and adrenergic receptors. All compounds have been tested ex vivo in guinea pig-ileum where a2A-ARs are prejunctionally and I2-IBS postjunctionally localized. Adrenergic component has been identified by the studying the interference of compounds on the electrically-evoked contraction while I2-IBs activity by testing the ability of compounds to inhibit the carbachol-evoked contractions in the presence of prazosin to mask the a1 adrenoceptors. Compounds 1 and 2 were found I2-IBs antago nists (pIC50=4.2 and 4.0, respectively whereas compound 3 was I2-IBs agonist (EC50=0.38 mM; All ligands were a2 adrenergic agonists. This paper suggests guinea-pig ileum as the first ex vivo approach for establishing both the intrinsic activity of I2-IBs ligands and the physiological correlation between IBs and adrenergic system.

  18. Complement-mediated bactericidal activity of human antibodies to poly alpha 2-->8 N-acetylneuraminic acid, the capsular polysaccharide of Neisseria meningitidis serogroup B.

    Science.gov (United States)

    Mandrell, R E; Azmi, F H; Granoff, D M

    1995-11-01

    Serum antibodies to Neisseria meningitidis group B (MenB) polysaccharide are reported not to elicit bacteriolysis in the presence of human complement. To reexamine this question, we evaluated the ability of two human IgM anti-MenB polysaccharide monoclonal antibodies (MAbs) and seven human MenB polysaccharide-reactive human IgM paraproteins to elicit bacteriolysis. In the presence of human complement, both MAbs and five of the seven paraproteins were bactericidal at antibody concentrations of 0.25-9.6 micrograms/mL (50% killing). Activity of the respective antibodies was enhanced 200- to > 10,000-fold when rabbit complement was used instead of human complement. With rabbit complement, the bactericidal activity of human IgM polyclonal antibody or MAb to Haemophilus influenzae type b (Hib) polysaccharide but not human IgG polyclonal antibody or MAb to Hib polysaccharide was similarly augmented. Thus, for both MenB and Hib, IgM antipolysaccharide antibodies elicit complement-mediated bactericidal activity in the presence of human complement, and the use of rabbit complement yields spuriously high activity. PMID:7594665

  19. Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case-control study.

    Science.gov (United States)

    Akiyama, Mitsuhiro; Kaneko, Yuko; Yamaoka, Kunihiro; Kondo, Harumi; Takeuchi, Tsutomu

    2016-06-01

    The objective of the study was to identify risk factors for acute exacerbation of interstitial lung disease (ILD) during tocilizumab treatment in patients with rheumatoid arthritis (RA). This is a retrospective, case-control study. We reviewed 395 consecutive RA patients who received tocilizumab. First, we divided the patients according to the presence (RA-ILD) or absence of ILD (non-ILD) assessed by chest X-ray or high-resolution computed tomography, and compared them for characteristics relevant to RA-ILD. Subsequently, focusing on the patients with RA-ILD, we assessed their baseline characteristics and clinical courses comparing patients with acute exacerbation to those without. Comparing 78 with ILD and 317 without ILD, the following were identified as factors related to RA-ILD on multivariate analysis: age 60 years or older (OR 4.5, 95 % CI 2.2-9.4, P smoking habit (OR 2.9, 95 % CI 1.5-5.5, P = 0.002), and high rheumatoid factor levels (OR 2.8, 95 % CI 1.4-5.5, P = 0.002). Of 78 RA-ILD patients, six developed acute exacerbation during tocilizumab treatment. The median duration between the initiation of tocilizumab treatment and the acute exacerbation occurrence was 48 weeks. While baseline characteristics did not differ between acute exacerbation and non-acute exacerbation groups, patients experiencing acute exacerbation had significantly higher Clinical Disease Activity Index (CDAI) at 24 weeks (20.8 vs. 6.2, P = 0.019). Univariate analysis showed that CDAI > 10 at 24 weeks was a risk factor for acute exacerbation (OR 4.7, 95 % CI 2.1-10.4, P = 0.02). Uncontrolled arthritis activity during tocilizumab treatment may be associated with acute exacerbation of RA-ILD, suggesting post-treatment monitoring of disease activity is important not only with respect to RA itself but also for RA-ILD. PMID:27072347

  20. 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. PMID:26711092

  1. 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; Raghupathi, Ramesh

    2016-03-01

    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

  2. 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

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

    International Nuclear Information System (INIS)

    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

  4. Latent cytomegalovirus infection exacerbates experimental pulmonary fibrosis by activating TGF-β1.

    Science.gov (United States)

    Li, Yonghuai; Gao, Jian; Wang, Guoliang; Fei, Guanghe

    2016-08-01

    The aim of the present study was to investigate the hypotheses that cytomegalovirus (CMV) may trigger idiopathic pulmonary fibrosis (IPF) in a susceptible host and/or that the presence of CMV may alter IPF in response to a well-defined trigger of pulmonary fibrosis. A mouse model of murine CMV (MCMV) infection was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor (TGF)‑β1 was measured, and the levels of E‑cadherin, Vimentin and phosphorylated (phospho)‑small mothers against decapentaplegic (SMAD)2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause pulmonary fibrosis. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E‑cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated pulmonary fibrosis in the mouse model, possibly through the activation of TGF-β1. PMID:27279470

  5. Oxcarbazepine and its active metabolite, (S)-licarbazepine, exacerbate seizures in a mouse model of genetic generalized epilepsy.

    Science.gov (United States)

    Kim, Tae Hwan; Reid, Christopher A; Petrou, Steven

    2015-01-01

    Oxcarbazepine (OXC), widely used to treat focal epilepsy, is reported to exacerbate seizures in patients with generalized epilepsy. OXC is metabolized to monohydroxy derivatives in two enantiomeric forms: (R)-licarbazepine and (S)-licarbazepine. Eslicarbazepine acetate is a recently approved antiepileptic drug that is rapidly metabolized to (S)-licarbazepine. It is not known whether (S)-licarbazepine exacerbates seizures. Here, we test whether OXC or either of its enantiomers exacerbates the number of spike-and-wave discharges (SWDs) in mice harboring the human γ-aminobutyric acid A receptor (GABAA)γ2(R43Q) mutation. OXC (20 mg/kg), (S)-licarbazepine (20 mg/kg), and (R)-licarbazepine (20 mg/kg) all significantly increased the number of SWDs, while their duration was unaffected. The potential for (S)-licarbazepine to exacerbate SWDs suggests that eslicarbazepine acetate should be used with caution in generalized epilepsy. Furthermore, generalized seizure exacerbation for first-, second-, and third-generation carbamazepine-based compounds is likely to occur through a common mechanism. PMID:25489632

  6. Isothermal oxidation behavior of alpha-2 titanium aluminide alloys

    International Nuclear Information System (INIS)

    Monolithic alpha-2 alloys are being considered for applications in gas turbine engines at temperature between 593 and 705C. The alpha-2 alloys have better creep and oxidation resistance than conventional Ti alloys in this temperature range, but concerns over low temperature mechanical properties, interstitial embrittlement and hot salt stress corrosion cracking have limited the application of these alloys. Protective coatings address environmental concerns, while improved processing and chemistry may improve mechanical properties. The compositions of alpha-2 alloys have evolved over time to obtain a better balance of properties. Two prospective alpha-2 compositions are Ti-25Al-10Nb-3V-1Mo and Ti-24.5Al-12.5Nb-1.5Mo. This work characterizes the isothermal oxidation behavior of these two alloys in the 593-705C temperature range and discusses observed differences. The isothermal oxidation behavior in air of Ti-24.5Al-12.5Nb-1.5Mo was superior to Ti-25Al-10Nb-3V-1Mo and T-6242 in the temperature range of 593-705C. The 12.5-1.5 alloy was better because an external alumina scale formed which grew more slowly than the TiO2-based scales observed on the 10-3-1 and Ti-6242. The alumina scale formed on the 12.5-1.5 alloy because interstitials like O, N and C lower the thermodynamic activity of Ti to levels where Al2O3 formation is favored. In the absence of microstructural effects, the V in 10-3-1 prevented continuous external alumina from forming

  7. 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.

  8. Human alpha 2-adrenergic receptor subtype distribution: widespread and subtype-selective expression of alpha 2C10, alpha 2C4, and alpha 2C2 mRNA in multiple tissues.

    Science.gov (United States)

    Eason, M G; Liggett, S B

    1993-07-01

    At present, molecular cloning and pharmacological studies have delineated three human alpha 2-adrenergic receptor (alpha 2AR) subtypes, alpha 2C10, alpha 2C4, and alpha 2C2. Assignment of the alpha 2AR subtypes to specific functions has been limited by an unclear definition of tissue alpha 2AR expression outside of the central nervous system. It has been suggested that alpha 2C4 expression is confined to the brain, that alpha 2C2 expression is only in the liver and kidney, and that there is nearly ubiquitous expression of alpha 2C10. However, this is based on studies of a limited number of rat tissues or on studies using non-species-specific approaches. Therefore, to define alpha 2C10, alpha 2C4, and alpha 2C2 tissue expression, we used reverse transcription of total RNA isolated from 20 human tissues, followed by amplification of alpha 2AR cDNA using the polymerase chain reaction. This technique provided two advantages: high sensitivity and, with the use of subtype-specific oligonucleotide primers and probes, differentiation between the alpha 2AR subtypes. The tissues studied were aorta, vena cava, heart (epicardium and endocardium), lung, skeletal muscle, liver, pancreas (head and tail), fat (perinephric and subcutaneous), kidney (cortex and medulla), prostate, stomach, ileum, jejunum, colon, adrenal gland, and spleen. We found that the majority of these tissues expressed alpha 2C10, with the exceptions being the head of the pancreas, subcutaneous fat, colon, and spleen. In marked distinction to other studies, however, we found a prolific expression of the alpha 2C4 and alpha 2C2 subtypes. Expression of alpha 2C4 was found in all tissues with the exception of liver, fat, stomach, and colon, and a virtually ubiquitous expression of alpha 2C2 was found, with the exception of epicardium. Of all tissues studied, only colon and subcutaneous fat expressed a single alpha 2AR subtype, which was alpha 2C2. Thus, the alpha 2AR subtypes do not have a confined expression but

  9. Aging Exacerbates Depressive-like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System

    OpenAIRE

    Godbout, Jonathan P.; Moreau, Maïté; Lestage, Jacques; Chen, Jing; Sparkman, Nathan L; O’Connor, Jason; Castanon, Nathalie; Kelley, Keith W.; Dantzer, Robert; Johnson, Rodney W.

    2007-01-01

    Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LP...

  10. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system.

    OpenAIRE

    Timmermans, Silke; Bogie, Jeroen; Vanmierlo, Tim; Lütjohann, Dieter; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J.A.

    2014-01-01

    Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND...

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

    OpenAIRE

    Wyatt, Amy R.; Kumita, Janet R.; Farrawell, Natalie E.; Dobson, Christopher M.; Wilson, Mark R.

    2015-01-01

    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 ...

  12. Role of signal transducer and activator of transcription 1 in murine allergen-induced airway remodeling and exacerbation by carbon nanotubes.

    Science.gov (United States)

    Thompson, Elizabeth A; Sayers, Brian C; Glista-Baker, Ellen E; Shipkowski, Kelly A; Ihrie, Mark D; Duke, Katherine S; Taylor, Alexia J; Bonner, James C

    2015-11-01

    Asthma is characterized by a T helper type 2 phenotype and by chronic allergen-induced airway inflammation (AAI). Environmental exposure to air pollution ultrafine particles (i.e., nanoparticles) exacerbates AAI, and a concern is possible exacerbation posed by engineered nanoparticles generated by emerging nanotechnologies. Signal transducer and activator of transcription (STAT) 1 is a transcription factor that maintains T helper type 1 cell development. However, the role of STAT1 in regulating AAI or exacerbation by nanoparticles has not been explored. In this study, mice with whole-body knockout of the Stat1 gene (Stat1(-/-)) or wild-type (WT) mice were sensitized to ovalbumin (OVA) allergen and then exposed to multiwalled carbon nanotubes (MWCNTs) by oropharygneal aspiration. In Stat1(-/-) and WT mice, OVA increased eosinophils in bronchoalveolar lavage fluid, whereas MWCNTs increased neutrophils. Interestingly, OVA sensitization prevented MWCNT-induced neutrophilia and caused only eosinophilic inflammation. Stat1(-/-) mice displayed increased IL-13 in bronchoalveolar lavage fluid at 1 day compared with WT mice after treatment with OVA or OVA and MWCNTs. At 21 days, the lungs of OVA-sensitized Stat1(-/-) mice displayed increased eosinophilia, goblet cell hyperplasia, airway fibrosis, and subepithelial apoptosis. MWCNTs further increased OVA-induced goblet cell hyperplasia, airway fibrosis, and apoptosis in Stat1(-/-) mice at 21 days. These changes corresponded to increased levels of profibrogenic mediators (transforming growth factor-β1, TNF-α, osteopontin) but decreased IL-10 in Stat1(-/-) mice. Finally, fibroblasts isolated from the lungs of Stat1(-/-) mice produced significantly more collagen mRNA and protein in response to transforming growth factor-β1 compared with WT lung fibroblasts. Our results support a protective role for STAT1 in chronic AAI and exacerbation of remodeling caused by MWCNTs. PMID:25807359

  13. A telehealth program for self-management of COPD exacerbations and promotion of an active lifestyle: a pilot randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Tabak M

    2014-09-01

    Full Text Available Monique Tabak,1,2 Marjolein Brusse-Keizer,3 Paul van der Valk,3,4 Hermie Hermens,1,2 Miriam Vollenbroek-Hutten1,2 1Telemedicine Group, Roessingh Research and Development, 2Telemedicine Group, University of Twente, 3Department of Pulmonary Medicine, Medisch Spectrum Twente, 4Medical School Twente, Medisch Spectrum Twente, Enschede, the Netherlands Abstract: The objective of this pilot study was to investigate the use of and satisfaction with a chronic obstructive pulmonary disease (COPD telehealth program applied in both primary and secondary care. The program consisted of four modules: 1 activity coach for ambulant activity monitoring and real-time coaching of daily activity behavior, 2 web-based exercise program for home exercising, 3 self-management of COPD exacerbations via a triage diary on the web portal, including self-treatment of exacerbations, and 4 teleconsultation. Twenty-nine COPD patients were randomly assigned to either the intervention group (telehealth program for 9 months or the control group (usual care. Page hits on the web portal showed the use of the program, and the Client Satisfaction Questionnaire showed satisfaction with received care. The telehealth program with decision support showed good satisfaction (mean 26.4, maximum score 32. The program was accessed on 86% of the treatment days, especially the diary. Patient adherence with the exercise scheme was low (21%. Health care providers seem to play an important role in patients' adherence to telehealth in usual care. Future research should focus on full-scale implementation in daily care and investigating technological advances, like gaming, to increase adherence. Keywords: COPD, physical activity, exacerbations, telehealth, self-management

  14. 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.

  15. Inhaled corticosteroids do not reduce initial high activity of matrix metalloproteinase (MMP)-9 in exhaled breath condensates of children with asthma exacerbation: a proof of concept study

    Science.gov (United States)

    Grzela, Katarzyna; Zagórska, Wioletta; Krejner, Alicja; Banaszkiewicz, Aleksandra; Litwiniuk, Małgorzata; Kulus, Marek

    2016-01-01

    Inhaled corticosteroids (ICS) are the key component of asthma treatment. However, it is unclear whether they could control the activity and level of matrix metalloproteinase (MMP)-9, which is an important factor in asthma-associated inflammation and airway remodeling. Therefore, the aim of this proof of concept study was to analyze the influence of increased doses of ICS on MMP-9 in exhaled breath condensates (EBC) of patients with allergic asthma exacerbation. Apart from MMP-9, the assessment concerned selected inflammation markers – exhaled nitric oxide (eNO) and cytokines (IL-8 and TNF). The study involved a small group (n = 4) of individuals with asthma exacerbation. The intervention concerned increased doses of ICS with β-mimetics for 4 weeks. In addition to clinical evaluation, eNO measurements and EBC collections were done before and after 4 weeks of intense ICS treatment. The biochemical assessment of EBC concerned MMP-9, IL-8 and TNF. The data were compared to results of healthy controls (n = 6). The initial levels of eNO, MMP-9 and TNF in EBC were higher in the asthma group than in controls. In all subjects IL-8 levels were below the detection limit. After 4 weeks of ICS treatment in all patients we observed improvement of clinical and laboratory parameters. Interestingly, despite reduction of eNO and TNF, the activity of MMP-9/EBC remained on the initial level. Practical relevance of our results is limited by a small group. Nevertheless, our data suggest that ICS, although sufficient to control symptoms and inflammatory markers, may be ineffective to reduce MMP-9/EBC activity in asthma exacerbation and, possibly, airway remodeling. PMID:27536209

  16. [Studies on human alpha-2 macroglobulin structure and its complexes with proteases, using polyacrylamide gel electrophoresis].

    Science.gov (United States)

    Fine, J M; Lambin, P; Steinbuch, M

    1975-09-01

    Pure alpha2M is prepared with fresh plasma as starting material, to prevent the interaction of alpha2M from proteolytic enzymes of plasma such as thrombin, plasmin and kallikrein. During the purification steps, polybrene and aprotin are used as inhibitors and plasminogen is absorbed onto bentonite. When alpha 2M is submitted to polyacrylamide gel electrophoresis (PAA) containing 0.1% SDS, a complete dissociation in two half-molecules of MW 380,000 occurs. When alpha2M is incubated in 1% SDS and 1% beta-mercaptoethanol as reducing agent, only one component of MW 190,000 is observed in PAA-SDS. This experiments show that the alpha2M molecule consist of two symetric halves of same MW (380,000) linked by non covalent bonds. Each two-half-molecules is made of two polypeptides chains MW 190,000 linked by disulfide bonds. Thus alpha2M molecule contains four polypeptides chains having a same MW. The same techniques were applied to the study of alaph2M proteinases complexes. Three different proteinases (plasmin, trypsin and papain) were used in these experiments. Trypsin and papain are commercialy available. Plasminogen was obtained by affinity chromatography and activated into plasmin by insoluble streptokinase fixed on PAB cellulose. PMID:59941

  17. 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.

  18. Activation of cerebral sodium-glucose transporter type 1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemia.

    Science.gov (United States)

    Yamazaki, Y; Ogihara, S; Harada, S; Tokuyama, S

    2015-12-01

    The regulation of post-ischemic hyperglycemia plays an important role in suppressing neuronal damage in therapeutic strategies for cerebral ischemia. We previously reported that the cerebral sodium-glucose transporter (SGLT) was involved in the post-ischemic hyperglycemia-induced exacerbation of cerebral ischemic neuronal damage. Cortical SGLT-1, one of the cerebral SGLT isoforms, is dramatically increased by focal cerebral ischemia. In this study, we focused on the involvement of cerebral SGLT-1 in the development of cerebral ischemic neuronal damage. It was previously reported that activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) increases SGLT-1 expression. Moreover, ischemic stress-induced activation of AMPK exacerbates cerebral ischemic neuronal damage. Therefore, we directly confirmed the relationship between cerebral SGLT-1 and cerebral AMPK activation using in vitro primary culture of mouse cortical neurons. An in vivo mouse model of focal cerebral ischemia was generated using a middle cerebral artery occlusion (MCAO). The development of infarct volume and behavioral abnormalities on day 3 after MCAO were ameliorated in cerebral SGLT-1 knock down mice. Cortical and striatal SGLT-1 expression levels were significantly increased at 12h after MCAO. Immunofluorescence revealed that SGLT-1 and the neuronal nuclear antigen (NeuN) were co-localized in the cortex and striatum of MCAO mice. In the in vitro study, primary cortical neurons were cultured for five days before each treatment with reagents. Concomitant treatment with hydrogen peroxide and glucose induced the elevation of SGLT-1 and phosphorylated AMPK/AMPK ratio, and this elevation was suppressed by compound C, an AMPK inhibitor in primary cortical neurons. Moreover, compound C suppressed neuronal cell death induced by concomitant hydrogen peroxide/glucose treatment in primary cortical neurons. Therefore, we concluded that enhanced cerebral SGLT-1 function mediated by post

  19. Efficacy and Tolerability of Peginterferon alpha-2a and Peginterferon alpha-2b in Iranian Patients With Chronic Hepatitis C

    OpenAIRE

    Pouresmaeeli, Mahdiyar; Alavian, Seyed Moayed; Keshvari, Maryam; Salimi, Shima; Mehrnoush, Leila

    2015-01-01

    Background: Nearly 0.5% of Iranians are infected with HCV. Peginterferon-alpha-2a and Peginterferon-alpha-2b are the two available types of interferon for the treatment of hepatitis C. Comparing the results of these two treatments is still a challenge. Objectives: The aim of this study was to compare the results of Peginterferon-alpha-2a and Peginterferon-alpha-2b in Iranian patients with chronic hepatitis C. Patients and Methods: 289 patients with chronic hepatitis C attending Tehran Hepatit...

  20. TRPV1 Activation Exacerbates Hypoxia/Reoxygenation-Induced Apoptosis in H9C2 Cells via Calcium Overload and Mitochondrial Dysfunction

    Directory of Open Access Journals (Sweden)

    Zewei Sun

    2014-10-01

    Full Text Available Transient potential receptor vanilloid 1 (TRPV1 channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene-related peptide (CGRP and substance P (SP. Recent studies show that TRPV1 channels are also expressed on cardiomyocytes and can exacerbate air pollutant-induced apoptosis. However, whether these channels present on cardiomyocytes directly modulate cell death and survival pathways during hypoxia/reoxygenation (H/R injury remains unclear. In the present study, we investigated the role of TRPV1 in H/R induced apoptosis of H9C2 cardiomyocytes. We demonstrated that TRPV1 was indeed expressed in H9C2 cells, and activated by H/R injury. Although neuropeptide release caused by TRPV1 activation on sensory neurons elicits a cardioprotective effect, we found that capsaicin (CAP; a TRPV1 agonist treatment of H9C2 cells paradoxically enhanced the level of apoptosis by increasing intracellular calcium and mitochondrial superoxide levels, attenuating mitochondrial membrane potential, and inhibiting mitochondrial biogenesis (measured by the expression of ATP synthase β. In contrast, treatment of cells with capsazepine (CPZ; a TRPV1 antagonist or TRPV1 siRNA attenuated H/R induced-apoptosis. Furthermore, CAP and CPZ treatment revealed a similar effect on cell viability and mitochondrial superoxide production in primary cardiomyocytes. Finally, using both CGRP8–37 (a CGRP receptor antagonist and RP67580 (a SP receptor antagonist to exclude the confounding effects of neuropeptides, we confirmed aforementioned detrimental effects as TRPV1−/− mouse hearts exhibited improved cardiac function during ischemia/reperfusion. In summary, direct activation of TRPV1 in myocytes exacerbates H/R-induced apoptosis, likely through calcium overload and associated mitochondrial dysfunction. Our study provides a novel understanding of the role of

  1. Use of synthetic peptides to locate novel integrin alpha2beta1-binding motifs in human collagen III.

    Science.gov (United States)

    Raynal, Nicolas; Hamaia, Samir W; Siljander, Pia R-M; Maddox, Ben; Peachey, Anthony R; Fernandez, Rafael; Foley, Loraine J; Slatter, David A; Jarvis, Gavin E; Farndale, Richard W

    2006-02-17

    A set of 57 synthetic peptides encompassing the entire triplehelical domain of human collagen III was used to locate binding sites for the collagen-binding integrin alpha(2)beta(1). The capacity of the peptides to support Mg(2+)-dependent binding of several integrin preparations was examined. Wild-type integrins (recombinant alpha(2) I-domain, alpha(2)beta(1) purified from platelet membranes, and recombinant soluble alpha(2)beta(1) expressed as an alpha(2)-Fos/beta(1)-Jun heterodimer) bound well to only three peptides, two containing GXX'GER motifs (GROGER and GMOGER, where O is hydroxyproline) and one containing two adjacent GXX'GEN motifs (GLKGEN and GLOGEN). Two mutant alpha(2) I-domains were tested: the inactive T221A mutant, which recognized no peptides, and the constitutively active E318W mutant, which bound a larger subset of peptides. Adhesion of activated human platelets to GER-containing peptides was greater than that of resting platelets, and HT1080 cells bound well to more of the peptides compared with platelets. Binding of cells and recombinant proteins was abolished by anti-alpha(2) monoclonal antibody 6F1 and by chelation of Mg(2+). We describe two novel high affinity integrin-binding motifs in human collagen III (GROGER and GLOGEN) and a third motif (GLKGEN) that displays intermediate activity. Each motif was verified using shorter synthetic peptides. PMID:16326707

  2. Boundary Harnack principle for $\\Delta + \\Delta^{\\alpha/2}$

    OpenAIRE

    Chen, Zhen-Qing; Kim, Panki; Song, Renming; Vondraček, Zoran

    2009-01-01

    For $d\\geq 1$ and $\\alpha \\in (0, 2)$, consider the family of pseudo differential operators $\\{\\Delta+ b \\Delta^{\\alpha/2}; b\\in [0, 1]\\}$ on $\\R^d$ that evolves continuously from $\\Delta$ to $\\Delta + \\Delta^{\\alpha/2}$. In this paper, we establish a uniform boundary Harnack principle (BHP) with explicit boundary decay rate for nonnegative functions which are harmonic with respect to $\\Delta +b \\Delta^{\\alpha/2}$ (or equivalently, the sum of a Brownian motion and an independent symmetric $\\a...

  3. SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-κB p65 acetylation and activation.

    Science.gov (United States)

    Yuan, Fang; Xu, Zhi-Ming; Lu, Li-Yan; Nie, Hui; Ding, Jun; Ying, Wei-Hai; Tian, Heng-Li

    2016-02-01

    Sirtuin 2 (SIRT2) is a member of the sirtuin family of NAD(+) -dependent protein deacetylases. In recent years, SIRT2 inhibition has emerged as a promising treatment for neurodegenerative diseases. However, to date, there is no evidence of a specific role for SIRT2 in traumatic brain injury (TBI). We investigated the effects of SIRT2 inhibition on experimental TBI using the controlled cortical impact (CCI) injury model. Adult male mice underwent CCI or sham surgery. A selective brain-permeable SIRT2 inhibitor, AK-7, was administrated 30 min before injury. The volume of the brain edema lesion and the water content of the brain were significantly increased in mice treated with AK-7 (20 mg/kg), compared with the vehicle group, following TBI (p aquaporin 4 (AQP4), MMP-9, and pro-inflammatory cytokines. Together, these data demonstrate that SIRT2 inhibition exacerbates TBI by increasing NF-κB p65 acetylation and activation. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2. SIRT2 is a member of the sirtuin family of NAD+-dependent protein deacetylases. Our study suggests that the SIRT2 inhibitor AK-7 exacerbates traumatic brain injury (TBI) via a potential mechanism involving increased acetylation and nuclear translocation of NF-κB p65, resulting in up-regulation of NF-κB target genes, including aquaporin 4 (AQP4), matrix metalloproteinase 9 (MMP-9), and pro-inflammatory cytokines. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2. PMID:26546505

  4. 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.

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

    International Nuclear Information System (INIS)

    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

  6. Alpha-2 agonists as pain therapy in horses.

    Science.gov (United States)

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  7. COPD exacerbations · 3: Pathophysiology

    OpenAIRE

    O'Donnell, D. E.; Parker, C M

    2006-01-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality. The effective management of COPD exacerbations awaits a better understanding of the underlying pathophysiological mechanisms that shape its clinical expression. The clinical presentation of exacerbations of COPD is highly variable and ranges from episodic symptomatic deterioration that is poorly responsive to usual treatment, to devastating life threatening events. This undersc...

  8. 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

  9. CHANGES IN LEVELS OF SOLUBLE T-CELL ACTIVATION MARKERS, SIL-2R, SCD4 AND SCD8, IN RELATION TO DISEASE EXACERBATIONS IN PATIENTS WITH SYSTEMIC LUPUS-ERYTHEMATOSUS - A PROSPECTIVE-STUDY

    NARCIS (Netherlands)

    SPRONK, P.E.; TERBORG, E.J.; HUITEMA, M.G.; Limburg, Piet; Kallenberg, Cees

    1994-01-01

    Objectives-To assess serial activation of T-cell subsets in relation to auto-antibody production and the occurrence of disease exacerbations in patients with systemic lupus erythematosus (SLE). Methods-To study the possible role of T-cells in the pathophysiology of the disease, 16 consecutive exacer

  10. Pivotal role of the alpha(2A-adrenoceptor in producing inflammation and organ injury in a rat model of sepsis.

    Directory of Open Access Journals (Sweden)

    Michael Miksa

    Full Text Available BACKGROUND: Norepinephrine (NE modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs. Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP-induced sepsis in rats, which then stimulates TNF-alpha production in Kupffer cells (KCs through the activation of the alpha(2-AR. It is important to know which of the three alpha(2-AR subtypes (i.e., alpha(2A, alpha(2B or alpha(2C is responsible for the upregulation of TNF-alpha production. The aim of this study was to determine the contribution of alpha(2A-AR in this process. METHODOLOGY/PRINCIPAL FINDINGS: Adult male rats underwent CLP and KCs were isolated 2 h later. Gene expression of alpha(2A-AR was determined. In additional experiments, cultured KCs were incubated with NE with or without BRL-44408 maleate, a specific alpha(2A-AR antagonist, and intraportal infusion of NE for 2 h with or without BRL-44408 maleate was carried out in normal animals. Finally, the impact of alpha(2A-AR activation by NE was investigated under inflammatory conditions (i.e., endotoxemia and CLP. Gene expression of the alpha(2A-AR subtype was significantly upregulated after CLP. NE increased the release of TNF-alpha in cultured KCs, which was specifically inhibited by the alpha(2A-AR antagonist BRL-44408. Equally, intraportal NE infusion increased TNF-alpha gene expression in KCs and plasma TNF-alpha which was also abrogated by co-administration of BRL-44408. NE also potentiated LPS-induced TNF-alpha release via the alpha(2A-AR in vitro and in vivo. This potentiation of TNF-alpha release by NE was mediated through the alpha(2A-AR coupled Galphai protein and the activation of the p38 MAP kinase. Treatment of septic animals with BRL-44408 suppressed TNF-alpha, prevented multiple organ injury and

  11. Superplasticity and diffusion bonding of microduplex Super Alpha 2

    International Nuclear Information System (INIS)

    Studies on a Super Alpha-2 sheet alloy with a microduplex structure have shown it to have a considerable potential for SPF at temperatures of 940--980 C, and to remain free from cavitation after large tensile strains. The material could be readily isostatically diffusion bonded in this temperature range but the pressures required were appreciably higher than those for the bonding of Ti-6Al-4V. The different pressure requirements reflected, at least partially, the higher flow stresses of Super Alpha-2 for comparable deformation conditions. The isostatic DB model of Pilling gave reasonable agreement with experiment within the limits of reliability of the materials property data available to test the model. The present investigation shows that microduplex Super Alpha-2 has a considerable potential for fabrication using a DB/SPF route

  12. Work-related exacerbation of asthma.

    Science.gov (United States)

    Henneberger, Paul K; Hoffman, Christopher D; Magid, David J; Lyons, Ella E

    2002-01-01

    Adults with asthma who had been enrolled in an HMO for at least a year were requested to complete a questionnaire about their health status. Approximately 25% of the 1,461 participants responded positively to "Does your current work environment make your asthma worse?" and were classified as having workplace exacerbation of asthma. Those with workplace exacerbation were more likely to have never attended college, be current or former smokers, have a history of other respiratory diseases, have missed work or usual activities at least one day in the past for weeks, and report their asthma was moderate, severe, or very severe. Percentages with workplace exacerbation of asthma were highest for mining and construction (36%), wholesale and retail trade (33%), and public administration (33%), and lowest for educational services (22%), finance, insurance, and real estate (22%), and non-medical and non-educational services (18%). Future studies are needed for objective validation of self-reported workplace exacerbation, and to follow subjects prospectively to clarify the temporal sequence of workplace exacerbation and asthma severity, and how other respiratory conditions and smoking might contribute to work-related worsening of asthma. PMID:12412844

  13. 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.

  14. The monomeric alpha beta form of the insulin receptor exhibits much higher insulin-dependent tyrosine-specific protein kinase activity than the intact alpha 2 beta 2 form of the receptor.

    OpenAIRE

    Fujita-Yamaguchi, Y; Kathuria, S.

    1985-01-01

    The relationship between the structure of the insulin receptor and its kinase activity was studied on the purified receptor treated with different concentrations of dithiothreitol. An enhanced autophosphorylation of the beta subunit (Mr, 90,000) was observed on NaDodSO4/PAGE under reducing conditions when the receptor was treated with 0.1-0.75 mM dithiothreitol in the presence of 1 microM insulin. Since we have previously observed (unpublished data) that incubation of the purified receptor wi...

  15. COPD exacerbations · 1: Epidemiology

    OpenAIRE

    Donaldson, G C; Wedzicha, J A

    2006-01-01

    The epidemiology of exacerbations of chronic obstructive pulmonary disease (COPD) is reviewed with particular reference to the definition, frequency, time course, natural history and seasonality, and their relationship with decline in lung function, disease severity and mortality. The importance of distinguishing between recurrent and relapsed exacerbations is discussed.

  16. Exogenous progesterone exacerbates running response of adolescent female mice to repeated food restriction stress by changing α4-GABAA receptor activity of hippocampal pyramidal cells.

    Science.gov (United States)

    Wable, G S; Chen, Y-W; Rashid, S; Aoki, C

    2015-12-01

    Adolescent females are particularly vulnerable to mental illnesses with co-morbidity of anxiety, such as anorexia nervosa (AN). We used an animal model of AN, called activity-based anorexia (ABA), to investigate the neurobiological basis of vulnerability to repeated, food restriction (FR) stress-evoked anxiety. Twenty-one of 23 adolescent female mice responded to the 1st FR with increased wheel-running activity (WRA), even during the limited period of food access, thereby capturing AN's symptoms of voluntary FR and over-exercise. Baseline WRA was an excellent predictor of FR-elicited WRA (severity of ABA, SOA), with high baseline runners responding to FR with minimal SOA (i.e., negative correlation). Nine gained resistance to ABA following the 1st FR. Even though allopregnanolone (3α-OH-5α-pregnan-20-one, THP), the metabolite of progesterone (P4), is a well-recognized anxiolytic agent, subcutaneous P4 to these ABA-resistant animals during the 2nd FR was exacerbative, evoking greater WRA than the counterpart resistant group that received oil vehicle, only. Moreover, P4 had no WRA-reducing effect on animals that remained ABA-vulnerable. To explain the sensitizing effect of P4 upon the resistant mice, we examined the relationship between P4 treatment and levels of the α4 subunit of GABAARs at spines of pyramidal cells of the hippocampal CA1, a parameter previously shown to correlate with resistance to ABA. α4 levels at spine membrane correlated strongly and negatively with SOA during the 1st ABA (prior to P4 injection), confirming previous findings. α4 levels were greater among P4-treated animals that had gained resistance than of vehicle-treated resistant animals or of the vulnerable animals with or without P4. We propose that α4-GABAARs play a protective role by counterbalancing the ABA-induced increase in excitability of CA1 pyramidal neurons, and although exogenous P4's metabolite, THP, enhances α4 expression, especially among those that can gain resistance

  17. TRPV1 Activation Exacerbates Hypoxia/Reoxygenation-Induced Apoptosis in H9C2 Cells via Calcium Overload and Mitochondrial Dysfunction

    OpenAIRE

    Zewei Sun; Jie Han; Wenting Zhao; Yuanyuan Zhang; Shuai Wang; Lifang Ye; Tingting Liu; Liangrong Zheng

    2014-01-01

    Transient potential receptor vanilloid 1 (TRPV1) channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene-related peptide (CGRP) and substance P (SP). Recent studies show that TRPV1 channels are also expressed on cardiomyocytes and can exacerbate air pollutant-induced apoptosis. However, whether these channels present on cardiomyocytes directly modulate cell death a...

  18. COPD exacerbations, inflammation and treatment

    OpenAIRE

    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 the exacerbation, it has a different pattern. To date, it has been difficult to efficiently suppress this inflammation, and the anti-inflammatory treatment currently so far has considerable side eff...

  19. 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

    International Nuclear Information System (INIS)

    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

  20. Acute exacerbations of chronic obstructive pulmonary disease: causes and impacts.

    Science.gov (United States)

    Chhabra, Sunil K; Dash, Devi Jyoti

    2014-01-01

    Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are recognised clinically as episodes of increased breathlessness and productive cough requiring a more intensive treatment. A subset of patients with this disease is especially prone to such exacerbations. These patients are labelled as 'frequent exacerbators'. Though yet poorly characterised in terms of host characteristics, including any genetic basis, these patients are believed to represent a distinct phenotype as they have a different natural history with a more progressive disease and a poorer prognosis than those who get exacerbations infrequently. Most exacerbations appear to be associated with infective triggers, either bacterial or viral, although 'non-infective' agents, such as air pollution and other irritants may also be important. Susceptibility to exacerbations is determined by multiple factors. Several risk factors have been identified, some of which are modifiable. Chronic obstructive pulmonary disease (COPD) exacerbations are major drivers of health status and patient-centered outcomes, and are a major reason for health care utilisation including hospitalisations and intensive care admissions. These are associated with considerable morbidity and mortality, both immediate and long-term. These episodes have a negative impact on the patient and the disease including high economic burden, increased mortality, worsening of health status, limitation of activity, and aggravation of comorbidities including cardiovascular disease, osteoporosis and neuro-psychiatric complications. Exacerbations also increase the rate of progression of disease, increasing the annual decline in lung function and leading to a poorer prognosis. Evaluation of risk of exacerbations is now included as a major component of the initial assessment of a patient with COPD in addition to the traditionally used lung function parameter, forced expiratory volume in one second (FEV1). Decreasing the risk of exacerbations

  1. Alpha-2 adrenergic receptor-mediated inhibition of thermogenesis

    OpenAIRE

    Madden, Christopher J.; Tupone, Domenico; Cano, Georgina; Morrison, Shaun F.

    2013-01-01

    Alpha2-adrenergic receptor (α2-AR) agonists have been use as anti-hypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since α2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by α2-AR agonists. Nanoinjection of the α2-AR agonist, clonidine (1.2 nmol), into the ros...

  2. 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

    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...... 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...

  3. 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

    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 regulated systems with particular reference to the complement components C3 and C4....

  4. Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways.

    Science.gov (United States)

    Kral, Julia Barbara; Kuttke, Mario; Schrottmaier, Waltraud Cornelia; Birnecker, Birgit; Warszawska, Joanna; Wernig, Christina; Paar, Hannah; Salzmann, Manuel; Sahin, Emine; Brunner, Julia Stefanie; Österreicher, Christoph; Knapp, Sylvia; Assinger, Alice; Schabbauer, Gernot

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTEN(MyKO)), after induction of BIPF, exhibit increased TGF-β1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTEN(MyKO) mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTEN(MyKO) mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis. PMID:26971883

  5. Treatment of carcinoid syndrome with recombinant interferon alpha-2a.

    Science.gov (United States)

    Di Bartolomeo, M; Bajetta, E; Zilembo, N; de Braud, F; Di Leo, A; Verusio, C; D'Aprile, M; Scanni, A; Barduagni, M; Barduagni A [corrected to Barduagni, M

    1993-01-01

    The prognosis and the quality of life of patients with carcinoid tumors is related either to symptoms from the substances secreted or to progressive tumor growth. Medical treatment with cytotoxic agents is of marginal value for increasing life expectancy and reducing clinical symptoms. Recent studies with interferon have shown interesting results. In the present investigation, 22 patients with carcinoid tumors and syndrome were treated with recombinant interferon alpha-2a (r-IFN alpha-2a) at the dose of 6 x 10(6) IU intramuscularly daily for 8 weeks and three times weekly thereafter. The primary tumor was localized in the foregut (n = 11), midgut (n = 7), hindgut (n = 1), and unknown site (n = 3). Most cases had liver metastasis. Seventeen patients had elevated 5-hydroxyindoloacetic acid (5-HIAA) excretion and 5 had flushing and/or diarrhea as the only clinical manifestation. Six cases presented a complete syndrome (flushing, diarrhea and 5-HIAA excretion). Control of symptoms was obtained in 80% and a 5-HIAA level reduction in 58% of the patients. The interferon treatment was more effective for control of the carcinoid syndrome than for control of tumor growth. The treatment was well tolerated and fever, myalgia, anorexia and fatigue were the most frequent side-effects. PMID:7686766

  6. Exacerbations of asthma during pregnancy

    DEFF Research Database (Denmark)

    Ali, Zarqa; 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 unit and longer postpartum hospital stay. Asthma has been associated with increased risk of intrauterine growth retardation, small-for-gestational age, low birth weight, infant hypoglycaemia and preterm birth, but more recent prospective studies have not revealed significant associations with...

  7. The importance of apoptotic activity and plasma NT-proBNP levels in patients with acute exacerbation of decompensated heart failure and their relation to different drugs and comorbidities

    International Nuclear Information System (INIS)

    Objective: To demonstrate the presence and importance of apoptotic activity in heart failure during acute exacerbations and to investigate the effects of different drugs used and co-morbidities on levels of N-Terminal pro-Brain Natriuretic Peptide and apoptotic activity on admission and during hospitalisation. Methods: The descriptive study was conducted at the emergency department of Istanbul University Cardiology Institute between October 2010 and May 2011 and comprised patients with complaints of shortness of breath, and who were evaluated as acutely exacerbated decompensated heart failure with an aetiology of ischaemic or dilated cardiomyopathy. Apoptotic activity and N-Terminal pro-Brain Natriuretic Peptide levels were measured on admission and on the seventh day of treatment. SPSS 15 was used for statistical analysis. Results: Of the 89 patients in the study, 67(75%) were males. Overall mean age of the study sample was 61+-12 years. Patients who had N-Terminal pro-Brain Natriuretic Peptide levels higher than 6000 pg/ml on admission had greater in-patient mortality rate (p<0.001). N-Terminal pro-Brain Natriuretic Peptide levels decreased significantly on the seventh day of treatment compared to the admission values (p<0.012). Apoptotic activity levels, although not statistically significant, increased on the seventh day compared with admission values (p<0.12). Apoptotic activity levels on the 7th day were associated with in-patient deaths (p<0.002). Dopamine infusion in the treatment group during hospitalisation significantly increased apoptotic activity (p<0.035), whereas there was a trend towards decreased apoptotic activity levels with spironolactone (p<0.07). Treatment with beta-blockers did not change apoptotic activity levels (p<0.751), whereas lack of beta-blocker therapy increased apoptotic activity (p<0.02). Conclusion: N-Terminal pro-Brain Natriuretic Peptide may be an important risk predictor in decompensated heart failure exacerbations during

  8. Effect of gonadotropins and alpha 2u-globulin on testicular steroidogenesis and spermatogenesis in melatonin-treated rats

    Directory of Open Access Journals (Sweden)

    R Biswas

    2012-09-01

    Full Text Available Administration of melatonin (400?g/100g bd.wt. for 14 days caused a fall in weights of the testes and accessory sex organs and testicular 17?-hydroxysteroid dehydrogenase (17?-HSD but rise in 3?-hydroxysteroid dehydrogenase (3?-HSD activity, decreased spermatogenesis, serum level of gonadotropins, testosterone and alpha 2u-globulin, The animals treated with melatonin when received gonadotropins or alpha 2u-globulin for the last seven days reversed the weight of testis and accessory sex organs, 3?-HSD, 17?-HSD activities, serum level of gonadotropins, testosterone and alpha 2u-globulin when compared with melatonin-treated rats. It is concluded that alpha 2u-globulin prevents testicular degeneration in melatonin-treated rats by stimulating the synthesis of gonadotropins. Journal of College of Medical Sciences-Nepal,2012,Vol-8,No-1, 7-12 DOI: http://dx.doi.org/10.3126/jcmsn.v8i1.6819

  9. Prejunctional alpha2A-autoreceptors in the canine saphenous vein.

    Science.gov (United States)

    Paiva, M Q; Mota, A; Moura, D; Guimarães, S

    1997-09-01

    The aim of the study was to determine the subtype of prejunctional alpha2-autoreceptors in the canine saphenous vein. Segments of the vein were incubated with 3H-noradrenaline and subsequently perifused with modified Krebs-Henseleit solution. Five periods of electrical stimulation were applied (S1-S5; each for 2 min, 1 Hz). Concentration-response curves for the inhibitory effect of the alpha2-adrenoceptor agonists oxymetazoline and UK-14,304 and for the facilitatory effect of nine antagonists were determined. Correlations between the pEC30%s for the antagonists obtained in the present study and the pKis for the same antagonists obtained in tissues expressing only alpha2A- (HT29 cells), alpha2B- (neonatal rat lung), alpha2C- (OK cells) or alpha2D-adrenoceptors (rat submaxillary gland) showed that the alpha2-autoreceptors in the canine saphenous vein resemble most closely the alpha2A-subtype. Furthermore, oxymetazoline was a highly potent agonist (pIC50% = 8.10) and prazosin was a weak antagonist (pEC30% = 6.46), confirming that the alpha2-adrenoceptors involved in the modulation of the response to electrical stimulation of the canine saphenous vein do not belong to either the alpha2B- or alpha2C-subtype. On the other hand, the EC30% ratios phentolamine/rauwolscine and idazoxan/rauwolscine were much closer to the ratios obtained at alpha2-autoreceptors of the rabbit- (alpha2A) than of the guinea-pig brain cortex (alpha2D). The results suggest that the sympathetic nerves of the canine saphenous vein are endowed with alpha2A-adrenoceptors. PMID:9303575

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

    International Nuclear Information System (INIS)

    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 [14C]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

  11. Spectrophotometric variability of the magnetic CP star alpha2 CVn

    CERN Document Server

    Sokolov, N A

    2011-01-01

    The spectrophotometric variability of the classical magnetic CP star alpha2 CVn in the ultraviolet spectral region from 1150 to 3200 A is investigated. This study is based on the archival International Ultraviolet Explorer data obtained at different phases of the rotational cycle. The brightness of the star at spectral region from 3015 to 3138 A is constant over the period of rotation which means that the so called 'null wavelength region' exist on these wavelengths. Moreover, the minima values of the amplitude of light curves are reached in the spectral region at \\lambda \\lambda 1660 and 1900 A. The monochromatic light curves in the 'pseudo-continuum' of this star change their shape with wavelength. All light curves with \\lambda 2505 A shows the phase displacement of the minimum from 0.0 at \\lambda 2505 A to 0.3 at \\lambda 2993 A.

  12. Antimigratory effect of TK1-2 is mediated in part by interfering with integrin alpha2beta1.

    Science.gov (United States)

    Kim, Hyun-Kyung; Oh, Dae-Shik; Lee, Sang-Bae; Ha, Jung-Min; Joe, Young Ae

    2008-07-01

    The recombinant two kringle domain of human tissue-type plasminogen activator (TK1-2) has been shown to inhibit endothelial cell proliferation, angiogenesis, and tumor cell growth despite of sharing a low amino acid sequence homology with angiostatin. Here, we explored a possible inhibitory mechanism of action of TK1-2 by focusing on antimigratory effect. TK1-2 effectively inhibited endothelial cell migration induced by basic fibroblast growth factor or vascular endothelial growth factor in a dose-dependent manner and tube formation on Matrigel. It blocked basic fibroblast growth factor-induced or vascular endothelial growth factor-induced phosphorylation of extracellular signal-regulated kinase 1/2 and formation of actin stress fibers and focal adhesions. Interestingly, TK1-2 alone induced the weak phosphorylation of focal adhesion kinase, whereas it inhibited focal adhesion kinase phosphorylation induced by growth factors. When immobilized, TK1-2 promoted adhesion and spreading of endothelial cells compared with bovine serum albumin. However, treatment with anti-alpha(2)beta(1) blocking antibody markedly diminished endothelial cell adhesion to immobilized TK1-2 compared with anti-alpha(v)beta(3) or anti-alpha(5)beta(1) antibody. Pretreatment of soluble TK1-2 also altered the binding level of anti-alpha(2)beta(1) antibody to endothelial cells in fluorescence-activated cell sorting analysis. Indeed, a blocking antibody against integrin alpha(2)beta(1) or knocking down of integrin alpha(2) expression prevented the inhibitory effect of TK1-2 in cell migration. Therefore, these results suggest that TK1-2 inhibits endothelial cell migration through inhibition of signaling and cytoskeleton rearrangement in part by interfering with integrin alpha(2)beta(1). PMID:18645023

  13. 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

    an exacerbation. Caregiver-reported information (daytime cough, breathing difficulties, limitation of activity, nighttime cough or awakening, daytime and nighttime beta2-agonist use) were analyzed using general estimating equations with an exchangeable within-subject log odds ratio regression...... structure to identify predictors of an exacerbation. RESULTS: Average symptom scores and beta2-agonist use increased significantly before exacerbation but at different rates. A combination of daytime cough and wheeze and nighttime beta2-agonist use 1 day before the exacerbation was identified as strongly...... predictive 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...

  14. [Human recombinant leukocyte interferon alpha-2-A in 22 cases of metastatic malignant melanoma].

    Science.gov (United States)

    Maral, J; Steinberg, M; Weil, M; Chleq, C; Khayat, D; Banzet, P; Jacquillat, C

    1987-06-01

    Twenty-two patients with metastatic malignant melanoma received either 36 X 10(6) U (15 patients) or 18 X 10(6) U (7 patients) of human recombinant interferon alpha-2-A daily for 3 months by the intramuscular route, with progressive increase of dosage. This was followed in responders by a maintenance treatment consisting of 3 intramuscular injections per week in the same doses as those received at the end of the induction treatment. Out of 18 patients assessable for effectiveness, 1 had complete remission (7 months +) and 3 had partial response (52,61 and 82 days respectively), an overall improvement rate of 22%. The main side-effects observed were: pseudoinfluenza syndrome (100%), fatigue (100%), somnolence (95%), anorexia (90%) and haematological disorders. Dosage reduction was necessary in 13 of the 15 patients receiving 36 MU. This study shows that human recombinant interferon alpha-2-A has antitumoral activity in metastatic malignant melanoma. Other studies, notably with therapeutic combinations, are needed to determine the optimal dosage regimen of the drug and to increase its effectiveness. PMID:2955323

  15. MOLECULAR CLONING AND HETEROLOGOUS EXPRESSION OF HUMAN INTERFERON ALPHA2b GENE

    Directory of Open Access Journals (Sweden)

    I. Made Artika

    2013-01-01

    Full Text Available Human alpha Interferons (hIFNα have been shown to have antiviral, antiproliferative and immunomodulatory activities. The human interferon alpha2b (hIFNα2b, is one of the human interferon alpha2 sub variants, naturally synthesized as a polypeptide of 188 amino acid residues, the first 23 residues of which represents a signal peptide. In the present study, the hIFNα2b gene was expressed after being fused with Glutathione S-Transferase (GST gene. The hIFNα2b gene was amplified from human genomic DNA by using a pair of specific primers, cloned into an Escherichia coli expression vector and expressed in E. coli cells under the direction of the tac promoter. The expressed protein was purified using a one-step affinity chromatography column containing immobilized gluthatione-bound resin. The purified protein was shown to react specifically with anti-human-interferon-alpha antibody, confirming that the protein was the human interferon alpha molecule. This strategy has the potential to be used as an alternative mean for production of pure human interferon α proteins for therapeutic purposes and for further studies on their molecular characterization and mechanism of action.

  16. Pharmacological evidence that alpha2A- and alpha2C-adrenoceptors mediate the inhibition of cardioaccelerator sympathetic outflow in pithed rats.

    Science.gov (United States)

    Cobos-Puc, Luis E; Villalón, Carlos M; Sánchez-López, Araceli; Lozano-Cuenca, Jair; Pertz, Heinz H; Görnemann, Tilo; Centurión, David

    2007-01-12

    It has been suggested that the alpha(2)-adrenoceptors mediating cardiac sympatho-inhibition in pithed rats closely resemble the pharmacological profile of the alpha(2A)-adrenoceptor subtype. However, several lines of evidence suggest that more than one subtype may be involved. Thus, the present study has pharmacologically re-evaluated the receptor subtype(s) involved in the inhibitory effect of the alpha(2)-adrenoceptor agonist, B-HT 933, on the tachycardic responses elicited by selective cardiac sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) in desipramine-pretreated pithed rats. I.v. continuous infusions of B-HT 933 (30 microg/kg min), which failed to modify the tachycardic responses to exogenous noradrenaline, inhibited those induced by preganglionic (C(7)-T(1)) stimulation of the cardiac sympathetic outflow at all frequencies of stimulation (0.03-3 Hz). This cardiac sympatho-inhibitory response to B-HT 933 was: (1) unaltered by saline (1 ml/kg) or the antagonists BRL44408 (100 microg/kg; alpha(2A)) or imiloxan (3000 and 10,000 microg/kg; alpha(2B)); (2) partially antagonized by BRL44408 (300 microg/kg) or MK912 (10 microg/kg; alpha(2C)) given separately; and (3) completely antagonized by rauwolscine (300 microg/kg; alpha(2)), MK912 (30 microg/kg) or the combination of BRL44408 (300 microg/kg) plus MK912 (10 microg/kg). Moreover, the above doses of antagonists, which are high enough to block their respective receptors, failed to block per se the tachycardic responses to sympathetic stimulation. These results suggest that the cardiac sympatho-inhibition induced by B-HT 933 in pithed rats is mainly mediated by stimulation of alpha(2A)- and alpha(2C)-adrenoceptors. PMID:17109851

  17. Accelerated extracellular matrix turnover during exacerbations of COPD

    DEFF Research Database (Denmark)

    Sand, Jannie M B; Knox, Alan J; Lange, Peter;

    2015-01-01

    BACKGROUND: 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. METHODS: 69 patients with COPD hospitalised...... 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....

  18. Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding

    OpenAIRE

    Lijnen, Roger; Okada, K.; Matsuo, O; Collen, Desire; Dewerchin, Mieke

    1999-01-01

    alpha2-antiplasmin (alpha2-AP) is the main physiologic plasmin inhibitor in mammalian plasma. Inactivation of the murine alpha2-AP gene was achieved by replacing, through homologous recombination in embryonic stem cells, a 7-kb genomic sequence encoding the entire murine protein (exon 2 through part of exon 10, including the stop codon) with the neomycin resistance expression cassette. Germline transmission of the mutated allele was confirmed by Southern blot analysis. Mendelian inheritance o...

  19. 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....... These findings exclude variations in the concentrations of these inhibitors as possible sources of a change in the antithrombotic potential caused by oral contraceptives....

  20. 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)

    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

  1. Synthesis of acute-phase alpha 2-macroglobulin during inflammation and pregnancy.

    Science.gov (United States)

    Panrucker, D E; Lorscheider, F L

    1983-01-01

    A recent investigation of acute-phase alpha 2-macroglobulin (AP alpha 2M) concentration in the rat during pregnancy demonstrated a bimodal distribution, for which we suggested a maternal source of AP alpha 2M in early gestation and a fetal source in late gestation. This interpretation was supported by the findings of the present study, which employed organ culture techniques, incorporation of [35S]methionine, immunoprecipitation of radioactivity, and fluorography to measure synthesis of AP alpha 2M in specific fetal, adult, and maternal tissues. Preliminary results indicated that in adult male rats treated with croton oil (compared with nontreated males), AP alpha 2M was synthesized in kidney, spleen, thymus, and lymphocytes by 48 hr post induction, but synthesis in the liver was not evident. In the pregnant rat from 12 to 16 days (compared with nonpregnant females), synthesis of AP alpha 2M was high in metrial gland, moderate in spleen, thymus and lymphocytes, and absent in liver; at 21 days, synthesis of AP alpha 2M in these four maternal tissues had declined. Fetal synthesis of AP alpha 2M in yolk sac (12 to 16 days) and in liver (15 to 16 days) was significantly elevated, and at 21 days fetal liver still displayed marked synthesis. These data are consistent with the interpretation that an early maternal source of AP alpha 2M synthesis is the metrial gland and that in the fetus both yolk sac and liver are major sources of AP alpha 2M, the latter tissue continuing synthesis into late gestation. Lymphopoietic and lymph-containing tissues appear to be major sites of AP alpha 2M synthesis during inflammation and pregnancy. PMID:6200027

  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...... substantially prevented the muscular dystrophy in these mice. However, dy(W)/dy(W) mice, expressing the human laminin alpha2 under the control of the striated muscle-specific portion of the desmin promoter, still developed muscular dystrophy. This failure to rescue is apparently because of insufficient...... production of laminin alpha2. This study provides additional evidence that the amount of laminin alpha2 is most critical for the prevention of muscular dystrophy. These data may thus be of significance for attempts to treat congenital muscular dystrophy in human patients....

  3. Function of glycoprotein VI and integrin alpha2beta1 in the procoagulant response of single, collagen-adherent platelets.

    Science.gov (United States)

    Heemskerk, J W; Siljander, P; Vuist, W M; Breikers, G; Reutelingsperger, C P; Barnes, M J; Knight, C G; Lassila, R; Farndale, R W

    1999-05-01

    Various collagen-based materials were used to assess the structural requirements of collagen for inducing the procoagulant response of adhering platelets, as well as the collagen receptors involved. Cross-linked or monomeric collagen-related peptide (CRP), Gly-Cys-Hyp-(Gly-Pro-Hyp)10-Gly-Cys-Hyp-Gly was highly adhesive for platelets in a glycoprotein VI-(GpVI-)dependent manner. Adhesion was followed by a prolonged increase in cytosolic [Ca2+]i, formation of membrane blebs, exposure of phosphatidylserine (PS) and generation of prothrombinase-stimulating activity. Fibrils of type-I collagen were less adhesive but, once adhered, many of the platelets presented a full procoagulant response. Monomeric type-I collagen was unable to support adhesion, unless Mg(2+)-dependent integrin alpha2beta1 interactions were facilitated by omission of Ca2+ ions. With all surfaces, however, post-addition of CaCl2 to adhering platelets resulted in a potent Ca(2+)-influx signal, followed by PS exposure and bleb formation. The procoagulant response elicited by binding to CRP was inhibited by anti-GpVI Fab fragments, but not by impeding integrin alpha2beta1-mediated events. With fibrillar collagen, it was inhibited by blocking either the GpVI- or integrin alpha2beta1-mediated interactions. This suggests that the triple-helical Gly-Pro-Hyp repeat in CRP and analogous sequences in fibrillar collagen stimulate the procoagulant response of adherent platelets by acting as ligands for GpVI. Influx of Ca2+ is required for this response, and adhesion via integrin alpha2beta1 serves to potentiate the signaling effects of GpVI. PMID:10365754

  4. COPD exacerbations: an evidence-based review

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2012-07-01

    Full Text Available COPD exacerbations are a major source of COPD morbidity, mortality and cost. Exacerbations tend to become more frequent as COPD progresses with the cause assumed to be infectious in about 80% of patients. The mainstay of management is inhaled bronchodilators with judicious use of oxygen, antibiotics, corticosteroids and assisted ventilation. Recent studies have examined strategies to prevent exacerbations of COPD including use of macrolide antibiotics and self-management education.

  5. COPD exacerbations: an evidence-based review

    OpenAIRE

    Robbins RA

    2012-01-01

    COPD exacerbations are a major source of COPD morbidity, mortality and cost. Exacerbations tend to become more frequent as COPD progresses with the cause assumed to be infectious in about 80% of patients. The mainstay of management is inhaled bronchodilators with judicious use of oxygen, antibiotics, corticosteroids and assisted ventilation. Recent studies have examined strategies to prevent exacerbations of COPD including use of macrolide antibiotics and self-management education.

  6. STAT1, STAT3 and p38MAPK are involved in the apoptotic effect induced by a chimeric cyclic interferon-{alpha}2b peptide

    Energy Technology Data Exchange (ETDEWEB)

    Blank, Viviana C.; Pena, Clara [Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956-C1113AAD Buenos Aires (Argentina); Roguin, Leonor P., E-mail: rvroguin@qb.ffyb.uba.ar [Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956-C1113AAD Buenos Aires (Argentina)

    2010-02-15

    In the search of mimetic peptides of the interferon-{alpha}2b molecule (IFN-{alpha}2b), we have previously designed and synthesized a chimeric cyclic peptide of the IFN-{alpha}2b that inhibits WISH cell proliferation by inducing an apoptotic response. Here, we first studied the ability of this peptide to activate intracellular signaling pathways and then evaluated the participation of some signals in the induction of apoptosis. Stimulation of WISH cells with the cyclic peptide showed tyrosine phosphorylation of Jak1 and Tyk2 kinases, tyrosine and serine phosphorylation of STAT1 and STAT3 transcription factors and activation of p38 MAPK pathway, although phosphorylation levels or kinetics were in some conditions different to those obtained under IFN-{alpha}2b stimulus. JNK and p44/42 pathways were not activated by the peptide in WISH cells. We also showed that STAT1 and STAT3 downregulation by RNA interference decreased the antiproliferative activity and the amount of apoptotic cells induced by the peptide. Pharmacological inhibition of p38 MAPK also reduced the peptide growth inhibitory activity and the apoptotic effect. Thus, we demonstrated that the cyclic peptide regulates WISH cell proliferation through the activation of Jak/STAT signaling pathway. In addition, our results indicate that p38 MAPK may also be involved in cell growth regulation. This study suggests that STAT1, STAT3 and p38 MAPK would be mediating the antitumor and apoptotic response triggered by the cyclic peptide in WISH cells.

  7. Infective Exacerbation of Pasteurella multocida

    Science.gov (United States)

    Hamada, Mayumi; Elshimy, Noha; Abusriwil, Hatem

    2016-01-01

    An 89-year-old lady presented with a one-day history of shortness of breath as well as a cough productive of brown sputum. Her medical history was significant for chronic obstructive pulmonary disease (COPD). She was in severe type one respiratory failure and blood tests revealed markedly raised inflammatory markers; however her chest X-ray was clear. On examination there was bronchial breathing with widespread crepitations and wheeze. She was treated as per an infective exacerbation of COPD. Subsequent blood cultures grew Pasteurella multocida, a common commensal in the oropharynx of domesticated animals. The patient was then asked about any contact with animals, after which she revealed she had a dog and was bitten on her left hand the day before admission. We should not forget to enquire about recent history of injuries or animal bites when patients present acutely unwell. She made a complete recovery after treatment with penicillin. PMID:26942025

  8. Site-specific insertion of 3-aminotyrosine into subunit alpha2 of E. coli ribonucleotide reductase: direct evidence for involvement of Y730 and Y731 in radical propagation.

    Science.gov (United States)

    Seyedsayamdost, Mohammad R; Xie, Jianming; Chan, Clement T Y; Schultz, Peter G; Stubbe, JoAnne

    2007-12-01

    E. coli ribonucleotide reductase (RNR) catalyzes the production of deoxynucleotides using complex radical chemistry. Active RNR is composed of a 1:1 complex of two subunits: alpha2 and beta2. Alpha2 binds nucleoside diphosphate substrates and deoxynucleotide/ATP allosteric effectors and is the site of nucleotide reduction. Beta2 contains the stable diiron tyrosyl radical (Y122.) cofactor that initiates deoxynucleotide formation. This process is proposed to involve reversible radical transfer over >35 A between the Y122 in beta2 and C439 in the active site of alpha2. A docking model of alpha2beta2, based on structures of the individual subunits, suggests that radical initiation involves a pathway of transient, aromatic amino acid radical intermediates, including Y730 and Y731 in alpha2. In this study the function of residues Y730 and Y731 is investigated by their site-specific replacement with 3-aminotyrosine (NH2Y). Using the in vivo suppressor tRNA/aminoacyl-tRNA synthetase method, Y730NH2Y-alpha2 and Y731NH2Y-alpha2 have been generated with high fidelity in yields of 4-6 mg/g of cell paste. These mutants have been examined by stopped flow UV-vis and EPR spectroscopies in the presence of beta2, CDP, and ATP. The results reveal formation of an NH2Y radical (NH2Y730. or NH2Y731.) in a kinetically competent fashion. Activity assays demonstrate that both NH2Y-alpha2s make deoxynucleotides. These results show that the NH2Y. can oxidize C439 suggesting a hydrogen atom transfer mechanism for the radical propagation pathway within alpha2. The observed NH2Y. may constitute the first detection of an amino acid radical intermediate in the proposed radical propagation pathway during turnover. PMID:17990884

  9. DOSE-ESCALATION OF DACARBAZINE COMBINED WITH INTERFERON ALPHA-2A, G-CSF AND ONDANSETRON IN PATIENTS WITH METASTATIC MELANOMA

    NARCIS (Netherlands)

    SLEIJFER, DT; WILLEMSE, PHB; VANDERGRAAF, WTA; DEVRIES, EGE; KOOPS, HS; MULDER, NH

    1994-01-01

    To define the activity of an individually escalated dacarbazine (DTIC) dose combined with interferon-alpha-2a (IFN), granulocyte-colony stimulating-factor (G-CSF) and ondansetron, 20 patients (pts) with metastatic melanoma were treated with DTIC, ondansetron 8 mg iv, G-CSF300 mu g sc and IFN 9 MU sc

  10. Epigallocatechin gallate exacerbates fluoride-induced oxidative stress mediated testicular toxicity in rats through the activation of Nrf2 signaling pathway

    Institute of Scientific and Technical Information of China (English)

    S. Thangapandiyan; S. Miltonprabu

    2015-01-01

    Objective:To explore the ameliorative potential of epigallocatechin gallate (EGCG) by evaluating markers of oxidative stress, apoptosis, and inflammation and antioxidant competence in Fl intoxicated rats.Methods:The animals were divided in to four groups that is control, EGCG alone, NaF, and EGCG with NaF. Group III animal were exposed to Fl as sodium Fluoride (NaF) (25 mg/kg BW) for 4 weeks. After the completion of the treatment, the testis tissues has been removed and used for the experimental observations.Results:Pre-administration of EGCG to Fl intoxicated rats showed a significant normalization in the levels of steroidogenic enzymes, testosterone, sperm functions, oxidative stress markers and antioxidant status. The altered levels of proinflammatory cytokines and apoptotic markers were also relapsed in close proximity to control. In addition, EGCG significantly improved antioxidant status and reduced the oxidative stress and pathological changes in testes. The mRNA and protein analysis also substantiated that EGCG pre-treatment markedly enhanced the expression of Nrf2 and its target genes HO-1, NQO1 andγGCS and suppressed the expression of Keap1 in testis.Conclusion: Altogether, our findings supports that EGCG attenuates Fl toxicity in testis through Nrf2 activation.

  11. Blood Eosinophils and Exacerbations in COPD

    DEFF Research Database (Denmark)

    Vedel-Krogh, Signe; Nielsen, Sune F; Lange, Peter; Vestbo, Jørgen; Nordestgaard, Børge G

    2015-01-01

    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 Copenhagen...... General Population Study, we examined 7,225 with COPD based on spirometry. We recorded blood eosinophils at baseline and future COPD exacerbations longitudinally, defined as moderate (short-course treatment of systemic corticosteroids) or severe (hospitalization). We also assessed exacerbation risk in a...... subgroup of 203 COPD individuals with clinical COPD, defined as participants with ≥ 10 pack-years, FEV1 < 70% of predicted value and ≥ 1 moderate or severe exacerbation in the year prior to baseline. MEASUREMENTS AND MAIN RESULTS: During a median of 3.3 years of follow-up (range 0.03-8.1), 1,439 severe and...

  12. Optimizing antibiotic selection in treating COPD exacerbations

    Directory of Open Access Journals (Sweden)

    Attiya Siddiqi

    2008-03-01

    Full Text Available Attiya Siddiqi, Sanjay SethiDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Veterans Affairs Western New York Health Care System and University of Buffalo, State University of New York, Buffalo, New York, USAAbstract: Our understanding of the etiology, pathogenesis and consequences of acute exacerbations of chronic obstructive pulmonary disease (COPD has increased substantially in the last decade. Several new lines of evidence demonstrate that bacterial isolation from sputum during acute exacerbation in many instances reflects a cause-effect relationship. Placebo-controlled antibiotic trials in exacerbations of COPD demonstrate significant clinical benefits of antibiotic treatment in moderate and severe episodes. However, in the multitude of antibiotic comparison trials, the choice of antibiotics does not appear to affect the clinical outcome, which can be explained by several methodological limitations of these trials. Recently, comparison trials with nontraditional end-points have shown differences among antibiotics in the treatment of exacerbations of COPD. Observational studies that have examined clinical outcome of exacerbations have repeatedly demonstrated certain clinical characteristics to be associated with treatment failure or early relapse. Optimal antibiotic selection for exacerbations has therefore incorporated quantifying the risk for a poor outcome of the exacerbation and choosing antibiotics differently for low risk and high risk patients, reserving the broader spectrum drugs for the high risk patients. Though improved outcomes in exacerbations with antibiotic choice based on such risk stratification has not yet been demonstrated in prospective controlled trials, this approach takes into account concerns of disease heterogeneity, antibiotic resistance and judicious antibiotic use in exacerbations.Keywords: COPD, exacerbation, bronchitis, antibiotics

  13. 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; Andersen, Ove; Svehag, SE

    1995-01-01

    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...

  14. Perioperative use of selective alpha-2 agonists and antagonists in small animals

    OpenAIRE

    Lemke, Kip A.

    2004-01-01

    Alpha-2 agonists are the only single class of anesthetic drugs that induce reliable, dose-dependent sedation, analgesia, and muscle relaxation in dogs and cats. Used at low doses, as adjuncts to injectable and inhalational anesthetics, selective alpha-2 agonists dramatically reduce the amount of anesthetic drug required to induce and maintain anesthesia. This reduction in anesthetic requirements is achieved without significant depression of pulmonary function and with limited effects on cardi...

  15. The presence of alpha 2u-globulin is necessary for d-limonene promotion of male rat kidney tumors.

    Science.gov (United States)

    Dietrich, D R; Swenberg, J A

    1991-07-01

    In a 2-year carcinogenesis bioassay, d-limonene (dL) induced kidney tumors in male F344 rats, but not in female F344 rats or either sex of mice, d-Limonene-1,2-oxide, a metabolite of dL, has been shown to bind reversibly the male rat-specific urinary protein, alpha2u-globulin (alpha 2u-G), lysosomal degradation than alpha 2u-G alone. This reduced degradation of alpha 2u-G-chemical complex leads to an accumulation of this protein in the proximal convoluted tubules of the male rat kidney and to the morphological changes characteristic for alpha 2u-globulin nephropathy. The only male rat strain known to be resistant to this renal disease is the alpha 2u-G deficient NCI-Black-Reiter (NBR) rat. The objectives of this study were to determine whether or not dL causes sustained increases in cell proliferation and has promoting activity for renal adenomas in male rats and if the male rat-specific urinary protein, alpha 2u-G, is required. In a 32-week initiation-promotion assay, male F344 and NBR rats were treated with either 0 or 500 ppm N-ethyl-N-hydroxyethylnitrosamine (EHEN) in the drinking water for 2 weeks. Experimental groups of 31 to 38 rats then received 0 or 150 mg d-limonene/kg/day in corn oil for 30 weeks by p.o. gavage 5 days/week. Cell proliferation in the proximal tubules was assessed via 5-bromo-2'-deoxyuridine-filled osmotic mini-pumps and immunohistochemistry after 7 weeks (2 weeks EHEN + 5 weeks dL) and at the end of the study (2 weeks EHEN + 30 weeks dL). Preneoplastic and neoplastic lesions were quantified in perfusion-fixed kidneys. A 5-fold increase in the labeling index of P2-cells was found after 5 weeks and 30 weeks of promotion in all dL-treated F344 rats, whereas no difference between treatment groups was detected in NBR rats. No increase in tumors or preneoplastic lesions was detected in dL-treated NBR rats, whereas a 10-fold increase in renal adenomas and atypical hyperplasias was found in the EHEN-dL-treated F344 rats compared with F344 rats

  16. Common evolutionary origin of alpha 2-macroglobulin and complement components C3 and C4

    DEFF Research Database (Denmark)

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

    1985-01-01

    A comparison of the sequence of the subunit of human alpha 2-macroglobulin (alpha 2M; 1451 amino acid residues) with that of murine complement component pro-C3 (1639 amino acid residues) reveals eight extended regions of sequence similarity. These regions contain between 19% and 31% identically...... placed residues and account for 75% and 67%, respectively, of the polypeptide chains of alpha 2M and pro-C3. Published sequence data for complement component C4 show that segments of this protein match well with corresponding stretches in alpha 2M and pro-C3. It is proposed that alpha 2M, C3 and C4...... common gross structure. The quartets of basic residues in pro-C3 and pro-C4, at which cleavage takes place to produce the mature subunits of these proteins, and most of the residues forming the anaphylatoxin peptides of C3 and C4 (C3a and C4a) are absent in alpha 2M. In addition, C3 and C4 contain large...

  17. 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

  18. Update on work-exacerbated asthma

    OpenAIRE

    Tarlo, Susan M

    2016-01-01

    Work-exacerbated asthma (WEA) is the term used to describe the worsening of asthma related to work but not the causation of asthma by work. It is common and has been reported to occur for 21.5% of working asthmatics on average. The frequency and severity may range from a single mild exacerbation that may lead to no time lost at work up to daily or severe exacerbations that may require a permanent change in work. Reports from general population surveys and primary care settings include more pa...

  19. Yohimbine increases submaxillary kallikrein release into the saliva in dogs: evidence for alpha 2-adrenoceptor-mediated inhibition of cholinergic pathways.

    OpenAIRE

    Girolami, J. P.; Bascands, J.L.; Pécher, C.; Berlan, M; Montastruc, J. L.; Montastruc, P.

    1991-01-01

    1. The effects of the alpha 2-adrenoceptor antagonist, yohimbine (0.5 mg kg-1, i.v.) on basal, sympathetic and parasympathetic stimulation-induced submaxillary kallikrein release were investigated in the anaesthetized dog. Kallikrein was measured by its kininogenase activity before and after trypsin activation which also allowed a study of the proportion of active to total enzyme. 2. Yohimbine induced a rapid, three fold increase in basal kallikrein release correlated with an increase in sali...

  20. alpha 2-macroglobulin adsorbed to colloidal gold: a new probe in the study of receptor-mediated endocytosis

    OpenAIRE

    1981-01-01

    alpha 2-Macroglobulin (alpha 2 M) was adsorbed to colloidal gold and used as a new tool in the study of receptor-mediated endocytosis. alpha 2 M-gold is easy to prepare and is clearly visualized at the electron microscope level. When cells were incubated with alpha 2 M-gold at 0 degrees C, gold was visualized both diffusely over the cell surface and concentrated in coated pits. After cells to which alpha 2 M-gold had been bound at 0 degrees C were warmed, the gold was rapidly internalized int...

  1. Dexrazoxane exacerbates doxorubicin-induced testicular toxicity.

    Science.gov (United States)

    Levi, Mattan; Tzabari, Moran; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2015-10-01

    Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5  mg/kg DXR, 100  mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity. PMID:26329125

  2. Changes in serum and histology of patients with chronic hepatitis B after interferon alpha-2b treatment

    Institute of Scientific and Technical Information of China (English)

    Hong-Lei Han; Zhen-Wei Lang

    2003-01-01

    AIM: Chronic hepatitis B is a serious health problem.Interferon has long been used to treat Chronic hepatitis B.To evaluate the effects of interferon on chronic hepatitis Bbetter, we designed the study to investigate the changes insera and liver histology of patients with chronic hepatitis Bafter interferon alpha-2b treatment.METHODS: Twenty-four patients with chronic hepatitis Bwere enrolled in this study. They all received interferon alpha-2b treatment as following: 3 million units, i.m.. t.i.w., for 18weeks. Sera of all patients were obtained respectively forevaluation of ALT, HBsAg, HBcAg, HBeAg, HBV DNA andTIMP-1 before and afterinterferon treatment, also a liverbiopsy pre- and post-treatment was performed forcomparison of HAI, HBsAg, HBcAg, HBeAg, TIMP-1 andactivated HSC in the liver tissue.RESULTS: Patients who had normalization of serum ALTand seroconversion of HBeAg and/or HBV DNA (blothybridization) after treatment were defined as responders.The response rate in this study group was 37.5 % (7/24).Compared to pretreatment, the serum HBV DNA and TIMP-1 decreased significantly (P<0.05), so did the HAI, HBo Ag,HBeAg, TIMP-1 and activated HSC (P<0.05).CONCLUSION: The significant decrease in HBV DNA insera, the seroconversion of HBeAg, and the decrease ofviral expression in liver indicated that interferon alpha-2btreatment can inhibit viral replication. The normalization ofALT in sera and the improvement of HAI in liver showedthat interferon alpha-2b can improve the liver histology ofpatients with chronic hepatitis B. At the same time, interferonalpha-2b treatment can reduce the TIMP-1 in serum andliver and decrease the number of activated HSC, which mayallievate or inhibit hepatic fibrosis. Although the responserate was unsatisfactory, interferon play a benefical role onpatients with chronic hepatitis B in other respects. We stillneed further studies to improve the therapy effects.

  3. Identification of karyopherin-alpha 2 as an Oct4 associated protein

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The POU domain transcription factor Oct4 is a master regulator in maintaining self-renewal and pluripotency of embryonic stem(ES) cells.To further explore the functional network of Oct4,the yeast two-hybrid system was used to search for Oct4 interacting proteins.PH domain(containing POU domain and homeodomain)of human OCT4 was used as a bait.From the human testis cDNA library,we identi fied a strong interaction between OCT4 and karyopherin-alpha 2(KPNA-2).KPNA2 is involved in active nuclear import of proteins.This finding was confirmed by glutathione S-transferase pull-down and co-immunoprecipitation assays.The interaction between OCT4 and KPNA-2 was further mapped to multiple regions of the two proteins.In addition,we studied nuclear localization signal(NLS)of mouse Oct4 and demonstrated that it is essential for Oct4 nuclear localization.Thus,our data suggest that Oct4 nuclear localization may be mediated by its interaction with KPNA-2.

  4. Predicting asthma exacerbations employing remotely monitored adherence.

    Science.gov (United States)

    Killane, Isabelle; Sulaiman, Imran; MacHale, Elaine; Breathnach, Aoife; Taylor, Terence E; Holmes, Martin S; Reilly, Richard B; Costello, Richard W

    2016-03-01

    This Letter investigated the efficacy of a decision-support system, designed for respiratory medicine, at predicting asthma exacerbations in a multi-site longitudinal randomised control trial. Adherence to inhaler medication was acquired over 3 months from patients with asthma employing a dose counter and a remote monitoring adherence device which recorded participant's inhaler use: n = 184 (23,656 audio files), 61% women, age (mean ± sd) 49.3 ± 16.4. Data on occurrence of exacerbations was collected at three clinical visits, 1 month apart. The relative risk of an asthma exacerbation for those with good and poor adherence was examined employing a univariate and multivariate modified Poisson regression approach; adjusting for age, gender and body mass index. For all months dose counter adherence was significantly (p research should focus on refining adherence and exacerbation measures. Decision-support systems based on remote monitoring may enhance patient-physician communication, possibly reducing preventable adverse events. PMID:27222733

  5. Acute exacerbation of airspace enlargement with fibrosis

    OpenAIRE

    Tomoyuki Kakugawa; Kazuhiro Tabata; Daiki Ogawara; Tomoshi Tsuchiya; Shintaro Hara; Noriho Sakamoto; Yuji Ishimatsu; Kazuto Ashizawa; Takeshi Nagayasu; Junya Fukuoka; Shigeru Kohno

    2014-01-01

    In 2008, Kawabata et al. described a lesion which they termed “airspace enlargement with fibrosis” that could be included on the spectrum of smoking-related interstitial lung diseases. This group also reported that patients with airspace enlargement with fibrosis but without coexisting interstitial pneumonia of another type had no acute exacerbations and favorable prognoses on clinical follow-up. Here we describe the first case, to our knowledge, of acute exacerbation of airspace enlargement ...

  6. COPD exacerbations by disease severity in England

    OpenAIRE

    Merinopoulou E; Raluy-Callado M; Ramagopalan S; MacLachlan S; Khalid JM

    2016-01-01

    Evie Merinopoulou,1 Mireia Raluy-Callado,1 Sreeram Ramagopalan,1 Sharon MacLachlan,1 Javaria Mona Khalid2 1Real-World Evidence, Evidera, 2Takeda Development Centre Europe Ltd, London, UK Objectives: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated disease progression and are important drivers of health care resource utilization. The study aimed to quantify the rates of COPD exacerbations in England and assess health care resource utilization by ...

  7. Management of acute exacerbations in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Ontaneda Daniel

    2009-01-01

    Full Text Available A key component of multiple sclerosis is the occurrence of episodes of clinical worsening with either new symptoms or an increase in older symptoms over a few days or weeks. These are known as exacerbations of multiple sclerosis. In this review, we summarize the pathophysiology and treatment of exacerbations and describe how they are related to the overall management of this disease.

  8. Exacerbations in cystic fibrosis: 2 · Prevention

    OpenAIRE

    Bell, Scott C; Robinson, Philip J

    2007-01-01

    The life span of people with cystic fibrosis (CF) has increased dramatically over the past 50 years. Many factors have contributed to this improvement. Respiratory exacerbations of CF lung disease are associated with the need for hospitalisation and antibiotic treatment, reduction in the quality of life, fragmented sleep and mortality. A number of preventive treatment strategies have been developed to reduce the frequency and severity of respiratory exacerbations in CF including mucolytic age...

  9. Exacerbations of Chronic Obstructive Pulmonary Disease

    OpenAIRE

    Garvey, Christine; Ortiz, Gabriel

    2012-01-01

    Epidemiologic data indicate that chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. Patients with poorly managed COPD are likely to experience exacerbations that require emergency department visits or hospitalization—two important drivers contributing to escalating healthcare resource use and costs associated with the disease. Exacerbations also contribute to worsening lung function and negative outcomes in COPD. The aim of this review is to present th...

  10. The Effects of Bronchiectasis on Asthma Exacerbation

    OpenAIRE

    Kang, Hye Ran; Choi, Gyu-Sik; Park, Sun Jin; Song, Yoon Kyung; Kim, Jeong Min; Ha, Junghoon; Lee, Yung Hee; Lee, Byoung Hoon; Kim, Sang-Hoon; Lee, Jae Hyung

    2014-01-01

    Background Bronchiectasis and asthma are different in many respects, but some patients have both conditions. Studies assessing the effect of bronchiectasis on asthma exacerbation are rare. The aim of this study is to investigate the effect of bronchiectasis on asthma exacerbation. Methods We enrolled 2,270 asthma patients who were followed up in our hospital. Fifty patients had bronchiectasis and asthma. We selected fifty age- and sex-matched controls from the 2,220 asthma patients without br...

  11. Prolyl hydroxylation of collagen type I is required for efficient binding to integrin alpha 1 beta 1 and platelet glycoprotein VI but not to alpha 2 beta 1.

    Science.gov (United States)

    Perret, Stéephanie; Eble, Johannes A; Siljander, Pia R-M; Merle, Christine; Farndale, Richard W; Theisen, Manfred; Ruggiero, Florence

    2003-08-01

    Collagen is a potent adhesive substrate for cells, an event essentially mediated by the integrins alpha 1 beta 1 and alpha 2 beta 1. Collagen fibrils also bind to the integrin alpha 2 beta 1 and the platelet receptor glycoprotein VI to activate and aggregate platelets. The distinct triple helical recognition motifs for these receptors, GXOGER and (GPO)n, respectively, all contain hydroxyproline. Using unhydroxylated collagen I produced in transgenic plants, we investigated the role of hydroxyproline in the receptor-binding properties of collagen. We show that alpha 2 beta 1 but not alpha 1 beta 1 mediates cell adhesion to unhydroxylated collagen. Soluble recombinant alpha 1 beta 1 binding to unhydroxylated collagen is considerably reduced compared with bovine collagens, but binding can be restored by prolyl hydroxylation of recombinant collagen. We also show that platelets use alpha 2 beta 1 to adhere to the unhydroxylated recombinant molecules, but the adhesion is weaker than on fully hydroxylated collagen, and the unhydroxylated collagen fibrils fail to aggregate platelets. Prolyl hydroxylation is thus required for binding of collagen to platelet glycoprotein VI and to cells by alpha 1 beta 1. These observations give new insights into the molecular basis of collagen-receptor interactions and offer new selective applications for the recombinant unhydroxylated collagen I. PMID:12771137

  12. Predicting an asthma exacerbation in children 2 to 5 years of age

    DEFF Research Database (Denmark)

    Swern, Arlene S; Tozzi, Carol A; Knorr, Barbara;

    2008-01-01

    an exacerbation. Caregiver-reported information (daytime cough, breathing difficulties, limitation of activity, nighttime cough or awakening, daytime and nighttime beta2-agonist use) were analyzed using general estimating equations with an exchangeable within-subject log odds ratio regression...

  13. Mechanism of concerted inhibition of alpha2beta2-type hetero-oligomeric aspartate kinase from Corynebacterium glutamicum.

    Science.gov (United States)

    Yoshida, Ayako; Tomita, Takeo; Kuzuyama, Tomohisa; Nishiyama, Makoto

    2010-08-27

    Aspartate kinase (AK) is the first and committed enzyme of the biosynthetic pathway producing aspartate family amino acids, lysine, threonine, and methionine. AK from Corynebacterium glutamicum (CgAK), a bacterium used for industrial fermentation of amino acids, including glutamate and lysine, is inhibited by lysine and threonine in a concerted manner. To elucidate the mechanism of this unique regulation in CgAK, we determined the crystal structures in several forms: an inhibitory form complexed with both lysine and threonine, an active form complexed with only threonine, and a feedback inhibition-resistant mutant (S301F) complexed with both lysine and threonine. CgAK has a characteristic alpha(2)beta(2)-type heterotetrameric structure made up of two alpha subunits and two beta subunits. Comparison of the crystal structures between inhibitory and active forms revealed that binding inhibitors causes a conformational change to a closed inhibitory form, and the interaction between the catalytic domain in the alpha subunit and beta subunit (regulatory subunit) is a key event for stabilizing the inhibitory form. This study shows not only the first crystal structures of alpha(2)beta(2)-type AK but also the mechanism of concerted inhibition in CgAK. PMID:20573952

  14. 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

  15. Alzheimer's Disease: An Exacerbation of Senile Phenoptosis.

    Science.gov (United States)

    Isaev, N K; Stelmashook, E V; Genrikhs, E E; Oborina, M V; Kapkaeva, M R; Skulachev, V P

    2015-12-01

    Alzheimer's disease is characterized by progressive memory loss and cognitive decline accompanied by degeneration of neuronal synapses, massive loss of neurons in the brain, eventually resulting in complete degradation of personality and death. Currently, the cause of the disease is not fully understood, but it is believed that the person's age is the major risk factor for development of Alzheimer's disease. People who have survived after cerebral stroke or traumatic brain injury have substantially increased risk of developing Alzheimer's disease. Social exclusion, low social activity, physical inactivity, poor mental performance, and low level of education are among risk factors for development of this neurodegenerative disease, which is consistent with the concept of phenoptosis (Skulachev, V. P., et al. (1999) Biochemistry (Moscow), 64, 1418-1426; Skulachev, M. V., and Skulachev, V. P. (2014) Biochemistry (Moscow), 79, 977-993) stating that rate of aging is related to psychological and social aspects in human behavior. Here we assumed that Alzheimer's disease might be considered as an exacerbation of senile phenoptosis. If so, then development of this disease could be slowed using mitochondria-targeted antioxidants due to the accumulated data demonstrating a link between mitochondrial dysfunction and oxidative stress both with normal aging and Alzheimer's disease. PMID:26638682

  16. Low dose rapamycin exacerbates autoimmune experimental uveitis.

    Directory of Open Access Journals (Sweden)

    Zili Zhang

    Full Text Available BACKGROUND: Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis. DESIGN AND METHODS: B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU. Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD using the MitoCapture assay and Annexin V staining. RESULTS: Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response. CONCLUSION: These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response.

  17. Interstitial pneumonia associated to peginterferon alpha-2a: A focus on lung function.

    Science.gov (United States)

    Cortés-Telles, Arturo

    2016-01-01

    Pulmonary toxicity related to the use of pegylated interferon alpha-2a during treatment of hepatitis C infections is rare; nonetheless, some cases with fatal outcomes have been reported. Evaluating patients' pulmonary function is a key to diagnosis, follow-up and prognosis of several respiratory diseases, but case reports of respiratory manifestations related to the use of pegylated interferon alpha-2a have limited their findings to only baseline measurements. This paper examines the case of a 65-year-old woman with chronic hepatitis C virus infection who developed interstitial pneumonitis associated with pegylated interferon alpha-2a. Initial lung function evaluation revealed a marked reduction compared to an earlier assessment; the results were consistent with a moderate restricted pattern. Fortunately, over the ensuing 8 weeks of follow-up after discontinuing the drug, the patient recovered her lung function and experienced an overall improvement in her respiratory symptoms. PMID:27051119

  18. Interstitial pneumonia associated to peginterferon alpha-2a: A focus on lung function

    Directory of Open Access Journals (Sweden)

    Arturo Cortés-Telles

    2016-01-01

    Full Text Available Pulmonary toxicity related to the use of pegylated interferon alpha-2a during treatment of hepatitis C infections is rare; nonetheless, some cases with fatal outcomes have been reported. Evaluating patients' pulmonary function is a key to diagnosis, follow-up and prognosis of several respiratory diseases, but case reports of respiratory manifestations related to the use of pegylated interferon alpha-2a have limited their findings to only baseline measurements. This paper examines the case of a 65-year-old woman with chronic hepatitis C virus infection who developed interstitial pneumonitis associated with pegylated interferon alpha-2a. Initial lung function evaluation revealed a marked reduction compared to an earlier assessment; the results were consistent with a moderate restricted pattern. Fortunately, over the ensuing 8 weeks of follow-up after discontinuing the drug, the patient recovered her lung function and experienced an overall improvement in her respiratory symptoms.

  19. 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.

  20. 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.

  1. Characterization of hydrogen interactions with the surface of alpha-2 titanium aluminide alloys

    Science.gov (United States)

    Shanabarger, Mickey R.

    1990-01-01

    The interaction of hydrogen at the surface of alpha-2 titanium aluminide alloys with Nb additions has been investigated with Auger electron spectroscopy (AES) and reflected electron energy loss (REELS) spectroscopy. The hydrogen was either adsorbed onto the alloy surface from the gas phase or it was pre-charged into the alloy forming an alpha-2 hydride. No effect of either adsorbed or absorbed hydrogen was observed in the Auger spectra. A shift in the bulk plasmon loss energy (observed with REELS) was measured for both conditions. The potential significance of these results in relation to hydrogen interactions in this alloy is discussed.

  2. Do females behave differently in COPD exacerbation?

    Directory of Open Access Journals (Sweden)

    Kilic H

    2015-04-01

    Full Text Available Hatice Kilic,1 Nurdan Kokturk,2 Gulcin Sari,3 Mustafa Cakir41Department of Pulmonary Medicine, Ankara Atatürk Training and Research Hospital, 2Department of Pulmonary Medicine, School of Medicine, Gazi University School of Medicine, 3Department of Pulmonary Medicine, Dr. Nafiz Körez Sincan Devlet Hastanesi, 4Department of Public Health, School of Medicine, Gazi University, Ankara, TurkeyIntroduction: Little is known about whether there is any sex effect on chronic obstructive lung disease (COPD exacerbations. This study is intended to describe the possible sex-associated differences in exacerbation profile in COPD patients.Methods: A total of 384 COPD patients who were hospitalized due to exacerbation were evaluated retrospectively for their demographics and previous and current exacerbation characteristics.Results: The study was conducted on 109 (28% female patients and 275 (72% male patients. The mean age was 68.30±10.46 years. Although females had better forced expiratory volume in 1 second and near-normal forced vital capacity, they had much impaired arterial blood gas levels (partial oxygen pressure [PO2] was 36.28 mmHg vs 57.93 mmHg; partial carbon dioxide pressure [PCO2] was 45.97 mmHg vs 42.49 mmHg; P=0.001, indicating severe exacerbation with respiratory failure. More females had two exacerbations and two hospitalizations, while more men had one exacerbation and one hospitalization. Low adherence to treatment and pulmonary embolism were more frequent in females. Females had longer time from the onset of symptoms till the admission and longer hospitalization duration than males. Comorbidities were less in number and different in women (P<0.05. Women were undertreated and using more oral corticosteroids.Conclusion: Current data showed that female COPD patients might be more prone to have severe exacerbations, a higher number of hospitalizations, and prolonged length of stay for hospitalization. They have a different comorbidity

  3. How do COPD patients respond to exacerbations?

    Directory of Open Access Journals (Sweden)

    Verheij Theo JM

    2011-08-01

    Full Text Available Abstract Background Although timely treatment of COPD exacerbations seems clinically important, nearly half of these exacerbations remain unreported and subsequently untreated. Recent studies have investigated incidence and impact of failure to seek medical treatment during exacerbations. Yet, little is known about type and timing of other self-management actions in periods of symptom deterioration. The current prospective study aims at determining the relative incidence, timing and determinants of three types of patient responses. Methods In a multicentre observational study, 121 patients (age 67 ± 11 years, FEV1pred. 48 ± 19 were followed for 6 weeks by daily diary symptom recording. Three types of action were assessed daily: planning periods of rest, breathing techniques and/or sputum clearing (type-A, increased bronchodilator use (type-B and contacting a healthcare provider (type-C. Results Type-A action was taken in 70.7%, type-B in 62.7% and type C in 17.3% of exacerbations (n = 75. Smokers were less likely to take type-A and B actions. Type-C actions were associated with more severe airflow limitation and increased number of hospital admissions in the last year. Conclusions Our study shows that most patients are willing to take timely self-management actions during exacerbations. Future research is needed to determine whether the low incidence of contacting a healthcare provider is due to a lack of self-management or healthcare accessibility.

  4. ALPHA spokesperson Jeffrey Hangst gives a tour of the new ALPHA-2

    CERN Multimedia

    CERN Video Productions

    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.

  5. 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...

  6. 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. PMID:2439383

  7. 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)

    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

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

    International Nuclear Information System (INIS)

    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 3H-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

  9. Acute exacerbation of airspace enlargement with fibrosis

    Directory of Open Access Journals (Sweden)

    Tomoyuki Kakugawa

    2014-01-01

    Full Text Available In 2008, Kawabata et al. described a lesion which they termed “airspace enlargement with fibrosis” that could be included on the spectrum of smoking-related interstitial lung diseases. This group also reported that patients with airspace enlargement with fibrosis but without coexisting interstitial pneumonia of another type had no acute exacerbations and favorable prognoses on clinical follow-up. Here we describe the first case, to our knowledge, of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of another type. An 82-year-old man was referred to our department for worsening dyspnea and new alveolar opacities on chest radiograph following left pulmonary segmentectomy (S6 for cancer. A diagnosis of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of other types was made, based on pathological evidence of airspace enlargement with fibrosis and organizing diffuse alveolar damage. Treatment with high-dose methylprednisolone followed by tapered oral prednisolone resulted in gradual improvement of the clinical condition and chest radiographic findings. Clinicians should be aware that patients with airspace enlargement with fibrosis may experience acute exacerbation.

  10. 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

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

    DEFF Research Database (Denmark)

    Larsen, T.S.; Pallisgaard, N.; Andersen, M.T.;

    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...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response Udgivelsesdato: 2008/10...

  12. 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...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response....

  13. Is type I alpha 2 collagen gene responsible for intracranial aneurysm in Northeast China?

    Institute of Scientific and Technical Information of China (English)

    Pengfei Wu; Bo Li; Anhua Wu; Yunjie Wang

    2013-01-01

    In this study, we investigated whether a single nucleotide polymorphism (rs42524 G > C) in the type I alpha 2 collagen gene was associated with sporadic ruptured intracranial aneurysm or its clinical characteristics in patients from Northeast China. Genotyping of the rs42524 G > C polymorphism was carried out using a polymerase chain reaction-restriction fragment length polymorphism assay. The data showed that the frequency of the rs42524 GC + CC genotype was significantly higher than the GG genotype among intracranial aneurysm patients whose Hunt and Hess grading scale was > 3. In addition, the rs42524 G > C genotype was found to have a statistically significant association with intracranial aneurysm risk. These findings indicate that the type I alpha 2 collagen gene gene may be involved in a predisposition to intracranial aneurysm in the Northeast Chinese population. Crucially, the rs42524 C allele may be an important risk factor for increased severity of the condition in patients with ruptured intracranial aneurysms.

  14. Prostate cancer serum biomarker discovery through proteomic analysis of alpha-2 macroglobulin protein complexes

    OpenAIRE

    Burgess, Earle F.; Ham, Amy-Joan L.; Tabb, David L.; Billheimer, Dean; Roth, Bruce J.; Chang, Sam S.; Cookson, Michael S.; Hinton, Timothy J.; Cheek, Kristin L.; Hill, Salisha; Jennifer A Pietenpol

    2008-01-01

    Alpha-2 macroglobulin (A2M) functions as a universal protease inhibitor in serum and is capable of binding various cytokines and growth factors. In this study, we investigated if immunoaffinity enrichment and proteomic analysis of A2M protein complexes from human serum could improve detection of biologically relevant and novel candidate protein biomarkers in prostate cancer. Serum samples from six patients with androgen-independent, metastatic prostate cancer and six control patients without ...

  15. On the evolution of the magnetic field of Ap star $\\alpha^2$ CVn

    CERN Document Server

    Bychkov, V D; Madej, J; Topilskaya, G P

    2016-01-01

    New high-precision measurements of the longitudinal magnetic field of Ap stars suggest the existence of secular intrinsic variations of the global magnetic field in some stars. We argue that such changes are apparent in the Ap star $\\alpha^2$ CVn in the time scale of $\\sim$ 10 years, which results from the analysis of literature data. Therefore, such an observation implies, that the rate of magnetic field evolution of Ap stars is much higher than was previously thought.

  16. Interleukin-2 and interferon-alpha-2a outpatient therapy for metastatic renal cell carcinoma.

    Science.gov (United States)

    Lipton, A; Harvey, H; Givant, E; Hopper, K; Lawler, J; Matthews, Y; Hirsh, M; Zeffren, J

    1993-02-01

    The combination of interleukin-2 (IL-2) and interferon-alpha-2a (IFN-alpha-2a) has synergistic bioactivity in numerous preclinical model systems. Thirty-nine patients with metastatic renal cell cancer were treated with continuous intravenous infusion IL-2 for 4-5 days plus intramuscular IFN-alpha-2a 2-3 days a week for 4 consecutive weeks. A 2- to 4-week rest period was permitted after each 4 weeks of treatment. Thirty-one of the 39 patients were assessable for response determination. Response rate (six complete+seven partial remissions) was 33.3% for all patients, or 41.9% when the analysis was restricted to the 31 evaluable patients. Three patients were unable to tolerate treatment due to anorexia, weight loss, and severe fatigue. This therapy was relatively well tolerated in the outpatient setting in the other patients despite fever, chills, fatigue, anorexia, and weight loss. There was no correlation of response with site of metastases or bulk of disease. PMID:8318497

  17. Intensive Farmaco- Surveillance of Interferon Alpha 2b Recombinant in Multiple Sclerosis.

    Directory of Open Access Journals (Sweden)

    Leslie Pérez Ruiz

    2007-12-01

    Full Text Available Background: The interferon alpha 2b recombinant, produced in Cuba, is used in the treatment of different illnesses, such as the multiple sclerosis. For its commercialization it is needed to know its safety scope. Objective: To assess the adverse reactions of interferon alpha 2b recombinant in the treatment of multiple sclerosis. Method: During the period between 1996 and 2006, 70 clinical histories and data collection notebooks of patients included in the randomized double blind national clinical trial phase IV were revised. This trial was developed in the Clinic of Multiple Sclerosis of the Hospital "Dr. Gustavo Aldereguía Lima" in Cienfuegos. With regard to the total of manifested adverse reactions we analyzed type, length, and use of a given treatment to counteract them, intensity level (light, moderate, serious or lethal and causality level (definitive, probable, possible, conditional or not related. Results: 53 patients out of the total presented 207 adverse reactions to interferon. The most frequent were: fever, migraine, chills, arthralgia, asthenia and myalgia, being most of them moderate collateral effects of definitive character. In 197 patients the outcome was favorable. Conclusion: The use of the interferon alpha 2b recombinant was safe in the treatment of the multiple sclerosis in these patients. 

  18. uPA deficiency exacerbates muscular dystrophy in MDX mice

    OpenAIRE

    Suelves, Mònica; Vidal, Berta; Serrano, Antonio L.; Tjwa, Marc; Roma, Josep; López-Alemany, Roser; Luttun, Aernout; de Lagrán, María Martínez; Díaz, Maria Àngels; Jardí, Mercè; Roig, Manuel; Dierssen, Mara; Dewerchin, Mieke; Carmeliet, Peter; Muñoz-Cánoves, Pura

    2007-01-01

    Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (...

  19. Changes in Cystic Fibrosis Airway Microbiota at Pulmonary Exacerbation

    OpenAIRE

    Carmody, Lisa A.; Zhao, Jiangchao; Schloss, Patrick D.; Petrosino, Joseph F; Murray, Susan; Young, Vincent B.; Li, Jun Z.; LiPuma, John J.

    2013-01-01

    Rationale: In persons with cystic fibrosis (CF), repeated exacerbations of pulmonary symptoms are associated with a progressive decline in lung function. Changes in the airway microbiota around the time of exacerbations are not well understood.

  20. Optimizing antibiotic selection in treating COPD exacerbations

    OpenAIRE

    Attiya Siddiqi; Sanjay Sethi

    2008-01-01

    Attiya Siddiqi, Sanjay SethiDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Veterans Affairs Western New York Health Care System and University of Buffalo, State University of New York, Buffalo, New York, USAAbstract: Our understanding of the etiology, pathogenesis and consequences of acute exacerbations of chronic obstructive pulmonary disease (COPD) has increased substantially in the last decade. Several new lines of evidence demonstrate that bacterial isola...

  1. Virus Infection-Induced Bronchial Asthma Exacerbation

    Directory of Open Access Journals (Sweden)

    Mutsuo Yamaya

    2012-01-01

    Full Text Available Infection with respiratory viruses, including rhinoviruses, influenza virus, and respiratory syncytial virus, exacerbates asthma, which is associated with processes such as airway inflammation, airway hyperresponsiveness, and mucus hypersecretion. In patients with viral infections and with infection-induced asthma exacerbation, inflammatory mediators and substances, including interleukins (ILs, leukotrienes and histamine, have been identified in the airway secretions, serum, plasma, and urine. Viral infections induce an accumulation of inflammatory cells in the airway mucosa and submucosa, including neutrophils, lymphocytes and eosinophils. Viral infections also enhance the production of inflammatory mediators and substances in airway epithelial cells, mast cells, and other inflammatory cells, such as IL-1, IL-6, IL-8, GM-CSF, RANTES, histamine, and intercellular adhesion molecule-1. Viral infections affect the barrier function of the airway epithelial cells and vascular endothelial cells. Recent reports have demonstrated augmented viral production mediated by an impaired interferon response in the airway epithelial cells of asthma patients. Several drugs used for the treatment of bronchial asthma reduce viral and pro-inflammatory cytokine release from airway epithelial cells infected with viruses. Here, I review the literature on the pathogenesis of the viral infection-induced exacerbation of asthma and on the modulation of viral infection-induced airway inflammation.

  2. Treatment of pulmonary exacerbations in cystic fibrosis - could do better?

    Science.gov (United States)

    Smyth, Alan

    2016-08-01

    This article describes the nature and significance of pulmonary exacerbations in cystic fibrosis (CF). The effectiveness and safety of current exacerbation treatment are explored. The article concludes with a summary of clinical trials (completed and ongoing) which aim to improve the efficacy and safety of exacerbation treatment. PMID:27349725

  3. Alpha-2 adrenergic and serotonin-1B receptors in the OK cell, an opossum kidney cell line

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, T.J.

    1988-01-01

    Alpha-2 adrenergic and serotonin-1B (5HT{sub 1B}) receptors, both negatively-coupled to adenylyl cyclase, were characterized in the OK cell line, a renal proximal tubule epithelial cell line derived from the kidney of a North American opossum. In membrane saturation radioligand binding experiments, ({sup 3}H)yohimbine and ({sup 3}H)rauwolscine labeled an equivalent number of binding sites. Detailed pharmacological analysis of OK cell alpha-2 adrenergic receptors in competition binding assays indicate this receptor is neither an alpha-2A nor an alpha-2B adrenergic receptor subtype, although the alpha-2B receptor subtype-selective drugs prazosin, ARC-239 and chlorpromazine have affinities for OK cell alpha-2 adrenergic receptors similar to those at the alpha-2B receptor subtype. Determinations of agonist potency for inhibition of PTH-stimulated cyclic AMP production and radioligand binding analysis using ({sup 125}I)({minus})-cyanopindolol indicate that a 5HT{sub 1B} receptor is expressed in the OK cell line. A biochemical effector system coupled to this receptor subtype has not been previously described. Several compounds appear to be potent agonists at the 5TH{sub 1B} receptor including the beta adrenergic antagonists cyanopindolol, pindolol, propranolol and alprenolol.

  4. Alpha-2 adrenergic and serotonin-1B receptors in the OK cell, an opossum kidney cell line

    International Nuclear Information System (INIS)

    Alpha-2 adrenergic and serotonin-1B (5HT1B) receptors, both negatively-coupled to adenylyl cyclase, were characterized in the OK cell line, a renal proximal tubule epithelial cell line derived from the kidney of a North American opossum. In membrane saturation radioligand binding experiments, [3H]yohimbine and [3H]rauwolscine labeled an equivalent number of binding sites. Detailed pharmacological analysis of OK cell alpha-2 adrenergic receptors in competition binding assays indicate this receptor is neither an alpha-2A nor an alpha-2B adrenergic receptor subtype, although the alpha-2B receptor subtype-selective drugs prazosin, ARC-239 and chlorpromazine have affinities for OK cell alpha-2 adrenergic receptors similar to those at the alpha-2B receptor subtype. Determinations of agonist potency for inhibition of PTH-stimulated cyclic AMP production and radioligand binding analysis using [125I](-)-cyanopindolol indicate that a 5HT1B receptor is expressed in the OK cell line. A biochemical effector system coupled to this receptor subtype has not been previously described. Several compounds appear to be potent agonists at the 5TH1B receptor including the beta adrenergic antagonists cyanopindolol, pindolol, propranolol and alprenolol

  5. Sodium modulation of 3H-agonist and 3H-antagonist binding to alpha 2-adrenoceptor subtypes.

    OpenAIRE

    MacKinnon, A. C.; Spedding, M.; Brown, C. M.(University of Victoria, V8W 3P6, Victoria, British Columbia, Canada)

    1993-01-01

    1. The alpha 2-adrenoceptors on human platelets and neonatal rat lung were characterized with the agonist and antagonist ligands [3H]-adrenaline and [3H]-RS-15385-197 respectively. A correlation of affinities for 3H-antagonist binding showed the receptors to be of the alpha 2A-(platelet) and alpha 2B-(neonatal rat lung) adrenoceptor subtypes, whereas a correlation of affinities for 3H-agonist binding showed the receptors to have similar characteristics (r = 0.88). 2. NaCl (100 mM) had no effe...

  6. Management of chronic obstructive pulmonary disease exacerbations in Internal Medicine

    Directory of Open Access Journals (Sweden)

    Gelorma Belmonte

    2013-03-01

    Full Text Available Introduction: Chronic obstructive pulmonary disease (COPD is the second leading cause of hospitalization in Internal Medicine departments in Italy and the fourth leading cause of death all over the word. By 2020, COPD will be the third leading cause of death and the fifth leading cause of disability. It is — along with chronic congestive heart failure — one of the most common causes of unscheduled hospital readmissions, and as such it represents a significant economic burden for the health-care system. Exacerbations of COPD are important events in the natural history of this prevalent condition. Discussion: This review provides a comprehensive state-of-the-art look at prevention and management of COPD exacerbations. Treatment of these episodes has to be tailored to the severity of the clinical presentation. We now have a wide range of therapeutic available options, based on the results of clinical trials. Management of the acute event should include the necessary measures (mainly the administration of inhaled short-acting bronchodilators, inhaled or oral corticosteroids, and antibiotics, with or without oxygen and ventilator support. Conclusions: To improve the management of COPD exacerbations, the focus of care must be shifted from the episodic acute complications to their systematic prevention. The management of COPD, which is often associated with multiple co-morbidities, is complex and requires a tailored, multifaceted and multidisciplinary approach. Integrated care for COPD also requires that patients be informed about their condition, that they participate actively in their care, and that they have easy access to the necessary health-care services.

  7. Dynamic expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors by human vascular smooth muscle cells. Alpha 2 beta 1 integrin is required for chemotaxis across type I collagen-coated membranes.

    OpenAIRE

    Skinner, M P; Raines, E W; Ross, R.

    1994-01-01

    Vascular smooth muscle cells (SMCs) in the media of normal arteries express alpha 1 beta 1 integrin with no detectable alpha 2 beta 1 as determined by immunocytochemistry. In contrast, immunoprecipitation of integrins expressed by human SMCs cultured from medial explants shows strong expression of alpha 2 beta 1 and no expression of alpha 1 beta 1. The apparent reciprocal expression of these two collagen and laminin receptors was confirmed by flow cytometric analysis of fluorescent labeled ce...

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

    International Nuclear Information System (INIS)

    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

  9. Intralesional interferon alpha - 2b in genital warts : A preliminary study

    OpenAIRE

    Pandhi R; Mittal Asit; Gupta Lalit

    1993-01-01

    Currently available therapy for condyloma acuminata (genital warts) is not consistently effective. Interferon (IFN) has both antiproliferatve and antiviral properties and has been used to treat genital warts with varying degree of success. We conducted an open study on 6 male patients with genital warts. A single wart of comparable area from each patient was injected with 2 x 106 IU of IFN alpha-2b, 3 times weekly for 3 weeks. The response to treatment was assessed during the therapy and at 1...

  10. Thyroiditis after treatment with interleukin-2 and interferon alpha-2a.

    OpenAIRE

    Pichert, G.; Jost, L. M.; Zöbeli, L.; Odermatt, B; Pedia, G.; Stahel, R. A.

    1990-01-01

    Serial thyroid functions studies were carried out in patients with melanoma and renal cell carcinoma treated with interleukin-2 (3 MU m-2 by continuous infusion days 1-4) and interferon alpha-2a (6 MU m-2 subcutaneously on days 1 and 4), both given on alternate weeks. The results on eight patients who completed at least three cycles of treatment are described. Four patients developed thyroid dysfunction with a hyperthyroid phase of 2 weeks followed by a hypothyroid phase ranging from 12 to 24...

  11. [Role of alpha 1-antitrypsin and alpha-2 macroglobulin in hepatopathies].

    Science.gov (United States)

    Triolo, L; Mian, G; Magris, D; Novello, E; D'Agnolo, B

    1979-02-18

    Two pictures of alpha 1-antitrypsin deficiency, one associated with alpha 2-macroglobulin deficiency and one isolated case of the latter deficiency have been observed in three patients suffering from cirrhosis of the liver and/or hepatoma. On the basis of these cases, the literature on the subject is reviewed. The unusually high incidence of such anti-enzymatic deficiencies (three cases in the first eleven patients studied) in severe liver pathology, calls for a reassessment of such research and suggests that these tests should be carried out on a routine basis in cases of cryptogenetic cirrhosis and probably for long-term prognosis in cases of viral hepatitis. PMID:86175

  12. Bilinexin, a snake C-type lectin from Agkistrodon bilineatus venom agglutinates platelets via GPIb and alpha2beta1.

    Science.gov (United States)

    Du, X Y; Navdaev, A; Clemetson, J M; Magnenat, E; Wells, T N; Clemetson, K J

    2001-11-01

    A new snake protein, named bilinexin, has been purified from Agkistrodon bilineatus venom by ion-exchange chromatography and gel filtration chromatography. Under non-reducing conditions it has a mass of 110 kDa protein on SDS-PAGE. On reduction, it can be separated into five subunits with masses in the range 13-25 kDa. The N-terminal sequences of these subunits are very similar to those of convulxin or the alboaggregins, identifying bilinexin as a new member of the snake C-type lectin family, unusual in having multiple subunits. Bilinexin agglutinates fixed platelets. washed platelets and platelet rich plasma (PRP) without obvious activation (shape change) as confirmed by light microscope examination. Both inhibitory and binding studies indicate that antibodies against alpha2beta1 inhibit not only platelet agglutination induced by bilinexin, but also bilinexin binding to platelets. VM16d, a monoclonal anti-GPIbalpha antibody, completely inhibits platelet agglutination induced by bilinexin, and polyclonal antibodies against GPIbalpha prevent its binding to platelets. However, neither convulxin, polyclonal anti-GPVI antibodies, nor GPIIb/IIIa inhibitors affect its binding to and agglutination of platelets. Bilinexin neither activates GPIIb/IIIa integrin on platelets nor induces tyrosine phosphorylation of platelet proteins, nor increases intracellular Ca2+ in platelets. Like alboaggregin B, bilinexin agglutinates platelets, which makes it a good tool to investigate the differences in mechanism between snake C-type lectins causing platelet agglutination and those that induce full activation. PMID:11816718

  13. Down-regulation of the alpha-2C adrenergic receptor: involvement of a serine/threonine motif in the third cytoplasmic loop

    OpenAIRE

    Deupree, Jean D; Borgeson, Claudia D.; Bylund, David B.

    2002-01-01

    Background The mechanisms by which alpha-2 adrenergic receptors are down-regulated following chronic exposure to agonist are not well understood. Interestingly, the human alpha-2C receptor does not down-regulate, whereas the opossum alpha-2C receptor does down-regulate. A comparison of the amino acid sequence of the third intracellular loop of these two receptors shows that the opossum alpha-2C receptor contains a potential G protein-coupled receptor kinase (GRK)phosphorylation motif (EESSTSE...

  14. The role of mean platelet volume predicting acute exacerbations of cystic fibrosis in children

    Directory of Open Access Journals (Sweden)

    Pinar Uysal

    2011-01-01

    Full Text Available Objective: The aim of this study is to evaluate the relationship between acute exacerbations and the mean platelet volume (MPV trend in children with cystic fibrosis (CF, to predict the exacerbations. Methods: A total of 46 children with CF and 37 healthy children were enrolled in the study. White blood cell count (WBC, hemoglobin level, platelet count, mean platelet volume (MPV, and mean corpuscular volume (MCV were retrospectively recorded. Results: Our study population consisted of 25 (54.3% males and 21 (45.7% females with CF and 20 (54.0% males and 17 (46.0% females in the healthy control group. The mean age of the CF patients was 6.32 ± 4.9 years and that of the healthy subjects was 7.02 ± 3.15 years. In the acute exacerbation period of CF, the MPV values were lower and WBC and platelet counts were higher than those in the healthy controls (P = 0.00, P = 0.00, P = 0.00, respectively. Besides, in acute exacerbation, the MPV values were lower and the WBC count was higher than the values in the non-exacerbation period (P 0= 0.01, P = 0.00, respectively. In the non-exacerbation period MPV was lower and platelet count was higher when compared to healthy subjects (P = 0.02, P = 0.04, respectively. Conclusion: This study suggests that MPV might be used as a simple, cost effective, diagnostic, predictive indicator for platelet activation in pediatric CF patients related to chronic inflammation, which might be helpful to discriminate or estimate exacerbations.

  15. The role of mean platelet volume predicting acute exacerbations of cystic fibrosis in children

    Science.gov (United States)

    Uysal, Pιnar; Tuncel, Tuba; Olmez, Duygu; Babayigit, Arzu; Karaman, Ozkan; Uzuner, Nevin

    2011-01-01

    OBJECTIVE: The aim of this study is to evaluate the relationship between acute exacerbations and the mean platelet volume (MPV) trend in children with cystic fibrosis (CF), to predict the exacerbations. METHODS: A total of 46 children with CF and 37 healthy children were enrolled in the study. White blood cell count (WBC), hemoglobin level, platelet count, mean platelet volume (MPV), and mean corpuscular volume (MCV) were retrospectively recorded. RESULTS: Our study population consisted of 25 (54.3%) males and 21 (45.7%) females with CF and 20 (54.0%) males and 17 (46.0%) females in the healthy control group. The mean age of the CF patients was 6.32 ± 4.9 years and that of the healthy subjects was 7.02 ± 3.15 years. In the acute exacerbation period of CF, the MPV values were lower and WBC and platelet counts were higher than those in the healthy controls (P = 0.00, P = 0.00, P = 0.00, respectively). Besides, in acute exacerbation, the MPV values were lower and the WBC count was higher than the values in the non-exacerbation period (P 0= 0.01, P = 0.00, respectively). In the non-exacerbation period MPV was lower and platelet count was higher when compared to healthy subjects (P = 0.02, P = 0.04, respectively). CONCLUSION: This study suggests that MPV might be used as a simple, cost effective, diagnostic, predictive indicator for platelet activation in pediatric CF patients related to chronic inflammation, which might be helpful to discriminate or estimate exacerbations. PMID:21977069

  16. Determining the diagnostic value of endogenous carbon monoxide in Chronic Obstructive Pulmonary Disease exacerbations

    International Nuclear Information System (INIS)

    Objective: To determine whether endogenous carbon monoxide levels in exacerbations of Chronic Obstructive Pulmonary Disease patients were higher compared to healthy individuals and to investigate alteration of carbon monoxide levels across the three different severity stages of Global Initiative for Chronic Obstructive Lung Disease criteria related to Chronic Obstructive Pulmonary Disease exacerbations. Methods: The prospective study was conducted from January to March 2011 at two medical institutions in Ankara, Turkey, and comprised patients of acute Chronic Obstructive Pulmonary Disease exacerbations. The severity of the exacerbations was based on the Global Initiative for Chronic Obstructive Lung Disease criteria. Patients with active tobacco smoking, suspicious carbon monoxide poisoning and uncertain diagnosis were excluded. healthy control subjects who did not have any comorbid diseases and smoking habitus were also enrolled to compare the differences between carboxyhaemoglobin levels A two-tailed Mann-Whitney U test with Bonferroni correction was done following a Kruskal-Wallis test for statistical purposes. Results: There were 90 patients and 81 controls in the study. Carboxyhaemoglobin levels were higher in the patients than the controls (p<0.001). As for the three severity stages, Group 1 had a median carboxyhaemoglobin of 1.6 (0.95-2.00). The corresponding levels in Group 2 (1.8 (1.38-2.20)) and Group 3 (1.9 (1.5-3.0)) were higher than the controls (p<0.001 and p<0.005 respectively). No statistically significant difference between Group 1 and the controls (1.30 (1.10-1.55)) was observed (p<0.434). Conclusion: Carboxyhaemoglobin levels were significantly higher in exacerbations compared with the normal population. Also, in more serious exacerbations, carboxyhaemoglobin levels were significantly increased compared with healthy individuals and mild exacerbations. (author)

  17. 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.

  18. Acute exacerbation of autoimmune hepatitis induced by Twinrix

    Institute of Scientific and Technical Information of China (English)

    Antal Csepregi; Gerhard Treiber; Christoph R(o)cken; Peter Malfertheiner

    2005-01-01

    We report on a 26-year-old man who presented with severe jaundice and elevated serum liver enzyme activities after having received a dose of Twinrix(○R). In his past medical history, jaundice or abnormal liver function tests were never recorded. Following admission, an elevated immunoglobulin G level and antinuclear antibodies at a titer of 320 with a homogenous pattern were found. Histology of a liver biopsy showed marked bridging liver fibrosis and a chronic inflammation, compatible with autoimmune hepatitis. Treatment was started with budesonide and ursodeoxycholic acid,and led to complete normalization of the pathological liver function tests. We believe that Twinrix(○R) led to an acute exacerbation of an unrecognized autoimmune hepatitis in our patient. The pathogenesis remains to be clarified. It is tempting to speculate that inactivated hepatitis A virus and/or recombinant surface antigen of the hepatitis B virus -as seen in patients with chronic hepatitis C and unrecognized autoimmune hepatitis who were treated with interferon alpha-might have been responsible for disease exacerbation.

  19. Functional display of an alpha2 integrin-specific motif (RKK) on the surface of baculovirus particles.

    Science.gov (United States)

    Riikonen, Reetta; Matilainen, Heli; Rajala, Nina; Pentikainen, Olli; Johnson, Mark; Heino, Jyrki; Oker-Blom, Christian

    2005-08-01

    The use of baculovirus vectors shows promise as a tool for gene delivery into mammalian cells. These insect viruses have been shown to transduce a variety of mammalian cell lines, and gene transfer has also been demonstrated in vivo. In this study, we generated two recombinant baculovirus vectors displaying an integrin-specific motif, RKK, as a part of two different loops of the green fluorescent protein (GFP) fused with the major envelope protein gp64 of Autographa californica M nucleopolyhedrovirus. By enzyme linked immunosorbent assays, these viruses were shown to bind a peptide representing the receptor binding site of an alpha2 integrin, the alpha2I-domain. However, the interaction was not strong enough to overcome binding of wild type gp64 to the unknown cellular receptor(s) on the surface of alpha2 integrin-expressing cells (CHO-alpha2beta1) or enhance the viral uptake. After treatment of these cells with phospholipase C, internalization of all viruses was blocked or decreased significantly. However, one of the RKK displaying viruses, AcGFP(K)gp64, was still able to internalize into CHO-alpha2beta1 cells, although at a lower level as compared to non-treated cells. This may indicate the possible utilization of a PLC independent alternative route via, in this case, the alpha2beta1 integrin. PMID:16029062

  20. Efficacy of interferon alpha-2b and lamivudine therapy for chronic hepatitis B in children

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Objective To evaluate the efficacy of interferon (IFN) alpha-2b and lamivudine therapy in children with chronic hepatitis B virus (HBV) infection.Method Ten children who developed chronic hepatitis B infection received IFN alpha-2b 10 million international units (IU)/m2 body surface area, subcutaneously three times a week for six months. IFN+lamivudine therapy began to be used in the cases who were unresponsive to IFN treatment. Results Among 27 HBsAg (+) subjects in this study, interferon treatment was given to 11 subjects who developed chronic hepatitis. One case was excluded from the study due to detection of Herpes type 1 encephalitis. At the end of six months of follow-up, complete response was obtained in three (30%) patients and partial response in four (40%) patients, whereas no response was detected in three (30%) patients. Fifty percent of the cases experienced serological response, 70% biochemical response, and all (100%) had histological response. In three cases started concomitant IFN+lamivudine therapy, HBV-DNA became negative at the second month of treatment. Conclusions IFN-alpha and lamivudine can be used for the treatment of chronic hepatitis B infection in children.

  1. Monitoring asthma in childhood: symptoms, exacerbations and quality of life.

    Science.gov (United States)

    Brand, Paul L P; Mäkelä, Mika J; Szefler, Stanley J; Frischer, Thomas; Price, David

    2015-06-01

    Monitoring asthma in children in clinical practice is primarily performed by reviewing disease activity (daytime and night-time symptoms, use of reliever medication, exacerbations requiring frequent use of reliever medication and urgent visits to the healthcare professional) and the impact of the disease on children's daily activities, including sports and play, in a clinical interview. In such an interview, most task force members also discuss adherence to maintenance therapy and the patients' (and parents') views and beliefs on the goals of treatment and the amount of treatment required to achieve those goals. Composite asthma control and quality of life measures, although potentially useful in research, have limited value in clinical practice because they have a short recall window and do not cover the entire spectrum of asthma control. Telemonitoring of children with asthma cannot replace face-to-face follow-up and monitoring because there is no evidence that it is associated with improved health outcomes. PMID:26028631

  2. 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. PMID:26552918

  3. Characterisation and prevention of exacerbations in frequently exacerbating patienst with COPD

    NARCIS (Netherlands)

    S. Uzun (Sevim)

    2014-01-01

    markdownabstract__Abstract__ Chronic obstructive pulmonary disease (COPD) is a disease which is characterised by airway inflammation and progressive airflow limitation with poor reversibility. Periods of acute deterioration lie in the natural course of the disease and are called exacerbations. In l

  4. Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence.

    Science.gov (United States)

    Li, Renzhong; Ma, Liwei; Huang, Yu; Zhang, Zongyu; Tong, Tanjun

    2011-12-01

    Alpha-2-macroglobulin (α2M), a protease inhibitor, is implicated in Alzheimer's disease, atherosclerosis, and other age-related diseases. The elevated level of α2M mRNA has been described in replicative senescence and it could be used as a biomarker of the aging cells. However, the mechanism responsible for the up-regulation of its expression is still unclear. This report identified a novel transcriptional regulatory element, the α2M transcription enhancement element (ATEE), within the α2M promoter. This element differentially activates α2M expression in senescent versus young fibroblasts. Electrophoretic mobility shift assays revealed abundant complexes in senescent cell nuclear extracts compared with young cell nuclear extracts. The DNase I footprint revealed the protein-binding core sequence through which the protein binds the ATEE. Mutation within ATEE selectively abolished α2M promoter activity in senescent (but not young) cells. These results indicated the ATEE, as a positive transcription regulatory element, contributes to the up-regulation of α2M during replicative senescence. PMID:21541797

  5. 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.

  6. Cytoplasmic androgen binding protein of rat liver: molecular characterization after photoaffinity labeling and functional correlation with the age-dependent synthesis of alpha 2u-globulin

    International Nuclear Information System (INIS)

    The liver of the mature male rat contains a moderate affinity (Kd = 10(-8)M), low-capacity, cytoplasmic androgen binding protein (CAB) whose appearance during puberty and disappearance during senescence correlate with the androgen-dependent synthesis of alpha 2u-globulin. Molecular properties of CAB were examined by photoaffinity labeling with tritiated methyltrienolone (R-1881), a synthetic androgen, and by its localization within the hepatocytes which are competent to produce alpha 2u-globulin. Photoaffinity labeling of the liver cytosol derived from postpubertal male rats, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography, showed a predominant androgen binding band corresponding to Mr 31,000. This 31-kilodalton (kDa) binding component was conspicuously absent in the liver of androgen-insensitive prepubertal and senescent male rats and in adult male rats treated with estradiol-17 beta. In addition, unlike the cytoplasmic extract, the nuclear lysate of the male rat hepatocytes did not contain the 31-kDa androgen binder. Disappearance of the 31-kDa androgen binding band from the cytosolic fraction of androgen-insensitive animals was associated with a concomitant appearance of a minor androgen binding component of apparent Mr 29,000. The livers of postpubertal male rats normally contain two subpopulations of hepatocytes, only one of which is highly active (competent) in alpha 2u-globulin synthesis. Separation of these two subpopulations through a fluorescence-activated cell sorter followed by whole cell labeling showed more than a 2-fold higher uptake of R-1881 by the competent cells

  7. Chronic obstructive pulmonary disease exacerbation frequency and severity

    Directory of Open Access Journals (Sweden)

    Stafyla E

    2013-11-01

    Full Text Available Eirini Stafyla, Theodora Kerenidi, Konstantinos I Gourgoulianis Respiratory Medicine Department, University of Thessaly Medical School, University Hospital of Larissa, Larissa, GreeceWe read with great interest the original work by Motegi et al1 comparing three multidimensional assessment systems – BODE (body mass index, obstruction, dyspnea, and exercise capacity index, DOSE (dyspnea, obstruction, smoking, exacerbations index and ADO (age, dyspnea, obstruction index – for predicting COPD (chronic obstructive pulmonary disease exacerbations. In this study, exacerbation rates for the first and second year were 0.57 and 0.48 per patient-year respectively, while previous exacerbations, DOSE index, FEV1% (% forced expiratory volume in 1 second predicted and long-term oxygen therapy (LTOT use were shown to be predictors of COPD exacerbations. However, this study seems to have quite different results from our own study that focused on exacerbation frequency and severity.View original paper by Motegi and colleagues.

  8. Association of airborne Aspergillus with asthma exacerbation in Southern Pakistan

    OpenAIRE

    Zubairi, Ali Bin Sarwar; Azam, Iqbal; Awan, Safia; Zafar, Afia; Imam, Asif Ali

    2014-01-01

    Background Exposure to airborne fungi has been related with exacerbation of asthma in adults and children leading to increased outpatient, emergency room visits, and hospitalizations. Hypersensitivity to these airborne fungi may be an important initial predisposing factor in the development and exacerbation of asthma. Objective This study was conducted to determine an association between fungal types and spore concentrations with the risk of asthma exacerbation in adults. Methods This cross-s...

  9. Fecal Microbial Composition of Ulcerative Colitis and Crohn’s Disease Patients in Remission and Subsequent Exacerbation

    OpenAIRE

    Edgar S Wills; Jonkers, Daisy M. A. E.; Paul H Savelkoul; Masclee, Ad A.; Pierik, Marieke J.; John Penders

    2014-01-01

    BACKGROUND: Limited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up. DESIGN: Fecal samples from 10 Crohn's disease (CD) and 9 ulcerative colitis (UC) patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion crit...

  10. ALPHA spokesperson Jeffrey Hangst gives a tour of the new ALPHA-2 french subtitles

    CERN Multimedia

    CERN Video Productions

    2012-01-01

    Alors qu’un grand nombre d’expériences se préparent à un rythme de travail soutenu pendant la longue période d’arrêt, il en est une dont l’activité est déjà intense : ALPHA-2. Les derniers éléments, qui sont arrivés le mois dernier, vont permettre de remplacer complètement le dispositif expérimental ALPHA. À la différence de celle qui l’a précédée, cette expérience a été spécialement conçue pour mesurer les propriétés de l’antimatière.

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

    Directory of Open Access Journals (Sweden)

    Ali Z

    2013-05-01

    Full Text Available Zarqa Ali, Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Copenhagen, DenmarkBackground: 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 during pregnancy.Methods: A narrative literature review was carried out using the PubMed database.Results: During pregnancy, up to 6% of women with asthma are hospitalized for an acute exacerbation. The maternal immune system is characterized by a very high T-helper-2:T-helper-1 cytokine ratio during pregnancy and thereby provides an environment essential for fetal survival but one that may aggravate asthma. Cells of the innate immune system such as monocytes and neutrophils are also increased during pregnancy, and this too can exacerbate maternal asthma. Severe or difficult-to-control asthma appears to be the major risk factor for exacerbations during pregnancy, but studies also suggest that nonadherence with controller medication and viral infections are important triggers of exacerbations during pregnancy. So far, inconsistent findings have been reported regarding the effect of fetal sex on exacerbations during pregnancy. Other risk factors for exacerbation during pregnancy include obesity, ethnicity, and reflux, whereas atopy does not appear to be a risk factor.Discussion: The incidence of asthma exacerbations during pregnancy is disturbingly high. Severe asthma – better described as difficult-to-control asthma – nonadherence with controller therapy, viral infections, obesity, and ethnicity are likely to be important risk factors for exacerbations of asthma during pregnancy, whereas inconsistent findings have been reported with regard to the importance of sex of the fetus.Keywords: acute exacerbations

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

    Science.gov (United States)

    Sjöberg, B; Pap, S; Järnberg, S E; Mortensen, K

    1991-09-01

    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 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, the half-life of the reaction at the lowest concentration of [2H]urea studied (2.70 M) is 328 h, whereas the same value at the highest concentration of [2H]urea (6.24 M) is only 8 min. Measurements were made both with [1H]urea in 1H2O and with [2H]urea in 99% 2H2O, and it was found that there is a pronounced kinetic isotope effect, i.e. the dissociation is 4 times faster in the 1H-containing medium as compared with the 2H-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 with a drastic change in structure. This is directly shown by the radius of gyration, which increases from about 7.4 nm immediately after the addition of urea up to about 9.4 nm when the protein is fully dissociated. A structural analysis shows that the scattering curve of urea-dissociated alpha 2-macroglobulin can best be explained by that of a Gaussian coil with a radius of gyration equal to 9.44 nm. These data indicate that the so-called non-covalent interaction of alpha 2-macroglobulin probably is more complicated than just a pure hydrophobic interaction. Finally, it is also shown that the dissociation is accompanied by a loss in trypsin-binding activity, which is directly related to the fraction of dissociated protein. PMID:1716880

  13. 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. PMID:27033585

  14. Actions of the prototypical 5-HT1A receptor agonist 8-OH-DPAT at human alpha2-adrenoceptors: (+)8-OH-DPAT, but not (-)8-OH-DPAT is an alpha2B subtype preferential agonist.

    Science.gov (United States)

    Heusler, Peter; Rauly-Lestienne, Isabelle; Tourette, Amélie; Tardif, Stéphanie; Ailhaud, Marie-Christine; Croville, Guillaume; Cussac, Didier

    2010-08-25

    8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] is the prototypical agonist at serotonin 5-HT1A receptors; however, activity at other targets contributes to the functional effects of the compound as well. We examined the properties of 8-OH-DPAT and its enantiomers at recombinant human (h)alpha2-adrenoceptor subtypes, using a panel of radioligand binding and functional tests. In competition binding experiments using [3H]-RX821002, about 10-fold selectivity of (+)8-OH-DPAT for the halpha2B subtype (pKi about 7) over halpha2A- and halpha2C-adrenoceptors was observed. In contrast, the S(-) enantiomer of 8-OH-DPAT showed similar weak affinities for the three receptor subtypes (pKis<6). The binding affinity of (+)8-OH-DPAT at the halpha2B- and the halpha2A-adrenoceptor was found sensitive to GTPgammaS, a receptor/G protein-uncoupling agent, indicating agonist properties of the drug. Furthermore, using [35S]GTPgammaS binding determination at CHO-halpha2B or CHO-halpha2A cell membranes and G protein coupled inwardly rectifying potassium (GIRK) current recordings in Xenopus oocytes expressing halpha2B, partial agonist activity of (+)8-OH-DPAT at the respective receptors was confirmed in these two different functional assays. Potency of (+)8-OH-DPAT for stimulation of [35S]GTPgammaS incorporation was lower at the halpha2A- than at the halpha2B-adrenoceptor, consistent with binding affinities. Thus, (+)8-OH-DPAT and, as a consequence, racemic (+/-)8-OH-DPAT are partial agonists at halpha2-adrenoceptors with selectivity for the halpha2B subtype, a property that might contribute to the effects of the compound described in native systems. PMID:20450907

  15. 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.

  16. Susceptibility to exacerbation in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Hurst, John R; Vestbo, Jørgen; Anzueto, Antonio; Locantore, Nicholas; Müllerova, Hana; Tal-Singer, Ruth; Miller, Bruce; Lomas, David A; Agusti, Alvar; Macnee, William; Calverley, Peter; Rennard, Stephen; Wouters, Emiel F M; Wedzicha, Jadwiga A; NN, NN

    2010-01-01

    COPD that is independent of disease severity. METHODS: We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider...

  17. 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...

  18. 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...

  19. Peyronie's disease: intralesional treatment with interferon alpha-2A and evaluation of the results by magnetic resonance imaging.

    Science.gov (United States)

    Polat, O; Gül, O; Ozbey, I; Ozdikici, M; Bayraktar, Y

    1997-01-01

    In this clinical study, to determine the therapeutic efficacy of interferon (IFN) treatment for Peyronie's disease, we applied interferon alpha-2A (IFN alpha-2A) intralesionally in the treatment of Peyronie plaques in 15 patients and results were evaluated by magnetic resonance imaging (MRI). Patients whose plaque sizes were 0.5 and 1 cm responded better to the treatment. There was about a 90% lessening in the sizes of the plaques of 1.5 cm, 83.3% of 2 cm, as the ones which were 0.5 cm and 1 cm disappeared completely after treatment. As a conclusion, the treatment of Peyronie's disease with IFN alpha-2A is effective and side effects are minimum. PMID:9406006

  20. Expression of human alpha 2-adrenergic receptors in adipose tissue of beta 3-adrenergic receptor-deficient mice promotes diet-induced obesity.

    Science.gov (United States)

    Valet, P; Grujic, D; Wade, J; Ito, M; Zingaretti, M C; Soloveva, V; Ross, S R; Graves, R A; Cinti, S; Lafontan, M; Lowell, B B

    2000-11-01

    Catecholamines play an important role in controlling white adipose tissue function and development. beta- and alpha 2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are co-expressed in human adipocytes. Previous studies have demonstrated increased adipocyte alpha 2/beta-AR balance in obesity, and it has been proposed that increased alpha 2-ARs in adipose tissue with or without decreased beta-ARs may contribute mechanistically to the development of increased fat mass. To critically test this hypothesis, adipocyte alpha 2/beta-AR balance was genetically manipulated in mice. Human alpha 2A-ARs were transgenically expressed in the adipose tissue of mice that were either homozygous (-/-) or heterozygous (+/-) for a disrupted beta 3-AR allele. Mice expressing alpha 2-ARs in fat, in the absence of beta 3-ARs (beta 3-AR -/- background), developed high fat diet-induced obesity. Strikingly, this effect was due entirely to adipocyte hyperplasia and required the presence of alpha2-ARs, the absence of beta 3-ARs, and a high fat diet. Of note, obese alpha 2-transgenic beta 3 -/- mice failed to develop insulin resistance, which may reflect the fact that expanded fat mass was due to adipocyte hyperplasia and not adipocyte hypertrophy. In summary, we have demonstrated that increased alpha 2/beta-AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia. This study also demonstrates one way in which two genes (alpha 2 and beta 3-AR) and diet interact to influence fat mass. PMID:10948198

  1. Binding of dopamine and 3-methoxytyramine as l-DOPA metabolites to human alpha(2)-adrenergic and dopaminergic receptors.

    Science.gov (United States)

    Alachkar, Amal; Brotchie, Jonathan M; Jones, Owen T

    2010-07-01

    The ability of l-3,4-dihydroxyphenylalanine (l-DOPA), l-DOPA-methyl ester and their major metabolites, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic (HVA), 3-O-methyldopa and 3-methoxytyramine (3-MT) to bind to alpha(2) adrenergic and D1 and D2 dopamine receptors was assessed by radioligand binding to cloned human receptors expressed in cell lines. As anticipated, dopamine bound with high affinity to D1 (IC(50) 1.1 + or - 0.16 microM) and D2 (IC(50) 0.7 + or - 0.3 microM) dopamine receptors. However, dopamine also bound with high affinity to alpha(2A) (IC(50) was 2.6 + or - 0.5 microM), alpha(2C) (IC(50) 3.2 + or - 0.7 microM). 3-MT bound to alpha(2A) with high affinity (IC(50), 3.6 + or - 0.2 microM) though moderate affinity to alpha(2)c, D1 and D2 receptors (values of IC(50) were 55 + or - 14, 121 + or - 43, 36 + or - 14 microM, respectively). l-DOPA-methyl ester bound with high affinity to alpha(2) (IC(50) 17-36 microM) but not dopamine receptors (IC(50) 0.9-2.5 mM). l-DOPA, 3-O-methyldopa and DOPAC had no observable effect on binding to any of the receptors tested. These data suggest that the effects of l-DOPA in Parkinson's disease may result from actions of its metabolites dopamine and 3-MT on both dopaminergic and non-dopaminergic receptors. These findings may provide explanations for the differences between l-DOPA and dopamine receptor agonists in mediating anti-parkinsonian effects and propensity to be associated with dyskinesia and motor complications such as wearing-off and on-off. PMID:20302892

  2. 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 at...

  3. Mepolizumab for the reduction of exacerbations in severe eosinophilic asthma.

    Science.gov (United States)

    Russell, Richard; Brightling, Christopher

    2016-06-01

    Asthma affects over 300 million people worldwide and is severe in 10% of sufferers. Severe asthma is associated with greater morbidity and mortality particularly as a consequence of frequent exacerbations. Advances in approaches to phenotype the heterogeneity of severe asthma has established the importance of eosinophilic inflammation and emerging new therapies are broadly designed to target T2-mediated eosinophilic inflammation with the aim to reduce exacerbation frequency. Here, we summarize the evidence that eosinophilic asthma is an important pheno(endo)type and identifies a group at risk of exacerbations; that established therapies reduce exacerbations, particularly in eosinophilic severe asthma; and discuss the role of mepolizumab, an IL-5 neutralising monoclonal antibody therapy, in reducing exacerbations in severe eosinophilic asthma compared to established and other emerging therapies. PMID:27058452

  4. Stokes IQUV mapping of $\\alpha^2$ CVn & other Ap stars using ESPaDOnS and NARVAL

    OpenAIRE

    Silvester, J.; Kochukhov, O.; Wade, G. A.

    2013-01-01

    New spectral line polarisation observations of 7 bright Ap stars have been obtained with the ESPaDOnS and Narval high resolution spectropolarimeters (Silvester et al. 2012). The aim of this data set is produce a series of surface magnetic field and surface chemistry maps for these Ap stars. We present new magnetic maps for the Ap star $\\alpha^2$ CVn using these new data and the MDI inversion code INVERS10. $\\alpha^2$ CVn is the first Ap star to be observed during two separate epochs using hig...

  5. Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C

    DEFF Research Database (Denmark)

    Manns, Michael P; Gane, Edward; Rodriguez-Torres, Maribel;

    2012-01-01

    Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this......Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV...

  6. Order \\alpha_s^2 Contributions to charm production in charged-current deep-inelastic lepton-hadron scattering

    OpenAIRE

    Buza, M.; van Neerven, W. L.

    1997-01-01

    The most important part of the order $\\alpha_s^2$ corrections to the charm component of the charged-current structure functions $F_2(x,Q^2)$ and $F_3(x,Q^2)$ have been calculated. This calculation is based on the asymptotic form of the heavy-quark coefficient functions corresponding to the higher order corrections to the W-boson-gluon fusion process. These coefficient functions which are in principle only valid for $Q^2 \\gg m^2$ can be also used to estimate the order $\\alpha_s^2$ contribution...

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

    International Nuclear Information System (INIS)

    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

  8. 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.

  9. Prostate cancer serum biomarker discovery through proteomic analysis of alpha-2 macroglobulin protein complexes

    Science.gov (United States)

    Burgess, Earle F.; Ham, Amy-Joan L.; Tabb, David L.; Billheimer, Dean; Roth, Bruce J.; Chang, Sam S.; Cookson, Michael S.; Hinton, Timothy J.; Cheek, Kristin L.; Hill, Salisha; Pietenpol, Jennifer A.

    2010-01-01

    Alpha-2 macroglobulin (A2M) functions as a universal protease inhibitor in serum and is capable of binding various cytokines and growth factors. In this study, we investigated if immunoaffinity enrichment and proteomic analysis of A2M protein complexes from human serum could improve detection of biologically relevant and novel candidate protein biomarkers in prostate cancer. Serum samples from six patients with androgen-independent, metastatic prostate cancer and six control patients without malignancy were analyzed by immunoaffinity enrichment of A2M protein complexes and MS identification of associated proteins. Known A2M substrates were reproducibly identified from patient serum in both cohorts, as well as proteins previously undetected in human serum. One example is heat shock protein 90 alpha (HSP90α), which was identified only in the serum of cancer patients in this study. Using an ELISA, the presence of HSP90α in human serum was validated on expanded test cohorts and found to exist in higher median serum concentrations in prostate cancer (n = 18) relative to control (n = 13) patients (median concentrations 50.7 versus 27.6 ng/mL, respectively, p = 0.001). Our results demonstrate the technical feasibility of this approach and support the analysis of A2M protein complexes for proteomic-based serum biomarker discovery. PMID:20107526

  10. Creep behavior of an alpha-2 and an orthorhombic Tl-based matrix

    International Nuclear Information System (INIS)

    It has been previously demonstrated that during longitudinal monotonic loading of unidirectionally reinforced composites at elevated temperature, the load is primarily carried by the fibers. Thus, changes in matrix composition, particularly with a given class, should be of secondary importance to longitudinal properties. Thus, the present study emphasizes changes in neat matrix creep response and correlation of such properties with transverse composite creep. Since creep performance is critical for applications under monotonic and/or cyclic loading at elevated temperatures, this study intends to: study the creep performance of an alpha-2 (Ti-24Al-11Nb) and an orthorhombic (Ti-21Al-22Nb) matrix in a microstructural condition, analogous to that produced in the fiber reinforced composite, and determine if a simple model could be used to predict transverse composite creep life from neat matrix data. The materials examined in this study include neat Ti-24Al-11Nb and Ti-21Al-22Nb composites as well as [0]4, 35v% SCS-6 reinforced composites of the latter matrix

  11. Intralesional interferon alpha - 2b in genital warts : A preliminary study

    Directory of Open Access Journals (Sweden)

    Pandhi R

    1993-01-01

    Full Text Available Currently available therapy for condyloma acuminata (genital warts is not consistently effective. Interferon (IFN has both antiproliferatve and antiviral properties and has been used to treat genital warts with varying degree of success. We conducted an open study on 6 male patients with genital warts. A single wart of comparable area from each patient was injected with 2 x 106 IU of IFN alpha-2b, 3 times weekly for 3 weeks. The response to treatment was assessed during the therapy and at 1, 5 and 9 weeks after the completion of treatment. Two of the injected lesions showed complete regression and in 2, there was a moderate reduction in size but not a complete regression. In 2 patients there was appearance of new lesions while still on therapy and only a slight reduction tn the size of injected lesions. All patients tolerated the therapy well and in none treatment had to be discontinued due to adverse reactions. The preliminary trial suggests that intralesional IFN is not a superior alternate to the currently available modalities of treatment in genital warts. High cost of the therapy is another limiting factor.

  12. Decreased expression of zinc-alpha2-glycoprotein in hepatocellular carcinoma associates with poor prognosis

    Directory of Open Access Journals (Sweden)

    Huang Yan

    2012-05-01

    Full Text Available Abstract Background Zinc-alpha2-glycoprotein (AZGP1, ZAG was recently demonstrated to be an important factor in tumor carcinogenesis. However, AZGP1 expression in hepatocellular carcinoma (HCC and its significance remain largely unknown. Methods Quantitative real-time polymerase chain reaction (qRT-PCR was applied to determine mRNA level of AZGP1 in 20 paired fresh HCC tissues. Clinical and pathological data of 246 HCC patients were collected. Tissue-microarray-based immunohistochemistry (IHC was performed to examine AZGP1 expression in HCC samples. Relationship between AZGP1 expression and clinicopathological features was analyzed by Chi-square test, Kaplan-Meier analysis and Cox proportional hazards regression model. Results AZGP1 expression was significantly lower in 80.0% (16/20 of tumorous tissues than that in the corresponding adjacent nontumorous liver tissues (P P P = 0.013, liver cirrhosis (P = 0.002 and tumor differentiation (P = 0.025. Moreover, HCC patients with high AZGP1 expression survived longer, with better overall survival (P = 0.006 and disease-free survival (P = 0.025. In addition, low AZGP1 expression associated with worse relapse-free survival (P = 0.046 and distant metastatic progression-free survival (P = 0.036. Conclusion AZGP1 was downregulated in HCC and could be served as a promising prognostic marker for HCC patients.

  13. 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

  14. Treatment of patients with COPD and recurrent exacerbations: the role of infection and inflammation

    Science.gov (United States)

    Santos, Salud; Marin, Alicia; Serra-Batlles, Joan; de la Rosa, David; Solanes, Ingrid; Pomares, Xavier; López-Sánchez, Marta; Muñoz-Esquerre, Mariana; Miravitlles, Marc

    2016-01-01

    Exacerbations of COPD represent an important medical and health care problem. Certain susceptible patients suffer recurrent exacerbations and as a consequence have a poorer prognosis. The effects of bronchial infection, either acute or chronic, and of the inflammation characteristic of the disease itself raise the question of the possible role of antibiotics and anti-inflammatory agents in modulating the course of the disease. However, clinical guidelines base their recommendations on clinical trials that usually exclude more severe patients and patients with more comorbidities, and thus often fail to reflect the reality of clinicians attending more severe patients. In order to discuss aspects of clinical practice of relevance to pulmonologists in the treatment and prevention of recurrent exacerbations in patients with severe COPD, a panel discussion was organized involving expert pulmonologists who devote most of their professional activity to day hospital care. This article summarizes the scientific evidence currently available and the debate generated in relation to the following aspects: bacterial and viral infections, chronic bronchial infection and its treatment with cyclic oral or inhaled antibiotics, inflammatory mechanisms and their treatment, and the role of computerized tomography as a diagnostic tool in patients with severe COPD and frequent exacerbations. PMID:27042040

  15. Increased expression of integrin alpha2 and abnormal response to TGF-beta1 in hereditary gingival fibromatosis.

    NARCIS (Netherlands)

    Zhou, J.; Meng, L.; Ye, X.Q.; Hoff, J.W. von den; Bian, Z.

    2009-01-01

    OBJECTIVE: To investigate the possible correlation between integrin alpha1, alpha2, and beta1 expression and excessive collagen synthesis in fibroblasts from 3 unrelated Chinese families with hereditary gingival fibromatosis (HGF). DESIGN: Gingival fibroblasts from three Chinese HGF patients and thr

  16. Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report

    Directory of Open Access Journals (Sweden)

    Ioannou Savvas

    2010-08-01

    Full Text Available Abstract Introduction Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment. Case presentation We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A. Conclusions The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.

  17. Stokes $IQUV$ magnetic Doppler imaging of Ap stars - III. Next generation chemical abundance mapping of Alpha 2 CVn

    CERN Document Server

    Silvester, James; Wade, Gregg A

    2014-01-01

    In a previous paper we presented an updated magnetic field map for the chemically peculiar star Alpha 2 CVn using ESPaDOnS and Narval time-resolved high-resolution Stokes $IQUV$ spectra. In this paper we focus on mapping various chemical element distributions on the surface of Alpha 2 CVn. With the new magnetic field map and new chemical abundance distributions we can investigate the interplay between the chemical abundance structures and the magnetic field topology on the surface of Alpha 2 CVn. Previous attempts at chemical abundance mapping of Alpha 2 CVn relied on lower resolution data. With our high resolution (R=65,000) dataset we present nine chemical abundance maps for the elements O, Si, Cl, Ti, Cr, Fe, Pr, Nd and Eu. We also derive an updated magnetic field map from Fe and Cr lines in Stokes $IQUV$ and O and Cl in Stokes $IV$. These new maps are inferred from line profiles in Stokes $IV$ using the magnetic Doppler imaging code Invers10. We examine these new chemical maps and investigate correlations...

  18. Surface characterization of hydrogen charged and uncharged alpha-2 and gamma titanium aluminide alloys using AES and REELS

    Science.gov (United States)

    Shanabarger, M. R.

    1990-01-01

    The surfaces of selected uncharged and hydrogen charged alpha-2 and gamma titanium aluminide alloys with Nb additions were characterized by Auger electron (AES) and reflected electron energy loss (REELS) spectroscopy. The alloy surfaces were cleaned before analysis at room temperature by ion sputtering. The low energy (500 eV) ion sputtering process preferentially sputtered the surface concentration. The surface concentrations were determined by comparing AES data from the alloys with corresponding data from elemental references. No differences were observed in the Ti or Nb Auger spectra for the uncharged and hydrogen charged alloys, even though the alpha-2 alloy had 33.4 atomic percent dissolved hydrogen. Also, no differences were observed in the AES spectra when hydrogen was adsorbed from the gas phase. Bulk plasmon energy shifts were observed in all alloys. The energy shifts were induced either by dissolved hydrogen (alpha-2 alloy) or hydrogen adsorbed from the gas phase (alpha-2 and gamma alloys). The adsorption induced plasmon energy shifts were greatest for the gamma alloy and cp-Ti metal.

  19. Identification and characterization of (3H)-rauwolscine binding to alpha2-adrenoceptors in the canine saphenous vein

    International Nuclear Information System (INIS)

    The biochemical exploration of the alpha2-adrenergic receptors was investigated in the canine saphenous vein using the highly selective alpha2-adrenergic antagonist rauwolscine as a tritiated ligand. Following an enzymatic digestive pretreatment, the authors isolated a purified smooth muscle cell membranes fraction from saphenous veins in quantity sufficient to permit them to study the venous alpha2-adrenoreceptor content. The binding of tritiated rauwolscine was rapid, specific, saturable and reversible. The presence of high affinity sites with a density of binding Bmax of 125.2 /+ -/ 43.1 fmol/mg protein was demonstrated on a unique class of non interacting sites. The kinetically derived Kd was 1.28 nM, in good agreement with the value obtained from saturation isotherms. The pharmacological profile of these sites was assessed by the comparison of the potency of alpha-adrenergic agonists and antagonists to inhibit 1 nM (3H)-rauwolscine. Their efficacy was respectively: rauwolscine > phentolamine > RX 781094 > clonidine >> prazosin > (-)-phenylephrine > (-)-noradrenaline. The results showed that (3H)-rauwolscine bound specifically to sites in their membranal preparation, which had the pharmacological characteristics of the alpha2-adrenoceptors. The correlation between biochemical and pharmacological data revealed the usefulness of binding methods in the further study of adrenergic mechanisms in the canine saphenous vein

  20. 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 of...... could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated...

  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

    2013-01-01

    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. PMID:24250210

  2. Phenytoin induced Stevens-Johnson syndrome exacerbated by cefepime

    OpenAIRE

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

    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.

  3. Phenytoin induced Stevens-Johnson syndrome exacerbated by cefepime

    Directory of Open Access Journals (Sweden)

    Varsha A Prabhu

    2013-01-01

    Full Text Available 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.

  4. 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...... (rs1800790, G>A) and FGB -448 (rs4220, G>A) and had plasma fibrinogen measured. Furthermore, 13 405 individuals were genotyped for the SERPINA1 S-allele (rs17580) and the Z-allele (rs28929474) and had measurements of plasma alpha(1)-antitrypsin. Exacerbations were defined as hospital admissions or...... 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...

  5. Interferon-alpha-2b induces autophagy in hepatocellular carcinoma cells through Beclin1 pathway

    International Nuclear Information System (INIS)

    To determine whether Interferon-alpha-2b (IFN-α2b) can modulate the autophagic response in hepatocellular carcinoma cells. Hepatocellular carcinoma cells were treated with IFN-α2b. Autophagy was assessed by acridine orange staining, GFP-LC3 dotted assay, transmission electron microscopy and immunoblotting. Acridine orange staining showed that IFN-α2b triggered the accumulation of acidic vesicular and autolysosomes in HepG2 cells. The acridine orange HepG2 cell ratios were (4.3±1.0)%, (6.9±1.4)%, and (13.1±2.3)%, respectively, after treatment with 100, 1,000, and 10,000 IU/mL IFN-α2b for 48 h. A markedly punctate pattern was observed in HepG2 cells treated with 10,000 IU/mL IFN-α2b for 48 h, but only diffuse and weakly fluorescent GFP-LC3 puncta was observed in control cells. HepG2 cells treated with 10,000 IU/mL IFN-α2b for 48 h developed autophagosome-like characteristics, including single- or double-membrane vacuoles containing intact and degraded cellular debris. The Beclin1 and LC3-II protein expression was up-regulated by IFN-α2b treatment. Autophagy can be induced in a dose-dependent manner by treatment with IFN-α2b in HepG2 cells, and the Beclin1 signaling pathway was stimulated by IFN-α2b

  6. Virus-induced exacerbations in asthma and COPD

    OpenAIRE

    DaisukeKurai

    2013-01-01

    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 respirato...

  7. Viral disruption of olfactory progenitors is exacerbated in allergic mice

    OpenAIRE

    Ueha, R.; Mukherjee, S.; Ueha, S.; de Almeida Nagata, D.E.; Sakamoto, T.; K. Kondo; Yamasoba, T.; Lukacs, N W; Kunkel, S. L.

    2014-01-01

    Upper airway viral infection in patients with airway allergy often exacerbates olfactory dysfunction, but the mechanism for this exacerbation remains unclear. Here, we examined the effects of respiratory syncytial virus (RSV) infection, in the presence or absence of airway allergy, on olfactory receptor neurons (ORNs) and their progenitors in mice. Immunohistological analyses revealed that cockroach allergen (CRA)-induced airway allergy alone did not affect the number of OMP+ mature ORNs and ...

  8. Relevance of human metapneumovirus in exacerbations of COPD

    OpenAIRE

    Bauer TT; Rausse R; Kronsbein J; Arinir U; Borg I; Rohde G; Bufe A; Schultze-Werninghaus G

    2005-01-01

    Abstract Background and methods Human metapneumovirus (hMPV) is a recently discovered respiratory virus associated with bronchiolitis, pneumonia, croup and exacerbations of asthma. Since respiratory viruses are frequently detected in patients with acute exacerbations of COPD (AE-COPD) it was our aim to investigate the frequency of hMPV detection in a prospective cohort of hospitalized patients with AE-COPD compared to patients with stable COPD and to smokers without by means of quantitative r...

  9. Exacerbations in cystic fibrosis · 1: Epidemiology and pathogenesis

    OpenAIRE

    Goss, Christopher H.; Burns, Jane L.

    2007-01-01

    With the improving survival of patients with cystic fibrosis (CF), the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the course, prognosis and complications of the disease. This review provides a summary of the pathophysio...

  10. Bacterial etiology in acute hospitalized chronic obstructive pulmonary disease exacerbations

    OpenAIRE

    Asli Gorek Dilektasli; Ezgi Demirdogen Cetinoglu; Nilufer Aylin Acet Ozturk; Funda Coskun; Guven Ozkaya; Ahmet Ursavas; Cuneyt Ozakin; Mehmet Karadag; Esra Uzaslan

    2016-01-01

    Introduction. The most common cause of acute COPD exacerbation (AECOPD) is the respiratory tract infections. We sought to determine the bacteriological etiology of hospitalized acute exacerbations of COPD requiring hospitalization in consecutive two years. Methods. We aimed to determine the bacteriological etiology underlying in patients whom admitted to Uludag University Faculty of Medicine, Department of Pulmonary Medicine and hospitalized with AECOPD in the last two years. Medical records ...

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

    OpenAIRE

    Ali Z; Ulrik CS

    2013-01-01

    Zarqa Ali, Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Copenhagen, DenmarkBackground: 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 during pregnancy.Methods: A narrative literature rev...

  12. Involvement of reversible binding to alpha 2u-globulin in 1,4-dichlorobenzene-induced nephrotoxicity.

    Science.gov (United States)

    Charbonneau, M; Strasser, J; Lock, E A; Turner, M J; Swenberg, J A

    1989-06-01

    Similarly to unleaded gasoline, 1,4-dichlorobenzene (1,4-DCB) administered for 2 years caused a dose-related increase in the incidence of renal tumors in male but not in female rats or in either sex of mice. Unleaded gasoline and 2,2,4-trimethylpentane (TMP), a component of unleaded gasoline, increased protein droplet formation and cell proliferation in male but not in female rat kidneys. These protein droplets contained, alpha 2u-globulin, a male rat-specific low-molecular-weight protein and 2,4,4-trimethyl-2-pentanol, a metabolite of TMP that was reversibly bound to this protein. Studies were undertaken to determine if 1,4-DCB produced similar effects; 1,2-DCB was used for comparison since it did not produce renal carcinogenesis in male rats. Gel filtration chromatography of a 116,000g supernatant prepared from kidneys of 1,4-[14C]DCB-treated rats showed that radiolabel coeluted with alpha 2u-globulin as one sharp peak as opposed to a multipeak pattern observed for 1,2-[14C]DCB; the maximal quantity of radiolabel for 1,4-DCB was twice that for 1,2-DCB. Equilibrium dialysis of kidney cytosol in the presence or absence of sodium dodecyl sulfate demonstrated that the radiolabel was reversibly bound to alpha 2u-globulin; the amount for 1,4-[14C]DCB-treated rats was almost twice as much as that for 1,2-[14C]DCB-treated rats. 1,2-DCB was also shown to be covalently bound to renal alpha 2u-globulin, and covalently bound to liver and plasma high-molecular-weight proteins. 1,4-DCB and, to a minor extent, 2,5-dichlorophenol, the major metabolite of 1,4-DCB, were reversibly bound to renal alpha 2u-globulin from 1,4-DCB-treated rats. 1,4-DCB increased protein droplet formation in male but not in female rat kidneys, whereas equimolar doses of 1,2-DCB showed no effect in either sex. Renal cell proliferation, measured by [3H]thymidine incorporation into renal DNA, was increased after 1,4-DCB but not after 1,2-DCB treatment. Nephrotoxicity and biochemical alterations induced by

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

    International Nuclear Information System (INIS)

    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

  14. Does a Nephron Deficit Exacerbate the Renal and Cardiovascular Effects of Obesity?

    OpenAIRE

    Seshini Gurusinghe; Brown, Russell D.; Xiaochu Cai; Samuel, Chrishan S.; Ricardo, Sharon D.; Thomas, Merlin C.; Kett, Michelle M

    2013-01-01

    It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity. We therefore examined the impact of diet-induced obesity on renal structure and function, and arterial pressure in a genetic model of reduced nephron endowment, the GDNF Heterozygous (HET) mouse. 6 wk-old male GDNF WT and HET mice were placed on control or high fat (HFF) diet for 20 weeks. 24 hr arterial pressure, heart rate and activity (radiotelemetry), creatinine clearance a...

  15. Pulmonary rehabilitation in copd exacerbation: is upper limbs exercise training safe and effective?

    OpenAIRE

    Ferreira, Dulce; Mendes, Eugénia; Noronha, Bruno; Preto, Leonel; Novo, André

    2015-01-01

    Pulmonary rehabilitation in COPD exacerbation has several advantages such as reduction of hospital readmission and mortality, the considerable increase of quality of life and functional improvement translated into a better outcome in the 6 min walking test. Upper limbs exercise is recommended in pulmonary rehabilitation guidelines because it reduces stress, decreases dyspnea and dynamic hyperinflation and improves functional capacity with impact on daily living activities. This study aimed to...

  16. 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

  17. Predictors of Virological Response in 3,235 Chronic HCV Egyptian Patients Treated with Peginterferon Alpha-2a Compared with Peginterferon Alpha-2b Using Statistical Methods and Data Mining Techniques.

    Science.gov (United States)

    El Raziky, Maissa; Fathalah, Waleed Fouad; Zakaria, Zeinab; Eldeen, Hadeel Gamal; Abul-Fotouh, Amr; Salama, Ahmed; Awad, Abubakr; Esmat, Gamal; Mabrouk, Mahasen

    2016-05-01

    Despite the appearance of new oral antiviral drugs, pegylated interferon (PEG-IFN)/RBV may remain the standard of care therapy for some time, and several viral and host factors are reported to be correlated with therapeutic effects. This study aimed to reveal the independent variables associated with failure of sustained virological response (SVR) to PEG-IFN alpha-2a versus PEG-IFN alpha-2b in treatment of naive chronic hepatitis C virus (HCV) Egyptian patients using both statistical methods and data mining techniques. This retrospective cohort study included 3,235 chronic hepatitis C patients enrolled in a large Egyptian medical center: 1,728 patients had been treated with PEG-IFN alpha-2a plus ribavirin (RBV) and 1,507 patients with PEG-IFN alpha-2b plus RBV between 2007 and 2011. Both multivariate analysis and Reduced Error Pruning Tree (REPTree)-based model were used to reveal the independent variables associated with treatment response. In both treatment types, alpha-fetoprotein (AFP) >10 ng/mL and HCV viremia >600 × 10(3) IU/mL were the independent baseline variables associated with failure of SVR, while male gender, decreased hemoglobin, and thyroid-stimulating hormone were the independent variables associated with good response (P 10 ng/mL and viral load >600 × 10(3) IU/mL are variables associated with failure of response in both treatment types. REPTree-based model could be used to assess predictors of response. PMID:26859168

  18. Design of an efficient medium for heterologous protein production in Yarrowia lipolytica: case of human interferon alpha 2b

    Directory of Open Access Journals (Sweden)

    Nicaud Jean-Marc

    2011-05-01

    Full Text Available Abstract Background The non conventional yeast Yarrowia lipolytica has aroused a strong industrial interest for heterologous protein production. However most of the studies describing recombinant protein production by this yeast rely on the use of complex media, such media are not convenient for large scale production particularly for products intended for pharmaceutical applications. In addition medium composition can also affect the production yield. Hence it is necessary to design an efficient medium for therapeutic protein expression by this host. Results Five different media, including four minimal media and a complex medium, were assessed in shake flasks for the production of human interferon alpha 2b (hIFN α2b by Y. lipolytica under the control of POX2 promoter inducible with oleic acid. The chemically defined medium SM4 formulated by Invitrogen for Pichia pastoris growth was the most suitable. Using statistical experimental design this medium was further optimized. The selected minimal medium consisting in SM4 supplemented with 10 mg/l FeCl3, 1 g/l glutamate, 5 ml/l PTM1 (Pichia Trace Metals solution and a vitamin solution composed of myo-inositol, thiamin and biotin was called GNY medium. Compared to shake flask, bioreactor culture in GNY medium resulted in 416-fold increase of hIFN α2b production and 2-fold increase of the biological activity. Furthermore, SM4 enrichment with 5 ml/l PTM1 solution contributed to protect hIFN α2b against the degradation by the 28 kDa protease identified by zymography gel in culture supernatant. The screening of the inhibitory effect of the trace elements present in PTM1 solution on the activity of this protease was achieved using a Box-Behnken design. Statistical data analysis showed that FeCl3 and MnSO4 had the most inhibitory effect. Conclusion We have designed an efficient medium for large scale production of heterologous proteins by Y. lipolytica. The optimized medium GNY is suitable for the

  19. [alpha]2A-Adrenoceptor Stimulation Improves Prefrontal Cortical Regulation of Behavior through Inhibition of cAMP Signaling in Aging Animals

    Science.gov (United States)

    Verduzco, Luis; van Dyck, Christopher H.; Arnsten, Amy F. T.; Ramos, Brian P.; Stark, David

    2006-01-01

    The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, [alpha]2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the [alpha]2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or…

  20. 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; Bendtzen, Klaus

    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...

  1. Stable expression of human thyrotropin (hTSH) in mammalian cells (CHO) expressing {alpha}2,6 sialyltransferase; Expressao estavel tireotrofina humana (r-hTSH) em celulas de mamifero (CHO) que expressam {alpha}2,6 sialiltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Damiani, Renata

    2009-07-01

    A CHO cell line, previously genetically modified by the introduction of rat {alpha}2,6-sialyltransferase cDNA, generated for the first time a human-like sialylated recombinant hTSH (hlsr-hTSH) more similar to the native hormone, with 61% of {alpha}2,3- and 39% of {alpha}2,6-linked sialic acid residues. The best clone, when submitted to gene amplification with up to 8 {mu}M methotrexate, presented a secretion level of {approx}2 {mu}g hTSH/10{sup 6} cells/day, useful for product purification and characterization. The relative molecular masses (M{sub r}) of the heterodimer and of the {alpha}- and {beta}-subunits of purified hlsr-hTSH, determined by MALDI-TOF mass spectrometry, and the relative hydrophobicities, determined by RP-HPLC, were not remarkably different from those presented by two r-hTSH preparations secreted by normal CHO cells. Some differences were observed, though, in N-glycan composition, with more tri- and much more tetra-sialylated structures in hlsr-hTSH. When analyzed via an in vivo bioassay based on hTSH-induced T{sub 4} release in mice, hlsr-hTSH was shown to be equipotent (p > 0.05) with the commercial preparation of r-hTSH (Thyrogen), and 1.5-fold more potent than native hTSH (p < 0.001). (author)

  2. STAT5-induced Lunatic Fringe during Th2 development alters Delta Like-4-mediated Th2 cytokine production in RSV exacerbated airway allergic disease

    OpenAIRE

    Mukherjee, Sumanta; Rasky, Andrew J.; Lundy, Phil A.; Kittan, Nicolai A.; Kunkel, Steven L.; Maillard, Ivan P.; Kowalski, Paul E.; Kousis, Philaretos C.; Guidos, Cynthia J.; Lukacs, Nicholas W

    2013-01-01

    Notch activation plays an important role in T cell development and mature T cell differentiation. In this study we investigated the role of Notch activation in a mouse model of Respiratory Syncytial Virus (RSV)-exacerbated allergic airway disease. During RSV exacerbation, in vivo neutralization of a specific Notch ligand, Delta-like 4 (Dll4) significantly decreased airway hyperreactivity (AHR), mucus production and Th2 cytokines. Lunatic Fringe (Lfng) a glycosyltransferase that enhances Notch...

  3. Markers of exacerbation severity in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    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

  4. Food-induced (allergic) arthritis. Inflammatory arthritis exacerbated by milk.

    Science.gov (United States)

    Panush, R S; Stroud, R M; Webster, E M

    1986-02-01

    Suggestive, but largely unproven, observations have associated arthritis with environmental antigens, including foods. We studied a patient with inflammatory arthritis in a prospective, "blinded," controlled fashion to determine whether her symptoms were associated with food sensitivities. This 52-year-old white woman with 11 years of class I, stage I, active disease, had symptomatic exacerbations allegedly associated with meat, milk, and beans. We observed an increase in symptoms following an unblinded food challenge and then studied her in our clinical research unit. On her normal diet for 6 days, she averaged 30 minutes of morning stiffness, 9 tender joints, 3 swollen joints, 87% subjective assessment (100% = best possible), and 89% examiner assessment. While she was fasting (3 days) or taking Vivonex (2 days), we noted no morning stiffness, tender joint score of 1, swollen joint score of 0, and assessments of 100% (P less than 0.05 versus normal diet). She was then nourished with Vivonex for 33 days without difficulty and challenged in a blinded fashion at mealtimes with lyophilized foods placed into opaque capsules. Four milk challenges (equivalent to greater than or equal to 8 ounces per meal) produced up to 30 minutes of morning stiffness, 14 tender joints, 4 swollen joints, subjective assessment of 85%, and objective assessment of 80% (P less than 0.05 versus fasting-Vivonex), peaking 24-48 hours postchallenge. Placebo and other foods (lettuce and carrots) were without effect.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3513771

  5. [Clinical contribution of the newer fluoroquinolones in acute bacterial exacerbation of chronic bronchitis].

    Science.gov (United States)

    Niederman, M S

    1999-01-01

    Acute exacerbations occur frequently in patients with chronic bronchitis and the majority of these patients benefit from antimicrobial therapy. The ideal antimicrobial agent for the management of acute exacerbations of chronic bronchitis (AECB) should have good activity against the common bacterial pathogens associated with these exacerbations (non-typable Haemophilus influenzae, Moraxella catarrhalis and pneumococci); it should be resistant to bacterial betalactamases; penetrate well into pulmonary tissues and secretions; kill bacteria without inducing excessive airway inflammation; be easy to take (given once or twice a day) in order to ensure high patient compliance, and be cost-effective. Fluoroquinolone antibiotics have demonstrated efficacy in the treatment of AECB, but because of the limited activity of certain older agents in this class when administered in standard doses against Streptococcus pneumoniae, they have not be extensively used for this indication. Newer agents including levofloxacin, grepafloxacin, sparfloxacin and trovafloxacin have excellent activity against both Gram positive and Gram negative pathogens likely to be involved in AECB. These agents can be administered once daily, making patient compliance and a successful therapeutic outcome more likely. The new quinolones offer promising alternatives for antimicrobial therapy in outpatients with AECB, particularly those with underlying co-morbidity and severe obstruction. PMID:10436551

  6. The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B

    DEFF Research Database (Denmark)

    Krogsgaard, K

    1998-01-01

    This study was performed to evaluate the long-term effects of interferon-alpha 2a (IFN-alpha 2a) vs no treatment in patients with chronic hepatitis B and to determine whether viral clearance, following therapy or occurring spontaneously, was sustained. Patients originating from three previously...... published multicentre, randomized, controlled trials were analysed. Information about survival and response during long-term follow-up was available in 340 (73%) and 308 (66%) of 469 randomized patients respectively. Response to therapy (viral clearance) was defined as: loss of hepatitis B virus (HBV) DNA...... and loss of hepatitis B e antigen (HBeAg) and improvement in alanine aminotransferase level. Scheduled treatment-free follow-up was 12 months in all studies. Median long-term follow-up time after inclusion in the individual studies was 4.7 years (range: 0.2-7.5 years). Viral clearance after IFN...

  7. Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

    Directory of Open Access Journals (Sweden)

    Bazer Fuller W

    2011-10-01

    Full Text Available Abstract Background Alpha 2 macroglobulin (A2M; also known as ovostatin, a homotetrameric protein with four disulfide-linked subunits, has the unique feature of inactivating/inhibiting most known proteases including serine-, threonine-, cysteine-, aspartic- and metalloproteases. In chickens, A2M has been identified and characterized biochemically, but little is known of its functional role(s in the oviduct, hormonal regulation of expression or its expression in ovarian carcinomas in chickens. Therefore, we investigated estrogen regulation of A2M gene expression during development of the chicken oviduct, and its expression in normal and cancerous ovaries from chickens. Methods To determine tissue-specific expression of A2M in chickens, we collected various organs from male and female chickens and performed RT-PCR analyses. To examine A2M gene expression in the oviduct of 1-week-old female chicks that received a subcutaneous implant of 15 mg DES in the abdominal region for 20 days, we performed RT-PCR, qPCR and in situ hybridization analyses using cDNAs from control- (n = 5 and DES-treated oviducts (n = 5, and then each segment of the oviduct from DES-treated chicks. To determine if A2M is a biomarker of ovarian cancer in hens, we collected cancerous (n = 10 ovaries from a total of 136 chickens which had completely stopped egg-laying and performed RT-PCR and in situ hybridization analyses. Results We found that A2M is most abundant in the chicken oviduct, specifically luminal (LE and glandular epithelia (GE, but it was not detected in any other tissues of either sex. We then determined that DES (dietylstilbestrol, a synthetic nonsteroidal estrogen increased A2M mRNA only in LE and GE of the oviduct of chicks. Further, expression of A2M was most abundant in GE of endometrioid adenocarcinoma of cancerous, but not normal ovaries of hens. Conclusions Collectively, results of the present study indicate that A2M is novel estrogen-stimulated gene

  8. Association Between the 1291-C/G Polymorphism in the Adrenergic alpha-2a Receptor and the Metabolic Syndrome

    OpenAIRE

    Risselada, Arne J; Vehof, Jelle; Bruggeman, Richard; Wilffert, Bob; Cohen, Dan; Al Hadithy, Asmar F.; Arends, Johan; Mulder, Hans

    2010-01-01

    The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic alpha-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an ass...

  9. Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report

    OpenAIRE

    Ioannou Savvas; Hatzis Gregorios; Vlahadami Ioanna; Voulgarelis Michael

    2010-01-01

    Abstract Introduction Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatm...

  10. Clebopride enhances contractility of the guinea pig stomach by blocking peripheral D2 dopamine receptor and alpha-2 adrenoceptor

    International Nuclear Information System (INIS)

    The mechanism of action of clebopride on the motility of guinea pig stomach was examined by the receptor binding assay for bovine brain membrane and by measuring gastric contractility and the release of acetylcholine from the stomach. The receptor binding assay revealed that clebopride bound to the D2 dopamine receptor with a high affinity and to the alpha-2 adrenoceptor and 5-HT2 serotonin receptor with relatively lower affinity, and not to D1 dopamine, alpha-1 adrenergic, muscarinic acetylcholine, H1 histamine, or opioid receptor. In strips of the stomach, clebopride at 10-8 M to 10-5 M enhanced the electrical transmural stimulation-evoked contraction and the release of acetylcholine. This enhancement was attributed to the blockade of the D2 dopamine receptor and alpha-2 adrenoceptor because: (1) Maximum responses obtained with specific D2 dopamine receptor antagonist, domperidone, and with specific alpha-2 adrenoceptor antagonist, yohimbine, were smaller than that with clebopride, and the sum of the effects of these two specific receptor antagonists is approximately equal to the effect of clebopride. (2) The facilitatory effect of clebopride was partially eliminated by pretreatment of the sample with domperidone or yohimbine, and the facilitatory effect of clebopride was not observed in preparations treated with the combination of domperidone and yohimbine. Clebopride also antagonized the inhibitory effects of dopamine and clonidine on the electrical transmural stimulation-evoked responses. These results indicate that clebopride acts on post ganglionic cholinergic neurons at D2 and alpha-2 receptors in this preparation to enhance enteric nervous system stimulated motility

  11. Efficiency of a combined peginterferon alpha-2a and ribavarin therapy in intravenous opiate substances abusers with chronic hepatitis C

    OpenAIRE

    Jovanović Maja; Konstantinović Ljiljana; Kostić Velimir; Vrbić Miodrag; Popović Lidija

    2009-01-01

    Background/Aim. The most important ethiology factor of chronic liver disease that progresses into terminal insufficiency is hepatitis C virus (HCV) infection. Intravenous (iv) drug abuse is the main cause for spreading HCV. Thus the therapy for such patients is of extreme importance in reducing the incidence of the disease. The aim of the study was to establish efficacy of a combined therapy with peginterferon alpha-2a and ribavirin in iv opiate substances abusers having chronic HCV infection...

  12. Molecular cloning, structure and bait region splice variants of alpha-2-macroglobulin from the soft tick Ornithodoros moubata

    Czech Academy of Sciences Publication Activity Database

    Saravanan, Thangamani; Weise, C.; Sojka, D.; Kopáček, Petr

    2003-01-01

    Roč. 33, č. 8 (2003), s. 841-851. ISSN 0965-1748 R&D Projects: GA ČR GA206/00/0266; GA AV ČR IAA6022307 Institutional research plan: CEZ:AV0Z6022909 Keywords : Ornithodoros moubata * innate immunity * alpha-2-macroglobulin Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.358, year: 2003

  13. Lymphatic route. VI. Distribution of recombinant interferon-alpha 2 in rabbit and pig plasma and lymph

    International Nuclear Information System (INIS)

    Human recombinant (R) interferon-alpha 2 (either cold or labeled with 125I or 131I) has been administered through different routes [intravenous (i.v.), intramuscular (i.m.), and subcutaneous (s.c.)] and its distribution in lymph and plasma has been evaluated in rabbits and pigs. After i.v. (bolus) administration, the lymph/plasma ratio was about 1. After s.c. and i.m. administration, the ratio varied from an average of 0.8 up to 2, respectively, indicating that R interferon-alpha 2 is preferentially absorbed via lymphatics when injected into the shank muscles. Another novel result is that the ratio is markedly increased after s.c. administration of interferon-alpha 2 with a solution containing 12.5% human albumin. In this case, albumin acts as an interstitial fluid expander, thereby increasing the fluid pressure and favoring lymphatic absorption. Similar results were obtained using either cold or labeled interferons in rabbits; moreover, the effect of albumin was confirmed in the pig by simultaneously injecting 131I-interferon (in saline) and 125I-interferon (in albumin solution) in the left and right subcutis of the shanks, respectively. All of these data suggest that the indirect lymphatic route is a feasible proposition, and that by modifying the absorption, the distribution and fate of interferon may improve the therapeutic index of biological response modifiers

  14. Distinct roles for laminin globular domains in laminin alpha1 chain mediated rescue of murine laminin alpha2 chain deficiency.

    Directory of Open Access Journals (Sweden)

    Kinga I Gawlik

    Full Text Available BACKGROUND: Laminin alpha2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A. Previously, we demonstrated that laminin alpha1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin alpha2 chain, alpha1 chain binds the receptors by separate domains; laminin globular (LG domains 4 and LG1-3, respectively. Thus, the laminin alpha1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide insights into the functions of laminin alpha1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin alpha1 chain that lacks the dystroglycan binding LG4-5 domains in alpha2 chain deficient mice resulted in prolonged lifespan and improved health. Importantly, diaphragm and heart muscles were corrected, whereas limb muscles were dystrophic, indicating that different muscles have different requirements for LG4-5 domains. Furthermore, the regenerative capacity of the skeletal muscle did not depend on laminin alpha1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly. CONCLUSIONS/SIGNIFICANCE: These results show that laminin alpha1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization of future medical treatment for MDC1A patients.

  15. Black-body radiation shift of atomic energy-levels:The $ (Z \\alpha)^2\\alpha T^2/m $ correction

    CERN Document Server

    Zhou, Wanping; Lu, Jingjun; Qiao, Haoxue

    2016-01-01

    The next-to-leading order black-body radiation(BBR) shift to atomic energy-levels, namely $ (Z\\alpha)^2\\alpha T^2/m $ correction, was studied by using the nonrelativistic quantum electrodynamics(NRQED) at first. This $T^{2}$-dependent correction has not been investigated before, and only contains the contribution of eletric-dipole of thermal photon. In order to study the contribution of multipolar. We estimate the two-loop contributions of BBR-shift by using quantum electrodynamics approach(QED), and find both one-loop and two-loop diagram contribute to the $ (Z\\alpha)^2\\alpha T^2/m $ correction. Integrating the results which are obtained by these two approaches, the $ (Z\\alpha)^2\\alpha T^2/m $ correction we derived is in principle applicable to multi-electron atoms and contains the contribution of multipolar. The order of magnitude BBR-shift indicates this next-to-leading order BBR-shift may be as significant as the leading order in the multi-electron atoms or cold ones.

  16. One Center’s Guide to Outpatient Management of Pediatric Cystic Fibrosis Acute Pulmonary Exacerbation

    Science.gov (United States)

    Muirhead, Corinne A.; Sanford, Jillian N.; McCullar, Benjamin G.; Nolt, Dawn; MacDonald, Kelvin D.

    2016-01-01

    Cystic fibrosis (CF) is a chronic disorder characterized by acute pulmonary exacerbations that comprise increased cough, chest congestion, increased mucus production, shortness of breath, weight loss, and fatigue. Typically, severe episodes are treated in the inpatient setting and include intravenous antimicrobials, airway clearance therapy, and nutritional support. Children with less-severe findings can often be managed as outpatients with oral antimicrobials and increased airway clearance therapy at home without visiting the specialty CF center to begin treatment. Selection of specific antimicrobial agents is dependent on pathogens found in surveillance culture, activity of an agent in patients with CF, and the unique physiology of these patients. In this pediatric review, we present our practice for defining acute pulmonary exacerbation, deciding treatment location, initiating treatment either in-person or remotely, determining the frequency of airway clearance, selecting antimicrobial therapy, recommending timing for follow-up visit, and recognizing and managing treatment failures. PMID:27429564

  17. 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.

  18. 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

  19. Glucose tolerance during pulmonary exacerbations in children with cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    John Widger

    Full Text Available BACKGROUND: Patients with Cystic Fibrosis (CF are relatively insulinopenic and are at risk of diabetes, especially during times of stress. There is a paucity of data in the literature describing glucose tolerance during CF pulmonary exacerbations. We hypothesised that glucose tolerance would be worse during pulmonary exacerbations in children with CF than during clinical stability. METHODS: Patients with CF, 10 years or older, admitted with a pulmonary exacerbation underwent an OGTT within 48 hours of admission. A repeat OGTT was performed 4 to 6 weeks post discharge when the patients were well. RESULTS: Nine patients completed the study. Four patients were found to have normal glucose tolerance, 3 with impaired and 2 with CF related diabetes during the exacerbation. Mean change in 2-hour glucose was 1.1 mmol (SD = 0.77. At the follow up OGTT, 8 of 9 (89% remained within their respective glucose tolerance status groupings. CONCLUSION: The findings of this study show that there is little difference in glucose tolerance during CF exacerbations compared to clinical stability in the majority of patients.

  20. Fecal microbial composition of ulcerative colitis and Crohn's disease patients in remission and subsequent exacerbation.

    Directory of Open Access Journals (Sweden)

    Edgar S Wills

    Full Text Available BACKGROUND: Limited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up. DESIGN: Fecal samples from 10 Crohn's disease (CD and 9 ulcerative colitis (UC patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion criteria were pregnancy, antibiotic use, enema use and/or medication changes between consecutive samples. The microbial composition was assessed by 16S rDNA pyrosequencing. RESULTS: After quality control, 6,194-11,030 sequences per sample were available for analysis. Patient-specific shifts in bacterial composition and diversity were observed during exacerbation compared to remission, but overarching shifts within UC or CD were not observed. Changes in the bacterial community composition between remission and exacerbation as assessed by Bray-Curtis dissimilarity, were significantly larger in CD versus UC patients (0.59 vs. 0.42, respectively; p = 0.025. Thiopurine use was found to be a significant cause of clustering as shown by Principal Coordinate Analysis and was associated with decreases in bacterial richness (Choa1 501.2 vs. 847.6 in non-users; p<0.001 and diversity (Shannon index: 5.13 vs. 6.78, respectively; p<0.01. CONCLUSION: Shifts in microbial composition in IBD patients with changing disease activity over time seem to be patient-specific, and are more pronounced in CD than in UC patients. Furthermore, thiopurine use was found to be associated with the microbial composition and diversity, and should be considered when studying the intestinal microbiota in relation to disease course.

  1. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes

    OpenAIRE

    Murphy, V E; Clifton, V.L.; Gibson, P G

    2006-01-01

    Exacerbations of asthma during pregnancy represent a significant clinical problem and may be related to poor pregnancy outcomes. A systematic review of the literature was conducted for publications related to exacerbations during pregnancy. Four studies with a control group (no asthma) and two groups of women with asthma (exacerbation, no exacerbation) were included in meta‐analyses using fixed effects models. During pregnancy, exacerbations of asthma which require medical intervention occur ...

  2. Paradoxical exacerbation of chronic plaque psoriasis by sorafenib.

    Science.gov (United States)

    Yiu, Z Z N; Ali, F R; Griffiths, C E M

    2016-06-01

    Vascular endothelial growth factor (VEGF) antagonists have been investigated as a potential treatment for psoriasis, but there have been reports of VEGF antagonists triggering and/or exacerbating pre-existing psoriasis. We present the case of a 61-year old-man with exacerbation of pre-existing psoriasis after treatment with sorafenib, a small molecule inhibitor of the tyrosine kinase domain of the VEGF receptor, and we review the literature for other published cases of sorafenib-induced or sorafenib-exacerbated psoriasis. Clinicians, including both dermatologists and oncologists, should be aware of this potential side-effect of sorafenib in addition to the other cutaneous side effects reported for this drug. PMID:26667599

  3. COPD exacerbations in general practice: variability in oral prednisolone courses

    Directory of Open Access Journals (Sweden)

    de Vries Marianne

    2012-01-01

    Full Text Available Abstract Background The use of oral corticosteroids as treatment of COPD exacerbations in primary care is well established and evidence-based. However, the most appropriate dosage regimen has not been determined and remains controversial. Corticosteroid therapy is associated with a number of undesirable side effects, including hyperglycaemias, so differences in prescribing might be relevant. This study examines the differences between GPs in dosage and duration of prednisolone treatment in patients with a COPD exacerbation. It also investigates the number of general practitioners (GPs who adjust their treatment according to the presence of diabetic co-morbidity. Methods Cross-sectional study among 219 GPs and 25 GPs in training, located in the Northern part of the Netherlands. Results The response rate was 69%. Nearly every GP prescribed a continuous dose of prednisolone 30 mg per day. Among GPs there were substantial differences in treatment duration. GPs prescribed courses of five, seven, ten, or fourteen days. A course of seven days was most common. The duration of treatment depended on exacerbation and disease severity. A course of five days was especially prescribed in case of a less severe exacerbation. In a more severe exacerbation duration of seven to fourteen days was more common. Hardly any GP adjusted treatment to the presence of diabetic co-morbidity. Conclusion Under normal conditions GPs prescribe prednisolone quite uniformly, within the range of the current Dutch guidelines. There is insufficient guidance regarding how to adjust corticosteroid treatment to exacerbation severity, disease severity and the presence of diabetic co-morbidity. Under these circumstances, there is a substantial variation in treatment duration.

  4. 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...... 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1...

  5. Primary structure of human alpha 2-macroglobulin. IV. Primary structure of two large CNBr fragments, located in the COOH-terminal part and accounting for 337 residues

    DEFF Research Database (Denmark)

    Kristensen, Torsten; Wierzbicki, D M; Sottrup-Jensen, Lars

    1984-01-01

    The amino acid sequences have been determined for two CNBr fragments of human alpha 2-macroglobulin which, due to the presence of an uncleaved Hse-Thr bond, form an Mr = 40,000 fragment. These fragments are located in the COOH-terminal part of alpha 2-macroglobulin (CB21, residues 955-1185 and CB......, residues 1186-1291). CB21 contains one glucosamine-based carbohydrate group attached to Asn-14 and one internal disulfide bridge (Cys-102 bound to Cys-150). CB21 and CB22 account for 337 of the 1451 residues of the subunit of alpha 2-macroglobulin....

  6. Superior neuroprotective effects of cerebrolysin in nanoparticle-induced exacerbation of hyperthermia-induced brain pathology.

    Science.gov (United States)

    Sharma, Aruna; Muresanu, Dafin Fior; Mössler, Herbert; Sharma, Hari Shanker

    2012-02-01

    In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world's population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose-response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed. PMID:22229316

  7. Association of response to combined interferon alpha-2b and ribavirin therapy in patients of chronic hepatitis C with serum alanine aminotransferase levels and severity of the disease on liver biopsy

    International Nuclear Information System (INIS)

    Raised serum alanine aminotransferase (serum ALT) levels indicate active liver disease while liver biopsy has been considered the 'gold standard' for assessing the severity of disease in patients of chronic Hepatitis C. The response of these patients to standard treatment regimen of interferon (INF)-alpha- 2b and ribavirin for 24 weeks have been studied. The objective of this study was to evaluate the association of response to combined INF alpha-2b and ribavirin therapy in patients of chronic hepatitis C with serum ALT levels and severity of the disease on liver biopsy. This quasi experimental study was conducted in Department of Physiology at Army Medical College and Military Hospital, Rawalpindi from January 2006 to February 2007. One hundred and even diagnosed non cirrhotic chronic hepatitis C patients were studied. Prior to the commencement of treatment, qualitative assay of Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) was done by Polymerase chain reaction (PCR). Knodell Histopathological Index (HPI) was determined on liver biopsy. The standard treatment of INF-alpha-2b, 3 million units 3 times a week subcutaneous, and Ribavirin 800-1200 mg per day was given for 24 weeks. Serum ALT levels were determined before the start of treatment and later at weeks 12 and 24. Qualitative assay of HCV RNA was done by PCR at the end of treatment to determine the response to treatment. Statistical analysis was done on SPSS 15. Out of 107 patients of chronic hepatitis C, 92 (69 males, 23 females) patients (84%) responded to INF-alpha-2b and ribavirin therapy and revealed negative qualitative assay of HCV RNA by PCR at the end of 24 weeks of treatment while serum ALT levels were normal in 88% of patients at 12 weeks and in 97% at the end of 24 weeks of treatment. Knodell HPI revealed mild, moderate and severe disease in 47.7%, 39.9% and 13.1% of patients respectively. No association was established between response to treatment and severity of the disease on liver biopsy (p<0

  8. Determination of molecular size of alpha-1 and alpha-2 adrenoceptors in rat mesenteric artery by radiation inactivation

    International Nuclear Information System (INIS)

    Radiation inactivation of alpha-1 and alpha-2 adrenoceptors in the purified plasma membranes of rat mesenteric artery has been performed with high energy electrons at -45 to -55 degrees C. Alpha-1 and alpha-2 adrenoceptor inactivation was monitored with [3H] prazosin and [3H]yohimbine binding, respectively. Internal endogenous and external standards of known molecular weight were used in these studies to determine the molecular size. The average value of D37 for the [3H]prazosin binding site was 6.75 +/- 0.62 Mrad (n = 4) with an estimated molecular size of 122,921 +/- 11,329 Daltons. However, the average value of D37 for the [3H] yohimbine binding site was higher (D37 = 10.05 +/- 0.91 Mrad) and accordingly the molecular size of this binding site was less than the [3H]prazosin binding sites (molecular weight = 82,540 +/- 7478 Daltons; n = 4). Irradiation did not change the dissociation constant of either radioligand, suggesting that the loss of the radioligand binding sites after radiation is due to receptor protein inactivation. These results confirm our earlier finding that [3H]prazosin and [3H]yohimbine bind to two distinct sites in the plasma membranes of rat mesenteric artery. Whether both of these sites are the subunits of a common macromolecule of alpha adrenoceptor on vascular smooth muscle in rat mesenteric artery cannot be concluded from these results. This report is the first one in the literature on the molecular size of alpha-1 and alpha-2 binding sites in vascular smooth muscle

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

    Directory of Open Access Journals (Sweden)

    Brill SE

    2014-11-01

    Full Text Available Simon E Brill, Jadwiga A Wedzicha Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK Abstract: Acute exacerbations of chronic obstructive pulmonary disease (COPD are important events in the history of this debilitating lung condition. Associated health care utilization and morbidity are high, and many patients require supplemental oxygen or ventilatory support. The last 2 decades have seen a substantial increase in our understanding of the best way to manage the respiratory failure suffered by many patients during this high-risk period. This review article examines the evidence underlying supplemental oxygen therapy during exacerbations of COPD. We first discuss the epidemiology and pathophysiology of respiratory failure in COPD during exacerbations. The rationale and evidence underlying oxygen therapy, including the risks when administered inappropriately, are then discussed, along with further strategies for ventilatory support. We also review current recommendations for best practice, including methods for improving oxygen provision in the future. Keywords: chronic obstructive pulmonary disease (COPD, exacerbation, oxygen therapy, respiratory failure, hypercapnia

  10. Chronic obstructive pulmonary disease exacerbation frequency and severity

    OpenAIRE

    Stafyla, Eirini

    2013-01-01

    Eirini Stafyla, Theodora Kerenidi, Konstantinos I Gourgoulianis Respiratory Medicine Department, University of Thessaly Medical School, University Hospital of Larissa, Larissa, GreeceWe read with great interest the original work by Motegi et al1 comparing three multidimensional assessment systems – BODE (body mass index, obstruction, dyspnea, and exercise capacity) index, DOSE (dyspnea, obstruction, smoking, exacerbations) index and ADO (age, dyspnea, obstruction) index – ...

  11. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchod......BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long......-acting bronchodilators has not been fully explored. METHODS: In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid...... fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric...

  12. Novel Human Rhinoviruses and Exacerbation of Asthma in Children 1

    OpenAIRE

    Khetsuriani, Nino; Lu, Xiaoyan; Teague, W. Gerald; Kazerouni, Neely; Anderson, Larry J.; Erdman, Dean D.

    2008-01-01

    To determine links between human rhinoviruses (HRV) and asthma, we used data from a case–control study, March 2003–February 2004, among children with asthma. Molecular characterization identified several likely new HRVs and showed that association with asthma exacerbations was largely driven by HRV-A and a phylogenetically distinct clade of 8 strains, genogroup C.

  13. Novel Human Rhinoviruses and Exacerbation of Asthma in Children1

    Science.gov (United States)

    Khetsuriani, Nino; Lu, Xiaoyan; Teague, W. Gerald; Kazerouni, Neely; Anderson, Larry J.

    2008-01-01

    To determine links between human rhinoviruses (HRV) and asthma, we used data from a case–control study, March 2003–February 2004, among children with asthma. Molecular characterization identified several likely new HRVs and showed that association with asthma exacerbations was largely driven by HRV-A and a phylogenetically distinct clade of 8 strains, genogroup C. PMID:18976575

  14. 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…

  15. Black-body radiation shift of atomic energy-levels:The $ (Z \\alpha)^2\\alpha T^2/m $ correction

    OpenAIRE

    Zhou, Wanping; Mei, Xuesong; Lu, Jingjun; Qiao, Haoxue

    2016-01-01

    The next-to-leading order black-body radiation(BBR) shift to atomic energy-levels, namely $ (Z\\alpha)^2\\alpha T^2/m $ correction, was studied by using the nonrelativistic quantum electrodynamics(NRQED). We also estimate the one-loop contribution of quadrupole and the two-loop contributions of BBR-shift of the thermal(real) photon. These corrections have not been investigated before. The order of magnitude BBR-shift indicates the one-loop contribution of quadrupole is stronger than the previou...

  16. The alpha2,3-Sialyltransferase Encoded by Myxoma Virus Is a Virulence Factor that Contributes to Immunosuppression.

    OpenAIRE

    Boutard, Berengere; Vankerckhove, Sophie; Markine-Goriaynoff, Nicolas; Sarlet, Mickael; Desmecht, Daniel; McFadden, Grant; Vanderplasschen, Alain; Gillet, Laurent

    2015-01-01

    Myxoma virus (MYXV) induces a lethal disease called Myxomatosis in European rabbits. MYXV is one of the rare viruses that encodes an alpha2,3-sialyltransferase through its M138L gene. In this study, we showed that although the absence of the enzyme was not associated with any in vitro deficit, the M138L deficient strains are highly attenuated in vivo. Indeed, while all rabbits infected with the parental and the revertant strains died within 9 days post-infection from severe myxomatosis, all b...

  17. Effect of methylamine and plasmin on the conformation of human alpha 2-macroglobulin as revealed by differential scanning calorimetric analysis.

    OpenAIRE

    Cummings, H S; Pizzo, S V; Strickland, D K; Castellino, F J

    1984-01-01

    Differential scanning calorimetric analysis was used as a probe of the conformational alteration in human alpha 2-macroglobulin (AM) upon its complex formation with methylamine and with the protease, human plasmin. The slow electrophoretic form of AM displayed a single thermal transition, characterized by a temperature midpoint (Tm) of 65.8 +/- 0.3 degrees, a calorimetric enthalpy (delta Hc) of 2,550 +/- 150 kcal/mol and a van't Hoff enthalpy (delta Hvh) of 140 kcal/mol. In the presence of su...

  18. Tyrosine dephosphorylation of nuclear proteins mimics transforming growth factor beta 1 stimulation of alpha 2(I) collagen gene expression.

    OpenAIRE

    Greenwel, P; Hu, W.; Kohanski, R A; Ramirez, F.

    1995-01-01

    Transforming growth factor beta 1 (TGF-beta 1) exerts a positive effect on the transcription of genes coding for several extracellular matrix-related products, including collagen I. We have previously identified a strong TGF-beta 1-responsive element (TbRE) in the upstream promoter sequence of the alpha 2(I) collagen (COL1A2) gene. Our experiments have shown that TGF-beta 1 stimulates COL1A2 transcription by increasing binding of an Sp1-containing complex (TbRC) to the TbRE. They have also su...

  19. Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin {alpha}2-chain in congenital muscular dystrophy with partial deficiency of the protein

    Energy Technology Data Exchange (ETDEWEB)

    Nissinen, M.; Xu Zhang; Tryggvason, K. [Univ. of Oulu (Finland)

    1996-06-01

    Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders of early onset. Approximately half of CMD patients present laminin {alpha}2-chain (merosin) deficiency in muscle biopsies, and the disease locus has been mapped to the region of the LAMA2 gene (6q22-23) in several families. Recently, two nonsense mutations in the laminin {alpha}2-chain gene were identified in CMD patients exhibiting complete deficiency of the laminin {alpha}2-chain in muscle biopsies. However, a subset of CMD patients with linkage to LAMA2 show only partial absence of the laminin {alpha}2-chain around muscle fibers, by immunocytochemical analysis. In the present study we have identified a homozygous missense mutation in the {alpha}2-chain gene of a consanguineous Turkish family with partial laminin {alpha}2-chain deficiency. The T{r_arrow}C transition at position 3035 in the cDNA sequence results in a Cys996{r_arrow}Arg substitution. The mutation that affects one of the conserved cysteine-rich repeats in the short arm of the laminin {alpha}2-chain should result in normal synthesis of the chain and in formation and secretion of a heterotrimeric laminin molecule. Muscular dysfunction is possibly caused either by abnormal disulfide cross-links and folding of the laminin repeat, leading to the disturbance of an as yet unknown binding function of the laminin {alpha}2-chain and to shorter half-life of the muscle-specific laminin-2 and laminin-4 isoforms, or by increased proteolytic sensitivity, leading to truncation of the short arm. 42 refs., 7 figs.

  20. Distinct roles of beta1 metal ion-dependent adhesion site (MIDAS), adjacent to MIDAS (ADMIDAS), and ligand-associated metal-binding site (LIMBS) cation-binding sites in ligand recognition by integrin alpha2beta1.

    Science.gov (United States)

    Valdramidou, Dimitra; Humphries, Martin J; Mould, A Paul

    2008-11-21

    Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding site, occupancy of which increases the affinity of Mg(2+) for the MIDAS. PMID:18820259

  1. Stokes $IQUV$ Magnetic Doppler Imaging of Ap stars II: Next Generation Magnetic Doppler Imaging of $\\alpha^2$ CVn

    CERN Document Server

    Silvester, J; Wade, G A

    2014-01-01

    We present updated magnetic field maps of the chemically peculiar B9p star $\\alpha^2$ CVn created using a series of time resolved observations obtained using the high resolution spectropolarimeters ESPaDOnS and Narval. We compare these new magnetic field maps with the original magnetic Doppler imaging maps based on spectra recorded with the MuSiCoS spectropolarimeter and taken a decade earlier. These new maps are inferred from line profiles in all four Stokes parameters using the magnetic Doppler imaging code INVERS10. With the addition of new lines exhibiting Stokes $IQUV$ signatures we have a unique insight into how the derived magnetic surface structure may be affected by the atomic lines chosen for inversion. We report new magnetic maps of $\\alpha^2$ CVn created using strong iron lines (directly comparable to the published MuSiCoS maps), weak iron lines and chromium lines, all of which yield a magnetic field structure roughly consistent with that obtained previously. We then derive an updated magnetic str...

  2. Stokes IQUV mapping of $\\alpha^2$ CVn & other Ap stars using ESPaDOnS and NARVAL

    CERN Document Server

    Silvester, J; Wade, G A

    2013-01-01

    New spectral line polarisation observations of 7 bright Ap stars have been obtained with the ESPaDOnS and Narval high resolution spectropolarimeters (Silvester et al. 2012). The aim of this data set is produce a series of surface magnetic field and surface chemistry maps for these Ap stars. We present new magnetic maps for the Ap star $\\alpha^2$ CVn using these new data and the MDI inversion code INVERS10. $\\alpha^2$ CVn is the first Ap star to be observed during two separate epochs using high resolution phase resolved spectropolarimetric $IQUV$ observations and as such allows us an insight into how stable the surface magnetic structure is over a decade timescale. We show that the new maps give a magnetic field structure consistent with the previous maps obtained by Kochukhov and Wade (2010) from lower quality MuSiCoS spectra taken a decade ago and that the field topology cannot be described by a dipolar or quadrupolar field.

  3. Order $\\alpha_{s}^{2}$ Contributions to charm production in charged-current deep-inelastic lepton-hadron scattering

    CERN Document Server

    Buza, M

    1997-01-01

    The most important part of the order $\\alpha_s^2$ corrections to the charm component of the charged-current structure functions $F_2(x,Q^2)$ and $F_3(x,Q^2)$ have been calculated. This calculation is based on the asymptotic form of the heavy-quark coefficient functions corresponding to the higher order corrections to the W-boson-gluon fusion process. These coefficient functions which are in principle only valid for $Q^2 \\gg m^2$ can be also used to estimate the order $\\alpha_s^2$ contributions at lower $Q^2$ values provided $x < 0.1$. It turns out that the above corrections are appreciable in the large $Q^2$-region and they explain the discrepancy found for the structure functions between the fixed-flavour scheme (FFS) and the variable-flavour-number scheme (VFNS). These corrections also hamper the extraction of the strange-quark density from the data obtained for the charged-current and the electromagnetic-current processes.

  4. Treatment of patients with COPD and recurrent exacerbations: the role of infection and inflammation

    Directory of Open Access Journals (Sweden)

    Santos S

    2016-03-01

    Full Text Available Salud Santos,1,2 Alicia Marin,2,3 Joan Serra-Batlles,4 David de la Rosa,5 Ingrid Solanes,6 Xavier Pomares,7 Marta López-Sánchez,1 Mariana Muñoz-Esquerre,1 Marc Miravitlles2,81Pneumology Department, Hospital Universitari de Bellvitge, Universidad de Barcelona, Bellvitge Biomedical Research Institute (IDIBELL, Hospitalet de Llobregat, Barcelona, 2Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES, Madrid, 3Pneumology Department, Hospital Universitari Germans Trias i Pujol, Badalona, 4Pneumology Department, Hospital Universitari de Vic, 5Pneumology Unit, Hospital Plató, 6Pneumology Department, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma, Barcelona, 7Pneumology Department, Hospital Universitari Parc Taulí, Sabadell, 8Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, SpainAbstract: Exacerbations of COPD represent an important medical and health care problem. Certain susceptible patients suffer recurrent exacerbations and as a consequence have a poorer prognosis. The effects of bronchial infection, either acute or chronic, and of the inflammation characteristic of the disease itself raise the question of the possible role of antibiotics and anti-inflammatory agents in modulating the course of the disease. However, clinical guidelines base their recommendations on clinical trials that usually exclude more severe patients and patients with more comorbidities, and thus often fail to reflect the reality of clinicians attending more severe patients. In order to discuss aspects of clinical practice of relevance to pulmonologists in the treatment and prevention of recurrent exacerbations in patients with severe COPD, a panel discussion was organized involving expert pulmonologists who devote most of their professional activity to day hospital care. This article summarizes the scientific evidence currently available and the debate generated in

  5. Acquired haemophilia complicated with gastrointestinal bleeding and spontaneous iliopsoas muscle haematoma in a woman with chronic C hepatitis under treatment with pegylated IFN alpha 2a and ribavirin.

    Science.gov (United States)

    Boţianu, Ana-Maria; Demian, Smaranda; Macarie, Ioan; Georgescu, Dan; Oltean, Galafteon; Băţagă, Simona

    2012-03-01

    Acquired haemophilia A is a very rare (1-2 cases per million people) but often life-threatening haemorrhagic disorder characterized by antibodies directed against coagulation factor VIII. We report the case of a 55-year old woman under treatment with Pegylated alpha 2a interferon (IFN) and Ribavirin for chronic viral C hepatitis, who developed a progressive severe haemorrhagic syndrome diagnosed as acquired haemophilia based on supplementary laboratory data (prolonged activated partial thromboplastin time, extremely low factor VIII level - 1%, high titre of factor VIII inhibitor - 30 Bethesda U/ml).The onset was insidious, about three months before presenting to our unit. Antiviral therapy had been stopped three weeks before current admission. Emergency intensive treatment included: haemostatic agents - rFVII (Novoseven), FEIBA (Factor VIII Inhibitor Bypassing Activity), vitamin K, adrenostazin, cryoprecipitate, fresh frozen plasma, as well as immunosuppressive therapy (high dose corticotherapy and cyclophoshamide), immunoglobulins (Humaglobin), prophylactic PPI and antibiotics. The evolution was slowly favourable with the remission of the haemorrhagic syndrome and regression of the iliopsoas muscle haematoma. Clinicians should be aware that acquired forms of haemophilia do exist, representing a rare diagnosis and a therapeutic challenge. To our knowledge, this is the first reported case of acquired haemophilia in Romania, in a patient with chronic viral C hepatitis under antiviral treatment. PMID:22457865

  6. Effect of alpha 2b interferon on inducement of mIL-2R and treatment of HCV in PBMC from patients with chronic viral hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Jian Wang; Gui-Ju Xiang; Bing-Xiang Liu

    2003-01-01

    AIM: To study the level of membrane interleukin-2 receptor (mIL-2R) on surface of peripheral blood mononuclear cells (PBMC) and the therapeutic efficacy of alpha 2b interferon on the treatment of HCV-RNA in PBMC of patients with chronic hepatitis C and to compare the negative rates of HCV-RNA in PBMC, HCV-RNA and anti-HCV in serum.METHODS: Before and after treatment of alpha 2b interferon, the level of mIL-2R of patients with chronic hepatitis C was detected by biotin-streptavidin (BSA). The therapeutic group (26 cases) was treated with alpha 2b interferon (3 MU/d) and control therapeutic group (22 cases)was treated with routine drugs (VitC, aspartic acid). The total course of treatment with alpha 2b interferon and routine drug was six months and per course of the treatment was three months. The levels of HCV-RNA in PBMC, HCV-RNA and anti-HCV in serum were detected before and after a course of the treatment.RESULTS: Before and after treatment of alpha 2b interferon and routine drugs, the levels of mIL-2R in silence stage were (3.44±0.77)% and (2.95±0.72)%, the levels of mIL-2R in inducement stage were (33.62±3.95)% and (30.04±3.73)%. There was a significant difference between two groups (P<0.01-P<0.05). After treatment of alpha 2b interferon with 3 MU/d for two courses of the treatment,the total negative rates of HCV-RNA in the PBMC and HCVRNA, anti-HCV in serum were 42.31% (11/26), 57.69%(15/26), 65.38%(17/26) respectively. After the treatment of routine drug, the negative rates of HCV-RNA in PBMC and HCV-RNA, anti-HCV in serum were 13.64% (3/22),22.73% (5/22), 27.27% (6/22) respectively. There was high significant difference in the group treated with alpha 2b interferon and the group treated with routine drugs (P<0.01-P<0.05).CONCLUSION: The mIL-2R can be induced by alpha 2b interferon during the treatment. The alpha 2b interferon has a definite effect on the treatment of HCV-RNA in PBMC.The curative effect of alpha 2b interferon is better than that

  7. IL-33–Dependent Type 2 Inflammation during Rhinovirus-induced Asthma Exacerbations In Vivo

    OpenAIRE

    Jackson, David J.; Makrinioti, Heidi; Rana, Batika M. J.; Shamji, Betty W.H.; Trujillo-Torralbo, Maria-Belen; Footitt, Joseph; Jerico del-Rosario,; Telcian, Aurica G.; Nikonova, Alexandra; Zhu, Jie; Aniscenko, Julia; Gogsadze, Leila; Bakhsoliani, Eteri; Traub, Stephanie; Dhariwal, Jaideep

    2014-01-01

    Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation.

  8. Genetic variation in BAFF and asthma exacerbations among African American individuals

    Science.gov (United States)

    Kumar, Rajesh; Williams, L. Keoki; Kato, Atsushi; Peterson, Edward L.; Favoreto, Silvio; Hulse, Katie; Wang, Deli; Beckman, Kenneth; Thyne, Shannon; LeNoir, Michael; Meade, Kelley; Lanfear, David E.; Levin, Albert M.; Favro, David; Yang, James J.; Weiss, Kevin; Boushey, Homer A.; Grammer, Leslie; Avila, Pedro C; Burchard, Esteban G.; Schleimer, Robert

    2012-01-01

    Capsule Summary A BAFF polymorphism is associated with asthma exacerbations and serum BAFF levels. BAFF expression in vivo increases in natural rhinovirus infection. BAFF may play a role in airway antiviral immunity and impact asthma exacerbation rates. PMID:22728080

  9. Aspirin-exacerbated respiratory disease: pathophysiological insights and clinical advances

    Directory of Open Access Journals (Sweden)

    Steinke JW

    2016-03-01

    Full Text Available John W Steinke, Jeff M Wilson Asthma and Allergic Disease Center, Carter Immunology Center, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA Abstract: Asthma and chronic rhinosinusitis are heterogeneous airway diseases of the lower and upper airways, respectively. Molecular and cellular studies indicate that these diseases can be categorized into unique endotypes, which have therapeutic implications. One such endotype is aspirin-exacerbated respiratory disease (AERD, which encompasses the triad of asthma, aspirin (or nonsteroidal anti-inflammatory drug hypersensitivity, and nasal polyposis. AERD has unique pathophysiological features that distinguish it from aspirin-tolerant asthma and other forms of chronic rhinosinusitis. This review details molecular and cellular features of AERD and highlights current and future therapies that are based on these insights. Keywords: leukotriene, cyclooxygenase, prostaglandin, aspirin-exacerbated respiratory disease, arachidonic acid

  10. Effects of N-acetylcysteine on asthma exacerbation.

    Science.gov (United States)

    Aliyali, Masoud; Poorhasan Amiri, Ali; Sharifpoor, Ali; Zalli, Fatemeh

    2010-06-01

    Airway mucus hypersecretion and increased oxidative stress are clinical and pathophysiological features of asthma exacerbation. We studied effects of N-acetylcysteine (NAC) as a mucolytic and antioxidant agent in asthma exacerbation. In this randomized, single-blinded, placebo-controlled study 50 patients ( 17 male, 33 female, mean age 48.94+/-13.68) with asthma exacerbation were randomized to receive either oral 600 mg b.d. N-acetylcysteine or placebo in addition to standard treatment during 5 days hospitalization. Daily measurements of wheezing, dyspnea, cough, sputum, expectoration, night sleep scores and morning PEFR were performed. There was no significant difference in wheezing score between patients assigned NAC and those assigned placebo in day 5(0.84[SD 0.94] VS 0.87[SD 0.79]) and also in cough score (0.72[SD 0.84] VS 0.79[SD 0.97]), dyspnea score (0.84[SD 1.06] VS 0.91[SD 1.01]), sputum score(0.79[SD 0.83] VS 0.62[SD 0.71]), expectoration score(0.79[SD 0.97] VS 0.83[SD 1.09]), night sleep score(1[SD 1.17] VS 0.67[SD 0.98] and morning PEFR (256[SD 96.36] VS 282[SD 98.86]). We concluded that addition of N-acetylcysteine to usual asthma medication has no significant effect in treatment of asthma exacerbation. PMID:20683104

  11. Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease

    OpenAIRE

    Nami Shrestha Palikhe; Seung-Hyun Kim; Hyun Jung Jin; Eui-Kyung Hwang; Young Hee Nam; Hae-Sim Park

    2011-01-01

    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 resp...

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

    OpenAIRE

    Wedzicha, Wisia

    2014-01-01

    Simon E Brill, Jadwiga A Wedzicha Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK Abstract: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the history of this debilitating lung condition. Associated health care utilization and morbidity are high, and many patients require supplemental oxygen or ventilatory support. The last 2 decades have seen a substantial increase in our understanding of the best way to ma...

  13. L-Arginine Pathway in COPD Patients with Acute Exacerbation

    DEFF Research Database (Denmark)

    Ruzsics, Istvan; Nagy, Lajos; Keki, Sandor; Sarosi, Veronika; Illes, Balazs; Illes, Zsolt; Horvath, Ildiko; Bogar, Lajos; Molnar, Tihamer

    BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains a major cause of mortality. Clinical criteria of AECOPD are subjective. Biomarkers for AECOPD may aid in the initiation of early treatment. Increased production of asymmetric and symmetric dimethylarginine (A......-arginine, ADMA and SDMA serum levels. In patients with AECOPD, production of ADMA and SDMA are more pronounced presumably due to more severe hypoxic insult. Methylated arginine derivatives in the sera may help early recognition of AECOPD....

  14. Chronic obstructive pulmonary disease exacerbation frequency and severity

    OpenAIRE

    Stafyla E; Kerenidi T; Gourgoulianis KI

    2013-01-01

    Eirini Stafyla, Theodora Kerenidi, Konstantinos I Gourgoulianis Respiratory Medicine Department, University of Thessaly Medical School, University Hospital of Larissa, Larissa, GreeceWe read with great interest the original work by Motegi et al1 comparing three multidimensional assessment systems – BODE (body mass index, obstruction, dyspnea, and exercise capacity) index, DOSE (dyspnea, obstruction, smoking, exacerbations) index and ADO (age, dyspnea, obstruction) index – for pred...

  15. Does aspirin-induced oxidative stress cause asthma exacerbation?

    OpenAIRE

    Kacprzak, Dorota; Pawliczak, Rafał

    2015-01-01

    Aspirin-induced asthma (AIA) is a distinct clinical syndrome characterized by severe asthma exacerbations after ingestion of aspirin or other non-steroidal anti-inflammatory drugs. The exact pathomechanism of AIA remains unknown, though ongoing research has shed some light. Recently, more and more attention has been focused on the role of aspirin in the induction of oxidative stress, especially in cancer cell systems. However, it has not excluded the similar action of aspirin in other inflamm...

  16. Inflamed psoriatic plaques: Drug toxicity or disease exacerbation?

    Directory of Open Access Journals (Sweden)

    Nidhi Jindal

    2013-01-01

    Full Text Available We are presenting a case of Methotrexate treated stable plaque psoriasis, in whom inflamed psoriatic plaques of drug toxicity were misdiagnosed as disease exacerbation. Erosive psoriatic plaques were present in the absence of biochemical or hematological derangements. Ulceration of psoriatic plaques in the presence of disturbed hematological profile is well described as a harbinger of methotrexate toxicity, but this kind of erosions in the absence of any systemic involvement is the first report of its kind.

  17. Comment je previens...une exacerbation de la dermatite atopique.

    OpenAIRE

    Xhauflaire, Emmanuelle; Pierard, Claudine; Nikkels, Arjen; Pierard, Gérald

    2006-01-01

    Atopic dermatitis is under the influence of series of environmental factors. The contact with unsuited cleaning agents and rough textiles can exacerbate pruritus and inflammation. Preventive and adjuvant measures can thus help the care procedures of the disease. Appropriate hygiene measures and the use of emollients are particularly helpful. Clothing measures are also in place. Undergarments and pyjamas made of knitted natural silk are available. Other measures, sometimes corresponding to ane...

  18. Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction.

    Science.gov (United States)

    Daniel, Laura L; Scofield, Stephanie L C; Thrasher, Patsy; Dalal, Suman; Daniels, Christopher R; Foster, Cerrone R; Singh, Mahipal; Singh, Krishna

    2016-08-01

    Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1-7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3β (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy. PMID:27288435

  19. [Combined treatment in recurrent laryngeal papillomatosis with CO2 laser microlaryngoscopic resection and interferon alpha 2b].

    Science.gov (United States)

    Montero Mora, P; Hernández Colín, D D; Enríquez Palomec, O; Mejía Ortega, J

    1996-01-01

    Laryngeal papillomatosis of viral origin and bad prognosis is characterized by multiple recurrence that induced obstruction of air pathways. Surgical remove with laser CO2 is the elected treatment and the its combination with interferon (INF) has improved the prognosis of this recurrent viral disease. Here is a presents a preliminary study based upon such therapeutic scheme. Twelve patients diagnosed with laryngeal papillomatosis; 6 women and 6 men from 32 to 72 years of age were included into two therapeutic schemes: Group B, Combined: One woman and 5 men to whom the surgical procedure was followed by a initial local dose of 3 x 10(6) IU of INF alpha 2b (Intron A) and subsequently 10 X 10(6) (of the same INF were administered intramuscular every days during 15 months the statistical analysis (Fisher test) between patients of the both groups of treatment showed a significant (p anorexia. PMID:9005006

  20. Social isolation-induced increase in NMDA receptors in the hippocampus exacerbates emotional dysregulation in mice.

    Science.gov (United States)

    Chang, Chih-Hua; Hsiao, Ya-Hsin; Chen, Yu-Wen; Yu, Yang-Jung; Gean, Po-Wu

    2015-04-01

    Epidemiological studies have shown that early life adverse events have long-term effects on the susceptibility to subsequent stress exposure in adolescence, but the precise mechanism is unclear. In the present study, mice on postnatal day 21-28 were randomly assigned to either a group or isolated cages for 8 weeks. The socially isolated (SI) mice exhibited a higher level of spontaneous locomotor activity, a longer duration of immobility in the forced swimming test (FST), significantly less prepulse inhibition (PPI) and an increase in aggressive (but not attack) behavior. However, acute stress markedly exacerbated the attack counts of the SI mice but did not affect the group housing (GH) mice. SI mice exhibited higher synaptosomal NR2A and NR2B levels in the hippocampus as compared to the GH mice. Whole-cell patch clamp recordings of CA1 neurons in hippocampal slices showed that the SI mice exhibited a higher input-output relationship of NMDAR-EPSCs as compared to the GH mice. Application of the NR2B -specific antagonist ifenprodil produced a greater attenuating effect on NMDAR-EPSCs in slices from the SI mice. NMDAR EPSCs recorded from the SI mice had a slower deactivation kinetic. MK-801, CPP and ifenprodil, the NMDA antagonists, reversed acute stress-induced exaggeration of aggressive and depressive behaviors. Furthermore, acute stress-induced exacerbation of attack behavior in the SI mice was abolished after the knockdown of NR2B expression. These results suggest that social isolation-induced increased expression of NMDA receptors in the hippocampus involves stress exacerbation of aggressive behaviors. Amelioration of aggressive behaviors by NMDA antagonists may open a new avenue for the treatment of psychopathologies that involve outbursts of emotional aggression in neglected children. PMID:25348768

  1. 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. PMID:26667827

  2. Induction of immunogenic cell death by radiation-upregulated karyopherin alpha 2 in vitro.

    Science.gov (United States)

    Song, Kyung-Hee; Jung, Seung-Youn; Kang, Seong-Mook; Kim, Mi-Hyoung; Ahn, Jiyeon; Hwang, Sang-Gu; Lee, Jun-Ho; Lim, Dae-Seog; Nam, Seon Young; Song, Jie-Young

    2016-01-01

    Accumulating evidence suggests the potential for radiation therapy to generate antitumor immune responses against tumor cells by inducing immunogenic cell death and phenotypic changes. We recently found that ionizing radiation upregulated karyopherin α2 (KPNA2) in HT-29 colorectal tumor cells using quantitative proteomic analysis. To determine whether this increased KPNA2 could function as a damage-associated molecular pattern to induce antitumor immune responses, mouse bone-marrow-derived dendritic cells (BMDCs) were treated with KPNA2. KPNA2 enhanced the surface expression of CD40, CD54, CD80, CD86, and MHC class I/II on BMDCs. DCs treated with KPNA2 exhibited increased secretion of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-23, and TNF-α. Co-culture of CD4(+) T cells and KPNA2-treated DCs resulted in induction of Th1/17 cytokines (IFN-γ and IL-17) and reduction of TGF-β production. Moreover, KPNA2-treated DCs were capable of increasing granzyme B and perforin expression in cytotoxic T lymphocytes. These results demonstrated that radiation-induced dying colorectal cancer cells released considerable amounts of KPNA2 that induce the maturation and activation of DCs for synergistic antitumor effect of radiation. PMID:27107455

  3. Sulphation of proteins secreted by a human hepatoma-derived cell line. Sulphation of N-linked oligosaccharides on alpha 2HS-glycoprotein.

    Science.gov (United States)

    Hortin, G; Green, E D; Baenziger, J U; Strauss, A W

    1986-01-01

    Several human glycoproteins, including alpha 1-antitrypsin, alpha 1-acid glycoprotein, transferrin, caeruloplasmin and alpha 2HS-glycoprotein, synthesized by the hepatoma-derived cell line HepG2 were observed to contain covalently linked sulphate. These proteins were estimated to contain about 0.1 mol of sulphate/mol of protein. The most abundant of the sulphated glycoproteins, alpha 2HS-glycoprotein, was analysed in detail. All of the sulphate on this protein was attached to N-linked oligosaccharides which contained sialic acid and resisted release by endoglycosidase H. Several independent analytical approaches established that approx. 10% of the molecules of alpha 2HS-glycoprotein contained sulphate. Our results suggest that a number of human plasma proteins contain small amounts of sulphate linked to oligosaccharides. Images Fig. 1. Fig. 2. Fig. 3. PMID:3017304

  4. 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

  5. IL-13R alpha 2 reverses the effects of IL-13 and IL-4 on bronchial reactivity and acetylcholine-induced Ca2+ signaling

    OpenAIRE

    Kellner, Julia; Gamarra, Fernando; Welsch, Ulrich; Joerres, Rudolf A.; Huber, Rudolf M; Bergner, Albrecht

    2007-01-01

    Background: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13R alpha 2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13R alpha 2 remains vague. Methods: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca2+ signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. Results: IL-4 or I...

  6. Update on the Management of Aspirin-Exacerbated Respiratory Disease.

    Science.gov (United States)

    Buchheit, Kathleen M; Laidlaw, Tanya M

    2016-07-01

    Aspirin-exacerbated respiratory disease (AERD) is an adult-onset upper and lower airway disease consisting of eosinophilic nasal polyps, asthma, and respiratory reactions to cyclooxygenase 1 (COX-1) inhibitors. Management includes guideline-based treatment of asthma and sinus disease, avoidance of COX-1 inhibitors, and for some patients aspirin desensitization followed by high-dose aspirin therapy. Despite this, many patients have inadequately controlled symptoms and require multiple sinus surgeries. In this review, we discuss the current standard approaches to the management of AERD, and we introduce several therapeutics under development that may hold promise for the treatment of AERD. PMID:27126722

  7. Aspirin-exacerbated respiratory disease: pathophysiological insights and clinical advances.

    Science.gov (United States)

    Steinke, John W; Wilson, Jeff M

    2016-01-01

    Asthma and chronic rhinosinusitis are heterogeneous airway diseases of the lower and upper airways, respectively. Molecular and cellular studies indicate that these diseases can be categorized into unique endotypes, which have therapeutic implications. One such endotype is aspirin-exacerbated respiratory disease (AERD), which encompasses the triad of asthma, aspirin (or nonsteroidal anti-inflammatory drug) hypersensitivity, and nasal polyposis. AERD has unique pathophysiological features that distinguish it from aspirin-tolerant asthma and other forms of chronic rhinosinusitis. This review details molecular and cellular features of AERD and highlights current and future therapies that are based on these insights. PMID:27022293

  8. Prediction of relapse within eight weeks after an acute asthma exacerbation in adults.

    Science.gov (United States)

    McCarren, M; McDermott, M F; Zalenski, R J; Jovanovic, B; Marder, D; Murphy, D G; Kampe, L M; Misiewicz, V M; Rydman, R J

    1998-02-01

    Associations between historical, presenting, and treatment-related characteristics and relapse within 8 weeks after a moderate to severe asthma exacerbation were studied in a cohort of 284 adult asthmatics. Data were collected prospectively, and a multivariate model was developed and internally validated. Within 10 days, only 8% had relapsed, increasing to 45% by 8 weeks. Three variables that could be identified at the time of discharge were independently associated with relapse. These included: having made three or more visits to an emergency department in the prior 6 months (hazard ratio (HR) = 2.3, 95% CI = 1.6-3.4); difficulty performing work or activities as a result of physical health in the 4 weeks prior (HR = 2.7, 95% CI = 1.6-4.3); discontinuing hospital-based treatment for the exacerbation within 24 hours without having achieved a peak expiratory flow rate of at least 50% of predicted (HR = 2.6, 95% CI = 1.6-4.1). These risk factors may help to identify patients with poorly controlled asthma in need of more intensive and comprehensive management. PMID:9474071

  9. Myeloid Deletion of α1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice.

    Science.gov (United States)

    Cao, Qiang; Cui, Xin; Wu, Rui; Zha, Lin; Wang, Xianfeng; Parks, John S; Yu, Liqing; Shi, Hang; Xue, Bingzhong

    2016-06-01

    Macrophage inflammation marks all stages of atherogenesis, and AMPK is a regulator of macrophage inflammation. We therefore generated myeloid α1AMPK knockout (MAKO) mice on the LDL receptor knockout (LDLRKO) background to investigate whether myeloid deletion of α1AMPK exacerbates atherosclerosis. When fed an atherogenic diet, MAKO/LDLRKO mice displayed exacerbated atherosclerosis compared with LDLRKO mice. To determine the underlying pathophysiological pathways, we characterized macrophage inflammation/chemotaxis and lipid/cholesterol metabolism in MAKO/LDLRKO mice. Myeloid deletion of α1AMPK increased macrophage inflammatory gene expression and enhanced macrophage migration and adhesion to endothelial cells. Remarkably, MAKO/LDLRKO mice also displayed higher composition of circulating chemotaxically active Ly-6C(high) monocytes, enhanced atherosclerotic plaque chemokine expression, and monocyte recruitment into plaques, leading to increased atherosclerotic plaque macrophage content and inflammation. MAKO/LDLRKO mice also exhibited higher plasma LDL and VLDL cholesterol content, increased circulating apolipoprotein B (apoB) levels, and higher liver apoB expression. We conclude that macrophage α1AMPK deficiency promotes atherogenesis in LDLRKO mice and is associated with enhanced macrophage inflammation and hypercholesterolemia and that macrophage α1AMPK may serve as a therapeutic target for prevention and treatment of atherosclerosis. PMID:26822081

  10. Prediction and course of symptoms and lung function around an exacerbation in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    van den Berge Maarten

    2012-06-01

    Full Text Available Abstract Background Frequent exacerbations induce a high burden to Chronic Obstructive Pulmonary Disease (COPD. We investigated the course of exacerbations in the published COSMIC study that investigated the effects of 1-year withdrawal of fluticasone after a 3-month run-in treatment period with salmeterol/fluticasone in patients with COPD. Methods In 373 patients, we evaluated diary cards for symptoms, Peak Expiratory Flow (PEF, and salbutamol use and assessed their course during exacerbations. Results There were 492 exacerbations in 224 patients. The level of symptoms of cough, sputum, dyspnea and nocturnal awakening steadily increased from 2 weeks prior to exacerbation, with a sharp rise during the last week. Symptoms of cough, sputum, and dyspnea reverted to baseline values at different rates (after 4, 4, and 7 weeks respectively, whereas symptoms of nocturnal awakening were still increased after eight weeks. The course of symptoms was similar around a first and second exacerbation. Increases in symptoms and salbutamol use and decreases in PEF were associated with a higher risk to develop an exacerbation, but with moderate predictive values, the areas under the receiver operating curves ranging from 0.63 to 0.70. Conclusions Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation. COPD exacerbations are preceded by increased symptoms and salbutamol use and lower PEF, yet predictive values are too low to warrant daily use in clinical practice.

  11. The importance of bacterial and viral infections associated with adult asthma exacerbations in clinical practice.

    Directory of Open Access Journals (Sweden)

    Motoyasu Iikura

    Full Text Available Viral infection is one of the risk factors for asthma exacerbation. However, which pathogens are related to asthma exacerbation in adults remains unclear.The relation between various infections and adult asthma exacerbations was investigated in clinical practice.The study subjects included 50 adult inpatients due to asthma exacerbations and 20 stable outpatients for comparison. The pathogens from a nasopharyngeal swab were measured by multiplex PCR analysis.Asthma exacerbations occurred after a common cold in 48 inpatients. The numbers of patients with viral, bacterial, or both infections were 16, 9, and 9, respectively. The dominant viruses were rhinoviruses, respiratory syncytial virus, influenza virus, and metapneumovirus. The major bacteria were S. pneumoniae and H. influenzae. Compared to pathogen-free patients, the patients with pathogens were older and non-atopic and had later onset of disease, lower FeNO levels, lower IgE titers, and a higher incidence of comorbid sinusitis, COPD, or pneumonia. Compared to stable outpatients, asthma exacerbation inpatients had a higher incidence of smoking and comorbid sinusitis, COPD, or pneumonia. Viruses were detected in 50% of stable outpatients, but a higher incidence of rhinovirus, respiratory syncytial virus, and metapneumovirus infections was observed in asthma exacerbation inpatients. H. influenzae was observed in stable asthmatic patients. Other bacteria, especially S. pneumoniae, were important in asthma exacerbation inpatients.Viral or bacterial infections were observed in 70% of inpatients with an asthma exacerbation in clinical practice. Infection with S. pneumoniae was related to adult asthma exacerbation.

  12. Relevance of human metapneumovirus in exacerbations of COPD

    Directory of Open Access Journals (Sweden)

    Bauer TT

    2005-12-01

    Full Text Available Abstract Background and methods Human metapneumovirus (hMPV is a recently discovered respiratory virus associated with bronchiolitis, pneumonia, croup and exacerbations of asthma. Since respiratory viruses are frequently detected in patients with acute exacerbations of COPD (AE-COPD it was our aim to investigate the frequency of hMPV detection in a prospective cohort of hospitalized patients with AE-COPD compared to patients with stable COPD and to smokers without by means of quantitative real-time RT-PCR. Results We analysed nasal lavage and induced sputum of 130 patients with AE-COPD, 65 patients with stable COPD and 34 smokers without COPD. HMPV was detected in 3/130 (2.3% AE-COPD patients with a mean of 6.5 × 105 viral copies/ml in nasal lavage and 1.88 × 105 viral copies/ml in induced sputum. It was not found in patients with stable COPD or smokers without COPD. Conclusion HMPV is only found in a very small number of patients with AE-COPD. However it should be considered as a further possible viral trigger of AE-COPD because asymptomatic carriage is unlikely.

  13. Expression of the alpha 1, alpha 2 and alpha 3 isoforms of the GABAA receptor in human alcoholic brain.

    Science.gov (United States)

    Lewohl, J M; Crane, D I; Dodd, P R

    1997-03-14

    The expression of the alpha 1, alpha 2 and alpha 3 isoforms of the GABAA receptor was studied in the superior frontal and motor cortices of 10 control, 10 uncomplicated alcoholic and 7 cirrhotic alcoholic cases matched for age and post-mortem delay. The assay was based on competitive RT/PCR using a single set of primers specific to the alpha class of isoform mRNA species, and was normalized against a synthetic cRNA internal standard. The assay was shown to be quantitative for all three isoform mRNA species. Neither the patient's age nor the post-mortem interval significantly affected the expression of any isoform in either cortical area. The profile of expression was shown to be significantly different between the case groups, particularly because alpha 1 expression was raised in both groups of alcoholics of controls. The two groups of alcoholics could be differentiated on the basis of regional variations in alpha 1 expression. In frontal cortex, alpha 1 mRNA expression was significantly increased when uncomplicated alcoholics were compared with control cases whereas alcoholic-cirrhotic cases were not significantly different from either controls or uncomplicated alcoholic cases. In the motor cortex, alpha 1 expression was elevated only when alcoholic-cirrhotic cases were compared with control cases. There was no significant difference between case groups or areas for any other isoform. PMID:9098573

  14. Variations of intensity of the flux in the large features and spectral lines in the ultraviolet of alpha2 CVn

    CERN Document Server

    Sokolov, N A

    2011-01-01

    Variation of intensity of the flux at the cores of large features and spectral lines of the classical magnetic CP star alpha2 CVn in the ultraviolet spectral region from 1150 to 3200 A is investigated. This study is based on the archival International Ultraviolet Explorer data obtained at different phases of the rotational cycle. The shapes of two light curves at \\lambda \\lambda 1375 and 1415 A at the core of large feature at \\lambda 1400 A curves significantly differ. The light curve at \\lambda 1375 A show similar shape as in the 'pseudo-continuum'. The same behavior of the flux is at the cores of Si II resonance lines at \\lambda \\lambda 1260--64 and 1485 A. While, the light curve at \\lambda 1415 A show the phase displacement of minimum of the flux. The phase displacement also is presented at the cores of Si II resonance lines at \\lambda \\lambda 1304--09 and 1485 A. The minimal values of the amplitude of the flux variations are reached at the cores of the large features at \\lambda \\lambda 1560 and 1770 A and...

  15. Na(+)-K(+)-ATPase alpha(2)-isoform expression in guinea pig hearts during transition from compensation to decompensation.

    Science.gov (United States)

    Trouve, P; Carre, F; Belikova, I; Leclercq, C; Dakhli, T; Soufir, L; Coquard, I; Ramirez-Gil, J; Charlemagne, D

    2000-10-01

    Disturbance in ionic gradient across sarcolemma may lead to arrhythmias. Because Na(+)-K(+)-ATPase regulates intracellular Na(+) and K(+) concentrations, and therefore intracellular Ca(2+) concentration homeostasis, our aim was to determine whether changes in the Na(+)-K(+)-ATPase alpha-isoforms in guinea pigs during transition from compensated (CLVH) to decompensated left ventricular hypertrophy (DLVH) were concomitant with arrhythmias. After 12- and 20-mo aortic stenosis, CLVH and DLVH were characterized by increased mean arterial pressure (30% and 52.7%, respectively). DLVH differed from CLVH by significantly increased end-diastolic pressure (34%), decreased sarco(endo)plasmic reticulum Ca(2+)-ATPase (-75%), and increased Na(+)/Ca(2+) exchanger (25%) mRNA levels and by the occurrence of ventricular arrhythmias. The alpha-isoform (mRNA and protein levels) was significantly lower in DLVH (2.2 +/- 0.2- and 1. 4 +/- 0.15-fold, respectively, vs. control) than in CLVH (3.5 +/- 0. 4- and 2.2 +/- 0.13-fold, respectively) and was present in sarcolemma and T tubules. Changes in the levels of alpha(1)- and alpha(3)-isoform in CLVH and DLVH appear physiologically irrelevant. We suggest that the increased level of alpha(2)-isoform in CLVH may participate in compensation, whereas its relative decrease in DLVH may enhance decompensation and arrhythmias. PMID:11009487

  16. Does cigarette smoking affect the diagnostic reliability of hemoglobin alpha 2 delta 2 (HbA2)?

    Science.gov (United States)

    Tarazi, Issa S; Sirdah, Mahmoud M; El Jeadi, Hesham; Al Haddad, Rami M

    2008-01-01

    Quantitation of hemoglobin alpha 2 delta 2 (HbA2) is a basic and confirmatory test in diagnosing the carrier state of beta-thalassemia. The present study was designed to investigate the effect of cigarette smoking on the diagnostic reliability of HbA2. A total of 2,867 (654 smokers and 2,213 never smokers) male subjects were involved in the present study. The subjects were categorized into three groups according to their laboratory findings: beta-thalassemia minor, iron deficient, and normal groups. Complete blood count (CBC) parameters and HbA2 levels were compared between smokers and never smokers of each group according to the independent-samples t-test using the SPSS program, significance results were reported at PHct]) and Hb concentration in smokers of all groups; however, no significant differences were reported in the HbA2 level between smokers and never smokers in all groups. It was concluded that cigarette smoking does not affect the diagnostic reliability of the HbA2 test. PMID:18348310

  17. 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.

  18. Comparison of the effect of alpha1- and alpha2-adrenoceptor agonists and antagonists on muscle contractility of the rabbit abdominal aorta in vitro.

    Science.gov (United States)

    Gnus, Jan; Rusiecka, Agnieszka; Czerski, Albert; Zawadzki, Wojciech; Witkiewicz, Wojciech; Hauzer, Willy

    2013-01-01

    The aim of the study was to demonstrate the effect of selected agonists and antagonists of alpha-adrenergic receptors on muscle contractility of the rabbit abdominal aorta in vitro with particular emphasis on alpha2-adrenergic receptor subtypes. The study was conducted on 30 New Zealand breed rabbits from which specimens of the abdominal aorta were collected. The sections were set up in an automatic water bath in a Krebs-Henseleit buffer at 37 degrees C. The experiments showed that alpha1-adrenergic receptors played the main role in the contractile response ofthe rabbit abdominal aorta. Stimulation of alpha1-adrenergic receptor by administration ofphenylephrine resulted in an increase in smooth muscle tonus ofthe rabbit abdominal aorta by an average of 4.75 mN. The reaction after stimulation of alpha2-adrenergic receptors by similar doses of their agonists was much weaker. Prolonged tissue response time and time needed to reach maximum tonus for alpha2-adrenergic receptor agonists were observed. The obtained results confirm the thesis that the alpha1-adrenergic receptor is the most important factor controlling the contractility of the rabbit abdominal aorta, but the alpha2-adrenergic receptor is also involved in maintaining muscle tissue tonus. PMID:23767297

  19. 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...

  20. On inequalities of Hermite-Hadamard type for co-ordinated \\((\\alpha_1,m_1\\-\\((\\alpha_2,m_2\\-convex functions

    Directory of Open Access Journals (Sweden)

    Shu-Ping Bai

    2015-11-01

    Full Text Available In the paper, the authors establish some Hermite-Hadamard type integral inequalities for co-ordinated \\((\\alpha_1,m_1\\-\\((\\alpha_2,m_2\\-convex functions on a rectangle of the plane \\(\\mathbb{R}_0^2\\.

  1. Fecal Microbial Composition of Ulcerative Colitis and Crohn’s Disease Patients in Remission and Subsequent Exacerbation

    Science.gov (United States)

    Wills, Edgar S.; Jonkers, Daisy M. A. E.; Savelkoul, Paul H.; Masclee, Ad A.; Pierik, Marieke J.; Penders, John

    2014-01-01

    Background Limited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up. Design Fecal samples from 10 Crohn’s disease (CD) and 9 ulcerative colitis (UC) patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion criteria were pregnancy, antibiotic use, enema use and/or medication changes between consecutive samples. The microbial composition was assessed by 16S rDNA pyrosequencing. Results After quality control, 6,194–11,030 sequences per sample were available for analysis. Patient-specific shifts in bacterial composition and diversity were observed during exacerbation compared to remission, but overarching shifts within UC or CD were not observed. Changes in the bacterial community composition between remission and exacerbation as assessed by Bray-Curtis dissimilarity, were significantly larger in CD versus UC patients (0.59 vs. 0.42, respectively; p = 0.025). Thiopurine use was found to be a significant cause of clustering as shown by Principal Coordinate Analysis and was associated with decreases in bacterial richness (Choa1 501.2 vs. 847.6 in non-users; p<0.001) and diversity (Shannon index: 5.13 vs. 6.78, respectively; p<0.01). Conclusion Shifts in microbial composition in IBD patients with changing disease activity over time seem to be patient-specific, and are more pronounced in CD than in UC patients. Furthermore, thiopurine use was found to be associated with the microbial composition and diversity, and should be considered when studying the intestinal microbiota in relation to disease course. PMID:24608638

  2. 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. 

  3. Variability of antibiotic prescribing in patients with chronic obstructive pulmonary disease exacerbations: a cohort study

    OpenAIRE

    Boggon, R; Hubbard, R.; Smeeth, L; Gulliford, M; Cassell, J; Eaton, S; Pirmohamed, M; Van Staa, TP

    2013-01-01

    Background: The role of antibiotics in treating mild or moderate exacerbations in patients with acute chronic obstructive pulmonary disease (COPD) is unclear. The aims were to: (i) describe patient characteristics associated with acute exacerbations amongst a representative COPD population, (ii) explore the relationship between COPD severity and outcomes amongst patients with exacerbations, and (iii) quantify variability by general practice in prescribing of antibiotics for COPD exacerba...

  4. 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...... 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...... exacerbations is needed. The proposed definition has been endorsed by the EMA Scientific Advice Working Party in 2011and needs to be trialled in forthcoming clinical studies....

  5. The Christmas Season as a Risk Factor for Chronic Obstructive Pulmonary Disease Exacerbations

    Directory of Open Access Journals (Sweden)

    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.

  6. Fine particulate matter in acute exacerbation of COPD.

    Science.gov (United States)

    Ni, Lei; Chuang, Chia-Chen; Zuo, Li

    2015-01-01

    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 (OS), 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. PMID:26557095

  7. Fine particulate matter in acute exacerbation of COPD

    Directory of Open Access Journals (Sweden)

    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.

  8. Will climate change exacerbate water stress in Central Asia?

    DEFF Research Database (Denmark)

    Siegfried, Tobias; Bernauer, Thomas; Guiennet, Renaud;

    2012-01-01

    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......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......, and politically unstable Fergana Valley. Targeted infrastructural developments will be required in the region. If the current mismanagement of water and energy resources can be replaced with more effective resource allocation mechanisms through the strengthening of transboundary institutions, Central...

  9. [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. PMID:27254941

  10. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.

    Directory of Open Access Journals (Sweden)

    Edith T Zemanick

    Full Text Available BACKGROUND: 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. OBJECTIVE: To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  11. Soluble CD93 as a Novel Biomarker in Asthma Exacerbation.

    Science.gov (United States)

    Sigari, Naseh; Jalili, Ali; Mahdawi, Laili; Ghaderi, Ebrahim; Shilan, Mohammadi

    2016-09-01

    Asthma research is shifting from studying symptoms and lung functions to the narrow-focus cellular profiles protein analysis, biomarkers, and genetic markers. The transmembrane glycoprotein CD93 is involved in endothelial cell migration, angiogenesis, leukocytes extravasation, apoptosis, innate immunity and inflammation. Relationships between the serum level of soluble CD93 (sCD93) and acute myocardial infarction/premature MI/inflammatory arthritis/skin sclerosis have recently been reported. We hypothesized that sCD93 would be elevated during the acute phase of asthma. We measured the serum level of sCD93 in 57 patients with asthma exacerbation and 57 age-and gender-matched healthy controls. Additionally, sCD93 was reassessed at the time of discharge from the hospital. Clinical characteristics and peak expiratory flow (PEF) of the patients were assessed. The primary outcome was the comparison of serum level of sCD93 between asthmatics and healthy subjects. The sCD93 values ranged from 128 to 789 ng/mL in asthmatics (345.83±115.81) and from 31 to 289 ng/mL in control subjects (169.46±62.43). The difference between the 2 groups was statistically significant (P<0.001). The association between sCD93 and asthma remained significant after adjusting for age, sex, and BMI. The differences between asthmatics and controls remained significant on the last day of hospital stay. The association between sCD93 and PEF was not significant. In conclusion, the serum level of soluble CD93 is increased in patients with asthma exacerbation. It also showed that serum levels of sCD93 decreased with treatment of asthma attack. The clinical usefulness of determination of sCD93 as a biomarker of asthma requires further studies. PMID:27334785

  12. Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Brent C. [Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037 (United States); Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States); Constant, Stephanie L. [Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037 (United States); Patierno, Steven R. [Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States); GW Cancer Institute, The George Washington University, Washington, DC 20037 (United States); Jurjus, Rosalyn A. [Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20037 (United States); Ceryak, Susan M., E-mail: phmsmc@gwumc.edu [Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States)

    2012-02-15

    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

  13. Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

    International Nuclear Information System (INIS)

    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

  14. 急性高血糖通过抑制 ALDH2活性加重大鼠心肌缺血/再灌注损伤%Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury by inhibiting aldehyde dehydrogenase 2 activity in rats

    Institute of Scientific and Technical Information of China (English)

    李明华; 王甲莉; 徐峰; 袁秋环; 刘宝山; 庞佼佼; 张运; 陈玉国

    2015-01-01

    Objective To investigate the activity changes and actions of aldehyde dehydrogenase 2 (ALDH2)in myocardial ischemia/reperfusion injury exacerbated by acute hyperglycemia.Methods A total of 48 male Wistar rats were randomly divided into 4 groups:sham operation (SHAM)group,normal saline control (CON)group,high blood glucose (HG)group,and HG with Alda-1 administration (HG +Alda-1)group,with 12 animals in each group. The left anterior descending artery (LAD)was occluded for 30 minutes followed by 1 hour reperfusion to establish my-ocardial ischemia-reperfusion rat models.Acute hyperglycemia rat models were established via jugular vein injection of 50% glucose (3 g /kg)during the ischemia period.Blood glucose levels were maintained at 20-28 mmol/L throughout the experiment by administration of glucose with trace pumping[4 mL/(kg·h)]during ischemia and reperfusion peri-od.The rats in CON group and HG +Alda-1 group were given normal saline (6 mL/kg).The rats in HG +Alda-1 group were given Alda-1 (8.5 mg /kg)with trace pumping during ischemia and reperfusion.After reperfusion,ALDH2 activity of heart was detected with colorimetric method,changes of myocardial tissue morphology were observed with HE staining,myocardial infarction size was determined with TTC staining,and myocardial cell apoptosis was tested with TUNEL method.Results Blood glucose level was significantly increased in HG group compared with that of CON group [(23.4 ±0.21 )vs (5.8 ±0.21 )mmol/L,P <0.01 ].Compared with CON group,the activity of ALDH2 in HG group was markedly decreased [(69.1 ±5.16)% vs (87.0 ±4.30)%,P <0.05].Myocardial infarct size of HG group was remarkably increased compared with the CON group [(38.2 ±3.30)% vs (26.8 ±2.53)%, P <0.05].Compared with HG group,myocardial infarct size of HG +Alda-1 group was notedly decreased [(27.8 ± 2.50)% vs (38.2 ±3.30)%,P <0.05].Myocardial apoptosis index of HG group was significantly higher than that of CON group [(16.1 ±0.83)% vs (13.1 ±0.39)%,P

  15. Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury by inhibiting aldehyde dehydrogenase 2 activity in rats%急性高血糖通过抑制 ALDH2活性加重大鼠心肌缺血/再灌注损伤

    Institute of Scientific and Technical Information of China (English)

    李明华; 王甲莉; 徐峰; 袁秋环; 刘宝山; 庞佼佼; 张运; 陈玉国

    2015-01-01

    及心肌细胞凋亡。%Objective To investigate the activity changes and actions of aldehyde dehydrogenase 2 (ALDH2)in myocardial ischemia/reperfusion injury exacerbated by acute hyperglycemia.Methods A total of 48 male Wistar rats were randomly divided into 4 groups:sham operation (SHAM)group,normal saline control (CON)group,high blood glucose (HG)group,and HG with Alda-1 administration (HG +Alda-1)group,with 12 animals in each group. The left anterior descending artery (LAD)was occluded for 30 minutes followed by 1 hour reperfusion to establish my-ocardial ischemia-reperfusion rat models.Acute hyperglycemia rat models were established via jugular vein injection of 50% glucose (3 g /kg)during the ischemia period.Blood glucose levels were maintained at 20-28 mmol/L throughout the experiment by administration of glucose with trace pumping[4 mL/(kg·h)]during ischemia and reperfusion peri-od.The rats in CON group and HG +Alda-1 group were given normal saline (6 mL/kg).The rats in HG +Alda-1 group were given Alda-1 (8.5 mg /kg)with trace pumping during ischemia and reperfusion.After reperfusion,ALDH2 activity of heart was detected with colorimetric method,changes of myocardial tissue morphology were observed with HE staining,myocardial infarction size was determined with TTC staining,and myocardial cell apoptosis was tested with TUNEL method.Results Blood glucose level was significantly increased in HG group compared with that of CON group [(23.4 ±0.21 )vs (5.8 ±0.21 )mmol/L,P <0.01 ].Compared with CON group,the activity of ALDH2 in HG group was markedly decreased [(69.1 ±5.16)% vs (87.0 ±4.30)%,P <0.05].Myocardial infarct size of HG group was remarkably increased compared with the CON group [(38.2 ±3.30)% vs (26.8 ±2.53)%, P <0.05].Compared with HG group,myocardial infarct size of HG +Alda-1 group was notedly decreased [(27.8 ± 2.50)% vs (38.2 ±3.30)%,P <0.05].Myocardial apoptosis index of HG group was significantly higher than that of CON group [(16.1 ±0.83)% vs (13.1 ±0.39)%,P <0

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

    Directory of Open Access Journals (Sweden)

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

    International Nuclear Information System (INIS)

    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)

  18. A novel D2-dopaminergic and alpha2-adrenoceptor receptor agonist induces substantial and prolonged IOP decrease in normotensive rabbits.

    Science.gov (United States)

    Savolainen, Jouko; Rautio, Jarkko; Razzetti, Roberta; Järvinen, Tomi

    2003-06-01

    The effects of a novel and selective D2-dopaminergic/alpha2-adrenoceptor agonist, CHF1035, and its metabolite CHF1024 on intraocular pressure (IOP) were determined in rabbits. Because CHF1035 is a mixture of two enantiomers, CHF1800 (+) and CHF1810 (-), pure enantiomers were also studied to determine possible differences in IOP-decreasing ability depending on the stereochemistry of the molecule. CHF1035, CHF1800 (+), CHF1810 (-), CHF1024, brimonidine and 0.9% NaCl were administered topically to rabbits and IOP was then measured at fixed time intervals. The dose-response profile (0.01-1.0% w/v) was determined for CHF1035. CHF1035 and its metabolite CHF1024 significantly lowered IOP in the treated eyes. CHF1035 showed a maximum IOP decrease (7.6 +/- 1.5 mmHg) 5 h post-dosing, whereas the metabolite CHF1024 showed a maximum decrease in IOP (7.0 +/- 0.8 mmHg) 3 h post-dosing. The maximum IOP decrease produced by CHF1035 in the treated eye was comparable with that produced by brimonidine (7.8 +/- 0.9 mmHg), but CHF1035 had a significantly longer duration of action. Unlike brimonidine, CHF1035 and CHF1024 did not decrease IOP in the untreated eye. CHF1810 (-) lowered the IOP more than CHF1800 (+). No irritation, evaluated as eyelid closure, was observed after topical administration of any of the compounds. Only in the case of CHF1035 1% solution, two rabbits out of six closed the eye for 30-45 s. In conclusion, CHF1035 and its metabolite CHF1024 significantly decreased the IOP in rabbits, and are potential novel IOP lowering agents. Especially, CHF1035 produced a substantial decrease in IOP for a prolonged period of time, and thus may prove useful in glaucoma therapy. PMID:12841939

  19. Paraphenylene diamine exacerbates platelet aggregation and thrombus formation in response to a low dose of collagen.

    Science.gov (United States)

    Zaid, Younes; Marhoume, Fatimazahra; Senhaji, Nezha; Kojok, Kevin; Boufous, Hicham; Naya, Abdallah; Oudghiri, Mounia; Darif, Youssef; Habti, Norddine; Zouine, Soukaina; Mohamed, Fekhaoui; Chait, Abderahmane; Bagri, Abdellah

    2016-02-01

    Paraphenylene daimine (PPD) is an aromatic amine that is widely used in several industrial products; however, its toxicity has been reported in several cases of cardiac arrests. As platelets play a key role in cardiovascular diseases, we aimed to determine the impact of PPD in vitro and in vivo on platelet function. Our findings demonstrated that platelet activation and aggregation were strongly enhanced by PPD. Treatment with PPD primed human platelets that became more reactive in response to low doses of collagen. Furthermore, PPD exacerbated thrombus formation in rats in comparison with those untreated. Our results suggest that PPD is an important platelet primer predisposing platelets to promote thrombus formation in response to vascular injury. This should prompt the authorities to consider controlling the marketing of this product. PMID:26763399

  20. Blocking rpS6 Phosphorylation Exacerbates Tsc1 Deletion-Induced Kidney Growth.

    Science.gov (United States)

    Wu, Huijuan; Chen, Jianchun; Xu, Jinxian; Dong, Zheng; Meyuhas, Oded; Chen, Jian-Kang

    2016-04-01

    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 theseTsc1-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,Tsc1single-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 ofTsc1andrpS6double-mutant mice. Furthermore, pharmacologic treatment ofTsc1single-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 inTsc1-deleted kidneys. PMID:26296742

  1. FACTORS ASSOCIATED WITH QUALITY OF LIFE IN ACUTE EXACERBATION OF COPD

    Institute of Scientific and Technical Information of China (English)

    CAO Zhen-ying; Tan Wan Cheng; Ng Tze Pin

    2005-01-01

    Objective To measure the QOL in patients with AECOPD and the frequency of potential risk factors, and to evaluate the association of risk factors with poor QOL in patients with AECOPD. Methods A study sample of 196 patients with moderate to severe COPD admitted for acute exacerbations to two large general hospitals were studied. The St George QOL (SGQOL) scale, socio-demographic, clinical and patient care characteristics, including depression and spirometry were ascertained in the stable state before discharge and at one-month post discharge. Results There was a high prevalence of current or ex-heavy smokers, depression and consumption of psychotropic drugs, and low prevalence of care giver support, pulmonary rehabilitation and vaccination. The mean scores for the different domains were 55.9 for Symptoms; 65.1 for Activity; 32.9 for Impact; and the mean of overall Total scores was 46.5. Multiple regression analysis showed that CMH, male, depression, previous frequent hospital readmissions and poor therapy compliance were independently related to worse Symptoms Scores. Previous frequent readmissions, depression, severe dyspnea and older age (>72 years) were related to worse Activity Scores of SGQOL. Depression, previous frequent readmissions, severe dyspnea, long COPD duration(≥5years) and severe smoking were related to worse Impact Scores of SGQOL. Depression, previous frequent readmissions, severe dyspnea and long COPD duration(≥5years) were independently related to worse Total Scores of SGQOL.Conclusion Poor QOL in patients with COPD exacerbation was associated with disease severity, psychosocial and health care factors which are modifiable.

  2. Long-acting muscarinic antagonists for the prevention of exacerbations of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Jones, Paul W

    2015-06-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD. Current guidelines recommend long-acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD. PMID:25801643

  3. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen.

    Science.gov (United States)

    Fishman, D A; Kearns, A; Chilukuri, K; Bafetti, L M; O'Toole, E A; Georgacopoulos, J; Ravosa, M J; Stack, M S

    1998-01-01

    Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the

  4. 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.

  5. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Wedzicha, Jadwiga A; Brill, Simon E; Allinson, James P; Donaldson, Gavin C

    2013-01-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the 'frequent exacerbator' phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities. PMID:23945277

  6. 77 FR 59929 - Guidance for Industry on Acute Bacterial Exacerbations of Chronic Bronchitis in Patients With...

    Science.gov (United States)

    2012-10-01

    ... August 22, 2008 (73 FR 49684), which in turn revised the draft guidance for industry entitled ``Acute... ``Acute Bacterial Exacerbations of Chronic Bronchitis in Patients With Chronic Obstructive Pulmonary... treatment of acute bacterial exacerbations of chronic bronchitis in patients with chronic...

  7. 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.

  8. A trial of beclomethasone/formoterol in COPD using EXACT-PRO to measure exacerbations

    DEFF Research Database (Denmark)

    Singh, Dave; Kampschulte, Jorg; Wedzicha, Jadwiga A;

    2013-01-01

    comparison of extrafine beclomethasone dipropionate and formoterol in a combination inhaler with extrafine formoterol; the co-primary end-points are exacerbation rates over 48 weeks and improvement in forced expiratory volume in 1 s over 12 weeks. The traditional physician diagnosis of exacerbations is a co...

  9. The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma.

    Science.gov (United States)

    Hewitt, Richard; Farne, Hugo; Ritchie, Andrew; Luke, Emma; Johnston, Sebastian L; Mallia, Patrick

    2016-04-01

    Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus-bacteria interactions and therapeutic advances. PMID:26611907

  10. 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.

  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. PMID:27535650

  12. 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

    A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin represents the standard of care for the treatment of chronic hepatitis C according to current guidelines. It is not established which of the two licensed products (peginterferon alpha-2a or peginterferon alfa-2b...... 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......-2a is associated with higher SVR than peginterferon alfa-2b. However, the paucity of evidence on adverse events curbs the decision to definitively recommend one peginterferon over the other, because any potential benefit must outweigh the risk of harm....

  13. An extremely rare case of delusional parasitosis in a chronic hepatitis C patient during pegylated interferon alpha-2b and ribavirin treatment

    Institute of Scientific and Technical Information of China (English)

    Geert Robaeys; Jozef De Bie; Marc Van Ranst; Frank Buntinx

    2007-01-01

    During treatment of chronic hepatitis C patients with interferon and ribavirin, a lot of side effects are described. Twenty-three percent to 44% of patients develop depression. A minority of patients evolve to psychosis. To the best of our knowledge, no cases of psychogenic parasitosis occurring during interferon therapy have been described in the literature. We present a 49-year-old woman who developed a delusional parasitosis during treatment with pegylated interferon alpha-2b weekly and ribavirin. She complained of seeing parasites and the larvae of fleas in her stools. This could not be confirmed by any technical examination. All the complaints disappeared after stopping pegylated interferon alpha-2b and reappeared after restarting it. She had a complete sustained viral response.

  14. Diet-induced hyperhomocysteinemia exacerbates vascular reverse remodeling of balloon-injured arteries in rat

    Institute of Scientific and Technical Information of China (English)

    GUO Yan-hong; CHEN Feng-ying; WANG Gui-song; CHEN Li; GAO Wei

    2008-01-01

    Background While hyperhomocysteinemia is associated with an increased risk of cardiovascular diseases,the effect of hyperhomocysteinemia on the vascular adventitia and vessel remodeling has not been clearly demonstrated.We investigated the effect of the hyperhomocysteinemia on adventitial hyperplasia and vascular remodeling following balloon injury in rats and the underlying mechanisms.Methods Rats were fed with diet containing methionine for 4 weeks to increase plasma homocysteine before balloon injury.Vascular geometrical changes were assessed at different time points following balloon injury.The collagen deposition was determined by picrosirius red staining and immunohistochemical staining.Results When compared with normal diet group,moderate hyperhomocysteinemia in methionine diet group significantly exacerbated adventitial hyperplasia at clay 7 and collagen deposition mainly in the adventitia at day 28 following balloon injury.The increased plasma homocysteine level significantly increased collagen deposition in the adventitia.There was a negative correlation (r=0.698;P <0.01) between the luminal area and the collagen content in the adventitia on day 28 following balloon injury.In cultured adventitial fibroblasts isolated from rat aorta,100 μmol/L L-homocysteine (L-Hcy) significantly down-regulated matrix metalloproteinase-2 activity by 43% as determined by in vitro gelatin zymography (P <0.05) and up-regulated the expression of collagen type 1 by 187% (P <0.05) assessed by Western blotting.Conclusions Hyperhomocysteinemia exacerbated vascular constrictive remodeling by accelerated neointima formation and collagen accumulation in the adventitia.Increased collagen deposition may be the underlying mechanism.

  15. Kupffer cell-mediated exacerbation of methimazole-induced acute liver injury in rats.

    Science.gov (United States)

    Akai, Sho; Uematsu, Yasuaki; Tsuneyama, Koichi; Oda, Shingo; Yokoi, Tsuyoshi

    2016-05-01

    Methimazole (MTZ), an anti-thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ-induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine-mediated immune responses; however, there is little evidence for immune responses associated with MTZ-induced liver injury in rats. To investigate species differences in MTZ-induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high-mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune-related genes significantly increased in BSO- and MTZ-treated rats, but the change in Th2-related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK) proteins were accompanied by an increase in Toll-like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1-TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell-mediated immune responses are crucial factors for the exacerbation of MTZ-induced liver injury in rats, indicating apparent species differences in the immune-mediated exacerbation of liver injury between mice and rats. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26177832

  16. Exacerbations of asthma during pregnancy: Impact on pregnancy complications and outcome.

    Science.gov (United States)

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

    2016-05-01

    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 unit and longer postpartum hospital stay. Asthma has been associated with increased risk of intrauterine growth retardation, small-for-gestational age, low birth weight, infant hypoglycaemia and preterm birth, but more recent prospective studies have not revealed significant associations with regard 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. PMID:26467747

  17. 16S rRNA sequences of Bartonella bacilliformis and cat scratch disease bacillus reveal phylogenetic relationships with the alpha-2 subgroup of the class Proteobacteria.

    OpenAIRE

    O'Connor, S P; Dorsch, M; Steigerwalt, A G; Brenner, D J; Stackebrandt, E

    1991-01-01

    The primary structures of 16S rRNAs of Bartonella bacilliformis, an isolate of the cat scratch disease (CSD) bacillus, and a strain phenotypically similar to the CSD bacillus were determined by reverse transcriptase sequencing. These microorganisms were found to be members of the alpha-2 subgroup of the class Proteobacteria. The sequence from B. bacilliformis was most closely related to the rRNA of Rochalimaea quintana (91.7% homology), the etiologic agent of trench fever. The sequence from t...

  18. 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

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ethanol, 2,2â²2â³-nitrilotris... Substances § 721.5356 Ethanol, 2,2′2″-nitrilotris-, compound with alpha-2,4,6-tris (1-phenylethyl)phenyl... subject to reporting. (1) The chemical substance identified as ethanol, 2,2′2″-nitrilotris-, compound...

  19. Comparison of synthesis and secretion of plasma albumin, fibrinogen and alpha 2-macroglobulin by slices of Morris hepatomas and rat liver.

    OpenAIRE

    Koj, A.

    1980-01-01

    Slices of rat liver or Morris Hepatomas 5123 GVI and 7777 were incubated for 2 h with 14C-leucine. Newly synthesized labelled proteins were determined independently in the medium and tissue homogenate, total protein after precipitation with trichloro-acetic acid, and albumin, fibrinogen and alpha 2-macroglobulin after immuno-precipitation with monospecific antisera. In comparison with control rat liver, synthesis and secretion of albumin were reduced four- to five-fold in the 2 heptomas exami...

  20. Presynaptic autoinhibition of central noradrenaline release in vitro: operational characteristics and effects of drugs acting at alpha-2 adrenoceptors in the presence of uptake inhibition

    International Nuclear Information System (INIS)

    Functional characteristics of autoinhibition of central noradrenaline release were studied in the presence of uptake inhibition. Slices of rat cerebral cortex were incubated with [3H]noradrenaline, superfused and field-stimulated with 1 to 16 monophasic rectangular pulses at frequencies of 0.02 to 40 Hz. 1) Substances acting at presynaptic alpha-2 adrenoceptors were identified as antagonists, agonists or partial agonists by comparing their effects on 3H-overflow evoked by a single pulse or by two consecutive pulses at 1 Hz. 2) When 1 to 16 pulses were delivered at 0.02, 0.08, 0.3 and 1 Hz to stimulate outflow of tritium, a frequency-dependent suppression of responses to the second and the following pulses was observed. In the presence of the alpha-2 adrenoceptor antagonist idazoxan (10(-6) M), comparable amounts of tritium were released by the first stimulus and each of the following stimuli at 0.02 Hz. In contrast, at 0.08, 0.3 and 1 Hz the amount of 3H-overflow evoked by the first pulse was not reached in response to the following pulses. Clonidine (10(-6) M) diminished markedly the response to the first as well as to the following stimuli, irrespective of the frequency of stimulation. 3) Using two consecutive pulses delivered with decreasing pulse intervals, an apparent reduction or complete abolition of autoinhibition was observed at intervals of less than 100 msec, indicated by reduction or loss of the facilitatory effects of alpha-2 adrenoceptor antagonists. The present results provide detailed insights in operational characteristics of alpha-2 adrenoceptor-mediated autoinhibition and the effects of drugs on this regulatory mechism

  1. Acute-phase reaction induces a specific complex between hepatic nuclear proteins and the interleukin 6 response element of the rat alpha 2-macroglobulin gene.

    OpenAIRE

    Hattori, M; Abraham, L J; Northemann, W; Fey, G H

    1990-01-01

    Interleukin 6 (IL-6) was established as a transcriptional inducer of the rat alpha 2-macroglobulin gene, a prototype liver acute-phase gene. Maximum induction occurred when the 5' flanking sequences of this gene (position -209 to -43) directed expression from the gene's own TATA box and transcription start site. Removal of the hexanucleotide CTGGGA (position -164 to -159) abolished 60-70% of the hormonal induction in FAO1 rat hepatoma cells. This hexanucleotide was defined as the IL-6 respons...

  2. Current asthma control predicts future risk of asthma exacerbation: a 12-month prospective cohort study

    Institute of Scientific and Technical Information of China (English)

    WEI Hua-hua; ZHOU Ting; WANG Lan; ZHANG Hong-ping; FU Juan-juan; WANG Lei; JI Yu-lin; WANG Gang

    2012-01-01

    Background The performance of asthma control test (ACT) at baseline for predicting future risk of asthma exacerbation has not been previously demonstrated.This study was designed to explore the ability of the baseline ACT score to predict future risk of asthma exacerbation during a 12-month follow-up.Methods This post hoc analysis included data from a 12-month prospective cohort study in patients with asthma (n=290).The time to the first asthma exacerbation was analyzed and the association between baseline ACT scores and future risk of asthma exacerbation was calculated as adjusted odds ratio (OR) using Logistic regression models.Further,sensitivity and specificity were estimated at each cut-point of ACT scores for predicting asthma exacerbations.Results The subjects were divided into three groups,which were uncontrolled (U,n=128),partly-controlled (PC,n=111),and well controlled (C,n=51) asthma.After adjustment,the decreased ACT scores at baseline in the U and PC groups were associated with an increased probability of asthma exacerbations (OR 3.65 and OR 5.75,respectively),unplanned visits (OR 8.03 and OR 8.21,respectively) and emergency visits (OR 20.00 and OR 22.60,respectively) over a 12-month follow-up period.The time to the first asthma exacerbation was shorter in the groups with U and PC asthma (all P<0.05).The baseline ACT of 20 identified as the cut-point for screening the patients at high risk of asthma exacerbations had an increased sensitivity of over 90.0% but a lower specificity of about 30.0%.Conclusion Our findings indicate that the baseline ACT score with a high sensitivity could rule out patients at low risk of asthma exacerbations and oredict future risk of asthma exacerbations in clinical practice.

  3. Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease

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    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.

  4. Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice.

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    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.

  5. Exacerbations of childhood asthma and ozone pollution in Atlanta

    Energy Technology Data Exchange (ETDEWEB)

    White, M.C.; Etzel, R.A.; Lloyd, C. (Centers for Disease Control and Prevention, Atlanta, GA (United States)); Wilcox, W.D. (Emory Univ. School of Medicine, Atlanta, GA (United States))

    1994-04-01

    Asthma prevalence and mortality due to asthma have been increasing during the last decade, and both the rates and the increases in rates have been higher for blacks than whites and higher for children than adults. Whether environmental factors such as air pollution contribute to these increases is unknown. The purpose of this study was to examine the relationship between emergency visits to a hospital for childhood asthma and exposure to ozone in an indigent, predominantly black population. Data were collected by abstracting clinical records for all children with asthma or reactive airway disease in one public hospital during the summer of 1990. From June 1, 1990, to August 31, 1990, 609 visits were made by children aged 1 to 16 years to an emergency clinic for treatment of asthma or reactive airway disease. Monitoring data indicated that maximum ozone levels equalled or exceeded 0.11 ppm on 6 days during the study period. The average number of visits for asthma or reactive airway disease was 37% higher on the days after those 6 days (from 6:00 PM to 6:00 PM the next day) than on other days (95% Cl, RR = 1.02-1.73). The results of the study suggest that among black children from low-income families, asthma may be exacerbated following periods of high ozone pollution. 45 refs., 1 fig., 4 tabs.

  6. Influence of Pseudomonas aeruginosa on exacerbation in patients with bronchiectasis

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    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.

  7. Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury

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    Bohacek Ivan

    2012-08-01

    Full Text Available Abstract Background Using a live imaging approach, we have previously shown that microglia activation after stroke is characterized by marked and long-term induction of the Toll-like receptor (TLR 2 biophotonic signals. However, the role of TLR2 (and potentially other TLRs beyond the acute innate immune response and as early neuroprotection against ischemic injury is not well understood. Methods TLR2−/− mice were subjected to transient middle cerebral artery occlusion followed by different reperfusion times. Analyses assessing microglial activation profile/innate immune response were performed using in situ hybridization, immunohistochemistry analysis, flow cytometry and inflammatory cytokine array. The effects of the TLR2 deficiency on the evolution of ischemic brain injury were analyzed using a cresyl violet staining of brain sections with appropriate lesion size estimation. Results Here we report that TLR2 deficiency markedly affects post-stroke immune response resulting in delayed exacerbation of the ischemic injury. The temporal analysis of the microglia/macrophage activation profiles in TLR2−/− mice and age-matched controls revealed reduced microglia/macrophage activation after stroke, reduced capacity of resident microglia to proliferate as well as decreased levels of monocyte chemotactic protein-1 (MCP-1 and consequently lower levels of CD45high/CD11b+ expressing cells as shown by flow cytometry analysis. Importantly, although acute ischemic lesions (24 to 72 h were smaller in TLR2−/− mice, the observed alterations in innate immune response were more pronounced at later time points (at day 7 after initial stroke, which finally resulted in delayed exacerbation of ischemic lesion leading to larger chronic infarctions as compared with wild-type mice. Moreover, our results revealed that TLR2 deficiency is associated with significant decrease in the levels of neurotrophic/anti-apoptotic factor Insulin-like growth factor-1 (IGF-1

  8. 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

  9. Tratamento clínico do linfangioma com alfa-2a-interferon Treatment of lymphangioma with interferon-alpha-2a

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    Reynaldo J.S.P. de Souza

    2001-04-01

    Full Text Available OBJETIVO: descrever os resultados obtidos com o uso do alfa-2a-interferon no tratamento de pacientes pediátricos com linfangiomas irressecáveis ou refratários a outros tratamentos. MÉTODO: após revisão da literatura sobre a patogenia e os tratamentos disponíveis para os linfangiomas, utilizamos o alfa-2a-interferon na dosagem de 3 milhões de unidades/m2/dia, via subcutânea, para tratamento de pacientes que apresentavam lesões irressecáveis. Para avaliar o grau de resposta e os efeitos colaterais foram realizadas avaliações clínicas e laboratoriais periódicas. RESULTADOS: observamos que os 6 pacientes com linfangiomas irressecáveis que utilizaram alfa-2a-interferon obtiveram uma resposta clínica satisfatória associada a efeitos colaterais mínimos. Cinco destes evoluíram com regressão parcial de suas lesões e 1 com estabilização da doença. CONCLUSÃO: concluímos que o alfa-2a-interferon constitui uma das armas disponíveis para o tratamento dos linfangiomas inoperáveis na infância.OBJECTIVE: to describe the results of the use of alpha-2a-interferon in the treatment of inoperable childhood lymphangiomas refractory to other therapeutic management. METHOD: we reviewed the literature about pathogenic events and the treatments available for lymphangiomas. Based on that, we used alpha-2a-interferon at a dose of 3 million units/m2/day administered subcutaneously to patients with inoperable disease and no response to other treatments. We conducted periodic clinical and laboratory control to evaluate the response and the adverse reactions to alpha-2a-interferon administration. RESULTS: we observed that the 6 patients with inoperable lymphangiomas who used alpha-2a-interferon had a satisfactory clinical response associated with minimum adverse reactions. Of these patients, 5 had partial regression of their lesions, and 1 remained stable. CONCLUSION: alpha-2a-interferon may be one more available treatment for inoperable childhood

  10. Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice.

    Science.gov (United States)

    Lu, Tong; Jiang, Bin; Wang, Xiao-Li; Lee, Hon-Chi

    2016-09-01

    The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes. PMID:27574914

  11. 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.

  12. Exacerbations of chronic obstructive pulmonary disease: when are antibiotics indicated? A systematic review

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    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.

  13. Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

    International Nuclear Information System (INIS)

    Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17β-estradiol (E2). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E2-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E2 pellets, co-exposure to quercetin did not protect rats from E2-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E2-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E2 group relative to those in the E2 group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F2α (8-iso-PGF2α) levels as a marker of oxidant stress showed that quercetin did not decrease E2-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E2-induced oxidant stress and may exacerbate breast carcinogenesis in E2-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E2 and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E2 and chronic exposure to oxidant stress as a result of metabolic redox cycling to estrogen metabolites, and thus quercetin may exacerbate E2-induced breast tumors in female

  14. Rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury.

    Science.gov (United States)

    García-Arroyo, Fernando E; Cristóbal, Magdalena; Arellano-Buendía, Abraham S; Osorio, Horacio; Tapia, Edilia; Soto, Virgilia; Madero, Magdalena; Lanaspa, Miguel A; Roncal-Jiménez, Carlos; Bankir, Lise; Johnson, Richard J; Sánchez-Lozada, Laura-Gabriela

    2016-07-01

    Recurrent dehydration, such as commonly occurs with manual labor in tropical environments, has been recently shown to result in chronic kidney injury, likely through the effects of hyperosmolarity to activate both vasopressin and aldose reductase-fructokinase pathways. The observation that the latter pathway can be directly engaged by simple sugars (glucose and fructose) leads to the hypothesis that soft drinks (which contain these sugars) might worsen rather than benefit dehydration associated kidney disease. Recurrent dehydration was induced in rats by exposure to heat (36°C) for 1 h/24 h followed by access for 2 h to plain water (W), a 11% fructose-glucose solution (FG, same composition as typical soft drinks), or water sweetened with noncaloric stevia (ST). After 4 wk plasma and urine samples were collected, and kidneys were examined for oxidative stress, inflammation, and injury. Recurrent heat-induced dehydration with ad libitum water repletion resulted in plasma and urinary hyperosmolarity with stimulation of the vasopressin (copeptin) levels and resulted in mild tubular injury and renal oxidative stress. Rehydration with 11% FG solution, despite larger total fluid intake, resulted in greater dehydration (higher osmolarity and copeptin levels) and worse renal injury, with activation of aldose reductase and fructokinase, whereas rehydration with stevia water had opposite effects. In animals that are dehydrated, rehydration acutely with soft drinks worsens dehydration and exacerbates dehydration associated renal damage. These studies emphasize the danger of drinking soft drink-like beverages as an attempt to rehydrate following dehydration. PMID:27053647

  15. 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.

  16. Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock

    Directory of Open Access Journals (Sweden)

    L.L. Li

    2014-05-01

    Full Text Available 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.

  17. Risk of Severe Acute Exacerbation of Chronic HBV Infection Cancer Patients Who Underwent Chemotherapy and Did Not Receive Anti-Viral Prophylaxis.

    Directory of Open Access Journals (Sweden)

    Chih-An Shih

    Full Text Available Reactivation of HBV replication with an increase in serum HBV DNA and alanine aminotransferase (ALT activity has been reported in 20-50% of hepatitis B carriers undergoing cytotoxic chemotherapy for cancer treatment. Manifestation of HBV reactivation ranges from asymptomatic self-limiting hepatitis to severe progressive hepatic failure and fatal consequences.To investigate the risk of severe acute exacerbation of chronic HBV infection in HBsAg-positive cancer patients with solid tumors or hematological malignancies who underwent chemotherapy without antiviral prophylaxis.A retrospective review of charts was conducted for HBsAg-positive cancer patients in our institution who underwent chemotherapy and did not receive anti-viral prophylaxis between the periods of July 2007 to January 2013. We investigate the incidence of severe acute exacerbation of chronic HBV infection if these patients with a variety of solid tumors and hematological malignancies.A total of 156 patients (hematological malignancies: 16; solid tumors: 140 were included. The incidence of severe acute HBV exacerbation in the patients with hematological malignancy was higher than that in solid tumors (25.0% [4/16] vs 4.3% [6/140]; P = 0.005. Additionally, patients receiving rituximab-based chemotherapy had higher acute exacerbation rate than those with non-rituximab-based chemotherapy (40.0% vs 4.1%, P = 0.001. Among the patients with solid tumors, the incidences of severe acute exacerbation of chronic HBV in hepatocellular carcinoma, colorectal cancer, lung cancer, breast cancer, gynecological cancer, urological tract cancer, head/neck cancer and other solid malignancies were 2.3%, 4.0%, 7.1%, 9.0%, 16.7%, 6.7%, 0% and 0%, respectively.Severe acute exacerbation of chronic HBV infection may occur in HBsAg-positive patients with a variety of solid tumors who received chemotherapy without adequate anti-viral prophylaxis. Hematological malignancy and rituximab-based chemotherapy are

  18. 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

    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 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 < 0.05) and...

  19. 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.

  20. CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids

    DEFF Research Database (Denmark)

    Dahlin, Amber; Denny, Joshua; Roden, Dan M;

    2015-01-01

    or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt...... candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P risk of exacerbations in both...... populations (OR = 1.07, 95% CI 1.03-1.11; joint P = 2.3 × 10(-06)). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778...

  1. 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...

  2. Bronchiectasis Exacerbations: The Role of Atypical Bacteria and Respiratory Syncytial Virus

    Directory of Open Access Journals (Sweden)

    Eugenios I Metaxas

    2015-01-01

    Full Text Available BACKGROUND: Aside from the known role of common bacteria, there is a paucity of data regarding the possible role of atypical bacteria and viruses in exacerbations of non-cystic fibrosis bronchiectasis.

  3. 14C-labeled pulegone and metabolites binding to alpha2u-globulin in kidneys of male F-344 rats.

    Science.gov (United States)

    Ferguson, Ling-Jen Chen; Lebetkin, Edward H; Lih, Fred B; Tomer, Kenneth B; Parkinson, Horace D; Borghoff, Susan J; Burka, Leo T

    2007-09-01

    Pulegone is a major constituent of pennyroyal oil and a minor component of peppermint oil. Pulegone is biotransformed to menthofuran and menthones (diastereomeric menthone and isomenthone) in pennyroyal and peppermint as well as in rodents. Pulegone and menthofuran are hepatotoxic to rodents, and menthones are less toxic. The metabolism and disposition of pulegone and menthofuran were previously studied in rodents, and higher concentrations of pulegone- and menthofuran-derived radioactivity were observed in male than female rat kidney. One explanation is the association of pulegone and metabolites with a male rat-specific protein, alpha2u-globulin. To test this hypothesis, male and female rats were dosed orally with 14C-labeled pulegone (80 mg/kg, 120 microCi/kg) or menthofuran (60 mg/kg, 120 microCi/kg) or menthones (80 mg/kg, 120 microCi/kg) in corn oil, and the kidney cytosol was prepared 24 h after dosing. An equilibrium dialysis experiment showed that in all three studies the radioactivity was associated with kidney cytosol proteins of male but not female rats. The chemicals present in the male rat kidney cytosol after dialysis were extracted with dichloromethane and characterized by high-performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC-MS). All parent compounds were detected, and the metabolites characterized included piperitone from pulegone or menthones treatment, menthones and possibly 8-hydroxymenthones from pulegone treatment, and mintlactones (diastereomeric mintlactone and isomintlactone) and 7a-hydroxymintlactone from menthofuran treatment. Analysis of the male rat kidney cytosol by a gel filtration column demonstrated that the retention was due to reversible binding of these chemicals with the male rat-specific protein alpha2u-globulin. However, binding of pulegone and/or metabolites to alpha2u-globulin did not produce accumulation of this protein in the kidney. PMID:17687727

  4. Climate change exacerbates interspecific interactions in sympatric coastal fishes.

    Science.gov (United States)

    Milazzo, Marco; Mirto, Simone; Domenici, Paolo; Gristina, Michele

    2013-03-01

    Biological responses to warming are presently based on the assumption that species will remain within their bioclimatic envelope as environmental conditions change. As a result, changes in the relative abundance of several marine species have been documented over the last decades. This suggests that warming may drive novel interspecific interactions to occur (i.e. invasive vs. native species) or may intensify the strength of pre-existing ones (i.e. warm vs. cold adapted). For mobile species, habitat relocation is a viable solution to track tolerable conditions and reduce competitive costs, resulting in 'winner' species dominating the best quality habitat at the expense of 'loser' species. Here, we focus on the importance of warming in exacerbating interspecific interactions between two sympatric fishes. We assessed the relocation response of the cool-water fish Coris julis (a potential 'loser' species in warming scenarios) at increasing relative dominance of the warm-water fish Thalassoma pavo (a 'winner' species). These wrasses are widespread in the Mediterranean nearshore waters. C. julis tolerates cooler waters and is found throughout the basin. T. pavo is common along southern coasts, although the species range is expanding northwards as the Mediterranean warms. We surveyed habitat patterns along a thermo-latitudinal gradient in the Western Mediterranean Sea and manipulated seawater temperature under two scenarios (present day vs. projected) in outdoor arenas. Our results show that the cool-water species relocates to a less-preferred seagrass habitat and undergoes lower behavioural performance in warmer environments, provided the relative dominance of its warm-water antagonist is high. The results suggest that expected warming will act synergistically with increased relative dominance of a warm-water species to cause a cool-water fish to relocate in a less-preferred habitat within the same thermal environment. Our study highlights the complexity of climate

  5. 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

  6. 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.; Mortensen, K.

    1991-01-01

    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......-macroglobulin can best be explained by that of a Gaussian coil with a radius of gyration equal to 9.44 nm. These data indicate that the so-called non-covalent interaction of alpha-2-macroglobulin probably is more complicated than just a pure hydrophobic interaction. Finally, it is also shown that the...

  7. Distribution of alpha-2-HS-glycoprotein (AHSG) phenotypes in Cabo Verde (west Africa): description of a new allele, AHSG*32.

    Science.gov (United States)

    Caeiro, J L; Parra, E J; Yuasa, I; Teixeira, C; Llano, C

    1994-04-01

    The genetic polymorphism of alpha-2-HS-glycoprotein (AHSG) was studied in the population of Cabo Verde (West Africa), using isoelectric focusing in polyacrylamide gels followed by immunofixation-silver stain. AHSG frequencies are reported for the first time in a subsaharan African population. In addition to the common variants, AHSG 1 and AHSG 2, five AHSG variants were observed, including a new variant, tentatively designated AHSG 32. The allele frequencies were, AHSG*1: 0.7289, AHSG*2: 0.2111, AHSG*10: 0.0276, AHSG*3: 0.0162, AHSG*11: 0.0081, AHSG*22: 0.0065, AHSG*32:0.0016. PMID:7619771

  8. Dynamic associations of transcription factors with the rat liver nuclear matrix are functionally related to differential alpha-2-macroglobulin gene expression

    OpenAIRE

    Dinić Svetlana; Mihailović Mirjana; Ivanović-Matić Svetlana; Uskoković Aleksandra; Grdović Nevena; Vidaković Melita; Poznanović G.

    2008-01-01

    Participation of the nuclear matrix in regulation of alpha-2-macroglobulin (α2M) gene transcription during rat liver development and the acute-phase (AP) response are examined. DNA affinity chromatography of fetal and adult liver internal nuclear matrix proteins under basal and AP conditions with the α2M gene promoter (-852/+12) and immunoblot analysis revealed diverse patterns of association of transcription factors with the nuclear matrix. HNF-6, C/EBPα, and STAT5b were involved in basal an...

  9. Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene.

    OpenAIRE

    Hocke, G M; Barry, D.; Fey, G H

    1992-01-01

    One class of genes coding for the acute-phase proteins (acute-phase genes) is induced by interleukin 6 (IL-6) through the human transcription factor NF-IL-6 and its rat homolog IL-6-DBP/LAP. A second class, represented by the rat alpha 2 macroglobulin gene, utilizes a different IL-6 response element (IL-6-RE) and different DNA-binding proteins interacting with this element, the so-called IL-6-RE binding proteins (IL-6 RE-BPs). Human Hep3B and HepG2 hepatoma, U266 myeloma, and CESS lymphoblast...

  10. A phase I pilot study of pelvic radiation and alpha-2a interferon in patients with locally advanced or recurrent rectal cancer

    International Nuclear Information System (INIS)

    Purpose: The purpose of this pilot study was to determine the maximum tolerated dose of alpha-2a interferon given by subcutaneous injection and combined with high dose pelvic radiation for locally advanced or recurrent rectal cancer. Methods and Materials: In this Phase I pilot study, patients with locally advanced, unresectable, or recurrent rectal cancer with or without distant metastases received external beam pelvic radiotherapy over 5 to 6 weeks combined with escalating doses of alpha-2a interferon. Interferon was escalated in increments of 3 million units for each patient cohort, starting at 3 million units subcutaneously 3 days weekly during pelvic radiation. Radiotherapy consisted of 44 Gy (2 Gy fractions) to the pelvis followed by a boost of 6 Gy or 16 Gy to gross pelvic tumor, depending on the presence or absence of small bowel in the boost field, respectively. Between 1991 and 1993, 10 patients were treated on this study, five with locally advanced and five with locally recurrent rectal cancer. Results: At 6 million units of interferon, Grade 3 (WHO criteria) toxicities were as follows: diarrhea (one), leukopenia (one), and neutropenia (one). One patient died of a massive GI bleed at this dose level. Death was not felt to be treatment related. The maximum tolerated dose of interferon was 3 million units three times weekly with radiation. Three patients had unusual complications at 4, 6, and 6 months possibly related to treatment. The first had a right distal ureteric stricture with a right urinoma. The second had a sudden left foot drop that has remained stable. The third had sudden onset of bilateral lower extremity paraplegia with spontaneous resolution. Conclusions: The maximally tolerated dose of interferon alpha-2a given three times weekly during pelvic radiation was 3 million units based on acute side effects. Nevertheless, even at this dose level there were three unusual subacute complications possibly related to treatment. Caution is advised when

  11. COPD management costs according to the frequency of COPD exacerbations in UK primary care [Corrigendum

    OpenAIRE

    Punekar YS; Shukla A; Müllerova H

    2014-01-01

    Punekar YS, Shukla A, Müllerova H. International Journal of COPD. 2014;9:65–73.On page 69, note that there was an error in the bar graph shown in Figure 1. The group with no exacerbations during the 12 months of follow-up should have a zero value for the cost of exacerbations. The corrected figure is provided below.View original paper by Punekar and colleagues.

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

    OpenAIRE

    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

    2014-01-01

    Background 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. Methods 49 hospitalised exacerbated COPD patients were randomized (1:1) to undergo physiotherapy alone or physiotherapy with the addition of whole body vibratio...

  13. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease

    OpenAIRE

    Wedzicha, J A; Brill, S E; Allinson, J. P.; Donaldson, G C

    2013-01-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the fr...

  14. Review of ventilatory techniques to optimize mechanical ventilation in acute exacerbation of chronic obstructive pulmonary disease

    OpenAIRE

    Reddy, Raghu M.; Guntupalli, Kalpalatha K.

    2007-01-01

    Chronic obstructive pulmonary disease (COPD) is a major global healthcare problem. Studies vary widely in the reported frequency of mechanical ventilation in acute exacerbations of COPD. Invasive intubation and mechanical ventilation may be associated with significant morbidity and mortality. A good understanding of the airway pathophysiology and lung mechanics in COPD is necessary to appropriately manage acute exacerbations and respiratory failure. The basic pathophysiology in COPD exacerbat...

  15. Comparison of Canadian versus United States Emergency Department Visits for Chronic Obstructive Pulmonary Disease Exacerbation

    OpenAIRE

    Rowe, Brian H; Rita K Cydulka; Chu-Lin Tsai; Sunday Clark; Douglas Sinclair; Camargo, Carlos A.

    2008-01-01

    INTRODUCTION: Despite the frequency of emergency department (ED) visits for chronic obstructive pulmonary disease (COPD) exacerbation, little is known about practice variation in EDs.OBJECTIVES: To examine the differences between Canadian and United States (US) COPD patients, and the ED management they receive.METHODS: A prospective multicentre cohort study was conducted involving 29 EDs in the US and Canada. Using a standard protocol, consecutive ED patients with COPD exacerbations were inte...

  16. Analgesia and Addiction in Emergency Department Patients with Acute Pain Exacerbations

    OpenAIRE

    Gorchynski, Julie; Kelly, Kevin

    2005-01-01

    Introduction: There is ongoing controversy regarding the appropriate use of narcotic analgesia for patients presenting frequently to the emergency department (ED) with subjective acute exacerbations of pain. "Are we treating pain or enabling addiction?” Objectives: To determine whether the presence o f specific factors could be used to identify adults complaining of acute exacerbations of pain for suspected drug addiction, to estimate the percentage of drug addicted patients, to asse...

  17. The Most Common Detected Bacteria in Sputum of Patients with the Acute Exacerbation of COPD

    OpenAIRE

    Cukic, Vesna

    2013-01-01

    Introduction: Acute exacerbation of COPD (AECOPD) may be triggered by infection with bacteria or viruses or by environmental pollutants; the cause of about one-third of exacerbations cannot be identified. Objective: To determine the most common bacteria in sputum culture of patients with AECOPD hospitalized in Intensive care unit of Clinic for pulmonary disease and TB “Podhrastovi” in the 2012. Material and methods: This is a retrospective analysis of sputum bacterial cultures of patients wit...

  18. Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients

    Directory of Open Access Journals (Sweden)

    Christini Takemi Emori

    2014-12-01

    Full Text Available Introduction:There is scarce information regarding clinical evolution of HBV infection in renal transplant patients.Aims: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.Materials and methods:HBV infected renal transplant patients who underwent regular follow-up visits at 6-month intervals were included in the study. The criteria adopted to characterize exacerbation were: ALT >5 × ULN and/or >3 × baseline level. Predictive factors of exacerbation evaluated were age, gender, time on dialysis, type of donor, post-transplant time, ALT, HBeAg, HBV-DNA, HCV-RNA, immunosuppressive therapy, and use of antiviral prophylaxis.Results:140 HBV-infected renal transplant patients were included (71% males; age 46 ±10 years; post-renal transplant time 8 ±5 years. During follow-up, 25% (35/140 of the patients presented exacerbation within 3.4 ±3 years after renal transplant. Viral replication was observed in all patients with exacerbation. Clinical and/or laboratory signs of hepatic insufficiency were present in 17% (6/35 of the patients. Three patients died as a consequence of liver failure. In univariate analysis variables associated with exacerbation were less frequent use of prophylactic/preemptive lamivudine and of mycophenolate mofetil. Lamivudine use was the only variable independently associated with exacerbation, with a protective effect.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.

  19. An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study

    Directory of Open Access Journals (Sweden)

    Mallia Patrick

    2006-09-01

    Full Text Available Abstract Background Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation. Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood. Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists. Methods We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients. We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II. Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage. Results All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage. These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV1. There were no severe exacerbations or other adverse events. Conclusion Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation.

  20. Three-month treatment response and exacerbation in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Lee, Jung Su; Rhee, Chin Kook; Yoo, Kwang Ha; Lee, Ji-Hyun; Yoon, Ho Il; Kim, Tae-Hyung; Kim, Woo Jin; Lee, JinHwa; Lim, Seong Yong; Park, Tai Sun; Lee, Jae Seung; Lee, Sei Won; Lee, Sang-Do; Oh, Yeon-Mok

    2015-01-01

    The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients. PMID:25552883

  1. The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD

    Directory of Open Access Journals (Sweden)

    Barbara P Yawn

    2010-06-01

    Full Text Available Barbara P Yawn1, Ibrahim Raphiou2, Judith S Hurley3, Anand A Dalal21Olmsted Medical Center, University of Minnesota, Rochester, Minnesota, USA; 2GlaxoSmithKline, Research Triangle Park, North Carolina, USA; 3Hurley Consulting, Placitas, New Mexico, USAAbstract: Exacerbations contribute significantly to the morbidity of COPD, leading to an accelerated decline in lung function, reduced functional status, reduced health status and quality of life, poorer prognosis and increased mortality. Prevention of exacerbations is thus an important goal of COPD management. In patients with COPD, treatment with a combination of the inhaled corticosteroid fluticasone propionate (250 μg and the long-acting β2-agonist salmeterol (50 μg in a single inhaler (250/50 μg is an effective therapy option that has been shown to reduce the frequency of exacerbations, to improve lung function, dyspnea and health status, and to be relatively cost-effective as a COPD maintenance therapy. Importantly, results of various studies suggest that fluticasone propionate and salmeterol have synergistic effects when administered together that improve their efficacy in controlling symptoms and reducing exacerbations. The present non-systematic review summarizes the role of fluticasone propionate/salmeterol combination therapy in the prevention of exacerbations of COPD and its related effects on lung function, survival, health status, and healthcare costs.Keywords: Advair, COPD, disease exacerbation, fluticasone propionate, salmeterol, combination drug therapy

  2. Bronchiectasis exacerbations: The role of atypical bacteria and respiratory syncytial virus

    Science.gov (United States)

    Metaxas, Eugenios I; Balis, Evangelos; Papaparaskevas, Joseph; Spanakis, Nicholas E; Tatsis, Georgios; Tsakris, Athanasios

    2015-01-01

    BACKGROUND: Aside from the known role of common bacteria, there is a paucity of data regarding the possible role of atypical bacteria and viruses in exacerbations of non-cystic fibrosis bronchiectasis. OBJECTIVE: To explore the possible role of atypical bacteria (namely, Mycoplasma pneumoniae and Chlamydophila pneumoniae) and respiratory syncytial virus (RSV) as causative agents of bronchiectasis exacerbations. METHODS: A cohort of 33 patients was studied over a two-year period (one year follow-up for each patient). Polymerase chain reaction for the detection of M pneumoniae, C pneumoniae and RSV in bronchoalveolar lavage samples were performed during all visits. Antibody titres (immunoglobulin [Ig]M and IgG) against the aforementioned pathogens were also measured. In addition, cultures for common bacteria and mycobacteria were performed from the bronchoalveolar lavage samples. RESULTS: Fifteen patients experienced a total of 19 exacerbations during the study period. Although RSV was detected by polymerase chain reaction during stable visits in four patients, it was never detected during an exacerbation. M pneumoniae and C pneumoniae were never detected at stable visits or during exacerbations. IgM antibody titres for these three pathogens were negative in all patient visits. CONCLUSIONS: Atypical pathogens and RSV did not appear to be causative agents of bronchiectasis exacerbations. PMID:25874735

  3. AAL exacerbates pro-inflammatory response in macrophages by regulating Mincle/Syk/Card9 signaling along with the Nlrp3 inflammasome assembly

    OpenAIRE

    Zhang, Zhijun; He, Long; Hu, Shuang; Wang, Yi; Lai, Qiaohong; Yang, Ping; Yu, Qilin; Zhang, Shu; Xiong, Fei; Simsekyilmaz, Sakine; Ning, Qin; Li, Jinxiu; Zhang, Dongshan; Zhang, Hongliang; Xiang, Xudong

    2015-01-01

    Previously, we demonstrated that Agrocybe aegerita lectin (AAL), a galectin isolated from edible mushroom Agrocybe aegerita, exerts potent anti-tumor activity, while the mechanisms by which AAL suppresses tumor growth are yet to be elucidated. Here, we conducted studies with focus for its impact on the cecal ligation and puncture (CLP)-induced innate immune response. Administration of AAL significantly exacerbated the severity of CLP-induced septic shock as manifested the increased lethality....

  4. Prevention of COPD exacerbation by lysozyme: a double-blind, randomized, placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Fukuchi Y

    2016-04-01

    Full Text Available Yoshinosuke Fukuchi,1 Koichiro Tatsumi,2 Hiromasa Inoue,3 Yukinori Sakata,4 Kai Shibata,4 Hideaki Miyagishi,4 Yasuhiro Marukawa,4 Masakazu Ichinose5 1Department of Respiratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, 2Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, 3Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 4Eisai Co., Ltd., Tokyo, 5Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan Background/aim: Lysozyme (mucopeptide N-acetyl-muramyl hydrolase is widely used as a mucolytic and anti-inflammatory agent in Japan. We evaluated the effects of long-term lysozyme administration on COPD exacerbation. Methods: In a 1-year, randomized, double-blind, placebo-controlled, parallel trial, patients with moderate-to-severe COPD and one or more episodes of COPD exacerbation in the previous year before enrollment were selected. Lysozyme (270 mg or placebo was administered orally for 52 weeks as an add-on to the standard therapies such as bronchodilators. COPD exacerbation, pulmonary function, and COPD assessment test scores were analyzed. An exacerbation was defined as worsening of more than one symptom of COPD (cough, sputum volume, purulent sputum, or breathlessness leading to a change in medication. The primary endpoint was exacerbation rate. Results: A total of 408 patients were randomly assigned to the lysozyme and placebo groups. The baseline characteristics were similar between the two groups. The exacerbation rate was not significantly different between the two groups (1.4 vs 1.2; P=0.292, Poisson regression. However, a subgroup analysis showed that lysozyme might reduce exacerbation rate in patients with airway-dominant phenotype (1.2 vs 1.6. Moreover, the median time to first exacerbation was longer in patients with airway-dominant phenotype in the lysozyme group than that

  5. Terbufos-sulfone exacerbates cardiac lesions in diabetic rats: a sub-acute toxicity study.

    Science.gov (United States)

    Nurulain, Syed M; Shafiullah, Mohamed; Yasin, Javed; Adem, Abdu; Kaabi, Juma Al; Tariq, Saeed; Adeghate, Ernest; Ojha, Shreesh

    2016-06-01

    Organophosphorus compounds (OPCs) have a wide range of applications, from agriculture to warfare. Exposure to these brings forward a varied kind of health issues globally. Terbufos is one of the leading OPCs used worldwide. The present study investigates the cardiac effect of no observable dose of a metabolite of terbufos, terbufos-sulfone (TS), under non-diabetic and streptozotocin-induced diabetic condition. One hundred nanomoles per rat (1/20 of LD50) was administered intraperitoneally to adult male Wister rats daily for fifteen days. The left ventricle was collected for ultrastructural changes by transmission electron microscopy. The blood samples were collected for biochemical tests including RBC acetylcholinesterase, creatinine kinase (CK), lactate dehydrogenase (LDH), cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, ALT, AST, and GGT. The study revealed about 10 % inhibition of RBC-AChE in two weeks of TS treatment in non-diabetic rats whereas RBC-AChE activity was significantly decreased in diabetic TS treated rats. CK, LDH, and triglycerides were significantly higher in diabetic TS treated rats. Electron microscopy of the heart showed derangement and lesions of the mitochondria of cardiomyocytes in the TS treated groups. The present study concludes that a non-lethal dose of TS causes cardiac lesions which exacerbate under diabetic condition. Biochemical tests confirmed the ultrastructural changes. It is concluded that a non-lethal dose of TS may be a risk factor for a cardiovascular disease, which may be fatal under diabetic condition. PMID:27331300

  6. CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids.

    Science.gov (United States)

    Dahlin, Amber; Denny, Joshua; Roden, Dan M; Brilliant, Murray H; Ingram, Christie; Kitchner, Terrie E; Linneman, James G; Shaffer, Christian M; Weeke, Peter; Xu, Hua; Kubo, Michiaki; Tamari, Mayumi; Clemmer, George L; Ziniti, John; McGeachie, Michael J; Tantisira, Kelan G; Weiss, Scott T; Wu, Ann Chen

    2015-12-01

    Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case-control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10(-05)). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03-1.11; joint P = 2.3 × 10(-06)). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples

  7. Costs and persistence of alpha-2 adrenergic agonists versus carbonic anhydrase inhibitors, both associated with prostaglandin analogues, for glaucoma as recorded by The United Kingdom General Practitioner Research Database

    Directory of Open Access Journals (Sweden)

    Philippe Denis

    2008-06-01

    Full Text Available Philippe Denis1, Antoine Lafuma2, Gilles Berdeaux31Hôpital Edouard Herriot, Lyon, France; 2Cemka, Bourg-la-Reine, France; 3Alcon France, Rueil-Malmaison, FranceAbstract: The persistence and costs of carbonic anhydrase inhibitors + prostaglandin analogues (CAIs + PGAs vs alpha-2 adrenergic agonists + prostaglandin analogues (alpha-2 agonists + PGAs were compared, based on The United Kingdom General Practitioner Research Database. Patients with a diagnosis of ocular hypertension, glaucoma, or treated for this, were selected. Selected patients were prescribed CAIs + PGAs or alpha-2 agonists + PGAs. Treatment failure was defined as a prescription change (adding, removing, or replacing glaucoma treatment, or initiating laser or surgery. Times to treatment failure were compared with a Cox model adjusted by a propensity score. Mean patient age was 69.0 years and 47.6% were males. Treatment failure at 1 year was experienced by 58.8% receiving CAIs + PGAs and 66.0% of patients receiving alpha-2 agonists + PGAs (p < 0.001. The hazard ratio for failure was 0.82 (p < 0.001 in favor of CAIs + PGAs after adjusting on age, gender, comorbidities, and duration of follow-up. Adjusted annual costs of glaucoma management did not differ significantly between treatments, £440.63 with alpha-2 agonists + PGAs and £413.37 with CAIs + PGAs. CAIs + PGAs therapies appear more persistent than alpha-2 agonist + PGA in everyday clinical practice, at a similar cost.Keywords: glaucoma, alpha-2 adrenergic agonists, carbonic anhydrase inhibitor, prostaglandin, effectiveness economics, costs

  8. Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma

    Directory of Open Access Journals (Sweden)

    Amatullah Hajera

    2011-02-01

    Full Text Available Abstract Background Arginase overexpression contributes to airways hyperresponsiveness (AHR in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR. Methods To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA and challenged with nebulized PBS (OVA/PBS or OVA (OVA/OVA for three consecutive days (sub-acute model or 12 weeks (chronic model, which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O3, or HEPA-filtered air (FA, for 4 hours. After the CAP+O3 exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization. Results Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O3-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O3-induced increase in AHR in both models. Conclusions This study demonstrates that arginase is upregulated following environmental exposures in murine models of

  9. The feasibility of a home-based sedentary behaviour intervention for hospitalised chronic obstructive pulmonary disease (COPD patients: Sitting and ExacerbAtions Trial (COPD-SEAT

    Directory of Open Access Journals (Sweden)

    Mark Orme

    2015-10-01

    COPD-SEAT will be one of the first trials aimed at reducing sedentary behaviour at home in patients hospitalised for an acute exacerbation of COPD. This trial will provide valuable insight into the feasibility of implementing an at-home technology-based feedback intervention for reducing sedentary behaviour into patients existing care. Findings will inform a future large-scale trial acting as an adjuvant to pulmonary rehabilitation.

  10. 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.

  11. Dynamic associations of transcription factors with the rat liver nuclear matrix are functionally related to differential alpha-2-macroglobulin gene expression

    Directory of Open Access Journals (Sweden)

    Dinić Svetlana

    2008-01-01

    Full Text Available Participation of the nuclear matrix in regulation of alpha-2-macroglobulin (α2M gene transcription during rat liver development and the acute-phase (AP response are examined. DNA affinity chromatography of fetal and adult liver internal nuclear matrix proteins under basal and AP conditions with the α2M gene promoter (-852/+12 and immunoblot analysis revealed diverse patterns of association of transcription factors with the nuclear matrix. HNF-6, C/EBPα, and STAT5b were involved in basal and C/EBPβ, STAT1, and STAT3 in AP-stimulated α2M expression. These findings support the assumption that transcription factor-nuclear matrix interactions serve to channel gene regulatory proteins to DNA sequences.

  12. Hb Sallanches [alpha104(G11)Cys-->Tyr, TGC-->TAC (alpha2)]: an unstable hemoglobin variant found in an Indian child.

    Science.gov (United States)

    Dash, Sumitra; Harano, Keiko; Menon, Santosh

    2006-01-01

    We report the fourth observation of Hb Sallanches [alpha104(G11)Cys-->Tyr, TGC-->TAC (alpha2)], an unstable alpha chain variant of intermediate severity in the homozygous state. Heterozygosity occasionally produces mild hypochromia and microcytosis in some patients. A balanced beta/alpha ratio, found in previously reported cases, points to unstable alphabeta dimers formed as a result of the Cys-->Tyr substitution at the alpha1beta1 contact site in this hemoglobin (Hb) variant. Our patient, and the previous two of the three cases reported in patients of Pakistani origin, points to a common population stock, separated by the mass population migration which occurred during the partition of Pakistan and India in 1947. PMID:16840231

  13. Complementary roles of glycoprotein VI and alpha2beta1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo

    DEFF Research Database (Denmark)

    Kuijpers, Marijke J E; Schulte, Valerie; Bergmeier, Wolfgang; Lindhout, Theo; Brakebusch, Cord; Offermanns, Stefan; Fässler, Reinhard; Heemskerk, Johan W M; Nieswandt, Bernhard

    2003-01-01

    function in ex vivo thrombus formation during perfusion of whole blood over collagen. With mice deficient in GPVI or blocking antibodies, we found that GPVI was indispensable for collagen-dependent Ca2+ mobilization, exposure of PS, and aggregation of platelets. Deficiency of integrin beta1 reduces the......Platelets interact vigorously with subendothelial collagens that are exposed by injury or pathological damage of a vessel wall. The collagen-bound platelets trap other platelets to form aggregates, and they expose phosphatidylserine (PS) required for coagulation. Both processes are implicated in...... the formation of vaso-occlusive thrombi. We previously demonstrated that the immunoglobulin receptor glycoprotein VI (GPVI), but not integrin alpha2beta1, is essential in priming platelet-collagen interaction and subsequent aggregation. Here, we report that these receptors have yet a complementary...

  14. Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited

    DEFF Research Database (Denmark)

    Keene, O N; Calverley, P M A; Jones, P W;

    2008-01-01

    Various statistical methods have been used to measure the impact of treatment on chronic obstructive pulmonary disease (COPD) exacerbations. Poisson regression has recently been recommended as the appropriate method but the model does not satisfactorily account for variability between patients....... In contrast, use of a negative binomial model, which corresponds to assuming a separate Poisson parameter for each patient, offers a more appealing approach. The present paper reviews analysis methods, with particular focus on the negative binomial model. To illustrate the differences that arise from using...... estimates of exacerbation rates on each treatment arm are higher and the confidence intervals for comparisons between treatments are wider, but the overall conclusions of TRISTAN and ISOLDE regarding reduction of exacerbations remain unchanged. The negative binomial approach appears to provide a better fit...

  15. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults

    DEFF Research Database (Denmark)

    Bjermer, Leif; Bisgaard, Hans; Bousquet, Jean;

    2003-01-01

    patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol. PARTICIPANTS: Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50......OBJECTIVES: To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which......-90% predicted, and a beta agonist improvement of > or = 12% in FEV1. MAIN OUTCOME MEASURES: The primary end point was the percentage of patients with at least one asthma exacerbation. RESULTS: 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19...

  16. Mesalamine induced symptom exacerbation of ulcerative colitis: Case report and brief discussion

    Institute of Scientific and Technical Information of China (English)

    Maneesh; Kumar; Gupta; Scott; Pollack; John; J; Hutchings

    2010-01-01

    This paper describes a rare case in which the oral ad-ministration of mesalamine resulted in the exacerbation of ulcerative colitis (UC) in a patient who was previously responsive to mesalamine and whose colitis had been in remission for eight years. Mesalamine and other 5-ami-nosalicylic acid compounds are the mainstay of treatment for UC; however up to 8% of patients are unable to take the medications due to intolerance or hypersensitivity reactions. Common drug reactions are fever, nausea, di-arrhea and abdominal pain; however, exacerbation of UC has rarely been reported. This study highlights the impor-tance of ruling out mesalamine as the causative agent in cases of UC exacerbations.

  17. Premenstrual Exacerbation of Life-Threatening Asthma: Effect of Gonadotrophin Releasing Hormone Analogue Therapy

    Directory of Open Access Journals (Sweden)

    Alun L Edwards

    1996-01-01

    Full Text Available Variability in the severity of asthma during various phases of the menstrual cycle has been frequently suspected. However, the hormonal changes that might affect mediators of bronchospasm have yet to be elucidated. The case of a 41-year-old woman suffering from longstanding asthma with life-threatening exacerbations is reported. The patient was treated with buserelin, a gonadotropin releasing hormone (GnRH analogue, which created a temporary chemical menopause and thus permitted diagnosis of a premenstrual exacerbation of asthma and offered insight into potential therapy. GnRH analogues may therefore be of value in assessing women with severe asthma suspected to vary with the menstrual cycle. The addition of estrogens and progestins at the same time as treatment with GnRH analogue may be of value in determining the role of these hormones in the pathogenesis of menstrually related exacerbations of asthma.

  18. Management of pulmonary exacerbations in cystic fibrosis: still an unmet medical need in clinical practice.

    Science.gov (United States)

    Justicia, José Luis; Solé, Amparo; Quintana-Gallego, Esther; Gartner, Silvia; de Gracia, Javier; Prados, Concepción; Máiz, Luis

    2015-04-01

    Pulmonary exacerbation (PEx) is a hallmark of cystic fibrosis. Although several criteria have been proposed for the definition of PEx, no consensus has yet been reached. Very often, many PEx cases go unreported. A standardized and validated definition is needed to reduce variability in clinical practice. The pathophysiology of recurrent episodes remains unclear, and both onset and risk are multifactorial. PEx leads to increased healthcare costs, impaired quality of life and a cycle in which PEx causes loss of lung function, which predisposes to further episodes. The number of episodes affects survival. Although early diagnosis and aggressive treatment are highly recommended, measures to prevent the emergence of new PEx are even more important. In particular, inhaled antibiotics administered under new treatment schedules could play a key role in preventing exacerbations and thus delay decline in lung function and reduce mortality. The primary objective is zero exacerbations. PMID:25692532

  19. Aspirin-Exacerbated Diseases: Advances in Asthma with Nasal Polyposis, Urticaria, Angioedema, and Anaphylaxis.

    Science.gov (United States)

    Stevens, Whitney; Buchheit, Kathleen; Cahill, Katherine N

    2015-12-01

    Aspirin-exacerbated diseases are important examples of drug hypersensitivities and include aspirin-exacerbated respiratory disease (AERD), aspirin- or non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema, and aspirin- or NSAID-induced anaphylaxis. While each disease subtype may be distinguished by unique clinical features, the underlying mechanisms that contribute to these phenotypes are not fully understood. However, the inhibition of the cyclooxygenase-1 enzyme is thought to play a significant role. Additionally, eosinophils, mast cells, and their products, prostaglandins and leukotrienes, have been identified in the pathogenesis of AERD. Current diagnostic and treatment strategies for aspirin-exacerbated diseases remain limited, and continued research focusing on each of the unique hypersensitivity reactions to aspirin is essential. This will not only advance the understanding of these disease processes, but also lead to the subsequent development of novel therapeutics that patients who suffer from aspirin-induced reactions desperately need. PMID:26475526

  20. A study of air pollutants and acute asthma exacerbations in urban areas: status report

    International Nuclear Information System (INIS)

    Details of a study to investigate the possible roles of a variety of hazardous air pollutants on asthma exacerbations at ambient air concentrations. - A study to try to better understand the interactions between various air contaminants and acute asthma exacerbations is described. The study evaluates temporal associations between a panel of air contaminants and acute asthmatic exacerbations as measured by emergency room visits for asthma in communities in the Bronx and Manhattan in New York City (NYC). In addition, ambient levels of various air pollutants in two NYC communities are being compared. Almost 2 years of daily data have been collected for most of the air contaminants to be investigated. The air contaminants measured include gaseous compounds (ozone, sulfur dioxide, nitrogen oxides, aldehydes, nitrous acid, nitric acid, hydrochloric acid and ammonia), particulate matter components (metals, elemental and organic carbon, sulfate, hydrogen ion, pollen, mold spores and particle mass and number)

  1. Efficacy and Tolerability of Eight Antimicrobial Regimens in the Outpatient Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease

    OpenAIRE

    Jordan Minov; Jovanka Karadzinska-Bislimovska; Tatjana Petrova; Kristin Vasilevska; Sasho Stoleski; Dragan Mijakoski; Snezhana Risteska-Kuc

    2014-01-01

    BACKGROUND: Bacterial infections are considered as the most important cause of exacerbations in patients with chronic obstructive pulmonary disease. AIM: To compare the efficacy and tolerability of eight antibiotics empirically administered for outpatient treatment of exacerbations of COPD. METHODS: We performed an observational study including 343 COPD patients with probable bacterial exacerbation (Group A and Group B COPD patients) managed in an outpatient setting. Eight antibiotic ...

  2. Endocytic activity of Sertoli cells grown in bicameral culture chambers

    International Nuclear Information System (INIS)

    Immature rat Sertoli cells were cultured for 7 to 14 days on Millipore filters impregnated with a reconstituted basement membrane extract in dual-environment (bicameral) culture chambers. Electron microscopy of the cultured cells revealed the presence of rod-shaped mitochondria, Golgi apparatus, rough endoplasmic reticulum, and Sertoli-Sertoli tight junctions, typical of these cells in vivo. The endocytic activity of both the apical and basal surfaces of the Sertoli cells was examined by either adding alpha 2-macroglobulin (alpha 2-M) conjugated to 20 nm gold particles to the apical chamber or by adding 125I labeled alpha 2-M to the basal chamber. During endocytosis from the apical surface of Sertoli cells, the alpha 2-M-gold particles were bound initially to coated pits and then internalized into coated vesicles within 5 minutes. After 10 minutes, the alpha 2-M-gold was found in multi-vesicular bodies (MVBs) and by 30 minutes it was present in the lysosomes. The proportion of alpha 2-M-gold found within endocytic cell organelles after 1 hour of uptake was used to estimate the approximate time that this ligand spent in each type of organelle. The alpha 2-M-gold was present in coated pits, coated vesicles, multivesicular bodies, and lysosomes for approximately 3, 11, 22, and 24 minutes, respectively. This indicates that the initial stages of endocytosis are rapid, whereas MVBs and lysosomes are relatively long-lived

  3. Expiratory flow limitation relates to symptoms during COPD exacerbations requiring hospital admission

    Science.gov (United States)

    Jetmalani, Kanika; Timmins, Sophie; Brown, Nathan J; Diba, Chantale; Berend, Norbert; Salome, Cheryl M; Wen, Fu-Qiang; Chen, Peng; King, Gregory G; Farah, Claude S

    2015-01-01

    Background Expiratory flow limitation (EFL) is seen in some patients presenting with a COPD exacerbation; however, it is unclear how EFL relates to the clinical features of the exacerbation. We hypothesized that EFL when present contributes to symptoms and duration of recovery during a COPD exacerbation. Our aim was to compare changes in EFL with symptoms in subjects with and without flow-limited breathing admitted for a COPD exacerbation. Subjects and methods A total of 29 subjects with COPD were recruited within 48 hours of admission to West China Hospital for an acute exacerbation. Daily measurements of post-bronchodilator spirometry, resistance, and reactance using the forced oscillation technique and symptom (Borg) scores until discharge were made. Flow-limited breathing was defined as the difference between inspiratory and expiratory respiratory system reactance (EFL index) greater than 2.8 cmH2O·s·L−1. The physiological predictors of symptoms during recovery were determined by mixed-effect analysis. Results Nine subjects (31%) had flow-limited breathing on admission despite similar spirometry compared to subjects without flow-limited breathing. Spirometry and resistance measures did not change between enrolment and discharge. EFL index values improved in subjects with flow-limited breathing on admission, with resolution in four patients. In subjects with flow-limited breathing on admission, symptoms were related to inspiratory resistance and EFL index values. In subjects without flow-limited breathing, symptoms related to forced expiratory volume in 1 second/forced vital capacity. In the whole cohort, EFL index values at admission was related to duration of stay (Rs=0.4, P=0.03). Conclusion The presence of flow-limited breathing as well as abnormal respiratory system mechanics contribute independently to symptoms during COPD exacerbations. PMID:25999709

  4. Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study

    Directory of Open Access Journals (Sweden)

    Goldring James JP

    2010-10-01

    Full Text Available Abstract Background The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this. Methods 40 patients with moderate-severe COPD collected daily data on changes in symptoms, heart-rate (HR, oxygen saturation (SpO2 and peak-expiratory flow (PEF over a total of 2705 days. 31 patients had data suitable for baseline analysis, and 13 patients experienced an exacerbation. Data were expressed as multiples of the standard deviation (SD observed from each patient when stable. Results In stable COPD, the SD for HR, SpO2 and PEF were approximately 5 min-1, 1% and 10l min-1. There were detectable changes in all three variables just prior to exacerbation onset, greatest 2-3 days following symptom onset. A composite Oximetry Score (mean magnitude of SpO2 fall and HR rise distinguished exacerbation onset from symptom variation (area under receiver-operating characteristic curve, AUC = 0.832, 95%CI 0.735-0.929, p = 0.003. In the presence of symptoms, a change in Score of ≥1 (average of ≥1SD change in both HR and SpO2 was 71% sensitive and 74% specific for exacerbation onset. Conclusion We have defined normal variation of pulse oximetry variables in a small sample of patients with COPD. A composite HR and SpO2 score distinguished exacerbation onset from symptom variation, potentially facilitating prompt therapy and providing validation of such events in clinical trials.

  5. Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers

    Directory of Open Access Journals (Sweden)

    Litonjua Augusto A

    2011-06-01

    Full Text Available Abstract Background Personalized health-care promises tailored health-care solutions to individual patients based on their genetic background and/or environmental exposure history. To date, disease prediction has been based on a few environmental factors and/or single nucleotide polymorphisms (SNPs, while complex diseases are usually affected by many genetic and environmental factors with each factor contributing a small portion to the outcome. We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics. Methods In this study, using emergency room visits or hospitalizations as the definition of a severe asthma exacerbation, we first identified a list of top Genome Wide Association Study (GWAS SNPs ranked by Random Forests (RF importance score for the CAMP (Childhood Asthma Management Program population of 127 exacerbation cases and 290 non-exacerbation controls. We predict severe asthma exacerbations using the top 10 to 320 SNPs together with age, sex, pre-bronchodilator FEV1 percentage predicted, and treatment group. Results Testing in an independent set of the CAMP population shows that severe asthma exacerbations can be predicted with an Area Under the Curve (AUC = 0.66 with 160-320 SNPs in comparison to an AUC score of 0.57 with 10 SNPs. Using the clinical traits alone yielded AUC score of 0.54, suggesting the phenotype is affected by genetic as well as environmental factors. Conclusions Our study shows that a random forests algorithm can effectively extract and use the information contained in a small number of samples. Random forests, and other machine learning tools, can be used with GWAS studies to integrate large numbers of predictors simultaneously.

  6. Outcomes of Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the United States, 1998–2008

    OpenAIRE

    Chandra, Divay; Stamm, Jason A.; Taylor, Brian; Ramos, Rose Mary; Satterwhite, Lewis; Krishnan, Jerry A.; Mannino, David; Sciurba, Frank C.; Holguín, Fernando

    2012-01-01

    Rationale: The patterns and outcomes of noninvasive, positive-pressure ventilation (NIPPV) use in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) nationwide are unknown.

  7. 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

    accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are...... the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are...

  8. COPD management costs according to the frequency of COPD exacerbations in UK primary care

    Directory of Open Access Journals (Sweden)

    Punekar YS

    2014-01-01

    Full Text Available Yogesh Suresh Punekar,1 Amit Shukla,2 Hana Müllerova31Global Health Outcomes, GlaxoSmithKline R&D, Uxbridge, UK; 2Worldwide Epidemiology, GlaxoSmithKline R&D, Upper Providence, PA, USA; 3Worldwide Epidemiology, GlaxoSmithKline R&D, Uxbridge, UKBackground: The economic burden of chronic obstructive pulmonary disease (COPD exacerbations is significant, but the impact of other sources on the overall cost of COPD management is largely unknown. We aimed to estimate overall costs for patients experiencing none, one, or two or more exacerbations per year in the UK.Methods: A retrospective cohort of prevalent COPD patients was identified in the Clinical Practice Research Datalink UK database. Patients with information recorded for at least 12 months before and after cohort entry date were included (first prevalent COPD diagnosis confirmed by spirometry on/after April 1, 2009. Patients were categorized as having none, one, or two or more moderate-to-severe COPD exacerbations in the 12 months after cohort entry and further classified by the Global initiative for chronic Obstructive Lung Disease (GOLD category of airflow obstruction and the Medical Research Council dyspnea scale. Study outcomes included counts of general practitioner interactions, moderate-severe COPD exacerbations, and non-COPD hospitalizations. Estimated resource use costs were calculated using National Health Service reference costs for 2010–2011.Results: The cohort comprised 58,589 patients (mean age 69.5 years, mean dyspnea grade 2.5, females 46.6%, current smokers 33.1%. The average total annual per patient cost of COPD management, excluding medications, was £2,108 for all patients and £1,523, £2,405, and £3,396 for patients experiencing no, one, or two or more moderate-to-severe exacerbations, respectively. General practitioner interactions contributed most to these annual costs, accounting for £1,062 (69.7%, £1,313 (54.6%, and £1,592 (46.9% in patients with no, one, or

  9. Management and survival of patients admitted with an exacerbation of COPD: comparison of two Danish patient cohorts

    DEFF Research Database (Denmark)

    Eriksen, Nanna; Vestbo, Jørgen

    2010-01-01

    discharged patients admitted in 2006-2007 with an exacerbation of chronic obstructive pulmonary disease from three respiratory departments. Data were collected from patient charts and compared with a replicate study done in 2001. RESULTS: The mean age was 72.1years; 61.7% were women. Mean forced expiratory...... volume in 1s was 37.6% of predicted. On admission, 11.3% were treated with non-invasive ventilation, and 84.3% were given systemic corticosteroids. In-hospital mortality was 4.7%. At discharge, treatment with inhaled corticosteroids or at least one long-acting bronchodilator was given to 86.7% and 89% of......months following discharge was 42.3%. Long-term oxygen treatment, treatment with anti-dysrhythmic drugs and lack of outpatient follow-up were independent predictors of 1-year mortality. Risk of readmission was increased with dependence in self-care activities, previous admissions and treatment with...

  10. Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration

    Directory of Open Access Journals (Sweden)

    Longato Lisa

    2010-03-01

    Full Text Available Abstract Background Type 2 diabetes mellitus (T2DM and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM. Hypothesis Limited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD or low fat (5%; LFD chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF deficiency and resistance in the context of neurodegeneration. Results HFD ± NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT, which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD ± NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3β (reflecting increased GSK-3β activity, glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats. Conclusions Early limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of

  11. Liquid fructose in pregnancy exacerbates fructose-induced dyslipidemia in adult female offspring.

    Science.gov (United States)

    Rodríguez, Lourdes; Panadero, María I; Rodrigo, Silvia; Roglans, Núria; Otero, Paola; Álvarez-Millán, Juan J; Laguna, Juan C; Bocos, Carlos

    2016-06-01

    Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and related events. Nevertheless, consumption of beverages sweetened with fructose is not regulated in gestation. Previously, we found that maternal fructose intake produces in the progeny, when fetuses, impaired leptin signaling and hepatic steatosis and then impaired insulin signaling and hypoadiponectinemia in adult male rats. Interestingly, adult females from fructose-fed mothers did not exhibit any of these disturbances. However, we think that, actually, these animals keep a programmed phenotype hidden. Fed 240-day-old female progeny from control, fructose- and glucose-fed mothers were subjected for 3weeks to a fructose supplementation period (10% wt/vol in drinking water). Fructose intake provoked elevations in insulinemia and adiponectinemia in the female progeny independently of their maternal diet. In accordance, the hepatic mRNA levels of several insulin-responsive genes were similarly affected in the progeny after fructose intake. Interestingly, adult progeny of fructose-fed mothers displayed, in response to the fructose feeding, augmented plasma triglyceride and NEFA levels and hepatic steatosis versus the other two groups. In agreement, the expression and activity for carbohydrate response element binding protein (ChREBP), a lipogenic transcription factor, were higher after the fructose period in female descendants from fructose-fed mothers than in the other groups. Furthermore, liver fructokinase expression that has been indicated as one of those responsible for the deleterious effects of fructose ingestion was preferentially augmented in that group. Maternal fructose intake does influence the adult female offspring's response to liquid fructose and so exacerbates fructose-induced dyslipidemia and hepatic steatosis. PMID:27142744

  12. Granulin exacerbates lupus nephritis via enhancing macrophage M2b polarization.

    Directory of Open Access Journals (Sweden)

    Xi Chen

    Full Text Available BACKGROUND AND AIMS: Lupus nephritis (LN, with considerable morbidity and mortality, is one of the most severe manifestations of systemic lupus erythematosus (SLE. Yet, the pathogenic mechanisms of LN have not been clearly elucidated, and efficient therapies are still in great need. Granulin (GRN, a multifunctional protein linked to inflammatory diseases, has recently been reported to correlate with the disease activity of autoimmune diseases. However, the role of GRN in the pathogenic process of LN still remains obscure. In this study, we explored its potential role and underlying mechanism in the pathogenesis of LN. METHODOLOGY/PRINCIPAL FINDINGS: We found that serum GRN levels were significantly up-regulated and were positively correlated with the severity of LN. Overexpression of GRN in vivo by transgenic injection remarkably exacerbated LN, whereas down-regulation of GRN with shRNA ameliorated LN, firmly demonstrating the critical role of GRN in the pathogenesis of LN. Notably, macrophage phenotype analysis revealed that overexpression of GRN could enhance macrophage polarization to M2b, a key mediator of the initiation and progression of LN. On the contrary, down-regulation of GRN resulted in impaired M2b differentiation, thus ameliorating LN. Moreover, we found that MAPK signals were necessary for the effect of GRN on macrophage M2b polarization. CONCLUSION/SIGNIFICANCE: We first demonstrated that GRN could aggravate lupus nephritis (LN via promoting macrophage M2b polarization, which might provide insights into the pathogenesis of LN as well as potential therapeutic strategies against LN.

  13. Tissue Injury and Related Mediators of Pain Exacerbation

    OpenAIRE

    Amaya, Fumimasa; Izumi, Yuta; Matsuda, Megumi; Sasaki, Mika

    2013-01-01

    Tissue injury and inflammation result in release of various mediators that promote ongoing pain or pain hypersensitivity against mechanical, thermal and chemical stimuli. Pro-nociceptive mediators activate primary afferent neurons directly or indirectly to enhance nociceptive signal transmission to the central nervous system. Excitation of primary afferents by peripherally originating mediators, so-called “peripheral sensitization”, is a hallmark of tissue injury-related pain. Many kinds of p...

  14. Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury.

    Science.gov (United States)

    Song, Yu; Pimentel, Corrin; Walters, Katherine; Boller, Lauren; Ghiasvand, Shabnam; Liu, Jing; Staley, Kevin J; Berdichevsky, Yevgeny

    2016-01-01

    Exogenous Insulin-Like Growth Factor-1 (IGF-1) is neuroprotective in animal models of brain injury, and has been considered as a potential therapeutic. Akt-mTOR and MAPK are downstream targets of IGF-1 signaling that are activated after brain injury. However, both brain injury and mTOR are linked to epilepsy, raising the possibility that IGF-1 may be epileptogenic. Here, we considered the role of IGF-1 in development of epilepsy after brain injury, using the organotypic hippocampal culture model of post-traumatic epileptogenesis. We found that IGF-1 was neuroprotective within a few days of injury but that long-term IGF-1 treatment was pro-epileptic. Pro-epileptic effects of IGF-1 were mediated by Akt-mTOR signaling. We also found that IGF-1 - mediated increase in epileptic activity led to neurotoxicity. The dualistic nature of effects of IGF-1 treatment demonstrates that anabolic enhancement through IGF-1 activation of mTOR cascade can be beneficial or harmful depending on the stage of the disease. Our findings suggest that epilepsy risk may need to be considered in the design of neuroprotective treatments for brain injury. PMID:27561791

  15. Targeting Protective Autophagy Exacerbates UV-Triggered Apoptotic Cell Death

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    Shih-Hwa Chiou

    2012-01-01

    Full Text Available Autophagy is activated by various stresses, including DNA damage, and previous studies of DNA damage-induced autophagy have focused on the response to chemotherapeutic drugs, ionizing radiation, and reactive oxygen species. In this study, we investigated the biological significance of autophagic response to ultraviolet (UV irradiation in A549 and H1299 cells. Our results indicated that UV induces on-rate autophagic flux in these cells. Autophagy inhibition resulting from the knockdown of beclin-1 and Atg5 reduced cell viability and enhanced apoptosis. Moreover, we found that ATR phosphorylation was accompanied by microtubule-associated protein 1 light chain 3B II (LC3B-II expression during the early phases following UV irradiation, which is a well-established inducer of ATR. Knocking down ATR further attenuated the reduction in LC3B-II at early stages in response to UV treatment. Despite the potential role of ATR in autophagic response, reduced ATR expression does not affect autophagy induction during late phases (24 and 48 h after UV treatment. The result is consistent with the reduced ATR phosphorylation at the same time points and suggests that autophagic response at this stage is activated via a distinct pathway. In conclusion, this study demonstrated that autophagy acts as a cytoprotective mechanism against UV-induced apoptosis and that autophagy induction accompanied with apoptosis at late stages is independent of ATR activation.

  16. [Hemoglobin Boumerdès alpha 2(37) (C2) Pro----Arg beta 2: a new variant of the alpha chain associated with hemoglobin S in an Algerian family].

    Science.gov (United States)

    Dahmane-Arbane, M; Blouquit, Y; Arous, N; Bardakdjian, J; Benamani, M; Riou, J; Benabadji, M; Rosa, J; Galacteros, F

    1987-01-01

    We report the first case of Hb Boumerdes, an alpha chain variant alpha 2(37) (C2) Pro----Arg beta 2, in an Algerian family. The propositus was also homozygous for the sickle cell gene. The abnormal hybrid Hb alpha 2Boum. beta 2S had an electrophoretic mobility on cellulose acetate pH 8.7 electrophoresis between those of Hb S and Hb A2. Its expression was about 16%. The alpha 2Boum. beta 2A fraction has a mobility between those of Hb F and Hb S. The effects of this mutation on Hb oxygen affinity and deoxy Hb S polymer formation were not studied. The propositus' sickle cell phenotype was benign. PMID:3438164

  17. Bacteriology in acute exacerbation of chronic obstructive pulmonary disease in patients admitted to hospital

    DEFF Research Database (Denmark)

    Larsen, Mette V; Janner, Julie H; Nielsen, Susanne D; Friis-Møller, Alice; Ringbaek, Thomas; Lange, Peter

    2009-01-01

    We investigated the bacterial flora and antimicrobial sensitivity in sputum from patients admitted to hospital with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in order to recommend the best empirical treatment for these patients. The survey was a retrospective study of a...... AECOPD we recommend either cefuroxime for intravenous treatment or amoxicillin-clavulanate for oral treatment....

  18. Acute exacerbations of chronic obstructive pulmonary disease provide a unique opportunity to take care of patients

    Directory of Open Access Journals (Sweden)

    Bianca Beghé

    2013-04-01

    Full Text Available Exacerbation of chronic obstructive pulmonary disease (ECOPD identifies the acute phase of COPD. The COPD patient is often frail and elderly with concomitant chronic diseases. This requires the physician not only looks at specific symptoms or organs, but to consider the patient in all his or her complexity.

  19. A collagen IV matrikine inhibits neutrophil recruitment in a mouse model of asthma exacerbation

    NARCIS (Netherlands)

    Weckmann, M.; Nissen, G.; Lundig, L.; Burgess, J.K.; Holst, O.; Wegmann, M.; Kopp, M.V.

    2015-01-01

    Background: Increased neutrophilic infiltration of the airways is a key feature of acute asthma exacerbation, which may lead to prolonged hospital admissions and an enhanced rate of decline of lung function. The increase in asthma severity in this subpobulation of patients is thought to be partially

  20. Reliever salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    Jenkins, Christine R.; Postma, Dirkje S.; Anzueto, Antonio R.; Make, Barry J.; Peterson, Stefan; Eriksson, Goran; Calverley, Peter M.

    2015-01-01

    Background: Debate exists regarding which endpoints most sensitively reflect day-to-day variation in chronic obstructive pulmonary disease (COPD) symptoms and are most useful in clinical practice to predict COPD exacerbations. We hypothesized that short-acting beta(2)-agonist (SABA) reliever use wou

  1. Aggression among Children with ADHD, Anxiety, or Co-Occurring Symptoms: Competing Exacerbation and Attenuation Hypotheses

    Science.gov (United States)

    Becker, Stephen P.; Luebbe, Aaron M.; Stoppelbein, Laura; Greening, Leilani; Fite, Paula J.

    2012-01-01

    Competing hypotheses for explaining the role of anxiety in the relation between attention-deficit/hyperactivity disorder (ADHD) symptoms and childhood aggression were evaluated. Two studies tested whether anxiety exacerbated, attenuated, or had no effect on the relation between ADHD and aggression subtypes among psychiatrically hospitalized…

  2. Trauma-focused treatment in PTSD patients with psychosis: Symptom exacerbation, adverse events, and revictimization

    NARCIS (Netherlands)

    Berg, D.P.G. van den; Bont, P.A.J.M. de; Vleugel, B.M. van der; Roos, C.J.A.M. de; Jongh, A. de; Minnen, A. van; Gaag, M. van der

    2016-01-01

    Objectives: 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). Methods: Analy

  3. Bronchodilator response following methacholine-induced bronchoconstriction predicts acute asthma exacerbations.

    Science.gov (United States)

    Park, Heung-Woo; Song, Woo-Jung; Chang, Yoon-Suk; Cho, Sang-Heon; Datta, Soma; Weiss, Scott T; Tantisira, Kelan G

    2016-07-01

    Methacholine bronchial provocation test provides the concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline (PC20). The dose-response slope (DRS), and other continuous indices of responsiveness (CIR; the percentage decline from the post-diluent baseline FEV1 after the last dose of methacholine), and per cent recovery index (PRI; the percentage increase from the maximally reduced FEV1 after bronchodilator inhalation) are alternative measures. The clinical relevance of these indices in predicting acute asthma exacerbations has not been fully evaluated.In two prospective cohorts of childhood and elderly asthmatics, baseline PC20, DRS, CIR and PRI were measured and evaluated as predictors of acute asthma exacerbations.We found that PRI was significantly related to the presence of asthma exacerbations during the first year of follow-up in both cohorts of childhood (p=0.025) and elderly asthmatics (p=0.003). In addition, PRI showed a significant association with the total number of steroid bursts during 4.3 years of follow-up in the cohort of childhood asthmatics (p=0.04).We demonstrated that PRI, an index of reversibility following methacholine-induced bronchoconstriction, was a good clinical predictor of acute exacerbations of asthma in both childhood and elderly asthmatics. PMID:27076579

  4. Prompt initiation of maintenance treatment following a COPD exacerbation: outcomes in a large insured population

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    Coutinho AD

    2016-06-01

    Full Text Available Anna D Coutinho,1 Tasneem Lokhandwala,1 Robert L Boggs,2 Anand A Dalal,2 Pamela B Landsman-Blumberg,1 Julie Priest,2 David A Stempel3 1Real World Evidence, Xcenda LLC, Palm Harbor, FL, 2US Health Outcomes, GlaxoSmithKline, Research Triangle Park, NC, 3US Medical Affairs, GlaxoSmithKline, Research Triangle Park, NC, USA Background: The aim of this study was to extend previous findings and determine the value of prompt initiation of maintenance treatment (MT following COPD exacerbations requiring hospitalization or an emergency department (ED visit.Patients and methods: Administrative claims data (collected between January 1, 2009 and June 30, 2012 from an employer-sponsored commercially insured population were retrospectively used to identify patients with a COPD exacerbation resulting in hospitalization or an ED visit. Patients initiating approved MT for COPD within 30 days of discharge/diagnosis (prompt were compared with those initiating MT within 31–180 days (delayed. COPD-related total, medical, and prescription drug costs during a 1-year follow-up period were evaluated using semilog ordinary least square regressions, controlling for baseline characteristics plus COPD-related costs from the previous year. The odds and number of subsequent COPD-related exacerbations during the follow-up were compared between the prompt and delayed cohorts using logistic regression and zero-inflated negative binomial models, respectively. Results: A total of 6,521 patients with a COPD-related hospitalization or an ED visit were included, of whom 4,555 received prompt MT and 1,966 received delayed MT. Adjusted COPD-related total and medical costs were significantly lower for the prompt MT than the delayed MT cohorts (US$3,931 vs US$4,857 and US$2,327 vs US$3,087, respectively; both P<0.010, as were COPD-related prescription costs (US$1,526 vs US$1,683, P<0.010 during the 1-year follow-up period. Patients receiving delayed MT were 68% more likely to have a

  5. Expiratory flow limitation relates to symptoms during COPD exacerbations requiring hospital admission

    Directory of Open Access Journals (Sweden)

    Jetmalani K

    2015-05-01

    Full Text Available Kanika Jetmalani,1,2 Sophie Timmins,1,3,4 Nathan J Brown,1,4 Chantale Diba,1,4 Norbert Berend,1,4,5 Cheryl M Salome,1,2,4 Fu-Qiang Wen,6 Peng Chen,6 Gregory G King,1-4 Claude S Farah1,2,7 1Woolcock Institute of Medical Research, 2Sydney Medical School, University of Sydney, 3Department of Respiratory Medicine, Royal North Shore Hospital, 4Cooperative Research Centre for Asthma and Airways, 5Department of Respiratory Research, George Institute of Global Health, Sydney, NSW, Australia; 6Department of Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, People’s Republic of China; 7Department of Respiratory Medicine, Concord Hospital, Sydney, NSW, Australia Background: Expiratory flow limitation (EFL is seen in some patients presenting with a COPD exacerbation; however, it is unclear how EFL relates to the clinical features of the exacerbation. We hypothesized that EFL when present contributes to symptoms and duration of recovery during a COPD exacerbation. Our aim was to compare changes in EFL with symptoms in subjects with and without flow-limited breathing admitted for a COPD exacerbation.Subjects and methods: A total of 29 subjects with COPD were recruited within 48 hours of admission to West China Hospital for an acute exacerbation. Daily measurements of postbronchodilator spirometry, resistance, and reactance using the forced oscillation technique and symptom (Borg scores until discharge were made. Flow-limited breathing was defined as the difference between inspiratory and expiratory respiratory system reactance (EFL index greater than 2.8 cmH2O·s·L-1. The physiological predictors of symptoms during recovery were determined by mixed-effect analysis.Results: Nine subjects (31% had flow-limited breathing on admission despite similar spirometry compared to subjects without flow-limited breathing. Spirometry and resistance measures did not change between enrolment and discharge. EFL index values improved

  6. A novel study design for antibiotic trials in acute exacerbations of COPD: MAESTRAL methodology

    Directory of Open Access Journals (Sweden)

    Wilson R

    2011-06-01

    Full Text Available Robert Wilson1, Antonio Anzueto2, Marc Miravitlles3, Pierre Arvis4, Geneviève Faragó5, Daniel Haverstock6, Mila Trajanovic5, Sanjay Sethi71Host Defence Unit, Royal Brompton Hospital, London, England, UK; 2University of Texas Health Science Center at San Antonio, South Texas Veterans HealthCare System, San Antonio, TX, USA; 3Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS, Ciber de Enfermedades Respiratorias (CIBERES, Hospital Clinic, Barcelona, Spain; 4Bayer HealthCare, Loos, France; 5Bayer Inc, Toronto, ON, Canada; 6Bayer HealthCare Pharmaceuticals, Montville, NJ, USA; 7Division of Pulmonary, Critical Care and Sleep Medicine, University at Buffalo, State University of New York, Buffalo, NY, USAAbstract: Antibiotics, along with oral corticosteroids, are standard treatments for acute exacerbations of chronic obstructive pulmonary disease (AECOPD. The ultimate aims of treatment are to minimize the impact of the current exacerbation, and by ensuring complete resolution, reduce the risk of relapse. In the absence of superiority studies of antibiotics in AECOPD, evidence of the relative efficacy of different drugs is lacking, and so it is difficult for physicians to select the most effective antibiotic. This paper describes the protocol and rationale for MAESTRAL (moxifloxacin in AECBs [acute exacerbation of chronic bronchitis] trial; www.clinicaltrials.gov: NCT00656747, one of the first antibiotic comparator trials designed to show superiority of one antibiotic over another in AECOPD. It is a prospective, multinational, multicenter, randomized, double-blind controlled study of moxifloxacin (400 mg PO [per os] once daily for 5 days vs amoxicillin/clavulanic acid (875/125 mg PO twice daily for 7 days in outpatients with COPD and chronic bronchitis suffering from an exacerbation. MAESTRAL uses an innovative primary endpoint of clinical failure: the requirement for additional or alternate treatment for the exacerbation at 8 weeks

  7. Systemic administration of the chemokine macrophage inflammatory protein 1α exacerbates inflammatory bowel disease in a mouse model

    OpenAIRE

    Pender, S L-F; Chance, V; Whiting, C V; Buckley, M; Edwards, M.; Pettipher, R; MacDonald, T T

    2005-01-01

    Introduction: Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1α (MIP-1α) exacerbates colitis in a mouse model.

  8. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

    NARCIS (Netherlands)

    Bonnelykke, Klaus; Sleiman, Patrick; Nielsen, Kasper; Kreiner-Moller, Eskil; Mercader, Josep M.; Belgrave, Danielle; den Dekker, Herman T.; Husby, Anders; Sevelsted, Astrid; Faura Tellez, Grissel; Mortensen, Li Juel; Paternoster, Lavinia; Flaaten, Richard; Molgaard, Anne; Smart, David E.; Thomsen, Philip F.; Rasmussen, Morten A.; Bonas-Guarch, Silvia; Holst, Claus; Nohr, Ellen A.; Yadav, Rachita; March, Michael E.; Blicher, Thomas; Lackie, Peter M.; Jaddoe, Vincent W. V.; Simpson, Angela; Holloway, John W.; Duijts, Liesbeth; Custovic, Adnan; Davies, Donna E.; Torrents, David; Gupta, Ramneek; Hollegaard, Mads V.; Hougaard, David M.; Hakonarson, Hakon; Bisgaard, Hans

    2014-01-01

    Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 yea

  9. Acute Exacerbations in COPD and their Control with Oral Immunisation with nontypeable Haemophilus influenzae

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    Robert eClancy

    2011-03-01

    Full Text Available Chronic obstructive pulmonary disease (COPD a term based on the demonstration of irreversible airways obstruction, introduced to unify a range of chronic progressive diseases of the airways consequent upon inhalation of toxins. While disease is initiated and progressed by inhaled toxins, an additional pathway of damage has emerged, with particular relevance to acute exacerbations. Exacerbations of disease due to an increase in the level of intra-bronchial inflammation have taken on a new significance as their role in determining both acute and chronic outcomes is better understood. This ‘second pathway’ of disease is a consequence of bacterial colonisation of damaged airways. Although bacteria have been linked to acute episodes in COPD over 50 years, only recently has quality data on antibiotic usage and the detection of ‘exacerbation isolates’ of non-typeable Haemophilus influenzae (NTHi provided strong argument in support of a pathogenic role. Yet a poor correlation between detection of colonising bacteria and clinical status remained a concern in attempts to explain a role for bacteria in a classical infection model. This presentation discusses a hypothesis that acute exacerbations reflect a T-cell dependent hypersensitivity response to colonising bacteria, with IL-17 dependent accumulation of neutrophils within the bronchus, as the main outcome measure. Critical protection against exacerbations following oral administration of NTHi, an immunotherapy that drives a TH17 Tcell response from Peyer’s patches, reduces the load of intrabronchial bacteria while preventing access of inhaled bacteria into small airways. Immunotherapy augments a physiological ‘loop’ based on aspiration of bronchus content into the gut. A second ‘hypersensitivity’ mechanism may cause bronchospasm – in both COPD and treatment-resistant asthma – due to specific IgE antibody directed against colonising bacteria, as oral NTHi abrogates wheeze in

  10. Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial

    Science.gov (United States)

    Hitchings, Andrew W; Lai, Dilys; Jones, Paul W; Baker, Emma H

    2016-01-01

    Background Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes. Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown. We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome. Methods This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations. Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo. The primary end point was mean in-hospital blood glucose concentration. Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool. Results 52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo). All were included in the primary end point analysis. The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference −0.9 mmol/L, 95% CI −2.1 to +0.3; p=0.273). No significant between-group differences were observed on any of the secondary end points. Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants. Conclusion Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes. Trial registration number ISRCTN66148745 and NCT01247870. PMID:26917577

  11. Mechanism of exacerbative effect of progesterone on drug-induced liver injury.

    Science.gov (United States)

    Toyoda, Yasuyuki; Endo, Shinya; Tsuneyama, Koichi; Miyashita, Taishi; Yano, Azusa; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-03-01

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is generally believed that women exhibit worse outcomes from DILI than men. Recently, we found that pretreatment of mice with estradiol attenuated halothane (HAL)-induced liver injury, whereas pretreatment with progesterone exacerbated it in female mice. To investigate the mechanism of sex difference of DILI, we focused on progesterone in this study. We found the exacerbating effect of progesterone in thioacetamide (TA), α-naphthylisothiocyanate, and dicloxacillin-induced liver injury only in female mice. Higher number of myeloperoxidase-positive mononuclear cells infiltrated into the liver and increased levels of Chemokine (C-X-C motif) ligand 1 and 2 (CXCL1 and CXCL2) and intercellular adhesion molecule-1 in the liver were observed. Interestingly, CXCL1 was slightly increased by progesterone pretreatment alone. Progesterone pretreatment increased the extracellular signal-regulated kinase (ERK) phosphorylation in HAL-induced liver injury. Pretreatment with U0126 (ERK inhibitor) significantly suppressed the exacerbating effect of progesterone and the expression of inflammatory mediators. In addition, pretreatment with gadolinium chloride (GdCl(3): inhibitor of Kupffer cells) significantly suppressed the exacerbating effect of progesterone pretreatment and the expression of inflammatory mediators. Moreover, posttreatment of RU486 (progesterone receptor antagonist) 1 h after the HAL or TA administration ameliorated the HAL- or TA-induced liver injury, respectively, in female mice. In conclusion, progesterone exacerbated the immune-mediated hepatotoxic responses in DILI via Kupffer cells and ERK pathway. The inhibition of progesterone receptor and decrease of the immune response may have important therapeutic implications in DILI. PMID:22157104

  12. Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease.

    Science.gov (United States)

    King, Nathaniel O; Anderson, Collin J; Dorval, Alan D

    2016-02-01

    Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. PMID:26498277

  13. Tabernaemontana divaricata leaves extract exacerbate burying behavior in mice

    Directory of Open Access Journals (Sweden)

    Raj Chanchal

    2015-06-01

    Full Text Available Objective: Tabernaemontana divaricata (TD from Apocynaceae family offers the traditional folklore medicinal benefits such as an anti-epileptic, anti-mania, brain tonic, and anti-oxidant. The aim of the present study was to evaluate the effect of ethanolic extract of TD leaves on burying behavior in mice. Materials and Methods:Mice were treated with oral administration (p.o. of ethanolic extract of TD (100, 200, and 300 mg/kg. Fluoxetine (FLX, a selective serotonin reuptake inhibitor was used as a reference drug. Obsessive-compulsive behavior was evaluated using marble-burying apparatus. Results:TD at doses of 100, 200, and 300 mg/kg dose-dependently inhibited the obsessive and compulsive behavior. The similar results were obtained from 5, 10, and 20 mg/kg of FLX. TD and FLX did not affect motor activity. Conclusion: The results indicated that TD and FLX produced similar inhibitory effects on marble-burying behavior.

  14. Did Bank Capital Regulation Exacerbate the Subprime Mortgage Crisis?

    Directory of Open Access Journals (Sweden)

    M. A. Petersen

    2009-01-01

    Full Text Available This contribution is the second in a series of papers on discrete-time modeling of bank capital regulation and its connection with the subprime mortgage crisis (SMC. The latter was caused by, amongst other things, the downturn in the U.S. housing market, risky lending and borrowing practices, inaccurate credit ratings, credit default swap contracts as well as excessive individual and corporate debt levels. The Basel II Capital Accord's primary tenet is that banks should be given more freedom to decide how much risk exposure to permit; a practice brought into question by the SMC. For instance, institutions worldwide have badly misjudged the risk related to investments ranging from subprime mortgage loans to mortgage-backed securities (MBSs. Also, analysts are now questioning whether Basel II has failed by allowing these institutions to provision less capital for subprime mortgage loan losses from highly rated debt, including MBSs. Other unintended consequences of Basel II include the procyclicality of credit ratings and changes in bank lending behavior. Our main objective is to model the dependence of bank credit and capital on the level of macroeconomic activity under Basel I and Basel II as well as its connection with banking behavior for the period before and during the SMC.

  15. Adverse effects of AMP-activated protein kinase alpha2-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 Keywords : AMP kinase * ischemia/reperfusion * myocardial infarction * aging * high-fat diet Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.293, year: 2014

  16. Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Yang Xu

    Full Text Available BACKGROUND: Acute respiratory distress syndrome (ARDS is a severe and life-threatening acute lung injury (ALI that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK-MAPK pathway, in lipopolysaccharide (LPS-induced acute lung inflammation. METHODS: Wild-type (WT mice and Spred-2(-/- mice were exposed to intratracheal LPS (50 µg in 50 µL PBS to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/- mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. RESULTS: LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/- mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/- mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. CONCLUSIONS: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls

  17. Value of procalcitonin, C-reactive protein, and neopterin in exacerbations of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Alicia Lacoma

    2011-02-01

    Full Text Available Alicia Lacoma1,4, Cristina Prat1,4, Felipe Andreo2,4, Luis Lores3, Juan Ruiz-Manzano2,4, Vicente Ausina1,4, Jose Domínguez1,41Servei de Microbiologia, 2Servei de Pneumologia, Hospital Universitari Germans Trias i Pujol, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain; 3Servei de Pneumologia, Hospital de Sant Boi, Sant Boi de Llobregat, Spain; 4CIBER Enfermedades Respiratorias (CIBERES, Instituto de Salud Carlos III, Madrid, SpainObjective: The identification of biological markers in order to assess different aspects of COPD is an area of growing interest. The objective of this study was to investigate whether levels of procalcitonin (PCT, C-reactive protein (CRP, and neopterin in COPD patients could be useful in identifying the etiological origin of the exacerbation and assessing its prognosis.Methods: We included 318 consecutive COPD patients: 46 in a stable phase, 217 undergoing an exacerbation, and 55 with pneumonia. A serum sample was collected from each patient at the time of being included in the study. A second sample was also collected 1 month later from 23 patients in the exacerbation group. We compared the characteristics, biomarker levels, microbiological findings, and prognosis in each patient group. PCT and CRP were measured using an immunofluorescence assay. Neopterin levels were measured using a competitive immunoassay.Results: PCT and CRP showed significant differences among the three patient groups, being higher in patients with pneumonia, followed by patients with exacerbation (P < 0.0001. For the 23 patients with paired samples, PCT and CRP levels decreased 1 month after the exacerbation episode, while neopterin increased. Neopterin showed significantly lower levels in exacerbations with isolation of pathogenic bacteria, but no differences were found for PCT and CRP. No significant differences were found when comparing biomarker levels

  18. Susceptibility effects of GABA receptor subunit alpha-2 (GABRA2) variants and parental monitoring on externalizing behavior trajectories: Risk and protection conveyed by the minor allele.

    Science.gov (United States)

    Trucco, Elisa M; Villafuerte, Sandra; Heitzeg, Mary M; Burmeister, Margit; Zucker, Robert A

    2016-02-01

    Understanding factors increasing susceptibility to social contexts and predicting psychopathology can help identify targets for prevention. Persistently high externalizing behavior in adolescence is predictive of psychopathology in adulthood. Parental monitoring predicts low externalizing behavior, yet youth likely vary in the degree to which they are affected by parents. Genetic variants of GABA receptor subunit alpha-2 (GABRA2) may increase susceptibility to parental monitoring, thus impacting externalizing trajectories. We had several objectives: (a) to determine whether GABRA2 (rs279827, rs279826, rs279858) moderates the relationship between a component of parental monitoring, parental knowledge, and externalizing trajectories; (b) to test the form of this interaction to assess whether GABRA2 variants reflect risk (diathesis-stress) or susceptibility (differential susceptibility) factors; and (c) to clarify GABRA2 associations on the development of problem behavior. This prospective study (N = 504) identified three externalizing trajectory classes (i.e., low, decreasing, and high) across adolescence. A GABRA2 × Parental Monitoring effect on class membership was observed, such that A-carriers were largely unaffected by parental monitoring, whereas class membership for those with the GG genotype was affected by parental monitoring. Findings support differential susceptibility in GABRA2. PMID:25797587

  19. New X-ray observations of IQ Aurigae and alpha2 Canum Venaticorum - Probing the magnetically channelled wind shock model in A0p stars

    CERN Document Server

    Robrade, J

    2011-01-01

    We present new X-ray observations of the A0p stars alpha^2 CVn (log Lx < 26.0 erg/s) and IQ Aur (log Lx = 29.6 erg/s) and find that their X-ray luminosities differ by at least three orders of magnitude. IQ Aur possesses a strong cool plasma component with X-ray emitting regions located well above the stellar surface, but also significant amounts of hot plasma. Further, a large X-ray flare is detected from IQ Aur, implying the presence of magnetic reconnection. Our comparison study of similar stars indicates that the occurrence of X-ray emission generated by magnetically channelled wind shocks (MCWS) strongly depends on stellar properties. X-ray emission is preferably generated by more luminous and massive objects such as IQ Aur. The MCWS scenario can consistently describe the X-ray emission of these A0p stars, assuming that the very strong magnetic confinement of the stellar wind has led to the build up of a rigidly rotating disk around the star, where magnetic reconnection and centrifugal breakout events ...

  20. ${\\cal{KK}}\\text{MC-hh}$: Resummed Exact ${\\cal O}(\\alpha^2L)$ EW Corrections in a Hadronic MC Event Generator

    CERN Document Server

    Jadach, S; Was, Z A; Yost, S A

    2016-01-01

    We present an improvement of the MC event generator Herwiri2, where we recall the latter MC was a prototype for the inclusion of CEEX resummed EW corrections in hadron-hadron scattering at high cms energies. In this improvement the new exact ${\\cal O}(\\alpha^2L)$ resummed EW generator ${\\cal{KK}}$ MC 4.22, featuring as it does the CEEX realization of resummation in the EW sector, is put in union with the Herwig parton shower environment. The {\\rm LHE} format of the attendant output event file means that all other conventional parton shower environments are available to the would-be user of the resulting new MC. For this reason (and others -- see the text) we henceforth refer to the new improvement of the Herwiri2 MC as ${\\cal{KK}}\\text{MC-hh}$. Since this new MC features exact ${\\cal O}(\\alpha)$ pure weak corrections from the DIZET EW library and features the CEEX and the EEX YFS-style resummation of large multiple photon effects, it provides already the concrete path to 0.05\\% precision on such effects if we...

  1. COPD exacerbations associated with the modified Medical Research Council scale and COPD assessment test among Humana Medicare members

    Directory of Open Access Journals (Sweden)

    Pasquale MK

    2016-01-01

    Full Text Available Margaret K Pasquale,1 Yihua Xu,1 Christine L Baker,2 Kelly H Zou,3 John G Teeter,4 Andrew M Renda,5 Cralen C Davis,1 Theodore C Lee,6 Joel Bobula2 1Comprehensive Health Insights, Inc., Humana Inc., Louisville, KY, 2Outcomes and Evidence, Global Health & Value, Pfizer Inc., 3Statistical Center for Outcomes, Real-World and Aggregate Data, Global Innovative Pharma Business, Pfizer Inc., New York, NY, 4Global Medical Development, Global Innovative Pharma Business, Pfizer Inc., Groton, CT, 5Retail Strategy & Execution, Humana Inc., Louisville, KY, 6Global Medical Affairs, Global Innovative Pharma Business, Pfizer Inc., New York, NY, USA Background: The Global initiative for chronic Obstructive Lung Disease guidelines recommend assessment of COPD severity, which includes symptomatology using the modified Medical Research Council (mMRC or COPD assessment test (CAT score in addition to the degree of airflow obstruction and exacerbation history. While there is great interest in incorporating symptomatology, little is known about how patient reported symptoms are associated with future exacerbations and exacerbation-related costs.Methods: The mMRC and CAT were mailed to a randomly selected sample of 4,000 Medicare members aged >40 years, diagnosed with COPD (≥2 encounters with International Classification of Dis­eases-9th Edition Clinical Modification: 491.xx, 492.xx, 496.xx, ≥30 days apart. The exacerbations and exacerbation-related costs were collected from claims data during 365-day post-survey after exclusion of members lost to follow-up or with cancer, organ transplant, or pregnancy. A logistic regression model estimated the predictive value of exacerbation history and symptomatology on exacerbations during follow-up, and a generalized linear model with log link and gamma distribution estimated the predictive value of exacerbation history and symptomatology on exacerbation-related costs.Results: Among a total of 1,159 members who returned the

  2. Self-reported sleep quality and acute exacerbations of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Geiger-Brown J

    2015-02-01

    Full Text Available Jeanne Geiger-Brown,1 Sarah Lindberg,2 Samuel Krachman,3 Charlene E McEvoy,4 Gerard J Criner,3 John E Connett,2 Richard K Albert,5 Steven M Scharf6 1Center for Health Outcomes Research, University of Maryland School of Nursing, Baltimore, MD, 2University of Minnesota School of Public Health, Division of Biostatistics, Minneapolis, MN, 3Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, 4Health Partners Institute of Education and Research, St Paul, MN, 5The Medicine Service, Denver Health and Department of Medicine, the University of Colorado Denver Health Sciences Center, Denver, CO, 6Department of Medicine, Pulmonary and Critical Care Division, University of Maryland School of Medicine, Baltimore, MD, USA Background: Many patients with chronic obstructive pulmonary disease (COPD suffer from poor sleep quality. We hypothesized that poor sleep quality in otherwise stable patients predicted exacerbations in these patients. Methods: This is a secondary analysis of the results of a previously published randomized trial of azithromycin in 1,117 patients with moderate to severe COPD who were clinically stable on enrollment. Sleep quality was measured using the Pittsburgh Sleep Quality Index. Other quality of life indices included the Medical Outcome Study 36-item Short Form Health Survey and the St Georges Respiratory Questionnaire. Outcomes included time to first exacerbation and exacerbation rate. Results: Sleep quality was “poor” (Pittsburgh Sleep Quality Index >5 in 53% of participants but was not related to age or severity of airflow obstruction. Quality of life scores were worse in “poor” sleepers than in “good” sleepers. Major classes of comorbid conditions, including psychiatric, neurologic, and musculoskeletal disease, were more prevalent in the “poor” sleepers. Unadjusted time to first exacerbation was shorter (190 versus 239 days and exacerbation rate (1

  3. Prompt initiation of maintenance treatment following a COPD exacerbation: outcomes in a large insured population

    Science.gov (United States)

    Coutinho, Anna D; Lokhandwala, Tasneem; Boggs, Robert L; Dalal, Anand A; Landsman-Blumberg, Pamela B; Priest, Julie; Stempel, David A

    2016-01-01

    Background The aim of this study was to extend previous findings and determine the value of prompt initiation of maintenance treatment (MT) following COPD exacerbations requiring hospitalization or an emergency department (ED) visit. Patients and methods Administrative claims data (collected between January 1, 2009 and June 30, 2012) from an employer-sponsored commercially insured population were retrospectively used to identify patients with a COPD exacerbation resulting in hospitalization or an ED visit. Patients initiating approved MT for COPD within 30 days of discharge/diagnosis (prompt) were compared with those initiating MT within 31–180 days (delayed). COPD-related total, medical, and prescription drug costs during a 1-year follow-up period were evaluated using semilog ordinary least square regressions, controlling for baseline characteristics plus COPD-related costs from the previous year. The odds and number of subsequent COPD-related exacerbations during the follow-up were compared between the prompt and delayed cohorts using logistic regression and zero-inflated negative binomial models, respectively. Results A total of 6,521 patients with a COPD-related hospitalization or an ED visit were included, of whom 4,555 received prompt MT and 1,966 received delayed MT. Adjusted COPD-related total and medical costs were significantly lower for the prompt MT than the delayed MT cohorts (US$3,931 vs US$4,857 and US$2,327 vs US$3,087, respectively; both P<0.010), as were COPD-related prescription costs (US$1,526 vs US$1,683, P<0.010) during the 1-year follow-up period. Patients receiving delayed MT were 68% more likely to have a subsequent exacerbation requiring hospitalization and 80% more likely to have an exacerbation requiring an ED visit. Conclusion Prompt initiation of MT following a COPD-related hospitalization or an ED visit was associated with a significant reduction in COPD-related costs and odds of exacerbation in the following year compared with

  4. Severe and Moderate Asthma Exacerbations in Asthmatic Children and Exposure to Ambient Air Pollutants

    Science.gov (United States)

    Tétreault, Louis-Francois; Doucet, Marieve; Gamache, Philippe; Fournier, Michel; Brand, Allan; Kosatsky, Tom; Smargiassi, Audrey

    2016-01-01

    Background: It is well established that short-term exposure to ambient air pollutants can exacerbate asthma, the role of early life or long-term exposure is less clear. We assessed the association between severe asthma exacerbations with both birth and annual exposure to outdoor air pollutants with a population-based cohort of asthmatic children in the province of Quebec (Canada). Method: Exacerbations of asthma occurring between 1 April 1996 and 31 March 2011 were defined as one hospitalization or emergency room visit with a diagnosis of asthma for children (<13 years old) already diagnosed with asthma. Annual daily average concentrations of ozone (O3) and nitrogen dioxide (NO2) were estimated at the child’s residential postal code. Satellite based levels of fine particulate (PM2.5) estimated for a grid of 10 km by 10 km were also assigned to postal codes of residence for the whole province. Hazard ratios (HRs) were estimated from Cox models with a gap time approach for both birth and time-dependant exposure. Results: Of the 162,752 asthmatic children followed (1,020,280 person-years), 35,229 had at least one asthma exacerbation. The HRs stratified by age groups and adjusted for the year of birth, the ordinal number of exacerbations, sex, as well as material and social deprivation, showed an interquartile range increase in the time-dependant exposure to NO2 (4.95 ppb), O3 (3.85 ppb), and PM2.5 (1.82 μg/m3) of 1.095 (95% CI 1.058–1.131), 1.052 (95% CI 1.037–1.066) and 1.025 (95% CI 1.017–1.031), respectively. While a positive association was found to PM2.5, no associations were found between exposure at birth to NO2 or O3. Conclusions: Our results support the conclusion, within the limitation of this study, that asthma exacerbations in asthmatic children are mainly associated with time dependent residential exposures less with exposure at birth. PMID:27490556

  5. 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

  6. Do metals that translocate to the brain exacerbate traumatic brain injury?

    Science.gov (United States)

    Kalinich, John F; Kasper, Christine E

    2014-05-01

    embedded metal fragment wound occurs simultaneously. Since the blood-brain barrier can be disrupted by traumatic brain injury, this raises the possibility of free access to the brain for any metals found in the body. Therefore, we hypothesize that this influx of metals overwhelms normal brain homeostasis, depletes the brain's antioxidant defense systems, and activates microglial cells resulting in the release of inflammatory mediators that can potentially exacerbate the adverse effects of traumatic brain injury. PMID:24613092

  7. Development and Evaluation of an Automated, Home-Based, Electronic Questionnaire for Detecting COPD Exacerbations

    Directory of Open Access Journals (Sweden)

    Francisco de B. Velazquez-Peña

    2015-01-01

    Full Text Available Collaboration between patients and their medical and technical experts enabled the development of an automated questionnaire for the early detection of COPD exacerbations (AQCE. The questionnaire consisted of fourteen questions and was implemented on a computer system for use by patients at home in an un-supervised environment. Psychometric evaluation was conducted after a 6-month field trial. Fifty-two patients were involved in the development of the questionnaire. Reproducibility was studied using 19 patients (ICC = 0.94. Sixteen out of the 19 subjects started the 6 month-field trial with the computer application. Cronbach’s alpha of 0.81 was achieved. In the concurrent validity analysis, a correlation of 0.80 (p = 0.002 with the CCQ was reported. The results suggest that AQCE is a valid and reliable questionnaire, showing that an automated home-based electronic questionnaire may enable early detection of exacerbations of COPD.

  8. Relationship of asthma management, socioeconomic status, and medication insurance characteristics to exacerbation frequency in children with asthma

    Science.gov (United States)

    Ungar, Wendy J.; Paterson, J. Michael; Gomes, Tara; Bikangaga, Peter; Gold, Milton; To, Teresa; Kozyrskyj, Anita L.

    2016-01-01

    Background Less than 25% of asthmatic children are well controlled. Objective To identify factors associated with asthma exacerbation causing emergency department (ED) visits or hospitalizations related to health status, socioeconomic status (SES), and drug insurance. Methods In this retrospective cohort study, complete data were collected on 490 asthmatic children regarding demographics, SES, drug plan characteristics, health status, health resource use, and symptoms. Interview data were linked to administrative data on asthma ED visits and hospitalizations occurring in the following year. Multiple Poisson regression identified independent variables associated with ED visits or hospitalizations in the full cohort and in a subgroup with prescription drug insurance. Results Younger age, previous emergency visits, nebulizer use, pet ownership, and receipt of asthma education but not an action plan were significantly associated with more frequent exacerbations. In the full cohort, children with high income adequacy had 28% fewer exacerbations than did children with low income adequacy. In the subgroup with drug insurance, girls had 26% fewer exacerbations than did boys, and children with food, drug, or insect allergies had 52% more exacerbations than did children without allergies. Children of families with annual insurance deductibles greater than $90 had 95% fewer exacerbations. Every percentage increase in the proportion of income spent out-of-pocket on asthma medications was associated with a 14% increase in exacerbations. Conclusions Asthma history, disease management factors, and SES were associated with exacerbations requiring urgent care. In families with drug plans, the magnitude of asthma medication cost-sharing as a proportion of household income, rather than income alone, was significantly associated with exacerbations. PMID:21195940

  9. Update on Recent Advances in the Management of Aspirin Exacerbated Respiratory Disease

    OpenAIRE

    Palikhe, Nami Shrestha; Kim, Joo-Hee; Park, Hae-Sim

    2009-01-01

    Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; howev...

  10. Action plans for COPD: strategies to manage exacerbations and improve outcomes

    OpenAIRE

    Jalota L; Jain VV

    2016-01-01

    Leena Jalota,1 Vipul V Jain1,2 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, 2Chronic Lung Disease Program, UCSF-Fresno, Community Regional Medical Center, Fresno, CA, USA Abstract: COPD is the third-largest killer in the world, and certainly takes a toll on the health care system. Recurrent COPD exacerbations accelerate lung-function decline, worsen mortality, and consume over US$50 billion in health care spendi...

  11. Post-operative acute exacerbation of pulmonary fibrosis in lung cancer patients undergoing lung resection

    OpenAIRE

    YANO, MOTOKI; Sasaki, Hidefumi; MORIYAMA, SATORU; HIKOSAKA, YU; YOKOTA, KEISUKE; Kobayashi, Susumu; HARA, MASAKI; Fujii, Yoshitaka

    2011-01-01

    Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) in lung cancer patients is a critical factor in post-operative mortality. The cause of AE development is unknown and AE may occur in patients without the diagnosis of IPF. We have conducted a retrospective study of consecutive patients who underwent lung cancer surgery since January 2004. Sixty-two patients with fibrous findings in preoperative high-resolution computed tomography were enrolled in the present study and clinicopatho...

  12. Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis

    OpenAIRE

    Kakugawa, Tomoyuki; Yokota, Shin-ichi; Ishimatsu, Yuji; Hayashi, Tomayoshi; Nakashima, Shota; Hara, Shintaro; Sakamoto, Noriho; Kubota, Hiroshi; Mine, Mariko; Matsuoka, Yasuhiro; Mukae, Hiroshi; Nagata, Kazuhiro; Kohno, Shigeru

    2013-01-01

    Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic diff...

  13. Comparison of Pressure Support Ventilation and Proportional Assist Ventilation Modes in Chronic Obstructive Pulmonary Disease Exacerbation

    OpenAIRE

    ŞENGÜL, Aysun; Başyiğit, İlknur; Boyacı, Haşim; Yıldız, Füsun; Ilgazlı, Ahmet

    2013-01-01

    Objective: To compare the effectiveness of pressure support ventilation and proportional assist ventilation which is two modes of non-invasive mechanical ventilation used in the treatment of chronic obstructive pulmonary disease exacerbation. Material and Methods: Total of 20 patients was included in the study. Mean age was 63±7 years. Patients were randomized as proportional assist ventilation and pressure support ventilation groups. Non-invasive mechanical ventilation was per...

  14. Moxifloxacin in the management of exacerbations of chronic bronchitis and COPD

    OpenAIRE

    Miravitlles, Marc

    2007-01-01

    Bacteria are isolated in more than 50% of exacerbations of chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD). The most prevalent respiratory pathogens include Gram-positive (Streptococcus pneumoniae) and Gram-negative (Haemophilus influenzae, Moraxella catarrhalis) microorganims. Moxifloxacin is a fourth-generation fluoroquinolone that has been shown to be effective against respiratory pathogens, including atypicals and those resistant to most common antibiotics. The bi...

  15. [Clinical pathway management of acute exacerbations of chronic obstructive pulmonary disease based on state machine].

    Science.gov (United States)

    Tan, Jian; Hao, Liwei; Cheng, Yuanxiong; Xu, Tongliang; Song, Yingnuo

    2014-04-01

    We propose a clinical pathway of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) based on state machine. Clinical event-driven response was utilized to control workflow execution of the AECOPD clinical pathway. By comparison with the traditional clinical pathway management, clinical numerical results showed that the proposed method was better in hospitalization days, average hospitalization expense and aberration rate, and better handled the variability in the AECOPD clinical pathway execution. PMID:24752111

  16. Mitochondrial iron accumulation exacerbates hepatic toxicity caused by hepatitis C virus core protein

    International Nuclear Information System (INIS)

    Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS). The overproduction of ROS in the liver is the net result of HCV core protein-induced dysfunction of the mitochondrial respiratory chain. This study examined the impact of ferric nitrilacetic acid (Fe-NTA)-mediated iron overload on mitochondrial damage and ROS production in HCV core protein-expressing HepG2 (human HCC) cells (Hep39b cells). A decrease in mitochondrial membrane potential and ROS production were observed following Fe-NTA treatment. After continuous exposure to Fe-NTA for six days, cell toxicity was observed in Hep39b cells, but not in mock (vector-transfected) HepG2 cells. Moreover, mitochondrial iron (59Fe) uptake was increased in the livers of HCV core protein-expressing transgenic mice. This increase in mitochondrial iron uptake was inhibited by Ru360, a mitochondrial Ca2+ uniporter inhibitor. Furthermore, the Fe-NTA-induced augmentation of mitochondrial dysfunction, ROS production, and cell toxicity were also inhibited by Ru360 in Hep39b cells. Taken together, these results indicate that Ca2+ uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein. - Highlights: • Iron accumulation in the livers of patients with hepatitis C virus (HCV) infection is thought to exacerbate oxidative stress. • The impact of iron overload on mitochondrial damage and ROS production in HCV core protein-expressing cells were examined. • Mitochondrial iron uptake was increased in the livers of HCV core protein-expressing transgenic mice. • Ca2+ uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by

  17. Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations

    OpenAIRE

    O'Reilly, Philip J.; Jackson, Patricia L; Wells, J. Michael; Dransfield, Mark T; Scanlon, Paul D.; Blalock, J Edwin

    2013-01-01

    Rationale Proline–glycine–proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown. Objectives We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbations to test wh...

  18. Higher serum CCL17 may be a promising predictor of acute exacerbations in chronic hypersensitivity pneumonitis

    OpenAIRE

    Miyazaki, Yasunari; Unoura, Koji; Tateishi, Tomoya; Akashi, Takumi; Takemura, Tamiko; Tomita, Makoto; Inase, Naohiko; Yoshizawa, Yasuyuki

    2013-01-01

    Background Recent research has suggested that the Th1 and Th2 chemokine/cytokine axis contributes to the development of chronic hypersensitivity pneumonitis (HP). Acute exacerbations (AE) are significant factors in the prognosis of chronic HP. Little is known, however, about these biomarkers in association with AE in chronic HP patients. Methods Fifty-six patients with chronic HP were evaluated, including 14 patients during episodes of AE. Th1 mediators (C-X-C chemokine ligand [CXCL]10 and in...

  19. Using bacterial biomarkers to identify early indicators of cystic fibrosis pulmonary exacerbation onset

    OpenAIRE

    Rogers, Geraint B.; Hoffman, Lucas R.; Johnson, Matt W; Mayer-Hamblett, Nicole; Schwarze, Jürgen; Carroll, Mary P; Bruce, Kenneth D.

    2011-01-01

    Acute periods of pulmonary exacerbation are the single most important cause of morbidity in cystic fibrosis patients, and may be associated with a loss of lung function. Intervening prior to the onset of a substantially increased inflammatory response may limit the associated damage to the airways. While a number of biomarker assays based on inflammatory markers have been developed, providing useful and important measures of disease during these periods, such factors are typically only elevat...

  20. A Comparison of Work-Exacerbated Asthma Cases from Clinical and Epidemiological Settings

    OpenAIRE

    Henneberger, Paul K; Xiaoming Liang; Catherine Lemière

    2013-01-01

    BACKGROUND: Clinical and epidemiological studies commonly use different case definitions in different settings when investigating work-exacerbated asthma (WEA). These differences are likely to impact characteristics of the resulting WEA cases.OBJECTIVES: To investigate this issue by comparing two groups of WEA cases, one identified using an intensive clinical evaluation and another that fulfilled epidemiological criteria.METHODS: A total of 53 clinical WEA cases had been referred for suspecte...

  1. Protective Effects of Quetiapine on Metabolic and Inflammatory Abnormalities in Schizophrenic Patients during Exacerbated Stage.

    Science.gov (United States)

    Kao, Yu-Chen; Ko, Chih-Yuan; Wang, Sheng-Chiang; Liu, Yia-Ping

    2016-04-30

    Inflammation has been considered important in the pathogenesis of schizophrenia. Increasing evidence reveals that patients with schizophrenia have abnormal expression of cytokines, which are related to development of metabolic abnormalities. Metabolic abnormality has become a critical issue, though its longitudinal relationship with the disorder, such as the antipsychotics influence, is unclear. We aimed to investigate whether abnormalities of metabolic parameters and cytokine levels in acute exacerbated schizophrenic patients existed, and whether intervention of antipsychotic could help. The present study analyzed peripheral cytokines and metabolic/hemodynamic parameters in healthy controls and acute exacerbated schizophrenic patients hospitalized for three weeks under the unique treatment of quetiapine, a well-known second-generation antipsychotic. Our results showed that patients with schizophrenia were predisposed to metabolic abnormalities in acute exacerbation, including body mass index (BMI) and waist circumference (WC). The patients were also prone to dysglycemia, lower high-density lipoprotein cholesterol (HDL-c) levels, and higher blood pressure with concomitant of elevation of interleukin (IL)-2, IL-6 and IL-10 in which IL-6 was associated with BMI. After quetiapine treatment, IL-2, IL-6 and IL-10 remained higher than the controls, but IL-10 was significantly decreased in follow-up comparison. Glycemic-related indexes, HDL-c and IL-10 levels were significantly changed by variance analysis. Results of the present study imply that acute exacerbated schizophrenic patients with metabolism abnormalities may involve disruption of expression of cytokines, and that quetiapine may have therapeutic effects. Nonetheless, metabolism parameters of patients undergoing treatment with quetiapine should be closely monitored. PMID:27080462

  2. Exacerbated Mechanical Hyperalgesia in Rats with Genetically Predisposed Depressive Behavior: Role of Melatonin and NMDA Receptors

    OpenAIRE

    Wang, Shuxing; Tian, Yinghong; Song, Li; Lim, Grewo; Tan, Yonghui; You, Zerong; Chen, Lucy; Mao, Jianren

    2012-01-01

    A connection between pain and depression has long been recognized in the clinical setting; however, its mechanism remains unclear. In this study, we showed that mechanical hyperalgesia induced by unilateral temporomandibular joint (TMJ) inflammation was exacerbated in Wistar-Kyoto (WKY) rats with genetically predisposed depressive behavior. Reciprocally, TMJ inflammation enhanced depressive behavior such that a lower nociceptive threshold correlated with a higher score of depressive behavior ...

  3. Determination of exacerbation predictors in patients with COPD in physical therapy - a longitudinal study

    Directory of Open Access Journals (Sweden)

    Diego M. Marino

    2014-05-01

    Full Text Available Background: Chronic obstructive pulmonary disease (COPD typically presents the characteristic clinical condition of exacerbation, with more intense symptoms associated with greater functional loss and consequently lower chances of patient survival. Objectives: This study sought to determine the predictors of exacerbation, alone or in combination, in patients with chronic obstructive pulmonary disease (COPD who received physical therapeutic treatment over 6 months. Method: This was an observational, longitudinal and prospective study in which 63 COPD patients residing within the municipality of São Carlos, SP, Brazil were evaluated. These patients had COPD stages II and III and were entered into a physical therapy program, consisting of 3 periods of assessment over 6 months. We evaluated the occurrence of acute exacerbation as well as the patients' body mass index (BMI, fat-free mass (FFM, fat-free mass index, forced expiratory volume in 1 second (FEV1, dyspnea, distance walked (DW in the 6-minute walk test (6MWT and handgrip strength. Results: When applying Cox settings with each covariate separately, the results revealed 5% significance only for the DW in the 6MWT, which demonstrated an interaction between BMI and FFM. Comparison of the 3 periods of assessment across the covariates measured showed a significant difference only for the DW between evaluations in the 3rd and 6th months. Conclusion: Upon analyzing the predictors of risk over 6 months of follow-up in patients with COPD, we found that the DW in the 6MWT was associated with the risk of exacerbation, although this risk also depended on the covariates BMI and FFM.

  4. Outcomes of acute exacerbations in COPD in relation to pre-hospital oxygen therapy

    OpenAIRE

    Ringbaek, Thomas J.; Terkelsen, Jakob; Lange, Peter

    2015-01-01

    Background: Pre-hospital, high-concentration oxygen therapy during acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has been associated with increased mortality. Recent COPD guidelines have encouraged titrated oxygen therapy with a target saturation range of 88–92%. Oxygen therapy leading to saturation above 92% is defined as ‘inappropriate oxygen therapy’.Objectives: To examine the frequency of inappropriate oxygen therapy and whether inappropriate oxygen therapy in the a...

  5. Effects of Vitamin D Intake on FEV1 and COPD Exacerbation: A Randomized Clinical Trial Study

    OpenAIRE

    2015-01-01

    Aim: This study aimed to evaluate the effects of vitamin D intake on COPD exacerbation and FEV1 in the patients with severe and very severe COPD. Methods: This double blind placebo control randomized clinical trial study was done in the Ashayer university hospital in Khorramabad in 2012. Eighty eight patients with severe and very severe COPD were randomly selected from those who recoursed to the internal medicine clinic of Ashayer hospital. They were randomly allocated to case and placebo gro...

  6. Implicit state guarantees exacerbate problem: Separated banking system alone not a solution

    OpenAIRE

    Klaus, Benjamin; Schäfer, Dorothea

    2013-01-01

    Many banks are now too big, complex, and closely interconnected to be liquidated. When they run into difficulties, they threaten the entire financial system of their economic area. Five years of financial crisis have not alleviated but exacerbated this problem. The cost of stabilizing banks is enormous, posing serious challenges to the states affected. In addition, such state guarantees create dangerously false incentives: they encourage managers and investors to engage into high risk-taking,...

  7. The Impact of Respiratory Viral Infection on Wheezing Illnesses and Asthma Exacerbations

    OpenAIRE

    Carroll, Kecia N.; Hartert, Tina V

    2008-01-01

    The etiology and morbidity associated with asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections.[1-7] Although it is unclear whether respiratory viral infections cause asthma, observational studies have demonstrated a high rate of asthma in children with a history of severe viral lower respiratory tract infections during infancy, and viruses are the associated with the majority of asthma exacerbations among both childr...

  8. Anxiety Interacts With Expressed Emotion Criticism in the Prediction of Psychotic Symptom Exacerbation

    OpenAIRE

    Docherty, Nancy M.; St-Hilaire, Annie; Aakre, Jennifer M.; Seghers, James P.; McCleery, Amanda; Divilbiss, Marielle

    2009-01-01

    Psychotic symptoms are exacerbated by social stressors in schizophrenia and schizoaffective disorder patients as a group. More specifically, critical attitudes toward patients on the part of family members and others have been associated with a higher risk of relapse in the patients. Some patients appear to be especially vulnerable in this regard. One variable that could affect the degree of sensitivity to a social stressor such as criticism is the individual’s level of anxiety. The present l...

  9. Spirometry for patients in hospital and one month after admission with an acute exacerbation of COPD

    OpenAIRE

    Rea H; Kenealy T; Adair J; Robinson E; Sheridan N

    2011-01-01

    Harry Rea1, Timothy Kenealy1, Jacqui Adair1, Elizabeth Robinson2, Nicolette Sheridan31Section of Integrated Care, South Auckland Clinical School, University of Auckland, 2Biostatistics and Epidemiology, School of Population Health, University of Auckland, 3Section of Integrated Care, South Auckland Clinical School and School of Nursing, University of Auckland, Auckland, New ZealandAim: To assess whether spirometry done in hospital during an admission for an acute exacerbation of chronic obstr...

  10. Confirmatory spirometry for adults hospitalized with a diagnosis of asthma or chronic obstructive pulmonary disease exacerbation

    OpenAIRE

    Prieto Centurion Valentin; Huang Frank; Naureckas Edward T; Camargo Jr Carlos A; Charbeneau Jeffrey; Joo Min J; Press Valerie G; Krishnan Jerry A

    2012-01-01

    Abstract Background Objective measurement of airflow obstruction by spirometry is an essential part of the diagnosis of asthma or COPD. During exacerbations, the feasibility and utility of spirometry to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD) are unclear. Addressing these gaps in knowledge may help define the need for confirmatory testing in clinical care and quality improvement efforts. This study was designed to determine the feasibility of spirometry...

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

    OpenAIRE

    Qin, Xu-Jun; Hudson, Laurie G.; Liu, Wenlan; Timmins, Graham S.; Liu, Ke Jian

    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,...

  12. Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

    OpenAIRE

    Gabriela A. Kulp; Tilton, Ronald G.; Herndon, David N.; Jeschke, Marc G.

    2012-01-01

    Hyperglycemia and inflammation are hallmarks of burn injury. In this study, we used a rat model of hyperglycemia and burn injury to investigate the effects of hyperglycemia on inflammatory responses in the liver. Hyperglycemia was induced in male Sprague-Dawley rats with streptozotocin (STZ) (35–40 mg/kg), followed by a 60% third-degree scald burn injury. Cytokine levels (by multiplex, in cytosolic liver extracts), hormones (by enzyme-linked immunosorbent assay [ELISA], in serum), nuclear fac...

  13. Linking Asthma Exacerbation and Air Pollution Data: A Step Toward Public Health and Environmental Data Integration

    Science.gov (United States)

    Faruque, Fazlay; Finley, Richard; Marshall, Gailen; Brackin, Bruce; Li, Hui; Williams, Worth; Al-Hamdan, Mohammad; Luvall, Jeffrey; Rickman, Doug; Crosson, Bill

    2006-01-01

    Studies have shown that reducing exposure to triggers such as air pollutants can reduce symptoms and the need for medication in asthma patients. However, systems that track asthma are generally not integrated with those that track environmental hazards related to asthma. Tlvs lack of integration hinders public health awareness and responsiveness to these environmental triggers. The current study is a collaboration between health and environmental professionals to utilize NASA-derived environmental data to develop a decision support system (DSS) for asthma prediction, surveillance, and intervention. The investigators link asthma morbidity data from the University of Mississippi Medical Center (UMMC) and Mississippi Department of Health (MDH) with air quality data from the Mississippi Department of Environmental Quality (MDEQ) and remote sensing data from NASA. Daily ambient environmental hazard data for PM2.5 and ozone are obtained from the MDEQ air quality monitoring locations and are combined with remotely sensed data from NASA to develop a state-wide spatial and time series profile of environmental air quality. These data are then used to study the correlation of these measures of air quality variation with the asthma exacerbation incidence throughout the state over time. The goal is to utilize these readily available measures to allow real-time risk assessment for asthma exacerbations. GeoMedStat, a DSS previously developed for biosurveillance, will integrate these measures to monitor, analyze and report the real-time risk assessment for asthma exacerbation throughout the state.

  14. Particulate matter air pollution exposure: role in the development and exacerbation of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Sean H Ling

    2009-06-01

    Full Text Available Sean H Ling, Stephan F van EedenJames Hogg iCAPTURE Centre for Pulmonary and Cardiovascular Research and Heart and Lung Institute, University of British Columbia, Vancouver, British Columbia, CanadaAbstract: Due to the rapid urbanization of the world population, a better understanding of the detrimental effects of exposure to urban air pollution on chronic lung disease is necessary. Strong epidemiological evidence suggests that exposure to particulate matter (PM air pollution causes exacerbations of pre-existing lung conditions, such as, chronic obstructive pulmonary disease (COPD resulting in increased morbidity and mortality. However, little is known whether a chronic, low-grade exposure to ambient PM can cause the development and progression of COPD. The deposition of PM in the respiratory tract depends predominantly on the size of the particles, with larger particles deposited in the upper and larger airways and smaller particles penetrating deep into the alveolar spaces. Ineffective clearance of this PM from the airways could cause particle retention in lung tissues, resulting in a chronic, low-grade inflammatory response that may be pathogenetically important in both the exacerbation, as well as, the progression of lung disease. This review focuses on the adverse effects of exposure to ambient PM air pollution on the exacerbation, progression, and development of COPD.Keywords: chronic obstructive pulmonary disease, particulate matter, air pollution, alveolar macrophage

  15. Time course and recovery of arterial blood gases during exacerbations in adults with Cystic Fibrosis.

    LENUS (Irish Health Repository)

    Waterhouse, D F

    2012-02-01

    INTRODUCTION: Hypoxia and hypercapnia are closely linked to morbidity and mortality in patients with Cystic Fibrosis (CF). The aims of this study were to describe the changes in blood gases during and following an acute pulmonary exacerbation in adults with CF. METHODS: We performed a prospective observational study of patients with CF admitted for management of an acute exacerbation. Blood gas and spirometric analysis was performed on admission, throughout the treatment period, and 31 days after discharge (day 45). RESULTS: At presentation, eight of nineteen patients had evidence of either hypoxia (PaO(2)<8 kPa) and\\/or hypercapnia (PaCO(2)>6.6 kPa). Blood gas parameters stabilized following two weeks of intravenous antibiotic therapy, with little difference evident in between treatment completion and subsequent review following discharge. Hypercapnia reversed in three patients, with persistent hypercapnia evident in two patients. CONCLUSION: In our study group, hypoxemia and hypercapnia were frequently observed at presentation of the acute exacerbation. Blood gases stabilized following two weeks of intravenous antibiotic therapy, with arterial PCO(2) one month following hospital discharge generally similar to that at time of discharge.

  16. Acute exacerbation of idiopathic pulmonary fibrosis as the initial presentation of the disease

    Directory of Open Access Journals (Sweden)

    K. Sakamoto

    2009-06-01

    Full Text Available The clinical course of patients with idiopathic pulmonary fibrosis (IPF is generally marked by a decline in pulmonary function over time, although recently there is increasing recognition that fatal deterioration from acute exacerbation can occur at any stage. The patient described in the present case study was a 65-yr-old male who presented with exertional dyspnoea and fever of 2 weeks' duration. He had no history of chronic lung disease or physiological or radiological hallmarks of pre-existing disease. He underwent surgical lung biopsy and the histological examination showed a background pattern of usual interstitial pneumonia (UIP with a pattern of focal acute diffuse alveolar damage (DAD in the area where normal lung architecture was preserved. It is notable that the pathological diagnosis of this rapidly progressive interstitial pneumonia was DAD on UIP, which is typically seen in acute exacerbations of IPF. Unusual findings on high-resolution computed tomography scan were also noted. We presume that in this case acute exacerbation developed in the very early course of IPF. Given the possibility that similar cases may have arisen among patients diagnosed with acute interstitial pneumonia or acute respiratory distress syndrome, the histopathology of rapidly progressive interstitial pneumonia may need to be revisited.

  17. Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD Audit.

    Science.gov (United States)

    Hartl, Sylvia; Lopez-Campos, Jose Luis; Pozo-Rodriguez, Francisco; Castro-Acosta, Ady; Studnicka, Michael; Kaiser, Bernhard; Roberts, C Michael

    2016-01-01

    Studies report high in-hospital and post-discharge mortality of chronic obstructive pulmonary disease (COPD) exacerbations varying depending upon patient characteristics, hospital resources and treatment standards. This study aimed to investigate the patient, resource and organisational factors associated with in-hospital and 90-day post-discharge mortality and readmission of COPD exacerbations within the European COPD Audit. The audit collected data of COPD exacerbation admissions from 13 European countries.On admission, only 49.7% of COPD patients had spirometry results available and only 81.6% had blood gases taken. Using logistic regression analysis, the risk associated with in-hospital and post-discharge mortality was higher age, presence of acidotic respiratory failure, subsequent need for ventilatory support and presence of comorbidity. In addition, the 90-day risk of COPD readmission was associated with previous admissions. Only the number of respiratory specialists per 1000 beds, a variable related to hospital resources, decreased the risk of post-discharge mortality.The European COPD Audit identifies risk factors associated with in-hospital and post-discharge mortality and COPD readmission. Addressing the deficiencies in acute COPD care such as making spirometry available and measuring blood gases and providing noninvasive ventilation more regularly would provide opportunities to improve COPD outcomes. PMID:26493806

  18. Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Huiying [Department of Molecular Biomedical Sciences, Center for Comparative Molecular Translational Research, College of Veterinary Medicine, NC State University, Raleigh, NC 27607 (United States); Department of Environmental and Molecular Toxicology, College of Agriculture and Life Sciences, NC State University, Raleigh, NC 27695 (United States); Newman, Donna R. [Department of Molecular Biomedical Sciences, Center for Comparative Molecular Translational Research, College of Veterinary Medicine, NC State University, Raleigh, NC 27607 (United States); Bonner, James C. [Department of Environmental and Molecular Toxicology, College of Agriculture and Life Sciences, NC State University, Raleigh, NC 27695 (United States); Sannes, Philip L., E-mail: philip_sannes@ncsu.edu [Department of Molecular Biomedical Sciences, Center for Comparative Molecular Translational Research, College of Veterinary Medicine, NC State University, Raleigh, NC 27607 (United States)

    2012-11-15

    Environmental exposure to cadmium is known to cause damage to alveolar epithelial cells of the lung, impair their capacity to repair, and result in permanent structural alterations. Cell surface heparan sulfate proteoglycans (HSPGs) can modulate cell responses to injury through their interactions with soluble effector molecules. These interactions are often sulfate specific, and the removal of sulfate groups from HS side chains could be expected to influence cellular injury, such as that caused by exposure to cadmium. The goal of this study was to define the role 6-O-sulfate plays in cellular responses to cadmium exposure in two pulmonary epithelial cancer cell lines (H292 and A549) and in normal human primary alveolar type II (hAT2) cells. Sulfate levels were modified by transduced transient over-expression of 6-O-endosulfatase (HSulf-1), a membrane-bound enzyme which specifically removes 6-O-sulfate groups from HSPG side chains. Results showed that cadmium decreased cell viability and activated apoptosis pathways at low concentrations in hAT2 cells but not in the cancer cells. HSulf-1 over-expression, on the contrary, decreased cell viability and activated apoptosis pathways in H292 and A549 cells but not in hAT2 cells. When combined with cadmium, HSulf-1 over-expression further decreased cell viability and exacerbated the activation of apoptosis pathways in the transformed cells but did not add to the toxicity in hAT2 cells. The finding that HSulf-1 sensitizes these cancer cells and intensifies the injury induced by cadmium suggests that 6-O-sulfate groups on HSPGs may play important roles in protection against certain environmental toxicants, such as heavy metals. -- Highlights: ► Primary human lung alveolar type 2 (hAT2) cells and H292 and A549 cells were used. ► Cadmium induced apoptosis in hAT2 cells but not in H292 or A549 cells. ► HSulf-1exacerbates apoptosis induced by cadmium in H292 and A549 but not hAT2 cells.

  19. Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial

    Directory of Open Access Journals (Sweden)

    Chang Anne B

    2012-08-01

    Full Text Available Abstract Background Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. Methods We are conducting a bronchiectasis exacerbation study (BEST, which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland. In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily with placebo-azithromycin; azithromycin (5 mg/kg daily with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. Discussion Effective, evidence-based management

  20. Efficacy and safety of pegylated interferon-alpha2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients.

    Science.gov (United States)

    Santin, Miguel; Shaw, Evelyn; Garcia, M Jose; Delejido, Antonio; de Castro, Eduardo Rodriguez; Rota, Rosa; Altés, Jordi; Baguena, Francisco; Valero, Silvia; Sala, Montserrat; Casanova, Aurora

    2006-04-01

    Low response rates and concerns about safety have limited the implementation of treatment for chronic hepatitis C (CHC) in patients with HIV infection. The efficacy and safety of pegylated interferon (peg-IFN) plus ribavirin in HIV-infected patients with CHC were evaluated in a prospective, open-label, multicenter study. Sixty patients with persistently high transaminases, positive HCV-RNA, CD4 count > or = 300 cells/microl, and HIVRNA Patients were given peg-IFN 80-150 microg/week plus ribavirin 800-1200 mg/day. Treatment was scheduled for 24 weeks for genotypes 2/3 and 48 weeks for genotypes 1/4. In an intent- to-treat analysis, 16 (26.7%) patients achieved a sustained virological response (SVR). Twenty patients (33.3%) discontinued treatment prematurely, but only in 10 (16.6%) was discontinuation due to adverse events. Negative predictive values for SVR on the basis of HCV-RNA decline between baseline and week 4 were 100% for 1- and 2-log10 fall, and positive predictive values were 40% and 58.3% for 1- and 2-log10 fall, respectively. CD4 fell by a median of 216 cells during treatment, but no HIV-associated complications occurred. In conclusion, treatment with peg-IFN alpha-2b plus ribavirin is safe and clears RNA-HCV in about one-quarter of HIV-infected patients with CHC. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment. Assessment of HCV-RNA at week 4 may help guide early therapeutic decision making. PMID:16623633