Sample records for factor cap alpha

  1. Identification and subcellular localization of a 21-kilodalton molecule using affinity-purified antibodies against. cap alpha. -transforming growth factor

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    Hazarika, P.; Pardue, R.L.; Earls, R.; Dedman, J.R.


    Monospecific antibodies were generated against each of six different peptide sequences derived from rat and human ..cap alpha..-transforming growth factor (..cap alpha..-TGF). The affinity-purified antibody to the 17 amino acid carboxyl-terminal portion of the molecule proved most useful in detecting ..cap alpha..-TGF. When used in a peptide-based radioimmunoassay, it was possible to measure nanogram quantities of native ..cap alpha..-TGF in conditioned cell culture media. When used to analyze cell lysate, these antibodies specifically recognized a 21-kilodalton protein species. Indirect immunofluorescence localization procedures revealed a high concentration of ..cap alpha..-TCF in a perinuclear ring with a diffuse cytoplasmic distribution. These results suggest that a precursor form of ..cap alpha..-TGF has a cellular role beyond that of an autocrine growth factor.

  2. Anti-pp,. cap alpha cap alpha. and p. cap alpha. elastic scattering at high energies and Chou-Yang conjecture

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    Saleem, M.; Fazal-e-Aleem; Rifique, M.


    The recent experimental measurements for anti-pp and ..cap alpha cap alpha.. elastic scattering at high energies have shown that the Chou-Yang conjecture regarding the relationship between the electromagnetic and the hadronic form factor of a particle is only an approximation. A new ansatz has been proposed to obtain hadronic form factors of proton and the ..cap alpha..-particle. These form factors have been used to explain the various characteristics of anti-pp, ..cap alpha cap alpha.. and p..cap alpha.. elastic scattering at high energies.

  3. /sup 56/Fe (. gamma. ,. cap alpha. /sub 0/) reaction

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    Tamae, T; Sugawara, M [Tohoku Univ., Sendai (Japan). Lab. of Nuclear Science; Tsubota, H


    The reaction cross section of /sup 56/Fe (..gamma.., ..cap alpha../sub 0/) was measured from the electron energy of 15 to 25 MeV. The measured data were compared with the calculated ones based on statistic theory. Both agreed with each other. Therefore, the affirmative result was obtained for the presumption that the reaction of (..gamma.., ..cap alpha../sub 0/) of the nuclei around these energy levels can be explained by the statistical theory. The angular distribution of /sup 56/Fe (..gamma.., ..cap alpha../sub 0/) with 17 MeV electron energy was also measured, and the E2/E1 ratio was obtained. In the measurement of the /sup 56/Fe ( Gamma , ..cap alpha../sub 0/) reaction cross section, a natural target of 2.69 mg/cm/sup 2/ was irradiated with an electron beam with energy from 15 MeV to 25 MeV at intervals of 0.5 MeV, and the emitted ..cap alpha.. particles were detected by a broad band magnetic distribution meter. The measured cross section of the (..gamma.., ..cap alpha../sub 0/) reaction agreed with the calculated one based on statistical theory. If this fact is recognized in many nuclei, the cross section of the (..gamma.., ..cap alpha../sub 0/) reaction on those nuclei has the following characteristics. When the increasing rate of the product of a complex nucleus formation cross section and ..cap alpha../sub 0/ penetration factor is larger than that of the sum of all penetration factors of possible channels, the cross section of the (..gamma.., ..cap alpha../sub 0/) reaction increases, and takes a peak value when the above two increasing rates agree with each other.

  4. /sup 58,60,62/Ni (. cap alpha. ,p) three--nucleon transfer reactions and. cap alpha. optical potential ambiguities

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    Yuanda, Wang; Xiuming, Bao; Zhiqiang, Mao; Rongfang, Yuan; Keling, Wen; Binyin, Huang; Zhifu, Wang; Shuming, Li; Jianan, Wang; Zuxun, Sun; others, and


    The differential cross sections are measured using 26.0 MeV ..cap alpha.. particle for /sup 58,62/Ni(..cap alpha.., ..cap alpha..) /sup 58,62/Ni and /sup 58,62/Ni(..cap alpha..,p) /sup 61,65/Cu reactions as well as 25.4 MeV ..cap alpha.. particle for /sup 60/Ni(..cap alpha.., ..cap alpha..)/sup 69/Ni and /sup 60/Ni(..cap alpha.., p)/sup 63/Cu reactions. Consistent calculations with optical model and ZR DWBA are made for (..cap alpha.., ..cap alpha..) and (..cap alpha.., p) reactions by using of single, two, three and four nucleon optical potential parameters. For elastic scattering due to the ..cap alpha.. optical potential ambiguities, all the above optical potential can reproduce the experimental angular distributions. However, the single, two and three nucleon potential, including the Baird's mass systematics and the Chang's energy systematics of ..cap alpha.. potentials, obviously can not provide a reasonable fitting with the (..cap alpha..,p) reaction experimental data. Only the results from the four nucleon potential is in good agreement with the (..cap alpha..,p) reaction experimental data. This reveals that in the ..cap alpha..-particle induced transfer reactions, the real depth of the ..cap alpha..-nucleus optical potential should be rather deep.

  5. X. cap alpha. method with pseudopotentials

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    Szasz, L. (Fordham Univ., New York (USA). Dept. of Physics)


    The X..cap alpha.. method for an atom or molecule is transformed into an all-electron pseudopotential formalism. The equations of the X..cap alpha.. method are exactly transformed into pseudo-orbital equations and the resulting pseudopotentials are replaced by simple density-dependent potentials derived from Thomas-Fermi model. It is shown that the new formalism satisfies the virial theorem. As the first application, it is shown that the model explains the shell-structure of atoms by the property that the pseudo-orbitals for the (ns), (np), (nd), etc. electrons are, in a very good approximation, the solutions of the same equation and have their maxima at the same point thereby creating the peaks in the radial density characterizing the shell structure.

  6. MFTF-. cap alpha. + T progress report

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    Nelson, W.D. (ed.)


    Early in FY 1983, several upgrades of the Mirror Fusion Test Facility (MFTF-B) at Lawrence Livermore National Laboratory (LLNL) were proposed to the fusion community. The one most favorably received was designated MFTF-..cap alpha..+T. The engineering design of this device, guided by LLNL, has been a principal activity of the Fusion Engineering Design Center during FY 1983. This interim progress report represents a snapshot of the device design, which was begun in FY 1983 and will continue for several years. The report is organized as a complete design description. Because it is an interim report, some parts are incomplete; they will be supplied as the design study proceeds. As described in this report, MFTF-..cap alpha..+T uses existing facilities, many MFTF-B components, and a number of innovations to improve on the physics parameters of MFTF-B. It burns deuterium-tritium and has a central-cell Q of 2, a wall loading GAMMA/sub n/ of 2 MW/m/sup 2/ (with a central-cell insert module), and an availability of 10%. The machine is fully shielded, allows hands-on maintenance of components outside the vacuum vessel 24 h after shutdown, and has provisions for repair of all operating components.

  7. Increased 5. cap alpha. -reductase activity in idiopathic hirsutism

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    Serafini, P.; Lobo, R.A.


    In vitro, genital skin 5..cap alpha..-reductase activity (5..cap alpha..-RA) was measured in ten hirsute women with normal androgen levels (idiopathic hirsutism (IH)) and in ten hirsute women with elevated androgen levels (polycystic ovary syndrome (PCO)) in order to determine the influence of secreted androgens on 5..cap alpha..-RA. In vitro 5..cap alpha..-RA was assessed by incubations of skin with /sup 14/C-testosterone (T) for 2 hours, after which steroids were separated and the radioactivity of dihydrotestosterone (DHT) and 5..cap alpha..-androstane 3..cap alpha..-17..beta..-estradiol (3..cap alpha..-diol) in specific eluates were determined. All androgens were normal in IH with the exception of higher levels of 3..cap alpha..-diol glucuronide which were similar to the levels of PCO. The conversion ratio (CR) of T to DHT in IH and PCO were similar, yet significantly greater than the CR of control subjects. The CR of T to 3..cap alpha..-diol in IH and PCO were similar, yet higher than in control subjects. Serum androgens showed no correlation with 5..cap alpha..-RA, while the CR of T to DHT showed a significant positive correlation with the Ferriman and Gallwey score. The increased 5..cap alpha..-RA in IH appears to be independent of serum androgen levels and is, therefore, an inherent abnormality. The term idiopathic is a misnomer, because hirsutism in these patients may be explained on the basis of increased skin 5..cap alpha..-RA.

  8. Synthesis of tritium or deuterium labelled 19-nor-3. cap alpha. -hydroxy-5. cap alpha. -androstan-17-one from nortestosterone

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    Protiva, J; Klinotova, E [Karlova Univ., Prague (Czechoslovakia). Prirodovedecka Fakulta; Filip, J [Ustav pro Vyzkum, Vyrobu a Vyuziti Radioisotopu, Prague (Czechoslovakia); Hampl, R [Research Inst. of Endocrinology, Praha (Czechoslovakia)


    Tritium and/or deuterium (5-H) labelled 19-nor-3..cap alpha..-hydroxy-5..cap alpha..-androstan-17-one (norandrosterone) was prepared from nortestosterone in view to use it as a radioligand for radioimmunoassay of the main nortestosterone metabolites. Based upon model experiments using testosterone and deuterium labelling, the following four step procedure was established: nortestosterone was oxidized with pyridine chlorochromate and the resulting 19-nor-4-androsten-3,17-dione was tritiated with tritium gas under catalysis with tris(triphenylphosphine)rhodium chloride to give (4,5..cap alpha..-/sup 3/H)19-nor-5..cap alpha..-androstan-3,17-dione. A selective reduction of the latter compound yielded (5-/sup 3/H)19-nor-3..cap alpha..-hydroxy-5..cap alpha..-androstan-17-one of the molar radioactivity 0.3 TBq (8.15 Ci)/mmol.

  9. Radioimmunological determination of. cap alpha. -MSH and ACTH in the rat

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    Usategui Echeverria, R; Oliver, C; Vaudry, H; Lombardi, G; Rozenberg, I; Vague, J [Centre Hospitalier Universitaire de la Timone, 13 - Marseille (France)


    Specific and sensitive radioimmunoassay methods for ..cap alpha..-MSH and ACTH are reported. They make possible specific measurements of each hormone in rat plasma or pituitary extracts. Endogenous ..cap alpha..-MSH and ACTH extracted from plasma or pituitary show the same immunoreactivity than synthetic ..cap alpha..-MSH and ACTH. ..cap alpha..-MSH and ACTH levels vary independently from each other in the following conditions: circadian rythm, corticoid treatment, adrenalectomy, ether stress, haloperidol injection.

  10. cap alpha. -spectra hyperfine structure resolution by silicon planar detectors

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    Eremin, V K; Verbitskaya, E M; Strokan, N B; Sukhanov, V L; Malyarenko, A M


    The lines with 13 keV step from the main one is ..cap alpha..-spectra of nuclei with an odd number of nucleons take place. Silicon planar detectors n-Si with the operation surface of 10 mm/sup 2/ are developed for resolution of this hyperfine structure. The mechanism of losses in detectors for short-range-path particles is analyzed. The results of measurements from detectors with 10 keV resolution are presented.

  11. Dynamic. cap alpha. -transfer polarisation potentials and the large angle scattering of /sup 16/O + /sup 28/Si

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    Hussein, M S; Aleixo, A N; Canto, L F; Carrilho, P; Donangelo, R; Paula, L.S. de


    A closed expression is derived for the dynamic ..cap alpha..-transfer polarisation potential for heavy-ion elastic scattering. The back-angle angular distributions for the elastic scattering of /sup 16/O + /sup 28/Si obtained by adding this polarisation potential to the E-18 interaction are shown to be in good agreement with the data if an ..cap alpha..-transfer spectroscopic factor of 0.4 is used.

  12. Szilard-Chalmers effect in natural. cap alpha. disintegrations

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    Haissinsky, M; Cottin, M


    The Szilard-Chalmers effect resulting from the reaction UI(/sup 238/U) ..-->.. UX1(/sup 234/Th) was investigated. The authors developed a chemical method adapted from a technique of Starke (Naturwissenschaften 30, 577(1942)) to separate UX1 which was formed by ..cap alpha.. emission. The experimental accuracy is insufficient to indicate the influence of the degree of dilution of the chemical solutions used on the efficiency of separation, but it is shown that there is a marked decrease in efficiency when solid compounds are used, which is consistent with a hypothesis of Franck and Rabinowitsch (Trans. Faraday Soc. 30, 120(1934)).

  13. Thermodynamics of hydrogen and deuterium solutions in. cap alpha. -zirconium

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    Vinokurov, Yu V; Mogutnov, B M [Tsentral' nyj Nauchno-Issledovatel' skij Inst. Chernoj Metallurgii, Moscow (USSR)


    Interaction of H/sub 2/ and D/sub 2/ with ..cap alpha..-Zr are studied in the 700-890 K temperature range using a high-temperature colorimeter. It is shown that hydrogen and deuterium partial enthalpies in zirconium do not depend on the temperature and concentration and compose -48.9+-1.0 and -46.2+-1.2 kJ/g-at. Calculated is an excess entropy of hydrogen in a solution and analyzed are contributions composing it.

  14. Neutron transition multipole moment for /sup 88/Sr(. cap alpha. ,. cap alpha. ')/sup 88/Sr (2/sup +/, 1. 84 MeV)

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    Datta, S.K.; Ray, S.; Majumdar, H.; Ghosh, S.K.; Samanta, C.; Dasgupta, P.; Chintalapudi, S.N.; Banerjee, S.R.


    The neutron transition multipole moment, M/sub n/, for (0/sup +/..-->..2/sup +/, 1.84 MeV) transition is inferred by measuring the (..cap alpha..,..cap alpha..') angular distribution at E/sub ..cap alpha../ = 50 MeV and comparing it with a microscopic distorted-wave Born approximation calculation. Proton transition densities are taken from electron scattering data. M/sub n//M/sub p/ is found to be substantially less than N/Z in agreement with the (p,p') result.

  15. Involvement of prostaglandins F/sub 2. cap alpha. / and E/sub 1/ with rabbit endometrium

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    Orlicky, D.J.


    Several growth factors and hormones are thought to play a role in the growth control of endometrial cells. The authors have shown that prostaglandin F/sub 2..-->../ (PGF/sub 2..cap alpha../) is a growth factor for primary cultures of rabbit endometrium cultured in chemically-defined serum-free medium and that prostaglandin E/sub 1/ (PGE/sub 1/) antagonizes the PGF/sub 2..-->../ induction of growth. Both (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ bind in a time and temperature dependent, dissociable, saturable and specific manner. The binding of (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ can be both down and up regulated and is enzyme sensitive. PGE /sub 1/ stimulates intracellular cAMP synthesis and accumulation in a time and concentration dependent manner. PGF/sub 2..cap alpha../ probably exerts its effects through an amiloride-sensitive intermediate. Both PGF/sub 2..cap alpha../ and PGE/sub 1/ are constitutively synthesized by these primary cultures, and they have shown this synthesis to be both drug and hormone sensitive. They hypothesize that it is the ratio, rather than the absolute quantities, of PGF/sub 2..cap alpha../ and PGE/sub 1/ which is of more importance in the regulation of endometrial cell growth. Furthermore, they believe this regulation of endometrial growth plays a role in control of proliferation during the decidual response and that a derangement in the ratio of these prostaglandins may lead to either infertility or hyperplasia. The ability of these cultures to synthesize prostaglandins in a hormonally regulatable manner may be of importance in the study of dysmenorrhea and uterine cramping as caused by the myometrial contracting prostaglandin, PGF/sub 2..cap alpha../.

  16. Nicotinic cholinergic receptor in brain detected by binding of. cap alpha. -(/sup 3/H)bungarotoxin

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    Eterovic, V A; Bennett, E L


    ..cap alpha..-(/sup 3/H)bungarotoxin was prepared by catalytic reduction of iodinated ..cap alpha..-bungarotoxin with tritium gas. Crude mitochondrial fraction from rat cerebral cortex bound 40 x 10/sup -15/ to 60 x 10/sup -15/ moles of ..cap alpha..-(/sup 3/H)bungarotoxin per mg of protein. This binding was reduced by 50% in the presence of approx. 10/sup -6/ M d-tubocurarine or nicotine, 10/sup -5/ M acetylcholine, 10/sup -4/ M carbamylcholine or decamethonium or 10/sup -3/ M atropine. Hexamethonium and eserine were the least effective of the drugs tested. Crude mitochondrial fraction was separated into myelin, nerve endings, and mitochondria. The highest binding of toxin per mg of protein was found in nerve endings, as well as the greatest inhibition of toxin binding by d-tubocurarine. Binding of ..cap alpha..-(/sup 3/H)bungarotoxin to membranes obtained by osmotic shock of the crude mitochondrial fraction indicates that the receptor for the toxin is membrane bound. /sup 125/I-labeled ..cap alpha..-bungarotoxin, prepared with Na/sup 125/I and chloramine T, was highly specific for the acetylcholine receptor in diaphragm, however, it was less specific and less reliable than ..cap alpha..-(/sup 3/H)bungarotoxin in brain. It is concluded that a nicotinic cholinergic receptor exists in brain, and that ..cap alpha..-(/sup 3/H)bungarotoxin is a suitable probe for this receptor.

  17. Increased concentration of. cap alpha. - and. gamma. -endorphin in post mortem hypothalamic tissue of schizophrenic patients

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    Wiegant, V.M.; Verhoef, C.J.; Burbach, J.P.H.; de Wied, D.


    The concentrations of ..cap alpha..-, ..beta..- and ..gamma..-endorphin were determined by radioimmunoassay in HPLC fractionated extracts of post mortem hypothalamic tissue obtained from schizophrenic patients and controls. The hypothalamic concentration of ..cap alpha..- and ..gamma..-endorphin was significantly higher in patients than in controls. No difference was found in the concentration of ..beta..-endorphin, the putative precursor of ..cap alpha..- and ..gamma..-endorphins. These results suggest a deviant metabolism of ..beta..-endorphin in the brain of schizophrenic patients. Whether this phenomenon is related to the psychopathology, or is a consequence of ante mortem farmacotherapy, remains to be established.

  18. Preparation of radioiodinated insulin and thyroid stimulating hormone using 1,3,4,6-tetrachloro-3. cap alpha. , 6. cap alpha. -diphenylglycouril (iodogen) for radioimmunoassay

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    Pillai, M R.A.; Gupte, J H; Jyotsna, T; Mani, R S


    Radioiodinated insulin and thyroid stimulating hormones were prepared using 1,3,4,6-tetrachloro-3..cap alpha.., 6..cap alpha..-diphenylglycouril (iodogen). Conditions of iodination like concentration of iodogen, reaction time, etc. were optimized to get maximum yield. Stability studies of iodogen coated tubes were carried out over a period of time. The dependence of iodination yield on varying amounts of activity and protein concentration were investigated. Iodination yield over a range of pH was also studied. The radiolabelled hormones prepared by this method were used in radioimmunoassay and compared with tracers prepared by the Chloramine-T method. (author) 16 refs.; 5 tabs.

  19. Pilot plant production of glucose from starch with soluble. cap alpha. -amylase and immobilized glucoamylase

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    Lee, D D; Reilly, P J; Collins, Jr, E V


    Pilot plant studies were conducted on cooking and thinning of corn starch with free ..cap alpha..-amylase and the conversion of the resulting dextrin with immobilized glucoamylase adsorbed on porous SiO/sub 2/. Feeds of intermediate DE values gave maximum yields unless the flow rate of low DE feeds was decreased. Final DE values and glucose concentrations after dextrin treated with Thermamyl 60 ..cap alpha..-amylase had been further hydrolyzed in an immobilized glucoamylase column, were slightly lower than they were when free glucoamylase was used. Similar results were obtained when dextrin, thinned with HT-1000 ..cap alpha..-amylase, was hydrolyzed at 38/sup 0/ and pH 4.4 in the immobilized glucoamylase column. Free glucoamylase yielded values of DE and glucose almost identical with dextrin thinned with Thermamyl 60 ..cap alpha..-amylase. Yields with the free glucoamylase were also slightly higher than they were with SiO/sub 2/-bound enzyme.

  20. Synthetic. cap alpha. subunit peptide 125-147 of human nicotinic acetylcholine receptor induces antibodies to native receptor

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    McCormick, D.J.; Griesmann, G.E.; Huang, Z.; Lennon, V.A.


    A synthetic peptide corresponding to residues 125-147 of the Torpedo acetylcholine receptor (AChR) ..cap alpha.. subunit proved to be a major antigenic region of the AChR. Rats inoculated with 50 of peptide (T ..cap alpha.. 125-147) developed T cell immunity and antibodies to native AChR and signs of experimental autoimmune myasthenia gravis. They report the synthesis and preliminary testing of a disulfide-looped peptide comprising residues 125-147 of the human AChR ..cap alpha.. subunit. Peptide H ..cap alpha.. 125-147 differs from T ..cap alpha.. 125-147 at residues 139 (Glu for Gln) and 143 (Ser for Thr). In immunoprecipitation assays, antibodies to Torpedo AChR bound /sup 125/I-labelled H..cap alpha.. 125-147 antibody bound H..cap alpha.. 125-147, but monoclonal antibodies to an immunodominant region of native AChR bound neither H..cap alpha.. 125-147 nor T ..cap alpha.. 125-147. Rats immunized with H ..cap alpha.. 125-147 produced anti-mammalian muscle AChR antibodies that induced modulation of AChRs from cultured human myotubes. Thus, region 125-147 of the human AChR ..cap alpha.. subunit is extracellular in muscle, and is both antigenic and immunogenic. It remains to be determined whether or not autoantibodies to this region may in part cause the weakness or myasthenia gravis in man.

  1. Angular correlation between short-range. cap alpha. particles and. gamma. quanta

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    Kul' chitskii, L A; Latyshev, G D; Bulyginskii, D G


    Chang (Phys. Rev. 69, 60(1946); 70, 632(1946)) has found that the intensities of short-range ..cap alpha.. rays of Po and Ra are considerably higher than the values given by the Geiger-Nuttall law. This can be explained by assuming surface vibrations of ..cap alpha..-radioactive nuclei, which produce deformations and corresponding lowerings of the potential barrier in certain directions. In this case an angular correlation should exist between the short-range ..cap alpha.. ray and the accompanying ..gamma.. quantum. The authors checked this conclusion by applying the coincidence method to the ..cap alpha.. and ..gamma.. radiations of a mixture of RdTh (/sup 228/Th) and ThC (/sup 212/Bi). Maxima of coincidence numbers occur at angles 45 and 135 deg., with lesser maxima at 0 and 180 deg. Theoretical considerations show that in cases (like the one investigated) where the nuclear spin before and after the ..cap alpha.. and ..gamma.. emissions is zero, the angular correlations are uniquely determined whatever the deformation caused by the vibration; in other cases, the correlation depends on the kind of deformation. Therefore, it would be interesting to investigate the case of Pa, whose nuclear spin is not zero and the decay exhibits intensive groups of short-range ..cap alpha.. particles.

  2. Mapping of the mouse actin capping protein {alpha} subunit genes and pseudogenes

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    Hart, M.C.; Korshunova, Y.O.; Cooper, J.A. [Washington Univ. School of Medicine, St. Louis, MO (United States)


    Capping protein (CP), a heterodimer of {alpha} and {beta} subunits, is found in all eukaryotes. CP binds to the barbed ends of actin filaments in vitro and controls actin assembly and cell motility in vivo. Vertebrates have three {alpha} isoforms ({alpha}1, {alpha}2, {alpha}3) produced from different genes, whereas lower organisms have only one gene and one isoform. We isolated genomic clones corresponding to the a subunits of mouse CP and found three {alpha}1 genes, two of which are pseudogenes, and a single gene for both {alpha}2 and {alpha}3. Their chromosomal locations were identified by interspecies backcross mapping. The {alpha}1 gene (Cappa1) mapped to Chromosome 3 between D3Mit11 and D3Mit13. The {alpha}1 pseudogenes (Cappa1-ps1 and Cappa1-ps2) mapped to Chromosomes 1 and 9, respectively. The {alpha}2 gene (Cappa2) mapped to Chromosome 6 near Ptn. The {alpha}3 gene (Cappa3) also mapped to Chromosome 6, approximately 68 cM distal from Cappa2 near Kras2. One mouse mutation, de, maps in the vicinity of the {alpha}1 gene. No known mouse mutations map to regions near the {alpha}2 or {alpha}3 genes. 29 refs., 3 figs., 1 tab.

  3. Distribution and excretion of. cap alpha. -naphthylthio-(/sup 14/C)urea in Albino rats

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    Patil, T N; Radhakrishnamurty, R [Central Food Technological Research Inst., Mysore (India)


    ..cap alpha..-naphthylthio-(/sup 14/C) urea was synthesised by allowing potassium (/sup 14/C)thiocyanate to react with ..cap alpha..-naphthylamine. Its distribution and excretion were studied in Albino rats following the administration of this rodenticide. Considerable radioactivity observed in liver and kidney, increased till 8 hr and later decreased. About 80% of the activities present in serum and pleural effusion were found in the respective albumin fractions. Approximately 40% of the dose administered was excreted in urine and less than 1% in faeces in 20 hr. About 36% of the total urinary activity was recovered as unchanged compound and the rest was distributed in three metabolites with low Rsyb(f) values. Decrease in cytochsome P-450 content and activities of N, N-dimethylaniline demethylase, aryl 4-hydroxylase and reduced NAD dehydrogenase were observed in ..cap alpha..-naphthylathiourea-treated rats.

  4. Structure of the radio emission from the NGC 1579/LkH. cap alpha. 101 region

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    Brown, R L [National Radio Astronomy Observatory, Charlottesville, Va. (USA); Broderick, J J; Knapp, G R


    Radio-frequency observations at 3.7 and 11 cm of the NGC 1579/LkH..cap alpha..101 region show that the radio emission arises in a compact, < 1'' core concentric with a more extended approximately 1' emission region. At these wavelengths the compact component is optically thick, with a spectrum increasing as, whereas the extended region is optically thin and contributes at least 80 per cent of the total flux density. LkH..cap alpha..101 appears to be the source of excitation for all of the radio emission; this result, together with the total infrared luminosity, suggests that an appropriate spectral classification for LkH..cap alpha..101 is B1 IIe.

  5. Application of multi-step direct reaction theory to 14 MeV neutron reaction, 3 (n,. cap alpha. )

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    Kumabe, I.; Matoba, M.; Fukuda, K. [Kyushu Univ., Fukuoka (Japan). Faculty of Engineering; Ikegami, H.; Muraoka, M [eds.


    Multi-step direct-reaction theory proposed by Tamura et al. has been applied to continuous spectra of the 14 MeV (n, ..cap alpha..) reaction with some modifications. Calculated results reproduce well the experimental energy and angular distributions of the 14 MeV (n, ..cap alpha..) reactions.

  6. Nickel doping effect on resistance to movement of edge dislocations in. cap alpha. -Fe

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    Brovkov, V.A.; Dudarev, E.F. (Tomskij Gosudarstvennyj Univ. (USSR). Sibirskij Fiziko-Tekhnicheskij Inst.)


    Microplastic deformation of ..cap alpha..-Fe polycrystals and Fe-Ni solid solutions is studied. Data on the concentration and temperature dependences of resistance to movement of edge dislocation at the expense of elastic interaction with atoms of the doping element are obtained.

  7. Agonist-induced affinity alterations of a central nervous system. cap alpha. -bungarotoxin receptor

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    Lukas, R.J.; Bennett, E.L.


    The ability of cholinergic agonists to block the specific interaction of ..cap alpha..-bungarotoxin (..cap alpha..-Bgt) with membrane-bound sites derived from rat brain is enhanced when membranes are preincubated with agonist. Thus, pretreatment of ..cap alpha..-Bgt receptors with agonist (but not antagonist) causes transformation of sites to a high-affinity form toward agonist. This change in receptor state occurs with a half-time on the order of minutes, and is fully reversible on dilution of agonist. The results are consistent with the identity of ..cap alpha..-Bgt binding sites as true central nicotinic acetylcholine receptors. Furthermore, this agonist-induced alteration in receptor state may represent an in vitro correlate of physiological desensitization. As determined from the effects of agonist on toxin binding isotherms, and on the rate of toxin binding to specific sites, agonist inhibition of toxin binding to the high-affinity state is non-competitive. This result suggests that there may exist discrete toxin-binding and agonist-binding sites on central toxin receptors.

  8. Characterization and application of a radioimmunoassay for reduced, carboxymethylated human luteinizing hormone. cap alpha. -subunit. [/sup 125/I tracer technique

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    Keutmann, H.T.; Beitins, I.Z.; Johnson, L.; McArthur, J.W.


    We have established a double antibody RIA using a rabbit antiserum prepared against reduced, carboxymethylated (RCXM) human LH ..cap alpha..-subunit, with RCXM-..cap alpha.. as tracer and standard. This antiserum did not cross-react with any native gonadotropins or subunit, and reacted only weakly with RCXM-..cap alpha... A tryptic digest of RCXM ..cap alpha..-subunit was completely reactive, while chymotryptic digestion abolished all immunoreactivity. By testing with separate tryptic fragments, the recognition site could be localized to a segment close to the amino-terminus of the peptide chain. When applied to measurement of serum and urine, an immunoreactive species, parallel to RCXM ..cap alpha..-subunit by serial dilution, was found in concentrations of 1-2 ng/ml in serum and 3-4 ng/ml in urine. Similar levels of the immunoreactive component were found in conditions of elevated gonadotropins (e.g. pregnancy) as well as gonadotropin deficiency (panhypopituitarism and Kallmann's syndrome). After stimulation with LHRH, no rise was noted at times up to 6 h despite the fact that both LH and LH-..cap alpha.. were elevated. The data indicate that the sequence-specific antiserum may be detecting an immunoreactive form of ..cap alpha..-subunit of LH whose kinetics of appearance and disappearance differs from those of the native subunit.

  9. Effects of local anesthetics on cholinergic agonist binding affinity of central nervous system. cap alpha. -bungarotoxin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Lukas, R.L.; Bennett, E.L.


    In general, pharmacological effects of local anesthetics may be attributed to their ability to reversibly block the propagation of nerve and muscle action potentials. At physiologically potent concentrations, local anesthetics (LA) also act as noncompetitive antagonists of the physiological response of post-synaptic nicotinic acetylcholine receptors (nAChR) to cholinergic agonists, and increase agonist binding affinities of nAChR from electric organ. It is postulated that the primary site of LA action on nAChR function is at the receptor-coupled ionophore. Furthermore, LA-nAChR ionophore interactions are thought to accelerate physiological desensitization of nAChR, manifest biochemically as increased affinity of nAChR for agonist. Specific receptors for ..cap alpha..-bungarotoxin (..cap alpha..-Bgt), a potent competitive antagonist at nAChR sites in the periphery, have been detected in rat central nervous system membrane preparations. The affinity of these central ..cap alpha..-Bgt receptors (..cap alpha..-BgtR) for cholinergic agonists is found to increase on exposure to agonist. Nevertheless, on the basis of inconsistent pharmacological and physiological results, uncertainty remains regarding the relationship between ..cap alpha..-BgtR and authentic nAChR in the CNS, despite a wide body of biochemical and histological evidence consistent with their identity. Reasoning that if CNS ..cap alpha..-BgtR are true in nAChR, coupled to functional ion channels, LA might be expected to cause biochemically measurable increases in ..cap alpha..-BgtR affinity for cholinergic agonists, we have undertaken a study of the effects of LA on the ability of acetylcholine (ACh) to inhibit interaction of ..cap alpha..-BgtR with /sup 3/H-labeled ..cap alpha..-Bgt.

  10. Alpha-cyclodextrins reversibly capped with disulfide bonds

    Czech Academy of Sciences Publication Activity Database

    Kumprecht, Lukáš; Buděšínský, Miloš; Bouř, Petr; Kraus, Tomáš


    Roč. 34, č. 10 (2010), s. 2254-2260 ISSN 1144-0546 R&D Projects: GA AV ČR IAA400550810 Institutional research plan: CEZ:AV0Z40550506 Keywords : cyclodextrins * disulfide bond * dynamic covalent bond Subject RIV: CC - Organic Chemistry Impact factor: 2.631, year: 2010

  11. Reconstruction of spin-tensor of 4. 43 MeV state density matrix of the /sup 12/C nucleus in the /sup 12/C(. cap alpha. ,. cap alpha. sub(1). gamma. sub(4,43))/sup 12/C reaction at Esub(. cap alpha. )=25 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Gurevich, G.S.; Lebedev, V.M.; Orlova, N.V.; Spasskij, A.V.; Teplov, I.B.; Shakhvorostova, G.V.; Belkina, M.R. (Moskovskij Gosudarstvennyj Univ. (USSR). Nauchno-Issledovatel' skij Inst. Yadernoj Fiziki)


    The results of measuring double differential cross sections of the reaction of inelastic scattering 24.8 MeV ..cap alpha..-particles sup(12)C(..cap alpha.., ..cap alpha..sub(1)..gamma..sub(4.43))sup(12)C in different planes of ..gamma..-quantum escape relatively to the plane of the reaction phisub(..gamma..)=30, 60 and 90 deg are presented. Non-monochromaticity of the beam made up 1%. Functions of angular correlation of the reaction are measured for four angles THETAsub(..cap alpha..)=21, 39, 59 and 135 deg corresponding to maxima of differential cross section in angular distribution of inelastically scattered ..cap alpha..-particles and for THETAsub(..cap alpha..)=89 deg corresponding to the minimum of angular distribution. The results of measurements permit to reconstruct all the components of irreducible spin-tensors of the matrix of state density 4.43 MeV (2/sup +/) formed in this reaction. The values of populations of substates by the projection of the spin of this state are obtained. The analysis of the obtained results testify to the fact that mechanism of inelastic scattering is not reduced to impulse approximation and mechanisms associated with delay in interaction do not make noticeable contribution for the given angles of ..cap alpha..-particle escape.

  12. Martensite. gamma. -->. cap alpha. transformations in various purity Fe-Ni-Mo alloys

    Energy Technology Data Exchange (ETDEWEB)

    Nikitina, I.I.; Rozhkova, A.S. (Tsentral' nyj Nauchno-Issledovatel' skij Inst. Chernoj Metallurgii, Moscow (USSR))


    Kinetics of isothermal and athermal ..gamma.. ..-->.. ..cap alpha.. martensitic transitions in the Fe-25.5% Ni-4.5% Mo alloys with different degree of purity is studied. The determinant role of dislocation blocking by interstitials in stabilization of isothermal martensitic transformation is displayed. Presented are the data permitting to consider that the character of martensitic transition kinetics is determined by the ratio of the process moving force and resistance to microplastic deformation.

  13. Purification and physicochemical properties of. cap alpha. -amylase from irradiated wheat

    Energy Technology Data Exchange (ETDEWEB)

    Machaiah, J P; Vakil, U K [Bhabha Atomic Research Centre, Bombay (India). Biochemistry and Food Technology Div.


    ..cap alpha..-Amylases from control and gamma-irradiated (at 0.2 and 2.0 kGy dose levels) wheat seedlings were purified to homogeneity and characterized. The molecular weight of the enzyme from a 2 kGy irradiated sample was slightly lower than that of the control; other general and catalytic properties also showed some differences. ..cap alpha..-Amylase from the irradiated (2kGy) sample had a narrow range of pH optimum and was inactivated faster at alkaline pH and by heat treatment than the enzyme from unirradiated wheat. A high apparent Michaelis constant (Ksub(m)) and a low maximal velocity (Vsub(max)) for the hydrolysis of soluble starch catalyzed by the enzyme from irradiated (2kGy) wheat, suggested some modifications in the formation of the substrate ..cap alpha..-amylase complex. Further, of the total number of amino acid residues lost on irradiation, dicarboxylic amino acids constituted the largest percentage; these structural alterations in the enzyme may be responsible for its partial inactivation. The total sugars liberated upon amylolysis of starch with the 2kGy irradiated enzyme were lower than control, and there was accumulation of higher maltodextrins in the place of maltose.

  14. Accumulation of glycation products in. cap alpha. -H pig lens crystallin and its bearing to diabetic cataract genesis

    Energy Technology Data Exchange (ETDEWEB)

    Vidal, P; Cabezas-Cerrato, J


    The incorporation of /sup 11/C-glucose in native pig crystalline by in vitro incubation was found, after subsequent dialysis, to affect all 5 classes of crystallin separated by Sepharose CL-6B column chromatography. Though the radioactivity of the ..cap alpha..-H fraction was three times greater than that of any of the others, autoradiographs of SDS-PAGE gels showed /sup 11/C-glucose adducts to be present in all soluble protein subunits, without there being any evidence of preferential glycation of the ..cap alpha..-H subunits. The concentration of stable glycation products in the ..cap alpha..-H chromatographic fraction of soluble crystallins is suggested to be due the addition of glycated material to this fraction as result of glycation-induced hyperaggregation, and not because the ..cap alpha..-H subunits were especially susceptible to glycation.

  15. Scattering of alpha particles from /sup 12/C and the /sup 12/C(. cap alpha. ,. gamma. )/sup 16/O stellar reaction rate

    Energy Technology Data Exchange (ETDEWEB)

    Plaga, R.; Becker, H.W.; Redder, A.; Rolfs, C.; Trautvetter, H.P.; Langanke, K.


    The elastic scattering of alpha particles from /sup 12/C has been investigated for 35 angles in the range theta/sub lab/ = 22/sup 0/ to 163/sup 0/ and for 51 energies at E/sub ..cap alpha../ = 1.0 to 6.6 MeV. The extracted phase shifts for l=0 to 6 partial waves have been parametrized in terms of the multilevel R-matrix formalism. Information on the deduced parameters of states in /sup 16/O is reported. The data reveal reduced ..cap alpha..-particle widths for the 6.92 and 7.12 MeV subthreshold states consistent with recent work. The implications for the stellar reaction rate of /sup 12/C(..cap alpha..,..gamma..)/sup 16/O are discussed.

  16. Release of /sup 3/H-. cap alpha. -methyl-m-tyramine from rat striatum in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Dorris, R L [Baylor College of Dentistry, Dallas, Tex. (USA). Dept. of Pharmacology


    Release of /sup 3/H-d-..cap alpha..-methyl-m-tyramine (/sup 3/H-MMTA), a false dopaminergic transmitter from rat striatum was studied in vitro. After its initial uptake, /sup 3/H-MMTA was released by high K/sup +/ and by amphetamine. The release requirements were essentially the same as those known to exist for release of dopamine in vitro. These studies indicate that /sup 3/H-MMTA might serve as a useful tool with which to study dopamine release mechanisms in vitro.

  17. Monoclonal antibodies for use in an immunoradiometric assay for. cap alpha. -foetoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Hunter, W.M.; Bennie, J.G. (Medical Research Council, Edinburgh (UK). Immunoassay Team); Brock, D.J.H.; Heyningen, V. van (Western General Hospital, Edinburgh (UK))


    The advantages offered by a mouse IgG/sub 1/ monoclonal antibody to human ..cap alpha..-foetoprotein (AFP) for the preparation of (/sup 125/I)antibody for use in an immunoradiometric assay (IRMA) have been investigated. The antibody was isolated from ascites fluid by sodium sulphate precipitation followed by gel filtration on Sephadex G-200. The freeze-dried powder and solutions thereof were stable and were used for iodination to 1 atom /sup 125/I/molecule antibody by the chloramine-T procedure. At high antigen concentrations 70-80% of the added (/sup 125/)Ab was present in the sandwich. Linear response curves in the range 1-100 antigen/l incubate were obtained when (/sup 125/I)Ab was in slight excess. In this region an Ag : Ab ratio 1.9 : 1 was obtained which is consistent with the saturation of a bifunctional antibody. Although non-specific binding (in the absence of antigen) was consistently <0.1% of added (/sup 125/I)Ab, this was the main factor in determining assay detection limits. The serum AFP levels from both non-pregnant and pregnant subjects as measured by the IRMA using the (/sup 125/I)monoclonal Ab and by radioimmunoassay (RIA) using a sheep antiserum to AFP were in excellent agreement. The IRMA was manipulatively simple, employed a shorter incubation time (2h), required shorter counting times than the RIA and gave a much wider working range. The provision of a monoclonal antibody for labelling removes the one major practicability barrier which otherwise limits the development and use of the potentially superior IRMA system.

  18. Secondary. cap alpha. -deuterium kinetic isotope effects in solvolyses of ferrocenylmethyl acetate and benzoate in ethanol

    Energy Technology Data Exchange (ETDEWEB)

    Sutic, D. (Univ. of Zagreb, Yugoslavia); Asperger, S.; Borcic, S.


    Secondary ..cap alpha..-deuterium kinetic isotope effects (KIE) in solvolyses of ferrocenyldideuteriomethyl acetate and benzoate were determined in 96% (v/v) ethanol, at 25/sup 0/C, as k/sub H//k/sub D/ = 1.24 and 1.26, respectively. The KIEs were also determined in the presence of 0.1 mol dm/sup -3/ lithium perchlorate: the k/sub H//k/ sub D/ values were 1.23 and 1.22 for acetate and benzoate complexes, respectively. The maximum KIE for the C-O bond cleavage of a primary substrate is as large as, or larger than, that of secondary derivatives, which is estimated to be 1.23 per deuterium. The measured KIE of about 12% per D therefore represents a strongly reduced effect relative to its maximum. The solvolyses exhibit ''a special salt effect''. This effect indicates the presence of solvent-separated ion pairs and the return to tight pairs. As the maximum KIE is expected in solvolyses involving transformation of one type of ion pair into another, the strongly reduced ..cap alpha..-D KIE supports the structure involving direct participation of electrons that in the ground state are localized at the iron atom. The alkyl-oxygen cleavage is accompanied by 10-15% acyl-oxygen cleavage.

  19. cap alpha. -bungarotoxin binding properties of a central nervous system nicotinic acetylcholine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lukasiewicz, R J; Bennett, E L


    High-affinity, specific binding of radiolabeled ..cap alpha..-bungarotoxin to particulate fractions derived from rat brain shows saturability (B/sub max/ approx. = 37fmol/mg, K/sub D//sup app/ = 1.7 nM) and insensitivity to ionic strength, and is essentially irreversible (K/sub on/ = 5 x 10/sup 6/ min/sup -1/ x mol/sup -1/; K(displacement) = 1.9 x 10/sup -4/ min/sup -1/, tau/sub 1/2/ = 62 h). Subcellular distribution of specific sites is consistent with their location on synaptic junctional complex and post-synaptic membranes. These membrane-bound binding sites exhibit unique sensitivity to cholinergic ligands; pretreatment of membranes with cholinergic agonists (but not antagonists) induces transformation of ..cap alpha..-bungarotoxin binding sites to a high affinity form toward agonist. The effect is most marked for the natural agonist, acetylcholine. These results strongly support the notion that the entity under study is an authentic nicotinic acetylcholine receptor.

  20. Fine structure of the magnetic spectrum of. cap alpha. -rays of ionium

    Energy Technology Data Exchange (ETDEWEB)

    Rosenblum, S; Valadares, M; Vial, J


    Using as source of Io--Th an electrolytic deposit on Pt made in 1945 (27% Io), the authors studied the magnetic spectrum of the ..cap alpha..-radiation of Io from long-exposure photographs (4 to 21 days) submitted to a microscopic counting. From a simultaneously obtained ..cap alpha..-spectrum of ThC a ratio was obtained which permitted the assigning of a value of 4682 +- 10 keV to the energy of the most rapid group of Io. This group is separated from another, of a similar order of intensity, by 69 keV. A still slower group seems to exist at 170 keV from the first one (cf Ward, Proc Cambridge Phil Soc 35 322(1939)). There are indications that the groups are of a complex nature, which points to the possible existence either of a soft gamma spectrum or of a complicated beta spectrum. The presence of Ra accumulated since 1945 is visible on the spectra obtained; in a few years it will be possible to determine directly, by the method used, the half life of Ra.

  1. Coincidence measurement between. cap alpha. -particles and projectile-like fragments in reaction of 82. 7 MeV /sup 16/O on /sup 27/Al

    Energy Technology Data Exchange (ETDEWEB)

    Wen-Qing, Shen; Wen-long, Zhan; Yong-tai, Zhu; Shu-zhi, Yin; Zhong-yan, Guo; Wei-min, Qiao; Guo-ying, Fan; Gen-ming, Jin; Song-ling, Li; Zhen, Zhang; others, and


    In the coincidence measurement between ..cap alpha..-particles and projectile-like fragments in the reaction of 82.7 MeV /sup 16/O on /sup 27/Al, the contour plot of the C-..cap alpha.. coincidence in the velocity plane and the coincident angular correlation are obtained. Different mechanisms of ..cap alpha..-particle emission are analysed. A possible reaction mechanism of incomplete DIC is discussed.

  2. Gating at the mouth of the acetylcholine receptor channel: energetic consequences of mutations in the alphaM2-cap.

    Directory of Open Access Journals (Sweden)

    Pallavi A Bafna


    Full Text Available Gating of nicotinic acetylcholine receptors from a C(losed to an O(pen conformation is the initial event in the postsynaptic signaling cascade at the vertebrate nerve-muscle junction. Studies of receptor structure and function show that many residues in this large, five-subunit membrane protein contribute to the energy difference between C and O. Of special interest are amino acids located at the two transmitter binding sites and in the narrow region of the channel, where CO gating motions generate a lowhigh change in the affinity for agonists and in the ionic conductance, respectively. We have measured the energy changes and relative timing of gating movements for residues that lie between these two locations, in the C-terminus of the pore-lining M2 helix of the alpha subunit ('alphaM2-cap'. This region contains a binding site for non-competitive inhibitors and a charged ring that influences the conductance of the open pore. alphaM2-cap mutations have large effects on gating but much smaller effects on agonist binding, channel conductance, channel block and desensitization. Three alphaM2-cap residues (alphaI260, alphaP265 and alphaS268 appear to move at the outset of channel-opening, about at the same time as those at the transmitter binding site. The results suggest that the alphaM2-cap changes its secondary structure to link gating motions in the extracellular domain with those in the channel that regulate ionic conductance.

  3. Effects of Pauli's principle in the. cap alpha. - /sup 16/O elastic scattering

    Energy Technology Data Exchange (ETDEWEB)

    Schechter, H; Canto, L F; Breitschaft, A M


    'Exact' microscopic methods like the RGM (Resonating Group Method) and the GCM (Generator Coordinate Method) and approximate methods like the OCM (Orthogonality Condition Model) are used to study the effects of Pauli's Principle in the ..cap alpha..-/sup 16/O elastic scattering. A method to derive 'exact' effective potentials for the OCM is introduced. These potentials, derived from RGM wave functions, make the OCM identical to the RGM and they have the advantage of being free from poles associated to the forbidden states. Numerical calculations are made with V2 and B1 nucleon-nucleon forces at energies in the range 0-30 MeV. The potentials and the resulting phase-shifts are compared to those obtained from the approximate method suggested by Friedrich and Canto. The problem of searching for local, state independent, potentials for the OCM is discussed.

  4. Study of. cap alpha. -/sup 16/O scattering by orthogonality condition models

    Energy Technology Data Exchange (ETDEWEB)

    Breitschaft, A M; Canto, L F; Schechter, H


    The use of approximate microscopic theories in ..cap alpha..-/sup 16/O scattering is investigated. The Orthogonality Condition Model (OCM) with both the direct potential of the Resonating Group Method (RMG) and with an effective local potential, V sub(eff), derived from Kernels of Generator Coordinate Method (GCM) is employed to study collisions at CM energies up to 30 MeV, for all relevant partial waves. Although the predictions of the OCM are consistent with exact RGM results in both cases, the nuclear phase-shifts obtained with the effective potential are better. The presence of ambiguities in the derivation of V sub(eff) is noticed. The nature of such ambiguities is discussed.

  5. Effects of thyroid status on presynaptic. cap alpha. 2-adrenoceptor and. beta. -adrenoceptor binding in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Atterwill, C.K.; Bunn, S.J.; Atkinson, D.J. (Development Neurobiology Unit, London (UK). Inst. of Neurology); Smith, S.L.; Heal, D.J. (Radcliffe Infirmary, Oxford (UK))


    The effect of thyroid status on noradrenergic synaptic function in the mature brain was examined by measuring presynaptic ..cap alpha..2- and postsynaptic ..beta..-adrenoceptors. Repeated triiodothyronine (T/sub 3/) administration to rats ( x 14 days hyperthyroid) caused an 18% increase in striatal ..beta..-adrenoceptors as shown by (/sup 3/H)-dihydroalprenolol binding with no change in membranes from cerebral cortex or hypothalamus. In contrast, hypothyroidism (propylthiouracil, PTU x 14 days) produced significant 12% and 30% reductions in striatal and hypothalamic ..beta..-adrenoceptors respectively with no change in the cerebral cortex. Presynaptic ..cap alpha..2-adrenoceptor function was measured in the two dysthyroid states using the clonidine-induced hypoactivity model. Experimental hyperthyroidism increased the degree of clonidine-induced hypoactivity, and suggests increased presynaptic ..cap alpha..2-adrenoceptor function compared with control rats, whereas hypothyroidism suppressed presynaptic ..cap alpha..2-adrenoceptor function. These results show firstly that changes of thyroid status in the mature rat may produce homeostatic alterations at central noradrenergic synapses as reflected by changes in pre- and postsynaptic adrenoceptor function. Secondly, there appear to be T/sub 3/-induced changes in ..beta..-adrenoceptors in the striatum where changes in dopaminergic neuronal activity have previously been demonstrated.

  6. Reaction /sup 56/Fe (. gamma. ,. cap alpha. /sub 0/) and /sup 56/Fe (. gamma. , p/sub 0/)

    Energy Technology Data Exchange (ETDEWEB)

    Tamae, T; Sugawara, M [Tohoku Univ., Sendai (Japan). Lab. of Nuclear Science; Tsubota, H


    Precise analysis was made on the cross section of the /sup 56/Fe (..gamma.., ..cap alpha../sub 0/) reaction and the angular distribution at Esub(e) = 17 MeV, including the systematic error. The (..gamma.., ..cap alpha../sub 0/) reaction cross section was compared with a calculation using the compound nucleus model, utilizing the photon absorption cross section derived from the experimental values of /sup 56/Fe (..gamma.., n) and /sup 56/Fe (..gamma.., p) cross sections. From the (..gamma.., ..cap alpha../sub 0/) reaction cross section data of various nuclei, an empirical formula was obtained for determining the position of a peak in the (..gamma.., ..cap alpha../sub 0/) reaction cross section. The /sup 56/Fe (..gamma.., p/sub 0/) reaction cross section measured at an excitation energy in the range of 14.6--25.0 MeV was compared with the calculated one with the compound nucleus model, but the form and size differ totally.

  7. Kinetic properties of /sup 3/H-16. cap alpha. -gitoxin in the isolated guinea-pig atrium

    Energy Technology Data Exchange (ETDEWEB)

    Haustein, K O; Glusa, E [Medizinische Akademie, Erfurt (German Democratic Republic)


    The accumulation and the loss of (/sup 3/H)-16..cap alpha..-gitoxin were estimated in correlation with its positive inotropic effect using the isolated spontaneously beating guinea-pig atrium. The properties of 16..cap alpha..-gitoxin were compared with those of (/sup 3/H)-ouabain and (/sup 3/H)-digitoxin. The experiments were performed with positive inotropic equieffective glycoside concentrations. During a 2-hr incubation period, 16..cap alpha..-gitoxin was accumulated to a low extent (2.05 nmoles per g w.w., tissue/medium (T/M) ratio =0.66). Similar results were obtained with ouabain (47.5 pmoles per g w.w.; T/M ratio = 0.51), while digitoxin was accumulated to a high extent (266 pmoles per g w.w.; T/M ratio = 2.98). Wash-out experiments demonstrated that the inotropic effect disappears more rapidly than the loss of tissue radioactivity occurred, the effects of 16..cap alpha..-gitoxin were diminished more easily after wash-out than those of ouabain and digitoxin. In the presence of 1.0 instead of 0.1 vol-% dimethylformamide, both the accumulation of radioactivity (5.0 nmoles per g w.w.; T/M ratio = 1.58) and the positive inotropic effect are enhanced. From the experiments it was concluded: (1) 16..cap alpha..-gitoxin has similar kinetic properties as ouabain. (2) The concentration of dimethylformamide used influences the kinetic behaviour on the tissue level. (3) No correlation exists neither between the extent of the positive inotropic effect and theamount of accumulated glycoside, nor between the loss of tissue radioactivity and the disappearance of positive inotropic effect.

  8. Comparative study of G2 delay and survival after /sup 241/Americium-. cap alpha. and /sup 60/Cobalt-. gamma. irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Luecke-Huhle, C.; Comper, W.; Hieber, L.; Pech, M.


    Survival and G2 delay following exposure to either /sup 60/Cobalt-..gamma..-rays or /sup 241/Americium-..cap alpha..-particles were studied in eight mammalian cell lines of human and animal origin including human fibroblasts from normal individuals and from patients with Ataxia telangiectasia or Fanconi's anemia. For both endpoints the effectiveness of alpha particle was greater as compared to ..gamma..-rays. RBE values for G2 delay (4.6-9.2) were in general comparable to RBE values derived from initial slopes of survival curves but higher compared to the ratio of mean inactivation doses. Ataxia cells were particularly sensitive to cell killing by ..gamma..-irradiation, however, showed average sensitivity to ..cap alpha..-particles of high LET. With the exception of Ataxia cells, cell killing and G2 delay seem to be related processes if individual cell cycle parameters are taken into account.

  9. Energy dependence of the zero-range DWBA normalization of the /sup 58/Ni(/sup 3/He,. cap alpha. )/sup 57/Ni reaction. [15 to 205 GeV, finite-range and nonlocality corrections

    Energy Technology Data Exchange (ETDEWEB)

    Shepard, J R; Zimmerman, W R; Kraushaar, J J [Colorado Univ., Boulder (USA). Dept. of Physics and Astrophysics


    Strong transitions in the /sup 58/Ni(/sup 3/He,..cap alpha..)/sup 57/Ni reaction were analyzed using both the zero-range and exact finite-range DWBA. Data considered covered a range of bombarding energies from 15 to 205 MeV. The zero-range DWBA described all data well when finite-range and non-locality corrections were included in the local energy approximation. Comparison of zero-range and exact finite-range calculations showed the local energy approximation correction to be very accurate over the entire energy region. Empirically determined D/sub 0/ values showed no energy dependence. A theoretical D/sub 0/ value calculated using an ..cap alpha.. wave function which reproduced the measured ..cap alpha.. rms charge radius and the elastic electron scattering form factor agreed well the empirical values. Comparison was made between these values and D/sub 0/ values quoted previously in the literature.

  10. Effect of dietary protein on the excretion of. cap alpha. /sub 2u/, the sex-dependent protein of the adult male rat

    Energy Technology Data Exchange (ETDEWEB)

    Neuhaus, O W; Flory, W


    Adult male rates were maintained on normal (20 percent casein), protein-free (0 percent casein), high protein (50 percent casein), deficient protein (20 percent zein), and a supplemented, deficient protein (20 percent zein plus L-lysine and L-tryptophan) diets. Rats on a protein-free diet excreted approximately 1 mg ..cap alpha../sub 2u//24 h compared with a normal of 10-15 mg/24 h. Depleted rats placed on the normal diet showed a rapid restoration of the normal ..cap alpha../sub 2u/ excretion as well as total urinary proteins. Accumulation of ..cap alpha../sub 2u/ in the blood serum was measured in nephrectomized rats. Rats on the protein free diet accumulated only 30 percent of the ..cap alpha../sub 2u/ compared to normals. On a 50 precent casein diet, rats excreted 30-50 mg ..cap alpha../sub 2u//24 h. However, the accumulation was normal in the serum of nephrectomized rats. A high protein diet did not stimulate ..cap alpha../sub 2u/ synthesis but probably increased the renal loss of all urinary proteins. The excretion of ..cap alpha../sub 2u/ on a zein diet was reduced to the same degree as with the protein-free diet. Supplementation with lysine and tryptophan restored the capacity to eliminate ..cap alpha../sub 2u/ to near normal levels. Accumulation of ..cap alpha../sub 2u/ in the serum of nephrectomized rats kept on the zein diets showed that the effect was to suppress the synthesis of the ..cap alpha../sub 2u/. Supplementation restored the biosynthesis of ..cap alpha../sub 2u/. It is concluded that the effect of dietary protein on the excretion of urinary proteins in the adult male rat is caused in a large part by an influence on the hepatic biosynthesis of ..cap alpha../sub 2u/. The biosynthesis of this protein, which represents approximately 30 percent of the total urinary proteins, is dependent on an adequate supply of dietary protein.

  11. Possibility of studying the activity of rocks by the observation of. cap alpha. -particle tracks in a photographic emulsion

    Energy Technology Data Exchange (ETDEWEB)

    Curie, I


    A detailed discussion is presented on the possibility of determining the uranium and thorium content of ordinary rocks by observing ..cap alpha..-particle tracks in a photographic film applied to the rocks' surface. Such determinations can be made only where radioactive equilibrium can be assumed. For the examination of normal granite, exposures of several months are needed. The same method can be used to study the distribution of radioactive elements within the rock.

  12. Effect of tamoxifen pre-treatment on the retention of tritiated oestradiol and 5. cap alpha. -dihydrotestosterone and on glucose metabolism in human breast carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Deshpande, N; Mitchell, I [Imperial Cancer Research Fund, London (UK). Labs.; Hughes, D


    The effect of pre-treatment with tamoxifen on glucose metabolism and retention of injected oestradiol-17B and 5..cap alpha..-dihydrotestosterone by human breast carcinomas were studied in patients undergoing mastectomy. The following effects were observed: the pretreatment reduced retention of oestradiol-17B whereas a small but statistically significant rise in 5..cap alpha..-dihydrotestosterone accumulation was observed. There was an increase in both phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G6PDH) activities in tumours from treated patients whereas ..cap alpha..-glycerolphosphate dehydrogenase (..cap alpha..-GPDH) activity was significantly reduced in the same tumours. The significance of these findings is discussed and it is argued that these changes in carbohydrate metabolism may not be due to the blocking of hormone receptors.

  13. Study of some features of coordination polymerization of. cap alpha. -oxides by the example of forming U(4) alkoxyhalides

    Energy Technology Data Exchange (ETDEWEB)

    Khvostik, G M; Minevich, V Ya; Shupik, A N


    The interaction of uranium tetrachloride with ..cap alpha..-oxides in THF has been studied by NMR and conductometry methods. The opening of the oxide cycle under the action of UCl/sub 4/ is shown. The formation of the coordinational bond between the oxygen atom of the polyester clain and the catalytic centre is found to result in retardation of the reactions of the chain propagation. The general scheme of the reactions of interaction of UCl/sub 4/ with oxides is proposed.

  14. Effects of x-ray irradiation on the induction of. cap alpha. -amylase synthesis by gibberelic acid in the aleurone system of barley

    Energy Technology Data Exchange (ETDEWEB)

    Zellner, H


    The influence of ionizing radiation on a system without DNA replication and cell division was investigated with the aid of GA/sub 3/-induced ..cap alpha..-amylase synthesis in aleurone cells of barley. The reaction of the system was determined by dose effect curves (after irradiation of one half of the endosperms in rest) for the synthesis and secretion of ..cap alpha..-amylase, protein, and reducing sugars. The system proves to be highly radiation-resistant. The course of the synthesis of ..cap alpha..-amylase after X-ray irradiation with varying doses during enzyme synthesis suggests that transcription occurs in the middle of the lag-phase and is the most sensitive stage in enzyme synthesis, while translation alone is less sensitive to radiation.

  15. Primary structure of the. cap alpha. -subunit of Na/sup +/, K/sup +/-ATPase. II. Isolation, reverse transcription, and cloning of messenger RNA

    Energy Technology Data Exchange (ETDEWEB)

    Petrukhin, K.E.; Broude, N.E.; Arsenyan, S.G.; Grishin, A.V.; Dzhandzhugazyan, K.N.; Modyanov, N.N.


    The messenger RNA coding the ..cap alpha..-subunit of Na/sup +/,K/sup +/-ATPase has been isolated from the outer medullary layer of porcine kidneys. The mRNA gives a specific hybridization band in the 25S-26S region with three oligonucleotide probes synthesized on the basis of information on the structure of three peptides isolated from a tryptic hydrolyzate of the ..cap alpha..-subunit of Na/sup +/,K/sup +/-ATPase. The translation of the mRNA in Xenopus laevis oocytes followed by immunochemical identification of the products of synthesis confirmed the presence of the mRNA of the ..cap alpha..-subunit of Na/sup +/,K/sup +/-ATPase in an enriched fraction of poly(A/sup +/)-RNA. This preparation has been used for the synthesis of cloning of double-stranded cDNA.

  16. Levels of /sup 209/Tl and /sup 211/Pb populated in the /sup 210/Pb(t,. cap alpha. )/sup 209/Tl and /sup 210/Pb(t,d)/sup 211/Pb reactions. [J,. pi.

    Energy Technology Data Exchange (ETDEWEB)

    Ellegaard, C; Barnes, P D [Carnegie-Mellon Univ., Pittsburgh, Pa. (USA); Flynn, E R [Los Alamos Scientific Lab., N.Mex. (USA)


    The reactions /sup 210/Pb(t,..cap alpha..)/sup 209/Tl and /sup 210/Pb(t,d)/sup 211/Pb have been studied with 20 MeV tritons. Seven levels in /sup 209/Tl have been identified in the /sup 210/Pb(t,..cap alpha..)/sup 209/Tl reaction. Level spins have been suggested by comparing the observed spectrum with that of the corresponding reaction on /sup 208/Pb. Nineteen levels in /sup 211/Pb were identified in the /sup 210/Pb(t,d)/sup 211/Pb reaction. Angular distributions were measured and lsub(n) values and spectroscopic factors were extracted by DWBA calculations. In both cases the spectra are very similar to the spectra obtained with /sup 208/Pb as a target. The deviations from these simple spectra would appear to be amenable to a description in terms of a coupling of the extra particle or hole to the /sup 210/Pb core.

  17. Ap/sub 4/A interactions with a multiprotein form of DNA polymerase. cap alpha. - primase from HeLa cells

    Energy Technology Data Exchange (ETDEWEB)

    Baril, E F; Owen, M W; Vishwanatha, J K; Zamecnik, P C


    In previous studies, it was shown that Ap/sub 4/A can function as a primer for in vitro DNA synthesis by the multiprotein form of DNA polymerase ..cap alpha.. with single-stranded DNA and an octadecamer double-stranded DNA template. In these studies, the authors show that Ap/sub 4/A that is greater than 99% pure by high performance liquid chromatography also stimulates the incorporation of (..cap alpha../sup 32/P)ATP into the 10-15 oligoribonucleotide primer with poly(dT) template by the primase that is resolved from the polymerase ..cap alpha.. core enzyme. Other dinucleotides or dinucleotide polyphosphates (e.g. ApA, Ap/sub 2/A or Ap/sub 3/A) do not enhance the incorporation of (..cap alpha../sup 32/P)ATP in this reaction. The results from phosphate transfer experiments demonstrate a covalent linkage between (/sup 3/H)Ap/sub 4/A and the /sup 32/P-labeled oligoriboadenylate that is synthesized by the primase.

  18. Radioimmunological determination of 5. cap alpha. -pregnane-3,20-dione in the peripheral venous blood of pregnant women showing pathological estriol values and/or HPL values or gestosis, on the basis of the gestational age. Radioimmunologische Bestimmung des 5. cap alpha. -Pregnan-3,20-dion im peripheren Venenblut schwangerer Frauen einer Gruppe mit pathologischen Oestriol- bzw. HPL-Werten und einer Gestosegruppe in Abhaengigkeit vom Gestationsalter

    Energy Technology Data Exchange (ETDEWEB)

    Klemm-Wolfgramm, E.


    A modified method of extraction and radioimmunological determination (iodine-125) is described, designed to monitor the concentrations of 5..cap alpha..-pregnandione (5..cap alpha..-DHP) in patients showing a pathological course of pregnancy and to examine the role of 5..cap alpha..-DHP blood levels in the development of gestosis. In this study, a control group was compared with two patient groups showing either (a) gestosis or (b) reduced levels of estriol and/or HPL. (1) In gestosis, the levels of 5..cap alpha..-DHP showed significant reductions that were proportionate to the degree of the disease, whereas decreases in these hormone levels were only observed to a minor extent in connection with pathological values of estriol and/or HPL. (2) The age of the patient had no influence on the hormone concentrations. (3) The increases in 5..cap alpha..-DHP seen in multiparae were only slight and did not attain any statistical significance. (4) No links were established between the concentrations of HPL and 5..cap alpha..-DHP in the maternal plasma and the development of the fetus. (5) Significantly reduced values of 5..cap alpha..-DHP were determined in mothers showing disorders of fetoplacental function (birth weights between 2500 and 3500 g) or gestosis (birth weights above 3500 g). (6) There were no relationships between the maternal serum levels of estriol, HPL and 5..cap alpha..-DHP and the sex of the fetus. (TRV).

  19. Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha.

    NARCIS (Netherlands)

    Netea, M.G.; Kullberg, B.J.; Vonk, A.G.; Verschueren, I.; Joosten, L.A.B.; Meer, J.W.M. van der


    BACKGROUND: The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue.

  20. cap alpha. -transfer reactions /sup 27/Al(/sup 6/Li, d)/sup 31/P, /sup 29/Si(/sup 6/Li, d)/sup 33/S and /sup 31/P(/sup 6/Li, d)/sup 35/Cl at 36 MeV. [Angular distributions, EFR DWBA, spectroscopic strengths

    Energy Technology Data Exchange (ETDEWEB)

    Eswaran, M A; Gove, H E; Cook, R; Sikora, B [Rochester Univ., NY (USA). Nuclear Structure Research Lab.


    The ..cap alpha..-transfer reactions /sup 27/Al(/sup 6/Li,d)/sup 31/P,/sup 29/Si(/sup 6/Li,d) /sup 33/S and /sup 31/P(Li,d)/sup 35/Cl have been studied at a /sup 6/Li energy of 36 MeV. Absolute cross sections and angular distributions have been measured and an exact finite-range distorted-wave Born approximation analysis assuming a direct cluster transfer has been used to extract from the data ..cap alpha..-particle spectroscopic strengths for levels populated in /sup 31/P, /sup 33/S and /sup 35/Cl in three reactions respectively. The results show that in the case of most of the low-lying excited states of /sup 31/P a single value of L of the transferred ..cap alpha..-particle contributes, though a multiplicity of L-values are allowed by angular momentum selection rules. It is also found that the ..cap alpha..-particle spectroscopic strength of the ground state of /sup 31/P is a factor of 2 more than the strengths of the ground states of /sup 33/S and /sup 35/Cl. The ..cap alpha..-spectroscopic strengths of ground states of these, as well as other odd-A s-d shell nuclei, are compared with the presently available shell model calculations.

  1. Human pro. cap alpha. 1)(I) collagen: cDNA sequence for the C-propeptide domain

    Energy Technology Data Exchange (ETDEWEB)

    Maekelae, J K; Raassina, M; Virta, A; Vuorio, E


    The authors have previously constructed a cDNA clone pHCAL1, covering most of the C-terminal propeptide domain of human pro..cap alpha..1(I) collagen mRNA,by inserting a 678 bp EcoRI-XhoI fragment of cDNA into pBR322. Since the XhoI/SalI ligation prevented removal of the insert, they used the same strategy to obtain a similar clone in pUC8. RNA was isolated from fetal calvarial bones. The cDNA was digested with EcoRI and XhoI and fractionated on a 1 % agarose gel. Fragments of 650-700 bp were cloned in pUC8 at the polylinker site, which now permits easy removal of the insert. The new clone was named pHCAL1U since the RNA was isolated from another individual. The approach outlined is useful for studies on individual variation which is important to recognize when searching for disease-related mutations in type I collagen.

  2. Quasi-exclusive measurement of /sup 12/C(/sup 12/C, 3. cap alpha. )X at 2. 1 GeV/nucleon

    Energy Technology Data Exchange (ETDEWEB)

    Engelage, J; Baumgartner, M; Greiner, D E; Lindstrom, P J; Olson, D L; Wada, R; Crawford, H J; Webb, M L


    A study of the reaction /sup 12/C(/sup 12/C,3..cap alpha..)X at 2.1 GeV/nucleon has been completed. The energy and momentum transferred to the /sup 12/C projectile and the cross section for the dissociation of /sup 12/C into three alpha particles have been measured, 9.7 (+5.0/-2.5) millibarns. It is found that the results from this analysis are inconsistent with the predictions of current theoretical models for peripheral relativistic heavy ion collisions.

  3. O(. cap alpha. sub(S))/sup 2/ calculation of energy-energy correlation in e/sup +/e/sup -/ annihilation and comparison with experimental data

    Energy Technology Data Exchange (ETDEWEB)

    Ali, A [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany, F.R.); Barreiro, F [Gesamthochschule Siegen (Germany, F.R.)


    We report, in the framework of quantum chromodynamics, an order ..cap alpha..sub(s)/sup 2/ calculation for the energy-energy correlation and the related asymmetry distribution in e/sup +/e/sup -/ annihilation. The normalized distributions are found to be stable and the correction to normalization moderate. The data from PETRA and PEP are analyzed and the QCD scale parameter ..lambda.. is determined. Effects due to the quark and gluon fragmentation are also discussed.

  4. Human placental Na/sup +/, K/sup +/-ATPase. cap alpha. subunit: cDNA cloning, tissue expression, DNA polymorphism, and chromosomal localization

    Energy Technology Data Exchange (ETDEWEB)

    Chehab, F.F.; Kan, Y.W.; Law, M.L.; Hartz, J.; Kao, F.T.; Blostein, R.


    A 2.2-kilobase clone comprising a major portion of the coding sequence of the Na/sup +/, K/sup +/-ATPase ..cap alpha.. subunit was cloned from human placenta and its sequence was identical to that encoding the ..cap alpha.. subunit of human kidney and HeLa cells. Transfer blot analysis of the mRNA products of the Na/sup +/, K/sup +/-ATPase gene from various human tissues and cell lines revealed only one band (approx. = 4.7 kilobases) under low and high stringency washing conditions. The levels of expression in the tissues were intestine > placenta > liver > pancreas, and in the cell lines the levels were human erythroleukemia > butyrate-induced colon > colon > brain > HeLa cells. mRNA was undetectable in reticulocytes, consistent with the authors failure to detect positive clones in a size-selected ( > 2 kilobases) lambdagt11 reticulocyte cDNA library. DNA analysis revealed by a polymorphic EcoRI band and chromosome localization by flow sorting and in situ hybridization showed that the ..cap alpha.. subunit is on the short is on the short arm (band p11-p13) of chromosome 1.

  5. Alpha Power Modulates Perception Independently of Endogenous Factors

    Directory of Open Access Journals (Sweden)

    Sasskia Brüers


    Full Text Available Oscillations are ubiquitous in the brain. Alpha oscillations in particular have been proposed to play an important role in sensory perception. Past studies have shown that the power of ongoing EEG oscillations in the alpha band is negatively correlated with visual outcome. Moreover, it also co-varies with other endogenous factors such as attention, vigilance, or alertness. In turn, these endogenous factors influence visual perception. Therefore, it remains unclear how much of the relation between alpha and perception is indirectly mediated by such endogenous factors, and how much reflects a direct causal influence of alpha rhythms on sensory neural processing. We propose to disentangle the direct from the indirect causal routes by introducing modulations of alpha power, independently of any fluctuations in endogenous factors. To this end, we use white-noise sequences to constrain the brain activity of 20 participants. The cross-correlation between the white-noise sequences and the concurrently recorded EEG reveals the impulse response function (IRF, a model of the systematic relationship between stimulation and brain response. These IRFs are then used to reconstruct rather than record the brain activity linked with new random sequences (by convolution. Interestingly, this reconstructed EEG only contains information about oscillations directly linked to the white-noise stimulation; fluctuations in attention and other endogenous factors may still modulate brain alpha rhythms during the task, but our reconstructed EEG is immune to these factors. We found that the detection of near-perceptual threshold targets embedded within these new white-noise sequences depended on the power of the ~10 Hz reconstructed EEG over parieto-occipital channels. Around the time of presentation, higher power led to poorer performance. Thus, fluctuations in alpha power, induced here by random luminance sequences, can directly influence perception: the relation between

  6. Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylation. (United States)

    Mazroui, Rachid; Sukarieh, Rami; Bordeleau, Marie-Eve; Kaufman, Randal J; Northcote, Peter; Tanaka, Junichi; Gallouzi, Imed; Pelletier, Jerry


    Cytoplasmic aggregates known as stress granules (SGs) arise as a consequence of cellular stress and contain stalled translation preinitiation complexes. These foci are thought to serve as sites of mRNA storage or triage during the cell stress response. SG formation has been shown to require induction of eukaryotic initiation factor (eIF)2alpha phosphorylation. Herein, we investigate the potential role of other initiation factors in this process and demonstrate that interfering with eIF4A activity, an RNA helicase required for the ribosome recruitment phase of translation initiation, induces SG formation and that this event is not dependent on eIF2alpha phosphorylation. We also show that inhibition of eIF4A activity does not impair the ability of eIF2alpha to be phosphorylated under stress conditions. Furthermore, we observed SG assembly upon inhibition of cap-dependent translation after poliovirus infection. We propose that SG modeling can occur via both eIF2alpha phosphorylation-dependent and -independent pathways that target translation initiation.

  7. The performance of multi-factor term structure models for pricing and hedging caps and swaptions

    NARCIS (Netherlands)

    Driessen, J.J.A.G.; Klaassen, P.; Melenberg, B.


    In this paper we empirically compare a wide range of different term structure models when it comes to the pricing and, in particular, hedging of caps and swaptions. We analyze the influence of the number of factors on the hedging and pricing results, and investigate which type of data "interest rate

  8. The Performance of Multi-Factor Term Structure Models for Pricing and Hedging Caps and Swaptions

    NARCIS (Netherlands)

    Driessen, J.J.A.G.; Klaassen, P.; Melenberg, B.


    In this paper we empirically compare different term structure models when it comes to the pricing and hedging of caps and swaptions.We analyze the influence of the number of factors on the pricing and hedging results, and investigate which type of data -interest rate data or derivative price data-

  9. Structure-function relationships in the Na,K-ATPase. cap alpha. subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine-122 to aspartic acid generates a ouabain-resistant enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Price, E.M.; Lingrel, J.B.


    Na,K-ATPases from various species differ greatly in their sensitivity to cardiac glycosides such as ouabain. The sheep and human enzymes are a thousand times more sensitive than the corresponding ones from rat and mouse. To define the region of the ..cap alpha..1 subunit responsible for this differential sensitivity, chimeric cDNAs of sheep and rat were constructed and expressed in ouabain-sensitive HeLa cells. The construct containing the amino-terminal half of the rat ..cap alpha..1 subunit coding region and carboxyl-terminal half of the sheep conferred the ouabain-resistant phenotype to HeLa cells while the reverse construct did not. This indicates that the determinants involved in ouabain sensitivity are located in the amino-terminal half of the Na,K-ATPase ..cap alpha.. subunit. By use of site-directed mutagenesis, the amino acid sequence of the first extracellular domain (H1-H2) of the sheep ..cap alpha..1 subunit was changed to that of the rat. When expressed in HeLa cells, this mutated sheep ..cap alpha..1 construct, like the rat/sheep chimera, was able to confer ouabain resistance to these cells. Furthermore, similar results were observed when HeLa cells were transfected with a sheep ..cap alpha..1 cDNA containing only two amino acid substitutions. The resistant cells, whether transfected with the rat ..cap alpha..1 cDNA, the rat/sheep chimera, or the mutant sheep ..cap alpha..1 cDNAs, exhibited identical biochemical characteristics including ouabain-inhibitable cell growth, /sup 86/Rb/sup +/ uptake, and Na,K-ATPase activity. These results demonstrate that the presence of arginine and aspartic acid on the amino end and carboxyl end, respectively, of the H1-H2 extracellular domain of the Na,K-ATPase ..cap alpha.. subunit together is responsible for the ouabain-resistant character of the rat enzyme and the corresponding residues in the sheep ..cap alpha..1 subunit (glutamine and asparagine) are somehow involved in ouabain binding.

  10. Fano factor evaluation of diamond detectors for alpha particles

    Energy Technology Data Exchange (ETDEWEB)

    Shimaoka, Takehiro; Kaneko, Junichi H.; Tsubota, Masakatsu; Shimmyo, Hiroaki [Graduate School of Engineering, Hokkaido University, Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido, 060-8628 (Japan); Sato, Yuki [Naraha Remote Technology Development Center, Japan Atomic Energy Agency, Naraha-machi, Futaba-gun, Fukushima, 979-0513 (Japan); Chayahara, Akiyoshi; Umezawa, Hitoshi; Mokuno, Yoshiaki [Advanced Power Electronics Research Center, National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorigaoka, Ikeda, Osaka, 563-8577 (Japan); Watanabe, Hideyuki [Research Institute for Electronics and Photonics, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, 305-8565 (Japan)


    This report is the first describing experimental evaluation of Fano factor for diamond detectors. High-quality self-standing chemical vapor deposited diamond samples were produced using lift-off method. Alpha-particle induced charge measurements were taken for three samples. A 13.1 ±0.07 eV of the average electron-hole pair creation energy and excellent energy resolution of approximately 0.3% were found for 5.486 MeV alpha particles from an {sup 241}Am radioactive source. The best Fano factor for 5.486 MeV alpha particles, calculated from experimentally obtained epsilon values and the detector intrinsic energy resolution, was 0.382 ± 0.007. (copyright 2016 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  11. Determination of /sup 240/Pu//sup 239/Pu ratio in the environmental samples based on the measurement of Lx/. cap alpha. -ray activity ratio

    Energy Technology Data Exchange (ETDEWEB)

    Komura, K.; Sakanoue, M.; Yamamoto, M.


    The determination of the /sup 240/Pu//sup 239/Pu isotopic ratio in environmental samples has been attempted by the measurement of the Lx/..cap alpha..-ray activity ratio using a Ge-LEPS (low-energy photon spectrometer) and a surface-barrier Si detector. By this method, interesting data were obtained for various samples collected from Thule, Greenland, Bikini Atoll and Nagasaki, as well as for some soils collected from near and off-site locations of atomic power stations.

  12. Detection of stable isotopes with a (n,. cap alpha. ) nuclear reaction: application to the measurement of unidirectional fluxes of borate in a plant

    Energy Technology Data Exchange (ETDEWEB)

    Duval, Y; Thellier, M; Heurteaux, C; Wissocq, J C [Centre National de la Recherche Scientifique, Mont-Saint-Aignan (France). Lab. ' ' Echanges cellulaires' '


    The unidirectional influx of borate has been studied in Lemna minor plants with the aid of purified boron isotopes, /sup 10/B and /sup 11/B. Isotope /sup 10/B was detected specifically by nuclear reaction /sup 10/B(n, ..cap alpha..)/sup 7/Li in the presence of ''homogeneous'' detectors. Despite technical difficulties in performing the /sup 10/B-estimations in the plant samples themselves, the results obtained here were consistent with those of efflux experiments, published previously, where the /sup 10/B-measurements were performed in the external solution. Kinetic parameters of borate transports in Lemna minor have been calculated.

  13. Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis. (United States)

    Acar, Leyla; Atalan, Nazan; Karagedik, E Hande; Ergen, Arzu


    The humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha. To investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels. Case-control study. Seventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay. We observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05). Our results showed the AA genotype and the A allele of the tumour necrosis factor-alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis.

  14. A study on the determination of Ca/P molar ratio in calcium-hydroxyapatite by alpha excited x-ray fluorescence spectrometry

    International Nuclear Information System (INIS)

    Mizumoto, Yoshihiko; Iwata, Shiro.


    Nondestructive powdery calcium-hydroxyapatite (HAp) target was prepared by electrodeposition method. The powdery HAp was deposited on the copper electrode plate of cathode in the electrodeposition solution such as ethyl alcohol, methyl alcohol, etc. The experiments were carried out as functions of different electrodeposition solution, ethyl alcohol concentration, distance between anode and cathode, electrodeposition time and HAp amount added in bath, and distribution of HAp on the copper electrode plate obtained from each experiment was investigated by alpha excited X-ray fluorescence analysis. Ca/P molar ratio of thin HAp target prepared with this method was determined by alpha excited X-ray fluorescence spectrometry. The nondestructive HAp targets of thickness in the range of 5 mu g/cm 2 to 10 mg/cm 2 were easily prepared with comparatively simple apparatus. The HAp on the copper electrode plate was uniform thickness over 15 x 20 mm copper plate within 5%. The Ca/P molar ratio of HAp was 1.64 +- 0.05, which agreed well with stoichiometric value of 1.67 in HAp within standard deviation. (author)

  15. Radiation-induced changes in production of prostaglandins Fsub(2. cap alpha. ), E, and thromboxane B/sub 2/ in guinea pig parenchymal lung tissues

    Energy Technology Data Exchange (ETDEWEB)

    Steel, L K; Catravas, G N [Armed Forces Radiobiology Research Inst., Bethesda, MD (USA)


    At 1 hour to 4 days after unilateral exposure of guinea pigs to a single dose (0.5, 1.5, or 3.0 Gy) of gamma-radiation, changes were detected in prostaglandin and thromboxane concentrations in parenchymal lung tissues. At 1-3 hours after exposure, tissue levels of PGFsub(2..cap alpha..), PGE, and thromboxane B/sub 2/ were significantly elevated in animals receiving 3.0 Gy, with the magnitude of alteration revealing a radiation dose effect. By 24 hours, tissue prostaglandin and thromboxane levels returned to near control values. Lung tissue synthesis of prostaglandins in response to H-1 receptor stimulation by the exogenous addition of histamine revealed similar radiation dose effects. The carboxylic acid ionophore A23187, exogenously applied to lung tissues, revealed a transient peak of increased sensitivity to ionophore stimulation for TxB/sub 2/ synthesis at 24 hours and for PGFsub(2..cap alpha..) at 72 hours post-irradiation. The data suggest that significant alterations in prostaglandin and thromboxane concentrations in parenchymal lung tissues occur following irradiation, in a dose-dependent manner, and that altered responsiveness to H-1 receptor stimulation and divalent cation transport also occur.

  16. Lifetime of the long-lived isomer of /sup 236/Np from. cap alpha. -,. beta. - and electron-capture decay measurements

    Energy Technology Data Exchange (ETDEWEB)

    Lindner, M.; Dupzyk, R.J.; Hoff, R.W.; Nagle, R.J. (California Univ., Livermore (USA). Lawrence Livermore National Lab.)


    The half-life of long-lived /sup 236/Np, due to ..cap alpha.., ..beta.. and electron-capture decay, was found to be 1.55 x 10/sup 5/ yr. Of all decays, 88% populate excited states in /sup 236/U and 12% populate levels in /sup 236/Pu. Lifetimes measured by growth of the ground states of /sup 236/U and /sup 236/Pu agree with values from corresponding ..gamma.. de-excitations in these daughter nuclei. Therefore, nearly all the electron-capture decays populate the 6/sup +/ level of the ground-state band in /sup 236/U. Similarly, essentially all the ..beta../sup -/ decay populates an analogous 6/sup +/ level in /sup 236/Pu, which de-excites through a previously unreported transition of 158.3 keV. If a very week ..gamma..-ray at 894 keV can be ascribed to a level in /sup 232/U populated by ..beta.. decay of /sup 232/Pa, its existence establishes a 0.2% ..cap alpha..-branching decay in /sup 236/Np.

  17. Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1alpha/2alpha is mediated through chelation of iron. (United States)

    Park, Sung-Soo; Bae, Insoo; Lee, Yong J


    Hypoxia-inducible factor-1 alpha (HIF-1alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1 that is the key regulator of cellular response to low oxygen tension. Under normoxic conditions, HIF-1alpha is continuously degraded by the ubiquitin-proteasome pathway through pVHL (von Hippel-Lindau tumor suppressor protein). Under hypoxic conditions, HIF-1alpha is stabilized and induces the transcription of HIF-1 target genes. Quercetin, a flavonoid with anti-oxidant, anti-inflammatory, and kinase modulating properties, has been found to induce HIF-1alpha accumulation and VEGF secretion in normoxia. In this study, the molecular mechanisms of quercetin-mediated HIF-1alpha accumulation were investigated. Previous studies have shown that, in addition to being induced by hypoxia, HIF-1alpha can be induced through the phosphatidylinositol 3-kinase (PI3K)/Akt and p53 signaling pathways. But our study revealed, through p53 mutant-type as well as p53 null cell lines, that neither the PI3K/Akt nor the p53 signaling pathway is required for quercetin-induced HIF-1alpha accumulation. And we observed that HIF-1alpha accumulated by quercetin is not ubiquitinated and the interaction of HIF-1alpha with pVHL is reduced, compared with HIF-1alpha accumulated by the proteasome inhibitor MG132. The use of quercetin's analogues showed that only quercetin and galangin induce HIF-1/2alpha accumulation and this effect is completely reversed by additional iron ions. This is because quercetin and galangin are able to chelate cellular iron ions that are cofactors of HIF-1/2alpha proline hydroxylase (PHD). These data suggest that quercetin inhibits the ubiquitination of HIF-1/2alpha in normoxia by hindering PHD through chelating iron ions.

  18. alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. (United States)

    Taherzadeh, S; Sharma, S; Chhajlani, V; Gantz, I; Rajora, N; Demitri, M T; Kelly, L; Zhao, H; Ichiyama, T; Catania, A; Lipton, J M


    The hypothesis that macrophages contain an autocrine circuit based on melanocortin [ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH)] peptides has major implications for neuroimmunomodulation research and inflammation therapy. To test this hypothesis, cells of the THP-1 human monocyte/macrophage line were stimulated with lipopolysaccharide (LPS) in the presence and absence of alpha-MSH. The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration. Similar inhibitory effects on TNF-alpha were observed with ACTH peptides that contain the alpha-MSH amino acid sequence and act on melanocortin receptors. Nuclease protection assays indicated that expression of the human melanocortin-1 receptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of RT-PCR product revealed that additional subtypes, hMC-3R and hMC-5R, also occur. Incubation of resting macrophages with antibody to hMC-1R increased TNF-alpha concentration; the antibody also markedly reduced the inhibitory influence of alpha-MSH on TNF-alpha in macrophages treated with LPS. These results in cells known to produce alpha-MSH at rest and to increase secretion of the peptide when challenged are consistent with an endogenous regulatory circuit based on melanocortin peptides and their receptors. Targeting of this neuroimmunomodulatory circuit in inflammatory diseases in which myelomonocytic cells are prominent should be beneficial.

  19. Transforming growth factor alpha and epidermal growth factor in laryngeal carcinomas demonstrated by immunohistochemistry

    DEFF Research Database (Denmark)

    Christensen, M E; Therkildsen, M H; Poulsen, Steen Seier


    the basal cell layer. The present investigation and our previous results confirm the existence of EGF receptors, TGF-alpha and EGF in laryngeal carcinomas. In addition, we conclude that the conditions do exist for growth factors to act through an autocrine system in poorly differentiated tumours and through......Fifteen laryngeal squamous cell carcinomas were investigated for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) using immunohistochemical methods. In a recent study the same material was characterized for epidermal growth factor receptors (EGF...... receptors) which were confined predominantly to the undifferentiated cells. The expression of this growth factor system in malignant cells may play a role in carcinogenesis and/or tumour growth. All carcinomas were positive for TGF-alpha and 12 were positive for EGF. In moderately-to-well differentiated...

  20. Immunoreactive transforming growth factor alpha and epidermal growth factor in oral squamous cell carcinomas

    DEFF Research Database (Denmark)

    Therkildsen, M H; Poulsen, Steen Seier; Bretlau, P


    Forty oral squamous cell carcinomas have been investigated immunohistochemically for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF). The same cases were recently characterized for the expression of EGF-receptors. TGF-alpha was detected...... previous results confirms the existence of TGF-alpha, EGF, and EGF-receptors in the majority of oral squamous cell carcinomas and their metastases......., the cells above the basal cell layer were positive for both TGF-alpha and EGF. The same staining pattern was observed in oral mucosa obtained from healthy persons. In moderately to well differentiated carcinomas, the immunoreactivity was mainly confined to the cytologically more differentiated cells, thus...

  1. Tumor necrosis factor alpha polymorphism correlates with deleterious effects of ultraviolet B light on cutaneous immunity

    NARCIS (Netherlands)

    Vincek, V.; Kurimoto, I.; Medema, J. P.; Prieto, E.; Streilein, J. W.


    Intradermally injected tumor necrosis factor alpha (TNF-alpha) mimics the effects of UV B light (UVB) radiation and neutralizing anti-TNF-alpha antibodies abolish the deleterious effects of UVB on induction of contact hypersensitivity suggesting that TNF-alpha is the major mediator of UVB effects on

  2. /sup 15/N(p,. cap alpha. )/sup 12/C reaction with polarized protons from 0. 34 to 1. 21 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Pepper, G H; Brown, L [Carnegie Institution of Washington, D.C. (USA). Dept. of Terrestrial Magnetism


    A polarized beam was used to measure angular distributions of the analyzing power of the /sup 15/N(p,..cap alpha..)/sup 12/C reaction at 0.34 MeV and at five energies from 0.92 to 1.21 MeV. The analyzing power can be fitted with associated Legendre polynomials, P/sub 1//sup 1/ and P/sub 2//sup 1/ sufficing to describe the results except near 1.2 MeV where P/sub 3//sup 1/ is also required. Polarization excitation functions were measured throughout the entire energy range at angles where the polynomials P/sub 2//sup 1/ and P/sub 3//sup 1/ are zero. A polarization contour map is given.

  3. Cervical Cap (United States)

    ... Videos for Educators Search English Español The Cervical Cap KidsHealth / For Teens / The Cervical Cap What's in ... Call the Doctor? Print What Is a Cervical Cap? A cervical cap is a small cup made ...

  4. Serum concentrations of interleukin-1 alpha, interleukin-6 and tumor necrosis factor-alpha in neonatal sepsis and meningitis

    International Nuclear Information System (INIS)

    Fida, Nadia M.; Fadelallah, Mohamed F.; Al-Mughales, Jamil A.


    To investigate whether serum levels of interleukin-1alpha (IL-1alpha), IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) are useful in the diagnosis of neonatal sepsis and meningitis and differentiate them. Blood samples were collected from 35 full term neonates with suspected infection who admitted to the Neonatology Unit, Pediatric Department, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia during January 2002 - June 2003. On the basis of laboratory and bacteriological results, newborns were classified into: sepsis (n=28), meningitis (n=7), and healthy controls (n=16). Sepsis groups were further subdivided according to culture results into: group 1 = proven sepsis (n=6), group 2 = clinical sepsis (n=14), and group 3 = possible-infected (n=8). Serum levels of IL-1alpha, IL-6, TNF-alpha were measured using Enzyme-Linked Immunosorbent Assay while CRP by nephelometer: In sepsis and meningitis patients, serum levels of CRP (p<0.01, p<0.05,) and IL-1alpha (p<0.001, p<0.05) were elevated than controls. C-reactive protein levels elevated in proven sepsis (p<0.001) and IL-1alpha elevated in all subgroups of sepsis (groups 1, 2, 3) compared with (p<0.05, p<0.001, p<0.01) controls. Interleukin-6, TNF-alpha showed no significant differences between studied groups. In sepsis and meningitis, IL-1alpha had a highest sensitivity (89%, 86%), and negative predictive values (89% and 93%). Interleukin-1alpha and CRP increased in neonatal sepsis and meningitis, but cannot differentiate between them. Interleukin-1alpha had a highest sensitivity in prediction of neonatal infection and its assessment may improve accuracy of diagnosis. (author)

  5. Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) through inhibiting protein synthesis. (United States)

    Lee, Dae-Hee; Lee, Yong J


    Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. In this study, under hypoxic conditions (1% O(2)), we examined the effect of quercetin on the intracellular level of HIF-1alpha and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1alpha accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1alpha accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O(2)) in the presence of 100 microM quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1alpha accumulation were observed under hypoxic conditions. Treatment with 100 microM cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1alpha accumulation during hypoxia. These results suggest that suppression of HIF-1alpha accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis. (c) 2008 Wiley-Liss, Inc.

  6. Expression and secretion of Bacillus amyloliquefaciens alpha-amylase by using the yeast pheromone alpha-factor promoter and leader sequence in Saccharomyces cerevisiae.


    Southgate, V J; Steyn, A J; Pretorius, I S; Van Vuuren, H J


    Replacement of the regulatory and secretory signals of the alpha-amylase gene (AMY) from Bacillus amylolique-faciens with the complete yeast pheromone alpha-factor prepro region (MF alpha 1p) resulted in increased levels of extracellular alpha-amylase production in Saccharomyces cerevisiae. However, the removal of the (Glu-Ala)2 peptide from the MF alpha 1 spacer region (Lys-Arg-Glu-Ala-Glu-Ala) yielded decreased levels of extracellular alpha-amylase.

  7. Influence of the. cap alpha. -,. beta. -, and. gamma. -subunits of the energy-transducing adenosine triphosphatase from Micrococcus lysodeikticus in the immunochemical properties of the protein and in their reconstitution studied by a radioimmunoassay method

    Energy Technology Data Exchange (ETDEWEB)

    Larraga, V; Mollinedo, F; Rubio, N; Munoz, E [Unidad de Biomembranas, Instituto de Inmunologia y Biologia Microbiana, Madrid (Spain)


    A sensitive radioimmunoassay was developed for the energy-transducing adenosine triphosphatase (F/sub 1/-ATPase, EC of Micrococcus lysodeikticus and the assay was extended to the ..cap alpha..-, ..beta..-, and ..gamma..-subunits of the enzyme. These subunits were isolated and cross-reactions studied.

  8. Search for aligned structure of /sup 12/C-. cap alpha. -/sup 12/C type at high excitation energy in /sup 28/Si. [46 MeV, J,. pi. , resonance, three-body problem

    Energy Technology Data Exchange (ETDEWEB)

    Burnereau, N


    The /sup 16/O+/sup 12/C..-->../sup 12/C+..cap alpha..+/sup 12/C reaction is studied mainly at 46MeV (at this energy a state of /sup 28/Si is presumably formed with a spin value of 14/sup +/; resonance of 19.7MeV c.m.). The motivation is to detect an ..cap alpha.. particle with a negligible energy in the c.m. system. This is the signature of the preformation of three aligned clusters in which the average location of the ..cap alpha.. particle is in between the two /sup 12/C's at the center of symmetry of the system. Such a detection is performed by detecting two /sup 12/C's in coincidence at specific angles. The data are understood by three-body calculations with a coupling of relative angular momenta governed by an unique J value. Experimentally, an ..cap alpha.. energy of 200keV is measured with good statistics, supporting the idea of aligned clusters as /sup 28/Si intrinsic shape, related to some highly excited states.

  9. Pulp tissue inflammation and angiogenesis after pulp capping with transforming growth factor β1

    Directory of Open Access Journals (Sweden)

    Sri Kunarti


    Full Text Available In Restorative dentistry the opportunity to develop biomemitic approaches has been signalled by the possible use of various biological macromolecules in direct pulp capping reparation. The presence of growth factors in dentin matrix and the putative role indicating odontoblast differentiation during embryogenesis has led to the examination on the effect of endogenous TGF-β1. TGF-β1 is one of the Growth Factors that plays an important role in pulp healing. The application of exogenous TGF-β1 in direct pulp capping treatment should be experimented in fibroblast tissue in-vivo to see the responses of inflammatory cells and development of new blood vessels. The increase in food supplies always occurs in the process of inflammation therefore the development of angiogenesis is required to fulfil the requirement. This in-vivo study done on orthodontic patients indicated for premolar extraction between 10–15 years of age. A class V cavity preparation was created in the buccal aspect 1 mm above gingival margin to pulp exposure. The cavity was slowly irrigated with saline solution and dried using a sterile small cotton pellet. The sterile absorbable collagen membrane was applied and soaked in 5 ml TGF-β1. It was covered by a Teflon pledge to separate from Glass Ionomer Cement restoration. Evaluation was performed on day 7; 14; and 21. All samples were histopathologycally examined and data was statistically analysed using one way ANOVA and Dunnet T3.There were no inflammatory symptoms in clinical examination on both Ca(OH2 and TGF-β1, but they increased the infiltration of inflammatory cells on histopathological examination. There were no significant differences (p > 0.05 between Ca(OH2 and TGF-β1 in inflammation cell and significant differences (p < 0.05 in angiogenesis on day 7 and 14. There were no significant differences (p > 0.05 in inflammation cell with in TGF-β1 groups and significant differences (p < 0.05 with in Ca(OH2 groups on day 7

  10. Immunolocalization of transforming growth factor alpha in normal human tissues

    DEFF Research Database (Denmark)

    Christensen, M E; Poulsen, Steen Seier


    anchorage-independent growth of normal cells and was, therefore, considered as an "oncogenic" growth factor. Later, its immunohistochemical presence in normal human cells as well as its biological effects in normal human tissues have been demonstrated. The aim of the present investigation was to elucidate...... the distribution of the growth factor in a broad spectrum of normal human tissues. Indirect immunoenzymatic staining methods were used. The polypeptide was detected with a polyclonal as well as a monoclonal antibody. The polyclonal and monoclonal antibodies demonstrated almost identical immunoreactivity. TGF......-alpha was found to be widely distributed in cells of normal human tissues derived from all three germ layers, most often in differentiated cells. In epithelial cells, three different kinds of staining patterns were observed, either diffuse cytoplasmic, cytoplasmic in the basal parts of the cells, or distinctly...

  11. Anti-tumor necrosis factor-alpha therapies attenuate adaptive arteriogenesis in the rabbit

    NARCIS (Netherlands)

    Grundmann, Sebastian; Hoefer, Imo; Ulusans, Susann; van Royen, Niels; Schirmer, Stephan H.; Ozaki, C. Keith; Bode, Christoph; Piek, Jan J.; Buschmann, Ivo


    The specific antagonists of tumor necrosis factor-alpha (TNF-alpha), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although the importance of TNF-alpha in chronic inflammatory diseases is well established,

  12. Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells.

    NARCIS (Netherlands)

    Paleolog, E.M.; Delasalle, S.A.; Buurman, W.A.; Feldmann, M.


    Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion

  13. Cervical Cap (United States)

    ... giving birth vaginally, which means the cervical cap may not fit as well. Inconsistent or incorrect use of the cervical cap increases your risk of pregnancy. For example, you may get pregnant when using the cervical cap if: ...

  14. Negative interference by rheumatoid factor in alpha-fetoprotein chemiluminescent microparticle immunoassay. (United States)

    Wang, Hui; Bi, Xiaohui; Xu, Lei; Li, Yirong


    Background Rheumatoid factor causes positive interference in multiple immunoassays. Recently, negative interference has also been found in immunoassays in the presence of rheumatoid factor. The chemiluminescent microparticle immunoassay is widely used to determine serum alpha-fetoprotein. However, it is not clear whether the presence of rheumatoid factor in the serum causes interference in the chemiluminescent microparticle immunoassay of alpha-fetoprotein. Methods Serum alpha-fetoprotein was determined using the ARCHITECT alpha-fetoprotein assay. The estimation of alpha-fetoprotein recovery was carried out in samples prepared by diluting high-concentration alpha-fetoprotein serum with rheumatoid factor-positive or rheumatoid factor-negative serum. Paramagnetic microparticles coated with hepatitis B surface antigen-anti-HBs complexes were used to remove rheumatoid factor from the serum. Results The average recovery of alpha-fetoprotein was 88.4% and 93.8% in the rheumatoid factor-positive and rheumatoid factor-negative serum samples, respectively. The recovery of alpha-fetoprotein was significantly lower in the rheumatoid factor-positive serum samples than in the rheumatoid factor-negative serum samples. In two of five rheumatoid factor-positive samples, a large difference was found (9.8%) between the average alpha-fetoprotein recoveries in the serially diluted and initial recoveries. Fourteen rheumatoid factor-positive serum samples were pretreated with hepatitis B surface antigen-anti-HBs complex-coated paramagnetic microparticles. The alpha-fetoprotein concentrations measured in the pretreated samples increased significantly. Conclusions It was concluded that the alpha-fetoprotein chemiluminescent microparticle immunoassay is susceptible to interference by rheumatoid factor, leading to significantly lower results. Eliminating the incidence of negative interference from rheumatoid factor should be an important goal for immunoassay providers. In the meantime

  15. Studies of Li, B and N in ancient oriental pottery and modern ceramic materials by means of (n,p) and (n,. cap alpha. ) spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Fink, D. (Hahn-Meitner-Institut fuer Kernforschung Berlin G.m.b.H. (Germany, F.R.)); Riederer, J. (Staatliche Museen Preussischer Kulturbesitz, Berlin (Germany, F.R.). Rathgen-Forschungslabor)


    The content of Li, B, and N is examined in ancient and modern pottery and its glazes by means of (n,p) and (n,..cap alpha..) reactions with thermal neutrons. Most samples exhibit a proportionality between B and Li concentrations with preferred values around 0.01 at.%. One group of pottery shows nearly constant Li abundance around 0.1 at.%, the B content varying from 10/sup -4/ at.% to 10 at.%. An explanation is given, and the individual groups of pottery are described in detail. Results for different archaeological sites of Sumerian, Babylonian, Assyrian, Phoenician and Roman provenience are presented. The data scattering of B and Li contents of samples from different places of origin varies considerably, and can be used as a measure of the economical importance of ancient centers. Local urban cultures, such as Ur, exhibit a relative data scattering around 0.2, cities with average trade relations show values around 0.4, and for the famous trade center Palmyra, 0.8 was found. The B/Li ratio of pottery indicates whether the clay used is a fresh water or a marine sediment. The B and Li contents of Euphrates pottery show systematic variations along the river valley. Several samples, found in the Mesopotamian region are highly enriched in nitrogen. This is probably due to salt precipitation in the surrounding soil after the destruction of the irrigation facilities by the Mongols in 1258.

  16. Reactions of saccharides catalyzed by molybdate ions. XXXIII. Use of. cap alpha. (U-/sup 14/C)glucan for preparation of /sup 14/C-labelled saccharides

    Energy Technology Data Exchange (ETDEWEB)

    Bilik, V; Biely, P [Institute of Chemistry, Centre for Chemical Research, Slovak Academy of Sciences, Bratislava (Czechoslovakia); Kolina, J [Ustav pro Vyzkum, Vyrobu a Vyuziti Radioisotopu, Prague (Czechoslovakia)


    D-(U-/sup 14/C)glucose obtained in acid hydrolysis of ..cap alpha..-(U-/sup 14/C)glucan (2 M-HCl) was epimerized under a catalytic action of molybdate ions to D-(U-/sup 14/C)mannose isolated with a 20% yield. Oxidative degradation of 4-nitrophenylhydrazones of D-(U-/sup 14/C)arabinose and D-(U-/sup 14/C)xylose resulted in D-(U-/sup 14/C)erythrose and D-(U-/sup 14/C)threose, respectively, with a 15% yield relative to the starting aldopentoses. Nitromethane synthesis with D-(U-/sup 14/C)lyxose followed by oxidative decomposition of the corresponding nitrohexitols yielded /sup 14/C-labelled D-galactose. Described is also the preparation of D-(U-/sup 14/C)arabinose from D-(U-/sup 14/C)glucose and the conversion of D-(U-/sup 14/C)arabinose to D-(U-/sup 14/C)xylose and D-(U-/sup 14/C)lyxose.

  17. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders. (United States)

    Bahia, Malkeet S; Silakari, Om


    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  18. Stromal cell-derived factor-1 alpha (SDF-1 alpha) improves neural recovery after spinal cord contusion in rats

    NARCIS (Netherlands)

    Zendedel, A.; Nobakht, M.; Bakhtiyari, M.; Beyer, C.; Kipp, M.; Baazm, M.; Joghataie, M.T.


    Stromal cell-derived factor-1 alpha (SDF-1α) is an important cytokine, implicated in the control of stem cell trafficking and bone marrow-derived stem cell mobilization. Generally, SDF-1α regulates multiple physiological processes such as embryonic development and organ homeostasis. There is also

  19. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth

    DEFF Research Database (Denmark)

    Greenberger, Lee M; Horak, Ivan D; Filpula, David


    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in angiogenesis, survival, metastasis, drug resistance, and glucose metabolism. Elevated expression of the alpha-subunit of HIF-1 (HIF-1alpha), which occurs in response to hypoxia or activation of growth facto...

  20. Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat

    NARCIS (Netherlands)

    Buttini, M; Appel, K; Sauter, A; GebickeHaerter, PJ; Boddeke, HWGM

    Induction of tumor necrosis factor alpha was studied in the brain of rats after focal cerebral ischaemia by occlusion of the left middle cerebral artery. Using a specific antisense riboprobe for in situ hybridization histochemistry, cells positive for tumor necrosis factor alpha messenger RNA were

  1. Structure and electrical conduction of the system La sub(1-x)Ca sub(x)FeO sub(3-. cap alpha. )

    Energy Technology Data Exchange (ETDEWEB)

    Hombo, Jukichi; Urabe, Noriake [Kumamoto Univ. (Japan). Faculty of Engineering; Hiroshige, Gota; Hamada, Kotaro


    Perovskite phases in the system, La sub(1-x)Ca sub(x)FeO sub(3-..cap alpha..) were prepared with La/sub 2/O/sub 3/, CaCO/sub 3/, and Fe/sub 2/O/sub 3/ by firing in air and in vacuo. The compositions of samples fired in vacuo and in air are represented as La sub(1-x)Ca sub(x)FeO sub(3-x 2) and La sub(1-x)Ca sub(x)Fe sub(1-y)sup(3+)Fe sub(y)sup(4+)O sub(3-x/2+y/2), respectively. That is, samples fired in vacuo contain some oxygen vacancies and no tetravalent iron; in contrast, samples fired in air contain both oxygen vacancies and tetravalent iron in the structures. The electrical conductivities of these synthesized oxides depended extensively upon the content of tetravalent iron. For instance, the conductivity of the sample x = 0.6 fired in air was larger by 10/sup 6/ than that of the sample fired in vacuo. In this system, except for the two terminal compositions of x = 0 and x = 1.0, the values of activation energy for conduction are considerably small, and from the results of thermo-electromotive force measurement, the charge carrier was positive. Furthermore, the conductivity increased somewhat with time during the conductivity measurement by the direct-current method. These facts suggest that the electric conduction would not be ionic but electronic. The electrical conduction would then be carried out by the so-called hopping mechanism by which the positive charge is transferred.

  2. Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo

    DEFF Research Database (Denmark)

    Hansen, P R; Svendsen, Jesper Hastrup; Høyer, S


    Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100...... in cardiac output and was associated with the appearance of areas with myocardial necrosis in the regional left ventricular wall. The myocardial plasma flow rate and maximum plasma flow rate in response to a 30-s coronary occlusion were not influenced by rTNF-alpha, although a decrease in the myocardial...... ng/kg for 60 min) on myocardial microvascular transport of a small hydrophilic indicator was examined by the single-injection, residue-detection method. Intracoronary infusion of rTNF-alpha increased myocardial microvascular transport after 120 min. This increase was preceded by a sustained decline...

  3. Tumor necrosis factor-alpha modulates human in vivo lipolysis

    DEFF Research Database (Denmark)

    Plomgaard, Peter; Fischer, Christian P; Ibfelt, Tobias


    CONTEXT: Low-grade systemic inflammation is a feature of most lifestyle-related chronic diseases. Enhanced TNF-alpha concentrations have been implicated in the development of hyperlipidemia. OBJECTIVE: We hypothesized that an acute elevation of TNF-alpha in plasma would cause an increase...... in lipolysis, increasing circulatory free fatty acid (FFA) levels. SUBJECTS AND METHODS: Using a randomized controlled, crossover design, healthy young male individuals (n = 10) received recombinant human (rh) TNF-alpha (700 ng/m(-2).h(-1)) for 4 h, and energy metabolism was evaluated using a combination...... of tracer dilution methodology and arterial-venous differences over the leg. RESULTS: Plasma TNF-alpha levels increased from 0.7 +/- 0.04 to 16.7 +/- 1.8 pg/ml, and plasma IL-6 increased from 1.0 +/- 0.2 to 9.2 +/- 1.0 pg/ml (P alpha infusion. Here, we demonstrate that 4-h rhTNF-alpha...

  4. A pragmatic approach to estimate alpha factors for common cause failure analysis

    International Nuclear Information System (INIS)

    Hassija, Varun; Senthil Kumar, C.; Velusamy, K.


    Highlights: • Estimation of coefficients in alpha factor model for common cause analysis. • A derivation of plant specific alpha factors is demonstrated. • We examine sensitivity of common cause contribution to total system failure. • We compare beta factor and alpha factor models for various redundant configurations. • The use of alpha factors is preferable, especially for large redundant systems. - Abstract: Most of the modern technological systems are deployed with high redundancy but still they fail mainly on account of common cause failures (CCF). Various models such as Beta Factor, Multiple Greek Letter, Binomial Failure Rate and Alpha Factor exists for estimation of risk from common cause failures. Amongst all, alpha factor model is considered most suitable for high redundant systems as it arrives at common cause failure probabilities from a set of ratios of failures and the total component failure probability Q T . In the present study, alpha factor model is applied for the assessment of CCF of safety systems deployed at two nuclear power plants. A method to overcome the difficulties in estimation of the coefficients viz., alpha factors in the model, importance of deriving plant specific alpha factors and sensitivity of common cause contribution to the total system failure probability with respect to hazard imposed by various CCF events is highlighted. An approach described in NUREG/CR-5500 is extended in this study to provide more explicit guidance for a statistical approach to derive plant specific coefficients for CCF analysis especially for high redundant systems. The procedure is expected to aid regulators for independent safety assessment

  5. Tumor necrosis factor-alpha-independent downregulation of hepatic cholesterol 7alpha-hydroxylase gene in mice treated with lead nitrate. (United States)

    Kojima, Misaki; Sekikawa, Kenji; Nemoto, Kiyomitsu; Degawa, Masakuni


    We previously reported that lead nitrate (LN), an inducer of hepatic tumor necrosis factor-alpha (TNF-alpha), downregulated gene expression of cholesterol 7alpha-hydroxylase. Herein, to clarify the role of TNF-alpha in LN-induced downregulation of cholesterol 7alpha-hydroxylase, effects of LN on gene expression of hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) in TNF-alpha-knockout (KO) and TNF-alpha-wild-type (WT) mice were comparatively examined. Gene expression of hepatic Cyp7a1 in both WT and KO mice decreased to less than 5% of the corresponding controls at 6-12 h after treatment with LN (100 mumol/kg body weight, iv). Levels of hepatic TNF-alpha protein in either WT or KO mice were below the detection limit, although expression levels of the TNF-alpha gene markedly increased at 6 h in WT mice by LN treatment, but not in KO mice. In contrast, in both WT and KO mice, levels of hepatic IL-1beta protein, which is known to be a suppressor of the cholesterol 7alpha-hydroxylase gene in hamsters, were significantly increased 3-6 h after LN treatment. Furthermore, LN-induced downregulation of the Cyp7a1 gene did not necessarily result from altered gene expression of hepatic transcription factors, including positive regulators (liver X receptor alpha, retinoid X receptor alpha, fetoprotein transcription factor, and hepatocyte nuclear factor 4alpha) and a negative regulator small heterodimer partner responsible for expression of the Cyp7a1 gene. The present findings indicated that LN-induced downregulation of the Cyp7a1 gene in mice did not necessarily occur through a TNF-alpha-dependent pathway and might occur mainly through an IL-1beta-dependent pathway.

  6. Serum and Urinary Levels of Tumor Necrosis Factor-Alpha in Renal Transplant Patients. (United States)

    Senturk Ciftci, Hayriye; Demir, Erol; Savran Karadeniz, Meltem; Tefik, Tzevat; Yazici, Halil; Nane, Ismet; Savran Oguz, Fatma; Aydin, Filiz; Turkmen, Aydin


    Allograft rejection is an important cause of early and long-term graft loss in kidney transplant recipients. Tumor necrosis factor-alpha promotes T-cell activation, the key reaction leading to allograft rejection. Here, we investigated whether serum and urinary tumor necrosis factor-alpha levels can predict allograft rejection. This study included 65 living related-donor renal transplant recipients with mean follow-up of 26 ± 9 months. Serum and urinary tumor necrosis factor-alpha levels were measured at pretransplant and at posttransplant time points (days 1 and 7 and months 3 and 6); serum creatinine levels were also monitored during posttransplant follow-up. Standard enzyme-linked immunoabsorbent assay was used to detect tumor necrosis factor-alpha levels. Clinical variables were monitored. Nine of 65 patients (13.8%) had biopsy-proven rejection during follow-up. Preoperative serum and urinary tumor necrosis factor-alpha levels were not significantly different when we compared patients with and without rejection. Serum tumor necrosis factor-alpha levels (in pg/mL) were significantly higher in the allograft rejection versus nonrejection group at day 7 (11.5 ± 4.7 vs 15.4 ± 5.8; P = .029) and month 1 (11.1 ± 4.8 vs 17.8 ± 10.9; P =.003). Urinary tumor necrosis factor-alpha levels (in pg/mL) were also elevated in the allograft rejection versus the nonrejection group at days 1 (10.2 ± 2.5 vs 14.1 ± 6.8; P = .002) and 7 (9.8 ± 2.2 vs 14.5 ± 2.7; P tumor necrosis factor-alpha has a role in diagnosing renal transplant rejection. Serum and urinary tumor necrosis factor-alpha levels may be a possible predictor for allograft rejection.

  7. Consideration of Real World Factors Influencing Greenhouse Gas Emissions in ALPHA (United States)

    Discuss a variety of factors that influence the simulated fuel economy and GHG emissions that are often overlooked and updates made to ALPHA based on actual benchmarking data observed across a range of vehicles and transmissions. ALPHA model calibration is also examined, focusin...

  8. Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils

    NARCIS (Netherlands)

    van den Berg, J. M.; Weyer, S.; Weening, J. J.; Roos, D.; Kuijpers, T. W.


    Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor alpha (TNF-alpha) was reported by some to have pro-apoptotic and by others to have antiapoptotic effects on neutrophils. The aim of this study was

  9. Factors affecting the solubility of Bacillus halmapalus alpha-amylase

    DEFF Research Database (Denmark)

    Faber, Cornelius; Hobley, Timothy John; Mollerup, Jørgen


    A detailed study of the solubility of recombinant Bacillus halmapalus alpha-amylase has been conducted. A semi-purified preparation from a bulk crystallisation was chos en that contained six isoforms with pI-values of between 5.5 and 6.1. The solubility was strongly affected by pH and could...

  10. Estimation of the Alpha Factor Parameters Using the ICDE Database

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Dae Il; Hwang, M. J.; Han, S. H


    Detailed common cause failure (CCF) analysis generally need for the data for CCF events of other nuclear power plants because the CCF events rarely occur. KAERI has been participated at the international common cause failure data exchange (ICDE) project to get the data for the CCF events. The operation office of the ICDE project sent the CCF event data for EDG to the KAERI at December 2006. As a pilot study, we performed the detailed CCF analysis of EDGs for Yonggwang Units 3 and 4 and Ulchin Units 3 and 4 using the ICDE database. There are two onsite EDGs for each NPP. When an offsite power and the two onsite EDGs are not available, one alternate AC (AAC) diesel generator (hereafter AAC) is provided. Two onsite EDGs and the AAC are manufactured by the same company, but they are designed differently. We estimated the Alpha Factor and the CCF probability for the cases where three EDGs were assumed to be identically designed, and for those were assumed to be not identically designed. For the cases where three EDGs were assumed to be identically designed, double CCF probabilities of Yonggwang Units 3/4 and Ulchin Units 3/4 for 'fails to start' were estimated as 2.20E-4 and 2.10E-4, respectively. Triple CCF probabilities of those were estimated as 2.39E-4 and 2.42E-4, respectively. As each NPP has no experience for 'fails to run', Yonggwang Units 3/4 and Ulchin Units 3/4 have the same CCF probability. The estimated double and triple CCF probabilities for 'fails to run' are 4.21E-4 and 4.61E-4, respectively. Quantification results show that the system unavailability for the cases where the three EDGs are identical is higher than that where the three EDGs are different. The estimated system unavailability of the former case was increased by 3.4% comparing with that of the latter. As a future study, a computerization work for the estimations of the CCF parameters will be performed.

  11. Energy response of detectors to alpha/beta particles and compatibility of the equivalent factors

    International Nuclear Information System (INIS)

    Lin Bingxing; Li Guangxian; Lin Lixiong


    By measuring detect efficiency and equivalent factors of alpha/beta radiation with different energies on three types of detectors, this paper compares compatibility of their equivalent factors and discusses applicability of detectors to measuring total alpha/beta radiation. The result shows the relationship between efficiency of alpha/beta radiation and their energies on 3 types of detectors, such as scintillation and proportional and semiconductor counters, are overall identical. Alpha count efficiency display exponential relation with alpha-particle energy. While beta count efficiency display logarithm relation with beta-particle energy, but the curves appears deflection at low energy. Comparison test of energy response also shows that alpha and beta equivalent factors of scintillation and proportional counters have a good compatibility, and alpha equivalent factors of the semiconductor counters are in good agreement with those of the above two types of counters, but beta equivalent factors have obvious difference, or equivalent factors of low energy beta-particle are lower than those of other detectors. So, the semiconductor counter can not be used for measuring total radioactivity or for the measurements for the purpose of food safety. (authors)

  12. Molecular cloning and functional characterization of the human platelet-derived growth factor alpha receptor gene promoter

    NARCIS (Netherlands)

    Afink, G. B.; Nistér, M.; Stassen, B. H.; Joosten, P. H.; Rademakers, P. J.; Bongcam-Rudloff, E.; van Zoelen, E. J.; Mosselman, S.


    Expression of the platelet-derived growth factor alpha receptor (PDGF alpha R) is strictly regulated during mammalian development and tumorigenesis. The molecular mechanisms involved in the specific regulation of PDGF alpha R expression are unknown, but transcriptional regulation of the PDGF alpha R

  13. SU-E-T-59: Calculations of Collimator Scatter Factors (Sc) with and Without Custom-Made Build-Up Caps for CyberKnife

    Energy Technology Data Exchange (ETDEWEB)

    Wokoma, S; Yoon, J; Jung, J [East Carolina University, Greenville, NC (United States); Lee, S [Rhode Island Hospital / Warren Alpert Medical, Providence, RI (United States)


    Purpose: To investigate the impact of custom-made build-up caps for a diode detector in robotic radiosurgery radiation fields with variable collimator (IRIS) for collimator scatter factor (Sc) calculation. Methods: An acrylic cap was custom-made to fit our SFD (IBA Dosimetry, Germany) diode detector. The cap has thickness of 5 cm, corresponding to a depth beyond electron contamination. IAEA phase space data was used for beam modeling and DOSRZnrc code was used to model the detector. The detector was positioned at 80 cm source-to-detector distance. Calculations were performed with the SFD, with and without the build-up cap, for clinical IRIS settings ranging from 7.5 to 60 mm. Results: The collimator scatter factors were calculated with and without 5 cm build-up cap. They were agreed within 3% difference except 15 mm cone. The Sc factor for 15 mm cone without buildup was 13.2% lower than that with buildup. Conclusion: Sc data is a critical component in advanced algorithms for treatment planning in order to calculate the dose accurately. After incorporating build-up cap, we discovered differences of up to 13.2 % in Sc factors in the SFD detector, when compared against in-air measurements without build-up caps.

  14. Cellular localization of transforming growth factor-alpha mRNA in rat forebrain. (United States)

    Seroogy, K B; Lundgren, K H; Lee, D C; Guthrie, K M; Gall, C M


    The cellular localization of transforming growth factor-alpha (TGF alpha) mRNA in juvenile and adult rat forebrain was examined using in situ hybridization with a 35S-labeled cRNA probe. TGF alpha cRNA-labeled neuronal perikarya were distributed across many forebrain regions including the olfactory bulb, caudate-putamen, nucleus accumbens, olfactory tubercle, ventral pallidum, amygdala, hippocampal stratum granulosum and CA3 stratum pyramidale, and piriform, entorhinal, and retrosplenial cortices. TGF alpha cRNA-hybridizing cells were also localized to several thalamic nuclei and to the suprachiasmatic, dorsomedial, and ventromedial nuclei of the hypothalamus. In addition, labeled cells were present in regions of white matter including the corpus callosum, anterior commissure, internal and external capsules, optic tract, and lateral olfactory tract. Thus, both neurons and glia appear to synthesize TGF alpha in normal brain. Hybridization densities were greater in neuronal fields at 2 weeks of age compared with the adult, suggesting a role for TGF alpha in the development of several forebrain systems. Our results demonstrating the prominent and wide-spread expression of TGF alpha mRNA in forebrain, combined with the extremely low abundance of epidermal growth factor mRNA in brain, support the argument that TGF alpha is the principal endogenous ligand for the epidermal growth factor receptor in normal brain.

  15. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis

    NARCIS (Netherlands)

    Baert, F. J.; D'Haens, G. R.; Peeters, M.; Hiele, M. I.; Schaible, T. F.; Shealy, D.; Geboes, K.; Rutgeerts, P. J.


    Anti-tumor necrosis factor alpha monoclonal antibody treatment (infliximab) reduces clinical signs and symptoms in patients with Crohn's disease. The effects of infliximab on mucosal histopathologic abnormalities in Crohn's ileocolitis were studied. Thirteen patients with steroid-refractory Crohn's

  16. Proposal of a weight factor for alpha radiation aiming biota radioprotection

    International Nuclear Information System (INIS)

    Pereira, Wagner de S.; Py Junior, Delcy de A.; Kelecom, Alphonse; Goncalves, Simone


    Several proposals based on the environmental radioprotection of calculating the absorbed dose in biota have been suggested. The absorbed dose expresses the deposition of energy per mass unit. The differences in biological effects of the absorbed dose can be quantified by applying a correction factor to the absorbed dose. The correction factor for radiation is easier to establish, because radiations exist in smaller number (alpha, beta, neutrons and photons) and can be set for groups of organisms. This work aims to propose a correction factor for radiation, in order to adequate the concept of absorbed dose currently used to the concept of equivalent dose. A survey of the literature on correction factors proposed for alpha radiation was carried out and, when possible, the biological endpoint was identified, as well as the radionuclide and the biological target. A variation of the weight factor for alpha radiation from 1 to 377 was observed and a number of biological endpoints, biological target and alpha emitter radionuclide were identified. Finally we propose a weight value for alpha radiation of 40, and we propose also the name of correction factor for radiation alpha as being ecological radiation weighting factor (WRE) the name 'equivalent dose for flora and fauna' (HTFF) to name of the new dose. (author)

  17. Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes (United States)

    Li, Y. P.; Atkins, C. M.; Sweatt, J. D.; Reid, M. B.; Hamilton, S. L. (Principal Investigator)


    Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.

  18. Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha. (United States)

    Anticevich, S Z; Hughes, J M; Black, J L; Armour, C L


    Tumour necrosis factor-alpha (TNF alpha) is implicated in the pathogenesis of asthma; however, little is known of its direct effect on smooth muscle reactivity. We investigated the effect of TNF alpha on the responsiveness of human bronchial tissue to electrical field stimulation in vitro. Incubation of non-sensitized tissue with 1 nM, 3 nM and 10 nM TNF alpha significantly increased responsiveness to electrical field stimulation (113 +/- 8, 110 +/- 4 and 112 +/- 2% respectively) compared to control (99 +/- 2%) (P 0.05) nor were responses to exogenous acetylcholine (93 +/- 4% versus 73 +/- 7%, n = 3, P = 0.38). These results show that TNF alpha causes an increase in responsiveness of human bronchial tissue and that this occurs prejunctionally on the parasympathetic nerve pathway. This is the first report of a cytokine increasing human airway tissue responsiveness.

  19. Hypoxia-inducible factor-1 alpha has a key role in hypoxic preconditioning. (United States)

    Taie, Satoshi; Ono, Junichiro; Iwanaga, Yasuyuki; Tomita, Shuhei; Asaga, Takehiko; Chujo, Kosuke; Ueki, Masaaki


    Sublethal hypoxia induces tolerance to subsequent hypoxic insults in a process known as hypoxic preconditioning (HP). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key transcription protein involved in the mechanism of HP. In this study, we investigated the effects of HP on tissue oxygenation and expression of HIF-1 alpha gene targets in the brain using neural cell-specific HIF-1 alpha-deficient mice. The animals were exposed to 8% oxygen for 3 hours. Twenty-four hours later, the oxygen partial pressure (pO(2)) of brain tissue and gene expression were measured during hypoxia. HP improved the pO(2) of brain tissue during subsequent hypoxia with upregulated inducible nitric oxide synthase in wild-type mice, whereas HP had no detectable effect in the mutant mice. Our results indicate that the protective effects of HP may be partially mediated by improving tissue oxygenation via HIF-1 alpha and inducible nitric oxide synthase.

  20. A review of the alpha-1 foundation: its formation, impact, and critical success factors. (United States)

    Walsh, John W; Snider, Gordon L; Stoller, James K


    Patient-advocacy organizations have proliferated because they can be an effective method to advance research and clinical care for those with the index condition, and can produce substantial benefits for the affected community, especially when the condition is uncommon. To clarify critical success factors in organizing a patient-advocacy organization and to provide a blueprint for others, including the respiratory-care advocacy community, this report examines features of one highly successful organization, the Alpha-1 Foundation, which is committed to helping those with the genetic condition alpha-1 antitrypsin deficiency. Features of the Alpha-1 Foundation that underlie its success include: consistently creating partnerships with key stakeholders, including the scientific and clinical communities, government, and pharmaceutical manufacturers; bringing passion to the cause (eg, by assuring that organizational leadership is provided by individuals affected by alpha-1 antitrypsin deficiency); and developing strategic business partnerships, as with a company that administers alpha-1 antitrypsin treatment (so-called intravenous augmentation therapy) and employs individuals with alpha-1 antitrypsin deficiency. Funds allocated by the company help to underwrite the foundation's research-funding commitment. The foundation also recruits and retains talent, including alpha-1 patients, to leadership roles (eg, on the board of directors) and has a voluntary group of committed scientists and clinicians. We believe that attention to these factors can help assure the success of patient-advocacy groups.

  1. Analysis of Factors Controlling Cell Cycle that Can Be Synchronized Nondestructively During Root Cap Development

    Energy Technology Data Exchange (ETDEWEB)

    Hawes, Martha


    Publications and presentations during the final funding period, including progress in defining the substrate specificity, the primary goal of the project, are listed below. Both short-term and long-term responses mediated by PsUGT1 have been characterized in transgenic or mutant pea, alfalfa, and Arabidopsis with altered expression of PsUGT1. Additional progress includes evaluation of the relationship between control of the cell cycle by PsUGT1 and other glycosyltransferase and glycosidase enzymes that are co-regulated in the legume root cap during the onset of mitosis and differentiation. Transcriptional profiling and multidimensional protein identification technology ('MudPIT') have been used to establish the broader molecular context for the mechanism by which PsUGT1 controls cell cycle in response to environmental signals. A collaborative study with the Norwegian Forest Research Institute (who provided $10,000.00 in supplies and travel funds for collaborator Dr. Toril Eldhuset to travel to Arizona and Dr. H. H. Woo to travel to Norway) made it possible to establish that the inducible root cap system for studying carbohydrate synthesis and solubilization is expressed in gymnosperm as well as angiosperm species. This discovery provides an important tool to amplify the potential applications of the research in defining conserved cell cycle machinery across a very broad range of plant species and habitats. The final work, published during 2009, revealed an additional surprising parallel with mammalian immune responses: The cells whose production is controlled by PsUGT1 appear to function in a manner which is analogous to that of white blood cells, by trapping and killing in an extracellular manner. This may explain why mutation within the coding region of PsUGT1 and its homolog in humans (UGT1) is lethal to plants and animals. The work has been the subject of invited reviews. A postdoctoral fellow, eight undergraduate students, four M.S. students and

  2. Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop

    Czech Academy of Sciences Publication Activity Database

    Stapelberg, M.; Gellert, N.; Swettenham, E.; Tomasetti, M.; Witting, P. K.; Procopio, A.; Neužil, Jiří


    Roč. 280, č. 27 (2005), s. 25369-25376 ISSN 0021-9258 Institutional research plan: CEZ:AV0Z50520514 Keywords : alpha-tocopheryl succinate * malignant mesothelioma * fibroblast growth factor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.854, year: 2005

  3. Hantaan Virus Nucleocapsid Protein Binds to Importin alpha Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B (United States)


    Microbiology . All Rights Reserved. Hantaan Virus Nucleocapsid Protein Binds to Importin Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced...Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702,1 and Department of Microbiology , Mount Sinai...34–36. 32. Prescott , J., C. Ye, G. Sen, and B. Hjelle. 2005. Induction of innate immune response genes by Sin Nombre hantavirus does not require

  4. Tumor necrosis factor alpha selectively sensitizes human immunodeficiency virus-infected cells to heat and radiation

    International Nuclear Information System (INIS)

    Wong, G.H.; McHugh, T.; Weber, R.; Goeddel, D.V.


    We report here that infection of the human T-cell line HUT-78 with human immunodeficiency virus (HIV) increases its sensitivity to heat and radiation toxicity. A possible explanation for this result may be the reduced expression of manganous superoxide dismutase (MnSOD) in HIV-infected cells compared to uninfected cells. Tumor necrosis factor alpha (TNF-alpha) further sensitizes HIV-infected cells but not uninfected cells to heat and radiation. This is consistent with the ability of TNF-alpha to induce the expression of MnSOD in uninfected but not in HIV-infected cells. HIV-infected HUT-78 cell lines engineered to overexpress MnSOD are more resistant to heat and radiation than HIV-infected cells that do not overexpress MnSOD. However, treatment with TNF-alpha still sensitizes these cells to heat and radiation

  5. Association of tumor necrosis factor alpha gene polymorphism G-308A with pseudoexfoliative glaucoma in the Pakistani population.

    NARCIS (Netherlands)

    Khan, M.I.; Micheal, S.; Rana, N.; Akhtar, F.; Hollander, A.I. den; Ahmed, A.; Qamar, R.


    PURPOSE: The purpose of the present study was to determine the role of the tumor necrosis factor alpha (TNF-alpha) gene polymorphism G-308A and total serum immunoglobulin E (TsIgE) levels in the onset of pseudoexfoliation glaucoma (PEXG) in Pakistani patients. METHODS: The TNF-alpha polymorphism

  6. Tumor necrosis factor-alpha and interleukin-4 gene polymorphisms in Chinese patients with gout. (United States)

    Chen, M-L; Tsai, F-J; Tsai, C-H; Huang, C-M


    The purpose of this study was to examine whether polymorphisms of interleukin-4 (IL-4) (promoter-590 and intron 3) and tumor necrosis factor-alpha (TNF-alpha) promoter-308 genes are markers of susceptibility to or clinical manifestations of gout in Taiwanese patients. The study included 196 Taiwanese patients with gout and 103 unrelated healthy control subjects living in central Taiwan. Polymorphisms of the IL-4 (promoter-590 and intron 3) and TNF-alpha (promoter-308) genes were typed from genomic DNA. Allelic frequencies and carriage rates were then compared between gout patients and control subjects. The correlation between allelic frequencies, carriage rates and clinical manifestations of gout were evaluated. No significant differences were observed in the allelic frequencies and carriage rates of the IL-4 (promoter-590 and intron 3) and TNF-alpha gene polymorphisms between patients with gout and healthy control subjects. Furthermore, the IL-4 (promoter-590 and intron 3) and TNF-alpha genotypes were not found to be associated with the clinical and laboratory profiles in gout patients. However, there was a significant difference in the TNF-alphapolymorphism genotype between patients with and without hypertriglyceridemia (P=0.001, xi2=11.47, OR=10.3, 95%CI=3.57-29.7). The results of our study suggest that polymorphisms of the IL-4 (promoter-590 and intron 3) and TNF-alpha promoter-308 genes are not related to gout in Chinese patients in Taiwan.

  7. The Role of Tumor Necrosis Factor- alpha and Resistin in Nonalcoholic Fatty Liver Disease

    International Nuclear Information System (INIS)

    Alkady, M.M.


    Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver diseases. It is strongly associated with obesity and insulin resistance and is thought to be a part of the metabolic syndrome. It can progress from simple fatty liver to steatohepatitis, cirrhosis and liver failure. Adipocytokines, synthesized in adipose tissue, are involved in the pathophysiology of many acute and chronic liver diseases. The aim of this study was to investigate the role of Tumor Necrosis Factor-alpha (TNF-alpha) and resistin in the pathogenesis of NAFLD and their correlation to the severity of the disease. Serum concentration of TNF-alpha and resistin were measured in 20 patients with NAFLD and 20 healthy controls with ELISA method. The results of this study revealed that serum levels of both adipokines were significantly elevated in NAFLD patients than controls (P<0.01). Moreover, they were significantly higher in patients with nonalcoholic steatohepatitis than in patients with simple fatty liver. There was a significant positive correlation between TNF-alpha, resistin and each of AST, ALT and HOMA. Similarly, the results showed a significant positive correlation between the two studied adipokines, TNF-alpha and resistin (P<0.001). We conclude that TNF-alpha and resistin have a role in the pathogenesis of NAFLD and they may be promising markers for the progressin to steatohepatitis and inhibition of their activities by drugs may be a new approach for the treatment of NAFLD

  8. Murine elongation factor 1 alpha (EF-1 alpha) is posttranslationally modified by novel amide-linked ethanolamine-phosphoglycerol moieties. Addition of ethanolamine-phosphoglycerol to specific glutamic acid residues on EF-1 alpha

    International Nuclear Information System (INIS)

    Whiteheart, S.W.; Shenbagamurthi, P.; Chen, L.; Cotter, R.J.; Hart, G.W.


    Elongation Factor 1 alpha (EF-1 alpha), an important eukaryotic translation factor, transports charged aminoacyl-tRNA from the cytosol to the ribosomes during poly-peptide synthesis. Metabolic radiolabeling with [ 3 H] ethanolamine shows that, in all cells examined, EF-1 alpha is the major radiolabeled protein. Radiolabeled EF-1 alpha has an apparent Mr = 53,000 and a basic isoelectric point. It is cytosolic and does not contain N-linked oligosaccharides. Trypsin digestion of murine EF-1 alpha generated two major [ 3 H]ethanolamine-labeled peptides. Three peptides were sequenced and were identical to two distinct regions of the human EF-1 alpha protein. Blank sequencing cycles coinciding with glutamic acid in the human cDNA-derived sequence were also found to release [ 3 H]ethanolamine, and compositional analysis of these peptides confirmed the presence of glutamic acid. Dansylation analysis demonstrates that the amine group of the ethanolamine is blocked. These results indicate that EF-1 alpha is posttranslationally modified by the covalent attachment of ethanolamine via an amide bond to at least two specific glutamic acid residues (Glu-301 and Glu-374). The hydroxyl group of the attached ethanolamine was shown by mass spectrometry and compositional analysis, to be further modified by the addition of a phosphoglycerol unit. This novel posttranslational modification may represent an important alteration of EF-1 alpha, comparable to the regulatory effects of posttranslational methylation of EF-1 alpha lysine residues

  9. Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency. (United States)

    Kos, Iaroslava; Patterson, Miranda J; Znaidi, Sadri; Kaloriti, Despoina; da Silva Dantas, Alessandra; Herrero-de-Dios, Carmen M; d'Enfert, Christophe; Brown, Alistair J P; Quinn, Janet


    Following phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogenCandida albicansby "stress pathway interference." Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression inC. albicans, is significantly delayed in response to combinatorial stress treatments and to high levels of H2O2 Cap1 is normally oxidized in response to H2O2; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H2O2, Cap1 becomes trapped in a partially oxidized form, Cap1(OX-1) Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1(OX-1)readily accumulates in the nucleus and binds to target genes following high-H2O2stress, the nuclear accumulation of Cap1(OX-1)following combinatorial H2O2and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival ofC. albicanswithin the host. Combinatorial stress-mediated synergistic killing represents a new unchartered area in the field of stress signaling. This phenomenon contrasts starkly with "stress cross-protection," where exposure to one stress protects against subsequent exposure to a different stress. Previously we

  10. Characterization of receptors for recombinant human tumor necrosis factor-alpha from human placental membranes

    International Nuclear Information System (INIS)

    Aiyer, R.A.; Aggarwal, B.B.


    High affinity receptors for recombinant human tumor necrosis factor-alpha (rhTNF-alpha) were identified on membranes prepared from full term human placenta. Highly purified rhTNF-alpha iodinated by the iodogen method was found to bind placental membranes in a displaceable manner with an approximate dissociation constant (KD) of 1.9 nM. The membrane bound TNF-alpha receptor could be solubilized by several detergents with optimum extraction being obtained with 1% Triton X-100. The binding of 125I-rhTNF-alpha to the solubilized receptor was found to be time and temperature dependent, yielding maximum binding within 1 h, 24 h and 48 h at 37 degrees C, 24 degrees C and 4 degrees C, respectively. However, the maximum binding obtainable at 4 degrees C was only 40% of that at 37 degrees C. The binding 125I-rhTNF-alpha to solubilized placental membrane extracts was displaceable by unlabeled rhTNF-alpha, but not by a related protein recombinant human tumor necrosis factor-beta (rhTNF-beta; previously called lymphotoxin). This is similar to the behavior of TNF-alpha receptors derived from detergent-solubilized cell extracts, although on intact cells, both rhTNF-alpha and rhTNF-beta bind with equal affinity to TNF receptors. The Scatchard analysis of the binding data of the solubilized receptor revealed high affinity binding sites with a KD of approximately 0.5 nM and a receptor concentration of about 1 pmole/mg protein. Gel filtration of the solubilized receptor-ligand complexes on Sephacryl S-300 revealed two different peaks of radioactivity at approximate molecular masses of 50,000 Da and 400,000 Da. The 400,000 dalton peak corresponded to the receptor-ligand complex. Overall, our results suggest that high affinity receptors for TNF-alpha are present on human placental membranes and provide evidence that these receptors may be different from that of rhTNF-beta

  11. Alpha-cluster preformation factor within cluster-formation model for odd-A and odd-odd heavy nuclei (United States)

    Saleh Ahmed, Saad M.


    The alpha-cluster probability that represents the preformation of alpha particle in alpha-decay nuclei was determined for high-intensity alpha-decay mode odd-A and odd-odd heavy nuclei, 82 CSR) and the hypothesised cluster-formation model (CFM) as in our previous work. Our previous successful determination of phenomenological values of alpha-cluster preformation factors for even-even nuclei motivated us to expand the work to cover other types of nuclei. The formation energy of interior alpha cluster needed to be derived for the different nuclear systems with considering the unpaired-nucleon effect. The results showed the phenomenological value of alpha preformation probability and reflected the unpaired nucleon effect and the magic and sub-magic effects in nuclei. These results and their analyses presented are very useful for future work concerning the calculation of the alpha decay constants and the progress of its theory.

  12. Inhibition of the release of soluble tumor necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-alpha antibody

    NARCIS (Netherlands)

    Jansen, J.; van der Poll, T.; Levi, M. [=Marcel M.; ten Cate, H.; Gallati, H.; ten Cate, J. W.; van Deventer, S. J.


    The role of tumor necrosis factor-alpha in the shedding of soluble tumor necrosis factor receptors in endotoxemia was investigated. The appearance of the soluble tumor necrosis factor receptors was assessed in four healthy volunteers following an intravenous injection of tumor necrosis factor-alpha

  13. Cradle Cap (For Parents) (United States)

    ... Safe Videos for Educators Search English Español Cradle Cap (Infantile Seborrheic Dermatitis) KidsHealth / For Parents / Cradle Cap ( ... many babies develop called cradle cap. About Cradle Cap Cradle cap is the common term for seborrheic ...

  14. Tumor necrosis factor alpha production in irradiated cells in vitro

    International Nuclear Information System (INIS)

    Koeteles, G.J.; Bognar, G.; Kubasova, T.


    Normal and tumor cell lines were used to investigate tumor necrosis factor (TNFα) production and its radiation sensitivity. The cells were irradiated with gamma rays using different doses from 0.25 Gy up to 5 Gy. The number of plated cells, changes of proliferation and TNFα production were determined during the following four post-irradiation days. For TNFα quantity measurement immuno-radiometric assay (IRMA) and enzyme amplified sensitivity assay (EASIA) was used. The results suggest that though gamma irradiation decreased cell proliferation in a dose dependent manner, the quantity produced in the post-irradiation period increased considerably in each irradiated sample. (N.T.) 3 refs.; 2 figs.; 1 tab

  15. Proton quasi-elastic scattering at 600MeV on the. cap alpha. -substructure of medium nuclei. [Differential cross sections

    Energy Technology Data Exchange (ETDEWEB)

    Anne, R [CEA Centre d' Etudes Nucleaires de Saclay, 91 - Gif-sur-Yvette (France). Service d' Entretien et de Developpement des Appareils de Physique; Delpierre, P; Kahane, J; Sene, R [College de France, 75 - Paris. Lab. de Physique Corpusculaire; Devaux, A; Landaud, G [Clermont-Ferrand Univ., 63 (France); Yonnet, J [Caen Univ., 14 (France). Lab. de Physique Corpusculaire


    Alpha knock out from light and medium nuclei up to /sup 40/Ca was investigated. Preliminary values of the differential cross sections are given for /sup 6/Li and /sup 12/C nuclei. The p(R) recoil momentum distributions show a maximum at p(R)=0.

  16. Comparative carbon-13 nuclear magnetic resonance study at 67. 9 MHz on lysozyme (human and egg-white) and. cap alpha. -lactalbumin (human and bovine) in their native and denatured state

    Energy Technology Data Exchange (ETDEWEB)

    van Binst, G; Biesemans, M [Brussels Univ. (Belgium). Faculte des Sciences


    A first detailed comparison of the /sup 13/C spectra at high field of two lysozymes (human and egg-white) and two ..cap alpha..-lactalbumins (human and bovine milk) is presented. Assignments were made on most of the resonance peaks in the aliphatic and aromatic regions of the denatured proteins. The relative peak intensities clearly demonstrate the differences in the amino acid composition of the related proteins. The broadening and the complexity of the spectra of the native proteins reflect the non equivalence of the chemical groups in the folded conformation. The usefulness of /sup 13/C nmr spectroscopy in the study of the interaction between small molecules and proteins was tested on N-acteyl-glucosamine in the presence of lysozyme.

  17. Effect of hypoxia-inducible factor 1-alpha (HIF-1α) on proliferation ...

    African Journals Online (AJOL)



    Jul 25, 2011 ... Full Length Research Paper. Effect of hypoxia-inducible factor 1-alpha ... 1Department of Neurosurgery, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025,. China. 2Department of Neurosurgery, Chaoyang Hospital, Huainan, Anhui, China. 3Department of Neurosurgery ...

  18. Tumor necrosis factor alpha gene polymorphism in multiple sclerosis and optic neuritis

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Sandberg-Wollheim, M


    The NcoI tumor necrosis factor (TNF alpha) polymorphism was studied in relapsing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the NcoI marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were...

  19. Effect of tumor necrosis factor-alpha infusion on the incretin effect in healthy volunteers

    DEFF Research Database (Denmark)

    Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke


    Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumor necrosis factor-alpha (TNF-α). Whereas TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce...

  20. Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha

    NARCIS (Netherlands)

    Zwaveling, Jan Harm


    The main function of tumor necrosis factor alpha (TNF-a), a small polypeptide shared by all mammals, is probably protection against invading bacteria, parasites and viruses; killing of these microorganisms is facilitated in the presence of TNF-a. However, as its name suggest, TNF-a is also capable

  1. Spectroscopic factors of the alpha decay of isoscalar giant resonances

    International Nuclear Information System (INIS)

    Smirnov, Yu.F.; Chuvil'skij, Yu.M.


    A system which enables to connect Ssub(α) spectroscopic factors (SF) for α-decay of the isoscalar giant resonance (GR) states E0 and E2 with SF values for ground and low lying nucleus states has been developed. This method permits to consider initial nucleus GR decay with a transition to the residual nucleus-GR. It is necessary to know only SF for GR decay to the daughter nucleus ground state with the emission of an excited cluster in the common case. The above method is based on properties of infinitesimal operators of Sp(2, R), Sp(6, R) groups and uses SU(3)-symmetry of wave functions of initial nucleus, cluster and residual nucleus, Values of ratios of α-particle SF are presented for 8 Be, HH2C, 16 O, 20 Ne, 24 Mg, 28 Si, 40 Ca, 44 Ti nuclei and Ssub(α) transitions to GR states of residual nucleus for 16 O, 20 Ne and 40 Ca nuclei. Noticeable Ssub(α) values for virtual α-decay of an initial nucleus ground state to residual nucleus GR poins out that α-particle knock out processes may be also accompanied by the final nucleus GR excitation

  2. Self-absorption alpha particle factor in water: interest in the monitoring of specific military sites

    International Nuclear Information System (INIS)

    Cazoulat, A.; Lecompte, Y.; Bohand, S.; Gerasimo, P.


    Self-absorption alpha particle factor validation in water: Interest in the monitoring of specific military sites. The population internal intake prevention by radionuclides present in water needs to monitor the radioactive Level of this water. The French public health legislation introduces four radiological parameters for monitoring water, such as the gross alpha radioactivity. Regarding the alpha particle characteristics, a self-absorption factor has to be established beforehand, not to underestimate the real alpha radioactivity in water samples. The aim of this paper is to describe the procedure used by the laboratory of the French army radioprotection service to determine this f factor, which depends on the water residue mass m after evaporation. The relation is f = 0.0253 m + 1.2813. This formula can be employed for such waters used in this experiment and for masses between 0 and 100 mg. The uncertainty associated is about 11% (k = 2). Some water monitoring examples are given. It is specially the case of depleted uranium shells experiment centres, localized in Gramat and Bourges. (authors)

  3. Epitope mapping of alpha-transforming growth factor: evidence of an immunodominant region

    International Nuclear Information System (INIS)

    Hazarika, P.; Dedman, J.R.


    Antisera were produced in rabbits and sheep against both full-length synthetic rat alpha-transforming growth factor and peptides corresponding to the carboxy-terminal 17 amino acids. These antisera were used to develop a peptide based radioimmunoassay of alpha-TGF. All antisera reacted only with a restricted region of the alpha-TGF corresponding to the 8 residues (43-50) at the carboxy-terminus: Cyslt. slash43, Glult. slash44, Hislt. slash45, Alalt. slash46, Asplt. slash47, Leult. slash48, Leult. slash49, Alalt. slash50. A series of synthetic peptides presenting deletions or substitutions of amino acids in this carboxy-terminal region were tested for competition with 125 I-alpha-TGF. All changes in the above peptide sequence resulted in a marked reduction in competition. All of the polyclonal antisera demonstrated similar specificity whether they were produced against the 50 amino acid, full-length alpha-TGF, against shorter 17 amino acid and 8 amino acid carboxy-terminal sequences

  4. Epitope mapping of alpha-transforming growth factor: evidence of an immunodominant region

    Energy Technology Data Exchange (ETDEWEB)

    Hazarika, P.; Dedman, J.R.


    Antisera were produced in rabbits and sheep against both full-length synthetic rat alpha-transforming growth factor and peptides corresponding to the carboxy-terminal 17 amino acids. These antisera were used to develop a peptide based radioimmunoassay of alpha-TGF. All antisera reacted only with a restricted region of the alpha-TGF corresponding to the 8 residues (43-50) at the carboxy-terminus: Cyslt. slash43, Glult. slash44, Hislt. slash45, Alalt. slash46, Asplt. slash47, Leult. slash48, Leult. slash49, Alalt. slash50. A series of synthetic peptides presenting deletions or substitutions of amino acids in this carboxy-terminal region were tested for competition with /sup 125/I-alpha-TGF. All changes in the above peptide sequence resulted in a marked reduction in competition. All of the polyclonal antisera demonstrated similar specificity whether they were produced against the 50 amino acid, full-length alpha-TGF, against shorter 17 amino acid and 8 amino acid carboxy-terminal sequences.

  5. Promoter of CaZF, a chickpea gene that positively regulates growth and stress tolerance, is activated by an AP2-family transcription factor CAP2.

    Directory of Open Access Journals (Sweden)

    Deepti Jain

    Full Text Available Plants respond to different forms of stresses by inducing transcription of a common and distinct set of genes by concerted actions of a cascade of transcription regulators. We previously reported that a gene, CaZF encoding a C2H2-zinc finger family protein from chickpea (Cicer arietinum imparted high salinity tolerance when expressed in tobacco plants. We report here that in addition to promoting tolerance against dehydration, salinity and high temperature, the CaZF overexpressing plants exhibited similar phenotype of growth and development like the plants overexpressing CAP2, encoding an AP2-family transcription factor from chickpea. To investigate any relationship between these two genes, we performed gene expression analysis in the overexpressing plants, promoter-reporter analysis and chromatin immunoprecipitation. A number of transcripts that exhibited enhanced accumulation upon expression of CAP2 or CaZF in tobacco plants were found common. Transient expression of CAP2 in chickpea leaves resulted in increased accumulation of CaZF transcript. Gel mobility shift and transient promoter-reporter assays suggested that CAP2 activates CaZF promoter by interacting with C-repeat elements (CRTs in CaZF promoter. Chromatin immunoprecipitation (ChIP assay demonstrated an in vivo interaction of CAP2 protein with CaZF promoter.

  6. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

    NARCIS (Netherlands)

    Pearson, E.R.; Pruhova, S.; Tack, C.J.J.; Johansen, A.; Castleden, H.A.; Lumb, P.J.; Wierzbicki, A.S.; Clark, P.M.; Lebl, J.; Pedersen, O.; Ellard, S.; Hansen, T.; Hattersley, A.T.


    AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and

  7. Expression of hypoxia-induced factor-1 alpha in early-stage and in metastatic oral squamous cell carcinoma. (United States)

    Ribeiro, Maisa; Teixeira, Sarah R; Azevedo, Monarko N; Fraga, Ailton C; Gontijo, Antônio Pm; Vêncio, Eneida F


    To investigate hypoxia-induced factor-1 alpha expression in distinct oral squamous cell carcinoma subtypes and topographies and correlate with clinicopathological data. Hypoxia-induced factor-1 alpha expression was assessed by immunohistochemistry in 93 cases of OSCC. Clinical and histopathological data were reviewed from medical records. Hypoxia-induced factor-1 alpha status was distinct according to tumor location, subtype and topography affect. In superficial oral squamous cell carcinomas, most tumor cells overexpressed hypoxia-induced factor-1 alpha, whereas hypoxia-induced factor-1 alpha was restricted to the intratumoral region in conventional squamous cell carcinomas. All basaloid squamous cell carcinomas exhibited downregulation of hypoxia-induced factor-1 alpha. Interestingly, metastatic lymph nodes (91.7%, p = 0.001) and the intratumoral regions of corresponding primary tumors (58.3%, p = 0.142) showed hypoxia-induced factor-1 alpha-positive tumor cells. Overall survival was poor in patients with metastatic lymph nodes. Hypoxia-induced factor-1 alpha has distinct expression patterns in different oral squamous cell carcinoma subtypes and topographies, suggesting that low oxygen tension promotes the growth pattern of superficial and conventional squamous cell carcinoma, but not basaloid squamous cell carcinoma. Indeed, a hypoxic environment may facilitate regional metastasis, making it a useful diagnostic and prognostic marker in primary tumors.

  8. The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease

    DEFF Research Database (Denmark)

    El-Hussuna, Alaa Abdul-Hussein H; Krag, Aleksander; Olaison, Gunnar


    Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications.......Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications....

  9. Death cap

    DEFF Research Database (Denmark)

    Rudbæk, Torsten R; Kofoed, Pernille Bouteloup; Bove, Jeppe


    Death cap (Amanita phalloides) is commonly found and is one of the five most toxic fungi in Denmark. Toxicity is due to amatoxin, and poisoning is a serious medical condition, causing organ failure with potential fatal outcome. Acknowledgement and clarification of exposure, symptomatic and focused...

  10. Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions

    DEFF Research Database (Denmark)

    Schuchmann, M; Hess, S; Bufler, P


    Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however......, demonstrates that TNF and LT alpha differ significantly with regard to their mitogenic and cytotoxic potentials. LT alpha's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under physiological conditions into biologically...... inactive monomers, the LT alpha trimer remained stable for several days. Accordingly, LT alpha more effectively induced fibroblast growth which demands long-term presence of the cytokine. TNF's superior cytotoxicity, which requires only short-term impact of the cytokine, could be attributed to a distinct...

  11. Charge form factors and alpha-cluster internal structure of 12C

    International Nuclear Information System (INIS)

    Luk'yanov, V.K.; Zemlyanaya, E.V.; Kadrev, D.N.; Antonov, A.N.; Spasova, K.; Anagnostatos, G.S.; Ginis, P.; Giapitzakis, J.


    The transition densities and form factors of 0 + , 2 + , and 3 - states in 12 C are calculated in alpha-cluster model using the triangle frame with clusters in the vertices. The wave functions of nucleons in the alpha clusters are taken as they were obtained in the framework of the models used for the description of the 4 He form factor and momentum distribution which are based on the one-body density matrix construction. They contain effects of the short-range NN correlations, as well as the d-shell admixtures in 4 He. Calculations and the comparison with the experimental data show that visible effects on the form and magnitude of the 12 C form factors take place, especially at relatively large momentum transfers

  12. Choosing an alpha radiation weighting factor for doses to non-human biota

    International Nuclear Information System (INIS)

    Chambers, Douglas B.; Osborne, Richard V.; Garva, Amy L.


    The risk to non-human biota from exposure to ionizing radiation is of current international interest. In calculating radiation doses to humans, it is common to multiply the absorbed dose by a factor to account for the relative biological effectiveness (RBE) of the radiation type. However, there is no international consensus on the appropriate value of such a factor for weighting doses to non-human biota. This paper summarizes our review of the literature on experimentally determined RBEs for internally deposited alpha-emitting radionuclides. The relevancy of each experimental result in selecting a radiation weighting factor for doses from alpha particles in biota was judged on the basis of criteria established a priori. We recommend a nominal alpha radiation weighting factor of 5 for population-relevant deterministic and stochastic endpoints, but to reflect the limitations in the experimental data, uncertainty ranges of 1-10 and 1-20 were selected for population-relevant deterministic and stochastic endpoints, respectively

  13. Apical cap

    International Nuclear Information System (INIS)

    McLoud, T.C.; Isler, R.J.; Novelline, R.A.; Putman, C.E.; Simeone, J.; Stark, P.


    Apical caps, either unilateral or bilateral, are a common feature of advancing age and are usually the result of subpleural scarring unassociated with other diseases. Pancoast (superior sulcus) tumors are a well recognized cause of unilateral asymmetric apical density. Other lesions arising in the lung, pleura, or extrapleural space may produce unilateral or bilateral apical caps. These include: (1) inflammatory: tuberculosis and extrapleural abscesses extending from the neck; (2) post radiation fibrosis after mantle therapy for Hodgkin disease or supraclavicular radiation in the treatment of breast carcinoma; (3) neoplasm: lymphoma extending from the neck or mediastinum, superior sulcus bronchogenic carcinoma, and metastases; (4) traumatic: extrapleural dissection of blood from a ruptured aorta, fractures of the ribs or spine, or hemorrhage due to subclavian line placement; (5) vascular: coarctation of the aorta with dilated collaterals over the apex, fistula between the subclavian artery and vein; and (6) miscellaneous: mediastinal lipomatosis with subcostal fat extending over the apices

  14. Are Ichthyosporea animals or fungi? Bayesian phylogenetic analysis of elongation factor 1alpha of Ichthyophonus irregularis. (United States)

    Ragan, Mark A; Murphy, Colleen A; Rand, Thomas G


    Ichthyosporea is a recently recognized group of morphologically simple eukaryotes, many of which cause disease in aquatic organisms. Ribosomal RNA sequence analyses place Ichthyosporea near the divergence of the animal and fungal lineages, but do not allow resolution of its exact phylogenetic position. Some of the best evidence for a specific grouping of animals and fungi (Opisthokonta) has come from elongation factor 1alpha, not only phylogenetic analysis of sequences but also the presence or absence of short insertions and deletions. We sequenced the EF-1alpha gene from the ichthyosporean parasite Ichthyophonus irregularis and determined its phylogenetic position using neighbor-joining, parsimony and Bayesian methods. We also sequenced EF-1alpha genes from four chytrids to provide broader representation within fungi. Sequence analyses and the presence of a characteristic 12 amino acid insertion strongly indicate that I. irregularis is a member of Opisthokonta, but do not resolve whether I. irregularis is a specific relative of animals or of fungi. However, the EF-1alpha of I. irregularis exhibits a two amino acid deletion heretofore reported only among fungi.

  15. Elevated levels of tumor necrosis factor alpha and mortality in centenarians

    DEFF Research Database (Denmark)

    Bruunsgaard, Helle; Andersen-Ranberg, Karen; Hjelmborg, Jacob v B


    BACKGROUND: Aging is accompanied by low-grade inflammation. Tumor necrosis factor (TNF) alpha initiates the cytokine cascade, and high levels are associated with dementia and atherosclerosis in persons aged 100 years. We hypothesized that TNF-alpha was also a prognostic marker for all......-cause mortality in these persons. METHODS: We enrolled 126 subjects at or around the time of their 100th birthday. Plasma levels of TNF-alpha, interleukin (IL)-6, IL-8, and C-reactive protein were measured at baseline, and we determined the associations between the markers of inflammation and mortality during...... the subsequent 5 years. RESULTS: Only 9 subjects were alive after 5 years. Elevated levels of TNF-alpha were associated with mortality in both men and women (hazard ratio = 1.34 per SD of 2.81 pg/mL; 95% confidence interval: 1.12 to 1.60, P = 0.001). Levels of IL-6 and IL-8 did not affect survival; levels of C...

  16. Endogenous endophthalmitis in a rheumatoid patient on tumor necrosis factor alpha blocker

    Directory of Open Access Journals (Sweden)

    Agarwal Pankaj


    Full Text Available The development of anti-tumor necrosis factor (TNF therapies is a milestone in the therapy of rheumatic diseases. It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe complications that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.

  17. Urinary transforming growth factors in neoplasia: separation of 125I-labeled transforming growth factor-alpha from epidermal growth factor in human urine

    International Nuclear Information System (INIS)

    Stromberg, K.; Hudgins, W.R.


    Purified human epidermal growth factor (hEGF) from urine promotes anchorage-independent cell growth in soft agar medium. This growth is enhanced by transforming growth factor-beta (TGF-beta), and is specifically inhibited by hEGF antiserum. Transforming growth factors of the alpha type (TGF-alpha), potentially present in normal human urine or urine from tumor-bearing patients, also promote anchorage-independent cell growth and compete with EGF for membrane receptor binding. Consequently, TGF-alpha cannot be distinguished from urinary hEGF by these two functional assays. Therefore, a technique for separation of TGF-alpha and related peptides from urinary EGF based on biochemical characteristics would be useful. Radioiodination of characterized growth factors [mouse EGF (mEGF), hEGF, and rat TGF-alpha (rTGF-alpha)], which were then separately added to human urine, was used to evaluate a resolution scheme that separates TGF-alpha from the high level of background hEGF present in human urine. Methyl bonded microparticulate silica efficiently adsorbed the 125 I-labeled mEGF, 125 I-labeled hEGF, and 125 I-labeled rTGF-alpha that were added to 24-h human urine samples. Fractional elution with acetonitrile (MeCN) of the adsorbed silica released approximately 70 to 80% of the 125 I-labeled mEGF and 125 I-labeled hEGF between 25 and 30% MeCN, and over 80% of the 125 I-labeled rTGF-alpha between 15 and 25% MeCN, with retention after dialysis of less than 0.2 and 1.7% of the original urinary protein, respectively. A single-step enrichment of about 400-fold for mEGF and hEGF, and 50-fold for rTGF-alpha were achieved rapidly. 125 I-labeled mEGF and 125 I-labeled hEGF eluted later than would be predicted on the basis of their reported molecular weight of approximately 6000, whereas 125 I-labeled rTGF-alpha eluted from Bio-Gel P-10 at an approximate molecular weight of 8000 to 9000

  18. Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha (TNF-alpha ) mRNA induction. Evidence for selective destabilization of TNF-alpha transcripts. (United States)

    Rutault, K; Hazzalin, C A; Mahadevan, L C


    Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine whose synthesis and secretion are implicated in diverse pathologies. Hence, inhibition of TNF-alpha transcription or translation and neutralization of its protein product represent major pharmaceutical strategies to control inflammation. We have studied the role of ERK and p38 mitogen-activated protein (MAP) kinase in controlling TNF-alpha mRNA levels in differentiated THP-1 cells and in freshly purified human monocytes. We show here that it is possible to produce virtually complete inhibition of lipopolysaccharide-stimulated TNF-alpha mRNA accumulation by using a combination of ERK and p38 MAP kinase inhibitors. Furthermore, substantial inhibition is achievable using combinations of 1 microm of each inhibitor, whereas inhibitors used individually are incapable of producing complete inhibition even at high concentrations. Finally, addressing mechanisms involved, we show that inhibition of p38 MAP kinase selectively destabilizes TNF-alpha transcripts but does not affect degradation of c-jun transcripts. These results impinge on the controversy in the literature surrounding the mode of action of MAP kinase inhibitors on TNF-alpha mRNA and suggest the use of combinations of MAP kinase inhibitors as an effective anti-inflammatory strategy.

  19. Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

    DEFF Research Database (Denmark)

    Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj


    BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin....../or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow....... Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (Palpha...

  20. Development of a sensitive ELISA for the quantification of human tumour necrosis factor-alpha using 4 polyclonal antibodies.

    NARCIS (Netherlands)

    Grebenchtchikov, N.J.; Ven-Jongekrijg, J. van der; Pesman, G.J.; Geurts-Moespot, A.; Meer, J.W.M. van der; Sweep, C.G.J.


    Despite the availability of many assays to measure concentrations of tumour necrosis factor alpha (TNF-alpha) in body fluids, these assays often lack specificity or sensitivity and are often of questionable reliability, resulting in inconsistent results. Therefore, we have developed an ELISA that is

  1. Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. (United States)

    Carrillo, Eddy H; Gordon, Laura E; Richardson, J David; Polk, Hiram C


    A systemic inflammatory response (SIR) is seen in approximately 75% of patients with complex blunt liver injuries treated nonoperatively. Many feel this response is caused by blood, bile, and necrotic tissue accumulation in the peritoneal cavity. Our current treatment for these patients is a delayed laparoscopic washout of the peritoneal cavity, resulting in a dramatic resolution of the SIR. Spectrophotometric analysis of the intraperitoneal fluid has confirmed the presence of high concentrations of free hemoglobin (Hb). We hypothesize that free Hb enhances the local peritoneal response by increasing tumor necrosis factor-alpha (TNF-alpha) production by monocytes, contributing to the local inflammatory response and SIR. Monocytes from five healthy volunteers were isolated and cultured in RPMI-1640 for 24 hours. Treatment groups included saline controls, lipopolysaccharide ([LPS], 10 ng/mL, from Escherichia coli), human Hb (25 microg/mL), and Hb + LPS. Supernatants were analyzed by enzyme-linked immunosorbent assay. Student's t test with Mann-Whitney posttest was used for statistical analysis with p < or = 0.05 considered significant. Free Hb significantly increased TNF-alpha production 915 +/- 223 pg/mL versus saline (p = 0.02). LPS and Hb + LPS further increased TNF-alpha production (2294 pg/mL and 2501 pg/mL, respectively, p < 0.001) compared with saline controls. These data confirm that free Hb is a proinflammatory mediator resulting in the production of significant amounts of TNF-alpha. These in vitro findings support our clinical data in which timely removal of intraperitoneal free hemoglobin helps prevent its deleterious local and systemic inflammatory effects in patients with complex liver injuries managed nonoperatively.

  2. High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes

    DEFF Research Database (Denmark)

    Sandmand, Marie; Bruunsgaard, Helle; Kemp, Kåre


    BACKGROUND: Aging is characterized by increased inflammatory activity reflected by increased plasma levels of proinflammatory cytokines, concomitant with an altered cytokine profile of T lymphocytes. High plasma levels of tumor necrosis factor (TNF)-alpha are strongly associated with morbidity...... and mortality in elderly humans. However, the cellular source and mechanisms for the increased circulating TNF-alpha levels are unknown. OBJECTIVE: The aim of the present study was to investigate if high plasma levels of TNF-alpha are associated with increased production of TNF-alpha by T lymphocytes in elderly...... humans. METHODS: TNF-alpha production by CD4+ and CD8+ T lymphocytes was measured by flow cytometry following stimulation with phorbol 12-myristate 13-acetate and ionomycin in 28 young controls, 14, 81-year-olds and 25 centenarians. RESULTS: Plasma levels of TNF-alpha increased with increasing age...

  3. Effect of ascorbic acid and alpha-tocopherol supplementations on serum leptin, tumor necrosis factor alpha, and serum amyloid A levels in individuals with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Mostafa Jamalan


    Full Text Available Objective: Diabetes mellitus Type 2 is one of the most widespread chronic metabolic diseases. In most cases, this type of diabetes is associated with alterations in levels of some inflammatory cytokines and hormones. Considering anti-inflammatory properties of plant extracts rich in ascorbic acid (vitamin C and alpha-tocopherol (vitamin E, anti-diabetic properties of these two well-known antioxidant vitamins were investigated through measurement of serum levels of high-sensitivity C-reactive protein (hs-CRP, insulin, leptin, tumor necrosis factor alpha (TNF-α, and serum amyloid A (SAA in patients with diabetes mellitus type 2. Methods: Male patients (n=80 were randomly divided into two groups each consisted of 40 subjects. Test groups were supplemented with ascorbic acid (1000 mg/day or alpha-tocopherol (300 mg/day orally during four weeks. Before and after treatment, serum biochemical factors of subjects were measured and compared. Results: Our results showed that both ascorbic acid and alpha-tocopherol could induce significant anti-inflammatory effects by decreasing the level of inflammatory factors such as TNF-α, SAA, and hs-CRP in diabetes mellitus type 2 patients. Effects of alpha-tocopherol and ascorbic acid in decreasing serum leptin level were similar. Ascorbic acid in contrast to alpha-tocopherol diminished fasting insulin and HOMA index but had no effect on LDL serum level. Conclusion: Concerning the obtained results, it is concluded that consumption of supplementary vitamins C and E could decrease induced inflammatory response in patients with diabetes mellitus type 2.  It is also possible that vitamin C and vitamin E supplementation can attenuate incidence of some proposed pathological effects of diabetes mellitus.

  4. Investigation of cascade regions of damage in alpha iron by a computer simulation method (crystal model). Issledovaniye kaskadnykh oblastey povrezhdeniya v. cap alpha. -zheleze metodom mashinnogo modelirovaniya (kristallicheskaya model)

    Energy Technology Data Exchange (ETDEWEB)

    Kevorkyan, Yu R


    A SPIKE program is used to study regions of structural damage that arise as a result of cascades of atomic collisions in single-crystal alpha iron. The model of the cascade process realized in the program uses a pair collision approximation and accounts for the influence of the crystal structure of the material. The following characteristics of regions of damage are found as a function of the energy of the primary knock-on atom: volume of the region, displacement effectiveness, size distribution of complexes of vacancies and injections. The results are compared with data in the literature. An appendix gives the text of the SPIKE program in FORTRAN.

  5. Interferon-alpha suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.

    LENUS (Irish Health Repository)

    Tajuddin, Tariq


    BACKGROUND AND AIM: Neutropenia, a major side-effect of interferon-alpha (IFN-alpha) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G-CSF), an important growth factor for neutrophils. We hypothesized that IFN-alpha might suppress G-CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll-like receptor (TLR) agonist might overcome this suppression. METHODS: Fifty-five patients who were receiving IFN-alpha\\/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G-CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme-linked immunosorbent assay following 18 h of culture in the absence or presence of IFN- alpha or the TLR7\\/8 agonist, CL097. RESULTS: Therapeutic IFN-alpha caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G-CSF. The reduction in ANC over the course of IFN-alpha treatment was paralleled by a decrease in the ability of PBMCs to produce G-CSF. In vitro G-CSF production by PBMCs was suppressed in the presence of IFN-alpha; however, co-incubation with a TLR7\\/8 agonist significantly enhanced G-CSF secretion by cells obtained both from HCV patients and healthy controls. CONCLUSIONS: Suppressed G-CSF production in the presence of IFN-alpha may contribute to IFN-alpha-induced neutropenia. However, a TLR7\\/8 agonist elicits G-CSF secretion even in the presence of IFN-alpha, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-alpha-induced neutropenia.

  6. Analysis of the local kinetics and localization of interleukin-1 alpha, tumour necrosis factor-alpha and transforming growth factor-beta, during the course of experimental pulmonary tuberculosis. (United States)

    Hernandez-Pando, R; Orozco, H; Arriaga, K; Sampieri, A; Larriva-Sahd, J; Madrid-Marina, V


    A mouse model of pulmonary tuberculosis induced by the intratracheal instillation of live and virulent mycobacteria strain H37-Rv was used to examine the relationship of the histopathological findings with the local kinetics production and cellular distribution of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and transforming growth factor-beta (TGF-beta). The histopathological and immunological studies showed two phases of the disease: acute or early and chronic or advanced. The acute phase was characterized by inflammatory infiltrate in the alveolar-capillary interstitium, blood vessels and bronchial wall with formation of granulomas. During this acute phase, which lasted from 1 to 28 days, high percentages of TNF-alpha and IL-1 alpha immunostained activated macrophages were observed principally in the interstium-intralveolar inflammatory infiltrate and in granulomas. Electron microscopy studies of these cells, showed extensive rough endoplasmic reticulum, numerous lysosomes and occasional mycobacteria. Double labelling with colloid gold showed that TNF-alpha and IL-1 alpha were present in the same cells, but were confined to separate vacuoles near the Golgi area, and mixed in larger vacuoles near to cell membrane. The concentration of TNF-alpha and IL-1 alpha as well as their respective mRNAs were elevated in the early phase, particularly at day 3 when the bacillary count decreased. A second peak was seen at days 14 and 21-28 when granulomas appeared and evolved to full maturation. In contrast, TGF-beta production and numbers of immunoreactive cells were low in comparison with the advanced phase of the disease. The chronic phase was characterized by histopathological changes indicative of more severity (i.e. pneumonia, focal necrosis and extensive interstitial fibrosis) with a decrease in the TNF-alpha and IL-1 alpha production that coincided with the highest level of TGF-beta. The bacillary counts were highest as the macrophages

  7. Oral clefts, tranforming growth factor alpha gene variants, and maternal smoking

    DEFF Research Database (Denmark)

    Christensen, Kaare; Olsen, Jørn; Nørgaard-Pedersen, Bent


    Studies in the United States have indicated that maternal first trimester smoking and infant transforming growth factor alpha (TGFA) locus mutations are associated with non-syndromic cleft lip and/or palate (CLP) and that a synergistic effect of these two risk factors occurs. Based on a Danish case-control......, and no synergistic effect with smoking was observed. The "rare" TGFA allele occurred in 25% of both cases and controls compared with an average of 14% in other white control groups. Furthermore, the frequency of CLP in Scandinavia is among the highest in the world. Hence, it is possible that the previously reported...

  8. TGF-alpha genotypes, oral clefts, and environmental risk factors: A population-based California study

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, G.M.; Wasserman, C.R. [CA Birth Defects Monitoring Program, Emeryville, CA (United States); Lammer, E.J. [Stanford Univ., Palo Alto, CA (United States)] [and others


    Several studies have shown a relation between genetic variation at the TGF-alpha locus and oral clefts. These studies had limited sample sizes and also lacked data on additional factors potentially related to clefting. We investigated the influence on clefting from risk factors, such as maternal smoking, dependent on TFG-alpha genotype. This was accomplished using a large population-bases case-control study of fetuses and liveborn infants with oral clefts among a 1987-89 cohort of California births (N=548,844). To obtain data on potential risk factors, telephone interviews were conducted with mothers of 731 (84.5% of eligible) cleft cases, and 734 (78.2%) nonmalformed controls. DNA was obtained from newborn screening bloodspots and genotyped by using SSCP designed to detect the Taq1 RFLP. Among mothers who completed an interview, genotyping results were available for 571 (78.1%) cases and 640 (87.2%) controls. Compared to controls, the risk estimate for TGF-alpha polymorphism as measured by the odds ratio was: 0.99 (95% confidence interval 0.64, 1.5) for isolated cleft lip {plus_minus}palate; 0.88 (0.33, 2.2) for nonisolated cleft lip {plus_minus}palate; 1.6 (0.94, 2.8) for isolated cleft palate; 1.9 (0.82, 4.3) for nonisolated cleft palate; and 2.2 (0.99, 5.0) for clefts with known etiology. This dataset also revealed 1.4 to 2-fold increased risks for maternal cigarette smoking > 19 cigs/day in early pregnancy. Among these heavy smokers, risk of clefting was even more increased for infants with the TGF-alpha polymorphism. Our data suggest an association between the TGF-alpha uncommon allele and some phenotypic subgroups as well as provide evidence for a genetic-environment interaction between maternal smoking and the variant in the etiology of clefting. The fraction of cases possibly attributed to this interaction, however, was small.

  9. Thioesterase activity and acyl-CoA/fatty acid cross-talk of hepatocyte nuclear factor-4{alpha}. (United States)

    Hertz, Rachel; Kalderon, Bella; Byk, Tamara; Berman, Ina; Za'tara, Ghadeer; Mayer, Raphael; Bar-Tana, Jacob


    Hepatocyte nuclear factor-4alpha (HNF-4alpha) activity is modulated by natural and xenobiotic fatty acid and fatty acyl-CoA ligands as a function of their chain length, unsaturation, and substitutions. The acyl-CoA site of HNF-4alpha is reported here to consist of the E-F domain, to bind long-chain acyl-CoAs but not the respective free acids, and to catalyze the hydrolysis of bound fatty acyl-CoAs. The free acid pocket, previously reported in the x-ray structure of HNF-4alpha E-domain, entraps fatty acids but excludes acyl-CoAs. The acyl-CoA and free acid sites are distinctive and noncongruent. Free fatty acid products of HNF-4alpha thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4alpha. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4alpha that inhibit its thioesterase activity. Hence, HNF-4alpha transcriptional activity is controlled by its two interrelated acyl ligands and two binding sites interphased in tandem by the thioesterase activity. The acyl-CoA/free-acid and receptor/enzyme duality of HNF-4alpha extends the paradigm of nuclear receptors.

  10. Purification of the labeled cyanogen bromide peptides of the. cap alpha. polypeptide from sodium and potassium ion-activated adenosinetriphosphatase modified with N-(/sup 3/H)ethylmaleimide

    Energy Technology Data Exchange (ETDEWEB)

    Le, D.T.


    Sodium and potassium ion-activated adenosinetriphosphatase, isolated from canine kidney, was reacted with N-(/sup 3/H)ethylmaleimide under three different conditions, defined by particular concentrations of ligands for the enzyme, such that after the same amount of time the remaining activity of then enzyme varied from 90% to 30%. The conformation of the enzyme also differed among the three conditions. In all cases, the ..cap alpha..-polypeptide was purified and subjected to cyanogen bromide digestion. Two distinct, radioactive peptides were separated by gel filtration of the cyanogen bromide digest on a column of Sephadex LH-60 equilibrated with 95% ethanol: 88% formic acid:4:1. One of the radioactive peptides was shown to contain the sulfhydryl residue whose reaction with N-ethylmaleimide inactivates the enzyme. The other radioactive peptide contained a sulfhydryl residue that seems to react with N-ethylmaleimide only when the binding site for ATP is not occupied. Alkylation of this residue, however, does not result in inactivation of enzyme. Both peptides were purified further by high-pressure liquid chromatography, and their amino-terminal sequences were determined by the manual dansyl-Edman or solid-phase techniques. The peptide containing the sulfhydryl protected by ATP has, as its amino terminus, the lysine that reacts exclusively with fluorescein-5'-isothiocyanate.

  11. Reactor neutron activation analysis for aluminium in the presence of phosphorus and silicon. Contributions of /sup 28/Al activities from /sup 31/P (n,. cap alpha. ) /sup 28/Al and /sup 28/Si (n,p) /sup 28/Al reactions

    Energy Technology Data Exchange (ETDEWEB)

    Mizumoto, Yoshihiko (Kinki Univ., Higashi-Osaka, Osaka (Japan). Faculty of Science and Technology); Iwata, Shiro; Sasajima, Kazuhisa; Yoshimasu, Fumio; Yase, Yoshiro


    Reactor neutron activation analysis for aluminium in samples containing phosphorus and silicon was studied. The experiments were performed by using pneumatic tube of the Kyoto University Reactor (KUR). At first, the ratios of the /sup 28/Al activity produced from /sup 27/Al(n, ..gamma..) /sup 28/Al reaction by thermal neutrons to that from /sup 31/P(n, ..cap alpha..)/sup 28/Al reaction by fast neutrons, and to that from /sup 28/Si(n, p)/sup 28/Al reaction were measured by ..gamma..-ray spectrometry. With a ratio of about 5 for the thermal to fast neutron flux of KUR, the ratio of the /sup 28/Al activity from aluminium to that from phosphorus was to be 812 +- 7, and to that from silicon 282 +- 3. Secondly, the contributions of /sup 28/Al activities from phosphorus and silicon and the determination limit of aluminium were calculated for various parameters, such as fast neutron flux, thermal to fast neutron flux ratio, amounts of phosphorus and silicon, etc. Thirdly, on the basis of these results, aluminium contents in spinal cords and brains of amyotrophic lateral sclerosis, Parkinsonism-dementia complex and control cases were determined.

  12. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab

    DEFF Research Database (Denmark)

    Bendtzen, Klaus; Geborek, Pierre; Svenson, Morten


    Infliximab, an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial...

  13. Generation of tumour-necrosis-factor-alpha-specific affibody molecules capable of blocking receptor binding in vitro. (United States)

    Jonsson, Andreas; Wållberg, Helena; Herne, Nina; Ståhl, Stefan; Frejd, Fredrik Y


    Affibody molecules specific for human TNF-alpha (tumour necrosis factor-alpha) were selected by phage-display technology from a library based on the 58-residue Protein A-derived Z domain. TNF-alpha is a proinflammatory cytokine involved in several inflammatory diseases and, to this day, four TNF-alpha-blocking protein pharmaceuticals have been approved for clinical use. The phage selection generated 18 unique cysteine-free affibody sequences of which 12 were chosen, after sequence cluster analysis, for characterization as proteins. Biosensor binding studies of the 12 Escherichia coli-produced and IMAC (immobilized-metal-ion affinity chromatography)-purified affibody molecules revealed three variants that demonstrated the strongest binding to human TNF-alpha. These three affibody molecules were subjected to kinetic binding analysis and also tested for their binding to mouse, rat and pig TNF-alpha. For ZTNF-alpha:185, subnanomolar affinity (KD=0.1-0.5 nM) for human TNF-alpha was demonstrated, as well as significant binding to TNF-alpha from the other species. Furthermore, the binding site was found to overlap with the binding site for the TNF-alpha receptor, since this interaction could be efficiently blocked by the ZTNF-alpha:185 affibody. When investigating six dimeric affibody constructs with different linker lengths, and one trimeric construct, it was found that the inhibition of the TNF-alpha binding to its receptor could be further improved by using dimers with extended linkers and/or a trimeric affibody construct. The potential implication of the results for the future design of affibody-based reagents for the diagnosis of inflammation is discussed.

  14. Using different drift gases to change separation factors (alpha) in ion mobility spectrometry (United States)

    Asbury; Hill


    The use of different drift gases to alter separation factors (alpha) in ion mobility spectrometry has been demonstrated. The mobility of a series of low molecular weight compounds and three small peptides was determined in four different drift gases. The drift gases chosen were helium, argon, nitrogen, and carbon dioxide. These drift gases provide a range of polarizabilities and molecular weights. In all instances, the compounds showed the greatest mobility in helium and the lowest mobility in carbon dioxide; however the percentage change of mobility for each compound was different, effectively changing the alpha value. The alpha value changes were primarily due to differences in drift gas polarizability but were also influenced by the mass of the drift gas. In addition, gas-phase ion radii were calculated in each of the different drift gases. These radii were then plotted against drift gas polarizability producing linear plots with r2 values greater than 0.99. The intercept of these plots provides the gas-phase radius of an ion in a nonpolarizing environment, whereas the slope is indicative of the magnitude of the ion's mobility change related to polarizability. It therefore, should be possible to separate any two compounds that have different slopes with the appropriate drift gas.

  15. Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Jacek Nikliński


    Full Text Available The aim of the present study was to characterize the expression pattern of tumor necrosis factor (TNF-alpha and its receptors (TNF-Rs in the epithelial ovarian cancer (EOC and compare these results with the outcome of 126 patients. Presence of TNF-alpha, TNFR-1 and TNFR-2 were studied by Western blotting and immunohistochemistry. The proportion of samples positive for TNF-alpha and TNF-R2 was higher in epithelial ovarian cancer patients than in benign ovarian diseases (p<0.001 and p=0.016, respectively. Immunostaining intensity of TNF-R2 were correlated with tumor stage (p<0.001 and with reduced mean survival time (MST (p=0.002. The results of the present study suggested that tissue expression of TNF-R2 in epithelial ovarian cancer was correlated with the highest risk of cancer progression. Thus, the clinical value of activated TNF system in epithelial ovarian cancer needs to be further investigated.

  16. Transforming growth factor alpha, Shope fibroma growth factor, and vaccinia growth factor can replace myxoma growth factor in the induction of myxomatosis in rabbits. (United States)

    Opgenorth, A; Nation, N; Graham, K; McFadden, G


    The epidermal growth factor (EGF) homologues encoded by vaccinia virus, myxoma virus, and malignant rabbit fibroma virus have been shown to contribute to the pathogenicity of virus infection upon inoculation of susceptible hosts. However, since the primary structures of these growth factors and the disease profiles induced by different poxvirus genera vary substantially, the degree to which the various EGF homologues perform similar roles in viral pathogenesis remains unclear. In order to determine whether different EGF-like growth factors can perform qualitatively similar functions in the induction of myxomatosis in rabbits, we created recombinant myxoma virus variants in which the native growth factor, myxoma growth factor (MGF), was disrupted and replaced with either vaccinia virus growth factor, Shope fibroma growth factor, or rat transforming growth factor alpha. Unlike the control virus containing an inactivated MGF gene, which caused marked attenuation of the disease syndrome and substantially less proliferation of the epithelial cell layers in the conjunctiva and respiratory tract, the recombinant myxoma virus strains expressing heterologous growth factors produced infections which were both clinically and histopathologically indistinguishable from wild-type myxomatosis. We conclude that these poxviral and cellular EGF-like growth factors, which are diverse with respect to primary structure and origin, have similar biological functions in the context of myxoma virus pathogenesis and are mitogenic for the same target cells.

  17. Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha (United States)

    DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu


    Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2–4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2–4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2–4) by fusing the variable region of mouse mAb 2–4 to the constant region of feline antibody. The chimeric mAb 2–4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2–4 and chimeric mAb 2–4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2–4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2–4 was reduced. In contrast, in cats treated with chimeric mAb 2–4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2–4-treated cats. PMID:27264736

  18. Retinal neuroprotection by hypoxic preconditioning is independent of hypoxia-inducible factor-1 alpha expression in photoreceptors. (United States)

    Thiersch, Markus; Lange, Christina; Joly, Sandrine; Heynen, Severin; Le, Yun Zheng; Samardzija, Marijana; Grimm, Christian


    Hypoxic preconditioning stabilizes hypoxia-inducible factor (HIF) 1 alpha in the retina and protects photoreceptors against light-induced cell death. HIF-1 alpha is one of the major transcription factors responding to low oxygen tension and can differentially regulate a large number of target genes. To analyse whether photoreceptor-specific expression of HIF-1 alpha is essential to protect photoreceptors by hypoxic preconditioning, we knocked down expression of HIF-1 alpha specifically in photoreceptor cells, using the cyclization recombinase (Cre)-lox system. The Cre-mediated knockdown caused a 20-fold reduced expression of Hif-1 alpha in the photoreceptor cell layer. In the total retina, RNA expression was reduced by 65%, and hypoxic preconditioning led to only a small increase in HIF-1 alpha protein levels. Accordingly, HIF-1 target gene expression after hypoxia was significantly diminished. Retinas of Hif-1 alpha knockdown animals did not show any pathological alterations, and tolerated hypoxic exposure in a comparable way to wild-type retinas. Importantly, the strong neuroprotective effect of hypoxic preconditioning against light-induced photoreceptor degeneration persisted in knockdown mice, suggesting that hypoxia-mediated survival of light exposure does not depend on an autocrine action of HIF-1 alpha in photoreceptor cells. Hypoxia-mediated stabilization of HIF-2 alpha and phosphorylation of signal transducer and activator of transcription 3 (STAT 3) were not affected in the retinas of Hif-1 alpha knockdown mice. Thus, these factors are candidates for regulating the resistance of photoreceptors to light damage after hypoxic preconditioning, along with several potentially neuroprotective genes that were similarly induced in hypoxic knockdown and control mice.

  19. Characterization of the primary interaction between the mating pheromone, alpha-factor, and its receptor in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Raths, S.K.


    Alpha-factor is a peptide of thirteen amino acids which is required for mating between the haploid mating types, a and α, in Saccharomyces cerevisiae. An analogue of alpha-factor, DHP 8 DHP 11 Nle 12 tridecapeptide, was catalytically reduced in the presence of 3 H gas for production of a radiolabeled pheromone suitable for use in binding studies. Incorporation of tritium resulted in 3 H-alpha-factor with high specific activity, purity, biological activity and long shelf-life. Binding studies revealed that alpha-factor interacts with its receptor via a simple, reversible process which obeys the law of mass action. Association and dissociation kinetics indicate values of 2.92 x 10 6 M/sup /minus/1/ min -1 for k 1 and between 4 and 7 x 10/sup /minus/2/ min/sup /minus/1/ for k/sub /minus/1/. Saturation binding studies reveal an equilibrium dissociation constant equal to 2.32 x 10/sup /minus/8/ M which approximate the kinetically-derived K/sub D/ of 2.12 x 10/sup /minus/8/ M. Scatchard and Hill analyses as well as dissociation behavior in the presence of excess unlabeled ligand indicate alpha-factor interacts with a homogeneous population of binding sites which do not interact and exhibit one affinity for the alpha-factor pheromone

  20. [Cardiovascular exercise on obese women: effects on adiponectine, leptine, and tumour necrosis factor-alpha]. (United States)

    Landeros-Olvera, Erick; López-Alvarenga, Juan Carlos; Nava-González, Edna J; Gallegos-Cabriales, Esther; Lavalle-González, Fernando; Bastarrachea, Raúl A; Salazar González, Bertha Cecilia


    The relationship of hormones adiponectin, leptin and tumor necrosis factor-alpha in adipose tissue on the atherogenic process is one of the most promising models in preventive medicine. The numerous tests performed to identify the effect of exercise on these hormones have not been clear on the type of exercise routine and physical effort calculated to contribute to changing plasma concentrations in obese women. Analyze controlledcardiovascular exercise effect on serum level of adiponectin, leptin, and tumournecrosis factor-alpha in obese young women. A simple blind clinical essay. The intervention covered a 10-week controlled, cardiovascular exercise program by 34 women (cases n=17, controls n=17) with a body mass index>27kg/m(2). Molecular analysis was performed by immune-fluorescence. Following the intervention, cases and controls means were as follows: adiponectin 19.0 vs. 12.2μ/ml (P=.008); leptin 20.0 vs. 28.0μ/L (P=.02); and tumour necrosis factor-alpha 4.7 vs. 5.1pg/ml (P=.05). The established exercise (5 sessions a week of exercise of 40min each for 10 weeks with a heart rate reserve of 40 to 80%) improved plasma concentrations of these hormones in the expected direction. This finding highlights an unpublished amount of exercise, controlled by the reserve cardiac frequency that might contribute the cardiovascular and metabolic protection to obese women. Copyright © 2013 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  1. A Point Mutation in the Exon Junction Complex Factor Y14 Disrupts Its Function in mRNA Cap Binding and Translation Enhancement* (United States)

    Chuang, Tzu-Wei; Lee, Kuo-Ming; Lou, Yuan-Chao; Lu, Chia-Chen; Tarn, Woan-Yuh


    Eukaryotic mRNA biogenesis involves a series of interconnected steps mediated by RNA-binding proteins. The exon junction complex core protein Y14 is required for nonsense-mediated mRNA decay (NMD) and promotes translation. Moreover, Y14 binds the cap structure of mRNAs and inhibits the activity of the decapping enzyme Dcp2. In this report, we show that an evolutionarily conserved tryptophan residue (Trp-73) of Y14 is critical for its binding to the mRNA cap structure. A Trp-73 mutant (W73V) bound weakly to mRNAs and failed to protect them from degradation. However, this mutant could still interact with the NMD and mRNA degradation factors and retained partial NMD activity. In addition, we found that the W73V mutant could not interact with translation initiation factors. Overexpression of W73V suppressed reporter mRNA translation in vitro and in vivo and reduced the level of a set of nascent proteins. These results reveal a residue of Y14 that confers cap-binding activity and is essential for Y14-mediated enhancement of translation. Finally, we demonstrated that Y14 may selectively and differentially modulate protein biosynthesis. PMID:26887951

  2. A Point Mutation in the Exon Junction Complex Factor Y14 Disrupts Its Function in mRNA Cap Binding and Translation Enhancement. (United States)

    Chuang, Tzu-Wei; Lee, Kuo-Ming; Lou, Yuan-Chao; Lu, Chia-Chen; Tarn, Woan-Yuh


    Eukaryotic mRNA biogenesis involves a series of interconnected steps mediated by RNA-binding proteins. The exon junction complex core protein Y14 is required for nonsense-mediated mRNA decay (NMD) and promotes translation. Moreover, Y14 binds the cap structure of mRNAs and inhibits the activity of the decapping enzyme Dcp2. In this report, we show that an evolutionarily conserved tryptophan residue (Trp-73) of Y14 is critical for its binding to the mRNA cap structure. A Trp-73 mutant (W73V) bound weakly to mRNAs and failed to protect them from degradation. However, this mutant could still interact with the NMD and mRNA degradation factors and retained partial NMD activity. In addition, we found that the W73V mutant could not interact with translation initiation factors. Overexpression of W73V suppressed reporter mRNA translation in vitro and in vivo and reduced the level of a set of nascent proteins. These results reveal a residue of Y14 that confers cap-binding activity and is essential for Y14-mediated enhancement of translation. Finally, we demonstrated that Y14 may selectively and differentially modulate protein biosynthesis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. A network of hydrophobic residues impeding helix alphaC rotation maintains latency of kinase Gcn2, which phosphorylates the alpha subunit of translation initiation factor 2. (United States)

    Gárriz, Andrés; Qiu, Hongfang; Dey, Madhusudan; Seo, Eun-Joo; Dever, Thomas E; Hinnebusch, Alan G


    Kinase Gcn2 is activated by amino acid starvation and downregulates translation initiation by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). The Gcn2 kinase domain (KD) is inert and must be activated by tRNA binding to the adjacent regulatory domain. Previous work indicated that Saccharomyces cerevisiae Gcn2 latency results from inflexibility of the hinge connecting the N and C lobes and a partially obstructed ATP-binding site in the KD. Here, we provide strong evidence that a network of hydrophobic interactions centered on Leu-856 also promotes latency by constraining helix alphaC rotation in the KD in a manner relieved during amino acid starvation by tRNA binding and autophosphorylation of Thr-882 in the activation loop. Thus, we show that mutationally disrupting the hydrophobic network in various ways constitutively activates eIF2alpha phosphorylation in vivo and bypasses the requirement for a key tRNA binding motif (m2) and Thr-882 in Gcn2. In particular, replacing Leu-856 with any nonhydrophobic residue activates Gcn2, while substitutions with various hydrophobic residues maintain kinase latency. We further provide strong evidence that parallel, back-to-back dimerization of the KD is a step on the Gcn2 activation pathway promoted by tRNA binding and autophosphorylation. Remarkably, mutations that disrupt the L856 hydrophobic network or enhance hinge flexibility eliminate the need for the conserved salt bridge at the parallel dimer interface, implying that KD dimerization facilitates the reorientation of alphaC and remodeling of the active site for enhanced ATP binding and catalysis. We propose that hinge remodeling, parallel dimerization, and reorientation of alphaC are mutually reinforcing conformational transitions stimulated by tRNA binding and secured by the ensuing autophosphorylation of T882 for stable kinase activation.

  4. Regulation of eukaryotic elongation factor 1 alpha (eEF1A) by dynamic lysine methylation

    DEFF Research Database (Denmark)

    Jakobsson, Magnus E; Małecki, Jędrzej; Falnes, Pål Ø


    Lysine methylation is a frequent post-translational protein modification, which has been intensively studied in the case of histone proteins. Lysine methylations are also found on many non-histone proteins, and one prominent example is eukaryotic elongation factor 1 alpha (eEF1A). Besides its...... essential role in the protein synthesis machinery, a number of non-canonical functions have also been described for eEF1A, such as regulation of the actin cytoskeleton and the promotion of viral replication. The functional significance of the extensive lysine methylations on eEF1A, as well as the identity...

  5. Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels (United States)

    Pierangeli, Silvia S.; Sonnenfeld, Gerald


    Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.

  6. [Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells]. (United States)

    Zheng, Yongchang; Du, Shunda; Xu, Haifeng; Xu, Yiyao; Zhao, Haitao; Chi, Tianyi; Lu, Xin; Sang, Xinting; Mao, Yilei


    To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha (TNF-α)-induced hepatocellular carcinoma cells with bioinformatics tools. Published microarray dataset of TNF-α-induced HepG2, human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network. In the signal transduction network, MYC and SP1 were the key nodes of signaling transduction. Several genes from the network were closely related with cellular adhesion.Epidermal growth factor receptor (EGFR) is a possible key gene of effectively regulating cellular adhesion during the induction of TNF-α. EGFR is a possible key gene for TNF-α-induced metastasis of hepatocellular carcinoma.

  7. Enhanced actions of insulin-like growth factor-I and interferon-alpha co-administration in experimental cirrhosis. (United States)

    Tutau, Federico; Rodríguez-Ortigosa, Carlos; Puche, Juan Enrique; Juanarena, Nerea; Monreal, Iñigo; García Fernández, María; Clavijo, Encarna; Castilla, Alberto; Castilla-Cortázar, Inma


    Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation. The liver is the major source of circulating insulin-like growth factor-I (IGF-I) whose plasma levels are diminished in cirrhosis. IGF-I supplementation has been shown to induce beneficial effects in cirrhosis, including antifibrogenic and hepatoprotective effects. On other hand, interferon-alpha (IFN-alpha) therapy seems to suppress the progression of hepatic fibrosis. The aim of this study was to investigate the effect of the co-administration of IGF-I+IFN-alpha to Wistar rats with CCl(4)-induced cirrhosis, exploring liver function tests, hepatic lipid peroxidation and histopathology. The mechanisms underlying the effects of these agents were studied by reverse transcription-polymerase chain reaction, determining the expression of some factors [hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin, collagen, tissular inhibitor of metalloproteinases-1 and pregnane X receptor (PXR)] involved in fibrogenesis, fibrolysis and/or hepatoprotection. Both IGF-I and IFN-alpha exerted significant effects on fibrogenesis. IGF-I significantly increased serum albumin and HGF whereas IFN-alpha-therapy did not. The inhibition of TGF-beta expression was only observed by the effect of IFN-alpha-therapy. In addition, only the co-administration of IGF-I and IFN-alpha was able to increase the PXR. The combined therapy with both factors improved liver function tests, hepatic lipid peroxidation and reduced fibrosis, inducing a relevant histological improvement, reducing fibrosis and recovering hepatic architecture. The co-administration IGF-I+IFN enhanced all the beneficial effects observed with each factor separately, showing an additive action on histopathology and PXR expression, which is involved in the inhibition of fibrogenesis.

  8. Effect of particle size on hydroxyapatite crystal-induced tumor necrosis factor alpha secretion by macrophages. (United States)

    Nadra, Imad; Boccaccini, Aldo R; Philippidis, Pandelis; Whelan, Linda C; McCarthy, Geraldine M; Haskard, Dorian O; Landis, R Clive


    Macrophages may promote a vicious cycle of inflammation and calcification in the vessel wall by ingesting neointimal calcific deposits (predominantly hydroxyapatite) and secreting tumor necrosis factor (TNF)alpha, itself a vascular calcifying agent. Here we have investigated whether particle size affects the proinflammatory potential of hydroxyapatite crystals in vitro and whether the nuclear factor (NF)-kappaB pathway plays a role in the macrophage TNFalpha response. The particle size and nano-topography of nine different crystal preparations was analyzed by X-ray diffraction, Raman spectroscopy, scanning electron microscopy and gas sorbtion analysis. Macrophage TNFalpha secretion was inversely related to hydroxyapatite particle size (P=0.011, Spearman rank correlation test) and surface pore size (P=0.014). A necessary role for the NF-kappaB pathway was demonstrated by time-dependent I kappaB alpha degradation and sensitivity to inhibitors of I kappaB alpha degradation. To test whether smaller particles were intrinsically more bioactive, their mitogenic activity on fibroblast proliferation was examined. This showed close correlation between TNFalpha secretion and crystal-induced fibroblast proliferation (P=0.007). In conclusion, the ability of hydroxyapatite crystals to stimulate macrophage TNFalpha secretion depends on NF-kappaB activation and is inversely related to particle and pore size, with crystals of 1-2 microm diameter and pore size of 10-50 A the most bioactive. Microscopic calcific deposits in early stages of atherosclerosis may therefore pose a greater inflammatory risk to the plaque than macroscopically or radiologically visible deposits in more advanced lesions.

  9. Increased pulmonary secretion of tumor necrosis factor-alpha in calves experimentally infected with bovine respiratory syncytial virus

    DEFF Research Database (Denmark)

    Rontved, C. M.; Tjørnehøj, Kirsten; Viuff, B.


    , of which 23 were experimentally infected with BRSV and five were given a mock inoculum. The presence of the cytokine tumor necrosis factor alpha (TNF-alpha) in the BAL fluids was detected and quantified by a capture ELISA. TNF-alpha was detected in 21 of the infected animals. The amount of TNF-alpha...... in the BAL fluid of calves killed post inoculation day (PID) 2 and 4 was at the same very low level as in the uninfected control animals. Large amounts of TNF-alpha were detected on PID 6, maximum levels of TNF-alpha were reached on PID 7, and smaller amounts of TNF-alpha were seen on PID 8. The high levels...... of TNF-alpha appeared on the days where severe lung lesions and clinical signs were obvious and the amounts of BRSV-antigen were at their greatest. Although Pasteurellaceae were isolated from some of the BRSV-infected calves, calves treated with antibiotics before and through the whole period...

  10. Interleukin-10 to tumor necrosis factor-alpha ratio is a predictive biomarker in nonalcoholic fatty liver disease: interleukin-10 to tumor necrosis factor-alpha ratio in steatohepatitis. (United States)

    Hashem, Reem M; Mahmoud, Mona F; El-Moselhy, Mohamed A; Soliman, Hala M


    Fatty liver disease is commonly associated with diabetes mellitus (DM). Insulin resistance (IR) as an investigative biomarker is only concerned with fatty liver that results from DM type 2 associated with metabolic syndrome. Irrespective of IR, DM is generally characterized by overproduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), whereas action of the latter is modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). The aim of this study was to investigate the efficacy of using TNF-alpha alone or IL-10/TNF-alpha ratio compared to IR, as a promising biomarker for fatty liver assessment in DM. Furthermore, we hypothesized that using garlic as an immunomodulator may decrease TNF-alpha and increase IL-10 production to improve steatohepatitis. DM was induced metabolically by a high-fat diet to bring about IR, or chemically by alloxan, producing insulin deficiency, in male albino rats. Garlic powder was supplemented (15 mg/kg per day) for 3 weeks. Fatty liver was depicted histologically and biochemically (aspartic aminotransferase, alanine aminotransferase, HOMA-IR, TNF-alpha, IL-10, IL-10/TNF-alpha ratio). We found that, in contrast to obese rats, garlic decreased IL-10/TNF-alpha ratio, despite decreasing TNF-alpha in alloxan diabetic rats in agreement with the histology, which revealed more prominent improvement in the obese group. Moreover, the effect of garlic was not linked to improvement of IR in obese rats. We conclude that IL-10/TNF-alpha ratio may be considered as a convenient biomarker for investigation of fatty liver of different grades, apart from being associated with IR, and immunomodulation of this ratio in favor of increasing it may exert significant improvement.

  11. Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

    NARCIS (Netherlands)

    Kuijper, Arno; Groep, P. van der; Wall, E. van der; Diest, P.J. van


    INTRODUCTION Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance

  12. Evaluation of angiopoietin 1 and 2, vascular endothelial growth factor, and tumor necrosis factor alpha levels in asthmatic children. (United States)

    Köksal, Burcu Tahire; Ozbek, Ozlem Yilmaz; Bayraktar, Nilufer; Yazici, Ayse Canan


    Asthma is characterized by chronic airway inflammation that is associated with structural changes termed airway remodeling. Recently, cytokines/mediators that augment inflammation have been attracting attention in this field. The aim of this study was to evaluate serum angiopoietin (Ang)-1, Ang-2, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF) alpha values, which have important roles in inflammation, angiogenesis, and remodeling in asthmatic children. We also documented correlations between demographic features, duration of asthma, and pulmonary function test (PFT) parameters. Randomly selected 40 children (20 male and 20 female children, aged 6-16 years) with mild or moderate persistent asthma and 32 healthy children (15 male and 17 female children, aged 6-16 years) enrolled in the study. All asthmatic children had been using inhaled corticosteroids at least for the last 3 months. Serum Ang-1 levels were significantly lower in asthmatic children than those in normal controls. The Ang-1/Ang-2 ratio was also significantly lower in asthmatic children compared with those in normal controls (p < 0.01). However, serum Ang-2, VEGF, and TNF-alpha levels were similar in the two groups. A significant positive correlation was found between VEGF and duration of asthma. No correlation between serum Ang-1, Ang-2, VEGF values, and PFT parameters was obtained. On the other hand, significant negative correlation was detected between serum TNF-alpha and forced expiratory volume in 1 second. We have shown that serum Ang-1 levels and Ang-1/Ang-2 ratio were significantly reduced and balance was toward Ang-2 in asthmatics children. This process may lead to inflammation, destabilization of blood vessels, and trigger remodeling.

  13. Amperometric magnetoimmunoassay for the direct detection of tumor necrosis factor alpha biomarker in human serum

    Energy Technology Data Exchange (ETDEWEB)

    Eletxigerra, U. [Micro-NanoFabrication Unit, IK4-Tekniker, Eibar (Spain); CIC microGUNE, Arrasate-Mondragón (Spain); Martinez-Perdiguero, J. [CIC microGUNE, Arrasate-Mondragón (Spain); Merino, S. [Micro-NanoFabrication Unit, IK4-Tekniker, Eibar (Spain); CIC microGUNE, Arrasate-Mondragón (Spain); Villalonga, R.; Pingarrón, J.M. [Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Madrid (Spain); Campuzano, S., E-mail: [Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Madrid (Spain)


    Highlights: • Electrochemical magnetoimmunosensor for tumor necrosis factor alpha (TNFα) biomarker. • Sensitive and selective detection of TNFα in undiluted serum. • LOD achieved lower than the cut-off value established for relevant illnesses. • Useful and affordable alternative to ELISAs for TNFα determination in serum. - Abstract: An amperometric immunoassay for the determination of tumor necrosis factor alpha (TNFα) protein biomarker in human serum based on the use of magnetic microbeads (MBs) and disposable screen-printed carbon electrodes (SPCEs) has been developed. The specifically modified microbeads were magnetically captured on the working electrode surface and the amperometric responses were measured at −0.20 V (vs. Ag pseudo-reference electrode), upon addition of hydroquinone (HQ) as electron transfer mediator and H{sub 2}O{sub 2} as the enzyme substrate. After a thorough optimization of the assay, extremely low limits of detection were achieved: 2.0 pg mL{sup −1} (36 fM) and 5.8 pg mL{sup −1} (105 fM) for standard solutions and spiked human serum, respectively. The simplicity, robustness and this clinically interesting LOD proved the developed TNFα immunoassay as a good contender for real clinical application.

  14. Amperometric magnetoimmunoassay for the direct detection of tumor necrosis factor alpha biomarker in human serum

    International Nuclear Information System (INIS)

    Eletxigerra, U.; Martinez-Perdiguero, J.; Merino, S.; Villalonga, R.; Pingarrón, J.M.; Campuzano, S.


    Highlights: • Electrochemical magnetoimmunosensor for tumor necrosis factor alpha (TNFα) biomarker. • Sensitive and selective detection of TNFα in undiluted serum. • LOD achieved lower than the cut-off value established for relevant illnesses. • Useful and affordable alternative to ELISAs for TNFα determination in serum. - Abstract: An amperometric immunoassay for the determination of tumor necrosis factor alpha (TNFα) protein biomarker in human serum based on the use of magnetic microbeads (MBs) and disposable screen-printed carbon electrodes (SPCEs) has been developed. The specifically modified microbeads were magnetically captured on the working electrode surface and the amperometric responses were measured at −0.20 V (vs. Ag pseudo-reference electrode), upon addition of hydroquinone (HQ) as electron transfer mediator and H 2 O 2 as the enzyme substrate. After a thorough optimization of the assay, extremely low limits of detection were achieved: 2.0 pg mL −1 (36 fM) and 5.8 pg mL −1 (105 fM) for standard solutions and spiked human serum, respectively. The simplicity, robustness and this clinically interesting LOD proved the developed TNFα immunoassay as a good contender for real clinical application

  15. Response of tumour necrosis factor alpha (TNF ) in blood and spleen mice that vaccinated with P.berghei radiation

    International Nuclear Information System (INIS)

    Darlina; Tur R; Teja K


    Tumor necrosis factor is a glycoprotein derived from helper T lymphocytes that play an important role in the body's response against malaria infection. However, TNF-α has double play that is on appropriate levels will provide protection and healing, while at excessive levels which may be a response to hyperparasitemia. Thus investigated the expression of TNF alpha secreted blood lymphocytes and spleen cells the mice that's infected with 1 x 10 7 P.berghei infectious or inactivated by radiation. Levels of TNF alpha serum and spleen cell culture medium was monitored on days 2, 7, 14 post infection. Monitoring of parasite growth every two days for 60 days. Determination of TNF alpha levels were measure using ELISA. The results showed parasitaemia mice infected with 175 Gy irradiated parasites have pre patent period of 16 days longer than the control (non-irradiated parasites) with low parasitaemia. TNF alpha concentration that secreted spleen cells of mice vaccinated higher than control mice. Concentration of TNF alpha that secreted blood lymphocyte of mice vaccinated lower than control mice. It was concluded that the secretion of TNF alpha by blood lymphocytes caused more pathogenic factors of the parasite, while the secretion of TNF alpha in spleen due to an immune response against the parasite. (author)

  16. Effect of salivary gland adenocarcinoma cell-derived alpha-N-acetylgalactosaminidase on the bioactivity of macrophage activating factor. (United States)

    Matsuura, Takashi; Uematsu, Takashi; Yamaoka, Minoru; Furusawa, Kiyofumi


    The aim of this study was to clarify the effects of alpha-N-acetylgalactosaminidase (alpha-NaGalase) produced by human salivary gland adenocarcinoma (SGA) cells on the bioactivity of macrophage-activating factor (GcMAF). High exo-alpha-NaGalase activity was detected in the SGA cell line HSG. HSG alpha-NaGalase had both exo- and endo-enzyme activities, cleaving the Gal-GalNAc and GalNAc residues linked to Thr/Ser but not releasing the [NeuAc2-6]GalNac residue. Furthermore, GcMAF enzymatically prepared from the Gc protein enhanced the superoxide-generation capacity and phagocytic activity of monocytes/macrophages. However, GcMAF treated with purified alpha-NaGalase did not exhibit these effects. Thus, HSG possesses the capacity to produce larger quantities of alpha-NaGalase, which inactivates GcMAF produced from Gc protein, resulting in reduced phagocytic activity and superoxide-generation capacity of monocytes/macrophages. The present data strongly suggest that HSG alpha-NaGalase acts as an immunodeficiency factor in cancer patients.

  17. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Dominguez, Helena; Storgaard, Heidi; Rask-Madsen, Christian


    OBJECTIVE: The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-alpha blockade with etanercept could reverse vascular and metabolic...... glucose uptake remained unchanged as well. Beta-cell function tended to improve. CONCLUSION: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed....

  18. NESHAP Area-Specific Dose-Release Factors for Potential Onsite Member-of-the-Public Locations at SRS using CAP88-PC Version 4.0

    Energy Technology Data Exchange (ETDEWEB)

    Trimor, P. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)


    The Environmental Protection Agency (EPA) requires the use of the computer model CAP88-PC to estimate the total effective doses (TED) for demonstrating compliance with 40 CFR 61, Subpart H (EPA 2006), the National Emission Standards for Hazardous Air Pollutants (NESHAP) regulations. As such, CAP88 Version 4.0 was used to calculate the receptor dose due to routine atmospheric releases at the Savannah River Site (SRS). For estimation, NESHAP dose-release factors (DRFs) have been supplied to Environmental Compliance and Area Closure Projects (EC&ACP) for many years. DRFs represent the dose to a maximum receptor exposed to 1 Ci of a specified radionuclide being released into the atmosphere. They are periodically updated to include changes in the CAP88 version, input parameter values, site meteorology, and location of the maximally exposed individual (MEI). In this report, the DRFs were calculated for potential radionuclide atmospheric releases from 13 SRS release points. The three potential onsite MEI locations to be evaluated are B-Area, Three Rivers Landfill (TRL), and Savannah River Ecology Lab Conference Center (SRELCC) with TRL’s onsite workers considered as members-of-the-public, and the potential future constructions of dormitories at SRELCC and Barracks at B-Area. Each MEI location was evaluated at a specified compass sector with different area to receptor distances and was conducted for both ground-level and elevated release points. The analysis makes use of area-specific meteorological data (Viner 2014). The resulting DRFs are compared to the 2014 NESHAP offsite MEI DRFs for three operational areas; A-Area, H-Area, and COS for a release rate of 1 Ci of tritium oxide at 0 ft. elevation. CAP88 was executed again using the 2016 NESHAP MEI release rates for 0 and 61 m stack heights to determine the radionuclide dose at TRL from the center-of-site (COS).

  19. [Effects of intermittent hypoxic exposure on the parameter of erythrocyte and serum hypoxia inducible factor-1 alpha and erythropoietin levels]. (United States)

    Zhang, Cheng-yan; Zhang, Ji-xin; Lü, Xiao-tao; Li, Bao-yu


    To investigate the effects of intermittent hypoxic exposure and normoxic convalescence on the parameter of erythrocyte and serum hypoxia inducible factor-1 alpha (HIF-1alpha) and erythropoietin (EPO) levels. Rat models of intermittent hypoxic exposure were established, combined with the clinical research on volunteers experiencing the intermittent plateau work. Blood samples for red blood cell (RBC) counts, hemoglobin (Hb) and hematocrit (HCT) were collected, serum HIF-1alpha and EPO levels were measured using enzyme linked immunosorbent assay. RBC counts, Hb concentration and HCT were significantly higher than the normoxic group (P hypoxic exposure can enhance serum hypoxia inducible factor-1 alpha and erythropointin levels and the generation of red blood cells, which leads to an increase in hemoglobin concentration and hematocrit. The results have changed with the hypoxic exposure period prolonged. Normoxic convalescence after intermittent hypoxic exposure can make the related indexes reduced, and contribute to the organism recovery.

  20. Buffett's Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting...

  1. Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor. (United States)

    Vassbotn, F S; Havnen, O K; Heldin, C H; Holmsen, H


    Human platelets contain platelet-derived growth factor (PDGF) in their alpha-granules which is released during platelet exocytosis. We show by immunoprecipitation and 125I-PDGF binding experiments that human platelets have functionally active PDGF alpha-receptors, but not beta-receptors. The PDGF alpha-receptor (PDGFR-alpha) was identified as a 170-kDa glycosylated protein-tyrosine kinase as found in other cell types. Stimulation of platelets with 0.1 unit/ml thrombin resulted in a significant increase (2-5-fold) of the tyrosine phosphorylation of the PDGFR-alpha, as determined by immunoprecipitation with phosphotyrosine antiserum as well as with PDGFR-alpha antiserum. The observed thrombin-induced autophosphorylation of the PDGFR-alpha was inhibited by the addition of a neutralizing monoclonal PDGF antibody. Thus, our results suggest that the platelet PDGFR-alpha is stimulated in an autocrine manner by PDGF secreted during platelet activation. Preincubation of platelets with PDGF inhibited thrombin-induced platelet aggregation and secretion of ATP + ADP and beta-hexosaminidase. Thrombin-induced platelet aggregation was also reversed when PDGF was added 30 s after thrombin stimulation. Inhibition of the autocrine PDGF pathway during platelet activation by the PDGF antibody led to a potentiation of thrombin-induced beta-hexosaminidase secretion. Thus, the PDGFR-alpha takes part in a negative feedback regulation during platelet activation. Our demonstration of PDGF alpha-receptors on human platelets and its inhibitory function during platelet activation identifies a new possible role of PDGF in the regulation of thrombosis.

  2. SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors. (United States)

    McGlade, C J; Ellis, C; Reedijk, M; Anderson, D; Mbamalu, G; Reith, A D; Panayotou, G; End, P; Bernstein, A; Kazlauskas, A


    The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains. The p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-tyrosine kinases, also contains two SH2 domains. Both p85 alpha SH2 domains, when expressed individually as fusion proteins in bacteria, bound stably to the activated beta receptor for platelet-derived growth factor (PDGF). Complex formation required PDGF stimulation and was dependent on receptor tyrosine kinase activity. The bacterial p85 alpha SH2 domains recognized activated beta PDGF receptor which had been immobilized on a filter, indicating that SH2 domains contact autophosphorylated receptors directly. Several receptor tyrosine kinases within the PDGF receptor subfamily, including the colony-stimulating factor 1 receptor and the Steel factor receptor (Kit), also associate with PI 3-kinase in vivo. Bacterially expressed SH2 domains derived from the p85 alpha subunit of PI 3-kinase bound in vitro to the activated colony-stimulating factor 1 receptor and to Kit. We infer that the SH2 domains of p85 alpha bind to high-affinity sites on these receptors, whose creation is dependent on receptor autophosphorylation. The SH2 domains of p85 are therefore primarily responsible for the binding of PI 3-kinase to activated growth factor receptors. Images PMID:1372092

  3. Synthesis of tritiated 1-alpha-methadol and 1-alpha-acetylmethadol

    Energy Technology Data Exchange (ETDEWEB)

    Thang, D.C.; Nam, N.H.; Pontikis, R. (Institut National de la Sante et de la Recherche Medicale (INSERM), Hopital Fernand Widal, 75 - Paris (France)); Pichat, L. (CEA Centre d' Etudes Nucleaires de Saclay, 91 - Gif-sur-Yvette (France). Service des Molecules Marquees)


    dl-Methadone was resolved by crystallization of its ammonium d- ..cap alpha.. -bromocamphor-..pi..-sulfonate salt to give d-methadone. The latter in ethyl acetate solution was reduced with tritium gas to 1-..cap alpha..-methadol /sup 3/H in presence of Adams platinum oxide at normal temperature and pressure. Acetylation of 1-..cap alpha..-carbinol hydrochloride by means of acetyl chloride afforded 1-..cap alpha..-acetylmethadol /sup 3/H, specific activity: 20 Ci/mMole. The positions and extent of tritium labelling were determined by /sup 3/H NMR spectroscopy.

  4. Low level tumor necrosis factor-alpha protects cardiomyocytes against high level tumor necrosis factor-alpha: brief insight into a beneficial paradox. (United States)

    Cacciapaglia, Fabio; Salvatorelli, Emanuela; Minotti, Giorgio; Afeltra, Antonella; Menna, Pierantonio


    Whether tumor necrosis factor-alpha (TNFα) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFα agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFα agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFα. To shed light on these mixed findings, we characterized the effects of TNFα in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFα, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFα and then re-challenged with increasing concentrations of TNFα and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFα increasing approximately 16-fold. TNFα preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFα receptors [(soluble TNFα receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFα at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNFα" helped cardiomyocyte to withstand toxicity from "high TNFα" or other agents. These results also suggested that beneficial or detrimental effects of anti-TNFα agents might well depend on whether these agents spared or intercepted discrete amounts of TNFα that preconditioned cardiomyocytes and made them more resistant to high

  5. Tumor necrosis factor alpha of teleosts: in silico characterization and homology modeling

    Directory of Open Access Journals (Sweden)

    Tran Ngoc Tuan


    Full Text Available Tumor necrosis factor alpha (TNF- is known to be crucial in many biological activities of organisms. In this study, physicochemical properties and modeling of TNF- protein of fish was analyzed using in silico approach. TNF- proteins selected from fish species, including grass carp (Ctenopharyngodon idella, zebra fish (Danio rerio, Nile tilapia (Oreochromis niloticus, goldfish (Carassius auratus, and rainbow trout (Oncorhynchus mykiss were used in this study. Physicochemical characteristics with molecular weight, theoretical isoelectric point, extinction coefficient, aliphatic index, instability index, total number of negatively charged residues and positively charged residues, and grand average of hydropathicity were computed. All proteins were classified as transmembrane proteins. The “transmembrane region” and “TNF” domain were identified from protein sequences. The function prediction of proteins was also performed. Alpha helices and random coils were dominating in the secondary structure of the proteins. Three-dimensional structures were predicted and verified as good structures for the investigation of TNF- of fish by online server validation.

  6. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy

    NARCIS (Netherlands)

    Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.


    OBJECTIVE: Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. METHODS: A total

  7. Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced endometriosis? A case report. (United States)

    Shakiba, Khashayar; Falcone, Tommaso


    Several studies have shown that tumour necrosis factor (TNF)-alpha levels are increased in the peritoneal fluid of women with endometriosis, with correlation between TNF-alpha concentrations and the degree of disease. It is also likely that elevation of peritoneal fluids' TNF-alpha levels may play a role in the pathogenesis of infertility associated with endometriosis. Use of drugs such as etanercept, a TNF-alpha receptor immunoglobulin fusion protein which inhibits TNF-alpha activity, showed in an animal study to reduce the severity of the disease, and the size of endometriotic foci. TNF-alpha blockers were recommended as a possible new line of therapy for endometriosis. Our case involved a 35-year-old Para 0, with rheumatic arthritis and stage 4 endometriosis. After 6 years of constant use of etanercept, she showed no improvement of endometriosis as demonstrated at laparoscopy. However, she underwent a successful IVF after the first attempt. TNF-alpha-blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. Some of the immunologic abnormalities in the pelvis of patients with endometriosis could be the consequence of the disease and not the cause, and possibly suppression of immune cells and their products may not have a major effect on endometriotic lesions at an advanced stage. This also could explain why suppression of TNF-alpha showed no effect on infertility. However, use of TNF-alpha-blockers before IVF might increase the success rate in advanced endometriosis.

  8. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

    DEFF Research Database (Denmark)

    Bruunsgaard, H; Ladelund, S; Pedersen, A N


    Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality...... in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF......% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate...

  9. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Ladelund, S.; Pedersen, Agnes Nadelmann


    Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha ) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality...... in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF......% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate...

  10. Mitigating high ‘equity capital’ risk exposure to ‘small cap’ sector in India: analysing ‘key factors of success’ for ‘Institutional Investors’ whilst Investing in small cap sector in India


    Narang, Anish


    This paper deals with the subject of mitigating high ‘Equity Capital’ Risk Exposure to ‘Small Cap’ Sector in India. Institutional investors in India are prone to be risk averse when it comes to investing in the small cap sector in India as they find the companies risky and volatile. This paper will help analyse ‘Key Factors of success’ for ‘Institutional Investors’ whilst investing in Small Cap sector in India as some of these Indian small cap stocks offer handsome returns despite economic do...

  11. Lifetime and g-factor measurements of excited states using Coulomb excitation and alpha transfer reactions

    Energy Technology Data Exchange (ETDEWEB)

    Guevara, Z. E., E-mail:; Torres, D. A., E-mail: [Physics Department, Universidad Nacional de Colombia, Bogotá D.C. (Colombia)


    In this contribution the challenges in the use of a setup to simultaneously measure lifetimes and g-factor values will be presented. The simultaneous use of the transient field technique and the Doppler Shift Attenuation Method, to measure magnetic moments and lifetimes respectively, allows to obtain a complete characterization of the currents of nucleons and the deformation in excited states close to the ground state. The technique is at the moment limited to Coulomb excitation and alpha-transfer reactions, what opens an interesting perspective to consider this type of experiments with radioactive beams. The use of deep-inelastic and fusion-evaporation reactions will be discussed. An example of a setup that makes use of a beam of {sup 106}Cd to study excited states of {sup 110}Sn and the beam nuclei itself will be presented.

  12. The role of hepatocyte nuclear factor 4 alpha in development and progression of liver diseases

    Directory of Open Access Journals (Sweden)

    YANG Jinlian


    Full Text Available Hepatocyte nuclear factor 4 alpha (HNF4α, a member of the nuclear receptor superfamily, has a high expression level in mature hepatocytes. HNF4α can regulate hepatocyte-specific gene expression at a transcriptional level, promote hepatocyte development and differentiation, participate in establishment and maintenance of hepatocyte polarity, and enhance the synthetic, metabolic, and detoxifying functions of the liver. Through inhibiting the activation of hepatic stellate cells, reversing epithelial-mesenchymal transition, and inhibiting the proliferation, invasion, and metastasis of hepatoma cells, HNF4α may be involved in the development and progression of various liver diseases including liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. This paper elaborates on the biological functions of HNF4α, and summarizes and analyzes the research advances in the mechanisms of action of HNF4α in the pathological process of liver diseases, in order to provide references for further investigation of the potential targeted therapies for liver diseases.

  13. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

    DEFF Research Database (Denmark)

    Clausen, Bettina H; Lambertsen, Kate L; Babcock, Alicia A


    BACKGROUND: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We inv...

  14. Dissociative symptoms reflect levels of tumor necrosis factor alpha in patients with unipolar depression

    Directory of Open Access Journals (Sweden)

    Bizik G


    Full Text Available Gustav Bizik,1 Petr Bob,1 Jiri Raboch,1 Josef Pavlat,1 Jana Uhrova,2 Hana Benakova,2 Tomas Zima2 1Center for Neuropsychiatric Research of Traumatic Stress, Department of Psychiatry and UHSL, 2Department of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Abstract: Recent evidence indicates that the nature of interactions between the nervous system and immune system is important in the pathogenesis of depression. Specifically, alterations in pro-inflammatory cytokines have been related to the development of several psychological and neurobiological manifestations of depressive disorder, as well as to stress exposure. A number of findings point to tumor necrosis factor alpha (TNF-α as one of the central factors in these processes. Accordingly, in the present study, we test the hypothesis that specific influences of chronic stressors related to traumatic stress and dissociation are related to alterations in TNF-α levels. We performed psychometric measurement of depression (Beck Depression Inventory [BDI]-II, traumatic stress symptoms (Trauma Symptom Checklist [TSC]-40, and psychological and somatoform dissociation (Dissociative Experiences Scale [DES] and Somatoform Dissociation Questionnaire [SDQ]-20, respectively, and immunochemical measure of serum TNF-α in 66 inpatients with unipolar depression (mean age 43.1 ± 7.3 years. The results show that TNF-α is significantly related to DES (Spearman R=−0.42, P<0.01, SDQ-20 (Spearman R=−0.38, P<0.01, and TSC-40 (Spearman R=−0.41, P<0.01, but not to BDI-II. Results of the present study suggest that TNF-α levels are related to dissociative symptoms and stress exposure in depressed patients. Keywords: depression, dissociation, TNF-alpha, traumatic stress

  15. Some characteristics of a raw starch digestion inhibitory factor from Aspergillus niger

    Energy Technology Data Exchange (ETDEWEB)

    Towprayoon, S.; Saha, B.C.; Fujio, Yusaku; Ueda, Seinosuke


    The effect of an inhibitory factor (IF) from Aspergillus niger 19 on raw starch digestion by pure glucoamylase I of black Aspergillus, pure glucoamylase of Rhizopus niveus, bacterial ..cap alpha..-amylase, fungal ..cap alpha..-amylase and various combination was investigated. The IF caused higher inhibition of raw starch hydrolysis by the combined action of glucoamylase and fungal ..cap alpha..-amylase than of hydrolysis by the individual enzymes. A protein moiety of IF might play an active part in this inhibition phenomenon. The IF was found to starch granules, preventing hydrolysis by the enzymes, and caused decreased raw starch hydrolysis yields.

  16. Insufficient intake of alpha-linolenic fatty acid (18:3n-3 during pregnancy and associated factors

    Directory of Open Access Journals (Sweden)

    Letícia Garcia VASCONCELOS

    Full Text Available ABSTRACT Objective: To analyze alpha-linolenic fatty acid intake in two cohorts of pregnant women, and to identify factors associated with alpha-linolenic acid intake. Methods: This is a cohort study involving pregnant women with low obstetric risk (N=353 in public health system from a municipality of São Paulo state, Brazil. In each trimester, two 24-hour food recalls were collected. Descriptive analyses of dietary lipid profiles were performed, followed by a multiple comparison test. According to the trimester of pregnancy, differences were assessed using the mean difference test. To evaluate the adequacy of linoleic fatty acid and alpha-linolenic acid intake, the adequate intake test was used. The association between alpha-linolenic acid intake adequacy and maternal characteristics was investigated using a binary logistic regression model. Results: Total lipids intake and the percentage contribution to dietary energy met recommended levels. One-third of the diets demonstrated a lower than daily recommended intake of alpha-linolenic acid. Overweight pregnant women were twice as likely to have inadequate alpha-linolenic acid intake. Pregnant women from a more disadvantaged socioeconomic situation had greater risks of inadequate intake. Conclusion: Over-intake of lipids is not problematic, but quality is an issue, with one third of the pregnant women and their fetuses exposed to adverse effects due to low intake of omega-3 fatty acids, indicating important nutritional vulnerability in this population.

  17. Expression of transforming growth factor alpha and epidermal growth factor receptor in rat lung neoplasms induced by plutonium-239

    International Nuclear Information System (INIS)

    Stegelmeier, B.L.; Gillett, N.A.; Hahn, F.F.; Kelly, G.; Rebar, A.H.


    Ninety-two rat lung proliferative lesions and neoplasms induced by inhaled 239 PuO 2 were evaluated for aberrant expression of transforming growth factor alpha (TGF-α) and epidermal growth factor receptor (EGFR). Expression of TGF-α protein, measured by immunohistochemistry, was higher in 94% of the squamous cell carcinomas and 87% of the foci of alveolar epithelial squamous metaplasia than that exhibited by the normal-appearing, adjacent lung parenchyma. In contrast, only 20% of adenocarcinomas and foci of epithelial hyperplasia expressed elevated levels of TGF-α. Many neoplasms expressing TGF-α also expressed excessive levels of EGFR mRNA. Southern and DNA slot blot analyses showed that the elevated EGFR expression was not due to amplification of the EGFR gene. These data suggest that increased amounts of TGF-α were early alterations in the progression of plutonium-induced squamous cell carcinoma, and these increases may occur in parallel with overexpression of the receptor for this growth factor. Together, these alterations create a potential autocrine loop for sustaining clonal expansion of cells initiated by high-LET radiation. 44 refs., 4 figs., 1 tab

  18. Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha. (United States)

    Montrucchio, G.; Lupia, E.; de Martino, A.; Battaglia, E.; Arese, M.; Tizzani, A.; Bussolino, F.; Camussi, G.


    We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells and in the in vivo angiogenic response elicited by platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF). The NO synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothelial cells induced in vitro by PAF and by TNF. The motogenic activity of TNF was also inhibited by WEB 2170, a specific PAF-receptor antagonist. In contrast, chemotaxis induced by bFGF was not prevented by L-NAME or by WEB 2170. Angiogenesis was studied in vivo in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model, the angiogenesis induced by PAF and TNF was inhibited by WEB 2170 and L-NAME but not by D-NAME. In contrast, angiogenesis induced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not bFGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced by TNF, which is dependent on the production of PAF. In contrast, the angiogenic effect of bFGF appears to be both PAF and NO independent. Images Figure 3 Figure 4 PMID:9250168

  19. The nematode eukaryotic translation initiation factor 4E/G complex works with a trans-spliced leader stem-loop to enable efficient translation of trimethylguanosine-capped RNAs. (United States)

    Wallace, Adam; Filbin, Megan E; Veo, Bethany; McFarland, Craig; Stepinski, Janusz; Jankowska-Anyszka, Marzena; Darzynkiewicz, Edward; Davis, Richard E


    Eukaryotic mRNA translation begins with recruitment of the 40S ribosome complex to the mRNA 5' end through the eIF4F initiation complex binding to the 5' m(7)G-mRNA cap. Spliced leader (SL) RNA trans splicing adds a trimethylguanosine (TMG) cap and a sequence, the SL, to the 5' end of mRNAs. Efficient translation of TMG-capped mRNAs in nematodes requires the SL sequence. Here we define a core set of nucleotides and a stem-loop within the 22-nucleotide nematode SL that stimulate translation of mRNAs with a TMG cap. The structure and core nucleotides are conserved in other nematode SLs and correspond to regions of SL1 required for early Caenorhabditis elegans development. These SL elements do not facilitate translation of m(7)G-capped RNAs in nematodes or TMG-capped mRNAs in mammalian or plant translation systems. Similar stem-loop structures in phylogenetically diverse SLs are predicted. We show that the nematode eukaryotic translation initiation factor 4E/G (eIF4E/G) complex enables efficient translation of the TMG-SL RNAs in diverse in vitro translation systems. TMG-capped mRNA translation is determined by eIF4E/G interaction with the cap and the SL RNA, although the SL does not increase the affinity of eIF4E/G for capped RNA. These results suggest that the mRNA 5' untranslated region (UTR) can play a positive and novel role in translation initiation through interaction with the eIF4E/G complex in nematodes and raise the issue of whether eIF4E/G-RNA interactions play a role in the translation of other eukaryotic mRNAs.

  20. The Nematode Eukaryotic Translation Initiation Factor 4E/G Complex Works with a trans-Spliced Leader Stem-Loop To Enable Efficient Translation of Trimethylguanosine-Capped RNAs ▿ † (United States)

    Wallace, Adam; Filbin, Megan E.; Veo, Bethany; McFarland, Craig; Stepinski, Janusz; Jankowska-Anyszka, Marzena; Darzynkiewicz, Edward; Davis, Richard E.


    Eukaryotic mRNA translation begins with recruitment of the 40S ribosome complex to the mRNA 5′ end through the eIF4F initiation complex binding to the 5′ m7G-mRNA cap. Spliced leader (SL) RNA trans splicing adds a trimethylguanosine (TMG) cap and a sequence, the SL, to the 5′ end of mRNAs. Efficient translation of TMG-capped mRNAs in nematodes requires the SL sequence. Here we define a core set of nucleotides and a stem-loop within the 22-nucleotide nematode SL that stimulate translation of mRNAs with a TMG cap. The structure and core nucleotides are conserved in other nematode SLs and correspond to regions of SL1 required for early Caenorhabditis elegans development. These SL elements do not facilitate translation of m7G-capped RNAs in nematodes or TMG-capped mRNAs in mammalian or plant translation systems. Similar stem-loop structures in phylogenetically diverse SLs are predicted. We show that the nematode eukaryotic translation initiation factor 4E/G (eIF4E/G) complex enables efficient translation of the TMG-SL RNAs in diverse in vitro translation systems. TMG-capped mRNA translation is determined by eIF4E/G interaction with the cap and the SL RNA, although the SL does not increase the affinity of eIF4E/G for capped RNA. These results suggest that the mRNA 5′ untranslated region (UTR) can play a positive and novel role in translation initiation through interaction with the eIF4E/G complex in nematodes and raise the issue of whether eIF4E/G-RNA interactions play a role in the translation of other eukaryotic mRNAs. PMID:20154140

  1. The rebirth of the cervical cap. (United States)

    Cappiello, J D; Grainger-Harrison, M


    In an effort to dispel myths surrounding the cervical cap, the historical and political factors affecting the cap's use in the U.S. are described. Clinical aspects of cap fitting are also included. The cervical cap has found only limited acceptance in the U.S. Skepticisms on the part of physicians may be the result of 2 factors: confusion of the cervical cap with intracervical devices used for artificial insemination and confusion with stem pessaries; and the lack of clinical research and statistical evaluation of efficacy rates. The latter factor prompted Tietze et al. to conduct the only U.S. statistical study of the cap in 1953. Of the 143 women studied, the pregnancy rate was 7.6/100 years of use. Of the 28 unplanned pregnancies, 6 were related to faulty technique or omission of a spermicide and 10 were instances of admittedly irregular use. When these failures are omitted, the theoretical effectiveness rate is about 98%. Some practitioners are concerned about an increased incidence of cervical erosion with cap use. Possibly currently conducted studies will show that cap and spermicide users have a lower incidence of cervical erosion than women using no contraceptive method. Study findings suggest that the cervical cap may afford protection without any spermicidal supplement, but the use of spermicides continues to be recommended to clients. Advantages of the cervical cap include the following: it can be left in place longer than a diaphragm without additional applications of spermicide in the vagina; and the insertion of the cap is unrelated to the time of intercourse. Despite research on toleration of the cap for 3 weeks at a time, it is recommended that the cap be worn for only a few days at a time. At this time there are no manufacturers of cervical caps for contraceptive use in the U.S. The cap is now being imported from England and it costs $6.00. A factor that has made the cap unpopular with many physicians is the lengthy time required for fitting. An

  2. Temporary reversal by topotecan of marked insulin resistance in a patient with myelodysplastic syndrome: case report and possible mechanism for tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance. (United States)

    Huntington, M O; Krell, K E; Armour , W E; Liljenquist, J E


    Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor. We report here a remarkable degree of insulin resistance in a patient with adult respiratory distress syndrome and myelodysplasia.

  3. [Characteristics of sublingual vein and expressions of vascular endothelial growth factor and hypoxia-inducible factor 1alpha proteins in sublingual tissues of Beagle dogs with portal hypertension]. (United States)

    Li, Bai-yu; Wang, Li-na; Yue, Xiao-qiang; Li, Bai


    To observe sublingual vein characteristics and the expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) proteins in sublingual tissues of Beagle dogs with cirrhotic portal hypertension. Twelve Beagle dogs were randomly divided into normal control group and cirrhotic portal hypertension group. There were 6 dogs in each group. A canine model of cirrhosis portal hypertension was established by injecting dimethylnitrosamine (DMN) into portal vein once a week for 7 weeks. The characteristics of sublingual vein were observed. Portal venous pressure was measured by using bioelectric recording techniques. The expressions of VEGF and HIF-1alpha proteins in sublingual vein were detected by immunohistochemical method. The shape and color of sublingual vein in beagle dogs in the cirrhotic portal hypertension group changed obviously as compared with the normal control group. Immunohistochemical results showed that there were almost no expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the normal control group; however, the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the cirrhotic portal hypertension group significantly increased. Changes of portal pressure may lead to the formation of the abnormal sublingual vein by increasing the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in Beagle dogs with portal hypertension.

  4. Effects of Socio demographic factors on plasma ascorbic acid and alpha tocopherol anti oxidants during pregnancy

    International Nuclear Information System (INIS)

    Sylvester, I.E.; Paul, A.


    Objectives: To assess the plasma levels of vitamins C and E at the various stages of pregnancy and to correlate their plasma levels with the socio-demographic factors of pregnant Nigerians. Methodology: The pregnant cases (n=180) were randomly selected according to gestational ages. And the controls (n=20) were non-pregnant women of the same age. Plasma levels of both vitamins were assayed with well established laboratory methods. Results: The mean plasma vitamins C and E in the pregnant cases was lower (by 17-23%) than controls across the three trimesters, p<0.0001. The correlation of vitamin C versus maternal age was significant; r = - 0.59, p<0.05; the mean plasma level of vitamin C declined by 57% as the maternal age increases from 22-37 years. Conclusion: The mean plasma Ascorbic acid and Alpha-tocopherol are reduced during pregnancy and socio-demographic factors have mild effects on the plasma levels of these vitamins. (author)

  5. Modulation of tumor necrosis factor {alpha} expression in mouse brain after exposure to aluminum in drinking water

    Energy Technology Data Exchange (ETDEWEB)

    Tsunoda, M.; Sharma, R.P. [Georgia Univ., Athens (Greece). College of Veterinary Medicine


    Aluminum, a known neurotoxic substance and a ground-water pollutant, is a possible contributing factor in various nervous disorders including Alzheimer's disease. It has been hypothesized that cytokines are involved in aluminum neurotoxicity. We investigated the alterations in mRNA expression of tumor necrosis factor {alpha} (TNF{alpha}), interleukin-1{beta} (IL-1{beta}), and interferon {gamma} (IFN{gamma}), cytokines related to neuronal damage, in cerebrum and peripheral immune cells of mice after exposure to aluminum through drinking water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An additional group received 250 ppm ammonium as ammonium sulfate. After treatment, the cerebrum, splenic macrophages and lymphocytes were collected. The expression of TNF{alpha} mRNA in cerebrum was significantly increased among aluminum-treated groups compared with the control, in a dose-dependent manner. Other cytokines did not show any aluminum-related effects. In peripheral cells, there were no significant differences of cytokine mRNA expressions among treatment groups. Increased expression of TNF{alpha} mRNA by aluminum in cerebrum may reflect activation of microglia, a major source of TNF{alpha} in this brain region. Because the aluminum-induced alteration in cytokine message occurred at aluminum concentrations similar to those noted in contaminated water, these results may be relevant in considering the risk of aluminum neurotoxicity in drinking water. (orig.)

  6. Three-Dimensional Conformal Radiotherapy in Prostate Cancer Patients: Rise in Interleukin 6 (IL-6) but not IL-2, IL-4, IL-5, Tumor Necrosis Factor-{alpha}, MIP-1-{alpha}, and LIF Levels

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira Lopes, Carlos [Universidade do Vale do Paraiba, Centro de Oncologia Radioterapica do Vale do Paraiba, Universidade do Vale do Paraiba Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, Sao Jose dos Campos, Sao Paulo (Brazil); Callera, Fernando, E-mail: [Centro de Hematologia Onco-hematologia e Transplantes de Medula Ossea do Vale do Paraiba, Sao Paulo (Brazil)


    Purpose: To investigate the effect of radiotherapy (RT) on serum levels of interleukin-2 (IL-2), IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-{alpha}), macrophage inflammatory protein-1-alpha (MIP-1-{alpha}) and leukemia inhibitory factor (LIF) in patients with prostate cancer. Methods and Materials: Forty eight patients with prostate cancer received three-dimensional conformal blocking radiation therapy with a linear accelerator. IL-2, IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were measured by the related immunoassay kit 1 day before the beginning of RT and during RT at days 15 and 30. Results: The mean IL-2 values were elevated before and during the RT in contrast with those of IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF, which were within the normal range under the same conditions. Regarding markers IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF, comparisons among the three groups (before treatment and 15 and 30 days during RT) did not show significant differences. Although values were within the normal range, there was a significant rise in IL-6 levels at day 15 of RT (p = 0.0049) and a decline at day 30 to levels that were similar to those observed before RT. Conclusions: IL-6 appeared to peak after 15 days of RT before returning to pre-RT levels. In contrast, IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were not sensitive to irradiation. The increased levels of IL-6 following RT without the concurrent elevation of other cytokines involved in the acute phase reaction did not suggest a classical inflammatory response to radiation exposure. Further studies should be designed to elucidate the role of IL-6 levels in patients with prostate cancer treated with RT.

  7. Induction of autocrine factor inhibiting cell motility from murine B16-BL6 melanoma cells by alpha-melanocyte stimulating hormone. (United States)

    Murata, J; Ayukawa, K; Ogasawara, M; Watanabe, H; Saiki, I


    We have previously reported that neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) successfully inhibited Matrigel invasion and haptotactic migration of B16-BL6 melanoma cells towards both fibronectin and laminin without affecting their growth. In the present study, we investigated the inhibitory mechanism of tumor cell motility by alpha-MSH. Alpha-MSH significantly blocked the autocrine motility factor (AMF)-enhanced cell motility. However, alpha-MSH did neither prevent the secretion of AMF from B16-BL6 cells nor alter the expression level of AMF receptor (gp78). On the other hand, alpha-MSH induced the secretion of the motility inhibitory factor(s) from B16-BL6 cells in a concentration- and time-dependent manner. The induction of the motility inhibitor(s) was proportional to increasing levels of intracellular cAMP induced by alpha-MSH as well as forskolin, and the activity was abolished by an adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA). The motility-inhibiting activity in conditioned medium (CM) from alpha-MSH-treated B16-BL6 cells was found to have a m.w. below 3 kDa after fractionation. This activity was abolished by boiling but insensitive to trypsin. The treatment of tumor cells with cycloheximide reduced the activity in alpha-MSH-stimulated CM. Our results suggest that alpha-MSH inhibited the motility of B16-BL6 cells through induction of autocrine factor(s).

  8. Advances toward DNA-based identification and phylogeny of North American Armillaria species using elongation factor-1 alpha gene (United States)

    Amy L. Ross-Davis; John W. Hanna; Mee-Sook Kim; Ned B. Klopfenstein


    The translation elongation factor-1 alpha gene was used to examine the phylogenetic relationships among 30 previously characterized isolates representing ten North American Armillaria species: A. solidipes (=A. ostoyae), A. gemina, A. calvescens, A. sinapina, A. mellea, A. gallica, A. nabsnona, North American biological species X, A. cepistipes, and A. tabescens. The...

  9. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma

    NARCIS (Netherlands)

    Wenzel, Sally E.; Barnes, Peter J.; Bleecker, Eugene R.; Bousquet, Jean; Busse, William; Dahlén, Sven-Erik; Holgate, Stephen T.; Meyers, Deborah A.; Rabe, Klaus F.; Antczak, Adam; Baker, James; Horvath, Ildiko; Mark, Zsuzsanna; Bernstein, David; Kerwin, Edward; Schlenker-Herceg, Rozsa; Lo, Kim Hung; Watt, Rosemary; Barnathan, Elliot S.; Chanez, Pascal; Chanez, P.; Tunon-de-Lara, M.; Antczak, A.; Pierzchala, W.; Bukowczan, Z.; Trawinska, E.; Baker, J.; Wenzel, S. E.; Katial, R.; Bernstein, D.; Kerwin, E.; Bensch, G.; Castro, M.; Noonan, M.; Nayak, A.; Chupp, G.; Kline, J.; Busse, W.; Kavuru, M. S.; Lang, D.; Wolfe, R.; Baughman, R.; Korenblat, P.; Mansfield, L.; Bleecker, E.; Lisberg, E.; Liu, M.; Panettieri, R.; Spangenthal, S.; Bel, E. H.


    RATIONALE: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. OBJECTIVES: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.

  10. Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients

    NARCIS (Netherlands)

    Feelders, R. A.; Swaak, A. J.; Romijn, J. A.; Eggermont, A. M.; Tielens, E. T.; Vreugdenhil, G.; Endert, E.; van Eijk, H. G.; Berghout, A.


    Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rTNF) and melphalan in patients with melanoma or sarcoma is accompanied by high systemic TNF levels. We examined the prolonged effects

  11. Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

    DEFF Research Database (Denmark)

    Bruun, Christine; Heding, Peter E; Rønn, Sif G


    Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction...

  12. Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells

    NARCIS (Netherlands)

    van Kooten, C.; Rensink, I.; Aarden, L.; van Oers, R.


    The proliferative response of purified malignant B cells from 26 patients with chronic lymphocytic leukemia (CLL) was investigated in vitro. In the majority of these patients, a proliferative response could be induced by the combination of tumor necrosis factor (TNF)-alpha and PMA. The concentration

  13. MutY DNA Glycosylase Protects Cells From Tumor Necrosis Factor Alpha-Induced Necroptosis. (United States)

    Tran, An Hue Vy; Han, Se Hee; Kim, Joon; Grasso, Francesca; Kim, In San; Han, Ye Sun


    Numerous studies have implied that mutY DNA glycosylase (MYH) is involved in the repair of post-replicative mispairs and plays a critical role in the base excision repair pathway. Recent in vitro studies have shown that MYH interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD), a key effector protein of tumor necrosis factor receptor-1 (TNFR1) signaling. The association between MYH and TRADD is reversed during tumor necrosis factor alpha (TNF-α)- and camptothecin (CPT)-induced apoptosis, and enhanced during TNF-α-induced survival. After investigating the role of MYH interacts with various proteins following TNF-α stimulation, here, we focus on MYH and TRADD interaction functions in necroptosis and its effects to related proteins. We report that the level of the MYH and TRADD complex was also reduced during necroptosis induced by TNF-α and zVAD-fmk. In particular, we also found that MYH is a biologically important necrosis suppressor. Under combined TNF-α and zVAD-fmk treatment, MYH-deficient cells were induced to enter the necroptosis pathway but primary mouse embryonic fibroblasts (MEFs) were not. Necroptosis in the absence of MYH proceeds via the inactivation of caspase-8, followed by an increase in the formation of the kinase receptor- interacting protein 1 (RIP1)-RIP3 complex. Our results suggested that MYH, which interacts with TRADD, inhibits TNF-α necroptotic signaling. Therefore, MYH inactivation is essential for necroptosis via the downregulation of caspase-8. J. Cell. Biochem. 118: 1827-1838, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  14. Time-differential observation of alpha -particle perturbed angular distribution; g-factor measurements for /sup 217/Ac/sup gs/ and /sup 217/Ac/sup m/

    CERN Document Server

    Maier, K H; Grawe, H; Kluge, H


    The g-factor measurements of the ground state and an isomeric level in /sup 217/Ac using the DPAD method with alpha -decay are described. The results of gamma -ray g-factor measurements for the isomer and a tentative decay scheme produced by alpha - gamma and gamma - gamma coincidence experiments are also presented. An analysis of the alpha - particle angular distributions suggests that nuclear deformation affects the observed anisotropy. (13 refs).

  15. Tumor necrosis factor-alpha release from rat pulmonary leukocytes exposed to ultrafine cobalt: in vivo and in vitro studies

    International Nuclear Information System (INIS)

    Zhang Qunwei; Kusaka, Yukinori; Sato, Kazuhiro; Wang Deweng; Donaldson, Kenneth


    Ultrafine cobalt (Uf-Co), one of the new category of ultrafine particles, is generated in some industrial situations and it also exists in environmental particles. The aim of this study was to investigate the ability of rat pulmonary leukocytes to release tumor necrosis factor alpha (TNF-alpha) after exposure to Uf-Co in vivo and in vitro. Rats were intratracheally instilled with 1 mg of Uf-Co, and then wet lung weight and bronchoalveolar lavage fluid (BASF) profile were analysed 1, 3, 7, 15, and 30 days later. The effects of Uf-Co on indices that can be presumed to reflect epithelial injury and permeability (lactate dehydrogenase (LDH) and total protein (TP)) were increased throughout the 30 day post-exposure period. Furthermore, at 3 days after exposure, leukocytes were collected by bronchoalveolar lavage (BAL). After 3, 6, 12, 24, 48, and 72 hours of incubation, TNF-alpha in supernatants were determined by ELISA method. The results showed that TNF-alpha secretion by activated leukocytes from rats instilled with Uf-Co was significantly higher than that of the controls. BAL leucocytes from the lung of exposed rats revealed time-and dose-related increases in TNF-alpha release. In conclusion, our results reveal, for the first time to our knowledge, that exposure to Uf-Co can stimulate leukocytes to secrete TNF-alpha. These data suggest that the TNF-alpha release from pulmonary leukocytes probably plays a role in the pathogenesis of 'cobalt lung'. (author)

  16. Expression of tumour necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesions retrieved by atherectomy. (United States)

    Clausell, N.; de Lima, V. C.; Molossi, S.; Liu, P.; Turley, E.; Gotlieb, A. I.; Adelman, A. G.; Rabinovitch, M.


    BACKGROUND--The formation of coronary artery neointima experimentally induced in piglets after cardiac transplantation is related to an immune-inflammatory reaction associated with increased expression of T cells and inflammatory mediators (tumour necrosis factor alpha and interleukin 1 beta) and upregulation of fibronectin. In vivo blockade of tumour necrosis factor alpha in rabbits after cardiac transplantation results in reduced neointimal formation. The objective of this study was to investigate the hypothesis that coronary restenosis after atherectomy or percutaneous balloon angioplasty is associated with a similar inflammatory cascade initiated by mechanical injury. METHODS--Specimens taken at coronary atherectomy were analysed from 16 patients. Nine had had the procedure performed twice, firstly, to remove a primary lesion, and secondly, to remove a restenotic lesion. Seven had percutaneous balloon angioplasty after removal of restenotic tissue. Coronary atherectomy specimens were analysed by immunohistochemistry for the presence of T cells, macrophages, major histocompatibility complex II, interleukin 1 beta, tumour necrosis factor alpha, fibronectin, and the receptor for hyaluronan mediated motility. RESULTS--The groups were clinically and angiographically similar with equivalent lumens before and after atherectomy. Restenotic lesions had increased expression of tumour necrosis factor alpha and fibronectin compared with the primary lesions (P < 0.05 for both). There was also a trend towards a greater number of T cells and increased expression of interleukin 1 beta. CONCLUSIONS--Restenosis is associated with increased expression of tumour necrosis factor alpha and fibronectin, suggesting that an immune-inflammatory reaction probably contributes to neointimal formation and may represent a form of wound healing and repair secondary to mechanical injury. Images PMID:7626352

  17. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Mushfiquddin Khan


    Full Text Available Mild traumatic brain injury (TBI, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1α, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

  18. DNA homologous recombination factor SFR1 physically and functionally interacts with estrogen receptor alpha.

    Directory of Open Access Journals (Sweden)

    Yuxin Feng

    Full Text Available Estrogen receptor alpha (ERα, a ligand-dependent transcription factor, mediates the expression of its target genes by interacting with corepressors and coactivators. Since the first cloning of SRC1, more than 280 nuclear receptor cofactors have been identified, which orchestrate target gene transcription. Aberrant activity of ER or its accessory proteins results in a number of diseases including breast cancer. Here we identified SFR1, a protein involved in DNA homologous recombination, as a novel binding partner of ERα. Initially isolated in a yeast two-hybrid screen, the interaction of SFR1 and ERα was confirmed in vivo by immunoprecipitation and mammalian one-hybrid assays. SFR1 co-localized with ERα in the nucleus, potentiated ER's ligand-dependent and ligand-independent transcriptional activity, and occupied the ER binding sites of its target gene promoters. Knockdown of SFR1 diminished ER's transcriptional activity. Manipulating SFR1 expression by knockdown and overexpression revealed a role for SFR1 in ER-dependent and -independent cancer cell proliferation. SFR1 differs from SRC1 by the lack of an intrinsic activation function. Taken together, we propose that SFR1 is a novel transcriptional modulator for ERα and a potential target in breast cancer therapy.

  19. Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO)

    Energy Technology Data Exchange (ETDEWEB)

    Shiang, R. (Univ. of California, Irvine, CA (United States)); Lidral, A.C.; Ardinger, H.H.; Murray, J.C.; Romitti, P.A.; Munger, R.G.; Buetow, K.H.


    Genetic analysis and tissue-specific expression studies support a role for transforming growth-factor alpha (TGFA) in craniofacial development. Previous studies have confirmed an association of alleles for TGFA with nonsyndromic cleft lip with or without cleft palate (CL/P) in humans. The authors carried out a retrospective association study to determine whether specific allelic variants of the TGFA gene are also associated with cleft palate only (CPO). The PCR products from 12 overlapping sets of primers to the TGFA cDNA were examined by using single-strand conformational polymorphism analysis. Four DNA polymorphic sites for TGFA were identified in the 3[prime] untranslated region of the TGFA gene. These variants, as well as previously identified RFLPs for TGFA, were characterized in case and control populations for CPO by using X[sup 2] analysis. A significant association between alleles of TGFA and CPO was identified which further supports a role for this gene as one of the genetic determinants of craniofacial development. Sequence analysis of the variants disclosed a cluster of three variable sites within 30 bp of each other in the 3[prime] untranslated region previously associated with an antisense transcript. These studies extend the role for TGFA in craniofacial morphogenesis and support an interrelated mechanism underlying nonsyndromic forms of CL/P. 46 refs., 3 figs., 3 tabs.

  20. Chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab in psoriasis

    Directory of Open Access Journals (Sweden)

    Sridhar J


    Full Text Available Background: Insights into the pathogenesis of psoriasis have provided opportunities to target key steps in the disease process. Tumor necrosis factor-alpha (TNF-a being crucial to the pathogenesis of psoriasis, monoclonal antibodies against this cytokine have proved useful in its treatment. Aim: To study the efficacy of chimeric monoclonal antibody to TNF-a (infliximab in Indian patients with recalcitrant psoriasis vulgaris. Materials and Methods: Three patients with recalcitrant psoriasis vulgaris were studied. Baseline haemogram, biochemical parameters, chest radiograph and Mantoux skin test were performed. A loading dose regimen of 5 mg/kg infliximab was administered at weeks 0, 2 and 6. PASI assessment, adverse drug event monitoring and laboratory assessments were carried out at 2-week intervals until week 10. Patients were followed up until week 22 for relapse. Results: Infliximab was well tolerated. The mean PASI was 25.4 at presentation and declined to 5.5 at 10 weeks. PASI 75 was attained at a mean of 9.6 weeks. Relapse occurred at a mean of 18.6 weeks after the first infusion. Conclusions: This study on Indian patients brings out the importance of cytokine-based therapies in psoriasis. Indigenous production could make these therapies a viable therapeutic option for psoriasis patients in the near future.

  1. Tumor necrosis factor alpha increases epithelial barrier permeability by disrupting tight junctions in Caco-2 cells

    Directory of Open Access Journals (Sweden)

    W. Cui


    Full Text Available The objectives of this study were to determine the effect of tumor necrosis factor alpha (TNF-α on intestinal epithelial cell permeability and the expression of tight junction proteins. Caco-2 cells were plated onto Transwell® microporous filters and treated with TNF-α (10 or 100 ng/mL for 0, 4, 8, 16, or 24 h. The transepithelial electrical resistance and the mucosal-to-serosal flux rates of the established paracellular marker Lucifer yellow were measured in filter-grown monolayers of Caco-2 intestinal cells. The localization and expression of the tight junction protein occludin were detected by immunofluorescence and Western blot analysis, respectively. SYBR-Green-based real-time PCR was used to measure the expression of occludin mRNA. TNF-α treatment produced concentration- and time-dependent decreases in Caco-2 transepithelial resistance and increases in transepithelial permeability to the paracellular marker Lucifer yellow. Western blot results indicated that TNF-α decreased the expression of phosphorylated occludin in detergent-insoluble fractions but did not affect the expression of non-phosphorylated occludin protein. Real-time RT-PCR data showed that TNF-α did not affect the expression of occludin mRNA. Taken together, our data demonstrate that TNF-α increases Caco-2 monolayer permeability, decreases occludin protein expression and disturbs intercellular junctions.

  2. Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

    Directory of Open Access Journals (Sweden)

    Nadia Belmellat


    Full Text Available Tumor necrosis factor-alpha (TNF-α blockade is an effective treatment for rheumatoid arthritis (RA and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept.

  3. Interleukin-6 and tumor necrosis factor-alpha values in elk neonates (United States)

    Barber-Meyer, S. M.; Johnson, C.R.; Murtaugh, M.P.; Mech, L.D.; White, P.J.


    Serological indicators of general condition would be helpful for monitoring or assessing ungulate wildlife. Toward that end, we report the 1st reference values for 2 cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-??), in neonatal elk (Cervus elaphus). We obtained blood samples from 140 calves ??? 6 days old in Yellowstone National Park during summer 2003-2005. TL-6 values ranged from 0 to 1.21 pg/ml with a median of 0.03 pg/ml. TNF-?? values ranged from 0 to 225.43 pg/ml with a median of 1.85 pg/ml. IL-6 and TNF-?? concentrations were not significant predictors of elk calf survival through 21 days. Development of ungulate-based IL-6 and TNF-?? assays that provide greater sensitivity than cross-reacting human-based assays could be helpful in monitoring ungulate condition and health status comparisons among herds. Such information could provide indirect assessments of range quality or environmental influences among herds. 

  4. Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes

    International Nuclear Information System (INIS)

    Kim, Young Jun; Nam, Chang-Hoon; Jin, Young-Hyun; Stieglitz, Thomas; Salieb-Beugelaar, Georgette B


    This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. (paper)

  5. Tumor Necrosis Factor-Alpha in Peripical Tissue Exudates of Teeth with Apical Periodontitis

    Directory of Open Access Journals (Sweden)

    Sonja Pezelj-Ribaric


    Full Text Available Aim. The aim of this study was to determine tumor necrosis factor-alpha (TNF-α levels in periapical exudates and to evaluate their relationship with radiological findings. Methodology. Periapical exudates were collected from root canals of 60 single-rooted teeth using absorbent paper points. TNF-α levels were determined by enzyme-linked immunosorbent assays. The samples were divided into three groups according to the periapical radiolucent area. Results. Nonparametric Kruskal-Wallis test revealed significant differences between TNF-α concentrations in control group (40, 57±28, 15 pg/mL and group with larger radiolucent areas (2365, 79±582, 95 pg/mL, as well as between control and canals with small radiolucent areas (507, 66±278, 97 (P<.05. Conclusions. The levels of TNF-α increase significantly in teeth with periapical pathosis, from smaller to bigger lesions. This research and its results have shown that objective analysis of the TNF-α levels enables establishment of a relationship between different concentrations of TNF-α and different radiological changes.

  6. Plasma Levels of Tumor Necrosis Factor-Alpha and Interleukin-6 in Obsessive Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    N. Konuk


    Full Text Available Aim. Recent research implicated place of an immune mechanism in the pathophysiology of obsessive-compulsive disorder (OCD. Despite increasing evidence involvement of cytokine release in OCD, results of the studies are inconsistent. The aim of this study was to evaluate the plasma levels of the cytokines; tumor necrosis factor-alpha (TNF-α and interleukin-6 (IL-6 in OCD patients. Methods. Plasma concentrations of TNF-α and IL-6 were measured in 31 drug-free outpatients with OCD, and 31-year age and sex-matched healthy controls. TNF-α and IL-6 concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA. Results. Both TNF-α and IL-6 levels showed statistically significant increases in OCD patients compared to controls (P<.000, P<.001, resp.. In addition, the age of onset was negatively correlated with TNF-α level (r=−.402, P=.025 and duration of illness was weakly correlated with IL-6 levels (r:.357; P:.048 in patients group. Conclusion. OCD patients showed increases in TNF-α and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflamatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD.

  7. Problems connected with the use of oligonucleotide probes with a high degree of degeneracy. Identification of mRNA and of cDNA clones corresponding to the gene of the. cap alpha. -subunit of Na/sup +/, K/sup +/-ATPase

    Energy Technology Data Exchange (ETDEWEB)

    Petrukhin, K.E.; Grishin, A.V.; Arsenyan, S.G.; Broude, N.E.; Grinkevich, V.A.; Filippova, L.Yu.; Severtsova, I.V.; Modyanov, N.N.


    To identify and search for nucleotide sequences containing the structural part of the gene of the ..cap alpha..-subunit of Na/sup +/, K/sup +/-ATPase, 17-membered oligonucleotide probes corresponding to the peptide Lys-Asp-Ala-Phe-Gln-Asn have been synthesized. It has been shown that, with a 64-fold degeneracyd, the 17-membered probe is suitable only for the identification of a specific sequence in mRNA. To search for clones containing cDNA fragments, preliminary fractionation of the probes with the aid of HPLC or the resynthesis of groups of oligonucleotides with a lower degeneracy is necessary.

  8. The cervical cap (image) (United States)

    The cervical cap is a flexible rubber cup-like device that is filled with spermicide and self-inserted over the cervix ... left in place several hours after intercourse. The cap is a prescribed device fitted by a health ...

  9. Hematologic interactions of endotoxin, tumor necrosis factor alpha (TNF alpha), interleukin 1, and adrenal hormones and the hematologic effects of TNF alpha in Corynebacterium parvum-primed rats. (United States)

    Ulich, T R; del Castillo, J; Ni, R X; Bikhazi, N


    Endotoxin reduces the release among other cytokines of tumor necrosis factor (TNF) and interleukin 1 (IL-1) and causes peripheral lymphopenia and a dose-response-dependent initial neutropenia followed by a monophasic neutrophilia. TNF alone induces lymphopenia and an initial neutropenia followed by a biphasic neutrophilia. IL-1 alone induces lymphopenia and a monophasic neutrophilia. TNF-plus-IL-1 caused a greater lymphopenia than either monokine alone, suggesting that both monokines contribute to LPS-induced lymphopenia. TNF-plus-IL-1 induced neutropenia similar in magnitude to that induced by TNF alone and induced a neutrophilia significantly greater than that induced by either monokine alone, suggesting that LPS-induced neutropenia is caused by TNF, while LPS-induced neutrophilia is due to the combined effects of TNF and II-1. TNF and IL-1 were administered together with LPS to simulate the in vivo condition of endogenous monokine release during gram-negative bacteremia. TNF combined with LPS increased both the duration and magnitude of LPS-induced lymphopenia, LPS-induced neutropenia, and LPS-induced neutrophilia. TNF-plus-LPS treated rats at 2 hours after injection exhibited a striking 93% decrease in bone marrow neutrophils even though no peripheral neutrophilia was yet apparent, suggesting that the subsequent neutrophilia was due to demargination and recirculation of neutrophils sequestered in the peripheral vasculature immediately after their release from the bone marrow. Epinephrine, which causes neutrophilia by demargination but not by release of marrow neutrophils, reversed the initial neutropenia in TNF-plus-LPS-treated rats and increased the neutrophilia. IL-1 combined with LPS increased LPS-induced neutrophilia, suggesting that endogenous IL-1 also contributed to LPS-induced neutrophilia. Corynebacterium parvum-primed rats with hyperplasia of the monocyte-macrophage system and treated with TNF differed from naive rats treated with TNF in that the

  10. Cradle Cap: Treatment (United States)

    Cradle cap Treatment Cradle cap usually doesn't require medical treatment. It clears up on its own within a few months. In the meantime, wash ... tips can help you control and manage cradle cap. Gently rub your baby's scalp with your fingers ...

  11. Role of tumor necrosis factor-alpha and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis. (United States)

    Lupia, E; Montrucchio, G; Battaglia, E; Modena, V; Camussi, G


    The aim of the present study was to investigate in vivo in a mouse model the stimulation of neoangiogenesis by synovial fluids of patients with rheumatoid arthritis (RA) and to determine the role of tumor necrosis factor (TNF)-alpha and platelet-activating factor (PAF) in the formation of new vessels. Angiogenesis was studied in a mouse model in which Matrigel, injected subcutaneously, was used as a vehicle for the delivery of potential angiogenic stimuli. Synovial fluids of patients with RA but not with osteoarthritis (OA) were shown to induce neoangiogenesis. Since synovial fluid of patients with RA contained significantly higher levels of TNF-alpha-like bioactivity and of PAF than that of patients with OA, the role of these mediators was evaluated by using an anti-TNF-alpha neutralizing monoclonal antibody (mAb) and a PAF receptor antagonist, WEB 2170. When added to Matrigel, anti-TNF-alpha mAb and particularly WEB 2170 significantly reduced neoangiogenesis induced by synovial fluids of RA patients. Moreover, PAF extracted and purified from synovial fluid induced angiogenesis. These results suggest that the neoangiogenesis observed in rheumatoid synovitis may be due, at least in part, to the angiogenic effect of locally produced TNF-alpha and PAF.

  12. Hepatocyte nuclear factor 4 alpha is a key factor related to depression and physiological homeostasis in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Kyosuke Yamanishi

    Full Text Available Major depressive disorder (MDD is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of

  13. Monte Carlo alpha calculation

    Energy Technology Data Exchange (ETDEWEB)

    Brockway, D.; Soran, P.; Whalen, P.


    A Monte Carlo algorithm to efficiently calculate static alpha eigenvalues, N = ne/sup ..cap alpha..t/, for supercritical systems has been developed and tested. A direct Monte Carlo approach to calculating a static alpha is to simply follow the buildup in time of neutrons in a supercritical system and evaluate the logarithmic derivative of the neutron population with respect to time. This procedure is expensive, and the solution is very noisy and almost useless for a system near critical. The modified approach is to convert the time-dependent problem to a static ..cap alpha../sup -/eigenvalue problem and regress ..cap alpha.. on solutions of a/sup -/ k/sup -/eigenvalue problem. In practice, this procedure is much more efficient than the direct calculation, and produces much more accurate results. Because the Monte Carlo codes are intrinsically three-dimensional and use elaborate continuous-energy cross sections, this technique is now used as a standard for evaluating other calculational techniques in odd geometries or with group cross sections.

  14. Internal and overall motions of the translation factor eIF4E: Cap binding and insertion in a CHAPS detergent micelle

    International Nuclear Information System (INIS)

    McGuire, Abigail Manson; Matsuo, Hiroshi; Wagner, Gerhard


    The mRNA cap-binding protein eIF4E is the limiting factor in the eIF4F translation initiation complex, which mediates the binding of the 40S ribosome to the mRNA. 15 N relaxation studies have been used to characterize the backbone dynamics of deuterated eIF4E in a CHAPS micelle for the apoprotein, the m 7 GDP-bound form, and the dinucleotide (m 7 GpppA)-bound form, as well as for CHAPS-free eIF4E. Large differences in overall correlation time between the CHAPS-free form (11.8 ns) and samples containing different concentrations of CHAPS (15.9-19.4 ns) indicate that eIF4E is embedded in a large micelle in the presence of CHAPS, with a total molecular weight in the range of 40-60 kDa. CHAPS seems to restrict the mobility of the a2-b3 and a4-b5 loops which are thought to be embedded in the micelle. No significant changes in overall mobility were seen between the m 7 GDP-bound form, the m 7 GpppA-bound form, and the apoprotein. Amide hydrogen exchange data indicate the presence of slowly exchanging amides in two surface-exposed helices (a2 and a4), as well as the a4-b5 loop, indicating protection by the CHAPS micelle. The micelle covers the convex side of the protein away from the cap-binding site

  15. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, G.M.; Wasserman, C.R.; O`Malley, C.D. [California Birth Defects Monitoring Program, Emeryville, CA (United States)] [and others


    Results of studies determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting. Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa. We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked {ge} 20 cigarrettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups. Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks. This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele. 56 refs., 5 tabs.

  16. Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination. (United States)

    Zhan, Shuqin; Cai, Guo-Qiang; Zheng, Anni; Wang, Yuping; Jia, Jianping; Fang, Haotian; Yang, Youfeng; Hu, Meng; Ding, Qiang


    Recent studies recognize that Hypocretin system (also known as Orexin) plays a critical role in sleep/wake disorders and feeding behaviors. However, little is known about the regulation of the Hypocretin system. It is also known that tumor necrosis factor alpha (TNF-α) is involved in the regulation of sleep/wake cycle. Here, we test our hypothesis that the Hypocretin system is regulated by TNF-α. Prepro-Hypocretin and Hypocretin receptor 2 (HcrtR2) can be detected at a very low level in rat B35 neuroblastoma cells. In response to TNF-α, Prepro-Hypocretin mRNA and protein levels are down-regulated, and also HcrtR2 protein level is down-regulated in B35 cells. To investigate the mechanism, exogenous rat Prepro-Hypocretin and rat HcrtR2 were overexpressed in B35 cells. In response to TNF-α, protein and mRNA of Prepro-Hypocretin are significantly decreased (by 93% and 94%, respectively), and the half-life of Prepro-Hypocretin mRNA is decreased in a time- and dose-dependent manner. The level of HcrtR2 mRNA level is not affected by TNF-α treatment; however, HcrtR2 protein level is significantly decreased (by 86%) through ubiquitination in B35 cells treated with TNF-α. Downregulation of cellular inhibitor of apoptosis protein-1 and -2 (cIAP-1 and -2) abrogates the HcrtR2 ubiquitination induced by TNF-α. The control green fluorescent protein (GFP) expression is not affected by TNF-α treatment. These studies demonstrate that TNF-α can impair the function of the Hypocretin system by reducing the levels of both Prepro-Hypocretin and HcrtR2. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitis patients. (United States)

    Varghese, Sheeja S; Thomas, Hima; Jayakumar, N D; Sankari, M; Lakshmanan, Reema


    Periodontitis is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown and alveolar bone destruction mediated by pro-inflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is an important pro-inflammatory mediator that produced causes destruction of periodontal tissues. The aim of the study is to estimate the salivary TNF-α in chronic and aggressive periodontitis and control participants and further correlate the levels with clinical parameter such as gingival index (GI), plaque index (PI), probing pocket depth (PPD) and clinical attachment loss. The study population consisted of 75 subjects age ranging from 25 to 55 years attending the outpatient section of Department of Periodontics, Saveetha Dental College and Hospital. The study groups included Groups 1, 2, and 3 with participants with healthy periodontium (n = 25), generalized chronic periodontitis (n = 25) and generalized aggressive periodontitis (n = 25), respectively. Salivary samples from the participants were used to assess the TNF-α levels using enzyme-linked immunosorbent assay. GI and PI were found to be significantly higher in chronic and aggressive periodontitis compared to the controls. The mean TNF-α value in chronic periodontitis patients (12.92 ± 17.21 pg/ml) was significantly higher than in control subjects (2.15 ± 3.60 pg/ml). Whereas, in aggressive periodontitis patients the mean TNF-α (7.23 ± 7.67) were not significantly different from chronic periodontitis or healthy subjects. Among periodontitis participants, aggressive periodontitis subjects exhibited a significant positive correlation between the salivary TNF-α and PPD. Salivary TNF-α levels are significantly higher in chronic periodontitis than in healthy subjects, but there was no significant correlation with the clinical parameters.

  18. Pharmacokinetics and tissue distribution of recombinant human tumor necrosis factor-alpha in mice

    International Nuclear Information System (INIS)

    Ferraiolo, B.L.; Moore, J.A.; Crase, D.; Gribling, P.; Wilking, H.; Baughman, R.A.


    The serum pharmacokinetics and the major organs of accumulation of recombinant human tumor necrosis factor-alpha (rHuTNF) were determined in BDF1 mice after intravenous and intramuscular administration. Serum concentrations of immunoreactive protein were determined by enzyme-linked immunosorbent assay, and radioactivity was quantitated by beta and gamma scintigraphy. The serum pharmacokinetics of labeled and unlabeled rHuTNF were identical when administered by the intravenous route. After intravenous doses of 165 to 320 micrograms/kg, the clearance was 2.9-3.6 ml/hr, the initial volume of distribution was 1.4-1.6 ml (70-80 ml/kg), and the half-life was 18.5-19.2 min. Intramuscular administration of 320 micrograms/kg resulted in a peak serum concentration of 112 ng/ml. The time of the peak concentration was 1 hr, and the bioavailability of the intramuscular dose was 12%. The data suggest that the disposition of this protein may be biexponential. If this is the case, the terminal phase would appear to account for less than 1% of the total AUC. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported. 125I-Labeled and metabolically labeled 3H-rHuTNF were used to examine tissue distribution. After intravenous 125I-rHuTNF administration, the rank order of accumulation of the 125I-radiolabel in the major organs (per cent dose per organ over 1440 min) was: liver greater than kidney greater than lung greater than heart greater than spleen. This rank order of accumulation was confirmed by intravenous 3H-rHuTNF administration

  19. Association of increased levels of plasma tumor necrosis factor alpha with primary open-angle glaucoma

    Directory of Open Access Journals (Sweden)

    Kondkar AA


    Full Text Available Altaf A Kondkar, Tahira Sultan, Faisal A Almobarak, Hatem Kalantan, Saleh A Al-Obeidan, Khaled K Abu-Amero Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia Purpose: Retinal ganglion cell (RGC death is a key feature of glaucoma. Elevated levels of tumor necrosis factor alpha (TNF-α, a pro-inflammatory cytokine, can induce RGC apoptosis and play a critical role in glaucomatous neurodegeneration. Based on the possible role of inflammation and oxidative stress in the pathogenesis of primary open-angle glaucoma (POAG, we investigated the association between plasma levels of TNF-α and POAG or its clinical indices in comparison to non-glaucomatous controls. Patients and methods: In a case–control retrospective cohort of 51 POAG cases and 88 controls, plasma TNF-α levels were measured using an enzyme-linked immunosorbent assay (ELISA. The assay was performed in duplicates on an automated ELISA analyzer. Results: Mean TNF-α level was significantly elevated in POAG cases (1.88 ± 2.17 pg/mL than the controls (0.93 ± 1.49 pg/mL; p = 0.003. The overall dose–response trend was significant (Χ2 = 6.12, df = 2; p = 0.047. No statistical difference was seen in age, gender and systemic disease distribution. A modest negative and significant correlation was seen between TNF-α level and number of antiglaucoma medications, an important clinical index of POAG severity. Moreover, logistic regression analysis showed that the risk of POAG was most significantly affected by TNF-α level and not by age and sex. Conclusion: High systemic level of an inflammatory cytokine, TNF-α, is associated with POAG; however, its possible use as a biomarker for early glaucoma diagnosis and/or disease severity needs further investigation. Keywords: apoptosis, biomarker, cytokines, ELISA, inflammation, neurodegeneration, oxidative stress

  20. Analysis and Quantitation of NF-[kappa]B Nuclear Translocation in Tumor Necrosis Factor Alpha (TNF-[alpha]) Activated Vascular Endothelial Cells (United States)

    Fuseler, John W.; Merrill, Dana M.; Rogers, Jennifer A.; Grisham, Matthew B.; Wolf, Robert E.


    Nuclear factor kappa B (NF-[kappa]B) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-[kappa]Bs, which prevent entry into the nucleus. Following cellular stimulation, the I-[kappa]Bs are rapidly degraded, activating NF-[kappa]B. The active form of NF-[kappa]B rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-[kappa]B is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-[kappa]B (p65 subunit, p65-NF-[kappa]B) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-[kappa]B protein in the nucleus determined biochemically. The appearance of p65-NF-[kappa]B in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-[kappa]B can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

  1. The tumor necrosis factor alpha - 308G>A polymorphism is associated with dementia in the oldest-old

    DEFF Research Database (Denmark)

    Bruunsgaard, Helle; Benfield, Thomas L; Andersen-Ranberg, Karen


    OBJECTIVES: To test the hypothesis that the tumor necrosis factor (TNF) -308 G>A promoter gene polymorphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish centenarians. PARTICIPANTS: One...... was investigated (Fischer exact test). Furthermore, whether the TNF -308 G>A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-alpha (analysis of variance), and mortality in the following 5 years (Cox regression analysis) within the cohort...... higher plasma levels of TNF-alpha, but the significance was questionable due to a low number of subjects with this genotype. CONCLUSION: It is possible that the TNF -308 A allele is maintained during aging because subjects who are heterozygous for this polymorphism possess the optimal inflammatory...

  2. Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression

    International Nuclear Information System (INIS)

    Simiantonaki, Nektaria; Taxeidis, Marios; Jayasinghe, Caren; Kurzik-Dumke, Ursula; Kirkpatrick, Charles James


    Hypoxia-inducible factor 1 alpha (HIF-1α) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1α during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas. Immunohistochemistry and Western blot is used to analyse HIF-1α expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1α inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry. In normal mucosa, HPP and TA-LGD HIF-1α was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1α were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1α overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1α expression was strongly accumulated in perinecrotic regions. In these cases HIF-1α activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1α was also seen in periiflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1α expression and nuclear translocation. We conclude that HIF-1α expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic

  3. Enhancement of alpha particles-induced cell transformation by oxygen free radicals and tumor necrosis factor released from phagocytes

    International Nuclear Information System (INIS)

    Gong Yifen; Guo Renfeng; Zhu Maoxiang; Shou Jiang; Ge Guixiu; Yang Zhihua; Hieber, L.; Peters, K.; Schippel, C.


    To illustrate the role of several endogenous factors released from phagocytes under chronic inflammation in radiation-induced cancer. C 3 T 10 T 1/2 and SHE cells were used as targets, and 238 Pu alpha source was used in alpha irradiation. The enhancement of TF in alpha particles-induced cell transformation by PMA-stimulated human blood and zymosan-stimulated U-937 cells was studied using formation of transformed foci. Transformation frequency (TF) of C 3 H 10 T 1/2 cells exposed to alpha particles of 0.5 Gy increased 2.1 and 2.8 fold by PMA-and PMA-stimulated neutrophils, respectively. TF of irradiated SHE cells at a dose of 0.5 Gy increased 12 fold by the addition of the supernatant of macrophage-like U-937 cell line. It was shown that TF of irradiated SHE cells at above dose increased 8 fold by the supernatant treated with anti-TNF-α could be subcultured continuously in vitro. The cells at 40 th passage and two lines of monoclone cells have the ability to develop malignant tumors in nude mice. The overdose of free radicals and TNF-α released from neutrophils and macrophages have played an important role in low dose radiation-induced cancer

  4. Characterization of a Canine Tetranucleotide Microsatellite Marker Located in the First Intron of the Tumor Necrosis Factor Alpha Gene


    WATANABE, Masashi; TANAKA, Kazuaki; TAKIZAWA, Tatsuya; SEGAWA, Kazuhito; NEO, Sakurako; TSUCHIYA, Ryo; MURATA, Michiko; MURAKAMI, Masaru; HISASUE, Masaharu


    ABSTRACT A polymorphic tetranucleotide (GAAT)n microsatellite in the first intron of the canine tumor necrosis factor alpha (TNFA) gene was characterized in this study; 139 dogs were analyzed: 22 Beagles, 26 Chihuahuas, 20 Miniature Dachshunds, 24 Miniature Poodles, 22 Pembroke Welsh Corgis and 25 Shiba Inus. We detected the presence of the 4 alleles (GAAT)5, (GAAT)6, (GAAT)7 and (GAAT)8, including 9 of the 10 expected genotypes. The expected heterozygosity (He) and the polymorphic informatio...

  5. The tumor necrosis factor-alpha-induced protein 8 family in immune homeostasis and inflammatory cancer diseases. (United States)

    Luan, Y Y; Yao, Y M; Sheng, Z Y


    Within the immune system homeostasis is maintained by a myriad of mechanisms that include the regulation of immune cell activation and programmed cell death. The breakdown of immune homeostasis may lead to fatal inflammatory diseases. We set out to identify genes of tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) family that has a functional role in the process of immune homeostasis. Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8), which functions as an oncogenic molecule, is also associated with enhanced cell survival and inhibition of apoptosis. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) governs immune homeostasis in both the innate and adaptive immune system and prevents hyper-responsiveness by negatively regulating signaling via T cell receptors and Toll-like receptors (TLRs). There also exist two highly homologous but uncharacterized proteins, TIPE1 and TIPE3. This review is an attempt to provide a summary of TNFAIP8 family associated with immune homeostasis and inflammatory cancer diseases.

  6. Hypoxia inducible factor 1-alpha (HIF-1 alpha is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival.

    Directory of Open Access Journals (Sweden)

    Elisa Conde

    Full Text Available Acute tubular necrosis (ATN caused by ischemia/reperfusion (I/R during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α, using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant.

  7. Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha. (United States)

    Lurton, J; Soto, H; Narayanan, A S; Raghu, G


    Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are two polypeptide mediators which are believed to play a role in the evolution of idiopathic pulmonary fibrosis (IPF). We have evaluated the effect of these two substances on the expression of receptors for collagen (cC1q-R) and globular (gC1q-R) domains of C1q and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in C1q receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on C1q binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to TGF-beta and TNF-alpha in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to TGF-beta and TNF-alpha contained 1.4 and 1.6 times as much cC1q-R mRNA, respectively, whereas in HH cells cC1q-R mRNA increased 2.0- and 2.4-fold. The gC1q-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of CC1q-R and gC1q-R, which were similar to or less than controls. Both TGF-beta and TNF-alpha also increased procollagen [I] mRNA levels in both cells. Overall, TNF-alpha caused a greater increase and the degree of response by HH fibroblasts to both TGF-beta and TNF-alpha was higher than NL cells. These results indicated that TGF-beta and TNF-alpha upregulate the mRNA levels for cC1q-R and collagen and that they do not affect gC1q-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.

  8. The fibroblast growth factor receptor (FGFR) agonist FGF1 and the neural cell adhesion molecule-derived peptide FGL activate FGFR substrate 2alpha differently

    DEFF Research Database (Denmark)

    Chen, Yongshuo; Li, Shizhong; Berezin, Vladimir


    Activation of fibroblast growth factor (FGF) receptors (FGFRs) both by FGFs and by the neural cell adhesion molecule (NCAM) is crucial in the development and function of the nervous system. We found that FGFR substrate 2alpha (FRS2alpha), Src homologous and collagen A (ShcA), and phospholipase-Cg...

  9. Intermitted pharmacologic pretreatment by xenon, isoflurane, nitrous oxide, and the opioid morphine prevents tumor necrosis factor alpha-induced adhesion molecule expression in human umbilical vein endothelial cells

    NARCIS (Netherlands)

    Weber, Nina C.; Kandler, Jennis; Schlack, Wolfgang; Grueber, Yvonne; Frädorf, Jan; Preckel, Benedikt


    BACKGROUND: The barrier properties of the endothelium are of critical importance during pathophysiologic processes. These barrier properties depend on an intact cytoskeleton and are regulated by cell adhesion molecules. Tumor necrosis factor alpha (TNF-alpha) is known to induce cell adhesion

  10. NcoI restriction fragment length polymorphism (RFLP) of the tumour necrosis factor (TNF alpha) region in primary biliary cirrhosis and in healthy Danes

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Ryder, L P


    The restriction fragment length polymorphism of the human tumour necrosis factor (TNF alpha) region was investigated by means of 20 different restriction enzymes and a human TNF alpha cDNA probe. Only one of the enzymes, NcoI, revealed a polymorphic pattern consisting of fragments of 10.5 and 5.5...

  11. An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles

    NARCIS (Netherlands)

    Wilson, A. G.; de Vries, N. [=Niek; Pociot, F.; di Giovine, F. S.; van der Putte, L. B.; Duff, G. W.


    The tumor necrosis factor (TNF) alpha gene lies within the class III region of the major histocompatibility complex (MHC), telomeric to the class II and centromeric to the class I region. We have recently described the first polymorphism within the human TNF-alpha locus. This is biallelic and lies

  12. Tumor necrosis factor-alpha induces activation of coagulation and fibrinolysis in baboons through an exclusive effect on the p55 receptor

    NARCIS (Netherlands)

    van der Poll, T.; Jansen, P. M.; van Zee, K. J.; Welborn, M. B.; de Jong, I.; Hack, C. E.; Loetscher, H.; Lesslauer, W.; Lowry, S. F.; Moldawer, L. L.


    Tumor necrosis factor-alpha (TNF-alpha) can bind to two distinct transmembrane receptors, the p55 and p75 TNF receptors. We compared the capability of two mutant TNF proteins with exclusive affinity for the p55 or p75 TNF receptor with that of wild type TNF, to activate the hemostatic mechanism in

  13. Reduction in high blood tumor necrosis factor-alpha levels after manipulative therapy in 2 cervicogenic headache patients. (United States)

    Ormos, Gábor; Mehrishi, J N; Bakács, Tibor


    This case report discusses the treatment of 2 patients with cervicogenic headache (CHA) attending the Outpatient Clinic of the Hungarian National Institute for Rheumatology and Physiotherapy (Budapest, Hungary) and reviews the pathophysiology, therapeutic strategy, and problems associated with the treatment of CHA. Patient 1 was a 27-year-old female who sustained a whiplash injury. A sharp, shooting headache developed, readily induced, and aggravated by just bending the neck backward or by turning her head. Magnetic resonance imaging revealed a disk protrusion at C4-C5 pressing the anterior cerebrospinal space. Patient 2 was a 62-year-old female who sustained a whiplash injury; her cervical movements became restricted, which precipitated headaches. Magnetic resonance imaging revealed a paramedian disk hernia between the C4 and C5 vertebrae that intruded into the right ventral cerebrospinal space. After 4 weeks of manipulative therapy for patient 1, both active and passive range of motion returned to normal, and the high tumor necrosis factor-alpha (TNF-alpha) level (63 pg/mL) was substantially reduced (28 pg/mL). Patient 2 was started on manipulative therapy twice a week for 4 weeks; after 2 months, the patient became symptom-free, and high TNF-alpha level (72 pg/mL) was reduced greatly (35 pg/mL). Two patients with whiplash injury and disk herniation developed CHA associated with very high TNF-alpha levels. After manipulative therapy, these patients became symptom-free, and their TNF-alpha levels decreased substantially.

  14. Changes in serum tumor necrosis factor (TNF-alpha) with kami-shoyo-san administration in depressed climacteric patients. (United States)

    Ushiroyama, Takahisa; Ikeda, Atsushi; Sakuma, Kou; Ueki, Minoru


    An herbal medicine (kampo) is widely used to prevent or treat climacteric symptoms. In order to investigate the potential involvement of tumor necrosis factor (TNF)-alpha in susceptibility to mood disorder in climacteric women and to clarify the relationship between immune function and the efficacy of herbal medicine, we compared serum TNF-alpha levels in two treated groups, with and without concurrent use of herbal medicine. This study included 113 consecutive depressed menopausal patients who visited the gynecological and psychosomatic medicine outpatient clinic of the Osaka Medical College Hospital in Japan. Fifty-eight patients were administered kami-shoyo-san according to the definition of above sho. In contrast, 55 patients who were different in sho of kami-shoyo-san were administered antidepressants. Hamilton Rating Scale for depression (HAM-D) scores were determined at baseline and 12 weeks after starting treatment (endpoint). TNF-alpha concentrations were analyzed before and after 12 weeks of treatment. Kami-shoyo-san significantly increased plasma concentrations of TNF-alpha after 12 weeks of treatment, to 17.22 +/- 6.13 pg/ml from a baseline level of 14.16 +/- 6.27 pg/ml (p = 0.048). The percent change in plasma concentration of TNF-alpha differed significantly between the kami-shoyo-san therapy group and the antidepressant therapy group at 4 weeks (12.0 +/- 7.8% and -1.22 +/- 0.25%, respectively, p emotional status via the central nervous system and may be regulated by herbal medicines, although the interactions are very complex.

  15. IgE-mediated basophil tumour necrosis factor alpha induces matrix metalloproteinase-9 from monocytes

    DEFF Research Database (Denmark)

    Falkencrone, Sidsel; Poulsen, Lars K.; Bindslev-Jensen, Carsten


    IgE-mediated activation of mast cells has been reported to induce the release of tumour necrosis alpha (TNF-α), which may display autocrine effects on these cells by inducing the generation of the tissue remodelling protease matrix metalloproteinase-9 (MMP-9). While mast cells and basophils have...

  16. Study on influences of experimental factors on energy and absolute activity measurements of alpha-emitters

    International Nuclear Information System (INIS)

    Terini, R.A.


    This work presents firstly a review of the fundamental results and conclusions obtained through alpha-spectrometry and alpha-counting, and the influence of energy straggling, energy loss, self-absorption and backscattering, on the determination of the energy and the absolute activity of alpha samples. Is is shown that the techniques of source fabrication and the methods of measurements play a capital influence on the obtained results. Moreover, measurements made by us, with a silicon surface barrier detector, show that the peak-asymmetry and peak-shift of an alpha-spectrum increases with the angle of emission, and that the magnitude of this effect depends on the thickness and homogeneity of the sample, as well as on the geometry of the measuring system. Through an analysis of the angular distribution of the emitted particles, the degree of isotropy of some thin Am sup(241) sources was measured and the influence of source backing and the geometry was analysed. We can conclude that, in general, there is a larger precision in measurements made under very small solid angles around the normal to the sample, and we enphasize the necessary cares required on the production of the source and on the set up of the measuring system. (author)

  17. Alveolar macrophage release of tumor necrosis factor-alpha in chronic alcoholics without liver disease. (United States)

    Omidvari, K; Casey, R; Nelson, S; Olariu, R; Shellito, J E


    Alcohol is an immunosuppressive drug, and chronic abuse has been associated with increased susceptibility to a variety of infections, including bacterial pneumonia and tuberculosis. Alveolar macrophages are the resident phagocytes of the lung and play a central role in lung host defenses against infection ranging from direct antibacterial activity to the release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha). TNFalpha, in particular, plays a key role in the development of the early inflammatory response. In this study, we investigated the effects of chronic alcohol consumption on alveolar macrophage release of TNFalpha in vitro. We prospectively studied lipopolysaccharide (LPS)-stimulated release of TNFalpha from alveolar macrophages obtained from bronchoalveolar lavage fluid (BALF) in 22 alcoholic (18 smokers, 4 nonsmokers) and 7 nondrinking healthy volunteers (3 smokers, 4 nonsmokers). The total number of cells recovered by bronchoalveolar lavage (BAL) and their differential distribution were not significantly different in alcoholics versus controls (43 +/- 8 x 10(6) and 39 +/- 13 x 10(6), respectively). However, the total number of cells recovered from BALF was significantly higher in smokers (51 +/- 8 x 10(6)) than in nonsmokers (19 +/- 5 x 10(6)). Spontaneous (basal) release of TNFalpha by alveolar macrophages was the same in alcoholics and controls. In contrast, LPS-stimulated release of TNFalpha was significantly suppressed in alcoholics compared with that of controls (1343 +/- 271 vs. 3806 +/- 926 U TNF/ml/10(6) cells, respectively, p < 0.015). When controlled for smoking, LPS-stimulated TNFalpha production was suppressed in alcoholic nonsmokers (563 +/- 413 U TNF/ml/10(6)) compared with control nonsmokers (5113 +/- 1264 U TNF/ml/10(6)). LPS-stimulated TNFalpha production was also less in control smokers (2063 +/- 386 U TNF/ml/10(6) cells) than in control nonsmokers (5113 +/- 1264 U TNF/ml/10(6) cells). There was no difference

  18. Expression of tumor necrosis factor-alpha and receptor I(P55in pterygium

    Directory of Open Access Journals (Sweden)

    Bing Wu


    Full Text Available AIM:To observe the expression of tumor necrosis factor- alpha(TNF-αand its receptor I(P55in different pterygium and discuss the role of TNF-α and receptor I(P55in pterygium.METHODS: Immunohistochemistical staining method(PVwas adopted to detect the expression of TNF-α and receptor I in pterygium(72 eyesand para-pterygium conjunctival tissue(30 eyes. The relationship between the expression and clinical-pathological parameters was also analyzed. RESULTS: The positive rates of TNF-α were 65.3%(47/72, 26.7%(8/30in pterygium and para-pterygium conjunctival tissue. The positive expression of TNF-α had statistic difference between the two groups(χ2=12.706, Pχ2=13.875, Pχ2=6.547, P=0.011. There had no statistically significance of the expression intensity between the two groups(F=1.288, P=0.393; the positive rate in advanced pterygium group was higher than quiescent pterygium group(χ2=4.082, P=0.043. The expression intensity had no statistically significance between the two groups(F=0.489, P=0.708. The positive rate of P55 in recurrent pterygium group was higher than primary pterygium group(χ2=9.907, P=0.002. There had no statistically significance of the two group's expression intensity(F=1.175, P=0.424; the positive rate in advanced pterygium group was higher than in quiescent pterygium group(χ2=11.140, P=0.001. The expression intensity had no statistically significance between the two groups(F=0.665, P=0.621. CONCLUSION:The expression of TNF-α and P55 are changing according to the development of clinical staging and onset. The expression of TNF-α and P55 may be related to clinical classification, staging and patient's working conditions of pterygium. There has no significant difference expression intensity of TNF-α and P55 in clinical staging and onset of pterygium.

  19. Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Bernardino, Liliana; Xapelli, Sara; Silva, Ana P


    The inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects...... of mouse recombinant TNF-alpha (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF-alpha to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol....... By using TNF-alpha receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF-alpha involves TNF receptor-1, whereas the neuroprotective effect is mediated by TNF receptor-2. AMPA exposure was associated with activation and proliferation of microglia as assessed...

  20. Internamento devido a PAC por Streptococcus pneumoniae - Avaliação de factores de mortalidade Streptococcus pneumoniae - caused CAP in hospitalised patients: mortality predictors

    Directory of Open Access Journals (Sweden)

    Sandra Figueiredo


    Full Text Available A avaliação da gravidade perante qualquer caso de pneumonia adquirida na comunidade (PAC é de suma importância, pois dela decorrem decisões como a necessidade de internamento e o tratamento empírico inicial. Os autores apresentam um estudo retrospectivo, que incluiu doentes internados devido a pneumonia por Streptococcus pneumoniae durante o ano de 2006, no Hospital de São João. A confirmação etiológica de infecção foi feita por isolamentos no sangue, líquido pleural, secreções traqueobrônquicas, lavado brônquico, lavado broncoalveolar e pesquisa de antigenúria. Foram analisados os factores de risco e avaliados, com base nas normas PSI (Pneumonia Severity Index e da British Thoracic Society (BTS - CURB-65. A análise estatística foi efectuada utilizando teste T para amostras independentes e ANOVA, usando o programa de análise estatística SPSS 14.0. Foram incluídos 104 doentes com idade mediana de 63 anos, sendo 67,3% do sexo masculino. O estudo revelou existir uma associação com significado estatístico entre os resultados de PSI e CURB-65 e a evolução para a mortalidade. Apesar da melhoria dos meios diagnósticos e profilácticos, e da terapêutica antibiótica, a pneumonia pneumocócica permanece uma entidade de grande morbilidade e mortalidade. O valor preditivo das normas PSI e CURB-65 foi confirmado nesta população de doentes, documentando uma correlação entre o número de factores de risco e a evolução da doença.Probably the most important decision in the management of Community-Acquired Pneumonia (CAP is patient site of care. Patients with Streptococcus pneumoniae-caused CAP admitted to our hospital between 1st January and 31st December 2006 were retrospectively analysed. Samples of blood, sputum, bronchial and bronchoalveolar lavage and urine were collected for microbiological testing using standard culture techniques and urine antigen detection. Pneumonia Severity Index (PSI and British Thoracic Society

  1. Determination of self absorption correction factor (SAF) for gross alpha measurement in water samples by BIS method

    International Nuclear Information System (INIS)

    Raveendran, Nanda; Baburajan, A.; Ravi, P.M.


    The laboratories accredited by AERB undertake the measurement of gross alpha and gross beta in packaged drinking water from manufactures across the country and analyze as per the procedure of Bureau of Indian standards. The accurate measurements of gross alpha in the drinking water sample is a challenge due to the self absorption of alpha particle from varying precipitate (Fe(OH) 3 +BaSO 4 ) thickness and total dissolved solids (TDS). This paper deals with a study on tracer recovery generation and self absorption correction factor (SAF). ESL, Tarapur has participated in an inter-laboratory comparison exercise conducted by IDS, RSSD, BARC as per the recommendation of AERB for the accredited laboratories. The thickness of the precipitate is an important aspect which affected the counting process. The activity was reported after conducting multiple experiments with uranium tracer recovery and precipitate thickness. Later on to make our efforts simplified, an average tracer recovery and Self Absorption correction Factor (SAF) was derived by the present experiment and the same was used for the re-calculation of activity from the count rate reported earlier

  2. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)


    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

  3. The pharmaceutical vial capping process: Container closure systems, capping equipment, regulatory framework, and seal quality tests. (United States)

    Mathaes, Roman; Mahler, Hanns-Christian; Buettiker, Jean-Pierre; Roehl, Holger; Lam, Philippe; Brown, Helen; Luemkemann, Joerg; Adler, Michael; Huwyler, Joerg; Streubel, Alexander; Mohl, Silke


    Parenteral drug products are protected by appropriate primary packaging to protect against environmental factors, including potential microbial contamination during shelf life duration. The most commonly used CCS configuration for parenteral drug products is the glass vial, sealed with a rubber stopper and an aluminum crimp cap. In combination with an adequately designed and controlled aseptic fill/finish processes, a well-designed and characterized capping process is indispensable to ensure product quality and integrity and to minimize rejections during the manufacturing process. In this review, the health authority requirements and expectations related to container closure system quality and container closure integrity are summarized. The pharmaceutical vial, the rubber stopper, and the crimp cap are described. Different capping techniques are critically compared: The most common capping equipment with a rotating capping plate produces the lowest amount of particle. The strength and challenges of methods to control the capping process are discussed. The residual seal force method can characterize the capping process independent of the used capping equipment or CCS. We analyze the root causes of several cosmetic defects associated with the vial capping process. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Factors affecting the energy resolution in alpha particle spectrometry with silicon diodes

    International Nuclear Information System (INIS)

    Camargo, Fabio de.


    In this work are presented the studies about the response of a multi-structure guard rings silicon diode for detection and spectrometry of alpha particles. This ion-implanted diode (Al/p + /n/n + /Al) was processed out of 300 μm thick, n type substrate with a resistivity of 3 kΩ·cm and an active area of 4 mm 2 . In order to use this diode as a detector, the bias voltage was applied on the n + side, the first guard ring was grounded and the electrical signals were readout from the p + side. These signals were directly sent to a tailor made preamplifier, based on the hybrid circuit A250 (Amptek), followed by a conventional nuclear electronic. The results obtained with this system for the direct detection of alpha particles from 241 Am showed an excellent response stability with a high detection efficiency (≅ 100 %). The performance of this diode for alpha particle spectrometry was studied and it was prioritized the influence of the polarization voltage, the electronic noise, the temperature and the source-diode distance on the energy resolution. The results showed that the major contribution for the deterioration of this parameter is due to the diode dead layer thickness (1 μm). However, even at room temperature, the energy resolution (FWHM = 18.8 keV) measured for the 5485.6 MeV alpha particles ( 241 Am) is comparable to those obtained with ordinary silicon barrier detectors frequently used for these particles spectrometry. (author)

  5. Estimated release from the saltstone landfill effect of landfill caps and landfill-cap/monolith-liner combinations

    International Nuclear Information System (INIS)

    Wilhite, E.L.


    The effect of capping the entire saltstone landfill is dependent on the effectiveness of the clay cap in preventing infiltration. A cap that is 99% effective will reduce releases from the saltstone landfill by a factor of 7.7. Several combinations of landfill design alterations will result in meeting ground water standards

  6. Microtubule's conformational cap

    DEFF Research Database (Denmark)

    Flyvbjerg, H.


    The molecular mechanisms that allow elongation of the unstable microtubule lattice remain unclear. It is usually thought that the GDP-liganded tubulin lattice is capped by a small layer of GTP- or GDP-P(i)-liganded molecules, the so called "GTP-cap". Here, we point-out that the elastic properties...

  7. The polymorphism -863C/A in tumour necrosis factor-alpha gene contributes an independent association to gout. (United States)

    Chang, S-J; Tsai, P-C; Chen, C-J; Lai, H-M; Ko, Y-C


    To investigate the associations between polymorphisms in the promoter of the tumour necrosis factor-alpha (TNF-alpha) gene and gout. The polymorphisms -308G/A and -863C/A in the TNF-alpha gene were determined in 106 gout patients and 159 healthy controls among male Taiwanese using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The biochemical markers, including Glutamic-oxaloacetic transaminase (GOT), Glutamic-pyruvic transaminase (GPT), uric acid, creatinine, total cholesterol (TC), triglycerides (TG), body mass index (BMI) and hypertension, as well as alcohol consumption were measured. The gout patients had 9.43% (10/106) with genotype AA at polymorphism -863C/A showing a significantly higher fraction than controls (0.63%; 1/159, P gout patients had significantly higher portions of abnormal GOT, GPT, creatinine, TC, TG, alcohol consumption, hypertension and hyperuricaemia than controls (P 0.05). After adjustment by a stepwise logistic regression method, the hyperuricaemia, creatinine, GPT, TG and alcohol consumption as well as genotype AA at polymorphism -863C/A were found to be significantly associated with gout. The genotype AA at polymorphism -863C/A in a recessive model showed a significant association with developing gout independent of hyperuricaemia, abnormal creatinine, higher TG, GPT and alcohol consumption.

  8. In vitro cytotoxicity of human recombinant tumor necrosis factor alpha in association with radiotherapy in a human ovarian carcinoma cell line

    International Nuclear Information System (INIS)

    Manetta, A.; Lucci, J.; Soopikian, J.; Granger, G.; Berman, M.L.; DiSaia, P.J.


    It has been speculated that tumor necrosis factor alpha (TNF-alpha) may decrease the cytotoxicity of radiotherapy by increasing the scavenging of toxic superoxide radicals. Because of the possible clinical implications, the cytotoxicity of TNF-alpha in combination with radiotherapy (RT) was compared with that of RT alone in a human ovarian cancer cell line. NIH:OVCAR-3 cells were incubated with TNF-alpha at 10.0, 1.0, 0.1, and 0.01 microgram/ml. Plates were divided into two groups; one received 150 cGy of radiotherapy and the other received no further therapy. Seventy-two hours later, supernatants were aspirated and viable cells were stained with a 1% solution of crystal violet. Survival of cells treated with RT plus TNF-alpha was expressed as a percentage of surviving irradiated controls. Analysis of results revealed minimal additive cell killing effect between TNF-alpha and radiotherapy at all concentrations of tumor necrosis factor, with the greatest difference noted in the group treated with 10 micrograms/ml TNF-alpha. A continued radiotherapy dose-response study with TNF-alpha showed a similar additive, not radioprotective, effect. This may have implication as a potentiator of RT in some human tumors

  9. Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-Tumor Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis. (United States)

    Yang, Chen; Huang, Junlin; Huang, Xiaowen; Huang, Shaozhuo; Cheng, Jiaxin; Liao, Weixin; Chen, Xuewen; Wang, Xueyi; Dai, Shixue


    The association between anti-tumor necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumor necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. MEDLINE, EMBASE and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Twelve studies comprising 285811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumor necrosis factor alpha agents exposed and anti-tumor necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR], 1.43 95%CI, 0.91-2.25, p= 0.116; random effects: risk ratio [RR], 0.83 95%CI, 0.47-1.48, p=0.534). However, monotherapy of anti-tumor necrosis factor alpha agents (random effects: IRR=1.65, 95%CI, 1.16-2.35; p=0.006; random effects: RR=1.00, 95%CI, 0.39-2.59; p=0.996) or combination therapy (random effects: IRR=3.36, 95%CI, 2.23-5.05; ptumor necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumor necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

  10. Epitope mapping of the alpha-chain of the insulin-like growth factor I receptor using antipeptide antibodies. (United States)

    Delafontaine, P; Ku, L; Ververis, J J; Cohen, C; Runge, M S; Alexander, R W


    Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells (VSMC). The IGF I receptor (IGF IR) is a heterotetramer composed of two cross-linked extracellular alpha-chains and two membrane-spanning beta-chains that contain a tyrosine-kinase domain. It has a high degree of sequence similarity to the insulin receptor (IR), and the putative ligand-specific binding site has been localized to a cysteine-rich region (CRR) of the alpha-chain. To obtain insights into antigenic determinants of the IGF IR, we raised a panel of site-specific polyclonal antibodies against short peptide sequences N-terminal to and within the CRR. Several antibodies raised against linear epitopes within the CRR bound to solubilized and native rat and human IGF IR by ELISA, did not cross-react with IR, but unexpectedly failed to inhibit 125I-IGF I binding. A polyclonal antibody directed against a 48-amino acid synthetic peptide, corresponding to a region of the CRR postulated to be essential for ligand binding, failed to react with either solubilized, reduced or intact IGF IR. Three antibodies specific for the N-terminus of the alpha-chain reacted with solubilized and native IGF IR. One of these, RAB 6, directed against amino acids 38-44 of the IGF IR, inhibited 125I-IGF I binding to rat aortic smooth muscle cells (RASM) and to IGF IR/3T3 cells (overexpressing human IGF IR) by up to 45%. Immunohistochemical analysis revealed strong IGF IR staining in the medial smooth muscle cell layer of rat aorta. These findings are consistent with a model wherein conformational epitopes within the CRR and linear epitopes within the N-terminus of the alpha-chain contribute to the IGF I binding pocket. These antibodies should provide a valuable tool to study structure-function relationships and in vivo regulation of the IGF IR.

  11. Phospholipase C-{delta}{sub 1} regulates interleukin-1{beta} and tumor necrosis factor-{alpha} mRNA expression

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eric; Jakinovich, Paul; Bae, Aekyung [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States); Rebecchi, Mario, E-mail: [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States)


    Phospholipase C-{delta}{sub 1} (PLC{delta}{sub 1}) is a widely expressed highly active PLC isoform, modulated by Ca{sup 2+} that appears to operate downstream from receptor signaling and has been linked to regulation of cytokine production. Here we investigated whether PLC{delta}{sub 1} modulated expression of the pro-inflammatory cytokines interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) in rat C6 glioma cells. Expression of PLC{delta}{sub 1} was specifically suppressed by small interfering RNA (siRNA) and the effects on cytokine mRNA expression, stimulated by the Toll-like receptor (TLR) agonist, lipopolysaccharide (LPS), were examined. Real-time polymerase chain reaction (RT-PCR) results showed that PLC{delta}{sub 1} knockdown enhanced expression IL-1{beta} and tumor necrosis factor-{alpha} (TNF-{alpha}) mRNA by at least 100 fold after 4 h of LPS stimulation compared to control siRNA treatment. PLC{delta}{sub 1} knock down caused persistently high Nf{kappa}b levels at 4 h of LPS stimulation compared to control siRNA-treated cells. PLC{delta}{sub 1} knockdown was also associated with elevated nuclear levels of c-Jun after 30 min of LPS stimulation, but did not affect LPS-stimulated p38 or p42/44 MAPK phosphorylation, normally associated with TLR activation of cytokine gene expression; rather, enhanced protein kinase C (PKC) phosphorylation of cellular proteins was observed in the absence of LPS stimulation. An inhibitor of PKC, bisindolylmaleimide II (BIM), reversed phosphorylation, prevented elevation of nuclear c-Jun levels, and inhibited LPS-induced increases of IL-1{beta} and TNF-{alpha} mRNA's induced by PLC{delta}{sub 1} knockdown. Our results show that loss of PLC{delta}{sub 1} enhances PKC/c-Jun signaling and up-modulates pro-inflammatory cytokine gene transcription in concert with the TLR-stimulated p38MAPK/Nf{kappa}b pathway. Our findings are consistent with the idea that PLC{delta}{sub 1} is a

  12. Platelet factor XIII increases the fibrinolytic resistance of platelet-rich clots by accelerating the crosslinking of alpha 2-antiplasmin to fibrin (United States)

    Reed, G. L.; Matsueda, G. R.; Haber, E.


    Platelet clots resist fibrinolysis by plasminogen activators. We hypothesized that platelet factor XIII may enhance the fibrinolytic resistance of platelet-rich clots by catalyzing the crosslinking of alpha 2-antiplasmin (alpha 2AP) to fibrin. Analysis of plasma clot structure by polyacrylamide gel electrophoresis and immunoblotting revealed accelerated alpha 2AP-fibrin crosslinking in platelet-rich compared with platelet-depleted plasma clots. A similar study of clots formed with purified fibrinogen (depleted of factor XIII activity), isolated platelets, and specific factor XIII inhibitors indicated that this accelerated crosslinking was due to the catalytic activity of platelet factor XIII. Moreover, when washed platelets were aggregated by thrombin, there was evidence of platelet factor XIII-mediated crosslinking between platelet alpha 2AP and platelet fibrin(ogen). Specific inhibition (by a monoclonal antibody) of the alpha 2AP associated with washed platelet aggregates accelerated the fibrinolysis of the platelet aggregate. Thus in platelet-rich plasma clots, and in thrombin-induced platelet aggregates, platelet factor XIII actively formed alpha 2AP-fibrin crosslinks, which appeared to enhance the resistance of platelet-rich clots to fibrinolysis.

  13. Proliferative and antiproliferative effects of interferon-gamma and tumor necrosis factor-alpha on cell lines derived from cervical and ovarian malignancies

    International Nuclear Information System (INIS)

    Mutch, D.G.; Massad, L.S.; Kao, M.S.; Collins, J.L.


    Four human cell lines derived from cervical carcinomas (ME-180, SiHa, HT-3, and MS751) and three human cell lines derived from ovarian carcinomas (SK-OV-3, Caov-3, and NIH:OVCAR-3) were analyzed in vitro to determine the effect of recombinant interferon-gamma and recombinant human tumor necrosis factor-alpha on cell growth and survival. The effects of interferon-gamma, tumor necrosis factor-alpha, and both interferon-gamma and tumor necrosis factor-alpha on cell growth were measured after 24 and 72 hours of incubation by the incorporation of chromium 51. The results of this analysis showed that all seven cell lines were resistant to the antiproliferative action of tumor necrosis factor-alpha, that the growth of most cell lines was inhibited by interferon-gamma by 72 hours of incubation, and that after 72 hours of incubation all cell lines demonstrated a synergistic antiproliferative response to the combination of interferon-gamma and tumor necrosis factor-alpha. However, the effects of these cytokines on cell growth were found to differ among cell lines and varied with the concentration and the duration of incubation. The growth of one cell line (Caov-3) was stimulated by both tumor necrosis factor-alpha and interferon-gamma. These results suggest that the clinical effects of these cytokines on the growth of gynecologic cancers may be more complex than previously supposed

  14. Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma


    Cai, Shao-hang; Lu, Shi-xun; Liu, Li-li; Zhang, Chris Zhiyi; Yun, Jing-ping


    Background: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. Methods: A total of 615 HCC specimens were obtained to construct tissue microarrays and pe...

  15. Dynamic observation of transforming growth factor-alpha content in plasma of pediatric patients with peptic ulcer disease

    International Nuclear Information System (INIS)

    Zhou Mingxiong; Zhang Xinlu


    Objective: To elicit the relationship between transforming growth factor alpha (TGF-α) and the pathogenesis as well as healing process of peptic ulcer disease (PUD) in pediatric patients. Methods: The levels of TGF-α in plasma were measured by radioimmunoassay in 57 Children with PUD. Results: TGF-α levels of plasma at active stage of peptic ulcer were significantly lower than those at healing stage as well as in controls (P 0.05). Conclusion: There is an abnormal secretion of TGF-α in PUD patients. Changes of TGF-α release might play a role in the pathogenesis of PUD

  16. Evaluation of tumor necrosis factor alpha serum level in obese and lean women with clomiphene citrate resistant polycystic ovary disease


    Seyam, Emaduldin; Hasan, Momen; Khalifa, Eissa M.; Ramadan, Ahmad; Hefzy, Enas


    Objective: The aim of this work was to investigate the level of the serum level of tumor necrosis factor alpha (TNF-α) as an inflammatory biomarker in lean and obese women with polycystic ovary disease (PCOD), who are resistant to clomiphene citrate (CCR-PCOD). Patients and design: It is a case controlled study, where one hundred and fifty (n = 150) PCOD women (study group), who are resistant to clomiphene citrate (CCR-PCOD) had been recruited, in addition to one hundred (n = 100) women wi...

  17. Site selection factors for repositories of solid high-level and alpha-bearing wastes in geological formations

    International Nuclear Information System (INIS)


    The purpose of this report is to provide guidelines for the selection and evaluation of suitable areas and sites for the disposal of solid high-level and alpha-bearing wastes into geological formations. This report is also intended to provide summary information on many types of geological formations underlying the land masses that might be considered as well as guidance on the geological and hydrological factors that should be investigated to demonstrate the suitability of the formations. In addition, other factors that should be considered in selecting a site for a radioactive waste repository are discussed briefly. The information, as presented, was developed to the extent of current technology for application to the evaluation of deep (greater than about 300 metres below ground level) geological formations in the selection of suitable areas for the disposal of solid or solidified high-level and alpha-bearing wastes. The extreme complexity of many geological environments and of the rock features that govern the presence and circulation of groundwater does not make it feasible to derive strict criteria for the selection of a site for a radioactive waste repository in a geological formation. Each potential repository location must be evaluated according to its own unique geological and hydrological setting. Therefore, only general guidance is offered, and this is done through discussion of the many factors that need to be considered in order to obtain the necessary assurances that the radionuclides will be confined in the geological repository over the required period of time

  18. Site selection factors for repositories of solid high-level and alpha-bearing wastes in geological formations

    Energy Technology Data Exchange (ETDEWEB)


    The purpose of this report is to provide guidelines for the selection and evaluation of suitable areas and sites for the disposal of solid high-level and alpha-bearing wastes into geological formations. This report is also intended to provide summary information on many types of geological formations underlying the land masses that might be considered as well as guidance on the geological and hydrological factors that should be investigated to demonstrate the suitability of the formations. In addition, other factors that should be considered in selecting a site for a radioactive waste repository are discussed briefly. The information, as presented, was developed to the extent of current technology for application to the evaluation of deep (greater than about 300 meters below ground level) geological formations in the selection of suitable areas for the disposal of solid or solidified high-level and alpha-bearing wastes. The extreme complexity of many geological environments and of the rock features that govern the presence and circulation of groundwater does not make it feasible to derive strict criteria for the selection of a site for a radioactive waste repository in a geological formation. Each potential repository location must be evaluated according to its own unique geological and hydrological setting. Therefore, only general guidance is offered, and this is done through discussion of the many factors that need to be considered in order to obtain the necessary assurances that the radionuclides will be confined in the geological repository over the required period of time.

  19. [Effects of feixin decoction on the contents of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in the rat model of hypoxic pulmonary hypertension]. (United States)

    He, Hong-Jun; Dai, Ai-Guo


    To explore the effects of Feixin Decoction (FXD) on the hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in the rat model of hypoxic pulmonary hypertension (HPH), and to study its mechanisms for treating HPH. Forty healthy male SD rats were randomly divided into four groups, i. e., the normal control group, the HPH model group, the FXD group, and the Nifedipine group, 10 rats in each group. The HPH rat model was prepared using normal pressure intermittent hypoxia method. Except the normal control group, rats in the rest groups were fed in a self-made hypoxic plexiglass cabin, with the poor oxygen condition for 8 h daily for 14 successive days. Then the distilled water (at 30 mL/kg) was given by gastrogavage to rats in the normal control group and the HPH model group. FXD (at 28 g/kg) and Nifedipine (at 20 mg/kg) were given by gastrogavage to rats in the FXD group and the Nifedipine group respectively, once daily, for 14 successive days. Besides, hypoxia was continued for 14 days while medicating. The mean pulmonary artery pressure (mPAP) was detected on the second day after the last medication. The morphology of the pulmonary arteriole was detected. The ratio of pulmonary artery wall area and tube area (WA%) was determined. The protein and mRNA expressions of HIF-1alpha and VEGF were detected using immunohistochemistry and in situ hybridization technique. Compared with the normal control group, mPAP, WA%, and the protein and mRNA expressions of HIF-1alpha and VEGF significantly increased in the model group (P < 0.01, P < 0.05). Compared with the HPH model group, mPAP, WA%, and the protein and mRNA expressions of HIF-1alpha and VEGF significantly decreased in the FXD group (P < 0.01, P < 0.05). FXD down-regulated the expression of VEGF through decreasing the expression of HIF-1alpha. One of its mechanisms for treating HPH might be partially due to reversing the remodeling of pulmonary vascular smooth muscle.

  20. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy


    by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h......-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine...

  1. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, SB; Andersen, O; Pedersen, Steen Bønløkke


    Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients...... with lipodystrophy (LIPO) and those without (controls). LIPOX was estimated by indirect calorimetry during fasting and steady state of a hyperinsulinemic euglycemic clamp in 36 (18 LIPO and 18 controls) normoglycemic HIV-infected men on highly active antiretroviral therapy. In LIPO, TNF-alpha correlated with clamp...... were significant in controls. In all patients, TNF-alpha correlated with clamp FFA (r = 0.61, P

  2. Human keratinocytes are a source for tumor necrosis factor alpha: Evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light

    International Nuclear Information System (INIS)

    Koeck, A.S.; Schwarz, T.; Kirnbauer, R.; Urbanski, A.; Perry, P.; Ansel, J.C.; Luger, T.A.


    Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human keratinocytes (HNK) and human epidermoid carcinoma cell lines (KB, A431) were tested both in a TNF-alpha-specific ELISA and a bioassay. In supernatants of untreated epidermal cells, no or minimal TNF-alpha activity was found, while after stimulation with lipopolysaccharide (LPS) or ultraviolet (UV) light, significant amounts were detected. Western blot analysis using an antibody directed against human TNF-alpha revealed a molecular mass of 17 kD for keratinocyte-derived TNF-alpha. These biological and biochemical data were also confirmed by Northern blot analysis revealing mRNA specific for TNF-alpha in LPS- or ultraviolet B (UVB)-treated HNK and KB cells. In addition, increased TNF-alpha levels were detected in the serum obtained from human volunteers 12 and 24 h after a single total body UVB exposure, which caused a severe sunburn reaction. These findings indicate that keratinocytes upon stimulation are able to synthesize and release TNF-alpha, which may gain access to the circulation. Thus, TNF-alpha in concert with other epidermal cell-derived cytokines may mediate local and systemic inflammatory reactions during host defense against injurious events caused by microbial agents or UV irradiation

  3. Molecular cloning of rock bream (Oplegnathus fasciatus) tumor necrosis factor-alpha and its effect on the respiratory burst activity of phagocytes. (United States)

    Kim, Min Sun; Hwang, Yoon Jung; Yoon, Ki Joon; Zenke, Kosuke; Nam, Yoon Kwon; Kim, Sung Koo; Kim, Ki Hong


    Rock bream (Oplegnathus fasciatus) tumor necrosis factor-alpha (rbTNF-alpha) gene was cloned, recombinantly produced, and the effect of the recombinant rbTNF-alpha on the respiratory burst activity of rock bream phagocytes was analyzed. Structurally, genomic DNA of rbTNF-alpha was comprised with four exons and three introns, and deduced amino acid sequence of its cDNA possessed the TNF family signature, a transmembrane domain, a protease cleavage site, and two cysteine residues, which are the typical characteristics of TNF-alpha gene in mammals and fish. The chemiluminescent (CL) response of rock bream phagocytes was significantly enhanced by pre-incubation with recombinant rbTNF-alpha, when opsonized zymosan was used as a stimulant of the respiratory burst. However, CL enhancing effect of the recombinant rbTNF-alpha was very weak when the respiratory burst activity of phagocytes was triggered with phorbol-12-myristate-13-acetate (PMA) instead of zymosan. These results suggest that rock bream TNF-alpha might have an ability to prime the respiratory burst activity of phagocytes against receptor-mediated phagocytosis inducing stimulants, such as zymosan, but have little ability against stimulants not accompanying receptor-mediated phagocytosis.

  4. Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1alpha through interaction with PSMA7, a component of the proteasome

    Energy Technology Data Exchange (ETDEWEB)

    Tandle, Anita T. [Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 (United States); Calvani, Maura; Uranchimeg, Badarch [DTP-Tumor Hypoxia Laboratory, SAIC Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702 (United States); Zahavi, David [Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 (United States); Melillo, Giovanni [DTP-Tumor Hypoxia Laboratory, SAIC Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702 (United States); Libutti, Steven K., E-mail: [Department of Surgery, Montefiore-Einstein Center for Cancer Care, Albert Einstein College of Medicine, Greene Medical Arts Pavilion, 4th Floor 3400, Bainbridge Avenue, Bronx, New York 10467 (United States)


    The majority of human tumors are angiogenesis dependent. Understanding the specific mechanisms that contribute to angiogenesis may offer the best approach to develop therapies to inhibit angiogenesis in cancer. Endothelial monocyte activating polypeptide-II (EMAP-II) is an anti-angiogenic cytokine with potent effects on endothelial cells (ECs). It inhibits EC proliferation and cord formation, and it suppresses primary and metastatic tumor growth in-vivo. However, very little is known about the molecular mechanisms behind the anti-angiogenic activity of EMAP-II. In the present study, we explored the molecular mechanism behind the anti-angiogenic activity exerted by this protein on ECs. Our results demonstrate that EMAP-II binds to the cell surface {alpha}5{beta}1 integrin receptor. The cell surface binding of EMAP-II results in its internalization into the cytoplasmic compartment where it interacts with its cytoplasmic partner PSMA7, a component of the proteasome degradation pathway. This interaction increases hypoxia-inducible factor 1-alpha (HIF-1{alpha}) degradation under hypoxic conditions. The degradation results in the inhibition of HIF-1{alpha} mediated transcriptional activity as well as HIF-1{alpha} mediated angiogenic sprouting of ECs. HIF-1{alpha} plays a critical role in angiogenesis by activating a variety of angiogenic growth factors. Our results suggest that one of the major anti-angiogenic functions of EMAP-II is exerted through its inhibition of the HIF-1{alpha} activities.

  5. Tumor necrosis factor alpha promotes the expression of immunosuppressive proteins and enhances the cell growth in a human bone marrow-derived stem cell culture

    Energy Technology Data Exchange (ETDEWEB)

    Miettinen, Johanna A., E-mail: [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Pietilae, Mika [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Salonen, Riikka J. [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Ohlmeier, Steffen [Proteomics Core Facility, Biocenter Oulu, Department of Biochemistry, University of Oulu, P.O. Box 3000, FIN-90014 Oulu (Finland); Ylitalo, Kari; Huikuri, Heikki V. [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Lehenkari, Petri [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland)


    Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-{alpha}) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-{alpha} exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-{alpha} exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-{alpha} exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-{alpha} exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-{alpha} exposure, which might influence MSC differentiation stage and capacity.

  6. Tumour necrosis factor-alpha (TNF-alpha) transcription and translation in the CD4+ T cell-transplanted scid mouse model of colitis

    DEFF Research Database (Denmark)

    Williams, A M; Whiting, C V; Bonhagen, K


    The adoptive transfer of activated CD4+ alpha/beta T cell blasts from the spleens of immunocompetent C.B-17+/+ or BALB/cdm2 mice into C.B-17scid/scid (scid) mice induces a colitis in the scid recipient within 8 weeks, which progresses to severe disease within 16 weeks. T cells isolated from......-labelled riboprobes were used. The prominent myeloid cell infiltrate in diseased tissues comprised F4/80+, Mac-l+ macrophages, neutrophils, dendritic cells and activated macrophages. TNF-alpha transcription and translation were associated with activated macrophages in the lamina propria. Activated macrophages...

  7. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. (United States)

    Rapisarda, Annamaria; Zalek, Jessica; Hollingshead, Melinda; Braunschweig, Till; Uranchimeg, Badarch; Bonomi, Carrie A; Borgel, Suzanne D; Carter, John P; Hewitt, Stephen M; Shoemaker, Robert H; Melillo, Giovanni


    We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1alpha protein accumulation by a DNA damage-independent mechanism. Here, we report that daily administration of topotecan inhibits HIF-1alpha protein expression in U251-HRE glioblastoma xenografts. Concomitant with HIF-1alpha inhibition, topotecan caused a significant tumor growth inhibition associated with a marked decrease of angiogenesis and expression of HIF-1 target genes in tumor tissue. These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients.

  8. General applicability of chicken egg yolk antibodies: the performance of IgY immunoglobulins raised against the hypoxia-inducible factor 1alpha


    Camenisch, G; Tini, M; Chilov, D; Kvietikova, I; Srinivas, V; Caro, J; Spielmann, P; Wenger, R H; Gassmann, M


    Avian embryos and neonates acquire passive immunity by transferring maternal immunoglobulins from serum to egg yolk. Despite being a convenient source of antibodies, egg yolk immunoglobulins (IgY) from immunized hens have so far received scant attention in research. Here we report the generation and rapid isolation of IgY from the egg yolk of hens immunized against the alpha subunit of the human hypoxia-inducible factor 1 (HIF-1alpha). Anti-HIF-1alpha IgY antibodies were affinity purified and...

  9. CENTRIFUGE END CAP (United States)

    Beams, J.W.; Snoddy, L.B.


    An end cap for ultra-gas centrifuges is designed to impart or remove angular momentum to or from the gas and to bring the entering gas to the temperature of the gas inside the centrifuge. The end cap is provided with slots or fins for adjusting the temperature and the angular momentum of the entering gas to the temperature and momentum of the gas in the centrifuge and is constructed to introduce both the inner and the peripheral stream into the centrifuge.

  10. Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and TNF-alpha. (United States)

    Wu, Shan; Ren, Jun


    Diabetes mellitus leads to thiamine deficiency and multiple organ damage including diabetic neuropathy. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cerebral oxidative stress. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg, i.p.). Fourteen days later, control and diabetic (fasting blood glucose >13.9 mM) mice received benfotiamine (100 mg/kg/day, i.p.) for 14 days. Oxidative stress and protein damage were evaluated by glutathione/glutathione disulfide (GSH/GSSG) assay and protein carbonyl formation, respectively. Pro-oxidative or pro-inflammatory factors including advanced glycation end-product (AGE), tissue factor and tumor necrosis factor-alpha (TNF-alpha) were evaluated by immunoblot analysis. Four weeks STZ treatment led to hyperglycemia, enhanced cerebral oxidative stress (reduced GSH/GSSG ratio), elevated TNF-alpha and AGE levels without changes in protein carbonyl or tissue factor. Benfotiamine alleviated diabetes-induced cerebral oxidative stress without affecting levels of AGE, protein carbonyl, tissue factor and TNF-alpha. Collectively, our results indicated benfotiamine may antagonize diabetes-induced cerebral oxidative stress through a mechanism unrelated to AGE, tissue factor and TNF-alpha.

  11. Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Hui-Hsuan [School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Tsai, Chia-Wen [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Chou, Fen-Pi [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Wang, Chau-Jong [Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Hsuan, Shu-Wen [Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, No.89, Wen Hwa 1st St., Rende Shiang, Tainan County 717, Taiwan (China); Wang, Cheng-Kun [E-Chyun Dermatology Clinic, No.70, Sec. 3, Jhonghua E. Rd., East District, Tainan, Taiwan (China); Chen, Jing-Hsien [Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, No.89, Wen Hwa 1st St., Rende Shiang, Tainan County 717, Taiwan (China)


    Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to inhibit non-small cell lung cancer (NSCLC) A549 cell migration and invasion via down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Here we demonstrated that Andro inhibited the expression of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) in A549 cells. HIF-1{alpha} plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1{alpha} was correlated with a rapid ubiquitin-dependent degradation of HIF-1{alpha}, and was accompanied by increased expressions of hydroxyl-HIF-1{alpha} and prolyl hydroxylase (PHD2), and a later decrease of vascular endothelial growth factor (VEGF) upon the treatment of Andro. The Andro-inhibited VEGF expression appeared to be a consequence of HIF-1{alpha} inactivation, because its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGF{beta}1/PHD2/HIF-1{alpha} pathway, as demonstrated by the transfection of TGF{beta}1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1{alpha} transduced VEGF expression in A549 cells and other NSCLC cell lines. In conclusion, these results highlighted the potential effects of Andro, which may be developed as a chemotherapeutic or an anti-angiogenesis agent for NSCLC in the future.

  12. Expression and function of hypoxia inducible factor-1 alpha in human melanoma under non-hypoxic conditions

    Directory of Open Access Journals (Sweden)

    Joshi Sandeep S


    Full Text Available Abstract Background Hypoxia inducible factor-1 alpha (HIF-1α protein is rapidly degraded under normoxic conditions. When oxygen tensions fall HIF-1α protein stabilizes and transactivates genes involved in adaptation to hypoxic conditions. We have examined the normoxic expression of HIF-1α RNA and protein in normal human melanocytes and a series of human melanoma cell lines isolated from radial growth phase (RGP, vertical growth phase (VGP and metastatic (MET melanomas. Results HIF-1α mRNA and protein was increased in RGP vs melanocytes, VGP vs RGP and MET vs VGP melanoma cell lines. We also detected expression of a HIF-1α mRNA splice variant that lacks part of the oxygen-dependent regulation domain in WM1366 and WM9 melanoma cells. Over-expression of HIF-1α and its splice variant in the RGP cell line SbCl2 resulted in a small increase in soft agar colony formation and a large increase in matrigel invasion relative to control transfected cells. Knockdown of HIF-1α expression by siRNA in the MET WM9 melanoma cell line resulted in a large decrease in both soft agar colony formation and matrigel invasion relative to cells treated with non-specific siRNA. There is a high level of ERK1/2 phosphorylation in WM9 cells, indicating an activated Ras-Raf-MEK-ERK1/2 MAPK pathway. Treatment of WM9 cells with 30 μM U0126 MEK inhibitor, decreased ERK1/2 phosphorylation and resulted in a decrease in HIF-1α expression. However, a 24 h treatment with 10 μM U0126 totally eliminated Erk1/2 phosphorylation, but did not change HIF-1alpha levels. Furthermore, siRNA knockdown of MEK siRNA did not change HIF-1alpha levels. Conclusion We speculate that metabolic products of U0126 decrease HIF-1alpha expression through "off target" effects. Overall our data suggest that increased HIF-1α expression under normoxic conditions contributes to some of the malignant phenotypes exhibited by human melanoma cells. The expanded role of HIF-1α in melanoma biology increases

  13. Affinity purification of human granulocyte macrophage colony-stimulating factor receptor alpha-chain. Demonstration of binding by photoaffinity labeling

    International Nuclear Information System (INIS)

    Chiba, S.; Shibuya, K.; Miyazono, K.; Tojo, A.; Oka, Y.; Miyagawa, K.; Takaku, F.


    The human granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha-chain, a low affinity component of the receptor, was solubilized and affinity-purified from human placenta using biotinylated GM-CSF. Scatchard analysis of 125 I-GM-CSF binding to the placental membrane extract disclosed that the GM-CSF receptor had a dissociation constant (Kd) of 0.5-0.8 nM, corresponding to the Kd value of the GM-CSF receptor alpha-chain on the intact placental membrane. Affinity labeling of the solubilized protein using a photoreactive cross-linking agent, N-hydroxysuccinimidyl-4-azidobenzoate (HSAB), demonstrated a single specific band of 70-95 kDa representing a ligand-receptor complex. Approximately 2 g of the placental membrane extract was subjected to a biotinylated GM-CSF-fixed streptavidin-agarose column, resulting in a single major band at 70 kDa on a silver-stained sodium dodecyl sulfate gel. The radioiodination for the purified material disclosed that the purified protein had an approximate molecular mass of 70 kDa and a pI of 6.6. Binding activity of the purified material was demonstrated by photoaffinity labeling using HSAB- 125 I-GM-CSF, producing a similar specific band at 70-95 kDa as was demonstrated for the crude protein

  14. The effect of combining recombinant human tumor necrosis factor-alpha with local radiation on tumor control probability of a human glioblastoma multiforme xenograft in nude mice

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Peigen; Allam, Ayman; Perez, Luis A; Taghian, Alphonse; Freeman, Jill; Suit, Herman D


    Purpose: To evaluate the antitumor activity of recombinant human tumor necrosis factor-alpha (rHuTNF-{alpha}) on a human glioblastoma multiforme (U87) xenograft in nude mice, and to study the effect of combining rHuTNF-{alpha} with local radiation on the tumor control probability of this tumor model. Methods and Materials: U87 xenograft was transplanted SC into the right hindleg of NCr/Sed nude mice (7-8 weeks old, male). When tumors reached a volume of about 110 mm{sup 3}, mice were randomly assigned to treatment: rHuTNF-{alpha} alone compared with normal saline control; or local radiation plus rHuTNF-{alpha} vs. local radiation plus normal saline. Parameters of growth delay, volume doubling time, percentage of necrosis, and cell loss factor were used to assess the antitumor effects of rHuTNF-{alpha} on this tumor. The TCD{sub 50} (tumor control dose 50%) was used as an endpoint to determine the effect of combining rHuTNF-{alpha} with local radiation. Results: Tumor growth in mice treated with a dose of 150 {mu}g/kg body weight rHuTNF-{alpha}, IP injection daily for 7 consecutive days, was delayed about 8 days compared to that in controls. Tumors in the treatment group had a significantly longer volume doubling time, and were smaller in volume and more necrotic than matched tumors in control group. rHuTNF-{alpha} also induced a 2.3 times increase of cell loss factor. The administration of the above-mentioned dose of rHuTNF-{alpha} starting 24 h after single doses of localized irradiation under hypoxic condition, resulted in a significant reduction in TCD{sub 50} from the control value of 60.9 Gy to 50.5 Gy (p < 0.01). Conclusion: rHuTNF-{alpha} exhibits an antitumor effect against U87 xenograft in nude mice, as evidenced by an increased delay in tumor growth as well as cell loss factor. Also, there was an augmentation of tumor curability when given in combination with radiotherapy, resulting in a significantly lower TCD{sub 50} value in the treatment vs. the

  15. Functional defect of truncated hepatocyte nuclear factor-1{alpha} (G554fsX556) associated with maturity-onset diabetes of the young

    Energy Technology Data Exchange (ETDEWEB)

    Kooptiwut, Suwattanee, E-mail: [Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Sujjitjoon, Jatuporn [Department of Immunology and Immunology Graduate Program, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Plengvidhya, Nattachet [Department of Immunology and Immunology Graduate Program, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Boonyasrisawat, Watip; Chongjaroen, Nalinee; Jungtrakoon, Prapapron [Department of Immunology and Immunology Graduate Program, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Semprasert, Namoiy [Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Furuta, Hiroto; Nanjo, Kishio [The First Department, Wakayama Medical University (Japan); Banchuin, Napatawn [Department of Immunology and Immunology Graduate Program, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Yenchitsomanus, Pa-thai [Division of Medical Molecular Biology, Medicine Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok (Thailand)


    A novel frameshift mutation attributable to 14-nucleotide insertion in hepatocyte nuclear factor-1{alpha} (HNF-1{alpha}) encoding a truncated HNF-1{alpha} (G554fsX556) with 76-amino acid deletion at its carboxyl terminus was identified in a Thai family with maturity-onset diabetes of the young (MODY). The wild-type and mutant HNF-1{alpha} proteins were expressed by in vitro transcription and translation (TNT) assay and by transfection in HeLa cells. The wild-type and mutant HNF-1{alpha} could similarly bind to human glucose-transporter 2 (GLUT2) promoter examined by electrophoretic mobility shift assay (EMSA). However, the transactivation activities of mutant HNF-1{alpha} on human GLUT2 and rat L-type pyruvate kinase (L-PK) promoters in HeLa cells determined by luciferase reporter assay were reduced to approximately 55-60% of the wild-type protein. These results suggested that the functional defect of novel truncated HNF-1{alpha} (G554fsX556) on the transactivation of its target-gene promoters would account for the {beta}-cell dysfunction associated with the pathogenesis of MODY.

  16. Tumor necrosis factor-alpha activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters. (United States)

    Amaral, Maria E; Barbuio, Raquel; Milanski, Marciane; Romanatto, Talita; Barbosa, Helena C; Nadruz, Wilson; Bertolo, Manoel B; Boschero, Antonio C; Saad, Mario J A; Franchini, Kleber G; Velloso, Licio A


    Tumor necrosis factor-alpha (TNF-alpha) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF-alpha in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF-alpha upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF-alpha activates canonical pro-inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin-1beta, interleukin-6, interleukin-10 and suppressor of cytokine signalling-3, respectively. In addition, TNF-alpha induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-alpha may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.

  17. Effects of anti-tumor necrosis factor-alpha and anti-intercellular adhesion molecule-1 antibodies on ischemia/reperfusion lung injury. (United States)

    Chiang, Chi-Huei


    Inhibition of neutrophil activation and adherence to endothelium by antibodies to tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecules (ICAM-1), respectively, might attenuate ischemia-reperfusion injury (I/R). I/R was conducted in an isolated rat lung model. Anti-TNF-alpha antibody and/or anti-ICAM-1 antibody were added before ischemia or after reperfusion. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficients (Kfc), and pathologic changes were assessed to evaluate the severity of I/R. The LWG, Kfc, pathological changes and lung injury score of treatment groups with anti-TNF-alpha antibody treatment, either pre-ischemia or during reperfusion, were less than those observed in control groups. Similar findings were found in group treated with anti-ICAM-1 antibody or combination therapy during reperfusion. In contrast, pre-I/R treatment with anti-ICAM-1 antibody induced severe lung edema and failure to complete the experimental procedure. No additional therapeutic effect was found in combination therapy. We conclude that TNF-alpha and ICAM-1 play important roles in I/R. Anti-TNF-alpha antibody has therapeutic and preventive effects on I/R. However, combined therapy with anti-TNF-alpha antibody and anti-ICAM-1 antibody may have no additive effect and need further investigation.

  18. CAPS Simulation Environment Development (United States)

    Murphy, Douglas G.; Hoffman, James A.


    The final design for an effective Comet/Asteroid Protection System (CAPS) will likely come after a number of competing designs have been simulated and evaluated. Because of the large number of design parameters involved in a system capable of detecting an object, accurately determining its orbit, and diverting the impact threat, a comprehensive simulation environment will be an extremely valuable tool for the CAPS designers. A successful simulation/design tool will aid the user in identifying the critical parameters in the system and eventually allow for automatic optimization of the design once the relationships of the key parameters are understood. A CAPS configuration will consist of space-based detectors whose purpose is to scan the celestial sphere in search of objects likely to make a close approach to Earth and to determine with the greatest possible accuracy the orbits of those objects. Other components of a CAPS configuration may include systems for modifying the orbits of approaching objects, either for the purpose of preventing a collision or for positioning the object into an orbit where it can be studied or used as a mineral resource. The Synergistic Engineering Environment (SEE) is a space-systems design, evaluation, and visualization software tool being leveraged to simulate these aspects of the CAPS study. The long-term goal of the SEE is to provide capabilities to allow the user to build and compare various CAPS designs by running end-to-end simulations that encompass the scanning phase, the orbit determination phase, and the orbit modification phase of a given scenario. Herein, a brief description of the expected simulation phases is provided, the current status and available features of the SEE software system is reported, and examples are shown of how the system is used to build and evaluate a CAPS detection design. Conclusions and the roadmap for future development of the SEE are also presented.

  19. Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha

    DEFF Research Database (Denmark)

    Brock, C; Brock, B; Aziz, Q


    -VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which...

  20. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice.

    Directory of Open Access Journals (Sweden)

    Mathieu Darsigny

    Full Text Available BACKGROUND: Hnf4alpha, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4alpha in the maintenance of gut inflammatory homeostasis in mice. METHODOLOGY/PRINCIPAL FINDINGS: We show here that specific epithelial deletion of Hnf4alpha in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4alpha null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4alpha mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4alpha gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease. CONCLUSION: Our results highlight the critical role of Hnf4alpha to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4alpha in the regulation of claudin-15 expression. This establishes Hnf4alpha as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.

  1. Evaluation of Serum Levels of Pregnancy Associated Plasma Protein-A, Tumor Necrosis Factor-alpha and Highly Sensitive C-Reactive Protein in Diabetic Children

    International Nuclear Information System (INIS)

    Abdel-Messeih, PH.L.; El-safie, A.I.; Said, A.I.


    Recent evidence favours the primary role of cellular auto immunity and its humoral mediators in the pathogenesis and follow up of children with type 1 diabetes mellitus (type 1 DM). The present study is carried out to investigate serum levels of pregnancy associated plasma protein-A (PAPP-A), tumor necrosis factor-alpha (TNF-alpha ) and highly sensitive C-reactive protein (hs-CRP) in children with type 1 DM. Potential role of body mass index (BMI) was evaluated. Circulating levels of TNF-alpha, PAPP-A and hs-CRP are significantly increased in children with type 1 DM as compared with healthy subjects suggesting activation of inflammatory immune response system. A significant negative correlation was obtained between TNF-alpha and BMI in diabetic patients. This is highly suggestive of the availability of these non invasive indices to help further examining type 1 DM pathophysiology and monitoring pharmacological interventions to interfere with disease development and progression.

  2. Tumor necrosis factor-alpha inhibits differentiation of myogenic cells in human urethral rhabdosphincter. (United States)

    Shinohara, Mayuka; Sumino, Yasuhiro; Sato, Fuminori; Kiyono, Tohru; Hashimoto, Naohiro; Mimata, Hiromitsu


    To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence. © 2017 The Japanese Urological Association.

  3. Cold atmospheric plasma (CAP changes gene expression of key molecules of the wound healing machinery and improves wound healing in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Stephanie Arndt

    Full Text Available Cold atmospheric plasma (CAP has the potential to interact with tissue or cells leading to fast, painless and efficient disinfection and furthermore has positive effects on wound healing and tissue regeneration. For clinical implementation it is necessary to examine how CAP improves wound healing and which molecular changes occur after the CAP treatment. In the present study we used the second generation MicroPlaSter ß® in analogy to the current clinical standard (2 min treatment time in order to determine molecular changes induced by CAP using in vitro cell culture studies with human fibroblasts and an in vivo mouse skin wound healing model. Our in vitro analysis revealed that the CAP treatment induces the expression of important key genes crucial for the wound healing response like IL-6, IL-8, MCP-1, TGF-ß1, TGF-ß2, and promotes the production of collagen type I and alpha-SMA. Scratch wound healing assays showed improved cell migration, whereas cell proliferation analyzed by XTT method, and the apoptotic machinery analyzed by protein array technology, was not altered by CAP in dermal fibroblasts. An in vivo wound healing model confirmed that the CAP treatment affects above mentioned genes involved in wound healing, tissue injury and repair. Additionally, we observed that the CAP treatment improves wound healing in mice, no relevant side effects were detected. We suggest that improved wound healing might be due to the activation of a specified panel of cytokines and growth factors by CAP. In summary, our in vitro human and in vivo animal data suggest that the 2 min treatment with the MicroPlaSter ß® is an effective technique for activating wound healing relevant molecules in dermal fibroblasts leading to improved wound healing, whereas the mechanisms which contribute to these observed effects have to be further investigated.

  4. Investigation of Epidermal Growth Factor, Tumor Necrosis Factor-alpha and Thioredoxin System in Rats Exposed to Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Erol-Demirbilek Melike


    Full Text Available Background: Thioredoxin reductase (TrxR, epidermal growth factor (EGF and tumor necrosis factor-α (TNF-α have neuroprotective/neurotoxic effects in cerebral ischemia. We aimed to investigate the TrxR activity, EGF and TNF-α levels in cerebral ischemic, sham-operated and non-ischemic rat brains.

  5. Characterization of a canine tetranucleotide microsatellite marker located in the first intron of the tumor necrosis factor alpha gene. (United States)

    Watanabe, Masashi; Tanaka, Kazuaki; Takizawa, Tatsuya; Segawa, Kazuhito; Neo, Sakurako; Tsuchiya, Ryo; Murata, Michiko; Murakami, Masaru; Hisasue, Masaharu


    A polymorphic tetranucleotide (GAAT)n microsatellite in the first intron of the canine tumor necrosis factor alpha (TNFA) gene was characterized in this study; 139 dogs were analyzed: 22 Beagles, 26 Chihuahuas, 20 Miniature Dachshunds, 24 Miniature Poodles, 22 Pembroke Welsh Corgis and 25 Shiba Inus. We detected the presence of the 4 alleles (GAAT)5, (GAAT)6, (GAAT)7 and (GAAT)8, including 9 of the 10 expected genotypes. The expected heterozygosity (He) and the polymorphic information content (PIC) value of this microsatellite locus varied from 0.389 to 0.749 and from 0.333 to 0.682, respectively, among the 6 breeds. The allelic frequency differed greatly among breeds, but this microsatellite marker was highly polymorphic and could be a useful marker for the canine TNFA gene.

  6. Generalised pustular psoriasis induced by cyclosporin a withdrawal responding to the tumour necrosis factor alpha inhibitor etanercept. (United States)

    Kamarashev, J; Lor, P; Forster, A; Heinzerling, L; Burg, G; Nestle, F O


    We report a 50-year-old male patient with a 15-year history of psoriasis including mutilating psoriatic arthritis, in whom the withdrawal of cyclosporin A induced a generalised pustular exacerbation and a aggravation of the joint condition. Two weekly injections of 25 mg of the tumour necrosis factor alpha inhibitor etanercept led to a rapid improvement of his psoriatic arthritis, as well as regression of the pustular eruption, while residual erythema was still present. The clinical response was reflected by an increase in circulating interleukin (IL) 10 and a decrease in IL-6 and IL-8 serum levels during treatment. We conclude that etanercept may be a safe and effective therapy not only in severe psoriatic arthritis, but also in cases of pustular rebound after withdrawal of immunosuppressive agents. Copyright 2002 S. Karger AG, Basel

  7. Characterization of cap binding proteins associated with the nucleus

    International Nuclear Information System (INIS)

    Patzelt, E.


    Eucaryotic mRNAs a carry 7-methylguanosine triphosphate residue (called cap structure) at their 5' terminus. The cap plays an important role in RNA recognition. Cap binding proteins (CBP) of HeLa cells were identified by photoaffinity labelling using the cap analogue γ-( 32 P)-(4-(benzoyl-phenyl)methylamido)-7-methylguanosine-5'-triphosphate (BP-m 7 GTP). Photoreaction of this cap analogue with HeLa cell initiation factors resulted in specific labelling of two polypeptides of Msub(r) 37000 and 26000. The latter was also labelled in crude initiation factors prepared from reticulocytes and is identical to the cap binding protein CBP I previously identified. These cap binding proteins were also affinity labelled in poliovirus infected cell extracts. Photoaffinity reaction with BP-m 7 GTP of whole HeLa cell homogenate showed three additional polypeptides with Msub(r) 120000, 89000 and 80000. These cap binding proteins were found to be associated with the nucleus and are therefore referred to as nuclear cap binding proteins, i.e. NCBP 1, NCBP 2 and NCBP 3. They were also present in splicing extracts. Photoaffinity labelling in these nuclear extracts was differentially inhibited by various cap analogues and capped mRNAs. Affinity chromatography on immobilized globin mRNA led to a partial separation of the three nuclear cap binding proteins. Chromatography on m 7 GTP-Sepharose resulted in a specific binding of NCBP 3. The different behaviour of the cap binding proteins suggests that they are functionally distinct and that they might be involved in different processes requiring cap recognition. (Author)

  8. MicroRNA-195 induced apoptosis in hypoxic chondrocytes by targeting hypoxia-inducible factor 1 alpha. (United States)

    Bai, R; Zhao, A-Q; Zhao, Z-Q; Liu, W-L; Jian, D-M


    The chondrocytes, the resident cells of cartilage, are maintained and take effects in the whole life upon chronic hypoxic exposure, which hypoxia-inducible factor 1 alpha (HIF-1α) play pivotal roles in response to. Dysregulation of some microRNA (miRNAs) have also been identified to be involved in hypoxia-related physiologic and pathophysiologic responses in some tissues or cell lines. However, the mechanism of miRNAs reponse to hypoxia remain largely unknown in chondrocytes, including the microRNA-195 (miR-195). AIM To investigate the effects of microRNAs (miRNAs) and hypoxia-inducible factor 1 alpha (HIF-1α) on chondrocytes in physiologic environment. We compared the expression of miR-195 and HIF-1α mRNA on hypoxia with that on normoxia in ATDC 5 cells by qRT-PCR. Further experiments was performed to confirmed the relationships of miR-195 and HIF-1α by bioinformatics analysis and dual reporter gene assay. we also assessed the effect of miR-195 on apoptosis in hypoxic ATDC 5 cells by transfect with miR-195 mimics. It was found the downregulated miR-195 and upregulated HIF-1α were present in hypoxic ATDC 5 cells. miR-195 negatively regulated HIF-1α by targeting its 3'-untranslated region. Moreover, the founding indicated miR-195 greatly increased apoptosis and downregulated HIF-1α mRNA occurred simultaneously in hypoxic chondrocytes. We concluded that miR-195 induced apoptosis in hypoxic chondrocytes by directly targeting HIF-1α.

  9. Specific inhibition of hypoxia-inducible factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids. (United States)

    Hasebe, Yuki; Egawa, Kiyoshi; Yamazaki, Yoko; Kunimoto, Setsuko; Hirai, Yasuaki; Ida, Yoshiteru; Nose, Kiyoshi


    Screening using a reporter under the control of the hypoxia-response element (HRE) identified several flavonoids and homoisoflavonoids that inhibit the activation of HRE under hypoxic conditions. Among various compounds, isorhamnetin, luteolin, quercetin, and methyl ophiopogonanone B (MOB) were effective at 3 to 9 microg/ml in inhibiting the reporter activity. The expression of vascular endothelial growth factor (VEGF) mRNA during hypoxia was also inhibited by MOB in HepG2 cells, but the effective doses were 10 to 20 microg/ml. MOB caused destabilization of hypoxia-inducible factor (HIF)-1alpha, as revealed by Western blotting, that was dependent on proteasome activity and the tumor suppressor, p53. The tubular formation and migration of human umbilical vein endothelial cells was also inhibited by MOB. MOB is expected to act as an inhibitor of angiogenesis.

  10. Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry. (United States)

    Rodríguez-Pintó, Ignasi; Moitinho, Marta; Santacreu, Irene; Shoenfeld, Yehuda; Erkan, Doruk; Espinosa, Gerard; Cervera, Ricard


    To analyze the clinical and immunologic manifestations of patients with catastrophic antiphospholipid syndrome (CAPS) from the "CAPS Registry". The demographic, clinical and serological features of 500 patients included in the website-based "CAPS Registry" were analyzed. Frequency distribution and measures of central tendency were used to describe the cohort. Comparison between groups regarding qualitative variables was undertaken by chi-square or Fisher exact test while T-test for independent variables was used to compare groups regarding continuous variables. 500 patients (female: 343 [69%]; mean age 38±17) accounting for 522 episodes of CAPS were included in the analysis. Forty percent of patients had an associated autoimmune disease, mainly systemic lupus erythematosus (SLE) (75%). The majority of CAPS episodes were triggered by a precipitating factor (65%), mostly infections (49%). Clinically, CAPS was characterized by several organ involvement affecting kidneys (73%), lungs (60%), brain (56%), heart (50%), and skin (47%). Lupus anticoagulant, IgG anticardiolipin and IgG anti-β2-glycprotein antibodies were the most often implicated antiphospholipid antibodies (83%, 81% and 78% respectively). Mortality accounted for 37% of episodes of CAPS. Several clinical differences could be observed based on the age of presentation and its association to SLE. Those cases triggered by a malignancy tended to occur in older patients, while CAPS episodes in young patients were associated with an infectious trigger and peripheral vessels involvement. Additionally, CAPS associated with SLE were more likely to have severe cardiac and brain involvement leading to a higher mortality (48%). Although the presentation of CAPS is characterized by multiorgan thrombosis and failure, clinical differences among patients exist based on age and underlying chronic diseases, e.g. malignancy and SLE. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. NESHAP Dose-Release Factor Isopleths for Five Source-to-Receptor Distances from the Center of Site and H-Area for all Compass Sectors at SRS using CAP88-PC Version 4.0

    Energy Technology Data Exchange (ETDEWEB)

    Trimor, P. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)


    The Environmental Protection Agency (EPA) requires the use of the computer model CAP88-PC to estimate the total effective doses (TED) for demonstrating compliance with 40 CFR 61, Subpart H (EPA 2006), the National Emission Standards for Hazardous Air Pollutants (NESHAP) regulations. As such, CAP88 Version 4.0 was used to calculate the receptor dose due to routine atmospheric releases at the Savannah River Site (SRS). For estimation, NESHAP dose-release factors (DRFs) have been supplied to Environmental Compliance and Area Closure Projects (EC&ACP) for many years. DRFs represent the dose to a maximum receptor exposed to 1 Ci of a specified radionuclide being released into the atmosphere. They are periodically updated to include changes in the CAP88 version, input parameter values, site meteorology, and location of the maximally exposed individual (MEI). This report presents the DRFs of tritium oxide released at two onsite locations, center-of-site (COS) and H-Area, at 0 ft. elevation to maximally exposed individuals (MEIs) located 1000, 3000, 6000, 9000, and 12000 meters from the release areas for 16 compass sectors. The analysis makes use of area-specific meteorological data (Viner 2014).

  12. Interaction of a gibberellin-induced factor with the upstream region of an alpha-amylase gene in rice aleurone tissue.


    Ou-Lee, T M; Turgeon, R; Wu, R


    The interaction between the DNA sequences of an alpha-amylase (EC gene and a tissue-specific factor induced in rice (Oryza sativa L.) aleurone tissue by gibberellin was studied. DNA mobility-shift during electrophoresis indicated that a 500-base-pair sequence (HS500) of a rice alpha-amylase genomic clone (OSamy-a) specifically interacted with a factor from gibberellin-induced rice aleurone tissue. The amount of complex formed between the HS500 DNA fragment and the gibberellin-induced...

  13. Epidemiology, risk factors and prognosis of Interferon alpha induced thyroid disorders. A Prospective Clinical Study

    Directory of Open Access Journals (Sweden)

    Łukasz Obołończyk


    In conclusion: Thyroid disorders are common during IFN-α therapy. Previous epidemiological data seem to be underestimated. Important risk factors for IITD development are: female sex, elevated serum TSH concentration (≥2.5 μU/mL, positive TPO-Ab and increased blood velocity in thyroid arteries.

  14. The short-term effects of treatment of chronic periodontitis on circulating levels of endotoxin, C-reactive protein, tumor necrosis factor-alpha, and interleukin-6. (United States)

    Ide, Mark; Jagdev, Daljit; Coward, Paula Y; Crook, Martin; Barclay, G Robin; Wilson, Ron F


    The acute-phase response involves molecules including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). This study aimed to determine whether subgingival scaling resulted in rapid changes in plasma concentrations of these molecules. Twenty-three non-smoking adults with chronic periodontitis received subgingival scaling for 60 minutes. Venous blood samples were taken at 0, 15, 30, 60, and 120 minutes. TNF-alpha and IL-6 were assayed from all samples and CRP from the baseline and final samples. Lipopolysaccharide (LPS) was assayed at 0, 15, and 30 minutes using limulus lysate assay (LAL) and EndoCAb Ig assays. LPS assays were suggestive of a transient low-grade bacteremia, but changes in LPS approaching significance (P=0.061) were seen with LAL only. There was a significant increase in circulating TNF-alpha (P=0.0387) and IL-6 (Pperiodontal breakdown (P=0.001). There was also a significant correlation between levels of IL-6 and TNF-alpha (Pperiodontitis patients undergoing an episode of subgingival scaling show a significant elevation in circulating TNF-alpha and IL-6. This may account for anecdotal reports of pyrexia following treatment and may be significant in terms of the relationship between periodontal disease, bacteremia, and cardiovascular disease.

  15. Effects of tumor necrosis factor-alpha and interferon-gamma on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells. (United States)

    Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G


    We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs.

  16. Localization of integrin alpha(v)beta3 and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in cutaneous and oral melanomas of dog. (United States)

    Rawlings, N G; Simko, E; Bebchuk, T; Caldwell, S J; Singh, B


    Melanomas are common neoplasms of dogs and arise from pigment-producing cells called melanocytes or melanoblasts. Melanomas of skin are often easily cured by surgical excision, but those of oral mucosa are aggressive, metastasize to the regional lymph nodes and lungs, and respond poorly to conventional therapy. Tumor growth is sustained by proliferation of microvessels via a process called angiogenesis. Integrin alpha(v)beta3 is expressed in proliferating but not in quiescent microvessels suggesting a role in angiogenesis. Vascular endothelial growth factor (VEGF) manifests its mitogenic and angiogenic effects mainly via VEGF receptor-2 (VEGFR-2/Flk-1). We conducted this immunocytochemical study to investigate the expression of integrin alpha(v)beta3 and VEGFR-2 in archival and fresh samples from cases of canine melanomas. Results show that integrin alpha(v)beta3 was expressed in 72% and 88% of cutaneous and oral melanomas, respectively, and the expression was restricted to and immediately around the melanocytes and endothelial cells. VEGFR-2 staining of selected cases of melanoma revealed that its expression overlapped with the alpha(v)beta3 integrin. Dual immuno-gold electron microscopy confirmed co-localization of integrin alpha(v)beta3 and VEGFR-2 in melanocytes and endothelial cells. These data demonstrate expression and co-localization of integrin alpha(v)beta3 and VEGFR-2 in cutaneous and oral melanomas of dogs.

  17. Tumor necrosis factor alpha and interleukin-1 stimulate bone resorption in vivo as measured by urinary [3H]tetracycline excretion from prelabeled mice

    International Nuclear Information System (INIS)

    Koenig, A.M.; Muehlbauer, R.C.F.; Fleisch, H.


    Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) have been shown to stimulate bone resorption in vitro. We have now investigated whether these cytokines also cause a similar action when administered in vivo. This was made possible by the adaptation of a newly developed technique that enables the continual assessment of bone resorption in vivo in mice by measuring urinary excretion of 3 H from [ 3 H]tetracycline-prelabeled animals. Experiments using maneuvers known to influence bone resorption, such as a change in dietary calcium or administration of parathyroid hormone or dichloromethylenebisphosphonate, indicate that the technique is reliable and sensitive in mice. Daily intravenous administration of either recombinant human or recombinant murine TNF-alpha, as well as subcutaneous administration of recombinant human IL-1 alpha, were found to stimulate bone resorption in a dose-dependent manner. The effect was maximal within 2 days. Thus, exogenous TNF-alpha and IL-1 alpha can stimulate bone resorption in vivo, suggesting that these cytokines may also exert a systemic effect on bone

  18. The major surface glycoprotein of Pneumocystis carinii induces release and gene expression of interleukin-8 and tumor necrosis factor alpha in monocytes

    DEFF Research Database (Denmark)

    Benfield, T L; Lundgren, Bettina; Levine, S J


    Recent studies suggest that interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) may play a central role in host defense and pathogenesis during Pneumocystis carinii pneumonia. In order to investigate whether the major surface antigen (MSG) of human P. carinii is capable of eliciting...... the release of IL-8 and TNF-alpha, human monocytes were cultured in the presence of purified MSG. MSG-stimulated cells released significant amounts of IL-8 within 4 h, and at 20 h, cells stimulated with MSG released 45.5 +/- 9.3 ng of IL-8/ml versus 3.7 +/- 1.1 ng/ml for control cultures (P = 0.......01). In a similar fashion, MSG elicited release of TNF-alpha. Initial increases were also seen at 4 h, and at 20 h, TNF-alpha levels reached 6.4 +/- 1.1 ng/ml, compared to 0.08 +/- 0.01 ng/ml for control cultures (P alpha secretion was observed at 20 h...

  19. Interaction with extracellular matrix proteins influences Lsh/Ity/Bcg (candidate Nramp) gene regulation of macrophage priming/activation for tumour necrosis factor-alpha and nitrite release. (United States)

    Formica, S; Roach, T I; Blackwell, J M


    The murine resistance gene Lsh/Ity/Bcg regulates activation of macrophages for tumour necrosis factor-alpha (TNF-alpha)-dependent production of nitric oxide mediating antimicrobial activity against Leishmania, Salmonella and Mycobacterium. As Lsh is differentially expressed in macrophages from different tissue sites, experiments were performed to determine whether interaction with extracellular matrix (ECM) proteins would influence the macrophage TNF-alpha response. Plating of bone marrow-derived macrophages onto purified fibrinogen or fibronectin-rich L929 cell-derived matrices, but not onto mannan, was itself sufficient to stimulate TNF-alpha release, with significantly higher levels released from congenic B10.L-Lshr compared to C57BL/10ScSn (Lshs) macrophages. Only macrophages plated onto fibrinogen also released measurable levels of nitrites, again higher in Lshr compared to Lshs macrophages. Addition of interferon-gamma (IFN-gamma), but not bacterial lipopolysaccharide or mycobacterial lipoarabinomannan, as a second signal enhanced the TNF-alpha and nitrite responses of macrophages plated onto fibrinogen, particularly in the Lshr macrophages. Interaction with fibrinogen and fibronectin also primed macrophages for an enhanced TNF-alpha response to leishmanial parasites, but this was only translated into enhanced nitrite responses in the presence of IFN-gamma. In these experiments, Lshr macrophages remained superior in their TNF-alpha responses throughout, but to a degree which reflected the magnitude of the difference observed on ECM alone. Hence, the specificity for the enhanced TNF-alpha responses of Lshr macrophages lay in their interaction with fibrinogen and fibronectin ECM, while a differential nitrite response was only observed with fibrinogen and/or IFN-gamma. The results are discussed in relation to the possible function of the recently cloned candidate gene Nramp, which has structural identity to eukaryote transporters and an N-terminal cytoplasmic

  20. New Onset Autoimmune Hepatitis during Anti-Tumor Necrosis Factor-Alpha Treatment in Children. (United States)

    Ricciuto, Amanda; Kamath, Binita M; Walters, Thomas D; Frost, Karen; Carman, Nicholas; Church, Peter C; Ling, Simon C; Griffiths, Anne M


    To evaluate a large anti-tumor necrosis factor (TNF)-treated pediatric inflammatory bowel disease cohort for drug-induced liver injury (DILI) following presentation of an index case with suspected DILI with autoimmune features after infliximab exposure. To characterize the incidence, natural history, and risk factors for liver enzyme elevation with anti-TNF use. We reviewed the index case and performed a retrospective cohort study of 659 children receiving anti-TNF therapy between 2000 and 2015 at a tertiary pediatric inflammatory bowel disease center. Patients with alanine aminotransferase (ALT) ≥×2 the upper limit of normal were included. The incidence, evolution, and risk factors for liver injury were examined with univariate and multivariable proportional hazards regression. Causality was assessed using the Roussel-Uclaf Causality Assessment Method. The index case, a teenage girl with Crohn's disease, developed elevated liver enzymes and features of autoimmune hepatitis on liver biopsy 23 weeks after starting infliximab. The injury resolved entirely within 4 months of withdrawing infliximab without additional therapy. Overall, 7.7% of our cohort developed new ALT elevations while on anti-TNF. Most ALT elevations were mild and transient and attributable to alternate etiologies. No additional clear cases of autoimmune hepatitis were identified. Transient liver enzyme abnormalities are relatively common among anti-TNF-treated children. Anti-TNF-related DILI with autoimmune features is rare but must be recognized so that therapy can be stopped. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. North Polar Cap (United States)


    [figure removed for brevity, see original site] This week we will be looking at five examples of laminar wind flow on the north polar cap. On Earth, gravity-driven south polar cap winds are termed 'catabatic' winds. Catabatic winds begin over the smooth expanse of the cap interior due to temperature differences between the atmosphere and the surface. Once begun, the winds sweep outward along the surface of the polar cap toward the sea. As the polar surface slopes down toward sealevel, the wind speeds increase. Catabatic wind speeds in the Antartic can reach several hundreds of miles per hour. In the images of the Martian north polar cap we can see these same type of winds. Notice the streamers of dust moving downslope over the darker trough sides, these streamers show the laminar flow regime coming off the cap. Within the trough we see turbulent clouds of dust, kicked up at the trough base as the winds slow down and enter a chaotic flow regime. The horizontal lines in these images are due to framelet overlap and lighting conditions over the bright polar cap. Image information: VIS instrument. Latitude 86.5, Longitude 64.5 East (295.5 West). 40 meter/pixel resolution. Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time. NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen

  2. A study of serum levels of leptin, ghrelin and tumour necrosis factor-alpha in child patients with cyanotic and acyanotic, congenital heart disease

    International Nuclear Information System (INIS)

    Shahramian, I.; Noori, N.M.


    Objective: To investigate the serum levels of leptin, ghrelin and tumour necrosis factor-alpha in children with cyanotic and acyanotic congenital heart disease. Methods: The prospective cohort study, was conducted at imam Ali Hospital, Zahedan University of Medical Sciences, Iran, in 2009-10 and comprised 64 subjects, including patients and controls. Using enzyme-linked immunosorpent assay kits, serum levels of ghrelin, leptin and tumour necrosis factor-alpha were measured and compared among patients (both cyanotic and acyanotic) and the controls, SPSS version 20 was used for statistical analysis. Results: Of the 64 subjects, 24 (37.5%) were cyanotic, 21(32.8%) were acynotic and 19(29.68%) were healthy controls. The three groups were homogenous in terms of age and gender characteristics. There was no significant difference among the groups leptin, ghrelin and tumour necrosis factor-alpha serum levels (p>0.05). There were also no significant differences in terms of weight, height and body mass index (P>0.05). Conclusion: Serum levels of ghrelin, leptin and tumour necrosis factor-alpha did not change in acyanotic and cyanotic patients with congenital heart disease, suggesting that other crucial factors may regulate individuals' nutrient intake, growth, weight and energy intake and output. (author)

  3. Influence of glucoregulation quality on C-reactive protein, interleukin-6 and tumor necrosis factor-alpha level in patients with diabetes type 1. (United States)

    Mitrović, Milena; Ilić, Tatjana; Stokić, Edita; Paro, Jovanka Novaković; Naglić, Dragana Tomić; Bajkin, Ivana; Icin, Tijana


    Results of studies which have proved an increased inflammatory activity in diabetes type 1, have been published over recent years. One of possible mechanisms that are used to explain chronic inflammation in diabetes is the state of hyperglycemia leading to the enhanced synthesis of glycosylation end products (AGEs) which activate macrophages, increase the oxidative stress and affect the synthesis of interleukins (IL-1, IL-6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP). The aim of the study was to determine the inflammatory markers (CRP, IL-6, TNF-alpha) in patients with diabetes type 1 and to establish their correlation with glucoregulation parameters and other cardiovascular risk factors as well as to compare them with the healthy controls. The study included 76 patients with diabetes type 1 and 30 healthy controls. We determined values of inflammatory markers (CRP, IL-6, TNF-alpha) and glucoregulation parameters (fasting glucose HbA(1c)). The values of CRP (p = 0.014), IL-6 (p = 0.020) and TNF-alpha (p = 0.037) were statistically significantly higher in the diabetic patients than in the healthy controls. There was a positive correlation between CRP with postprandial glycemia (p = 0.004); the multivariate regression analysis revealed a statistically significant correlation between CRP and age (p = 0.001), smoking (p = 0.055), fasting glucose (p = 0.021) and triglycerides (p = 0.048) as well as between IL-6 and LDL-cholesterol (p = 0.009). No statistically significant correlations were found between glycosilated hemoglobin (HbA(1c)) and the inflammatory markers (CRP, IL-6 and TNF-alpha). The patients with type 1 diabetes were found to have a low level of inflammatory activity manifested by the increased values of CRP, IL-6 and TNF-alpha.

  4. Kinetic Stability May Determine the Interaction Dynamics of the Bifunctional Protein DCoH1, the Dimerization Cofactor of the Transcription Factor HNF-1[alpha

    Energy Technology Data Exchange (ETDEWEB)

    Rho, H.; Jones, C.N.; Rose, R.B. (NCSU)


    The two disparate functions of DCoH1 (dimerization cofactor of HNF-1)/PCD (pterin-4a-carbinolamine dehydratase) are associated with a change in oligomeric state. DCoH dimers enhance the activity of the diabetes-associated transcription factor HNF-1{alpha} (hepatocyte nuclear factor-1{alpha}), while the PCD activity of DCoH1 homotetramers aids in aromatic amino acid metabolism. These complexes compete for the same interface of the DCoH dimer. Formation of the DCoH1/HNF-1{alpha} complex requires cofolding. The homotetramer of the DCoH1 paralogue, DCoH2, interacts with HNF-1{alpha} through simple mixing. To further investigate regulation of DCoH/HNF-1{alpha} complex formation, we measured the stability of the DCoH1 homotetramer through unfolding studies by intrinsic tryptophan fluorescence. DCoH2 unfolding is reversible. Surprisingly, the DCoH1 homotetramer is resistant to guanidine unfolding but refolds at a much lower guanidine concentration. We show that a point mutation at the DCoH1 tetramer interface, Thr 51 Ser, overcomes the dissociation barrier of the homotetramer and increases the interaction with HNF-1{alpha}. The 1.8 {angstrom} resolution crystal structure of DCoH1 T51S shows the presence of an ordered water molecule at the tetramer interface, as in DCoH2, which may destabilize the homotetramer. The equilibrium unfolding data were fit to a two-state model with no apparent intermediate. Folding intermediates were detectable by size exclusion chromatography. For wild-type DCoH1 the intermediates changed with time, suggesting a kinetic origin for the unfolding barrier of the homotetramer. We propose an unfolding pathway in which the tetramer unfolds slowly, but the dimer folds reversibly. Implications for regulation of DCoH1/HNF-1{alpha} complex formation are discussed.

  5. Tumor necrosis factor-{alpha} enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Song, Kai; Zhu, Fei; Zhang, Han-zhong [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan (China); Shang, Zheng-jun, E-mail: [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan (China); First Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan (China)


    Fusion between cancer cells and host cells, including endothelial cells, may strongly modulate the biological behavior of tumors. However, no one is sure about the driving factors and underlying mechanism involved in such fusion. We hypothesized in this study that inflammation, one of the main characteristics in tumor microenvironment, serves as a prominent catalyst for fusion events. Our results showed that oral cancer cells can fuse spontaneously with endothelial cells in co-culture and inflammatory cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) increased fusion of human umbilical vein endothelium cells and oral cancer cells by up to 3-fold in vitro. Additionally, human oral squamous cell carcinoma cell lines and 35 out of 50 (70%) oral squamous carcinoma specimens express VLA-4, an integrin, previously implicated in fusions between human peripheral blood CD34-positive cells and murine cardiomyocytes. Expression of VCAM-1, a ligand for VLA-4, was evident on vascular endothelium of oral squamous cell carcinoma. Moreover, immunocytochemistry and flow cytometry analysis revealed that expression of VCAM-1 increased obviously in TNF-{alpha}-stimulated endothelial cells. Anti-VLA-4 or anti-VCAM-1 treatment can decrease significantly cancer-endothelial adhesion and block such fusion. Collectively, our results suggested that TNF-{alpha} could enhance cancer-endothelial cell adhesion and fusion through VCAM-1/VLA-4 pathway. This study provides insights into regulatory mechanism of cancer-endothelial cell fusion, and has important implications for the development of novel therapeutic strategies for prevention of metastasis. -- Highlights: Black-Right-Pointing-Pointer Spontaneous oral cancer-endothelial cell fusion. Black-Right-Pointing-Pointer TNF-{alpha} enhanced cell fusions. Black-Right-Pointing-Pointer VCAM-1/VLA-4 expressed in oral cancer. Black-Right-Pointing-Pointer TNF-{alpha} increased expression of VCAM-1 on endothelial cells. Black

  6. Combination of interferon-alpha and 5-fluorouracil inhibits endothelial cell growth directly and by regulation of angiogenic factors released by tumor cells

    International Nuclear Information System (INIS)

    Wada, Hiroshi; Tanemura, Masahiro; Umeshita, Koji; Doki, Yuichiro; Mori, Masaki; Nagano, Hiroaki; Yamamoto, Hirofumi; Noda, Takehiro; Murakami, Masahiro; Kobayashi, Shogo; Marubashi, Shigeru; Eguchi, Hidetoshi; Takeda, Yutaka


    The combination therapy of interferon (IFN)-alpha and 5-fluorouracil (5-FU) improved the prognosis of the patients with hepatocellular carcinoma (HCC). To determine the molecular mechanisms of the anti-tumor and anti-angiogenic effects, we examined the direct anti-proliferative effects on human umbilical vein endothelial cells (HUVEC) and indirect effects by regulating secretion of angiogenic factors from HCC cells. The direct effects on HUVEC were examined by TUNEL, Annexin-V assays and cell cycles analysis. For analysis of the indirect effects, the apoptosis induced by the conditioned medium from HCC cell treated by IFN-alpha/5-FU and expression of angiogenic factors was examined. IFN-alpha and 5-FU alone had anti-proliferative properties on HUVEC and their combination significantly inhibited the growth (compared with control, 5-FU or IFN alone). TUNEL and Annexin-V assays showed no apoptosis. Cell cycle analysis revealed that IFN-alpha and 5-FU delayed cell cycle progression in HUVEC with S-phase accumulation. The conditioned medium from HuH-7 cells after treatment with IFN/5-FU significantly inhibited HUVEC growth and induced apoptosis, and contained high levels of angiopoietin (Ang)-1 and low levels of vascular endothelial growth factor (VEGF) and Ang-2. Knockdown of Ang-1 in HuH-7 cells abrogated the anti-proliferative effects on HUVEC while knockdown of Ang-2 partially rescue the cells. These results suggested that IFN-alpha and 5-FU had direct growth inhibitory effects on endothelial cells, as well as anti-angiogenic effects through regulation of angiogenic factors released from HCC cells. Modulation of VEGF and Angs secretion by IFN-alpha and 5-FU may contribute to their anti-angiogenic and anti-tumor effects on HCC

  7. PPAR-alpha agonist treatment increases trefoil factor family-3 expression and attenuates apoptosis in the liver tissue of bile duct-ligated rats. (United States)

    Karakan, Tarkan; Kerem, Mustafa; Cindoruk, Mehmet; Engin, Doruk; Alper, Murat; Akın, Okan


    Peroxisome proliferators-activated receptor alpha activation modulates cholesterol metabolism and suppresses bile acid synthesis. The trefoil factor family comprises mucin-associated proteins that increase the viscosity of mucins and help protect epithelial linings from insults. We evaluated the effect of short-term administration of fenofibrate, a peroxisome proliferators activated receptor alpha agonist, on trefoil factor family-3 expression, degree of apoptosis, generation of free radicals, and levels of proinflammatory cytokines in the liver tissue of bile duct-ligated rats. Forty male Wistar rats were randomly divided into four groups: 1 = sham operated, 2 = bile duct ligation, 3 = bile duct-ligated + vehicle (gum Arabic), and 4 = bile duct-ligated + fenofibrate (100 mg/kg/day). All rats were sacrificed on the 7 th day after obtaining blood samples and liver tissue. Liver function tests, tumor necrosis factor-alpha and interleukin 1 beta in serum, and trefoil factor family-3 mRNA expression, degree of apoptosis (TUNEL) and tissue malondialdehyde (malondialdehyde, end-product of lipid peroxidation by reactive oxygen species) in liver tissue were evaluated. Fenofibrate administration significantly reduced serum total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and tumor necrosis factor-alpha and interleukin-1β levels. Apoptosis and malondialdehyde were significantly reduced in the fenofibrate group. Trefoil factor family-3 expression increased with fenofibrate treatment in bile duct-ligated rats. The peroxisome proliferators-activated receptor alpha agonist fenofibrate significantly increased trefoil factor family-3 expression and decreased apoptosis and lipid peroxidation in the liver and attenuated serum levels of proinflammatory cytokines in bile duct-ligated rats. Further studies are needed to determine the protective role of fenofibrate in human cholestatic disorders.

  8. Alpha Momentum and Price Momentum

    Directory of Open Access Journals (Sweden)

    Hannah Lea Hühn


    Full Text Available We analyze a novel alpha momentum strategy that invests in stocks based on three-factor alphas which we estimate using daily returns. The empirical analysis for the U.S. and for Europe shows that (i past alpha has power in predicting the cross-section of stock returns; (ii alpha momentum exhibits less dynamic factor exposures than price momentum and (iii alpha momentum dominates price momentum only in the U.S. Connecting both strategies to behavioral explanations, alpha momentum is more related to an underreaction to firm-specific news while price momentum is primarily driven by price overshooting due to momentum trading.


    Directory of Open Access Journals (Sweden)

    E. N. Zotina


    Full Text Available The prognostic value of tumor necrosis factor-alfa (TNFα, a pro-inflammatory cytokine was studied in 140 patients with a newly diagnosed chronic lymphocytic leukemia (CLL. TNFα contents in blood serum was determined using ELISA method. A significant increase of serum TNFα was shown in patients with newly diagnosed CLL, as compared to healthy individuals. Dependence of the cytokine concentration on clnical stage and course of disease was revealed: the highest levels of serum TNFα were registered in patients with advanced disease and/or CLL progression. Distinct correlations were revealed between the studied cytokine amounts and clinical laboratory parameters reflecting the cell proliferative activity and tumor clone size. Immunochemotherapy was accompanied by a significant reduction of TNFα levels. According to the data from multivariate regression analysis. TNFα level of at the time of the diagnosis was an independent predictor of overall survival. Hence, TNFα plays an important role in CLL pathogenesis and may be used as an additional predictive factor for CLL outcomes.

  10. The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition.

    Directory of Open Access Journals (Sweden)

    Darren M Hutt

    Full Text Available Hypoxia inducible factor 1α (HIF-1α is a master regulator of tumor angiogenesis being one of the major targets for cancer therapy. Previous studies have shown that Histone Deacetylase Inhibitors (HDACi block tumor angiogenesis through the inhibition of HIF-1α expression. As such, Vorinostat (Suberoylanilide Hydroxamic Acid/SAHA and Romidepsin, two HDACis, were recently approved by the Food and Drug Administration (FDA for the treatment of cutaneous T cell lymphoma. Although HDACis have been shown to affect HIF-1α expression by modulating its interactions with the Hsp70/Hsp90 chaperone axis or its acetylation status, the molecular mechanisms by which HDACis inhibit HIF-1α expression need to be further characterized. Here, we report that the FDA-approved HDACi Vorinostat/SAHA inhibits HIF-1α expression in liver cancer-derived cell lines, by a new mechanism independent of p53, prolyl-hydroxylases, autophagy and proteasome degradation. We found that SAHA or silencing of HDAC9 mechanism of action is due to inhibition of HIF-1α translation, which in turn, is mediated by the eukaryotic translation initiation factor--eIF3G. We also highlighted that HIF-1α translation is dramatically inhibited when SAHA is combined with eIF3H silencing. Taken together, we show that HDAC activity regulates HIF-1α translation, with HDACis such as SAHA representing a potential novel approach for the treatment of hepatocellular carcinoma.

  11. Evaluation of salivary tumor necrosis factor-alpha in patients with the chronic periodontitis: A case-control study. (United States)

    Yousefimanesh, Hojatollah; Maryam, Robati; Mahmoud, Jahangirnezhad; Mehri, Ghafourian Boroujerdnia; Mohsen, Taghipour


    Periodontitis is a chronic infectious disease that leads to inflammation of the tissues supporting the teeth, bone loss, attachment loss progressively. In chronic periodontitis for starting the host response and inflammatory reaction, the presence of the infectious agent is necessary. One of inflammatory factors is tumor necrosis factor-alpha (TNF-α) that appear to be important in the destruction of periodontal tissues that were examined in this study. This study was performed in the laboratory and case-control study. The samples of study collected from 30 individuals with chronic periodontitis and 30 healthy controls that matched for age and sex, together. Unstimulated saliva samples were collected from patients and then TNF-α level were measured by enzyme-linked immunosorbent assay and were compared with the control group. In this study for statistical analysis, Mann-Whitney was used. There were differences in mean salivary concentrations of TNF-α in controls and patients. The average concentration in the case group was 9.1 (pg/ml) and the control group was 8.7 (pg/ml), but there was no significant difference between case and control groups (P > 0.05). The results of this analysis showed no significant relationship between two groups TNF-α concentration. This biomarker can not seem to be a good index to evaluate or predict periodontal disease.

  12. Evaluation of salivary tumor necrosis factor-alpha in patients with the chronic periodontitis: A case-control study

    Directory of Open Access Journals (Sweden)

    Hojatollah Yousefimanesh


    Full Text Available Context: Periodontitis is a chronic infectious disease that leads to inflammation of the tissues supporting the teeth, bone loss, attachment loss progressively. In chronic periodontitis for starting the host response and inflammatory reaction, the presence of the infectious agent is necessary. Aims: One of inflammatory factors is tumor necrosis factor-alpha (TNF-α that appear to be important in the destruction of periodontal tissues that were examined in this study. Materials and Methods: This study was performed in the laboratory and case-control study. The samples of study collected from 30 individuals with chronic periodontitis and 30 healthy controls that matched for age and sex, together. Unstimulated saliva samples were collected from patients and then TNF-α level were measured by enzyme-linked immunosorbent assay and were compared with the control group. Statistical Analysis Used: In this study for statistical analysis, Mann-Whitney was used. Results: There were differences in mean salivary concentrations of TNF-α in controls and patients. The average concentration in the case group was 9.1 (pg/ml and the control group was 8.7 (pg/ml, but there was no significant difference between case and control groups (P > 0.05. Conclusions: The results of this analysis showed no significant relationship between two groups TNF-α concentration.This biomarker can not seem to be a good index to evaluate or predict periodontal disease.

  13. Effects of Alpha-Lipoic Acid Supplementation on Plasma Adiponectin Levels and Some Metabolic Risk Factors in Patients with Schizophrenia. (United States)

    Vidović, Bojana; Milovanović, Srđan; Stefanović, Aleksandra; Kotur-Stevuljević, Jelena; Takić, Marija; Debeljak-Martačić, Jasmina; Pantović, Maja; Đorđević, Brižita


    Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and anti-inflammatory properties and is suggested to be a biomarker of metabolic disturbances. The aim of this study was to investigate the effects of alpha-lipoic acid (ALA) on plasma adiponectin and some metabolic risk factors in patients with schizophrenia. The plasma adipokine levels (adiponectin and leptin), routine biochemical and anthropometric parameters, markers of oxidative stress, and the serum phospholipid fatty acid profile in eighteen schizophrenic patients at baseline, in the middle, and at the end of a 3-month long supplementation period with ALA (500 mg daily) were determined. A significant increase in the plasma adiponectin concentrations, as well as a decrease in fasting glucose and aspartate aminotransferase activity (AST), was found. Baseline AST activity was independently correlated with the adiponectin concentrations. Our data show that ALA can improve plasma adiponectin levels and may play a potential role in the treatment of metabolic risk factor in patients with schizophrenia. Future randomized controlled trials are needed to confirm these preliminary investigations.

  14. Critical roles of mucin-1 in sensitivity of lung cancer cells to tumor necrosis factor-alpha and dexamethasone. (United States)

    Xu, Menglin; Wang, Xiangdong


    Lung cancer is the leading cause of death from cancer. Mucins are glycoproteins with high molecular weight, responsible for cell growth, differentiation, and signaling, and were proposed to be correlated with gene heterogeneity of lung cancer. Here, we report aberrant expression of mucin genes and tumor necrosis factor receptors in lung adenocarcinoma tissues compared with normal tissues in GEO datasets. Mucin-1 (MUC1) gene was selected and considered as the target gene; furthermore, the expression pattern of adenocarcinomic cells (A549, H1650, or H1299 cells) was validated under the stimulation with tumor necrosis factor-alpha (TNFα) or dexamethasone (DEX), separately. MUC1 gene interference was done to A549 cells to show its role in sensitivity of lung cancer cells to TNFα and DEX. Results of our experiments indicate that MUC1 may regulate the influence of inflammatory mediators in effects of glucocorticoids (GCs), as a regulatory target to improve therapeutics. It shows the potential effect of MUC1 and GCs in lung adenocarcinoma (LADC), which may help in LADC treatment in the future.

  15. Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha. (United States)

    Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya


    Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

  16. Protective effect of ciliary neurotrophic factor (CNTF) in a model of endotoxic shock: action mechanisms and role of CNTF receptor alpha. (United States)

    Demitri, M T; Benigni, F; Meazza, C; Zinetti, M; Fratelli, M; Villa, P; Acheson, A; Panayotatos, N; Ghezzi, P


    Ciliary neurotrophic factor (CNTF) inhibits the production of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-treated mice and protects against LPS lethality when coadministered with its soluble receptor (sCNTFR alpha). Both of these activities are abolished in adrenalectomized (ADX) mice. LPS-induced pulmonary polymorphonuclear neutrophil (PMN) infiltration and nitric oxide (NO) production were also inhibited by CNTF + sCNTFR alpha but not by CNTF alone. sCNTFR alpha did not alter the clearance or tissue distribution of CNTF. Furthermore, CNTF variants coadministered with sCNTFR alpha protected against LPS toxicity in a manner related to their affinity for the beta components of CNTFR. Thus, inhibition of TNF production and protection against LPS lethality by CNTF/sCNTFR alpha require an intact hypothalamus-pituitary-adrenal axis (HPAA) and may be mediated by endogenous glucocorticoids. This protective effect is, at least in part, due to the inhibition of PMN infiltration and NO production, and appears to be mediated by cells displaying only beta-receptor subtypes.

  17. EEG alpha power as an intermediate measure between brain-derived neurotrophic factor Val66Met and depression severity in patients with major depressive disorder. (United States)

    Zoon, Harriët F A; Veth, C P M; Arns, Martijn; Drinkenburg, W H I M; Talloen, Willem; Peeters, Pieter J; Kenemans, J L


    Major depressive disorder has a large impact on patients and society and is projected to be the second greatest global burden of disease by 2020. The brain-derived neurotrophic factor (BDNF) gene is considered to be one of the important factors in the etiology of major depressive disorder. In a recent study, alpha power was found to mediate between BDNF Met and subclinical depressed mood. The current study looked at a population of patients with major depressive disorder (N = 107) to examine the association between the BDNF Val66Met polymorphism, resting state EEG alpha power, and depression severity. For this purpose, repeated-measures analysis of variance, partial correlation, and multiple linear models were used. Results indicated a negative association between parietal-occipital alpha power in the eyes open resting state and depression severity. In addition, Met/Met patients showed lower global absolute alpha power in the eyes closed condition compared with Val-carriers. These findings are in accordance with the previously uncovered pathway between BDNF Val66Met, resting state EEG alpha power, and depression severity. Additional research is needed for the clarification of this tentative pathway and its implication in personalized treatment of major depressive disorder.

  18. Tumor necrosis factor alpha inhibitors in the treatment of toxic epidermal necrolysis. (United States)

    Woolridge, Katelyn F; Boler, Patrick L; Lee, Brian D


    Toxic epidermal necrolysis (TEN) is a rare, life-threatening adverse drug reaction for which there is no standardized or consistently effective treatment. Due to a greater understanding of disease pathogenesis and the identification of tumor necrosis factor (TNF) α as a mediator of keratinocyte death, TNF-α antagonists have been used in the treatment of TEN. Specifically, infliximab and etanercept have been shown to be effective at halting disease progression. The objective of this study is to review published case reports and case series using anti-TNF-α medications in the treatment of TEN. Results of many of the articles reviewed support the use of TNF-α inhibitors in TEN in both adult and pediatric populations; however, the risks caused by these potent immunosuppressants must be weighed, and if administered, patients must be closely monitored for infections. Additional studies are needed to further characterize the role of TNF-α inhibition in the treatment of TEN.

  19. Serum concentrations of interleukin (IL-)1alpha, 1beta, 6 and tumor necrosis factor (TNF-) alpha in patients with thyroid eye disease (TED). (United States)

    Laban-Guceva, Nevenka; Bogoev, Milko; Antova, Magdalena


    Serum proinflamatory cytokines were found to be altered in Graves disease (GD) and in TED. Serum values of IL1alpha, IL-1beta, IL-6, TNF-alpha were assessed in 22 patients with TED before and after treatment (aged 46.82 +/- 12.47, M:F=16:6). Free thyroxin was high, TSH low, thyroid ultrasound showed diffuse thyroid enlargement, treatment with antithyroid drugs propylthyouracil (PTU) or methymasol (MMI) resulted in clinical and hormonal remission. Several months after the initiation of the signs of hyperthyroidism, a progression in the ophthalmopathy was observed (Hertel up to 25 mm: normal 15-17 mm) while patients were clinically and hormonally euthyroid. Blood was collected in euthyroid state (with TED signs present, before corticosteroid therapy (CS) treatment) and after 3 months of treatment (patients without TED and without TED treatment). CS resulted in response of 8/22 patients. Ophthalmic irradiation (01) given with CS therapy, resulted in a response in twelve patients (12/12). Lack of response to CS treatment, with rapid increase in proptosis, and loss of visual acuity prompted ophthalmic decompression (OD) in two patients. Both recovered visual acuity, while proptosis fell under 25 mm Hertel. The control group had 29 persons (aged 51.86 +/-10.52, M:F = 16:13). A significant difference was found in the serum levels of IL-1alpha between the groups of controls (0.74+/-0.55 pg/ml) and patients before treatment (1.85 +/- 1.85 pg/ml; p TED treatment its concentration raised to 2.07 +/- 1.82 pg/ml (higher than the pretreatment; NS). For patients with low Clinical Activity Score (CAS) scores (1-5) there was no change in IL-6 concentrations before (1.03+/-o.64 pg/ml) and after treatment (1.07 +/- 0.63 pg/ml). Patients with higher CAS scores (6-10) had a change in IL-6 levels (from 1.32+/-1.00 to 2.67 +/- 4.84; p > 0.05). In addition, patients with pathological VEP had no changes in IL-6 (from 0.93 +/- 0.53 to 0.97 +/- 0.32 pg/ml), while patients with normal VEP had

  20. Transcription regulation of the alpha-glucanase gene agn1 by cell separation transcription factor Ace2p in fission yeast

    NARCIS (Netherlands)

    Dekker, Nick; de Haan, Annett; Hochstenbach, Frans


    During the final stage of the cell division cycle in the fission yeast Schizosaccharomyces pombe, transcription factor Ace2p activates expression of genes involved in the separation of newly formed daughter cells, such as agn1+, which encodes the alpha-glucanase Agn1p. The agn1 promoter contains

  1. Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53

    NARCIS (Netherlands)

    Sleijfer, S; Le, T. K. P.; de Jong, S.; Timmer-Bosscha, H; Withoff, S; Mulder, NH

    Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects

  2. Reactivation of pulmonary tuberculosis (TBC) with the use of antagonist of the tumor necrosis factor alpha (FNTα) in rheumatoid arthritis: On purpose of a case

    International Nuclear Information System (INIS)

    Martinez V, Jose B; Medina V, Yimy F; Parga, Roberto; Restrepo, Jose Felix; Iglesias G, Antonio; Rondon, Federico


    Woman 56 years old, with history of rheumatoid arthritis who develops reactivation of pulmonary tuberculosis (TBC) after 1 year of treatment with biological therapy (antagonist of the tumor necrosis factor alpha). It is discussed pathophysiologic mechanisms, diagnostic approach, treatment of TBC and some recommendations for the use of biological therapy in patients with rheumatic disease

  3. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma : Three time periods at risk for amputation

    NARCIS (Netherlands)

    van Ginkel, Robert J.; Thijssens, Katja M. J.; Pras, Elisabeth; van der Graaf, Winette T. A.; Suurmeijer, Albert J. H.; Hoekstra, Harald J.

    Background: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). Methods: From 1991 to 2003, 73 patients (36 men, 37 women,

  4. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma : The value of adjuvant radiotherapy

    NARCIS (Netherlands)

    Thijssens, KMJ; van Ginkel, RJ; Pras, E; Suurmeijer, AJH; Hoekstra, HJ

    Background: The aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan followed by limb-saving surgery. Methods: From 1991 to 2003, 73 patients (median age, 54

  5. Plasma endothelin-1 and tumor necrosis factor-alpha concentrations in pregnant and cyclic rats after low-dose endotoxin infusion

    NARCIS (Netherlands)

    Faas, MM; Bakker, WW; Valkhof, N; Baller, JFW; Schuiling, GA

    Plasma endothelin-1 and tumor necrosis factor-alpha were determined in pregnant and cyclic rats after infusion of either endotoxin (1.0 mu g/kg of body weight) or saline solution. After endotoxin, but not after saline solution, administration there was a transient endothelin-1 response in pregnant

  6. Engineering of factors determining alpha-amylase and cyclodextrin glycosyltransferase specificity in the cyclodextrin glycosyltransferase from Thermoanaerobacterium thermosulfurigenes EM1

    NARCIS (Netherlands)

    Wind, RD; Buitelaar, RM; Dijkhuizen, L


    The starch-degrading enzymes alpha-amylase and cyclodextrin glycosyltransferase (CGTase) are functionally and structurally closely related, with CGTases containing two additional domains (called D and E) compared to the three domains of alpha-amylases (A, B and C). Amino acid residue 196

  7. The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence.

    Directory of Open Access Journals (Sweden)

    Mehtap Kilic Eren

    Full Text Available Oncogene induced senescence (OIS is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR, senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on RasV12-induced senescence in human diploid fibroblasts (HDFs. We showed here that hypoxia prevents execution of oncogene induced senescence (OIS, through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21CIP1 and p16INK4a in association with induction of hypoxia inducible factor-1α (HIF-1α. In addition, hypoxia also decreased marks of H-RasV12-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21CIP1 but not p16INK4a. In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21CIP1. In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.

  8. Transforming growth factor alpha is a critical mediator of radiation lung injury. (United States)

    Chung, Eun Joo; Hudak, Kathryn; Horton, Jason A; White, Ayla; Scroggins, Bradley T; Vaswani, Shiva; Citrin, Deborah


    Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-α, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-α(-/-)) and control C57Bl/6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ≥ 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson's trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-α on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-α(-/-) mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-α(-/-) mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 μg/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-α (-/-) mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1β, IL-4, TNF-α, TGF-β and EGF at multiple time points after irradiation were similar in C57-WT and TGF-α(-/-) mice. TGF-α in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-α(-/-) mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-α(-/-) mice. Treatment of NIH-3T3 fibroblasts with TGF

  9. Prognostic role of hypoxia-inducible factor-1 alpha expression in osteosarcoma: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Ren HY


    Full Text Available Hai-Yong Ren,1 Yin-Hua Zhang,1,2 Heng-Yuan Li,1 Tao Xie,1 Ling-Ling Sun,1 Ting Zhu,1 Sheng-Dong Wang,1 Zhao-Ming Ye1 1Department of Orthopaedics, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 2The First Department of Orthopaedics, Hospital of Zhejiang General Corps of Armed Police Forces, Jiaxing, People’s Republic of China Background: Hypoxia-inducible factor-1α (HIF-1α plays an important role in tumor progression and metastasis. A number of studies have investigated the association of HIF-1α with prognosis and clinicopathological characteristics of osteosarcoma but yielded inconsistent results.  Method: Systematic computerized searches were performed in PubMed, Embase, and Web of Science databases for relevant original articles. The pooled hazard ratios (HRs and odds ratios (ORs with corresponding confidence intervals (CIs were calculated to assess the prognostic value of HIF-1α expression. The standard mean difference was used to analyze the continuous variable.  Results: Finally, nine studies comprising 486 patients were subjected to final analysis. Protein expression level of HIF-1α was found to be significantly related to overall survival (HR =3.0; 95% CI: 1.46–6.15, disease-free survival (HR =2.23; 95% CI: 1.26–3.92, pathologic grade (OR =21.33; 95% CI: 4.60–98.88, tumor stage (OR =10.29; 95% CI: 3.55–29.82, chemotherapy response (OR =9.68; 95% CI: 1.87–50.18, metastasis (OR =5.06; 95% CI: 2.87–8.92, and microvessel density (standard mean difference =2.83; 95% CI: 2.28–3.39.  Conclusion: This meta-analysis revealed that overexpression of HIF-1α is a predictive factor of poor outcomes for osteosarcoma. HIF-1α appeared to play an important role in prognostic evaluation and may be a potential target in antitumoral therapy. Keywords: HIF-1α, osteosarcoma, prognosis, meta-analysis

  10. Buffett’s Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting...

  11. Tumor necrosis factor alpha inhibits in vitro bovine embryo development through a prostaglandin mediated mechanism

    Directory of Open Access Journals (Sweden)

    Jackson Lauren R


    Full Text Available Abstract Mastitis or other infectious diseases have been related to reduced fertility in cattle. Inflammatory cytokines such as tumor necrosis factor α (TNFα are released in response to infection and may have negative effects on embryo development. In the current study the effect of exposure to TNFα on the development of in vitro fertilized bovine embryos was examined. Indomethacin, a prostaglandin synthesis inhibitor, was used to determine if blockade of prostaglandin synthesis would alter the effects of TNFα. Ovaries were obtained from a local abattoir and immature COC were isolated from 2-10 mm follicles, in vitro matured and fertilized. After fertilization, groups of presumptive zygotes were randomly placed into either control development medium, medium containing 25 ng/mL TNFα or medium containing 25 ng/mL TNFα plus 1 μg/mL indomethacin. The proportion of blastocysts formed was assessed at day 7 of culture. Fewer embryos exposed to TNFα alone reached the blastocyst stage (17.5 ± 2.4%, P

  12. Systemic use of tumor necrosis factor alpha as an anticancer agent (United States)

    Roberts, Nicholas J.; Zhou, Shibin; Diaz, Luis A.; Holdhoff, Matthias


    Tumor necrosis factor-α (TNF-α) has been discussed as a potential anticancer agent for many years, however initial enthusiasm about its clinical use as a systemic agent was curbed due to significant toxicities and lack of efficacy. Combination of TNF-α with chemotherapy in the setting of hyperthermic isolated limb perfusion (ILP), has provided new insights into a potential therapeutic role of this agent. The therapeutic benefit from TNF-α in ILP is thought to be not only due to its direct anti-proliferative effect, but also due to its ability to increase penetration of the chemotherapeutic agents into the tumor tissue. New concepts for the use of TNF-α as a facilitator rather than as a direct actor are currently being explored with the goal to exploit the ability of this agent to increase drug delivery and to simultaneously reduce systemic toxicity. This review article provides a comprehensive overview on the published previous experience with systemic TNF-α. Data from 18 phase I and 10 phase II single agent as well as 18 combination therapy studies illustrate previously used treatment and dose schedules, response data as well as the most prominently observed adverse effects. Also discussed, based on recent preclinical data, is a potential future role of systemic TNF-α in combination with liposomal chemotherapy to facilitate increased drug uptake into tumors. PMID:22036896

  13. Designing Smart Charter School Caps (United States)

    Dillon, Erin


    In 2007, Andrew J. Rotherham proposed a new approach to the contentious issue of charter school caps, the statutory limits on charter school growth in place in several states. Rotherham's proposal, termed "smart charter school caps," called for quality sensitive caps that allow the expansion of high-performing charter schools while also…

  14. Determination of '14 MeV' cross sections for (n,p), (n,. cap alpha. ), (n,2n), and (n,np + pn + d) reactions on the elements Sc, Ni, Ge, Pd, Cd, Sm, Dy, Gd, and Yb in consideration of the 'effective' n-energy spectra

    Energy Technology Data Exchange (ETDEWEB)

    Weigel, H; Michel, R; Herr, W [Koeln Univ. (F.R. Germany). Inst. fuer Kernchemie


    A total of 24 cross sections was determined for (n,p), (n,..cap alpha..), (n,2n), and (n,np + pn + d) reactions of fast (so called '14-MeV') neutrons on the elements Sc, Ni, Ge, Pd, Cd, Sm, Dy, Gd, and Yb. /sup 58/Ni(n,p)/sup 58/Co served as monitor reaction. It is a special feature of this work that calculated neutron energy spectra for the '14 MeV' n-tube (Type Philips 18602) were considered; each individual sigma value could thus be supplied with the respective n-energy distribution. On the basis of an extensive literature search (up to the beginning of 1973), the sigma data were compared with experimental results of other authors and with those deduced from the statistical model. For some nuclides (e.g. /sup 58/Ni, /sup 154/Gd, /sup 168/Yb, /sup 176/Yb) it was possible to show the limits of applicability of the latter model. Summarizing, 12 cross sections and 3 isomeric ratios, nearly all of which belong to reaction products with rather long half-lifes, were determined for the first time.

  15. Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE): discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1' substituents. (United States)

    Lu, Zhonghui; Ott, Gregory R; Anand, Rajan; Liu, Rui-Qin; Covington, Maryanne B; Vaddi, Krishna; Qian, Mingxin; Newton, Robert C; Christ, David D; Trzaskos, James; Duan, James J-W


    Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.

  16. Polymorphisms in the hypoxia-inducible factor 1 alpha gene in Mexican patients with preeclampsia: A case-control study

    Directory of Open Access Journals (Sweden)

    Nava-Salazar Sonia


    Full Text Available Abstract Background Although the etiology of preeclampsia is still unclear, recent work suggests that changes in circulating angiogenic factors play a key role in its pathogenesis. In the trophoblast of women with preeclampsia, hypoxia-inducible factor 1 alpha (HIF-1α is over-expressed, and induces the expression of non-angiogenic factors and inhibitors of trophoblast differentiation. This observation prompted the study of HIF-1α and its relation to preeclampsia. It has been described that the C1772T (P582S and G1790A (A588T polymorphisms of the HIF1A gene have significantly greater transcriptional activity, correlated with an increased expression of their proteins, than the wild-type sequence. In this work, we studied whether either or both HIF1A variants contribute to preeclampsia susceptibility. Results Genomic DNA was isolated from 150 preeclamptic and 105 healthy pregnant women. Exon 12 of the HIF1A gene was amplified by PCR, and the genotypes of HIF1A were determined by DNA sequencing. In preeclamptic women and controls, the frequencies of the T allele for C1772T were 4.3 vs. 4.8%, and the frequencies of the A allele for G1790A were 0.0 vs. 0.5%, respectively. No significant differences were found between groups. Conclusion The frequency of the C1772T and G1790A polymorphisms of the HIF1A gene is very low, and neither polymorphism is associated with the development of preeclampsia in the Mexican population.

  17. Translation initiation on mRNAs bound by nuclear cap-binding protein complex CBP80/20 requires interaction between CBP80/20-dependent translation initiation factor and eukaryotic translation initiation factor 3g. (United States)

    Choe, Junho; Oh, Nara; Park, Sungjin; Lee, Ye Kyung; Song, Ok-Kyu; Locker, Nicolas; Chi, Sung-Gil; Kim, Yoon Ki


    In the cytoplasm of mammalian cells, either cap-binding proteins 80 and 20 (CBP80/20) or eukaryotic translation initiation factor (eIF) 4E can direct the initiation of translation. Although the recruitment of ribosomes to mRNAs during eIF4E-dependent translation (ET) is well characterized, the molecular mechanism for CBP80/20-dependent translation (CT) remains obscure. Here, we show that CBP80/20-dependent translation initiation factor (CTIF), which has been shown to be preferentially involved in CT but not ET, specifically interacts with eIF3g, a component of the eIF3 complex involved in ribosome recruitment. By interacting with eIF3g, CTIF serves as an adaptor protein to bridge the CBP80/20 and the eIF3 complex, leading to efficient ribosome recruitment during CT. Accordingly, down-regulation of CTIF using a small interfering RNA causes a redistribution of CBP80 from polysome fractions to subpolysome fractions, without significant consequence to eIF4E distribution. In addition, down-regulation of eIF3g inhibits the efficiency of nonsense-mediated mRNA decay, which is tightly coupled to CT but not to ET. Moreover, the artificial tethering of CTIF to an intercistronic region of dicistronic mRNA results in translation of the downstream cistron in an eIF3-dependent manner. These findings support the idea that CT mechanistically differs from ET.

  18. Neomycin is a platelet-derived growth factor (PDGF) antagonist that allows discrimination of PDGF alpha- and beta-receptor signals in cells expressing both receptor types. (United States)

    Vassbotn, F S; Ostman, A; Siegbahn, A; Holmsen, H; Heldin, C H


    The aminoglycoside neomycin has recently been found to affect certain platelet-derived growth factor (PDGF) responses in C3H/10T1/2 C18 fibroblasts. Using porcine aortic endothelial cells transfected with PDGF alpha- or beta-receptors, we explored the possibility that neomycin interferes with the interaction between the different PDGF isoforms and their receptors. We found that neomycin (5 mM) inhibited the binding of 125I-PDGF-BB to the alpha-receptor with only partial effect on the binding of 125I-PDGF-AA; in contrast, the binding of 125I-PDGF-BB to the beta-receptor was not affected by the aminoglycoside. Scatchard analyses showed that neomycin (5 mM) decreased the number of binding sites for PDGF-BB on alpha-receptor-expressing cells by 87%. Together with cross-competition studies with 125I-labeled PDGF homodimers, the effect of neomycin indicates that PDGF-AA and PDGF-BB bind to both common and unique structures on the PDGF alpha-receptor. Neomycin specifically inhibited the autophosphorylation of the alpha-receptor by PDGF-BB, with less effect on the phosphorylation induced by PDGF-AA and no effect on the phosphorylation of the beta-receptor by PDGF-BB. Thus, neomycin is a PDGF isoform- and receptor-specific antagonist that provides a possibility to compare the signal transduction pathways of alpha- and beta-receptors in cells expressing both receptor types. This approach was used to show that activation of PDGF beta-receptors by PDGF-BB mediated a chemotactic response in human fibroblasts, whereas activation of alpha-receptors by the same ligand inhibited chemotaxis.

  19. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. (United States)

    Alijotas-Reig, Jaume; Esteve-Valverde, Enrique; Ferrer-Oliveras, Raquel; Llurba, Elisa; Gris, Josep Maria


    Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all "idiopathic" or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain "refractory" cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic

  20. Down-regulation of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor by HEXIM1 attenuates myocardial angiogenesis in hypoxic mice. (United States)

    Yoshikawa, Noritada; Shimizu, Noriaki; Ojima, Hidenori; Kobayashi, Hiroshi; Hosono, Osamu; Tanaka, Hirotoshi


    Pulmonary hypertension (PH) sustains elevation of pulmonary vascular resistance and ultimately leads to right ventricular (RV) hypertrophy and failure and death. Recently, proangiogenic factors hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) have been known to promote left ventricular myocardial angiogenesis and lead to cardiac hypertrophy, and this would be involved in RV hypertrophy of PH patients. Previously, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice ameliorates RV hypertrophy in hypoxia-induced PH model. Given these results, here we analyzed the effect of HEXIM1 on the expression of HIF-1α and VEGF and on myocardial angiogenesis of RV in PH. We revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of HIF-1α protein and its target genes including VEGF in the cultured cardiac myocytes and fibroblasts, and that cardiomyocyte-specific HEXIM1 transgenic mice repressed RV myocardial angiogenesis in hypoxia-induced PH model. Thus, we conclude that HEXIM1 could prevent RV hypertrophy, at least in part, via suppression of myocardial angiogenesis through down-regulation of HIF-1α and VEGF in the myocardium under hypoxic condition. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Post-transcriptional regulation of osteoblastic platelet-derived growth factor receptor-alpha expression by co-cultured primary endothelial cells

    DEFF Research Database (Denmark)

    Finkenzeller, Günter; Mehlhorn, Alexander T; Schmal, Hagen


    -alpha downregulation is dependent on time and cell number. This effect was specific to endothelial cells and was not observed when hOBs were co-cultured with human primary chondrocytes or fibroblasts. Likewise, HUVEC-mediated suppression of PDGFR-alpha expression was only seen in hOBs and mesenchymal stem cells......Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in osteoblast function. Inhibition of PDGFR activity leads to a suppression of osteoblast proliferation, whereas mineralized matrix production is enhanced. In previous experiments, we showed that co......-cultivation of human primary endothelial cells and human primary osteoblasts (hOBs) leads to a cell contact-dependent downregulation of PDGFR-alpha expression in the osteoblasts. In this study, we investigated this effect in more detail, revealing that human umbilical vein endothelial cell (HUVEC)-mediated PDGFR...

  2. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

    DEFF Research Database (Denmark)

    Kolsum, Umme; Roy, Kay; Starkey, Cerys


    BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...... (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R...

  3. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

    DEFF Research Database (Denmark)

    Kolsum, Umme; Roy, Kay; Starkey, Cerys


    BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...... (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R...

  4. Medicinal flowers. XXVII. New flavanone and chalcone glycosides, arenariumosides I, II, III, and IV, and tumor necrosis factor-alpha inhibitors from everlasting, flowers of Helichrysum arenarium. (United States)

    Morikawa, Toshio; Wang, Li-Bo; Nakamura, Seikou; Ninomiya, Kiyofumi; Yokoyama, Eri; Matsuda, Hisashi; Muraoka, Osamu; Wu, Li-Jun; Yoshikawa, Masayuki


    The methanolic extract from the flowers of Helichrysum arenarium L. MOENCH was found to show inhibitory effect on tumor necrosis factor-alpha (TNF-alpha, 1 ng/ml)-induced cytotoxicity in L929 cells. From the methanolic extract, 50 constituents including four new flavanone and chalcone glycosides named arenariumosides I (1), II (2), III (3), and IV (4) were isolated. The stereostructures of 1-4 were elucidated on the basis of chemical and physicochemical evidence. Among the constituents, naringenin 7-O-beta-D-glucopyranoside (7), apigenin 7-O-beta-D-glucopyranoside (14), apigenin 7-O-gentiobioside (16), and apigenin 7,4'-di-O-beta-D-glucopyranoside (17) significantly inhibited TNF-alpha-induced cytotoxicity in L929 cells at 30 microM.

  5. A low concentration of ethanol reduces the chemiluminescence of human granulocytes and monocytes but not the tumor necrosis factor alpha production by monocytes after endotoxin stimulation

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Diedrich, J. P.; Schäfer, Christian


    necrosis factor alpha (TNF-alpha) from Mphi. Further, the efficiency of ethanol to inactivate chemically generated ROS was tested. Significant stimulation of ROS release occurred at endotoxin concentrations of 1 ng/ml or higher in both PMNs and Mphi. Ethanol significantly suppressed the formation of ROS...... immunogens and to increase the susceptibility of alcohol abusers to infectious diseases. As endotoxemia is common in alcohol abusers, we investigated the effect of ethanol (21.7 mmol/liter) on the luminol-amplified chemiluminescence of PMNs and Mphi after endotoxin stimulation and the release of tumor...... identical (6 to 8 ng/ml) in both PMNs and Mphi, independent of the presence of ethanol. In contrast to ROS formation, ethanol had no effect on the amount of TNF-alpha produced by endotoxin-stimulated Mphi. Ethanol was shown to be unable to decrease the levels of chemically generated ROS under physiological...

  6. Garlic (Allium sativum) stimulates lipopolysaccharide-induced tumor necrosis factor-alpha production from J774A.1 murine macrophages. (United States)

    Sung, Jessica; Harfouche, Youssef; De La Cruz, Melissa; Zamora, Martha P; Liu, Yan; Rego, James A; Buckley, Nancy E


    Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion. © 2014 The Authors. Phytotherapy Research published by John Wiley & Sons, Ltd.

  7. Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn's disease: a prospective study. (United States)

    Ryan, B M; Russel, M G V M; Schurgers, L; Wichers, M; Sijbrandij, J; Stockbrugger, R W; Schoon, E


    Patients with Crohn's disease are at increased risk of osteoporosis. Disease activity and circulating proinflammatory cytokines are thought to play a role in this process. Infliximab, a chimaeric antitumour necrosis factor-alpha antibody is effective in the treatment of Crohn's disease. The aim of this study was to investigate the impact of treatment with infliximab on bone turnover in Crohn's disease patients. This was a prospective trial. Twenty-four patients with active Crohn's disease were treated with infliximab (5 mg/kg). Bone markers were assayed pre- and post-treatment. Bone formation was measured using serum bone-specific alkaline phosphatase and total osteocalcin and bone resorption using serum N-telopeptide cross-linked type 1 collagen. Infliximab therapy caused a significant increase in both markers of bone formation in patients with active Crohn's disease. No significant change in the bone resorption marker serum N-telopeptide cross-linked type 1 was found. Infliximab therapy had a significant beneficial effect on bone metabolism in patients with active Crohn's disease. These findings further support the theory that active ongoing inflammation and high levels of circulating cytokines play a pivotal role in the pathogenesis of bone loss in patients with Crohn's disease.

  8. Tumor Necrosis Factor Alpha Signaling in Trigeminal Ganglion Contributes to Mechanical Hypersensitivity in Masseter Muscle During Temporomandibular Joint Inflammation. (United States)

    Ito, Reio; Shinoda, Masamichi; Honda, Kuniya; Urata, Kentaro; Lee, Jun; Maruno, Mitsuru; Soma, Kumi; Okada, Shinji; Gionhaku, Nobuhito; Iwata, Koichi

    To determine the involvement of tumor necrosis factor alpha (TNFα) signaling in the trigeminal ganglion (TG) in the mechanical hypersensitivity of the masseter muscle during temporomandibular joint (TMJ) inflammation. A total of 55 male Sprague-Dawley rats were used. Following injection of Complete Freund's Adjuvant into the TMJ, the mechanical sensitivities of the masseter muscle and the overlying facial skin were measured. Satellite glial cell (SGC) activation and TNFα expression in the TG were investigated immunohistochemically, and the effects of their inhibition on the mechanical hypersensitivity of the masseter muscle were also examined. Student t test or two-way repeated-measures analysis of variance followed by Bonferroni multiple comparisons test were used for statistical analyses. P < .05 was considered to reflect statistical significance. Mechanical allodynia in the masseter muscle was induced without any inflammatory cell infiltration in the muscle after TMJ inflammation. SGC activation and an increased number of TNFα-immunoreactive cells were induced in the TG following TMJ inflammation. Intra-TG administration of an inhibitor of SGC activity or of TNFα-neutralizing antibody depressed both the increased number of TG cells encircled by activated SGCs and the mechanical hypersensitivity of the masseter following TMJ inflammation. These findings suggest that persistent masseter hypersensitivity associated with TMJ inflammation was mediated by SGC-TG neuron interactions via TNFα signaling in the TG.

  9. Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha

    Directory of Open Access Journals (Sweden)

    Ge Li


    Full Text Available Tumor necrosis factor alpha (TNFα plays a key role in the pathogenesis of rheumatoid arthritis (RA. Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases.

  10. Tumor necrosis factor-alpha is a potential diagnostic biomarker for chronic neuropathic pain after spinal cord injury. (United States)

    Xu, Jun; E, Xiaoqiang; Liu, Huiyong; Li, Feng; Cao, Yanhui; Tian, Jun; Yan, Jinglong


    Neuropathic pain (NP) is one of the most common complications after spinal cord injury (SCI), but no protein biomarkers has ever been introduced into clinical diagnosis. Previous studies implicated that toll-like receptor (TLR) 4 played a critical role in the development of NP in animal SCI models. Here, a total of 140 participants were recruited, 70 of them were SCI-NP subject and the rest 70 controls did not show neuropathic symptoms. TLR4 was upregulated significantly in SCI-NP patients compared with SCI-noNP subjects. Furthermore, we measured the concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), two TLR4 downstream pro-inflammatory cytokines, to assess their diagnostic values. Receiver operating characteristics (ROC) analysis revealed that TNF-α had great potential advantages to predict the progression of neuropathy, the risks of NP were strongly increased in SCI subjects with higher levels of TNF-α (odds ratio: 4.92; 95% confidence interval: 1.89-12.32). These results suggested neuro-immune activation contributed to the development of neuropathic disorder after SCI, and TNF-α could be a potential sensitive diagnostic biomarker for chronic neuropathic pain in SCI patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1. (United States)

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


    Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1. Copyright 2009 Elsevier Inc. All rights reserved.

  12. Peri-implant parameters, tumor necrosis factor-alpha, and interleukin-1 beta levels in vaping individuals. (United States)

    Al-Aali, Khulud A; Alrabiah, Mohammed; ArRejaie, Aws S; Abduljabbar, Tariq; Vohra, Fahim; Akram, Zohaib


    To the author's knowledge, there has been no study that has assessed clinical, radiographic, and immunological peri-implant parameters among individuals vaping e-cigarette (e-cig). This pilot study aimed to compare clinical and radiographic peri-implant parameters and levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β levels among individuals vaping e-cigs and never smoker (NS). Forty-seven individuals vaping e-cigs (group-1) and 45 NS (group-2) were included. Demographic and implant-related data were collected using a structured baseline questionnaire. Peri-implant plaque index (PI), bleeding on probing (BOP), and probing depth (PD) were recorded and peri-implant bone loss (PIBL) were assessed using standardized digital radiographs. Enzyme-linked immunosorbent assay was used to assess the levels of TNF-α and IL-1β in peri-implant sulcular fluid. Bleeding on probing showed statistically significantly higher values in group-2 patients as compared to group-1 patients (P vaping individuals. Increased levels of proinflammatory cytokines in peri-implant sulcular fluid may suggest greater local inflammatory response in vaping individuals for peri-implant inflammation. © 2018 Wiley Periodicals, Inc.

  13. Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha. (United States)

    Petkova-Kirova, Polina S; Gursoy, Erdal; Mehdi, Haider; McTiernan, Charles F; London, Barry; Salama, Guy


    Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.

  14. The effect of salvianolate on serum levels of tumor necrosis factor-alpha in ApoE-/- mice

    International Nuclear Information System (INIS)

    Gao Yuqi; Wu Zonggui; Liang Chun; Luo Nanping; Zhang Hongming; Xu Jun; Li Xiaoyan; Xu Lin


    Objective: To study the possible antiatherosclerotic mechanism of salvianolate, through examination of the effect of salvianolate on serum levels of tumor necrosis factor-alpha (TNF-α) in C57BL/6J ApoE -/- mice. Methods: Fifty C57BL/6J ApoE -/- mice of 8 week-old were fed high cholesterol diet for 12 weeks. After sacrificing 2 mice to examine formation of atheromatous plaques at root of aorta, the remaining 48 C57BL/6J ApoE -/- mice were divided randomly into 4 groups: (1) model group (without salvianolate treatment) (2) low dosage of salvianolate (60mg/kg) group (3) medium dosage of salvianolate (120mg/kg) group and (4) high dosage of salvianolate(240mg/kg) group. Ten C57BL/6 wild-type mice served as controls. At the end of 32nd week, serum levels of TNF-α were measured with specific radioimmunoassay. Results: The serum levels of TNF-α were decreased in ApoE -/- mice with the increase of salvianolate dosage (P 0.05). Conclusion: Salvianolate treatment can decrease the serum levels of TNF-α in C57BL/6 ApoE -/- mice and inhibit inflammation process. This may be one of the possible mechanism of antiatherosclerosis of salvianolate. (authors)

  15. A Polymorphism in Hepatocyte Nuclear Factor 1 Alpha, rs7310409, Is Associated with Left Main Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Rui Liu


    Full Text Available Coronary artery disease is the leading cause of mortality and morbidity in the world. Left main coronary artery disease (LMCAD is a particularly severe phenotypic form of CAD and has a genetic basis. We hypothesized that some inflammation- and hyperhomocysteinemia-related gene polymorphisms may contribute to LMCAD susceptibility in a Chinese population. We studied the association between polymorphisms in the genes hepatocyte nuclear factor 1 alpha (HNF1A; rs7310409, G/A, C-reactive protein (rs1800947 and rs3093059 T/C, methylenetetrahydrofolate reductase (rs1801133, C/T, and methylenetetrahydrofolate dehydrogenase (rs1076991, A/G in 402 LMCAD and 804 more peripheral CAD patients in a Chinese population. Genotyping was performed using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. When the HNF1A rs7310409 GG homozygote genotype was used as the reference group, both the individual, GA and AA, and combined GA/AA genotypes were associated with an increased risk of LMCAD. This single nucleotide polymorphism (rs7310409 is strongly associated with plasma CRP levels. In conclusion, the present study provides evidence that the HNF1A rs7310409 G/A functional polymorphism may contribute to the risk of LMCAD.

  16. Rapid detection of hypoxia-inducible factor-1-active tumours: pretargeted imaging with a protein degrading in a mechanism similar to hypoxia-inducible factor-1{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Ueda, Masashi [Kyoto University, Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto (Japan); Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto (Japan); Kudo, Takashi; Konishi, Hiroaki; Miyano, Azusa; Ono, Masahiro; Saji, Hideo [Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto (Japan); Kuge, Yuji [Kyoto University, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto (Japan); Hokkaido University, Central Institute of Isotope Science, Sapporo (Japan); Mukai, Takahiro [Kyushu University, Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Fukuoka (Japan); Tanaka, Shotaro; Kizaka-Kondoh, Shinae; Hiraoka, Masahiro [Kyoto University, Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto (Japan)


    Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumour progression. For the imaging of HIF-1-active tumours, we previously developed a protein, POS, which is effectively delivered to and selectively stabilized in HIF-1-active cells, and a radioiodinated biotin derivative, (3-{sup 123}I-iodobenzoyl)norbiotinamide ({sup 123}I-IBB), which can bind to the streptavidin moiety of POS. In this study, we aimed to investigate the feasibility of the pretargeting method using POS and {sup 123}I-IBB for rapid imaging of HIF-1-active tumours. Tumour-implanted mice were pretargeted with POS. After 24 h, {sup 125}I-IBB was administered and subsequently, the biodistribution of radioactivity was investigated at several time points. In vivo planar imaging, comparison between {sup 125}I-IBB accumulation and HIF-1 transcriptional activity, and autoradiography were performed at 6 h after the administration of {sup 125}I-IBB. The same sections that were used in autoradiographic analysis were subjected to HIF-1{alpha} immunohistochemistry. {sup 125}I-IBB accumulation was observed in tumours of mice pretargeted with POS (1.6%ID/g at 6 h). This result is comparable to the data derived from {sup 125}I-IBB-conjugated POS-treated mice (1.4%ID/g at 24 h). In vivo planar imaging provided clear tumour images. The tumoral accumulation of {sup 125}I-IBB significantly correlated with HIF-1-dependent luciferase bioluminescence (R=0.84, p<0.01). The intratumoral distribution of {sup 125}I-IBB was heterogeneous and was significantly correlated with HIF-1{alpha}-positive regions (R=0.58, p<0.0001). POS pretargeting with {sup 123}I-IBB is a useful technique in the rapid imaging and detection of HIF-1-active regions in tumours. (orig.)

  17. Subaqueous Cap Design: Selection of Bioturbation Profiles, Depths, and Process Rates

    National Research Council Canada - National Science Library

    Clarke, Douglas


    .... For either practice to satisfy the requirement of isolation of the contaminated sediments, design of caps of clean material must account for multiple factors affecting the long-term stability of the cap...


    Directory of Open Access Journals (Sweden)

    Buslov Anatoliy Semenovich


    The data has proven that cap-covered piles are substantially more economical (over 40 % in terms of materials consumption rate if compared to constant cross-section piles (cap-free or broadening piles, all other factors being equal.

  19. Relationship of tumor necrosis factor alpha genotypes with various biochemical parameters of normal, over weight and obese human subjects

    International Nuclear Information System (INIS)

    Raza, M.; Chaudhary, B.; Shakoori, A.R.


    Tumor Necrosis Factor (TNF-alpha) is expressed primarily in adipocytes and elevated levels of this cytokine have been associated with obesity. The purpose of this investigation was to test whether the TNF-alpha -308 polymorphism were associated with insulin resistance or obesity related traits in non-diabetic and diabetic patients visiting Sheikh Zayed Hospital, Lahore, Fatima Hospital and Irfan Clinic in Sargodha. In non diabetic subjects the AA allele carriers, compared with homozygous G allele carriers had significantly lower (28%) triglyceride values and 15% higher HDL yal ues, whereas other parameters tested 81id not show any significant variation. In diabetic patients the AA allele carriers, compared with GG allele carriers, besides having 31 % higher FBS and 26% higher creatinine, had 20% higher cholesterol and 34% higher triglycerides. The HDL values were 14% less, compared to GG allele carriers. In normal subjects (BMI 22.85:1:0.25 kgim2), the AA allele carriers showed 132%, 125%, 65% and 112% higher triglycerides, cholesterol and LDL values compared with GG allele carriers. The HDL and creatinine did not show any significant change. In the overweight subjects (BMI: 27.17+-0.17 kgim/sup 2/) all these values were lower than in AA allele carriers compared with GG allele carriers. The AA allele carries had FBS, triglycerides, cholesterol and LDL 28%, 48%, 14% and 14% lower than in the GG allele' carriers, respectively. In obese subjects, (BMI: 36.73+-0.78kgm/sup 2/), however, the FBS, triglycerides, cholesterol and creatinine values were 5%, 8%, 7% and 14% higher in AA allele carries compared to GG allele carriers, respectively. The LDL content was 8% lower in AA allele carrier as compared with the respective GG allele carriers, It is concluded that replacement of G at -308 with A leads to reduced risk for cardiovascular disease in non-diabetic subject, whereas in diabetic patients this mutation-increases the risk of CVD. Using BMI as index of obesity, it was

  20. Added Mass of a Spherical Cap Body

    Czech Academy of Sciences Publication Activity Database

    Šimčík, Miroslav; Punčochář, Miroslav; Růžička, Marek


    Roč. 118, OCT 18 (2014), s. 1-8 ISSN 0009-2509 R&D Projects: GA MŠk(CZ) LD13018 Institutional support: RVO:67985858 Keywords : spherical cap * added mass * single particle Subject RIV: CI - Industrial Chemistry, Chemical Engineering Impact factor: 2.337, year: 2014

  1. Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Ljungdahl, A; Höjeberg, B


    in cryosections of spinal cords using in situ hybridization technique with synthetic oligonucleotide probes. Three stages of cytokine mRNA expression could be distinguished: (i) interleukin (IL)-12, tumor necrosis factor (TNF)-beta (= lymphotoxin-alpha) and cytolysin appeared early and before onset of clinical...... signs of EAE; (ii) TNF-alpha peaked at height of clinical signs of EAE; (iii) IL-10 appeared increasingly at and after clinical recovery. The early expression of IL-12 prior to the expression of interferon-gamma (IFN-gamma) mRNA shown previously is consistent with a role of IL-12 in promoting...... proliferation and activation of T helper 1 (Th1) type cells producing IFN-gamma. The TNF-beta mRNA expression prior to onset of clinical signs favours a role for this cytokine in disease initiation. A pathogenic effector role of TNF-alpha was suggested from these observations that TNF-alpha mRNA expression...

  2. Time of hepatocellular carcinoma recurrence after liver resection and alpha-fetoprotein are important prognostic factors for salvage liver transplantation. (United States)

    Lee, Sanghoon; Hyuck David Kwon, Choon; Man Kim, Jong; Joh, Jae-Won; Woon Paik, Seung; Kim, Bong-Wan; Wang, Hee-Jung; Lee, Kwang-Woong; Suh, Kyung-Suk; Lee, Suk-Koo


    Salvage liver transplantation (LT) is considered a feasible option for the treatment of recurrent hepatocellular carcinoma (HCC). We performed this multicenter study to assess the risk factors associated with the recurrence of HCC and patient survival after salvage LT. Between January 2000 and December 2011, 101 patients who had previously undergone liver resection (LR) for HCC underwent LT at 3 transplant centers in Korea. Sixty-nine patients' data were retrospectively reviewed for the analysis. The recurrence of HCC was diagnosed at a median of 10.6 months after the initial LR, and patients underwent salvage LT. Recurrences were within the Milan criteria in 48 cases and were outside the Milan criteria in 21 cases. After salvage LT, 31 patients had HCC recurrence during a median follow-up period of 24.5 months. There were 24 deaths, and 20 were due to HCC recurrence. The 5-year overall survival rate was approximately 54.6%, and the 5-year recurrence-free survival rate was 49.3%. HCC recurrence within the 8 months after LR [hazard ratio (HR) = 3.124, P = 0.009], an alpha-fetoprotein level higher than 200 ng/mL (HR = 2.609, P = 0.02), and HCC outside the Milan criteria at salvage LT (HR = 2.219, P = 0.03) were independent risk factors for poor recurrence-free survival after salvage LT. In conclusion, the timing and extent of HCC recurrence after primary LR both play significant roles in the outcome of salvage LT. © 2014 American Association for the Study of Liver Diseases.

  3. The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Beggs, Kevin M., E-mail: [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160 (United States); McGreal, Steven R., E-mail: [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160 (United States); McCarthy, Alex [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160 (United States); Gunewardena, Sumedha, E-mail: [Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd, 2027 HLSIC, Kansas City, KS 66160 (United States); Lampe, Jed N., E-mail: [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160 (United States); Lau, Christoper, E-mail: [Developmental Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Apte, Udayan, E-mail: [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, 4052 HLSIC, Kansas City, KS 66160 (United States)


    Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers. - Highlights: • PFOA and PFOS cause decreased HNF4α protein expression in human hepatocytes. • PFOA and PFOS promote changes associated with lipid metabolism and carcinogenesis. • PFOA and PFOS induced changes in gene expression associated with cellular dedifferentiation. • PFOA and PFOS induce expression of Nanog, a transcription factor involved in stem cell development.

  4. Quantitative assessment of the influence of tumor necrosis factor alpha polymorphism with gastritis and gastric cancer risk. (United States)

    Li, Ming; Wang, Yinping; Gu, Yahong


    Tumor necrosis factor alpha (TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations.

  5. Infection of Human Fallopian Tube Epithelial Cells with Neisseria gonorrhoeae Protects Cells from Tumor Necrosis Factor Alpha-Induced Apoptosis (United States)

    Morales, Priscilla; Reyes, Paz; Vargas, Macarena; Rios, Miguel; Imarai, Mónica; Cardenas, Hugo; Croxatto, Horacio; Orihuela, Pedro; Vargas, Renato; Fuhrer, Juan; Heckels, John E.; Christodoulides, Myron; Velasquez, Luis


    Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection (MOI) of Pil+ Opa+ gonococci. Bacteria showed a dose-dependent association with cells and induced the secretion of tumor necrosis factor alpha (TNF-α). A significant finding was that gonococcal infection (MOI = 1) induced apoptosis in approximately 30% of cells, whereas increasing numbers of bacteria (MOI = 10 to 100) did not induce apoptosis. Apoptosis was observed in only 11% of cells with associated bacteria, whereas >84% of cells with no adherent bacteria were apoptotic. TNF-α was a key contributor to apoptosis, since (i) culture supernatants from cells infected with gonococci (MOI = 1) induced apoptosis in naïve cultures, suggesting that a soluble factor was responsible; (ii) gonococcal infection-induced apoptosis was inhibited with anti-TNF-α antibodies; and (iii) the addition of exogenous TNF-α induced apoptosis, which was inhibited by the presence of increasing numbers of bacteria (MOI = 10 to 100). These data suggest that TNF-α-mediated apoptosis of FT epithelial cells is likely a primary host defense mechanism to prevent pathogen colonization. However, epithelial cell-associated gonococci have evolved a mechanism to protect the cells from undergoing TNF-α-mediated apoptosis, and this modulation of the host innate response may contribute to establishment of infection. Understanding the antiapoptotic mechanisms used by Neisseria gonorrhoeae will inform the pathogenesis of salpingitis and could suggest new intervention strategies for prevention and treatment of the disease. PMID:16714596

  6. The serum concentration of tumor necrosis factor alpha is not an index of growth-hormone- or obesity-induced insulin resistance. (United States)

    Pincelli, A I; Brunani, A; Scacchi, M; Dubini, A; Borsotti, R; Tibaldi, A; Pasqualinotto, L; Maestri, E; Cavagnini, F


    The tumor necrosis factor alpha (TNF-alpha) might play a central role in insulin resistance, a frequent correlate of obesity likely contributing to some obesity-associated complications. Adult growth hormone (GH) deficiency syndrome (GHDA) shares with obesity excessive fat mass, hyperlipidemia, increased cardiovascular risk, and insulin resistance. On the other hand, GH has been shown to induce transient deterioration of glucose metabolism and insulin resistance when administered in normal humans and in GHDA patients. No information is presently available on the relationship between serum TNF-alpha levels and insulin sensitivity in GHDA. We compared the serum TNF-alpha levels found in 10 GHDA patients before and after a 6-month recombinant human GH therapy (Genotropin), in an insulin resistance prone population of 16 obese (OB) patients and in 38 normal-weight healthy blood donors (controls). The insulin sensitivity was assessed by a euglycemic-hyperinsulinemic glucose clamp in all the GHDA patients and in 10 OB and in 6 control subjects. The serum TNF-alpha levels were not significantly different in OB patients (42.2 +/- 12.81 pg/ml), in GHDA patients at baseline (71.3 +/- 23.97 pg/ml), and in controls (55.3 +/- 14.28 pg/ml). A slight decrease of TNF-alpha values was noted in GHDA patients after 6 months of recombinant human GH treatment (44.5 +/- 20.19 pg/ml; NS vs. baseline). The insulin sensitivity (M) was significantly reduced in OB patients (2.4 +/- 0.30 mg/kg/min) as compared with control subjects (7.5 +/- 0.39 mg/kg/min) and in GHDA patients both at baseline (6.6 +/- 0.6 mg/kg/min) and after recombinant human GH therapy (5.6 +/- 0.7 mg/kg/min). The insulin sensitivity in the GHDA patients, similar to that of controls at baseline, worsened after recombinant human GH treatment (p < 0.05 vs. baseline; p = 0.05 vs. controls). Linear regression analysis showed no correlation between TNF-alpha and M values (see text) in all patient groups. These data indicate

  7. Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic

    DEFF Research Database (Denmark)

    Theibich, Ali; Dreyer, Lene; Magyari, Melinda


    Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AEs) are primarily infections and hypersensitivity reactions. Demyelinizing neurological symptoms resembling...... multiple sclerosis (MS) have been described as a rare AE. During about 10-year use of anti TNF-alpha, the Danish Medicines Agency has recorded eight cases of MS like AEs. The objective of this study was to estimate the incidence of demyelinizing AEs both in the central and peripheral nervous system after...... treatment with anti TNF-alpha in a cohort of patients from a large rheumatologic outpatient clinic in Copenhagen. In a 4-year period from January 2008 to December 2011, approximately 550 patients annually were undergoing treatment with anti TNF-alpha inhibitors in our department. We collected data on all...

  8. Pre-radiotherapy PSA progression is a negative prognostic factor in prostate cancer patients using 5-alpha-reductase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Taussky, Daniel; Lambert, Carole; Bahary, Jean-Paul; Beauchemin, Marie-Claude; Barkati, Maroie; Menard, Cynthia; Delouya, Guila [Hopital Notre-Dame, Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); CRCHUM-Centre de Recherche du Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Piotte, Julie [Hopital Notre-Dame, Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, QC (Canada); Zorn, Kevin C.; Zanaty, Marc [Centre Hospitalier de l' Universite de Montreal, Section of Urology, Department of Surgery, Montreal, QC (Canada); Krishnan, Vimal [Centre Hospitalier de l' Universite de Montreal, Department of Pathology, Montreal, Quebec (Canada)


    To investigate the impact of 5-alpha-reductase inhibitor (5-ARI) use on radiotherapy outcomes for localized prostate cancer. We included 203 patients on a 5-ARI from our institutional database comprising over 2500 patients who had been treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients received a 5-ARI for urinary symptoms or active surveillance. Cancer progressions at the time of definitive treatment were analyzed according to the following criteria: (a) progression of Gleason score or increase in cancer volume on biopsy, (b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and (c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis. At a median follow-up of 38.2 months (standard deviation 22.2 months), 10 (4.9%) patients experienced BF. Concerning prostate cancer progression criteria, 52% of men demonstrated none, 37% showed only one criterion, and 11% showed two. Using univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) were significant predictive factors for BF, while Gleason progression (p = 0.3) was not. In multivariate analysis adjusted for cancer aggressiveness, rising PSA (hazard ratio, HR, 5.7; 95% confidence interval, CI, 1.1-28.8; p = 0.04) and the number of cancer progression factors (HR 2.9, 95% CI 1.2-7.0, p = 0.02) remained adverse risk factors. PSA progression experienced during 5-ARI treatment before radiotherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy. (orig.) [German] Untersuchung des Einflusses einer Behandlung mit einem 5-Alpha-Reduktaseinhibitor (5-ARI) auf das Ergebnis der Strahlentherapie beim lokalisierten Prostatakarzinom. In die Studie eingeschlossen wurden 203

  9. Functional characterization of an alpha-factor-like Sordaria macrospora peptide pheromone and analysis of its interaction with its cognate receptor in Saccharomyces cerevisiae. (United States)

    Mayrhofer, Severine; Pöggeler, Stefanie


    The homothallic filamentous ascomycete Sordaria macrospora possesses genes which are thought to encode two pheromone precursors and two seven-transmembrane pheromone receptors. The pheromone precursor genes are termed ppg1 and ppg2. The putative products derived from the gene sequence show structural similarity to the alpha-factor precursors and a-factor precursors of the yeast Saccharomyces cerevisiae. Likewise, sequence similarity has been found between the putative products of the pheromone receptor genes pre2 and pre1 and the S. cerevisiae Ste2p alpha-factor receptor and Ste3p a-factor receptor, respectively. To investigate whether the alpha-factor-like pheromone-receptor pair of S. macrospora is functional, a heterologous yeast assay was used. Our results show that the S. macrospora alpha-factor-like pheromone precursor PPG1 is processed into an active pheromone by yeast MATalpha cells. The S. macrospora PRE2 protein was demonstrated to be a peptide pheromone receptor. In yeast MATa cells lacking the endogenous Ste2p receptor, the S. macrospora PRE2 receptor facilitated all aspects of the pheromone response. Using a synthetic peptide, we can now predict the sequence of one active form of the S. macrospora peptide pheromone. We proved that S. macrospora wild-type strains secrete an active pheromone into the culture medium and that disruption of the ppg1 gene in S. macrospora prevents pheromone production. However, loss of the ppg1 gene does not affect vegetative growth or fertility. Finally, we established the yeast assay as an easy and useful system for analyzing pheromone production in developmental mutants of S. macrospora.

  10. Inhibition of sup 125 I organification and thyroid hormone release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture

    Energy Technology Data Exchange (ETDEWEB)

    Sato, K.; Satoh, T.; Shizume, K.; Ozawa, M.; Han, D.C.; Imamura, H.; Tsushima, T.; Demura, H.; Kanaji, Y.; Ito, Y. (Institute of Clinical Endocrinology, Tokyo (Japan))


    To elucidate the mechanism of decreased 131I uptake by the thyroid gland in patients with subacute thyroiditis and painless thyroiditis, human thyroid follicles were cultured with interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF alpha), and/or interferon-gamma (IFN gamma), and the effects of these cytokines on thyroid function were studied in vitro. When human thyrocytes were cultured in RPMI-1640 medium containing 0.5% fetal calf serum and TSH for 5-8 days, the cells incorporated 125I, synthesized de novo (125I)iodotyrosines and (125I)iodothyronines, and secreted (125I)T4 and (125I)T3 into the medium. IL-1 alpha and IL-1 beta inhibited 125I incorporation and (125I)iodothyronine release in a concentration-dependent manner. The minimal inhibitory effect was detected at 10 pg/ml. Electron microscopic examination revealed a marked decrease in lysosome formation in IL-1-treated thyrocytes. TNF alpha and IFN gamma also inhibited thyroid function in a concentration-dependent manner. Furthermore, when thyrocytes were cultured with IL-1, TNF alpha and IFN gamma, these cytokines more than additively inhibited thyroid function. Although the main mechanism of 131I uptake suppression in the thyroid gland in subacute thyroiditis is due to cellular damage and suppression of TSH release, our present findings suggest that IL-1, TNF alpha, and IFN gamma produced in the inflammatory process within the thyroid gland further inhibit iodine incorporation and at least partly account for the decreased 131I uptake by the thyroid gland in destruction-induced hyperthyroidism.

  11. Inhibition of 125I organification and thyroid hormone release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture

    International Nuclear Information System (INIS)

    Sato, K.; Satoh, T.; Shizume, K.; Ozawa, M.; Han, D.C.; Imamura, H.; Tsushima, T.; Demura, H.; Kanaji, Y.; Ito, Y.


    To elucidate the mechanism of decreased 131I uptake by the thyroid gland in patients with subacute thyroiditis and painless thyroiditis, human thyroid follicles were cultured with interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF alpha), and/or interferon-gamma (IFN gamma), and the effects of these cytokines on thyroid function were studied in vitro. When human thyrocytes were cultured in RPMI-1640 medium containing 0.5% fetal calf serum and TSH for 5-8 days, the cells incorporated 125I, synthesized de novo [125I]iodotyrosines and [125I]iodothyronines, and secreted [125I]T4 and [125I]T3 into the medium. IL-1 alpha and IL-1 beta inhibited 125I incorporation and [125I]iodothyronine release in a concentration-dependent manner. The minimal inhibitory effect was detected at 10 pg/ml. Electron microscopic examination revealed a marked decrease in lysosome formation in IL-1-treated thyrocytes. TNF alpha and IFN gamma also inhibited thyroid function in a concentration-dependent manner. Furthermore, when thyrocytes were cultured with IL-1, TNF alpha and IFN gamma, these cytokines more than additively inhibited thyroid function. Although the main mechanism of 131I uptake suppression in the thyroid gland in subacute thyroiditis is due to cellular damage and suppression of TSH release, our present findings suggest that IL-1, TNF alpha, and IFN gamma produced in the inflammatory process within the thyroid gland further inhibit iodine incorporation and at least partly account for the decreased 131I uptake by the thyroid gland in destruction-induced hyperthyroidism

  12. Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line. (United States)

    Baker, Olga J; Camden, Jean M; Redman, Robert S; Jones, Jonathan E; Seye, Cheikh I; Erb, Laurie; Weisman, Gary A


    Sjögren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) is elevated in exocrine glands of patients with SS, although little is known about the effects of these cytokines on salivary epithelial cell functions necessary for saliva secretion, including tight junction (TJ) integrity and the establishment of transepithelial ion gradients. The present study demonstrates that chronic exposure of polarized rat parotid gland (Par-C10) epithelial cell monolayers to TNF-alpha and IFN-gamma decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current (I(sc)) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y(2) nucleotide receptor agonist. In contrast, TNF-alpha and IFN-gamma had no effect on agonist-induced increases in the intracellular calcium concentration [Ca(2+)](i) in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-alpha and IFN-gamma increased paracellular permeability to normally impermeant proteins, altered cell and TJ morphology, and downregulated the expression of the TJ protein, claudin-1, but not other TJ proteins expressed in Par-C10 cells. The decreases in TER, agonist-induced transepithelial anion secretion, and claudin-1 expression caused by TNF-alpha, but not IFN-gamma, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-gamma causes irreversible inhibition of cellular activities associated with fluid secretion in salivary glands. Our results suggest that cytokine production is an important contributor to secretory dysfunction in SS by disrupting TJ integrity of salivary epithelium.

  13. Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

    Directory of Open Access Journals (Sweden)

    Bernhard F Gibbs

    Full Text Available Stem cell factor (SCF is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1 in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

  14. Cleft lip with or without cleft palate: Associations with transforming growth factor alpha and retinoic acid receptor loci

    Energy Technology Data Exchange (ETDEWEB)

    Chenevix-Trench, G.; Jones, K. (Queensland Inst. of Medical Research (Australia) Univ. of Queensland (Australia)); Green, A.C.; Duffy, D.L.; Martin, N.G. (Queensland Inst. of Medical Research (Australia))


    The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus. This finding has since been replicated, in whole or in part, in three independent studies. Here the authors extend their original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls. The other candidate genes were the retinoic acid receptor (RARA), the bcl-2 oncogene, and the homeobox genes 2F, 2G, and EN2. Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance. Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing). The effect on risk of the A2 allele appears to be additive, and although the A2A2 homozygote only has an odds ratio of about 2 and recurrence risk to first-degree relatives ([lambda][sub 1]) of 1.06, because it is so common it may account for as much as a third of the attributable risk of clefting. There is no evidence of interaction between the TGFA and RARA polymorphisms on risk, and jointly they appear to account for almost half the attributable risk of clefting. 43 refs., 1 fig., 4 tabs.

  15. The effect of anti-tumor necrosis factor alpha agents on the outcome in pediatric uveitis of diverse etiologies. (United States)

    Deitch, Iris; Amer, Radgonde; Tomkins-Netzer, Oren; Habot-Wilner, Zohar; Friling, Ronit; Neumann, Ron; Kramer, Michal


    This study aimed to report the clinical outcome of children with uveitis treated with anti-tumor necrosis factor alpha (TNF-α) agents. This included a retrospective cohort study. Children with uveitis treated with infliximab or adalimumab in 2008-2014 at five dedicated uveitis clinics were identified by database search. Their medical records were reviewed for demographic data, clinical presentation, ocular complications, and visual outcome. Systemic side effects and the steroid-sparing effect of treatment were documented. The cohort included 24 patients (43 eyes) of whom 14 received infliximab and 10 received adalimumab after failing conventional immunosuppression therapy. Mean age was 9.3 ± 4.0 years. The most common diagnosis was juvenile idiopathic arthritis-related uveitis (n = 10), followed by Behçet's disease (n = 4), sarcoidosis (n = 1), and ankylosing spondylitis (n = 1); eight had idiopathic uveitis. Ocular manifestations included panuveitis in 20 eyes (46.5%), chronic anterior uveitis in 19 (44.2%), and intermediate uveitis in 4 (9.3%). The duration of biologic treatment ranged from 6 to 72 months. During the 12 months prior to biologic treatment, while on conventional immunosuppressive therapy, mean visual acuity deteriorated from 0.22 to 0.45 logMAR, with a trend of recovery to 0.25 at 3 months after initiation of biologic treatment, remaining stable thereafter. A full corticosteroid-sparing effect was demonstrated in 16 of the 19 patients (84.2%) for whom data were available. Treatment was well tolerated. Treatment of pediatric uveitis with anti-TNF-α agents may improve outcome while providing steroid-sparing effect, when conventional immunosuppression fails. The role of anti-TNF-α agents as first-line treatment should be further investigated in controlled prospective clinical trials.

  16. Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma. (United States)

    Cai, Shao-Hang; Lu, Shi-Xun; Liu, Li-Li; Zhang, Chris Zhiyi; Yun, Jing-Ping


    Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan-Meier analysis was conducted to assess the prognostic value of P2-HNF4α. The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression ( p  = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC ( p = 0.002) and vascular invasion ( p = 0.017). Kaplan-Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group ( p = 0.01), validation group ( p = 0.034), and overall group of patients with HCC ( p P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

  17. Serum Tumor Necrosis Factor-alpha associates with Myocardial Oxygen Demand and Exercise Tolerance in Postmenopausal Women. (United States)

    Carter, Stephen J; Bryan, David R; Neumeier, William H; Glasser, Stephen P; Hunter, Gary R


    The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO 2max ). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest and during two submaximal workloads (i.e., ≈55% and ≈75% VO 2max ). RPP was calculated by dividing the product of heart rate and systolic blood pressure (via auscultation) by 100. Exercise tolerance corresponded with the cessation of the graded exercise test. During higher-intensity exertion, ≈75% VO 2max , multiple linear regression revealed a positive association ( r = 0.43; p = 0.015) between TNF-α and RPP while adjusting for maximal heart rate, VO 2max , large artery compliance, and percent body fat. Path analyses revealed a significant indirect effect of large artery compliance on exercise tolerance through TNF-α, β = 0.13, CI [0.03, 0.35], indicating greater levels of TNF-α associated with poorer exercise tolerance. These data suggest TNF-α independently associates with myocardial oxygen demand during physical exertion, thus highlighting the utility of higher-intensity efforts to expose important phenomena not apparent at rest. TNF-α also appears to be indirectly associated with the link between large artery compliance and exercise tolerance.

  18. Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series. (United States)

    Eisenberg, Elon; Sandler, Ifat; Treister, Roi; Suzan, Erica; Haddad, May


    Evidence suggests tumor necrosis factor-alpha (TNF-α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti-TNF-α adalimumab was assessed. Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira(®) ) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. Three subgroups of patients were identified (3 patients in each): "nonresponders", "partial responders", and "robust responders" in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT χ² = 13.83, P = 0.008; PP χ² = 10.29, P = 0.036). These results suggest adalimumab, and possibly other anti-TNF-α, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-α in the pathogenesis of CRPS justify further studies in this area. © 2013 World Institute of Pain.

  19. [Genetic cloning and expression of hypoxia inducible factor 1 alpha in high altitude hypoxic adaptation species Tibetan antelope (Pantholops hodgsonii)]. (United States)

    Liu, Fang; Wuren, Tana; Ma, Lan; Yang, Ying-Zhong; Ge, Ri-Li


    In order to investigate the role of the hypoxia inducible factor 1 alpha (HIF-1α) in the adaptation mechanism to high altitude hypoxia, the cloning of the HIF-1α gene cDNA of Tibetan antelope (Pantholops hodgsonii), using RT-PCR and RACE, was applied, and the comparative analysis of the tissue-specific expressions of HIF-1α among Tibetan antelope, Tibetan sheep and plain sheep was performed using real-time PCR and Western blot. The sequence analysis indicated that the cDNA sequences acquired by cloning from the HIF-1α gene of Tibetan antelope comprised a 2 471-bp open reading frame (ORF) and a 1 911-bp 3'UTR. The similarity between its coding sequence, predicted amino acid sequence and HIF-1α of other mammals exceeded 87%, in which the similarity with cow was up to more than 98%, which showed that this sequence was the cDNA of HIF-1α of Tibetan antelope. The results of real-time PCR and Western blot showed that expressions of HIF-1α mRNA and protein appeared in Tibetan antelope's lung, cardiac muscle and skeletal muscle, with the highest expression in lung. HIF-1α mRNA and protein had obvious differential expression in these tissues. Further research showed that Tibetan antelope and Tibetan sheep possessed higher expressions of HIF-1α protein in the three tissues above-mentioned compared with plain sheep, and the expressions of HIF-1α mRNA and protein in Tibetan antelope's lung, cardiac muscle and skeletal muscle were higher than those of Tibetan sheep. It illustrates that the hypoxic HIF-1α-specific expression is one of the molecular bases of high altitude hypoxia adaptation in Tibetan antelope.

  20. Alteration of serum tumor necrosis factor-alpha level in gestational diabetes mellitus and correlation with insulin resistance

    International Nuclear Information System (INIS)

    Zou Gang; Li Cuiyin; Shao Hao; Lu Zeyuan; Lai Liping; Liu Lan; Hu Xiaorong


    Objective: To explore the dynamic of tumor necrosis factor-alpha (TNF-α)and its correlation with insulin resistance (IR)during different stages of gestational diabetes mellitus (GDM). Methods: Thirty-two subjects with GDM and 31 cases of normal pregnant women nonnal glucose tolerance, NGT were enrolled in the study, serum TNF-α and insulin were determined by radioimmunoassay. The plasma glucose was measured by using glucose oxidase. Tests repeated for each group according different stages of prenatal 25-28 weeks, 29-32 weeks, 37-38 weeks and postpartum 6-8 weeks. IR was assessed by the homeostasis model of assessment for insulin resistance index (HOMA-IR). Results: (1)Serum TNF-α levels in CDM and NGT group rose with gestational age, and both significantly decreased at postpartum. (2) Serum TNF-α levels in GDM of above-mentioned four stages respectively were (7.05±0.67) ng/L, (7.11± 0.75) ng/L, (7.36±0.79) ng/L, (5.46±0.37) ng/L respectively. All significantly increased than those in the same stage group (t=7.81, 7.05, 7.15, P<0.01). (3) Maternal serum TNF-α levels were in positive correlation with HOMA-IR in GDM (r=0.571, P<0.05). Conclusions: Serum TNF-α levels in GDM rose with gestational age, but significantly decreased at postpartum. The dynamic changes of serum TNF-α contribute to occurrence of insulin resistance. (authors)

  1. Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia. (United States)

    Hill, M R; Clarke, S; Rodgers, K; Thornhill, B; Peters, J M; Gonzalez, F J; Gimble, J M


    Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARalpha) as a potential target to modulate regulation of the immune response. Since PPARalpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARalpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARalpha wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARalpha. PPARalpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARalpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARalpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARalpha in vivo can be masked by other

  2. Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers. (United States)

    Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke; Solomon, Thomas P J; Lehrskov-Schmidt, Lars; Holst, Jens Juul; Møller, Kirsten


    Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect. Copyright © 2013 John Wiley & Sons, Ltd.

  3. Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma. (United States)

    Zhao, Xianda; Fan, Wei; Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia


    Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.

  4. Preliminary characterisation of tumor necrosis factor alpha and interleukin-10 responses to Chlamydia pecorum infection in the koala (Phascolarctos cinereus.

    Directory of Open Access Journals (Sweden)

    Marina Mathew

    Full Text Available Debilitating infectious diseases caused by Chlamydia are major contributors to the decline of Australia's iconic native marsupial species, the koala (Phascolarctos cinereus. An understanding of koala chlamydial disease pathogenesis and the development of effective strategies to control infections continue to be hindered by an almost complete lack of species-specific immunological reagents. The cell-mediated immune response has been shown to play an influential role in the response to chlamydial infection in other hosts. The objective of this study, hence, was to provide preliminary data on the role of two key cytokines, pro-inflammatory tumour necrosis factor alpha (TNFα and anti-inflammatory interleukin 10 (IL10, in the koala Chlamydia pecorum response. Utilising sequence homology between the cytokine sequences obtained from several recently sequenced marsupial genomes, this report describes the first mRNA sequences of any koala cytokine and the development of koala specific TNFα and IL10 real-time PCR assays to measure the expression of these genes from koala samples. In preliminary studies comparing wild koalas with overt chlamydial disease, previous evidence of C. pecorum infection or no signs of C. pecorum infection, we revealed strong but variable expression of TNFα and IL10 in wild koalas with current signs of chlamydiosis. The description of these assays and the preliminary data on the cell-mediated immune response of koalas to chlamydial infection paves the way for future studies characterising the koala immune response to a range of its pathogens while providing reagents to assist with measuring the efficacy of ongoing attempts to develop a koala chlamydial vaccine.

  5. Preliminary characterisation of tumor necrosis factor alpha and interleukin-10 responses to Chlamydia pecorum infection in the koala (Phascolarctos cinereus). (United States)

    Mathew, Marina; Beagley, Kenneth W; Timms, Peter; Polkinghorne, Adam


    Debilitating infectious diseases caused by Chlamydia are major contributors to the decline of Australia's iconic native marsupial species, the koala (Phascolarctos cinereus). An understanding of koala chlamydial disease pathogenesis and the development of effective strategies to control infections continue to be hindered by an almost complete lack of species-specific immunological reagents. The cell-mediated immune response has been shown to play an influential role in the response to chlamydial infection in other hosts. The objective of this study, hence, was to provide preliminary data on the role of two key cytokines, pro-inflammatory tumour necrosis factor alpha (TNFα) and anti-inflammatory interleukin 10 (IL10), in the koala Chlamydia pecorum response. Utilising sequence homology between the cytokine sequences obtained from several recently sequenced marsupial genomes, this report describes the first mRNA sequences of any koala cytokine and the development of koala specific TNFα and IL10 real-time PCR assays to measure the expression of these genes from koala samples. In preliminary studies comparing wild koalas with overt chlamydial disease, previous evidence of C. pecorum infection or no signs of C. pecorum infection, we revealed strong but variable expression of TNFα and IL10 in wild koalas with current signs of chlamydiosis. The description of these assays and the preliminary data on the cell-mediated immune response of koalas to chlamydial infection paves the way for future studies characterising the koala immune response to a range of its pathogens while providing reagents to assist with measuring the efficacy of ongoing attempts to develop a koala chlamydial vaccine.

  6. Effects of polymorphic variations in tumor necrosis factor alpha and occupational exposure to grain dust on longitudinal decline in pulmonary function. (United States)

    Pahwa, Punam; Nakagawa, Kazuko; Koehncke, Niels; McDuffie, Helen H


    Longitudinal declines in pulmonary function are associated with individuals experiencing occupational exposure to organic dusts in combination with lifestyle factors such as cigarette smoking and with genetic factors, and interactions between these factors. To investigate the relationship between polymorphism of genes encoding Tumor Necrosis Factor Alpha (TNF-alpha) and longitudinal lung function decline in grain workers exposed to grain dust. Male grain handlers who participated in the Saskatchewan Grain Workers Surveillance Program from 2002 through 2005 provided demographic, occupational, lifestyle, and respiratory symptoms information as well as pulmonary function measurements and DNA for genotyping. Marginal models using the generalized estimating equations approach were fitted by using a SAS PROC GENMOD to predict the annual decline in Forced Expired Volume in one second (FEV(1)) and Forced Vital Capacity (FVC). Smoking intensity contributed to the decline in FEV(1.)Among *1/*1 homozygotes and *1/*2 heterozygotes, grain workers with grain industry had significantly lower FEV(1)declines compared to those of the other two exposure groups (>10 and 20 years in the grain industry). The annual declines in FEV(1)for grain workers who were either *1/*1 homozygote or *1/*2 heterozygote and had been in the grain industry for grain workers who were *2/*2 genotype and had been in the industry for grain industry is an effect modifier between TNF-alpha 308 genotype and longitudinal decline in FEV(1)in male subjects exposed to grain dust.

  7. Secretion of mature mouse interleukin-2 by Saccharomyces cerevisiae: use of a general secretion vector containing promoter and leader sequences of the mating pheromone alpha-factor. (United States)

    Miyajima, A; Bond, M W; Otsu, K; Arai, K; Arai, N


    We have constructed a general expression vector which allows the synthesis and secretion of processed gene products in Saccharomyces cerevisiae. This vector contains yeast DNA, including the promoter of the mating pheromone (alpha-factor), its downstream leader sequence, and the TRP5 terminator. A cDNA [encoding mature mouse interleukin-2 (IL-2); Yokota et al., Proc. Natl. Acad. Sci. USA 82 (1984) 68-72] was fused immediately downstream to the alpha-factor leader sequence. The resulting recombinant plasmid directed the synthesis of mature mouse IL-2 in S. cerevisiae, with most of the T-cell growth-factor (TCGF) activity secreted into the culture fluid and extracellular space. TCGF activities in the cell extract, as well as in the culture fluid, increased in parallel with cell growth. Production of mature mouse IL-2 was inhibited by tunicamycin (TM), with precursor molecules accumulating in the cell extract. The precursor was processed accurately at the junction between the alpha-factor peptide leader sequence and the coding sequence downstream, yielding mature IL-2. The Mr of the secreted mouse IL-2 determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) was 17 kDal, a value expected for the mature mouse IL-2 polypeptide based on the nucleotide (nt) sequence.

  8. A prevalent amino acid polymorphism at codon 98 (Ala98Val) of the hepatocyte nuclear factor-1alpha is associated with maturity-onset diabetes of the young and younger age at onset of type 2 diabetes in Asian Indians

    DEFF Research Database (Denmark)

    Anuradha, Shekher; Radha, Venkatesan; Deepa, Raj


    Among Europeans, mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene are associated with the most common form of maturity-onset diabetes of the young (MODY)3. In Asian Indians, type 2 diabetes occurs earlier and often overlaps with MODY, but the genetics of the latter are unknown....... The aim of this study was to estimate the prevalence of Ala98Val polymorphism of the HNF1alpha gene in different types of diabetes in Asian Indians....

  9. Inhibition of hypoxia inducible factor-1alpha by dihydroxyphenylethanol, a product from olive oil, blocks microsomal prostaglandin-E synthase-1/vascular endothelial growth factor expression and reduces tumor angiogenesis. (United States)

    Terzuoli, Erika; Donnini, Sandra; Giachetti, Antonio; Iñiguez, Miguel A; Fresno, Manuel; Melillo, Giovanni; Ziche, Marina


    2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity. To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1beta (IL-1beta) and prostaglandin E-2 (PGE-2). DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 mumol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1beta-mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1alpha. Moreover, DPE blocked mPGEs-1-dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1alpha, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal-related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1alpha expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1alpha translation. We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1alpha/mPGEs-1/VEGF axis.

  10. Potentiation of the isoproterenol-induced net /sup 45/Ca uptake into the ventricular myocardium of rats by means of 9. cap alpha. -fluorocortisoleacetate, dihydrotachysterole or NaH/sub 2/PO/sub 4/. Cancelling of the potentiation by organic Ca/sup 2 +/ antagonists or K/sup +/ and Mg/sup 2 +/ ions

    Energy Technology Data Exchange (ETDEWEB)

    Hein, R


    Myocardial necroses resembling infarctions as well as disseminated myocardial necroses can be induced in rats by high doses of isoprotenerol which effects a maximum stimulation of the decomposition of energy-rich phosphate. This leads to an isoprotenerol-induced increase of the transmembranous Ca/sup + +/ influx, flooding the myocardium with Ca/sup + +/ ions. It is these Ca/sup + +/ ions which then trigger the break-down of the ATP and creatine phosphate fractions by activating the myofibrit-ATPase and impairing the mitochondrial function. It seems that physiological Ca/sup + +/ antagonists such as K/sup +/- or Mg/sup + +/-salts counteract the loss of energy-rich phosphate, thus preventing necroses. A new group of organic Ca/sup + +/ antagonists (verapamil, substance D 600, prenylamine) appears to be even more effective in this respect. Given in appropriate doses, these substances may prevent the isoprotenerol-induced Ca/sup + +/ flooding of the myocardium to a large extent, so that a break-down of the ATP and creatine phosphate fractions is avoided. On the other hand, the isoprotenerol-induced increase of the Ca/sup + +/ influx may be further potentiated by a preliminary treatment of the animals with 9..cap alpha..-fluorocortisoleacetate, dihydrotachysterole or NaH/sub 2/PO/sub 4/. This results in an extreme loss of energy-rich phosphate from the myocardium with excessive enhancement of necrosis production. The findings suggest that - unrecognized so far - Ca/sup + +/ ions play a key role in the generation of myocardial necroses: the present assumption, according to which increased Ca/sup + +/ uptake into damaged myocardial fibres is only a result - or at the most an accompanying symptom - of necrosis can thus no longer be considered valid.

  11. Evaluation of accuracy and uncertainty of ELISA assays for the determination of interleukin-4, interleukin-5, interferon-gamma and tumor necrosis factor-alpha

    DEFF Research Database (Denmark)

    Borg, Lone; Kristiansen, Jesper; Christensen, Jytte M


    . However, models for establishing the traceability and uncertainty of immunoassay results are lacking. Sandwich enzyme-linked immunosorbent assays (ELISAs) were developed for determination of the human cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), interferon-y (IFN-gamma) and tumor necrosis factor-alpha...... (TNF-alpha). The accuracy of each of the assays was evaluated in the ranges of 1-15 microg/l (IL-4), 0.001-1 microg/l (IL-5), 0.5-2.5 microg/l (IFN-T) and 0.14-2.2 microg/l (TNF-alpha). Other evaluated performance characteristics were the limit of detection (LOD), immunological specificity......) of the assessed ELISAs was found to be in the range of 11-18%, except for IL-5 where RSDA increased at decreasing concentrations. The LOD was 0.12 microg/l, 0.0077 microg/l, 0.0069 microg/l and 0.0063 microg/l for IL-4, IL-5, IFN-gamma and TNF-alpha, respectively. Traceability to the WHO IS was established...

  12. Differential Effects of Self-Reported Lifetime Marijuana Use on Interleukin-1 Alpha and Tumor Necrosis Factor in African American Adults


    Keen, Larry; Turner, Arlener D.; Callender, Clive; Campbell, Alfonso


    It is unknown how lifetime marijuana use affects different proinflammatory cytokines. The purpose of the current study is to explore potential differential effects of lifetime marijuana use on interleukin-1 alpha (IL-1α) and tumor necrosis factor (TNF) in a community based sample. Participants included 168 African American adults (51% female, median age= 47 years). Upon study entry, blood was drawn and the participants completed questions regarding illicit drug use history whose answers were ...

  13. Supernatants from Staphylococcus epidermidis grown in the presence of different antibiotics induce differential release of tumor necrosis factor alpha from human monocytes.


    Mattsson, E; Van Dijk, H; Verhoef, J; Norrby, R; Rollof, J


    Bacterial products from gram-positive bacteria, such as peptidoglycan, teichoic acid, and toxins, activate mononuclear cells to produce tumor necrosis factor alpha (TNF). The present study evaluated the release of soluble cell wall components from Staphylococcus epidermidis capable of inducing TNF after exposure of the bacteria to various antibiotics. A clinical S. epidermidis isolate (694) was incubated with either penicillin, oxacillin, vancomycin, or clindamycin at five times the MIC. Supe...

  14. MicroRNA-212 post-transcriptionally regulates oocyte-specific basic-helix-loop-helix transcription factor, factor in the germline alpha (FIGLA, during bovine early embryogenesis.

    Directory of Open Access Journals (Sweden)

    Swamy K Tripurani

    Full Text Available Factor in the germline alpha (FIGLA is an oocyte-specific basic helix-loop-helix transcription factor essential for primordial follicle formation and expression of many genes required for folliculogenesis, fertilization and early embryonic survival. Here we report the characterization of bovine FIGLA gene and its regulation during early embryogenesis. Bovine FIGLA mRNA expression is restricted to gonads and is detected in fetal ovaries harvested as early as 90 days of gestation. FIGLA mRNA and protein are abundant in germinal vesicle and metaphase II stage oocytes, as well as in embryos from pronuclear to eight-cell stage but barely detectable at morula and blastocyst stages, suggesting that FIGLA might be a maternal effect gene. Recent studies in zebrafish and mice have highlighted the importance of non-coding small RNAs (microRNAs as key regulatory molecules targeting maternal mRNAs for degradation during embryonic development. We hypothesized that FIGLA, as a maternal transcript, is regulated by microRNAs during early embryogenesis. Computational predictions identified a potential microRNA recognition element (MRE for miR-212 in the 3' UTR of the bovine FIGLA mRNA. Bovine miR-212 is expressed in oocytes and tends to increase in four-cell and eight-cell stage embryos followed by a decline at morula and blastocyst stages. Transient transfection and reporter assays revealed that miR-212 represses the expression of FIGLA in a MRE dependent manner. In addition, ectopic expression of miR-212 mimic in bovine early embryos dramatically reduced the expression of FIGLA protein. Collectively, our results demonstrate that FIGLA is temporally regulated during bovine early embryogenesis and miR-212 is an important negative regulator of FIGLA during the maternal to zygotic transition in bovine embryos.

  15. Effects of tumor necrosis factor alpha antagonist, platelet activating factor antagonist, and nitric oxide synthase inhibitor on experimental otitis media with effusion. (United States)

    Kim, Dong-Hyun; Park, Yong-Soo; Jeon, Eun-Ju; Yeo, Sang-Won; Chang, Ki-Hong; Lee, Seung Kyun


    We studied the inflammatory responses in otitis media with effusion induced by lipopolysaccharide (LPS) in rats, and compared the preventive effects of tumor necrosis factor (TNF) soluble receptor type I (sTNFRI, a TNF-alpha antagonist), platelet activating factor antagonist, and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). We used 2 control groups of Sprague Dawley rats (untreated and saline-treated) and 4 experimental groups, which all received an intratympanic injection of LPS, followed in 3 groups by experimental treatment of the same ear. The LPS group had no additional treatment. The L-NAME group received intraperitoneal injection of L-NAME and was reinjected after 12 hours. The A-85783 group was first given an intraperitoneal injection of A-85783. The sTNFRI group was first given an intratympanic injection of sTNFRI. Twenty-four hours after the initial intratympanic injection of LPS, temporal bones from each group were examined histopathologically and the vascular permeability of the middle ear mucosa was measured by Evans blue vital dye staining. The L-NAME, A-85783, and sTNFRI groups showed significantly reduced capillary permeability, subepithelial edema, and infiltration of inflammatory cells in comparison with the LPS group. There were no differences in capillary permeability, subepithelial edema, or infiltration of inflammatory cells between the A-85783 and sTNFRI groups. The L-NAME group showed no difference in vascular permeability or subepithelial edema in comparison with the A-85783 and sTNFRI groups, but showed more infiltration of inflammatory cells. We conclude that sTNFRI, A-85783, and L-NAME can be proposed as alternative future treatments for otitis media with effusion. However, L-NAME may be the least effective of these agents.

  16. Impact Response Study on Covering Cap of Aircraft Big-Size Integral Fuel Tank (United States)

    Wang, Fusheng; Jia, Senqing; Wang, Yi; Yue, Zhufeng


    In order to assess various design concepts and choose a kind of covering cap design scheme which can meet the requirements of airworthiness standard and ensure the safety of fuel tank. Using finite element software ANSYS/LS- DYNA, the impact process of covering cap of aircraft fuel tank by projectile were simulated, in which dynamical characteristics of simple single covering cap and gland double-layer covering cap impacted by titanium alloy projectile and rubber projectile were studied, as well as factor effects on simple single covering cap and gland double-layer covering cap under impact region, impact angle and impact energy were also studied. Though the comparison of critical damage velocity and element deleted number of the covering caps, it shows that the external covering cap has a good protection effect on internal covering cap. The regions close to boundary are vulnerable to appear impact damage with titanium alloy projectile while the regions close to center is vulnerable to occur damage with rubber projectile. Equivalent strain in covering cap is very little when impact angle is less than 15°. Element deleted number in covering cap reaches the maximum when impact angle is between 60°and 65°by titanium alloy projectile. While the bigger the impact angle and the more serious damage of the covering cap will be when rubber projectile impact composite covering cap. The energy needed for occurring damage on external covering cap and internal covering cap is less than and higher than that when single covering cap occur damage, respectively. The energy needed for complete breakdown of double-layer covering cap is much higher than that of single covering cap.

  17. Studies of the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene and the relationship to beta-cell function during an OGTT in glucose-tolerant women with and without previous gestational diabetes mellitus

    DEFF Research Database (Denmark)

    Lauenborg, J; Damm, P; Ek, J


    In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene has been associated with decreased serum insulin and C-peptide r...

  18. Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum

    NARCIS (Netherlands)

    Prins, J. M.; Kuijper, E. J.; Mevissen, M. L.; Speelman, P.; van Deventer, S. J.


    The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production

  19. Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme. (United States)

    Lee, Meng-Huee; Verma, Vandana; Maskos, Klaus; Nath, Deepa; Knäuper, Vera; Dodds, Philippa; Amour, Augustin; Murphy, Gillian


    We previously reported that full-length tissue inhibitor of metalloproteinase-3 (TIMP-3) and its N-terminal domain form (N-TIMP-3) displayed equal binding affinity for tissue necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE). Based on the computer graphic of TACE docked with a TIMP-3 model, we created a number of N-TIMP-3 mutants that showed significant improvement in TACE inhibition. Our strategy was to select those N-TIMP-3 residues that were believed to be in actual contact with the active-site pockets of TACE and mutate them to amino acids of a better-fitting nature. The activities of these mutants were examined by measuring their binding affinities (K(app)(i)) and association rates (k(on)) against TACE. Nearly all mutants at position Thr-2 exhibited slightly impaired affinity as well as association rate constants. On the other hand, some Ser-4 mutants displayed a remarkable increase in their binding tightness with TACE. In fact, the binding affinities of several mutants were less than 60 pM, beyond the sensitivity limits of fluorimetric assays. Further studies on cell-based processing of pro-TNF-alpha demonstrated that wild-type N-TIMP-3 and one of its tight-binding mutants, Ser-4Met, were capable of inhibiting the proteolytic shedding of TNF-alpha. Furthermore, the Ser-4Met mutant was also significantly more active (P<0.05) than the wild-type N-TIMP-3 in its cellular inhibition. Comparison of N-TIMP-3 and full-length TIMP-3 revealed that, despite their identical TACE-interaction kinetics, the latter was nearly 10 times more efficient in the inhibition of TNF-alpha shedding, with concomitant implications for the importance of the TIMP-3 C-terminal domain in vivo. PMID:11988096

  20. Protective specific immunity induced by cyclophosphamide plus tumor necrosis factor alpha combination treatment of EL4-lymphoma-bearing C57BL/6 mice. (United States)

    Krawczyk, C M; Verstovsek, S; Ujházy, P; Maccubbin, D; Ehrke, M J


    A combination treatment protocol initiated 12 days after tumor injection, when the tumor was large, by administering cyclophosphamide (CY, 150 or 250 mg/kg) intraperitoneally followed by intravenous tumor necrosis factor alpha (TNF alpha, 1000 units injection) on days 13, 16, 18, 21, and 23, resulted in about 60% long-term survival (i.e., survival for at least 60 days) in the syngeneic C57BL/6 mouse/EL4 lymphoma model system. The establishment of a specific antitumor immune memory and its possible therapeutic relevance was verified by reinjecting 60-day survivors with EL4 cells; all 60-day survivors that had received the combination treatments rejected the implants and survived for a further 60 days. Thymic cellularity was reduced during treatment and its recovery appeared to correlate with long-term survival and immunity. Thymocytes from mice treated with the combination were found to express significant levels of specific anti-EL4 cytolytic activity following a 4-day stimulation culture with X-irradiated EL4 cells and low concentrations of interleukin-2. This response could not be generated with thymocytes from naive animals. In each case the effect seen with the combination of a moderate CY dose (150 mg/kg) with TNF alpha was better than that seen with either dose of CY alone and equal to or better than that seen with the higher dose of CY combined with TNF alpha. These results indicate that treatment with a single moderate dose of CY in combination with TNF alpha is effective against a large, established tumor in this murine model. Furthermore, all the long-term survivors induced by this treatment developed protective immunity against reimplanted tumor and demonstrated a long-term specific immune memory in the thymus.

  1. Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha. (United States)

    Jawaid, Talha; Shakya, Ashok K; Siddiqui, Hefazat Hussain; Kamal, Mehnaz


    Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-α) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-α in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-α in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain.

  2. Doxorubicin plus tumor necrosis factor alpha combination treatments in EL4-lymphoma-bearing C57BL/6 mice. (United States)

    Ehrke, M J; Verstovsek, S; Ujházy, P; Meer, J M; Eppolito, C; Maccubbin, D L; Mihich, E


    The therapeutic efficacy of a total of 42 single-agent or combination protocols involving doxorubicin (Adriamycin, ADM) and tumor necrosis factor alpha (TNFalpha) were evaluated in the syngeneic murine lymphoma model, C57BL/6-EL4. Combination treatments were the most effective and the therapeutic effects were schedule-dependent; e.g. it was generally advantageous for ADM to precede TNFalpha administration. Two protocols selected for further study were 4 mg/kg ADM i.v. on days 1 and 8 plus TNFalpha, i.v., at either 16000 U (7 microg)/injection, on days 1 and 8 or 4000 U (1.7 microg)/injection, on days 11-15. Survival of mice bearing one of four EL4 sublines having different in vitro drug sensitivities was assessed. These sublines were E10 (ADM-sensitive/TNFalpha-resistant), E16 (sensitive/sensitive), ER2 (ADM-resistant/TNFalpha-sensitive) and ER13 (resistant/resistant). Between 80% and 100% long-term survivors (i.e. tumor free on day 60) were obtained with the two treatments in mice bearing ADM-sensitive sublines, even though one of these sublines, E10, was resistant to TNFalpha in vitro. Induction of long-term survival appeared, therefore, to correlate with in vitro defined sensitivity/resistance to ADM, but not to TNFalpha Treatment-induced modulations of tumoricidal immune effector functions were also examined. Taken together, the results indicated that induction of long-term survival involved complex interactions of: (1) ADM-induced tumor modifications, including, but not limited to, tumor debulking, (2) combination-treatment-induced modifications of splenic cytolytic T cell and macrophage activities, and (3) the restoration of thymus cellularity. Finally, when long-term survivors resulting from treatment of E10- or E16-bearing mice were implanted with ER2 on day 120, the majority survived, indicating that long-term immune memory, capable of recognizing drug resistant variants, had been established.

  3. Alpha Blockers (United States)

    ... quickly, but their effects last only a few hours. Long-acting medications take longer to work, but their effects last longer. Which alpha blocker is best for you depends on your health and the condition being treated. Alpha blockers are ...

  4. Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus (United States)

    Veron, Delma; Villegas, Guillermo; Aggarwal, Pardeep Kumar; Bertuccio, Claudia; Jimenez, Juan; Velazquez, Heino; Reidy, Kimberly; Abrahamson, Dale R.; Moeckel, Gilbert; Kashgarian, Michael; Tufro, Alda


    Podocyte or endothelial cell VEGF-A knockout causes thrombotic microangiopathy in adult mice. To study the mechanism involved in acute and local injury caused by low podocyte VEGF-A we developed an inducible, podocyte-specific VEGF-A knockdown mouse, and we generated an immortalized podocyte cell line (VEGFKD) that downregulates VEGF-A upon doxycycline exposure. Tet-O-siVEGF:podocin-rtTA mice express VEGF shRNA in podocytes in a doxycycline-regulated manner, decreasing VEGF-A mRNA and VEGF-A protein levels in isolated glomeruli to ∼20% of non-induced controls and urine VEGF-A to ∼30% of control values a week after doxycycline induction. Induced tet-O-siVEGF:podocin-rtTA mice developed acute renal failure and proteinuria, associated with mesangiolysis and microaneurisms. Glomerular ultrastructure revealed endothelial cell swelling, GBM lamination and podocyte effacement. VEGF knockdown decreased podocyte fibronectin and glomerular endothelial alphaVbeta3 integrin in vivo. VEGF receptor-2 (VEGFR2) interacts with beta3 integrin and neuropilin-1 in the kidney in vivo and in VEGFKD podocytes. Podocyte VEGF knockdown disrupts alphaVbeta3 integrin activation in glomeruli, detected by WOW1-Fab. VEGF silencing in cultured VEGFKD podocytes downregulates fibronectin and disrupts alphaVbeta3 integrin activation cell-autonomously. Collectively, these studies indicate that podocyte VEGF-A regulates alphaVbeta3 integrin signaling in the glomerulus, and that podocyte VEGF knockdown disrupts alphaVbeta3 integrin activity via decreased VEGFR2 signaling, thereby damaging the three layers of the glomerular filtration barrier, causing proteinuria and acute renal failure. PMID:22808199

  5. ATLAS end-cap detector

    CERN Multimedia

    Maximilien Brice


    Three scientists from the Institute of Nuclear Phyiscs at Novossibirsk with one of the end-caps of the ATLAS detector. The end-caps will be used to detect particles produced in the proton-proton collisions at the heart of the ATLAS experiment that are travelling close to the axis of the two beams.

  6. The North Zealand CAP Monitor

    DEFF Research Database (Denmark)

    Nielsen, Minna; Ravn, Pernille; Notander Clausen, Lise

    with CAP. We started with 34 audit variables. Through repeated cycles of testing, feedback and discussions, we reduced the number of indicators to 22 and time per audit from 20 to 10 minutes. Strategy for change To link the monitoring system with our patient pathway for CAP we established an improvement...... Designing a database Designing and testing a dashboard to present indicators in a balanced way Messages for others Auditing patients with a common disease as CAP is useful to identify areas for improvement for a large group of patients. The baseline audit can serve as a basis for a monitoring system......Contect We describe how we developed a monitoring system for community acquired pneumonia (CAP) at North Zealand Regional hospital. We serve 310.000 inhabitants and annually around 3200 patients with CAP are admitted. As part of a program of clinical pathways for common conditions, a pathway...

  7. Tumor necrosis factor-alpha and interleukin -6 as diagnostic markers of diabetic complications in children with type I diabetes mellitus

    International Nuclear Information System (INIS)

    El-Nashar, N.A.; Moawad, A.T.; Nassar, E.M.


    This study aimed to determine the role of cellular auto immunity and its humoral mediators in pathogenesis and following up of type I diabetes mellitus (TIDM). Therefore, serum concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), glycemic control, body mass index, duration of the disease and microalbuminuria in children with TIDM were evaluated. This study was conducted on 30 patients suffered from type I diabetes mellitus (TIDM), 14 males and 16 females with mean age of 11.40 ±3.67 years and 20 apparently healthy children served as control (10 male and 10 female). Children with TIDM were classified according to duration: diabetic children for 5 years or less duration (n= 15, duration means: 2.74 ± 1.34 years) and diabetic children > 5 years (n=15, duration means: 7.35 ± 1.49 years); according to glycemic control: children with good glycemic control (n=16, HbAIc: 7.82 ± 2.70) and diabetic children with poor glycemic control (n=14, HbAIc: 10.49 ± 2.72) and according to complication: diabetic children without complications (n= 20) and diabetic children with microvascular or neurological complications (n= 10, nephritic, retinal or neurological complications). Patients and controls were subjected to careful history, clinical examination and laboratory investigations. The following investigations were done for all children; random blood glucose, Glycated hemoglobin (HbAIc %), microalbuminuria and kidney function tests. Serum tumour necrosis factor-alpha (TNF-alpha) and serum interleukin-6 (IL-6) were measured using immuno-enzymometric assay (ELISA). Patients with TIDM with duration more than 5 years, with poor glycemic control and with complications had higher serum glucose levels, higher HbAIc%, higher level of blood urea nitrogen (BUN), serum creatinine, microalbuminuria and elevated serum TNF-alpha (p<0.0001) and IL-6 (p<0.0001) in comparison to the same diabetic patients with 5 years duration or less, with good glycemic control

  8. Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors

    DEFF Research Database (Denmark)

    Oxboel, Jytte; Binderup, Tina; Knigge, Ulrich


    , in neuroendocrine tumors. We used quantitative real-time PCR for measuring mRNA gene-expression of vascular endothelial growth factor (VEGF), integrin alphaV, and integrin beta3, and CD34 for a group of patients with neuroendocrine tumors (n=13). Tissue from patients with colorectal cancer liver metastases (n=14...... compared to both colorectal liver metastases (p=0.10) and normal liver tissue (p=0.06). In neuroendocrine tumors, gene-expression was highly variable of VEGF (530-fold), integrin alphaV (23-fold) and integrin beta3 (106-fold). Quantitative gene-expression levels of the key angiogenesis molecules VEGF......Anti-angiogenesis treatment is a promising new therapy for cancer that recently has also been suggested for patients with neuroendocrine tumors. The aim of the present study was therefore to investigate the level of tumor angiogenesis, and thereby the molecular basis for anti-angiogenesis treatment...

  9. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

    DEFF Research Database (Denmark)

    Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M


    The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas......-mediated signaling during early implantation. Here we show that ESCs are primarily resistant to Fas-mediated apoptosis independently of their state of hormonal differentiation. Pre-treatment of ESCs with interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha sensitizes them to become apoptotic upon stimulation...... of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN-gamma and TNF-alpha was accompanied by a significant upregulation of Fas and FLICE...

  10. Human T-cell lymphotropic virus type 1-infected T lymphocytes impair catabolism and uptake of glutamate by astrocytes via Tax-1 and tumor necrosis factor alpha. (United States)

    Szymocha, R; Akaoka, H; Dutuit, M; Malcus, C; Didier-Bazes, M; Belin, M F; Giraudon, P


    Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of a chronic progressive myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In this disease, lesions of the central nervous system (CNS) are associated with perivascular infiltration by lymphocytes. We and others have hypothesized that these T lymphocytes infiltrating the CNS may play a prominent role in TSP/HAM. Here, we show that transient contact of human or rat astrocytes with T lymphocytes chronically infected by HTLV-1 impairs some of the major functions of brain astrocytes. Uptake of extracellular glutamate by astrocytes was significantly decreased after transient contact with infected T cells, while the expression of the glial transporters GLAST and GLT-1 was decreased. In two-compartment cultures avoiding direct cell-to-cell contact, similar results were obtained, suggesting possible involvement of soluble factors, such as cytokines and the viral protein Tax-1. Recombinant Tax-1 and tumor necrosis factor alpha (TNF-alpha) decreased glutamate uptake by astrocytes. Tax-1 probably acts by inducing TNF-alpha, as the effect of Tax-1 was abolished by anti-TNF-alpha antibody. The expression of glutamate-catabolizing enzymes in astrocytes was increased for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 transcripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T cells impair the ability of astrocytes to manage the steady-state level of glutamate, which in turn may affect neuronal and oligodendrocytic functions and survival.

  11. The aryl hydrocarbon receptor and estrogen receptor alpha differentially modulate nuclear factor erythroid-2-related factor 2 transactivation in MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Lo, Raymond; Matthews, Jason, E-mail:


    Nuclear factor erythroid-2-related factor 2 (NRF2; NFE2L2) plays an important role in mediating cellular protection against reactive oxygen species. NRF2 signaling is positively modulated by the aryl hydrocarbon receptor (AHR) but inhibited by estrogen receptor alpha (ERα). In this study we investigated the crosstalk among NRF2, AHR and ERα in MCF-7 breast cancer cells treated with the NRF2 activator sulforaphane (SFN), a dual AHR and ERα activator, 3,3′-diindolylmethane (DIM), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 17β-estradiol (E2). SFN-dependent increases in NADPH-dependent oxidoreductase 1 (NQO1) and heme oxygenase I (HMOX1) mRNA levels were significantly reduced after co-treatment with E2. E2-dependent repression of NQO1 and HMOX1 was associated with increased ERα but reduced p300 recruitment and reduced histone H3 acetylation at both genes. In contrast, DIM + SFN or TCDD + SFN induced NQO1 and HMOX1 mRNA expression to levels higher than SFN alone, which was prevented by RNAi-mediated knockdown of AHR. DIM + SFN but not TCDD + SFN also induced recruitment of ERα to NQO1 and HMOX1. However, the presence of AHR at NQO1 and HMOX1 restored p300 recruitment and histone H3 acetylation, thereby reversing the ERα-dependent repression of NRF2. Taken together, our study provides further evidence of functional interplay among NRF2, AHR and ERα signaling pathways through altered p300 recruitment to NRF2-regulated target genes. - Highlights: • We examined crosstalk among ERα, AHR, and NRF2 in MCF-7 breast cancer cells. • AHR enhanced the mRNA expression levels of two NRF2 target genes – HMOX1 and NQO1. • ERα repressed HMOX1 and NQO1 expression via decreased histone acetylation. • AHR prevented ERα-dependent repression of HMOX1 and NQO1.

  12. The aryl hydrocarbon receptor and estrogen receptor alpha differentially modulate nuclear factor erythroid-2-related factor 2 transactivation in MCF-7 breast cancer cells

    International Nuclear Information System (INIS)

    Lo, Raymond; Matthews, Jason


    Nuclear factor erythroid-2-related factor 2 (NRF2; NFE2L2) plays an important role in mediating cellular protection against reactive oxygen species. NRF2 signaling is positively modulated by the aryl hydrocarbon receptor (AHR) but inhibited by estrogen receptor alpha (ERα). In this study we investigated the crosstalk among NRF2, AHR and ERα in MCF-7 breast cancer cells treated with the NRF2 activator sulforaphane (SFN), a dual AHR and ERα activator, 3,3′-diindolylmethane (DIM), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 17β-estradiol (E2). SFN-dependent increases in NADPH-dependent oxidoreductase 1 (NQO1) and heme oxygenase I (HMOX1) mRNA levels were significantly reduced after co-treatment with E2. E2-dependent repression of NQO1 and HMOX1 was associated with increased ERα but reduced p300 recruitment and reduced histone H3 acetylation at both genes. In contrast, DIM + SFN or TCDD + SFN induced NQO1 and HMOX1 mRNA expression to levels higher than SFN alone, which was prevented by RNAi-mediated knockdown of AHR. DIM + SFN but not TCDD + SFN also induced recruitment of ERα to NQO1 and HMOX1. However, the presence of AHR at NQO1 and HMOX1 restored p300 recruitment and histone H3 acetylation, thereby reversing the ERα-dependent repression of NRF2. Taken together, our study provides further evidence of functional interplay among NRF2, AHR and ERα signaling pathways through altered p300 recruitment to NRF2-regulated target genes. - Highlights: • We examined crosstalk among ERα, AHR, and NRF2 in MCF-7 breast cancer cells. • AHR enhanced the mRNA expression levels of two NRF2 target genes – HMOX1 and NQO1. • ERα repressed HMOX1 and NQO1 expression via decreased histone acetylation. • AHR prevented ERα-dependent repression of HMOX1 and NQO1.

  13. Investigations of (. cap alpha. ,. cap alpha. 'x) reactions up to 40 MeV/A bombarding energy

    Energy Technology Data Exchange (ETDEWEB)

    Machner, H [Kernforschungsanlage Juelich G.m.b.H. (Germany, F.R.). Inst. fuer Kernphysik; Feldmeier, H [ed.


    The angle integrated cross sections of continuous nucleon spectra from light ion induced reactions could be well reproduced within nonequilibrium statistical models. An extended exciton model even allows the calculations of angular distributions. Energy and linear momentum dissipation are treated with the help of a generalized master equation. The Exciton Coalescence Model (ECM) reproduces the angular distributions of complex particles emitted in nuclear reactions at moderate energies.

  14. Nuclear Waste Vitrification Efficiency: Cold Cap Reactions

    International Nuclear Information System (INIS)

    Kruger, A.A.; Hrma, P.R.; Pokorny, R.


    The cost and schedule of nuclear waste treatment and immobilization are greatly affected by the rate of glass production. Various factors influence the performance of a waste-glass melter. One of the most significant, and also one of the least understood, is the process of batch melting. Studies are being conducted to gain fundamental understanding of the batch reactions, particularly those that influence the rate of melting, and models are being developed to link batch makeup and melter operation to the melting rate. Batch melting takes place within the cold cap, i.e., a batch layer floating on the surface of molten glass. The conversion of batch to glass consists of various chemical reactions, phase transitions, and diffusion-controlled processes. These include water evaporation (slurry feed contains as high as 60% water), gas evolution, the melting of salts, the formation of borate melt, reactions of borate melt with molten salts and with amorphous oxides (Fe 2 O 3 and Al 2 O 3 ), the formation of intermediate crystalline phases, the formation of a continuous glass-forming melt, the growth and collapse of primary foam, and the dissolution of residual solids. To this list we also need to add the formation of secondary foam that originates from molten glass but accumulates on the bottom of the cold cap. This study presents relevant data obtained for a high-level-waste melter feed and introduces a one-dimensional (1D) mathematical model of the cold cap as a step toward an advanced three-dimensional (3D) version for a complete model of the waste glass melter. The 1D model describes the batch-to-glass conversion within the cold cap as it progresses in a vertical direction. With constitutive equations and key parameters based on measured data, and simplified boundary conditions on the cold-cap interfaces with the glass melt and the plenum space of the melter, the model provides sensitivity analysis of the response of the cold cap to the batch makeup and melter

  15. Cryopyrin-Associated Autoinflammatory Syndromes (CAPS) - Juvenile (United States)

    ... all ethnic groups can be affected. What are CAPS? Cryopyrin-associated autoinflammatory syndromes (CAPS) consist of three ... ears by magnetic resonance imaging (MRI). How is CAPS treated? Medications that target interleukin-1 are very ...

  16. Tumor necrosis factor (TNF-alpha) and C-reactive protein (CRP) are positively associated with the risk of chronic kidney disease in patients with type 2 diabetes. (United States)

    Yeo, Eun-Sil; Hwang, Ji-Yun; Park, Ji Eun; Choi, Young Ju; Huh, Kap Bum; Kim, Wha Young


    Chronic low-grade inflammation may induce chronic kidney disease in patients with type 2 diabetes. This study investigated the relation between inflammatory biomarkers and chronic kidney disease in patients with type 2 diabetes, which has not yet been reported in Asian populations. A cross-sectional study was performed in 543 patients recruited from diabetic clinics for an ongoing, prospective study. Multivariate logistic regression was used to evaluate the association between inflammatory biomarkers and the presence of chronic kidney disease (estimated glomerular filtration rate Disease equation using plasma creatinine). The risk of chronic kidney disease increased in the highest quartiles of C-reactive protein (CRP) [multivariate odds ratio (OR) = 3.73; 95% CI = 1.19-1.70] and tumor necrosis factor-alpha (multivariate OR = 4.45; 95% CI = 1.63-12.11) compared to the lowest quartiles after adjustments for age, sex, zinc intake, and other putative risk factors for chronic kidney disease. Our results suggest that CRP and tumor necrosis factor-alpha may be independent risk factors for chronic kidney disease in patients with type 2 diabetes. A causal mechanism of this association should be evaluated in a followup study of Korean patients with type 2 diabetes.

  17. Transcriptional activation of transforming growth factor alpha by estradiol: requirement for both a GC-rich site and an estrogen response element half-site. (United States)

    Vyhlidal, C; Samudio, I; Kladde, M P; Safe, S


    17beta-Estradiol (E2) induces transforming growth factor alpha (TGFalpha) gene expression in MCF-7 cells and previous studies have identified a 53 bp (-252 to -200) sequence containing two imperfect estrogen responsive elements (EREs) that contribute to E2 responsiveness. Deletion analysis of the TGFalpha gene promoter in this study identified a second upstream region of the promoter (-623 to -549) that is also E2 responsive. This sequence contains three GC-rich sites and an imperfect ERE half-site, and the specific cis-elements and trans-acting factors were determined by promoter analysis in transient transfection experiments, gel mobility shift assays and in vitro DNA footprinting. The results are consistent with an estrogen receptor alpha (ERalpha)/Sp1 complex interacting with an Sp1(N)(30) ERE half-site ((1/2)) motif in which both ERalpha and Sp1 bind promoter DNA. The ER/Sp1-DNA complex is formed using nuclear extracts from MCF-7 cells but not with recombinant human ERalpha or Sp1 proteins, suggesting that other nuclear factor(s) are required for complex stabilization. The E2-responsive Sp1(N)(x)ERE(1/2) motif identified in the TGFalpha gene promoter has also been characterized in the cathepsin D and heat shock protein 27 gene promoters; however, in the latter two promoters the numbers of intervening nucleotides are 23 and 10 respectively.

  18. Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter. (United States)

    Fonseca, João Eurico; Cavaleiro, João; Teles, José; Sousa, Elsa; Andreozzi, Valeska L; Antunes, Marília; Amaral-Turkman, Maria A; Canhão, Helena; Mourão, Ana F; Lopes, Joana; Caetano-Lopes, Joana; Weinmann, Pamela; Sobral, Marta; Nero, Patrícia; Saavedra, Maria J; Malcata, Armando; Cruz, Margarida; Melo, Rui; Braña, Araceli; Miranda, Luis; Patto, José V; Barcelos, Anabela; da Silva, José Canas; Santos, Luís M; Figueiredo, Guilherme; Rodrigues, Mário; Jesus, Herberto; Quintal, Alberto; Carvalho, Teresa; da Silva, José A Pereira; Branco, Jaime; Queiroz, Mário Viana


    The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-alpha) promoter genotype/haplotype markers. Each patient's disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-alpha gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-alpha promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.

  19. Detection of Alpha-Toxin and Other Virulence Factors in Biofilms of Staphylococcus aureus on Polystyrene and a Human Epidermal Model. (United States)

    den Reijer, P M; Haisma, E M; Lemmens-den Toom, N A; Willemse, J; Koning, R I; Koning, R A; Demmers, J A A; Dekkers, D H W; Rijkers, E; El Ghalbzouri, A; Nibbering, P H; van Wamel, W


    The ability of Staphylococcus aureus to successfully colonize (a)biotic surfaces may be explained by biofilm formation and the actions of virulence factors. The aim of the present study was to establish the presence of 52 proteins, including virulence factors such as alpha-toxin, during biofilm formation of five different (methicillin resistant) S. aureus strains on Leiden human epidermal models (LEMs) and polystyrene surfaces (PS) using a competitive Luminex-based assay. All five S. aureus strains formed biofilms on PS, whereas only three out of five strains formed biofilms on LEMs. Out of the 52 tested proteins, six functionally diverse proteins (ClfB, glucosaminidase, IsdA, IsaA, SACOL0688 and nuclease) were detected in biofilms of all strains on both PS and LEMs. At the same time, four toxins (alpha-toxin, gamma-hemolysin B and leukocidins D and E), two immune modulators (formyl peptide receptor-like inhibitory protein and Staphylococcal superantigen-like protein 1), and two other proteins (lipase and LytM) were detectable in biofilms by all five S. aureus strains on LEMs, but not on PS. In contrast, fibronectin-binding protein B (FnbpB) was detectable in biofilms by all S. aureus biofilms on PS, but not on LEMs. These data were largely confirmed by the results from proteomic and transcriptomic analyses and in case of alpha-toxin additionally by GFP-reporter technology. Functionally diverse virulence factors of (methicillin-resistant) S. aureus are present during biofilm formation on LEMs and PS. These results could aid in identifying novel targets for future treatment strategies against biofilm-associated infections.

  20. The correlation analysis of tumor necrosis factor-alpha-308G/A polymorphism and venous thromboembolism risk: A meta-analysis. (United States)

    Gao, Quangen; Zhang, Peijin; Wang, Wei; Ma, He; Tong, Yue; Zhang, Jing; Lu, Zhaojun


    Venous thromboembolism is a common complex disorder, being the resultant of gene-gene and gene-environment interactions. Tumor necrosis factor-alpha is a proinflammatory cytokine which has been implicated in venous thromboembolism risk. A promoter 308G/A polymorphism in the tumor necrosis factor-alpha gene has been suggested to modulate the risk for venous thromboembolism. However, the published findings remain inconsistent. In this study, we conducted a meta-analysis of all available data regarding this issue. Eligible studies were identified through search of Pubmed, EBSCO Medline, Web of Science, and China National Knowledge Infrastructure (CNKI, Chinese) databases up to June 2014. Pooled Odd ratios (ORs) with 95% confidence intervals were applied to estimating the strength of the genetic association in the random-effects model or fixed-effects model. A total of 10 studies involving 1999 venous thromboembolism cases and 2166 controls were included in this meta-analysis to evaluate the association between tumor necrosis factor-alpha-308G/A polymorphism and venous thromboembolism risk. Overall, no significantly increased risk venous thromboembolism was observed in all comparison models when all studies were pooled into the meta-analysis. However, in stratified analyses by ethnicity, there was a pronounced association with venous thromboembolism risk among West Asians in three genetic models (A vs. G: OR = 1.82, 95%CI = 1.13-2.94; GA vs. GG: OR = 1.82, 95%CI = 1.08-3.06; AA/GA vs. GG: OR = 1.88, 95%CI = 1.12-3.16). When stratifying by source of controls, no significant result was detected in all genetic models. This meta-analysis demonstrates that tumor necrosis factor-alpha 308G/A polymorphism may contribute to susceptibility to venous thromboembolism among West Asians. Studies are needed to ascertain these findings in larger samples and different racial groups. © The Author(s) 2015.

  1. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. (United States)

    Welsh, Sarah J; Bellamy, William T; Briehl, Margaret M; Powis, Garth


    Hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and HIF-1beta subunits, is a transcriptional activator central to the cellular response to low oxygen that includes metabolic adaptation, angiogenesis, metastasis, and inhibited apoptosis. Thioredoxin-1 (Trx-1) is a small redox protein overexpressed in a number of human primary tumors. We have examined the effects of Trx-1 on HIF activity and the activation of downstream genes. Stable transfection of human breast carcinoma MCF-7 cells with human Trx-1 caused a significant increase in HIF-1alpha protein levels under both normoxic (20% oxygen) and hypoxic (1% oxygen) conditions. Trx-1 increased hypoxia-induced HIF-1 transactivation activity measured using a luciferase reporter under the control of the hypoxia response element. Changes in HIF-1alpha mRNA levels did not account for the changes observed at the protein level, and HIF-1beta protein levels did not change. Trx-1 transfection also caused a significant increase in the protein products of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF) and nitric oxide synthase 2 in a number of different cell lines (MCF-7 human breast and HT29 human colon carcinomas and WEHI7.2 mouse lymphoma cells) under both normoxic and hypoxic conditions. The pattern of expression of the different isoforms of VEGF was not changed by Trx-1. Transfection of a redox-inactive Trx-1 (C32S/C35S) markedly decreased levels of HIF-1alpha protein, HIF-1 transactivating activity, and VEGF protein in MCF-7 cells compared with empty vector controls. In vivo studies using WEHI7.2 cells transfected with Trx-1 showed significantly increased tumor VEGF and angiogenesis. The results suggest that Trx-1 increases HIF-1alpha protein levels in cancer cells and increases VEGF production and tumor angiogenesis.

  2. C.A.P. Follow up of the transients and use factors for the most loaded elements of the primary circuit

    International Nuclear Information System (INIS)

    Gaouditz, N.; Chabre, A.; Lecourtois, Y.


    The control authorities of all countries lay down increasingly stricter rules for the definition, fabrication and maintenance of nuclear capacities under pressure. In particular the operator has to ensure that the apparatus does not have to withstand stresses greater in number, intensity and rapidity than those allowed for in the project. In other words he must workout, classify and combine the various transients supported by the apparatus throughout its lifetime. The account method enables the actual transients to be classified in relation to the reference transients and their cumulated number followed periodically. This number can then be used to find the use factor which, when extrapolated to the lifetime of the element concerned, must be lower or equal to the use factor provided in the design always less than one. In point of fact, although simple in formulation, this becomes fairly complicated in application for a particular point of the capacity may be subjected to a great number of various types of stresses, each one leading to a particular damage of which the use factors, f, will be cumulated in accordance with the rules stipulated in the ASME Code, section III [fr

  3. Antithetical effect of tumor necrosis factor-alpha gene polymorphism on coal workers' pneumoconiosis (CWP)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, X.T.; Ohtsuka, Y.; Kimura, K.; Muroi, M.; Ishida, T.; Saito, J.; Munakata, M. [Fukushima Medical University, Fukushima (Japan). School of Medicine


    Inter-individual variation in the severity of pneumoconiosis has been described, even with the same environmental exposure. We hypothesized that TNF-alpha promoter polymorphisms associate with lung responses to environmental exposure in coal worker's pneumoconiosis (CWP) patients. We examined polymorphisms at -238, -308, and -376 in 124 patients with CWP who had similar dust exposure history and in 122 non-exposed controls. CWP patients were divided into two groups: (1) nodular CWP (n = 84): (2) progressive massive fibrosis (PMF) (n = 44). The -308 A allele frequency was higher in patients with CWP compared to controls (6.35% and 2.05%, P {lt} 0.01). It was also higher in patients with nodular CWP compared to PMF (P {lt} 0.05). Logistic regression analysis revealed that patients with the -308 A allele were 3.8 times (P = 0.036) and those with smoking habit were 2.3 times (P {lt} 0.002) more likely to have nodular CWP than PMF. Thus TNF-alpha-308 A allele might interact with smoking to enhance susceptibility to nodular CWP.

  4. The acute effects of alpha and beta irradiation of mouse skin and the factors affecting the response

    International Nuclear Information System (INIS)

    Needham, S.G.; Coggle, J.E.


    Several problems regarding acute effects of alpha and beta irradiation were investigated in order to clarify protection problems of localised doses to the skin. A study into the acute biological effects of different energy beta emitters and the effects of energy and area on the response showed direct relationships between these criteria for a range of different acute responses with different time courses. Three different types of acute response were found and these are described as 'moist desquamation', 'acute ulceration' and 'acute epidermal necrosis'. An unexpected finding was that the lower energy beta emitter 170 Tm was as efficient at inducing scab formation as the higher energy 90 Sr sources for the same area of exposure. Experiments using 2x4 cm 2 exposures to 224 Cm alpha particles showed that the response to this poorly penetrating radiation was minimal after doses as high as 180 Gy measured at 10 μm into the skin. In comparison, large area exposure to 170 Tm produced areas of prolonged scabbing after doses up to 100 Gy. However, the intensity of the reaction varied between strains. (author)

  5. Influence of G308A polymorphism of tumor necrosis factor-alpha gene on inflammatory markers in postsurgical head and neck cancer patients with early enteral nutrition. (United States)

    de Luis, Daniel Antonio; Sagrado, Manue Gonzalez; Vallejo, Luis Angel; Carcedo, Luis María Gil; Izaola, Olatz; Cuellar, Luis; Terroba, María Concepción; Aller, Rocío


    Although immune dysfunction in patients with cancer could be multifactorial, the immune system may be modulated by nutritional substrates and genetic background. Our study evaluated the effect of G308A polymorphism of the tumor necrosis factor-alpha (TNF-alpha) gene on inflammatory markers in patients after surgery for head and neck cancer who received early enteral nutrition. A population of 60 patients with oral and laryngeal cancer was enrolled. At surgery patients were treated with a hyperproteic enteral diet. Perioperatively and on postoperative day 6 the following parameters were evaluated: serum values of prealbumin, transferrin, total number of lymphocytes, interleukin-6, TNF-alpha, and C-reactive protein. In addition, genotyping of G308A gene polymorphism was assessed. Patients' mean age was 61.1 +/- 14.6 y (four women, 56 men) with a body mass index of 25.4 +/- 5.2 kg/m(2) and a previous weight loss of 0.35 +/- 0.2 kg. Forty patients (37 men, 3 women; 66.6%) had the genotype G308/G308 (wild group) and 20 patients (19 men, 1 woman; 23.4%) had the genotype G308/A308 (mutant group). A significant increase in prealbumin and transferrin levels was detected in both groups. C-reactive protein decreased in both groups (wild group: 105.1 +/- 60 versus 53.8 +/- 62.3 mg/dL, P < 0.05; mutant group: 99.5 +/- 46 versus 43.9 +/- 51.9 mg/dL, P < 0.05). Interleukin-6 decreased in both groups (wild group: 20.1 +/- 22 versus 6.2 +/- 4.1 pg/mL, P < 0.05; mutant group: 22.3 +/- 38 versus 9.2 +/- 7.4 pg/mL, P = NS). Lymphocytes increased in both groups (wild group: 1102 +/- 468 versus 1600 +/- 537 10(3)/mL, P = NS; mutant group: 1441 +/- 739 10(3)/mL versus 1669 +/- 614 10(6)/mL, P = NS). TNF-alpha showed no changes. The G308A polymorphism of the TNF-alpha gene did not affect levels of inflammatory markers in patients after surgery for head and neck cancer who were treated with early enteral nutrition.

  6. A Role for Protein Phosphatase 2A in Regulating p38 Mitogen Activated Protein Kinase Activation and Tumor Necrosis Factor-Alpha Expression during Influenza Virus Infection

    Directory of Open Access Journals (Sweden)

    Anna H. Y. Law


    Full Text Available Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF-alpha through p38 mitogen activated protein kinase (MAPK. However, the detailed mechanisms of p38MAPK activation and TNF-alpha hyperinduction following influenza virus infections are not known. Negative feedback regulations of cytokine expression play important roles in avoiding overwhelming production of proinflammatory cytokines. Here we hypothesize that protein phosphatases are involved in the regulation of cytokine expressions during influenza virus infection. We investigated the roles of protein phosphatases including MAPK phosphatase-1 (MKP-1 and protein phosphatase type 2A (PP2A in modulating p38MAPK activation and downstream TNF-alpha expressions in primary human monocyte-derived macrophages (PBMac infected with H9N2/G1 or H1N1 influenza virus. We demonstrate that H9N2/G1 virus activated p38MAPK and hyperinduced TNF-alpha production in PBMac when compared with H1N1 virus. H9N2/G1 induced PP2A activity in PBMac and, with the treatment of a PP2A inhibitor, p38MAPK phosphorylation and TNF-alpha production were further increased in the virus-infected macrophages. However, H9N2/G1 did not induce the expression of PP2A indicating that the activation of PP2A is not mediated by p38MAPK in virus-infected PBMac. On the other hand, PP2A may not be the targets of H9N2/G1 in the upstream of p38MAPK signaling pathways since H1N1 also induced PP2A activation in primary macrophages. Our results may provide new insights into the control of cytokine dysregulation.



    Brouwer, Floor M.; Godeschalk, Frans E.


    The integration of nature management, landscape and environmental concerns into the Common Agricultural Policy (CAP) has gained momentum with the CAP reforms adopted in June 2003. The report explores instruments and approaches that contribute to the inte-gration of nature conservation and landscape concerns into the CAP. A broader use of the CAP instruments might help to achieve nature types in the Netherlands.

  8. 47 CFR 54.623 - Cap. (United States)


    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Cap. 54.623 Section 54.623 Telecommunication... Universal Service Support for Health Care Providers § 54.623 Cap. (a) Amount of the annual cap. The annual cap on federal universal service support for health care providers shall be $400 million per funding...

  9. 47 CFR 54.507 - Cap. (United States)


    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Cap. 54.507 Section 54.507 Telecommunication... Universal Service Support for Schools and Libraries § 54.507 Cap. (a) Amount of the annual cap. The annual funding cap on federal universal service support for schools and libraries shall be $2.25 billion per...

  10. Ultraviolet B irradiation of skin induces mast cell degranulation and release of tumour necrosis factor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Walsh, L.J. [University of Queensland, Brisbane, QLD (Australia). Dept. of Dentistry, Immunopathology Unit


    In the `sunburn` response in skin, dermal blood vessels are activated and traffic of dendritic Langerhans` cells altered. While these changes have been attributed to the cytokine TNF-{alpha}, the source of this acutely released TNF has not been identified. This report demonstrates that the `sunburn` response, both in vivo and in vitro, is accompanied by rapid degranulation of cutaneous mast cells, with consequential release of intracellular stores of TNF. Epidermal keratinocytes were only minor contributors to local TNF production. Expression of the TNF-inducible CD62E (E-selectin/ELAM-1) and CD54 adhesion molecules on cutaneous endothelium occurred 2 hours following mast cell degranulation, and this event was sensitive to blockade of mast cells with disodium cromoglycate. These results indicate that TNF release in skin in the acute sunburn response can largely be attributed to mast cells. 47 refs., 5 tabs., 2 figs.

  11. Cap-independent translation of plant viral RNAs. (United States)

    Kneller, Elizabeth L Pettit; Rakotondrafara, Aurélie M; Miller, W Allen


    The RNAs of many plant viruses lack a 5' cap and must be translated by a cap-independent mechanism. Here, we discuss the remarkably diverse cap-independent translation elements that have been identified in members of the Potyviridae, Luteoviridae, and Tombusviridae families, and genus Tobamovirus. Many other plant viruses have uncapped RNAs but their translation control elements are uncharacterized. Cap-independent translation elements of plant viruses differ strikingly from those of animal viruses: they are smaller (translation factors, and speculate on their mechanism of action and their roles in the virus replication cycle. Much remains to be learned about how these elements enable plant viruses to usurp the host translational machinery.

  12. Modelling the Common Agricultural Policy with the Modular Agricultural GeNeral Equilibrium Tool (MAGNET). Effects of the 2014-2020 CAP financial agreement on welfare, trade, factor and product markets




    This JRC report presents methodological development of the Modular Applied GeNeral Equilibrium Tool (MAGNET), a global computable general equilibrium (CGE) model, for representing the Common Agricultural Policy (CAP). Using original data on European Union (EU) domestic support, it examines some likely macroeconomic effects of the expected CAP budget over the period 2014-2020. Results suggest that agreed budget cuts, in constant price, have limited impacts on EU and world markets, given the br...

  13. Granulocyte-Macrophage Colony-Stimulating Factor Amplification of Interleukin-1β and Tumor Necrosis Factor Alpha Production in THP-1 Human Monocytic Cells Stimulated with Lipopolysaccharide of Oral Microorganisms


    Baqui, A. A. M. A.; Meiller, Timothy F.; Chon, Jennifer J.; Turng, Been-Foo; Falkler, William A.


    Cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), are used to assist in bone marrow recovery during cancer chemotherapy. Interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) play important roles in inflammatory processes, including exacerbation of periodontal diseases, one of the most common complications in patients who undergo this therapy. A human monocyte cell line (THP-1) was utilized to investigate IL-1β and TNF-α production following GM-CSF suppl...

  14. Granulocyte-macrophage colony-stimulating factor amplification of interleukin-1beta and tumor necrosis factor alpha production in THP-1 human monocytic cells stimulated with lipopolysaccharide of oral microorganisms. (United States)

    Baqui, A A; Meiller, T F; Chon, J J; Turng, B F; Falkler, W A


    Cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), are used to assist in bone marrow recovery during cancer chemotherapy. Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) play important roles in inflammatory processes, including exacerbation of periodontal diseases, one of the most common complications in patients who undergo this therapy. A human monocyte cell line (THP-1) was utilized to investigate IL-1beta and TNF-alpha production following GM-CSF supplementation with lipopolysaccharide (LPS) from two oral microorganisms, Porphyromonas gingivalis and Fusobacterium nucleatum. LPS of P. gingivalis or F. nucleatum was prepared by a phenol-water extraction method and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and determination of total protein and endotoxin contents. Resting THP-1 cells were treated with LPS of P. gingivalis or F. nucleatum and/or GM-CSF (50 IU/ml) by using different concentrations for various time periods. Production of IL-1beta and TNF-alpha in THP-1 cells was measured by solid-phase enzyme-linked immunosorbent assay. Reverse transcription (RT)-PCR was used to evaluate the gene expression of resting and treated THP-1 cells. IL-1beta was not detected in untreated THP-1 cells. IL-1beta production was, however, stimulated sharply at 4 h. GM-CSF amplified IL-1beta production in THP-1 cells treated with LPS from both oral anaerobes. No IL-1beta-specific mRNA transcript was detected in untreated THP-1 cells. However, IL-1beta mRNA was detected by RT-PCR 2 h after stimulation of THP-1 cells with LPS from both organisms. GM-CSF did not shorten the IL-1beta transcriptional activation time. GM-CSF plus F. nucleatum or P. gingivalis LPS activated THP-1 cells to produce a 1.6-fold increase in TNF-alpha production at 4 h over LPS stimulation alone. These investigations with the in vitro THP-1 model indicate that there may be an increase in the cellular immune response to oral

  15. Human recombinant interleukin-1 beta- and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells

    International Nuclear Information System (INIS)

    Kobayashi, M.; Shimada, K.; Ozawa, T.


    Cytokines are known to tip the balance of the coagulant-anticoagulant molecules on the endothelial cell surface toward intravascular coagulation. Their effects on endothelial cell surface-associated heparin-like compounds have not been examined yet. Incorporation of [35S]sulfate into heparan sulfate on cultured porcine aortic endothelial cells was suppressed by human recombinant interleukin-1 beta (rIL-1 beta) or tumor necrosis factor alpha (rTNF alpha) in a dose- and time-dependent manner with little effect on cell number, protein content, and [3H]leucine incorporation of cells. Maximal inhibition was achieved by incubation of cells with 100 ng/ml of rIL-1 beta or 5 ng/ml of rTNF alpha for 12-24 hours, resulting in a reduction of the synthesis of heparan sulfate on the cell surface by approximately 50%. The dose dependency was consistent with that seen in the stimulation of endothelial cell procoagulant activity by each cytokine. The suppression of heparan sulfate synthesis was sustained for at least 48 hours after pretreatment of cells with cytokines and was unchanged after the addition of indomethacin or polymyxin B. The rate of degradation of prelabeled 35S-heparan sulfate on the cell surface was not altered by cytokine treatments. Neither the size, the net negative charge, nor the proportion of the molecule with high affinity for antithrombin III of endothelial cell heparan sulfate was changed by cytokines. Furthermore, specific binding of 125I-labeled antithrombin III to the endothelial cell surface was reduced to 40-60% of control by cytokines. In parallel with reduction in binding, antithrombin III cofactor activity was partially diminished in cytokine-treated endothelial cells. Thus, cytokine-mediated suppression of heparin-like substance on endothelial cells appears to be another cytokine-inducible endothelial effects affecting coagulation

  16. Molecular evidence for the existence of lipopolysaccharide-induced TNF-alpha factor (LITAF) and Rel/NF-kB pathways in disk abalone (Haliotis discus discus). (United States)

    De Zoysa, Mahanama; Nikapitiya, Chamilani; Oh, Chulhong; Whang, Ilson; Lee, Jae-Seong; Jung, Sung-Ju; Choi, Cheol Young; Lee, Jehee


    The lipopolysaccharide-induced TNF-alpha factor (LITAF) and Rel family nuclear factor kappaB (Rel/NF-kB) are two important transcription factors which play major roles in the regulating inflammatory cytokine, apoptosis and immune related genes. Here, we report the discovery of disk abalone LITAF (AbLITAF) and Rel/NF-kB (AbRel/NF-kB) homologues and their immune responses. Full-length cDNA of AbLITAF consists of 441 bp open reading frame (ORF) that translates into putative peptide of 147 aa. Analysis of AbLITAF sequence showed it has characteristic LITAF (Zn(+2)) binding domain with two CXXC motifs. Phylogenetic analysis results further revealed that AbLITAF is a member of LITAF family. AbRel/NF-kB is 584 aa protein that contains several characteristic motifs including Rel homology domain (RHD), Rel protein signature, DNA binding motif, nuclear localization signal (NLS) and transcription factor immunoglobulin - like fold (TIG) similar to their invertebrate and vertebrate counterparts. Tissue specific analysis results showed that both AbLITAF and AbRel/NF-kB mRNA was expressed ubiquitously in all selected tissues in constitutive manner. However, constitutive expression of AbLITAF was higher than AbRel/NF-kB in all tissues except mantle. Upon immune challenge by bacteria (Vibrio alginolyticus, Vibrio parahemolyticus and Lysteria monocytogenes) and viral hemoragic septicemia virus (VHSV), AbLITAF showed the significant up-regulation in gills while AbRel/NF-kB transcription was not change significantly. Based on transcriptional response against immune challenge, we could suggest that regulation of TNF-alpha expression may have occurred mainly by LITAF activation rather than NF-kB in disk abalone. The cumulative data from other molluscs and our data with reference to TNF-alpha, LITAF and Rel/NF-kB from disk abalone provide strong evidence that LITAF and NF-kB are independent pathways likely to occur throughout the Phylum mollusca. 2010 Elsevier Ltd. All rights reserved.

  17. Treatment of alpha bearing wastes

    International Nuclear Information System (INIS)


    This report deals with the current state of the art of alpha waste treatment, which is an integral part of the overall nuclear waste management system. The International Atomic Energy Agency (IAEA) defines alpha bearing waste as 'waste containing one or more alpha emitting radionuclides, usually actinides, in quantities above acceptable limits'. The limits are established by national regulatory bodies. The limits above which wastes are considered as alpha contaminated refer to the concentrations of alpha emitters that need special consideration for occupational exposures and/or potential safety, health, or environmental impact during one or more steps from generation through disposal. Owing to the widespread use of waste segregation by source - that is, based upon the 'suspect origin' of the material - significant volumes of waste are being handled as alpha contaminated which, in fact, do not require such consideration by reason of risk or environmental concern. The quantification of de minimis concepts by national regulatory bodies could largely contribute to the safe reduction of waste volumes and associated costs. Other factors which could significantly contribute to the reduction of alpha waste arisings are an increased application of assaying and sorting, instrumentation and the use of feedback mechanisms to control or modify the processes which generate these wastes. Alpha bearing wastes are generated during fabrication and reprocessing of nuclear fuels, decommissioning of alpha contaminated facilities, and other activities. Most alpha wastes are contact handled, but a small portion may require shielding or remote handling because of high levels of neutron (n), beta (β), or gamma (γ) emissions associated with the waste material. This report describes the sources and characteristics of alpha wastes and strategies for alpha waste management. General descriptions of treatment processes for solid and liquid alpha wastes are included. 71 refs, 14 figs, 9 tabs

  18. Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells.

    Directory of Open Access Journals (Sweden)

    Mahendran Botlagunta


    Full Text Available DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1α is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1α and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region.

  19. Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Ainsworth, Mark A; Bendtzen, Klaus; Brynskov, Jørn


    To investigate if the combined assessment of anti-infliximab antibodies (Ab) and the degree of TNF-alpha binding capacity (TNF-alpha-BC) afforded by infliximab may predict the response to infliximab treatment in patients with Crohn's disease (CD).......To investigate if the combined assessment of anti-infliximab antibodies (Ab) and the degree of TNF-alpha binding capacity (TNF-alpha-BC) afforded by infliximab may predict the response to infliximab treatment in patients with Crohn's disease (CD)....

  20. The interaction between menstrual cycle, Tumour Necrosis Factor alpha receptors and sex hormones in healthy non-obese women – results from an observational study

    Directory of Open Access Journals (Sweden)

    Paweł Rzymski


    Full Text Available There is growing evidence that TNF-alpha and its two receptors play an important role in hormonal regulation, metabolism, inflammation and cancer. The biological effects of TNF-alpha are mediated by two receptors, p55 and p75. The aim of this study was to analyze serum concentrations of p55 and p75 and hormonal status in healthy women during the normal menstrual cycle. Eight women aged 20–22 with regular menstrual cycles were scheduled for examination on 3[sup]rd[/sup] , 8[sup]th[/sup] , 14[sup]th[/sup] and 25[sup]th [/sup] day of their menstrual cycle. We only observed a positive correlation of p75 subunit with prolactin level (correlation coefficient 0.417; p=0.0116 and negative correlation with insulin level (correlation coefficient -0.35; p=0.032 and HOMA[sub]IR[/sub] insulin resistance index correlation coefficient 0.39; p=0.0185. Furthermore, a negative correlation of p55/p75 ratio with prolactin (correlation coefficient -0.42; p=0.0101 and a positive correlations of p55/p75 ratio with insulin level (correlation coefficient 0.43; p=0.008 and HOMA[sub]IR[/sub] insulin resistance factor correlation coefficient 0.45; p=0.0065 were found.

  1. Triple helix-forming oligonucleotide corresponding to the polypyrimidine sequence in the rat alpha 1(I) collagen promoter specifically inhibits factor binding and transcription. (United States)

    Kovacs, A; Kandala, J C; Weber, K T; Guntaka, R V


    Type I and III fibrillar collagens are the major structural proteins of the extracellular matrix found in various organs including the myocardium. Abnormal and progressive accumulation of fibrillar type I collagen in the interstitial spaces compromises organ function and therefore, the study of transcriptional regulation of this gene and specific targeting of its expression is of major interest. Transient transfection of adult cardiac fibroblasts indicate that the polypurine-polypyrimidine sequence of alpha 1(I) collagen promoter between nucleotides - 200 and -140 represents an overall positive regulatory element. DNase I footprinting and electrophoretic mobility shift assays suggest that multiple factors bind to different elements of this promoter region. We further demonstrate that the unique polypyrimidine sequence between -172 and -138 of the promoter represents a suitable target for a single-stranded polypurine oligonucleotide (TFO) to form a triple helix DNA structure. Modified electrophoretic mobility shift assays show that this TFO specifically inhibits the protein-DNA interaction within the target region. In vitro transcription assays and transient transfection experiments demonstrate that the transcriptional activity of the promoter is inhibited by this oligonucleotide. We propose that TFOs represent a therapeutic potential to specifically influence the expression of alpha 1(I) collagen gene in various disease states where abnormal type I collagen accumulation is known to occur.

  2. Rotation of nucleotide sites is not required for the enzymatic activity of chloroplast coupling factor

    Energy Technology Data Exchange (ETDEWEB)

    Musier, K.M.; Hammes, G.G.


    New heterobifunctional photoaffinity cross-linking reagents, 6-maleimido-N-(4-benzoylphenyl)hexanamide, 12-maleimido-N-(4-benzoylphenyl)dodecanamide, and 12-(/sup 14/C)maleimido-N-(4-benzoylphenyo)dodecanamide, were synthesized to investigate the mechanism of ATP hydrolysis by chloroplast coupling factor 1. These reagents react with sulfhydryl groups on the ..gamma..-polypeptide. Subsequent photolysis cross-links the ..gamma..-polypeptide covalently to ..cap alpha..- and ..beta..-polypeptides. The cross-linkers prevent major movements of the ..gamma..-polypeptide with respect to the ..cap alpha..- and ..beta..-polypeptides but are sufficiently long to permit some flexibility in the enzyme structure. When approx. 50% of the ..gamma..-polypeptide was cross-linked to a ..cap alpha..- and ..beta..-polypeptides, a 7% loss in ATPase activity was observed for the longer cross-linker and a 12% loss for the shorter. These results indicate that large movements of ..cap alpha..- and ..beta..-polypeptides with respect to the ..gamma..-polypeptide are not essential for catalysis. In particular, rotation of the polypeptide chains to crease structurally equivalent sites during catalysis is not a required feature of the enzyme mechanism.

  3. Evaluation of management alternatives for LWR hulls and caps

    International Nuclear Information System (INIS)

    Chaudon, L.; Mehling, O.; Cecille, L.; Thiels, G.; Kowa, S.


    Hulls and caps resulting from the reprocessing of LWR spent fuels represent one of the major sources of alpha-bearing solid waste generated during the nuclear fuel cycle. The Commission of the European Communities has undertaken considerable R and D efforts on the development of advanced treatment and conditioning methods for this type of waste. In view of the encouraging results achieved, the Commission launched a theoretical assessment study on cladding waste management. Six practical or potential schemes were identified and elaborated: direct cementation, decontamination prior to cementation, rolling before cementation, rolling followed by embedding in graphite, compaction, and melting in a cold crucible. The economic aspects of each management option were also investigated. This included the assessment of the plant (treatment, conditioning and interim storage), transport and disposal costs. Further consideration will be required to define the best management option for 'cap' wastes. Transport and disposal costs will also require further analysis from an industrial standpoint

  4. Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. (United States)

    Koshikawa, Nobuko; Hayashi, Jun-Ichi; Nakagawara, Akira; Takenaga, Keizo


    Lewis lung carcinoma-derived high metastatic A11 cells constitutively overexpress hypoxia-inducible factor (HIF)-1alpha mRNA compared with low metastatic P29 cells. Because A11 cells exclusively possess a G13997A mutation in the mitochondrial NADH dehydrogenase subunit 6 (ND6) gene, we addressed here a causal relationship between the ND6 mutation and the activation of HIF-1alpha transcription, and we investigated the potential mechanism. Using trans-mitochondrial cybrids between A11 and P29 cells, we found that the ND6 mutation was directly involved in HIF-1alpha mRNA overexpression. Stimulation of HIF-1alpha transcription by the ND6 mutation was mediated by overproduction of reactive oxygen species (ROS) and subsequent activation of phosphatidylinositol 3-kinase (PI3K)-Akt and protein kinase C (PKC) signaling pathways. The up-regulation of HIF-1alpha transcription was abolished by mithramycin A, an Sp1 inhibitor, but luciferase reporter and chromatin immunoprecipitation assays indicated that Sp1 was necessary but not sufficient for HIF-1alpha mRNA overexpression in A11 cells. On the other hand, trichostatin A, a histone deacetylase (HDAC) inhibitor, markedly suppressed HIF-1alpha transcription in A11 cells. In accordance with this, HDAC activity was high in A11 cells but low in P29 cells and in A11 cells treated with the ROS scavenger ebselene, the PI3K inhibitor LY294002, and the PKC inhibitor Ro31-8220. These results suggest that the ROS-generating ND6 mutation increases HIF-1alpha transcription via the PI3K-Akt/PKC/HDAC pathway,