| 1. |
- Andres, E., et al.
(författare)
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Selected recent results from AMANDA
- 2001
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Ingår i: ICHEP 2000. Proceedings of the 30th International Conference on High Energy Physics. - : World Scientific. ; , s. 965-968
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Konferensbidrag (refereegranskat)abstract
- We present a selection of results based on data taken in 1997 with the 302-PMT Antarctic Muon and Neutrino Detector Array-B10 ("AMANDA-B10") array. Atmospheric neutrinos created in the northern hemisphere are observed indirectly through their charged current interactions which produce relativistic, Cherenkov-light-emitting upgoing muons in the South Pole ice cap. The reconstructed angular distribution of these events is in good agreement with expectation and demonstrates the viability of this ice-based device as a neutrino telescope. Studies of nearly vertical upgoing muons limit the available parameter space for WIMP dark matter under the assumption that WIMPS are trapped in the earth's gravitational potential well and annihilate with one another near the earth's center.
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| 2. |
- Wiebusch, C., et al.
(författare)
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Results from AMANDA
- 2002
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Ingår i: Modern Physics Letters A. - : Institution of Electrical Engineers (IEE). - 0217-7323 .- 1793-6632. ; 17:31, s. 2019-2037
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Tidskriftsartikel (refereegranskat)abstract
- The Antarctic Muon and Neutrino Detector Array (AMANDA) is a high-energy neutrino telescope operating at the geographic South Pole. It is a lattice of photomultiplier tubes buried deep in the polar ice. The primary goal of this detector is to discover astrophysical sources of high energy neutrinos. We describe the detector methods of operation and present results from the AMANDA-B10 prototype. We demonstrate the improved sensitivity of the current AMANDA-II detector. We conclude with an outlook to the envisioned sensitivity of the future IceCube detector.
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| 3. |
- Ahrens, J., et al.
(författare)
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Initial results from AMANDA
- 2001
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Ingår i: 21st Rencontres de Moriond Workshop on Very High-Energy Phenomena in the Universe.
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Konferensbidrag (refereegranskat)
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| 4. |
- Karle, A., et al.
(författare)
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Observation of high energy atmospheric neutrinos with AMANDA
- 2000
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Ingår i: AIP Conference Proceedings. - : American Institute of Physics (AIP). ; , s. 823-827
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Konferensbidrag (refereegranskat)abstract
- In 1997 the Antarctic Muon and Neutrino Detector Array (AMANDA) started operating with 10 strings. In an analysis of data taken during the first year of operation 188 atmospheric neutrino candidates were found. Their zenith angle distribution agrees with expectations based on Monte Carlo simulations. A preliminary upper limit is given on a diffuse flux of high energy neutrinos of astrophysical origin.
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| 5. |
- Ahrens, J., et al.
(författare)
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Results from AMANDA
- 2001
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Ingår i: Proceedings, 9th International Workshop, Venice, Italy, March 6-9, 2001. Vol. 1, 2. ; , s. 569-580
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Konferensbidrag (refereegranskat)
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| 6. |
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| 7. |
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| 8. |
- Niessen, Peter, et al.
(författare)
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Recent results from the amanda experiment
- 2003
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Ingår i: Proceedings of 38th Rencontres de Moriond on Electroweak Interactions and Unified Theories 15-22 Mar 2003. Les Arcs, France.
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Konferensbidrag (refereegranskat)abstract
- AMANDA (Antarctic Muon And Neutrino Detector Array) is a neutrino telescope built under the southern polar icecap and its scope is to explore the possibility to detect high energy cosmic neutrinos. This should generate insight into the powerful celestial objects where acceleration mechanisms can bring up to 10 20 eV. We describe the achievements and results from the AMANDA-B10 prototype and the preliminary results from the current AMANDA-II detector which show dramatic increase in sensitivity.
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| 9. |
- Halzen, F., et al.
(författare)
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From the first neutrino telescope, the antarctic muon and neutrino detector array AMANDA, to the IceCube observatory
- 1999
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Ingår i: Proceedings of the 26th International Cosmic Ray Conference, August 17-25, 1999, Salt Lake City : Invited, Rapporteur, and Highlight Papers. - : American Institute of Physics (AIP). ; , s. 428-431
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Konferensbidrag (refereegranskat)
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| 10. |
- Adlarson, Patrik, et al.
(författare)
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Abashian-Booth-Crowe Effect in Basic Double-Pionic Fusion : A New Resonance?
- 2011
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 106:24, s. 242302-
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Tidskriftsartikel (refereegranskat)abstract
- We report on an exclusive and kinematically complete high-statistics measurement of the basic double-pionic fusion reaction pn -> d pi(0)pi(0) over the full energy region of the ABC effect, a pronounced low-mass enhancement in the pi pi-invariant mass spectrum. The measurements, which cover also the transition region to the conventional t- channel Delta Delta process, were performed with the upgraded WASA detector setup at COSY. The data reveal the Abashian-Booth-Crowe effect to be uniquely correlated with a Lorentzian energy dependence in the integral cross section. The observables are consistent with a narrow resonance with m = 2.37 GeV, Gamma approximate to 70 MeV and I(J(P)) = 0(3(+)) in both pn and Delta Delta systems. Necessary further tests of the resonance interpretation are discussed.
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| 11. |
- Barwick, S. W., et al.
(författare)
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Initial results from the AMANDA high-energy neutrino detector
- 1998
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Ingår i: High-energy physics. Proceedings, 29th International Conference, ICHEP'98, Vancouver, Canada, July 23-29, 1998. Vol. 1, 2. ; , s. 1447-1452
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Konferensbidrag (refereegranskat)
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| 12. |
- Miller, T. C., et al.
(författare)
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Particle astrophysics in antarctica
- 1996
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Ingår i: International School of Cosmic Ray Astrophysics: 10th Course: Toward the Millennium in Astrophysics: Problems and Prospects 16-26 Jun 1996. Erice, Italy. ; , s. 157-166
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Konferensbidrag (refereegranskat)
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| 13. |
- Bergstrom, L., et al.
(författare)
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The AMANDA experiment : Status and prospects for indirect dark matter detection
- 1996
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Ingår i: The identification of dark matter. Proceedings, 1st International Workshop, Sheffield, UK, September 8-12, 1996. ; , s. 521-528
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Konferensbidrag (refereegranskat)abstract
- At the AMANDA South Pole site, four new holes were drilled to depths 2050m to 2180 m and instrumented with 86 photomultipliers (PMTs) at depths1520-2000 m. Of these PMTs 79 are working, with 4-ns timing resolutionand noise rates 300 to 600 Hz. Various diagnostic devices were deployedand are working. An observed factor 60 increase in scattering length anda sharpening of the distribution of arrival times of laser pulses relative tomeasurements at 800-1000 m showed that bubbles are absent below 1500 m.Absorption lengths are 100 to 150 m at wavelengths in the blue and UV to337 nm. Muon coincidences are seen between the SPASE air shower arrayand the AMANDA PMTs at 800-1000 m and 1500-1900 m. The muon trackrate is 30 Hz for 8-fold triggers and 10 Hz for 10-fold triggers. The presentarray is the nucleus for a future expanded array. The potential of AMANDAfor SUSY dark matter search through the detection of high-energy neutrinosfrom the centre of the Sun or Earth is discussed.
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| 14. |
- Hulth, P. O., et al.
(författare)
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The AMANDA experiment
- 1996
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Ingår i: Neutrino '96. Proceedings, 17th International Conference on Neutrino Physics and Astrophysics, Helsinki, Finland, June 13-19, 1996. ; , s. 518-523
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Konferensbidrag (refereegranskat)abstract
- At the AMANDA South Pole site, four new holes were drilled to depths 2050 m to 2180 m and instrumented with 86 photomultipliers (PMTs) at depths 1520-2000 m. Of these PMTs 79 are working, with 4-ns timing resolution and noise rates 300 to 600 Hz. Various diagnostic devices were deployed and are working. An observed factor 60 increase in scattering length and a sharpening of the distribution of arrival times of laser pulses relative to measurements at 800-1000 m showed that bubbles are absent below 1500 m. Absorption lengths are 100 to 150 m at wavelengths in the blue and UV to 337 nm. Muon coincidences are seen between the SPASE air shower array and the AMANDA PMTs at 800-1000 m and 1500-1900 m. The muon track rate is 30 Hz for 8-fold triggers and 10 Hz for 10-fold triggers. The present array is the nucleus for a future expanded array.
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| 15. |
- de Walle, J. V., et al.
(författare)
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Coulomb excitation of the N=50 nucleus Zn-80
- 2008
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Ingår i: AIP Conference Proceedings. - 1551-7616 .- 0094-243X. ; 1012, s. 291-295 453
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Konferensbidrag (refereegranskat)abstract
- Neutron rich Zinc isotopes, including the N=50 nucleus Zn-80, were produced and post-accelerated at the Radioactive Ion Beam (RIB) facility REX-ISOLDE (CERN). Low-energy Coulomb excitation was induced on these isotopes after post-acceleration, yielding B(E2) strengths to the first excited 2(+) states. For the first time, an excited state in Zn-80 was observed and the 2(1)(+) state in Zn-78 was established. The measured B(E2,2(1)(+) -> 0(1)(+)) values are compared to two sets of large scale shell model calculations. Both calculations reproduce the observed B(E2) systematics for the full Zinc isotopic chain. The results for N=50 isotones indicate a good N=50 shell closure and a strong Z=28 proton core polarization. The new results serve as benchmarks to establish theoretical models, predicting the nuclear properties of the doubly magic nucleus Ni-78.
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| 16. |
- Walle, J. Van de, et al.
(författare)
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Coulomb Excitation of Neutron-Rich Zn Isotopes: First Observation of the 2[sub 1][sup +] State in [sup 80]Zn
- 2007
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Ingår i: Physical Review Letters. ; 99:14, s. 142501-
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-rich, radioactive Zn isotopes were investigated at the Radioactive Ion Beam facility REX-ISOLDE (CERN) using low-energy Coulomb excitation. The energy of the 21+ state in 78Zn could be firmly established and for the first time the 2+-->01+ transition in 80Zn was observed at 1492(1) keV. B(E2,21+-->01+) values were extracted for 74,76,78,80Zn and compared to large scale shell model calculations. With only two protons outside the Z=28 proton core, 80Zn is the lightest N=50 isotone for which spectroscopic information has been obtained to date. Two sets of advanced shell model calculations reproduce the observed B(E2) systematics. The results for N=50 isotones indicate a good N=50 shell closure and a strong Z=28 proton core polarization. The new results serve as benchmarks to establish theoretical models, predicting the nuclear properties of the doubly magic nucleus 78Ni.
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| 17. |
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| 18. |
- Belczynski, K., et al.
(författare)
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Evolutionary roads leading to low effective spins, high black hole masses, and O1/O2 rates for LIGO/Virgo binary black holes
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 636:A&A
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Tidskriftsartikel (refereegranskat)abstract
- All ten LIGO/Virgo binary black hole (BH-BH) coalescences reported following the O1/O2 runs have near-zero effective spins. There are only three potential explanations for this. If the BH spin magnitudes are large, then: (i) either both BH spin vectors must be nearly in the orbital plane or (ii) the spin angular momenta of the BHs must be oppositely directed and similar in magnitude. Then there is also the possibility that (iii) the BH spin magnitudes are small. We consider the third hypothesis within the framework of the classical isolated binary evolution scenario of the BH-BH merger formation. We test three models of angular momentum transport in massive stars: A mildly efficient transport by meridional currents (as employed in the Geneva code), an efficient transport by the Tayler-Spruit magnetic dynamo (as implemented in the MESA code), and a very-efficient transport (as proposed by Fuller et al.) to calculate natal BH spins. We allow for binary evolution to increase the BH spins through accretion and account for the potential spin-up of stars through tidal interactions. Additionally, we update the calculations of the stellar-origin BH masses, including revisions to the history of star formation and to the chemical evolution across cosmic time. We find that we can simultaneously match the observed BH-BH merger rate density and BH masses and BH-BH effective spins. Models with efficient angular momentum transport are favored. The updated stellar-mass weighted gas-phase metallicity evolution now used in our models appears to be key for obtaining an improved reproduction of the LIGO/Virgo merger rate estimate. Mass losses during the pair-instability pulsation supernova phase are likely to be overestimated if the merger GW170729 hosts a BH more massive than 50âMâŠ. We also estimate rates of black hole-neutron star (BH-NS) mergers from recent LIGO/Virgo observations. If, in fact. angular momentum transport in massive stars is efficient, then any (electromagnetic or gravitational wave) observation of a rapidly spinning BH would indicate either a very effective tidal spin up of the progenitor star (homogeneous evolution, high-mass X-ray binary formation through case A mass transfer, or a spin-up of a Wolf-Rayet star in a close binary by a close companion), significant mass accretion by the hole, or a BH formation through the merger of two or more BHs (in a dense stellar cluster).
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| 19. |
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| 21. |
- Aidas, Kestutis, et al.
(författare)
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The Dalton quantum chemistry program system
- 2014
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Ingår i: WIREs Computational Molecular Science. - : Wiley. - 1759-0876 .- 1759-0884. ; 4:3, s. 269-284
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Tidskriftsartikel (refereegranskat)abstract
- Dalton is a powerful general-purpose program system for the study of molecular electronic structure at the Hartree-Fock, Kohn-Sham, multiconfigurational self-consistent-field, MOller-Plesset, configuration-interaction, and coupled-cluster levels of theory. Apart from the total energy, a wide variety of molecular properties may be calculated using these electronic-structure models. Molecular gradients and Hessians are available for geometry optimizations, molecular dynamics, and vibrational studies, whereas magnetic resonance and optical activity can be studied in a gauge-origin-invariant manner. Frequency-dependent molecular properties can be calculated using linear, quadratic, and cubic response theory. A large number of singlet and triplet perturbation operators are available for the study of one-, two-, and three-photon processes. Environmental effects may be included using various dielectric-medium and quantum-mechanics/molecular-mechanics models. Large molecules may be studied using linear-scaling and massively parallel algorithms. Dalton is distributed at no cost from for a number of UNIX platforms.
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| 22. |
- Andres, EC, et al.
(författare)
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The AMANDA neutrino telescope
- 1999
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Ingår i: NUCLEAR PHYSICS B-PROCEEDINGS SUPPLEMENTS. - : ELSEVIER SCIENCE BV. - 0920-5632. ; 77, s. 474-485
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- With an effective telescope area of order 10(4) m(2) for TeV neutrinos, a threshold near similar to 50 GeV and a pointing accuracy of 2.5 degrees per muon track, the AMANDA detector represents the first of a new generation of high energy neutrino telescop
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| 23. |
- Bolling-Sternevald, Elisabeth, et al.
(författare)
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Effect of Profound Acid Suppression in Functional Dyspepsia : a Double-Blind, Randomized, Placebo-Controlled Trial
- 2002
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 37:12, s. 1395-1402
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Tidskriftsartikel (refereegranskat)abstract
- Background: Functional dyspepsia (FD) is defined as persistent or recurrent pain/discomfort centred in the upper abdomen, where no structural explanation for the symptoms is found. The role of drug treatment remains controversial. The aim in this study was to evaluate the effect of omeprazole 20 mg twice daily (b.i.d) and to test methods for symptom assessment.Methods: 197 patients fulfilling the criteria for FD were randomly allocated to double-blind treatment with omeprazole 20 mg b.i.d ( n = 100) or placebo ( n = 97) for 14 days. Patients with a known gastrointestinal disorder or with main symptoms indicating gastro-oesophageal reflux disease or irritable bowel syndrome were excluded. Helicobacter pylori testing and 24-h intra-oesophageal 24-h pH-metry were performed before randomization. The patients recorded dyspeptic symptoms on diary cards.Results: A stringent endpoint, 'complete symptom relief on the last day of treatment', was the primary efficacy variable. For the APT cohort, this was achieved in 29.0% and 17.7% on omeprazole and placebo, respectively (95% CI of difference (11.3%): -0.4%-23.0%, P = 0.057). Similar figures in the PP cohort were 31.0% and 15.5%, respectively (95% CI of difference (15.5%): 3.2%-27.7%, P = 0.018). The benefit of omeprazole in the PP cohort was confirmed by secondary endpoints such as, no dyspeptic symptoms on the last 2 days of treatment and overall treatment response. H. pylori status and the level of oesophageal acid exposure did not significantly influence the response to therapy.Conclusion: A subset of patients with FD will respond to therapy with omeprazole.
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| 30. |
- Ekstrom, M, et al.
(författare)
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Systemic inflammation activates the nuclear factor-kappaB regulatory pathway in adipose tissue
- 2010
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 299:2, s. E234-E240
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue (AT) is a store of energy but also an endocrine organ with the capacity to produce and release proinflammatory mediators into the circulation. The mechanism that may trigger human AT inflammation on a cellular level still remains largely unknown. The aim of this study was to investigate whether an acute systemic inflammation increases AT inflammatory activity, focused on innate immunity. Open heart surgery results in an extensive acute systemic inflammation. Therefore, we investigated the in vivo gene expression and production of inflammatory mediators in omental and subcutaneous AT stimulated by surgery. Biopsies from omental and subcutaneous AT were collected before and after cardiopulmonary bypass. Blood samples were collected at the same time as the AT biopsies and plasma IL-6 levels were measured with ELISA. RT-PCR was used for quantification of relative AT gene expression. To verify the gene expression results on a protein level, we used immunohistochemistry and microdialysis. After surgery, in both omental and subcutaneous AT, there was a strong upregulation of nuclear factor-κB-regulated genes, e.g., chemokine ligand-2, E-selectin, IL-1β, IL-6, IL-8, and Toll-like receptor-2. Immunohistochemistry showed staining for E-selectin associated with a high number of macrophages in close contact with and in the vascular wall. Increased levels of IL-6 were detected in microdialysate from subcutaneous AT. In conclusion, we present the novel finding that this model of inflammation induced a strong inflammatory response in both omental and subcutaneous AT including adhesion of macrophages to an activated endothelium and release of IL-6 from AT interstitium. It can be hypothesized that AT exerts a modulatory effect on innate immunity in humans.
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| 31. |
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| 32. |
- Ekstrom, S., et al.
(författare)
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Body mass index status and peripheral airway obstruction in school-age children: a population-based cohort study
- 2018
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 73:6, s. 538-545
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Tidskriftsartikel (refereegranskat)abstract
- Background Few large prospective studies have investigated the impact of body mass index (BMI) on lung function during childhood. Methods Using data collected between 2002 and 2013, we analysed associations between BMI status and lung function (assessed by spirometry) from 8 to 16 years, as well as cross-sectional associations with small airway function (impulse oscillometry) at 16 years in the BAMSE cohort (n=2889). At 16 years, cross-sectional associations with local and systemic inflammation were investigated by analysing FE NO, blood eosinophils and neutrophils. Results Overweight and obesity at 8 years were associated with higher FVC, but lower FEV 1 /FVC ratio at 8 and 16 years. In boys, but not girls, obesity at 8 years was associated with a further reduction in FEV 1 /FVC between 8 and 16 years. In cross-sectional analyses, overweight and obesity were associated with higher frequency dependence of resistance (R 5-20) and larger area under the reactance curve (AX0.5) at 16 years. Increased blood neutrophil counts were seen in overweight and obese girls, but not in boys. No association was found between BMI status and FE NO. Persistent, but not transient, overweight/obesity between 8 and 16 years was associated with higher R 5-20 and AX0.5 and lower FEV 1 /FVC (-2.8% (95% CI -4.1 to -1.2) in girls and -2.7% (95% CI -4.4 to -1.1) in boys) at 16 years, compared with persistent normal weight. Conclusion I n childhood and adolescence, overweight and obesity, particularly persistent overweight, were associated with evidence of airway obstruction, including the small airways.
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| 47. |
- Navarro, C. M., et al.
(författare)
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Treatment of humerus fractures in the elderly: A systematic review covering effectiveness, safety, economic aspects and evolution of practice
- 2018
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The objective of this Health Technology Assessment was to evaluate effectiveness, complications and cost-effectiveness of surgical or non-surgical treatment for proximal, diaphyseal or distal fractures of the humerus in elderly patients. Secondary objectives were to evaluate the intervention costs per treatment of proximal humerus fractures (PHF) and to investigate treatment traditions of PHF in Sweden. The assessment contains a systematic review of clinical and health economic studies comparing treatment options for humerus fractures in elderly patients. The results regarding the effectiveness of treatments are summarized in meta-analyses. The assessment also includes a cost analysis for treatment options and an analysis of registry data of PHF. For hemiarthroplasty (HA) and non-operative treatment, there was no clinically important difference for moderately displaced PHF at one-year follow-up regarding patient rated outcomes, (standardized mean difference [SMD]) -0.17 (95% CI: -0.56; 0.23). The intervention cost for HA was at least USD 5500 higher than non-surgical treatment. The trend in Sweden is that surgical treatment of PHF is increasing. When functional outcome of percutaneous fixation/plate fixation/prosthesis surgery and non-surgical treatment was compared for PHF there were no clinically relevant differences, SMD -0.05 (95% CI: -0.26; 0.15). There was not enough data for interpretation of quality of life or complications. Evidence was scarce regarding comparisons of different surgical options for humerus fracture treatment. The cost of plate fixation of a PHF was at least USD 3900 higher than non-surgical treatment, costs for complications excluded. In Sweden the incidence of plate fixation of PHF increased between 2005 and 2011. There is moderate/low certainty of evidence that surgical treatment of moderately displaced PHF in elderly patients has not been proven to be superior to less costly non-surgical treatment options. Further research of humerus fractures is likely to have an important impact.
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| 48. |
- Navarro, C. M., et al.
(författare)
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Treatment of radius or ulna fractures in the elderly: A systematic review covering effectiveness, safety, economic aspects and current practice
- 2019
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Background The objective of the present study was to evaluate effectiveness, complications and cost-effectiveness of any surgical or non-surgical treatment for radius or ulna fractures in elderly patients. Secondary objectives were to analyze present treatment traditions of distal radius fractures (DRF) in Sweden and to calculate resource usage for its treatment. The assessment contains a systematic review of clinical and health economic studies comparing treatment options for radius or ulna fractures. The results regarding the effectiveness of the treatments are summarized in meta-analyses. In addition, the assessment contains a cost analysis for different treatment options commonly used for DRF care, and an analysis of registry data on the incidence and treatment of DRF. In total 31 randomized controlled trials were included in meta-analyses. When comparing functional outcome for plate fixation versus non-surgical treatment for DRF, there were no clinically important differences at one-year follow-up (mean difference [MD], -3.29, 95% CI, -7.03; 0.44). Similar results were found when comparing plating and percutaneous methods with respect to functional outcome (standardized mean difference [SMD], -0.07, 95% CI, -0.21; 0.07) and grip strength (MD, -3.47, 95% CI, -11.21; 4.28). There were no differences for minor complications, (risk difference [RD], -0.01, 95% CI, -0.07; 0.05) whereas major complications were less common for the percutaneous group, (RD, 0.02, 95% CI, 0.02; 0.03). Given the low number of studies, the evidence above was rated as moderate certainty. The cost for plate fixation versus plaster cast was estimated to 1698 compared to 137 US dollars. For DRF, plate fixation increased in Sweden between 2005 and 2013, and was the most common surgical method in 2013. Surgical treatment of moderately displaced distal radius fractures in elderly patients offers no clear benefit compared to non-surgical treatment. Plating procedures have become more common during the second millennium and involve higher costs and higher risk of major complications than percutaneous options. BASZADEGAN H, 1990, ACTA ORTHOPAEDICA SCANDINAVICA, V61, P528
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| 49. |
- Paquet-Durand, F., et al.
(författare)
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Systemic and intraocular administration of the liposomal formulation of the cyclic GMP analogue CN03 : An exploratory safety and tolerability study in non-human primates
- 2019
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Ingår i: Investigative Ophthalmology and Visual Science. - : ASSOC RESEARCH VISION OPHTHALMOLOGY INC. - 0146-0404 .- 1552-5783. ; 60:9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose : The cGMP analogue CN03 targets cGMP signalling, a disease driver common to different types of retinal degeneration. For efficient targeting to the neuroretina CN03 was combined with a liposomal (LP) drug delivery system. In rodents, LP-CN03 has shown significant photoreceptor protection and preservation of in vivo retinal function, without major adverse events. The objective of the study was to determine the toxicity of CN03 and LP-CN03, following intravitreal (IVT) or intravenous (IV) administration. IVT administration is the intended human therapeutic route, IV injection was tested to investigate systemic toxicity.Methods : Cynomolgus monkeys were assigned to five different groups, consisting of one male and one female (n=2). Group 1 served as saline control for IVT and IV dosing, group 2 served as liposome (LP) control. Groups 3 and 4 received IVT injections of either 1X or 10X of the intended therapeutic dose, of either LP-CN03 (left eye) or CN03 (right). Group 5 received 100X IV bolus injections of LP-CN03 (Day 1) and CN03 (Day 25). Toxicity was assessed based on clinical observations, body weights, ophthalmology, intraocular pressure (IOP), electroretinography (ERG), and clinical and anatomic pathology.Results : IVT administration of LP caused transient white opacity in the vitreous body of all treated eyes, related to the milky consistency of LP. IVT injection of 1X and 10X CN03 was well-tolerated and only showed temporary pupil dilation in one male. IVT injection of 1X and 10X LP-CN03 was additionally associated with particles in the anterior chamber and vitreous body. At 10X, pigmented dots were also noted in the anterior lens capsule. IV injection of 100X LP-CN03 and CN03 was well tolerated and did not cause systemic toxicity. Comparison of pre- and post-dosing ERG did not reveal significant differences (p>0.05) in any of the groups, nor were there any indications of pathological changes in retinal morphology.Conclusions : IVT injection of CN03 and LP-CN03 at the intended therapeutic dose was not associated with any changes in ophthalmoscopy, electroretinography or histopathology, and only revealed slight pupil dilation in one animal. IV slow bolus injection at 100X the intended therapeutic dose was well tolerated.
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