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  • 151.
    Gedda, L
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Olsson, P
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Ponten, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Carlsson, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Development and in vitro studies of epidermal growth factor-dextranconjugates for boron neutron capture therapy.1996Inngår i: Bioconjug Chem, Vol. 7, s. 584-Artikkel i tidsskrift (Fagfellevurdert)
  • 152.
    Gedda, L
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Silvander, M
    Sjoberg, S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Tjarks, W
    Carlsson, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Cytotoxicity and subcellular localization of boronated phenanthridinium analogues.1998Inngår i: Anti-Cancer Drug Des., Vol. 12, s. 671-Artikkel i tidsskrift (Fagfellevurdert)
  • 153.
    Gedda, L
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Silvander, M
    Sjoberg, S
    Tjarks, W
    Carlsson, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Two step targeting: EGF-conjugate for delivery of DNA-binding compounds.1997Konferansepaper (Annet vitenskapelig)
  • 154.
    Gedda, L
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Silvander, M
    Sjoberg, S
    Tjarks, W
    Carlsson, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Two-step targeting: EGF-based conjugate for deliverance of nucleus-specific boron compounds.1996Inngår i: Seventh International Symposium on Neutron Capture Therapy for Cancer, s. 67-Artikkel, omtale (Annet vitenskapelig)
  • 155.
    Gedda, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Fondell, Amelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Park, John
    Department of medicine, Division of Haematology-Oncology, Cancer research institute, University of California San Fransisco, USA.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Experimental radionuclide therapy of HER2-expressing xenografts using two-step targeting Nuclisome-particles2012Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, nr 3, s. 480-487Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The therapeutic potential of Auger-electron emitting radionuclides is strongly dependent on their close vicinity to DNA, since the energy deposition is mainly localized within a few cubic nanometers around the site of decay. Thus, apart from specificity, successful tumor therapy relies on a nuclear delivery strategy. We recently presented a two-step targeting strategy to transport Auger-electron-emitting radionuclides into the cell nucleus by means of nuclide-filled liposomes (Nuclisome particles), that is, polyethylene glycol-stabilized, tumor-cell-targeting liposomes loaded with (125)I-labeled anthracyclines. In the present study, the survival of mice intraperitoneally inoculated with human HER2-expressing SKOV-3 tumor cells and treated with HER2-targeting Nuclisome particles was studied.

    METHODS:

    BALB/c nu/nu mice were inoculated with 10(7) SKOV-3 cells intraperitoneally and thereafter directly injected with Nuclisome particles with increasing specific radioactivity. Groups of 10-12 mice were treated with 0.01 MBq/mouse up to 2 MBq/mouse, and survival was monitored and compared with that in control groups (n = 33). Organs were analyzed for HER2 expression and radiotoxic effects histologically. Absorbed doses were estimated using dose factors from the online Radiation Dose Assessment Resource model.

    RESULTS:

    The results showed a clear correlation between administered radioactive dose and survival. No such dose-dependent survival was observed for mice treated with Nuclisome particles lacking HER2-targeting ability. With HER2-targeting Nuclisome particles, a significant increase in survival, compared with that of untreated control mice, could already be seen at an administered activity of 0.1 MBq/mouse (P = 0.0301). At the highest activity administered, 2 MBq/mouse (P < 0.0001), 70% of the mice survived the study and most were tumor-free. Neither macroscopic nor microscopic radiotoxic side effects were observed. Dosimetric calculations, assuming nonreceptor targeting, revealed that the radioactive doses to normal tissues were low.

    CONCLUSION:

    Taken together the results show that with successful targeting to the tumor-cell nucleus it is possible to obtain a therapeutic effect from Auger-electron-emitting radionuclides administered at radioactive doses low enough to spare normal tissue from radiotoxic side effects.

  • 156. Geitmann, Matthis
    et al.
    Elinder, Malin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Seeger, Christian
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Brandt, Peter
    de Esch, Iwan J P
    Danielson, U Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Biokemi.
    Identification of a Novel Scaffold for Allosteric Inhibition of Wild Type and Drug Resistant HIV-1 Reverse Transcriptase by Fragment Library Screening2011Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 3, s. 699-708Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel scaffold inhibiting wild type and drug resistant variants of human immunodeficiency virus type 1 reverse transcriptase (HIV-1RT) has been identified in a library consisting of 1040 fragments. The fragments were significantly different from already known non-nucleoside reverse transcriptase inhibitors (NNRTIs), as indicated by a Tversky similarity analysis. A screening strategy involving SPR biosensor-based interaction analysis and enzyme inhibition was used. Primary biosensor-based screening, using short concentration series, was followed by analysis of nevirapine competition and enzyme inhibition, thus identifying inhibitory fragments binding to the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Ten hits were discovered, and their affinities and resistance profiles were evaluated with wild type and three drug resistant enzyme variants (K103N, Y181C, and L100I). One fragment exhibited submillimolar K(D) and IC(50) values against all four tested enzyme variants. A substructure comparison between the fragment and 826 structurally diverse published NNRTIs confirmed that the scaffold was novel. The fragment is a bromoindanone with a ligand efficiency of 0.42 kcal/mol(-1).

  • 157. Genovese, Giulio
    et al.
    Kaehler, Anna K.
    Handsaker, Robert E.
    Lindberg, Johan
    Rose, Samuel A.
    Bakhoum, Samuel F.
    Chambert, Kimberly
    Mick, Eran
    Neale, Benjamin M.
    Fromer, Menachem
    Purcell, Shaun M.
    Svantesson, Oscar
    Landen, Mikael
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Lehmann, Sören
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Gabriel, Stacey B.
    Moran, Jennifer L.
    Lander, Eric S.
    Sullivan, Patrick F.
    Sklar, Pamela
    Groenberg, Henrik
    Hultman, Christina M.
    McCarroll, Steven A.
    Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence2014Inngår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, nr 26, s. 2477-2487Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers.

  • 158.
    Gerdin, Martin
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Silaborations of Unsaturated Compounds2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis deals with the development of transition metal-catalyzed silaborations of 1,3-dienes and 1,6-enynes.

    The first part of the thesis describes the development of the enantioselective 1,4-silaboration of 1,3-cyclohexadiene. A number of chiral metal-ligand complexes were evaluated. Up to 82% enantiomeric excess was obtained using a catalyst system derived from Pt(acac)2 and a phosphoramidite ligand. The product formed was employed in allylborations of aldehydes, giving homo-allylic alcohols in good yields with good to moderate diastereoselectivity. In attempts to widen the scope of silaborations to include acyclic, terminally substituted 1,3-dienes, products from H-B exchange with, and H-Si addition to, the dienes were obtained.

    The second part describes the development of silaborative carbocyclization of 1,6-enynes. A Pd N-heterocylic carbene complex was found to be effective for the silaborative carbocyclization of unsubstituted enynes, giving the products in good to excellent yields. Employing terminally substituted enynes resulted in low or no yields.

    The last part describes investigations into the reaction mechanisms of the processes developed in the first part. It was found that the silylborane undergoes oxidative addition to a Pt(0) complex generated from Pt(acac)2 and DIBALH. After insertion of 1,3-cyclohexadiene into the Pt-B bond a π-allyl complex was observed experimentally. In the addition of silylborane to acyclic, terminally substituted, 1,3-dienes it was shown by deuterium labeling experiments that one diene loses a hydride via H-B exchange and that this hydride is then added to another diene via H-Si addition. A reaction mechanism was proposed for this process.

  • 159.
    Ghalebani, Leila
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Probing Dynamics of Oligosaccharides by Interference Phenomena in NMR Relaxation2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Oligosaccharides (carbohydrates) are a large class of biological molecules that are important as energy sources in the human body and have enormously varied biological functions. It is generally believed that biological activities of carbohydrates are related to their internal dynamics. The dynamic properties of some oligosaccharides in solution are studied in this thesis, by NMR relaxation. We have employed relaxation interference effects to investigate the conformational dynamics within oligosaccharides (in-tramolecular dynamics) and paramagnetic relaxation enhancement (PRE) as an experimental tool to study intermolecular dynamics. Most of the thesis concerns the dynamics of the methylene group in the two possibly mobile parts of the oligosaccharide: in the exocyclic hydroxymethyl moiety and in the glycosidic linkage position. To perform conformational dynamic studies, the more traditional auto-relaxation pa-rameters are combined with the relaxation interference terms or the cross-correlated relaxation rates (CCRRs). Some experimental schemes based on the initial-rate technique were developed for measuring CCRRs. The techniques are useful for labelled sugars as well as naturally abundant ones. Furthermore, various dynamical models ranging from the Lipari–Szabo approach to several more informative and complicated models such as the two-site jump model, restricted internal rotation and slowly relaxing local structure (SRLS), have been employed to interpret our experimental data. We have combined and com-pared different models; we have also developed a novel approach to existing models, by scaling dipolar coupling constants (DCC), to extract the dynamic behaviour and structural properties of the system. We found that the auto- and cross-correlated relaxation data analyses yield a consistent picture of the dynam-ics in all cases. Additionally, our investigations show that CCRRs are practically important for verifica-tion of certain dynamical and structural information that is difficult to be determined by other means. Moreover, the anisotropy of the carbon-13 chemical shielding tensor in the methylene group has been estimated, using the interference between dipole-dipole and chemical shift anisotropy.

    This thesis also discusses using the PRE to investigate sugar dynamics relative to a paramagnetic MRI contrast agent in solution, which might be important in medicine. We have studied the intramolecu-lar dynamics of the trisaccharide raffinose in the presence of a gadolinium complex. We also investigated the effect of translational diffusion instead of rotational diffusion, which is normally more important in NMR. The paramagnetically enhanced spin–lattice relaxation rates of aqueous protons over a wide range of magnetic fields and of carbon-13 and protons of the sugar at high fields have been measured. The nuclear magnetic relaxation dispersion of water protons and the PREs of proton and carbon in the sugar are interpreted in terms of the model recently developed in our laboratory, allowing both outer- and inner-sphere PREs for water protons, but allowing only the outer sphere PRE for nuclei in the sugar. We found that the relative diffusion has a stronger effect on the PRE than the electron spin relaxation.

  • 160.
    Gharibyan, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Amyloids here, amyloids there…What’s wrong with them?2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical properties of different amyloid species and the nature of their influence on tissues and cells.  It is important to understand the mechanisms by which amyloids interact with different types of cells, as the leading hypothesis in amyloid field suggests that amyloids and especially their intermediate states are the main harmful, toxic species causing tissue and cell degeneration.

    Using de-novo synthesized protein albebetin as a model of amyloidogenic protein, we demonstrated that it forms amyloid-like structures under physiological conditions (pH 7 and 37°C). During aggregation it forms 2 different types of intermediate oligomers — cross-b sheet containing and lacking β-sheet oligomers. Only the former induces cellular toxicity in a dose dependent manner. Further aggregation leads to the formation of fully mature amyloid-like fibrils, which are not toxic to the cells during studied period of incubation.

    Another model protein in our studies was hen egg white lysozyme, which readily forms amyloid under denaturing conditions (pH 2,2 and 57°C). In contrast to albebetin and many other proteins reported in the literature, we showed that both oligomers and mature fibrils from hen lysozyme affect cell viability. Targeting different mechanisms involved in cellular death, we revealed that oligomers induce slow and apoptotic-like cell death, while mature fibrils cause rapid and mainly necrotic-like cellular death.   

    One of the important aspects of amyloid studies is to develop measures for inhibiting or re-directing the process of amyloid formation to abolish or neutralize toxic amyloid species. Among the agents having inhibitory or modulatory properties small, phenol containing molecules are widely studied. We investigated the effect of the novel nootropic drug noopept on amyloid formation process of α-synuclein, as this drug is a small dipeptide containing a phenol ring. We showed that noopept is able to modulate amyloid formation process by accelerating it to rapid conversion of α-synuclein into fully mature fibrils, thus eliminating the stage of population of toxic oligomeric species.  Using wide range of cytotoxicity assays we showed that amyloid-like fibrils formed in the presence of noopept have no cytotoxic properties.  As this medicine is becoming popular and freely available in some countries as a cognitive enhancer, neuroprotective and nootropic agent, further detailed investigations and clinical trials are needed to assess the safety and benefit of noopept in particular for the patients with amyloid related neurodegenerative diseases (such as Parkinson’s or Alzheimer’s diseases).    

    While in vitro models are useful to study some specific aspects of protein aggregation, their properties and effects on cell viability, it is very difficult or practically impossible to create an absolutely accurate model of in vivo situation. Therefore, it is important to turn to in vivo/ex vivo studies to relate the knowledge accumulated from in vitro studies to the real situation in the body.

    Using human brain hippocampus tissues from individuals with Alzheimer’s disease, we found that besides well-known and widely accepted main pathological hallmark — Ab peptide deposition, S100A9 and S100A8 pro-inflammatory calcium-binding proteins are also localized in the plaques and in surrounding tissues and very explicitly co-localized with Ab. Moreover, we found the presence of S100A9 within the neuronal cells, which has not been reported before and can be an important clue for understanding the mechanisms of neurodegeneration. In vitro cytotoxicity studies showed that S100A9 protein can efficiently induce cytotoxicity when added exogenously to the neuronal cell culture. These findings suggest that S100A8 and S100A9 proteins play an important role in Alzheimer’s pathology, and potentially can be candidates for the amyloid plaque formation and neurodegeneration. Whether they are associated with inflammatory processes underlying the early onset of disease or produced and accumulated as a consequence of A-beta induced pathology remain to be clarified.

    We found that Alzheimer’s disease is not the only pathology associated with A-beta and S100A9 deposition in a form of plaques. Immunohistochemical studies of an aortic valve surgically removed from a patient with aortic stenosis revealed plaque-like structures positively stained with A-beta and S100A9 proteins. These areas are also positively stained with fibril-specific antibodies as well as with Congo red, which also shows very distinct apple-green birefringence under the polarized light. Besides, there is intracellular localization and co-localization of both proteins in interstitial cells throughout the whole fibrous tissue of the valve. The presented case report is the first finding suggesting inflammatory protein S100A9 as well as A-beta peptide as potential candidates for amyloid formation in aortic stenosis valves.  We suggest that there is a specific interaction between A-beta and S100A9 during amyloid formation, which can be involved in amyloid-associated pathology in various tissues and organs in the body, which can potentially be caused by inflammatory processes, particularly by its chronic, long lasting forms.

  • 161.
    Ghulam Shazari, Sohaila
    Högskolan i Gävle, Akademin för hälsa och arbetsliv, Avdelningen för hälso- och vårdvetenskap.
    Nutritionens betydelse för trycksårsprevention och sårläkning hos äldre personer som vårdas på vårdinrättningar inom landsting och kommun: -en allmän litteraturstudie2012Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Abstrakt

    Bakgrund: En viktig förutsättning för att man ska hålla sig frisk är att kroppen tillförs de ämne som är nödvändiga för att cellerna ska kunna fungera. Vätska och näring i tillräcklig mängd är en grundläggande mänsklig rättighet. Syfte: Syftet med litteraturstudien var att utifrån litteratur beskriva nutritionens betydelse för trycksårsprevention och sårläkning hos äldre personer, som vistas inom olika vårdinrättningar inom landsting och kommun.

    Metod: En litteraturstudie som baserades på 12 vetenskaplig artiklar med kvantitativ ansats. Resultat: Litteraturstudiens resultat visade att personer som drabbas av trycksår hade större behov av energi och näringsämnen till läkningsprocessen och behovet av näring och energi ökade med sårets svårighetsgrad. God nutrition främjade sårläkningen och förebyggde att fler trycksår uppstod.  Även tillskott av näringstillskott utöver den vanliga kosten förebyggde uppkom av nya trycksår och påskyndade sårläkningen hos de äldre personerna. En av sjuksköterskans grundläggande uppgifter var att kartlägga patientens näringsstatus för att bedöma om vätske- och näringsbehovet var tillgodosett.  Sjuksköterskan ansvarade också för att identifiera patienter som var undernärda eller låg i riskzonen för undernäring.

    Slutsats: Föreliggande litteraturstudie kom fram till att nutrition är en viktig del i en trycksår behandlingsplan. Det innebär att läkning främjas, ökat välbefinnandet för äldre personer med trycksår och bidrar till förkortad behandlingstid.

  • 162.
    Gil, Harveth
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Korrosionslära.
    Leygraf, Christofer
    KTH, Skolan för kemivetenskap (CHE), Kemi, Korrosionslära.
    Quantitative in situ analysis of initial atmospheric corrosion of copper induced by acetic acid.2007Inngår i: Journal of the Electrochemical Society, ISSN 0013-4651, E-ISSN 1945-7111, Vol. 154, nr 5, s. 272-278Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The initial atmospheric corrosion of copper was investigated by means of a quantitative in situ analysis in an atmospherecontaining 120 ppb of acetic acid and 95% relative humidity using a quartz crystal microbalance (QCM) integrated with infraredreflection absorption spectroscopy (IRAS). Crystalline cuprous oxide (various structural forms of Cu2O) and hydrated copperacetate were detected as corrosion products during up to 100 h of exposure. The quantification of data was made possible throughan observed linear relationship between the absorbance of vibrations (IRAS)of both phases and the corresponding mass (QCM).The quantification of cuprous oxide was further supported by ex situ coulometric reduction of the corrosion products. The growthrate of cuprous oxide was initially very fast but almost zero after 20 h exposure where it reached an average thickness of13 ± 1 nm. Copper acetate exhibited a more constant growth rate. Atomic force microscopy showed a uniform growth of cuprousoxide with surface roughness that increased with time and localized formation of copper acetate. The quantified data are consistentwith a previously proposed model that involves proton- and acetate-induced dissolution of copper and subsequent precipitation ofcuprous oxide and copper acetate.

  • 163. Gillman, Anna
    et al.
    Muradrasoli, Shaman
    Söderström, Hanna
    Holmberg, Fredrik
    Latorre-Margalef, Neus
    Tolf, Conny
    Waldenström, Jonas
    Gunnarsson, Gunnar
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap.
    Olsen, Björn
    Järhult, Josef D
    Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards2015Inngår i: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 81, nr 7, s. 2378-2383Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Influenza A virus (IAV) has its natural reservoir in wild waterfowl and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate (OC)), stockpiled as Tamiflu® for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may there exert evolutionary pressure on avian IAV in waterfowl, resulting in development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo Mallard (Anas platyrhynchos) study we tested if an OC-resistant avian IAV strain (A(H1N1)/NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected Mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission in 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV, induced by OC exposure of the natural host, can persist in absence of the drug. Thus, there is a risk that human pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir resistant pandemic IAV would be a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment and resistance surveillance of IAV in wild birds.

  • 164. Golyakov, A M
    et al.
    Shchukarev, Andrey V
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pak, V N
    Shagisultanova, G A
    Borisov, A N
    Electrochemical Synthesis and Spectroscopy of the Polymeric Form of N,N '-Bis(3-methoxysalicylidene)-1,3-propylenediamine2011Inngår i: Russian journal of applied chemistry, ISSN 1070-4272, E-ISSN 1608-3296, Vol. 84, nr 2, s. 317-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Electrochemical oxidation of N,N '-bis(3-methoxysalicylidene)-1,3-propylenediamine leads to the formation of a conducting polymer on the electrode surface. The diffusion coeffi cient and activation barrier of the charge transfer in the bulk of the polymer in an electrolyte medium were determined. The Schiff base and its polymeric form in the oxidized and reduced states were characterized by IR, X-ray photoelectron, and electronic absorption spectroscopy. Reversible changes in the polymer structure, accompanying its electrochemical oxidation–reduction, are substantiated.

  • 165.
    Greis, Christina
    et al.
    Örebro universitet, Institutionen för naturvetenskap.
    Karlsson, Stefan
    Örebro universitet, Institutionen för naturvetenskap.
    Düker, Anders
    Örebro universitet, Institutionen för naturvetenskap.
    Pettersson, Håkan
    Radiofysikavdelningen, O-centrum US, Universitetssjukhuset, Linköping, Sweden .
    Allard, Bert
    Örebro universitet, Institutionen för naturvetenskap.
    Determination of plutonium in environmental samples with quadrupole ICP-MS2008Inngår i: Journal of Radioanalytical and Nuclear Chemistry, ISSN 0236-5731, E-ISSN 1588-2780, Vol. 275, nr 1, s. 55-70Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A method for rapid determination of plutonium isotopes in environmental samples with ultrasonic nebulisation and quadrupole ICP-MS detection was established. Techniques for sample dissolution, pre-concentration and chemical separation were evaluated and the optimal scheme outlined. Comparisons with α-spectrometry and high resolution ICP-MS confirmed the suitability of the method when applied to different environmental matrices within the global fallout concentration range in the northern hemisphere as well as more contaminated sites. Operational detection limits were 0.5–1.5 fg/l for fresh waters and 0.03–0.1 ng/kg for lake sediments and saline marsh sediments.

  • 166. Gruden, Marina A
    et al.
    Davydova, Tatiana V
    Narkevich, Victor B
    Fomina, Valentina G
    Wang, Chao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kudrin, Vladimir S
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sewell, Robert D E
    Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms2015Inngår i: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 279, s. 191-201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alpha-synuclein (α-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of α-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated α-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay. Levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected using HPLC with electrochemical detection in the substantia nigra (SN) and striatum. The oligomers or fibrils administered alone or in a 50:50 combination (total dose of 0.48mg/kg) were given intranasally for 14 days and "open-field" behaviour was tested on days 0, 15 and 28 of the protocol, at which time brain structures were sampled. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e. 14 days after treatment completion) induced hypokinesia and immobility whilst the aggregate combination additionally produced rigidity. The α-Syn oligomer/fibril mixture also instigated PD-like motor symptoms which correlated heterochronically with elevated NA levels in the striatum but then later in the SN while intranasal fibrils alone augmented 5-HT and 5-HIAA nigral concentrations throughout the protocol. In contrast, α-syn oligomers displayed a delayed serotonin upsurge in the SN. Neurodegenerative and/or actions on neurotransmitter transporters (such as NET, SERT and VMAT2) are discussed as being implicated in these α-syn amyloid induced neurochemical and motoric disturbances.

  • 167.
    Guerrero-Bosagna, Carlos
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Optimized method for methylated DNA immuno-precipitation2015Inngår i: MethodsX, ISSN 1258-780X, E-ISSN 2215-0161, Vol. 2, s. e432-e439, artikkel-id eArtikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Methylated DNA immunoprecipitation (MeDIP) is one of the most widely used methods to evaluate DNA methylation on a whole genome scale, and involves the capture of the methylated fraction of the DNA by an antibody specific to methyl-cytosine. MeDIP was initially coupled with microarray hybridization to detect local DNA methylation enrichments along the genome. More recently, MeDIP has been coupled with next generation sequencing, which highlights its current and future applicability. In previous studies in which MeDIP was applied, the protocol took around 3 days to be performed. Given the importance of MeDIP for studies involving DNA methylation, it was important to optimize the method in order to deliver faster turnouts. The present article describes optimization steps of the MeDIP method. The length of the procedure was reduced in half without compromising the quality of the results. This was achieved by:

    • Reduction of the number of washes in different stages of the protocol, after a careful evaluation of the number of indispensable washes.

    • Reduction of reaction times for detaching methylated DNA fragments from the complex agarose beads:antibody.

    • Modification of the methods to purify methylated DNA, which incorporates new devices and procedures, and eliminates a lengthy phenol and chloroform:isoamyl alcohol extraction.

  • 168.
    Gunnarsson, Stina
    et al.
    Region Östergötland, Sinnescentrum, Rehabiliteringsmedicinska kliniken. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten.
    Samuelsson, Kersti
    Östergötlands Läns Landsting, Sinnescentrum, Rehabiliteringsmedicinska kliniken. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten.
    Patient experiences with intrathecal baclofen as a treatment for spatsticity - a pilot study2015Inngår i: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 37, nr 10, s. 834-841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: This study describes how patients experience intrathecal baclofen (ITB) treatment. Methods: Data were collected from interviews with 14 patients (19–76 years old) who were diagnosed with spinal cord injury (SCI), multiple sclerosis (MS), or cerebral palsy (CP). Data were analyzed using conventional content analysis. Result: The analysis resulted in 16 subcategories arranged into five main categories: procedures before treatment, the effect of ITB on daily life and activities, continuous follow-up, expected and unexpected consequences of ITB, and overall level of satisfaction with ITB. Together these categories described the patients' experiences with ITB treatment. When the patients were asked whether they would undergo ITB again, they all stated that they would. Conclusion: Patients stated that they were highly satisfied with the ITB treatment. However, the patients identified several areas that could be improved. Specifically, the patients wanted more information about the different steps in the treatment process and what to expect from ITB treatment.Implications for Rehabilitation

    • An overall satisfaction with the effect from ITB treatment was shown, but some areas still need to be improved.

    • Complications following ITB treatment still remain a major concern for the patient group.

    • Future clinical practice, should address how to take into account patients' expectations and define relevant goals with respect to ITB treatment as well as how to supply professional information.

  • 169.
    Gunnesson, Linnea
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Zetterlund, Anna
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Fysisk aktivitetsnivå, smärtintensitet och funktionsnedsättning hos personer med ländryggssmärta: - En enkätstudie2018Independent thesis Advanced level (degree of Master (One Year)), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Bakgrund

    Ländryggssmärta är mycket vanligt förekommande i västvärlden. Det innebär stort

    lidande för individen och stora kostnader för samhället. Idag behandlas ryggsmärta

    med information om att vara aktiv och vid behov rådgivning om smärtstillande

    läkemedel. Mer kunskap behövs gällande fysisk träning som prevention och

    behandling av akut- och subakut ländryggssmärta.

    Syfte

    Syftet med studien var att, för patienter med akut- och subakut ländryggsmärta,

    beskriva den fysiska aktivitetsnivån samt eventuella skillnader i smärtintensitet

    och funktionsnedsättning mellan grupper med olika aktivitetsnivåer. Syftet var

    även att undersöka samband mellan aktivitetsnivå och smärtintensitet respektive

    aktivitetsnivå och funktionsnedsättning.

    Metod

    Studien var en enkätstudie med tvärsnittsdesign. Deltagarna var 15 patienter, 9

    kvinnor och 6 män, medelålder 49,2 år, som sökt vård för akuta eller subakuta

    ländryggsbesvär till 4 olika primärvårdsenheter. Fysisk aktivitetsnivå skattades via

    Socialstyrelsens indikatorfrågor för fysisk aktivitet, smärtan med numerisk

    skattningsskala 0-10 (NRS) och Roland Morris Disability Questionnaire (RMDQ)

    besvarades. Data sammanställdes med deskriptiv statistik, skillnader testades med

    Mann-Whitney U-test och samband analyserades med Spearmans

    korrelationskoefficient.

    Resultat

    Åtta av 15 deltagare uppnådde Världshälsoorganisationens (WHO)

    rekommendationer för fysisk aktivitet (> 150 minuter i veckan). De som ägnade

    sig åt fysisk träning minst 90 minuter per vecka hade medianvärde NRS 5,5 och

    RMDQ 8, för de som tränade mindre var motsvarande värden NRS 7,5 (p=0,153)

    och RMDQ 11,5 (p=0,175). Ett svagt negativt samband identifierades mellan NRS

    (r=-0,316,) och nivå av fysisk aktivitet medans sådant samband mellan RMDQ och

    fysisk aktivitetsnivå var negligerbart (r=-0,158).

    Slutsats

    Det var ingen statistiskt signifikant skillnad mellan grupperna som tränade minst

    90 minuter per vecka och de som tränade mindre gällande varken smärtintensitet

    eller funktionsnedsättning. Ett svagt negativt men ej statistiskt signifikant

    samband kan ses mellan fysisk aktivitetsnivå och smärtintensitet.

  • 170. Gustafson, D
    et al.
    Rothenberg, Elisabet
    Göteborgs universitet.
    Blennow, K
    Steen, B
    Skoog, I
    An 18-year follow-up of overweight and risk of Alzheimer disease2003Inngår i: Archives of Internal Medicine, ISSN 0003-9926, E-ISSN 1538-3679, Vol. 163, nr 13, s. 1524-1528Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background  Overweight and obesity are epidemic in Western societies and constitute a major public health problem because of adverse effects on vascular health. Vascular factors may play a role in the development of a rapidly growing disease of late life, Alzheimer disease (AD). Using body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), we examined whether overweight is a risk factor for dementia and AD.

    Methods  The relationship between BMI and dementia risk was investigated in a representative cohort of 392 nondemented Swedish adults who were followed up from age 70 to 88 years, with the use of neuropsychiatric, anthropometric, and other measurements. Multivariate Cox proportional hazards regression analyses included BMI, blood pressure, cardiovascular disease, cigarette smoking, socioeconomic status, and treatment for hypertension.

    Results:  During the 18-year follow-up (4184.8 risk-years), 93 participants were diagnosed as having dementia. Women who developed dementia between ages 79 and 88 years were overweight, with a higher average BMI at age 70 years (27.7 vs 25.7; P = .007), 75 years (27.9 vs 25.0; P<.001), and 79 years (26.9 vs 25.1; P = .02) compared with nondemented women. A higher degree of overweight was observed in women who developed AD at 70 years (29.3; P = .009), 75 years (29.6; P<.001), and 79 years (28.2; P = .003) compared with nondemented women. For every 1.0 increase in BMI at age 70 years, AD risk increased by 36%. These associations were not found in men.

    Conclusions  Overweight is epidemic in Western societies. Our data suggest that overweight at high ages is a risk factor for dementia, particularly AD, in women. This may have profound implications for dementia prevention.

  • 171.
    Gustafsson, Ann-Sofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Radiation response in human cells: DNA damage formation, repair and signaling2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ionizing radiation induces a range of different DNA lesions. In terms of mutation frequency and mammalian cell survival, the most critical of these lesions is the DNA double-strand break (DSB). DSB left unrepaired or mis-repaired may result in chromosomal aberrations that can lead to permanent genetic changes or cell death. The complexity of the DNA damage and the capacity to repair the DSB will determine the fate of the cell. This thesis focuses on the DNA damage formation, repair and signaling after irradiation of human cells.

    Radiation with high linear energy transfer (LET) produces clustered damaged sites in the DNA that are difficult for the cell to repair. Within these clustered sites, non-DSB lesions are formed that can be converted into a DSB and add to the damage complexity and affect DSB repair and the measurement. Heat-labile sites in DNA are converted into DSB at elevated temperatures. We show that heat-released DSB are formed post-irradiation with high-LET ions and increase the initial yield of DSB by 30%-40%, which is similar to yields induced by low-LET radiation.

    DNA-PKcs, a central player in non-homologous end-joining (NHEJ), the major mammalian DSB repair pathway, has been found to be both up- and downregulated in different tumor types. In Paper II we show that low levels of DNA-PKcs lead to extreme radiosensitivity but, surprisingly, had no effect on the DSB repair. However, the fraction of cells in G2/M phase increased two-fold in cells with low levels of DNA-PKcs. The study continued in Paper IV, where cells were synchronized to unmask potential roles of DNA-PKcs in specific cell cycle phases. Irradiation of DNA-PKcs suppressed cells in the G1/S phase caused a delay in cell cycle progression and an increase in accumulation of G2 cells. Further, these cells showed defects in DNA repair, where a significant amount of 53BP1 foci remained after 72 h. This further strengthens the hypothesis that DNA-PKcs has a role in regulation of mitotic progression.

    Several cellular signaling pathways are initiated in response to radiation. One of these downstream signaling proteins is AKT. We identified an interaction between DNA-PKcs and AKT. Knockouts of both AKT1 and AKT2 impaired DSB rejoining after radiation and low levels of DNA-PKcs increased radiosensitivity and decreased DNA repair further.  

  • 172.
    Gustafsson, Åsa
    et al.
    KTH, Tidigare Institutioner, Kemi.
    Molera, Mireia
    KTH, Tidigare Institutioner, Kemi.
    Puigdomenech, Ignasi
    KTH, Tidigare Institutioner, Kemi.
    Study of Ni(II) sorption on chlorite - a fracture filling mineral in granites2004Inngår i: 28th Symposium on the Scientific Basis for Nuclear Waste Management held at the 2004 MRS Spring Meeting San Francisco, CA, APR 13-16, 2004, 2004, Vol. 824, s. 373-378Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Chlorite is an Fe(II)-containing phyllosilicate which is often present as a fracture filling mineral in e.g. granitic rocks. It may therefore be significant in influencing redox conditions and sorption processes in granitic groundwaters. The sorption properties of chlorite may therefore be important when modelling the migration of radionuclides under reducing conditions around nuclear waste repositories or in sites contaminated by mining waste. The sorption behaviour of Ni(II) onto a natural chlorite (Karlsborg, Sweden) was investigated using a batch technique. The effects of three different background electrolyte concentrations (0.01 M, 0.1 M and 0.5 M NaClO4) different pH values (ranging from 4 to 11) and different Ni(II) concentrations (10(-6) and 10(-8) M) were studied under anoxic conditions in a glove-box. Ni(II) solutions were spiked with 63 Ni and beta-Liquid scintillation counting (LSC) was used to determine the concentration of nickel in the bulk solution, allowing the calculation of solid-water distribution coefficients for the metal ion. The results of the sorption experiments show strong pH dependence at pH > 5, but the sorption is independent of ionic strength. The maximum adsorption is found in the pH range between 7 and 11 with K-d values approximate to10(3) cm(3)/g. A diffuse double layer model has been used to describe the experimental results.

  • 173.
    Günaltay, Sezin
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Dysregulated mucosal immune responses in microscopic colitis patients2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC) is a common cause of chronic watery diarrhea. The diagnosis relies on typical histopathological changes observed upon microscopic examination. The studies in this thesis investigated innate and adaptive immune responses in the colonic mucosa of MC patients, also comparing patients with active disease (CC and LC) and histopathologically in remission (CC/LC-HR). We first analyzed expression of interleukin-1/Toll-like receptor (IL-1/TLR) signaling regulators in MC patients (Paper I). Our results showed enhanced IRAK-M, microRNA-146a, -155 and -21 expressions, whereas IL-37 gene expression was reduced in CC and LC patients as compared to non-inflamed controls. These results suggest different pathophysiological mechanisms in MC patients. The mixed inflammatory cell infiltrations seen in the lamina propria of MC patients might be a result of dysregulated expression of chemotactic mediators. In Paper II, we showed that MC patients display mainly an increased expression of chemokines and chemokine receptors in active disease as compared to noninflamed controls. In Paper III, we examined if the decreased IL-37 expression seen in Paper I could mediate the upregulation of chemokines seen in Paper II. We showed that a relatively small reduction in the ability of epithelial cells to produce IL-37 results in mainly increased chemokine expressions in a pattern similar to the findings in Paper II. In order to understand the nature of infiltrating T cells commonly observed in MC patients, we analyzed the T cell receptor (TCR) β chains in colonic biopsies of MC patients (Paper IV). Our results showed significant differences in TCRβ repertoire, which suggests selectively expanded T cell clones in active MC and histopathologically in remission patients. Altogether, these results i) increase the knowledge of MC pathogenesis by showing changes in TLR signaling regulators, enhanced chemokine and their receptor expressions involved in a mixed immune cell infiltrations and selectively expanded T cell clones in CC and LC patients, as well as in histopathological remission ii) might potentially increase the possibility of more target-specific therapies based on IL-37 induction, chemokines or chemokine receptor inhibitions, or hindering T cell infiltration according to TCR clonality.

  • 174.
    Günaltay, Sezin
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Ghiboub, Mohammed
    Amsterdam university.
    Hultgren, Olof
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Hultgren-Hörnquist, Elisabeth
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cellsManuskript (preprint) (Annet vitenskapelig)
  • 175.
    Günaltay, Sezin
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Repsilber, Dirk
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Nyhlin, Nils
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Bohr, Johan
    Örebro universitet, Institutionen för hälsovetenskaper.
    Hultgren-Hörnquist, Elisabeth
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuskript (preprint) (Annet vitenskapelig)
  • 176.
    Hadrévi, Jenny
    Högskolan i Gävle, Akademin för hälsa och arbetsliv, Avdelningen för arbets- och folkhälsovetenskap, CBF. Högskolan i Gävle, Centrum för belastningsskadeforskning. Umeå universitet, Institutionen för integrativ medicinsk biologi (IMB).
    Applying proteomics and metabolomics for studying human skeletal muscle with a focus on chronic trapezius myalgia2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Work related musculoskeletal disorders are the dominating causes of reported ill-health in industrialized countries. These chronic pain conditions are one of the most costly public health problems in Europe and North America. When work related musculoskeletal disorders are considered to be of muscular origin and the trapezius muscle is affected, the common appellation is trapezius myalgia. Since little is known about the genesis or how it is maintained, it is of great importance to better understand the pathophysiology of trapezius myalgia; doing so will better enable recommendations for prevention, treatment and rehabilitation. Several hypotheses have been presented based on biochemical alterations in the muscle, suggesting increased signaling of inflammatory substances and altered metabolism. Previous research has not been able to present the comprehensive picture of the muscle in pain. Thus there is a demand for more comprehensive research regarding the biochemical milleu of the chronic trapezius muscle.

    Proteomic and metabolomic methods allow non-targeted simultaneous analyses of a large number of proteins and metabolites. The main emphasis in this thesis is on a proteomic method, two-dimensional differential gel electrophoresis (2D-DIGE). The method is validated to human skeletal muscle biopsy research with laboratory specific settings. In the baseline study, there were 14 metabolic, contractile, structural and regulatory proteins that differed significantly in abundance when trapezius and vastus lateralis muscles were compared. Using the validated 2D-DIGE method and the baseline study, a comparison between healthy and myalgic muscles was made. Biopsies from female cleaners with and without myalgia were compared to obtain results from women with the same type of work exposure. In the multivariate model, 28 identified unique proteins separated healthy and myalgic muscle and were grouped according to function: metabolic (n=10), contractile (n=9), regulatory (n=3), structural (n=4), and other (n=2). Finally, a second screening method, metabolomics, was introduced to analyze differences in metabolite content as a complement to and verification of the proteomic results. Gas chromatography-mass spectrometry (GC-MS) was performed on muscle interstitial fluid samples obtained with microdialysis, and differences in the abundance of extracellular metabolites were revealed.

     The 2D-DIGE method is a reliable method to analyze human skeletal muscle. The outcomes of the proteomic analyses were dependant on the statistical approach. Systematic differences in protein and metabolite content were detected using a multivariate approach. Univariate analyses were used to analyze individual proteins for their significance. The significant proteins in the baseline study were predominately related to muscle fiber type which correlated with the differences in fiber type content between trapezius and vastus lateralis. The proteomic and metabolomics studies where myalgic and healthy muscles were compared provide us with new clues and new aspects regarding the pathophysiology of the myalgic muscle.

    Technically advanced methods employed in the thesis enabled an explorative screening of proteins of relevance for the pathophysiology of the myalgic muscle. The results of these analyses may contribute to the formulation of future hypothesis that need to be further evaluated.

  • 177.
    Hadrévi, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Applying proteomics and metabolomics for studying human skeletal muscle with a focus on chronic trapezius myalgia2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Work related musculoskeletal disorders are the dominating causes of reported ill-health in industrialized countries. These chronic pain conditions are one of the most costly public health problems in Europe and North America. When work related musculoskeletal disorders are considered to be of muscular origin and the trapezius muscle is affected, the common appellation is trapezius myalgia. Since little is known about the genesis or how it is maintained, it is of great importance to better understand the pathophysiology of trapezius myalgia; doing so will better enable recommendations for prevention, treatment and rehabilitation. Several hypotheses have been presented based on biochemical alterations in the muscle, suggesting increased signaling of inflammatory substances and altered metabolism. Previous research has not been able to present the comprehensive picture of the muscle in pain. Thus there is a demand for more comprehensive research regarding the biochemical milleu of the chronic trapezius muscle.

    Proteomic and metabolomic methods allow non-targeted simultaneous analyses of a large number of proteins and metabolites. The main emphasis in this thesis is on a proteomic method, two-dimensional differential gel electrophoresis (2D-DIGE). The method is validated to human skeletal muscle biopsy research with laboratory specific settings. In the baseline study, there were 14 metabolic, contractile, structural and regulatory proteins that differed significantly in abundance when trapezius and vastus lateralis muscles were compared. Using the validated 2D-DIGE method and the baseline study, a comparison between healthy and myalgic muscles was made. Biopsies from female cleaners with and without myalgia were compared to obtain results from women with the same type of work exposure. In the multivariate model, 28 identified unique proteins separated healthy and myalgic muscle and were grouped according to function: metabolic (n=10), contractile (n=9), regulatory (n=3), structural (n=4), and other (n=2). Finally, a second screening method, metabolomics, was introduced to analyze differences in metabolite content as a complement to and verification of the proteomic results. Gas chromatography-mass spectrometry (GC-MS) was performed on muscle interstitial fluid samples obtained with microdialysis, and differences in the abundance of extracellular metabolites were revealed.

     The 2D-DIGE method is a reliable method to analyze human skeletal muscle. The outcomes of the proteomic analyses were dependant on the statistical approach. Systematic differences in protein and metabolite content were detected using a multivariate approach. Univariate analyses were used to analyze individual proteins for their significance. The significant proteins in the baseline study were predominately related to muscle fiber type which correlated with the differences in fiber type content between trapezius and vastus lateralis. The proteomic and metabolomics studies where myalgic and healthy muscles were compared provide us with new clues and new aspects regarding the pathophysiology of the myalgic muscle.

    Technically advanced methods employed in the thesis enabled an explorative screening of proteins of relevance for the pathophysiology of the myalgic muscle. The results of these analyses may contribute to the formulation of future hypothesis that need to be further evaluated.

  • 178.
    Hadrévi, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Ghafouri, Bijar
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Sjörs, Anna
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden; Institute of Stress Medicine, Carl Skottsbergs gata 22B, SE 41319 Gothenburg, Sweden.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Larsson, Britt
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Crenshaw, A. G.
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Gerdle, Björn
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Hellström, Fredrik
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Comparative metabolomics of muscle interstitium fluid in human trapezius myalgia: an in vivo microdialysis study2013Inngår i: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 113, nr 12, s. 2977-2989Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The mechanisms behind trapezius myalgia are unclear. Many hypotheses have been presented suggesting an altered metabolism in the muscle. Here, muscle microdialysate from healthy and myalgic muscle is analysed using metabolomics. Metabolomics analyse a vast number of metabolites, enabling a comprehensive explorative screening of the cellular processes in the muscle.

    Microdialysate samples were obtained from the shoulder muscle of healthy and myalgic subjects that performed a work and stress test. Samples from the baseline period and from the recovery period were analysed using gas chromatography-mass spectrometry (GC-MS) together with multivariate analysis to detect differences in extracellular content of metabolites between groups. Systematic differences in metabolites between groups were identified using multivariate analysis and orthogonal partial least square discriminate analysis (OPLS-DA). A complementary Mann-Whitney U test of group difference in individual metabolites was also performed.

    A large number of metabolites were detected and identified in this screening study. At baseline, no systematic differences between groups were observed according to the OPLS-DA. However, two metabolites, l-leucine and pyroglutamic acid, were significantly more abundant in the myalgic muscle compared to the healthy muscle. In the recovery period, systematic difference in metabolites between the groups was observed according to the OPLS-DA. The groups differed in amino acids, fatty acids and carbohydrates. Myristic acid and putrescine were significantly more abundant and beta-d-glucopyranose was significantly less abundant in the myalgic muscle.

    This study provides important information regarding the metabolite content, thereby presenting new clues regarding the pathophysiology of the myalgic muscle.

  • 179.
    Haemig, Paul D.
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Sjöstedt de Luna, S
    Grafström, A
    Lithner, Stefan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Lundkvist, Åke
    Waldenström, Jonas
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Kindberg, Jonas
    Stedt, Johan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Olsen, Björn
    Forecasting risk of tick-borne encephalitis (TBE): using data from wildlife and climate to predict next year's number of human victims.2011Inngår i: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 43, nr 5, s. 366-372Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Over the past quarter century, the incidence of tick-borne encephalitis (TBE) has increased in most European nations. However, the number of humans stricken by the disease varies from year to year. A method for predicting major increases and decreases is needed.

    METHODS: We assembled a 25-y database (1984-2008) of the number of human TBE victims and wildlife and climate data for the Stockholm region of Sweden, and used it to create easy-to-use mathematical models that predict increases and decreases in the number of humans stricken by TBE.

    RESULTS: Our best model, which uses December precipitation and mink (Neovison vison, formerly Mustela vison) bagging figures, successfully predicted every major increase or decrease in TBE during the past quarter century, with a minimum of false alarms. However, this model was not efficient in predicting small increases and decreases.

    CONCLUSIONS: Predictions from our models can be used to determine when preventive and adaptive programmes should be implemented. For example, in years when the frequency of TBE in humans is predicted to be high, vector control could be intensified where infested ticks have a higher probability of encountering humans, such as at playgrounds, bathing lakes, barbecue areas and camping facilities. Because our models use only wildlife and climate data, they can be used even when the human population is vaccinated. Another advantage is that because our models employ data from previously-established databases, no additional funding for surveillance is required.

  • 180.
    Hagberg, Jessika
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Analysis of brominated dioxins and furans by high resolution gas chromatography/high resolution mass spectrometry2009Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1216, nr 3, s. 376-384Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    This article reviews the available literature on the analysis of brominated dibenzo-p dioxins and furans(PBDD/Fs) by high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS).Sample extraction and clean up, injection techniques, chromatographic separation, labelled standardsand QA/QC works are discussed. Furthermore, full separation of PBDD/Fs from polybrominated diphenylethers (PBDEs) during clean up and control of possible chromatographic interference of PBDEs duringinstrumental analysis as well as possible actions to further enhance the quality of published data arediscussed in detail.

  • 181.
    Hagfeldt, Anders
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Fysikalisk kemi (stängd 20110630).
    Boschloo, Gerrit
    Sun, Licheng
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Kloo, Lars
    KTH, Skolan för kemivetenskap (CHE), Kemi, Oorganisk kemi (stängd 20110630).
    Pettersson, Henrik
    Dye-Sensitized Solar Cells2010Inngår i: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 110, nr 11, s. 6595-6663Artikkel, forskningsoversikt (Fagfellevurdert)
  • 182.
    Halin Lejonklou, Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Johansson, Térèse
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Ekeblad, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Notch signaling factors in the transforming Men1 mouse pancreasManuskript (preprint) (Annet vitenskapelig)
  • 183.
    Hall, Håkan
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten.
    Takahashi, Kayo
    Erlandsson, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Estrada, Sergioa
    Bergström, Elisabeth
    Långström, Bengt
    Pharmacological characterization of 18F-labeled vorozole analogues.Manuskript (Annet vitenskapelig)
    Abstract [en]

    Two 18F-labeled analogues of vorozole ([18F]FVOZ and [18F]FVOO) have been developed as potential tools for the in vivo characterization of aromatase. The purpose of the project was to evaluate the pharmacological properties of these radioligands using a combination of in vitro binding and in vivo distribution studies in the rat and primate. Saturation binding studies with the radioligands in homogenates of rat ovary gave KD and Bmax values of 0.21 ± 0.1 nM and 210 ± 20 fmol/mg, respectively, for [18F]FVOZ, and 7.6 ± 1 nM and 293 ± 12 fmol/mg, respectively, for [18F]FVOO. Organ distribution studies in rats showed the highest accumulation in the adrenal glands, with standardized uptake values (SUVs) of 15 to 20, followed by ovaries and liver with SUVs of approximately 5. The SUVs in the remaining organs were between 0.5 and 1.5. There was probably some defluorination of both radioligands, as the accumulation of radioactivity in bone increased with time. The regional distribution in the brain was studied using ex vivo and in vitro autoradiography. In the brain, specific binding of both [18F]FVOZ and [18F]FVOO were found mainly in the amygdala. PET studies were performed in the Rhesus monkey, and these showed displaceable binding in the amygdala and the preoptic area of the hypothalamus. These studies suggest that [18F]FVOZ might be to be a suitable tracer for the study of aromatase in vitro and in vivo, and could be an alternative to [11C]vorozole in human PET-studies.

  • 184.
    Hallander, Hans O.
    et al.
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Ljungman, Margretha
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Jahnmatz, Maja
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Storsaeter, Jann
    Norwegian institute of Public Health, Oslo, Norway.
    Nilsson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Allergicentrum. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US.
    Gustafsson, Lennart
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Should fimbriae be included in pertussis vaccines? Studies on ELISA IgG anti-Fim2/3 antibodies after vaccination and infection2009Inngår i: APMIS: Acta pathologica, microbiologica et immunologica Scandinavica. Supplementum, ISSN 0903-465X, E-ISSN 1600-5503, Vol. 117, nr 9, s. 660-671Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The anti-Fim response and long-term persistence after vaccination and infection may be of importance in understanding population immunity. Longitudinal serum samples (n = 1330) from 542 non-infected children related to a Swedish vaccine trial showed that the post vaccination (DTPa5) antibody decay curve for pertussis ELISA IgG anti-fimbriae2/3 (anti-Fim2/3) was bi-phasic. A slower one followed an initial rapid decay approximately 5-6 months after the third dose at 12 months of age. After 71 months, however, 60% still had concentrations above > or =5 EU/ml, a level that had been shown to correlate with decreased risk of disease. Booster responses after re-vaccination with DTPa5 at 4, 5 and 6 years of age were strong and appeared within 1 week after vaccination, indicating immune memory. Ninety-six young children with verified pertussis infection, for whom we had serum samples both before, during and after the infection, showed a high response if they had been primed with fimbriae (either DTPa5 or DTPwc). In contrast, 76% of infected children not primed with fimbriae (a DTPa2 or DT group) only had concentrations below the minimum level of detection in all samples taken during and after the infection. In two Swedish seroepidemiological surveys, one from 1997 just after reintroduction of universal childhood vaccination against pertussis and one from 2007, the proportion of children 2-3 years with anti-Fim2/3 concentrations <5 EU/ml was similar and above 90%. This reflects that the two- or three-component pertussis vaccines (DTPa2 and DTPa3) that were introduced in Sweden in 1996 do not induce anti-Fim2/3 antibodies. In previous studies it was shown in multivariate analyses that levels of IgG anti-Fim2/3 > or =5 EU/ml reduced short-term risk of pertussis in small children. As the antibody response to Fim2/3 after infection is poor in children who have not been primed earlier in life, inclusion of immunogenic Fim2/3 in future pertussis vaccines should be considered.

  • 185.
    Hammar, Peter
    et al.
    KTH, Skolan för bioteknologi (BIO), Teoretisk kemi.
    Córdova, Armando
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Himo, Fahmi
    KTH, Skolan för bioteknologi (BIO), Teoretisk kemi.
    Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions2008Inngår i: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 19, s. 1617-1621Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The origins of the stereoselection of the dipeptide-catalyzed intermolecular aldol reaction are explored by means of hybrid density functional theory. Transition states were located for the (S)-ala-(S)-ala-catalyzed aldol reaction with cyclohexanone as the donor and benzaldehyde as the acceptor. The calculations reproduce the experimental trends very satisfactorily. It is demonstrated that the main Source of stereoselectivity is the interaction of the N-terminal amino acid side chain of the dipeptide with the cyclohexene ring.

  • 186.
    Hammarsten, Peter
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Winther, Johanna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Rudolfsson, Stina H
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Häggström, Jenny
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Karalija, Amar
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm.
    Granfors, Torvald
    Department of Urology, Central Hospital, Västerås, Sweden.
    Fowler, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 9, artikkel-id e105063Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).

    METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.

    CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

  • 187.
    Hansson, Helena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    A Novel Miniaturised Dynamic Hollow-Fibre Liquid-Phase Micro-Extraction Method for Xenobiotics in Human Plasma Samples2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Bioanalytical chemistry is a challenging field, often involving complex samples, such as blood, plasma, serum or urine. In many applications, sample cleanup is the most demanding and time-consuming step.

    In the work underlying this thesis a novel dynamic miniature extractor, known as a hollow-fibre liquid-phase microextractor (HF-LPME), was designed, evaluated and studied closely when used to clean plasma samples. Aqueous-organic-aqueous liquid extraction, in which the organic liquid is immobilised in a porous polypropylene membrane, was the principle upon which the extractor was based, and this is discussed in all the papers associated with this thesis. This type of extraction is known as supported-liquid membrane extraction (SLM). The aim of this work was the development of a dynamic system for SLM. It was essential that the system could handle small sample volumes and had the potential for hyphenations and on-line connections to, for instance, LC/electrospray-MS. The design of a miniaturised HF-LPME device is presented in Paper I. The extraction method was developed for some weakly acidic pesticides and these were also used for evaluation. In the work described in Paper II, the method was optimised on the basis of an experimental design using spiked human plasma samples. Paper III presents a detailed study of the mass-transfer over the liquid membrane. The diffusion through the membrane pores was illustrated by a computer-simulation. Not surprisingly, the more lipophilic, the greater the retention of the compounds, as a result of dispersive forces. The main focus of the work described in Paper IV was to make the HF/LPME system more versatile and user-friendly; therefore, the extractor was automated by hyphenation to a SIA system.

  • 188.
    Hansson, Helena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Colmsjö, Anders
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Nilsson, Ulrika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Study of mass transfer in a dynamic hollow-fibreliquid phase microextraction system2010Inngår i: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 33, nr 1, s. 112-119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The extraction characteristics of a dynamic hollow-fibre liquid phase microextractionsystem were investigated by studying the mass transfer and diffusion rates of dinitrophenolsfrom plasma samples over the liquid membrane (dihexylether). The measureddiffusion coefficients were compared with theoretical values calculated from Stokesdiameters. The diffusion mechanism was simulated by computer and the most polarcompounds, 2,4-dinitrophenol and 4,6-o-dinitrocresol, had associated diffusion coefficientsthat were close to the calculated theoretical values. 2-sec-Butyl-4,6 dinitrophenoland 2-tert-butyl-4,6-dinitrophenol, the compounds with the highest log P values, wereretained by the polypropylene membrane, which reduced the experimentally observeddiffusion rates to about half of the theoretical values. The retention was most likely due todispersive forces interacting with the pore inner walls. Extraction was linearly correlatedwith time for all compounds and the repeatability was high (RSDs 7–11%), even for theshortest extraction times. Method LOD as the amount injected ranged between 0.3 and3.1 ng for an extraction cycle of 213 s.

  • 189.
    Hansson, Helena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Karlberg, Bo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Nilsson, Ulrika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Dynamic hollow-fibre liquid phase microextraction for human plasma samples automated by sequential injection analysisManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    This paper presents an easily handled, hollow-fibre liquid phase microextraction (HF-LPME) sample clean-up method, automated by the use of a programmable sequential injection analysis (SIA) system. Use of a SIA system significantly reduces the need for manual sample handling. This new type of clean-up system was assessed and compared with manual HF-LPME for the extraction of acidic compounds (dinitrophenols) from human plasma, in terms of human intervention requirements, efficiency, repeatability and carry-over. Its application to a SIA system for basic compounds (b-blockers) is also presented. The sample aliquots collected off-line from the SIA system were subsequently subjected to separation with LC and the various analytes were detected with ESI-MS.

    Extraction efficiency values between 28 and 56% (RSD 5-10%, n = 7) were achieved for the dinitrophenol compounds after an extraction cycle of 58 min including a 30 min washing step. According to the MS analysis the SIA/HF-LPME method yielded clean chromatograms with no detectable interfering peaks. Ion suppression in positive ESI-MS was between 4 and 21% when tested on extracts with b-blockers.

  • 190.
    Hansson, Helena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Nilsson, Ulrika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Assessment of a dynamic hollow-fibre liquid phase microextraction system forhuman blood plasma samples2009Inngår i: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 77, nr 4, s. 1309-1314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A dynamic liquid phase microextraction (LPME) system, based on hollow-fibre supported liquid membrane(SLM) extraction, was developed for extracting ionisable xenobiotics from human plasma, andits performance was evaluated (in terms of extraction efficiency, reproducibility, durability and carryover)using nitrophenolic compounds as model analytes at concentrations of 0.1–0.5gmL−1 in aqueousstandards. The efficiency and repeatability were tested also on spiked human plasma. The system isnon-expensive, convenient, requires minimal manual handling and enables samples with volumes assmall as 0.2mL to be extracted. For plasma samples extraction efficiencies of between 30 and 58% wereachieved within 20 min, including washing steps. The limit of detection (LOD) values were in the range0.02–0.03gmL−1. The developed system can provide enrichment factors up to eight, based on theinjection-to-acceptor volume ratio (in this case 0.2–0.025 mL). The same hollow-fibre membrane wasused up to 8 days with no loss of efficiency. Carry-over was lower than detection limit.

  • 191. Hansson, Petra M.
    et al.
    Skedung, Lisa
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Claesson, Per Martin
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Swerin, Agne
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Schoelkopf, Joachim
    Gane, Patrick A. C.
    Rutland, Mark W.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Thormann, Esben
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Robust Hydrophobic Surfaces Displaying Different Surface Roughness Scales While Maintaining the Same Wettability2011Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, nr 13, s. 8153-8159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A range of surfaces coated with spherical silica particles, covering the size range from nanometer to micrometer, have been produced using Langmuir-Blodgett (LB) deposition. The particles were characterized both in suspension and in the Langmuir trough to optimize the surface preparation procedure. By limiting the particle aggregation and surface layer failures during the preparation steps, well-defined monolayers with a close-packed structure have been obtained for all particle sizes. Thus, this procedure led to structured surfaces with a characteristic variation in the amplitude and spatial roughness parameters. In order to obtain robust surfaces, a sintering protocol and an AFM-based wear test to determine the stability of the deposited surface layer were employed. Hydrophobization of the LB films followed by water contact angle measurements showed, for all tested particle sizes, the same increase in contact angle compared to the contact angle of a flat hydrophobic surface. This indicates nearly hexagonal packing and gives evidence for nearly, complete surface wetting of the surface features.

  • 192.
    Hasjakjan, Mikael
    Mälardalens högskola, Akademin för hållbar samhälls- och teknikutveckling.
    Program för lakvattenrening för Lilla Nyby2008Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
  • 193.
    Haylock, Anna-Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Nilvebrant, Johan
    KTH.
    Mortensen, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Falk, Ronny
    KI.
    Generation and evaluation of antibody agents for molecular imaging of CD44v6 expressing cancersManuskript (preprint) (Annet vitenskapelig)
  • 194.
    Hedberg, Jonas
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Leygraf, Christofer
    KTH, Skolan för kemivetenskap (CHE), Kemi, Korrosionslära.
    Adsorption and Structure of Octadecanethiol on Zinc Surfaces As Probed by SumFrequency Generation Spectroscopy, Imaging, and Electrochemical Techniques2007Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 111, nr 47, s. 17587-17596Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Octadecanethiol (ODT) adsorbed onto zinc has been studied with sum frequency generation (SFG), sum frequency generation imaging microscopy (SFG-IM), X-ray photoelectron spectroscopy (XPS), cyclic voltammetry (CV), and electrical impedance spectroscopy (EIS) in order to investigate its corrosion protective ability and conformational ordering. SFG shows that ODT forms an ordered adsorbate on both reduced and oxidized zinc within short times after immersion in 1 mM ODT/ethanol solution. The corrosion protection, deduced by EIS, is also improved after immersion in the ODT solution. After longer immersion times, the corrosion protection decreases as well as the conformational order of the adsorbed ODT. Increasing the ODT concentration avoids this degradation with prolonged immersion time. The ODT is seen in the XPS spectra to adsorb to the reduced as well as the oxidized zinc by forming a Zn-S bond for both short and long immersion times. The SFG-IM completes the picture, showing a heterogeneous surface with areas corresponding to ordered ODT as well as disordered or uncovered regions. The density of adsorbed ODT after 24 h immersion time for both reduced and oxidized zinc was deduced from CV and was found to be approximately 6.7 x 10(-9) mol/cm(2).

  • 195.
    Hedberg, Jonas
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Leygraf, Christofer
    KTH, Skolan för kemivetenskap (CHE), Kemi, Korrosionslära.
    Molecular in-situ observations of hydroxyl groups and ligand exchange during initial atmospheric corrosionManuskript (preprint) (Annet vitenskapelig)
  • 196.
    Hedberg, Jonas
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Leygraf, Christofer
    KTH, Skolan för kemivetenskap (CHE), Kemi, Korrosionslära.
    Molecular structural information of the atmospheric corrosion of zinc studied by vibrational spectroscopy techniques: Part I. Experimental approachManuskript (preprint) (Annet vitenskapelig)
  • 197.
    Hedberg, Jonas
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Yt- och korrosionsvetenskap.
    Leygraf, Christofer
    KTH, Skolan för kemivetenskap (CHE), Kemi, Korrosionslära.
    Molecular structural information of the atmospheric corrosion of zinc studied by vibrational spectroscopy techniques: Part II. Two and three dimensional growth of reaction products induced by formic and acetic acidManuskript (preprint) (Annet vitenskapelig)
  • 198.
    Heldin, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Identification and Characterization of Proteins and MicroRNAs that Modulate Receptor Signaling, Vesicular Trafficking and Cell Migration in Vascular Cells2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Blood vessels deliver nutrients and oxygen to tissues. Importantly, the functions and growth of blood vessels are commonly altered in disease. The inside of all blood vessels are lined with endothelium, a thin specialized layer of endothelial cells that separate the blood from other tissues. This thesis deals with the identification and functional characterization of proteins and microRNAs that have key roles as modulators of growth factor signaling and directed cell migration of endothelial cells and other vascular cells.

    A previously uncharacterized protein of the exocyst complex, Exocyst complex component 3-like 2 (ExoC3L2) was identified and shown to be highly expressed in endothelial cells of sprouting vessels. Suppression of ExoC3L2 resulted in reduced VEGF-A signaling together with reduced chemotaxis in response to VEGF-A gradients. VEGF-A-signaling via its receptor VEGFR-2 is thus modulated by the exocyst complex and ExoC3L2.

    Expression profiling of highly vascularized tissues were used to identify several microRNAs selectively expressed in blood vessels. miR-145, targeting the transcription factor Fli1, was shown to be expressed in pericytes and mural cells. Elevated levels of miR-145 reduced chemotaxis of both endothelial cells and fibroblasts in response to growth factor gradients. miR-145 depletion in fibroblasts was shown to inhibit chemotaxis in response to PDGF-BB.

    The guanine nucleotide exchange factor FGD5 was shown to be selectively expressed in endothelial cells and to regulate Cdc42 activity. FGD5 was shown to regulate the turnover of activated VEGF-receptors. Suppression of FGD5 impaired endothelial cell chemotaxis, suggesting that FGD5 is required for efficient and sustained VEGF-A signaling.

    Inactivation of RhoD, a regulator of endosomal trafficking, resulted in an increased pool of acetylated and stable microtubules. Knockdown of RhoD in human fibroblasts resulted in a loss of cell polarity. A link between PDGFR-β and RhoD was implicated by the finding that PDGF-BB was shown to trigger formation of GTP-bound RhoD. Chemotaxis towards PDGF-BB was severely inhibited in cells with reduced RhoD expression, suggesting a role for RhoD in chemotaxis via its regulation of microtubule dynamics.

  • 199.
    Hellström, Sten
    et al.
    Department of CLINTEC/Otorhinolaryngology, Karolinska Medical University.
    Shen, Yue
    University of British Columbia.
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A reply to the commentary on "Animal models of chronic tympanic membrane perforation: in response to plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice" by Wang AY, Shen Y, Wang JT, Eikelboom RH and Dilley RJ; Clin Translat Med, 2014; 32015Inngår i: Clinical and translational medicine, ISSN 2001-1326, Vol. 4, nr 8Artikkel i tidsskrift (Fagfellevurdert)
  • 200. Hepburn, Lucy
    et al.
    Prajsnar, Tomasz K
    Klapholz, Catherine
    Moreno, Pablo
    Loynes, Catherine A
    Ogryzko, Nikolay V
    Brown, Karen
    Schiebler, Mark
    Hegyi, Krisztina
    Antrobus, Robin
    Hammond, Katherine L
    Connolly, John
    Ochoa, Bernardo
    Bryant, Clare
    Otto, Michael
    Surewaard, Bas
    Seneviratne, Suranjith L
    Grogono, Dorothy M
    Cachat, Julien
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kaser, Arthur
    Török, M Estée
    Peacock, Sharon J
    Holden, Matthew
    Blundell, Tom
    Wang, Lihui
    Ligoxygakis, Petros
    Minichiello, Liliana
    Woods, C Geoff
    Foster, Simon J
    Renshaw, Stephen A
    Floto, R Andres
    A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus2014Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 346, nr 6209, s. 641-646Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.

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