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  • 1. Abdallah, Qasem M. A.
    et al.
    Phillips, Roger M.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cosentino, Laura
    Abdel-Rahman, Hamdy
    Etzad, Jasarat
    Wheelhouse, Richard T.
    Kiakos, Konstantinos
    Bingham, John P.
    Hartley, John A.
    Patterson, Laurence H.
    Pors, Klaus
    Minor structural modifications to alchemix influence mechanism of action and pharmacological activity2012In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 83, no 11, p. 1514-1522Article in journal (Refereed)
    Abstract [en]

    Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

  • 2.
    Abdel Rehim, Abbi
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Abdel Rehim, Mohamed
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Screening and determination of drugs in human saliva utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry2013In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 27, no 9, p. 1188-1191Article in journal (Refereed)
    Abstract [en]

    This study presents a new method for collecting and handling saliva samples using an automated analytical microsyringe and microextraction by packed syringe (MEPS). The screening and determination of lidocaine in human saliva samples utilizing MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. An exact volume of saliva could be collected. The MEPS C-8-cartridge could be used for 50 extractions before it was discarded. The extraction recovery was about 60%. The pharmacokinetic curve of lidocaine in saliva using MEPS-LC-MS/MS is reported.

  • 3.
    Abramsson-Zetterberg, Lilianne
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ilback, Nils-Gunnar
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, p. 86-89Article in journal (Refereed)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 4. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Swedish Toxicology Sciences Research Center (Swetox), Sweden.
    Andersson, Patrik L.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, p. 164-173Article in journal (Refereed)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 5.
    Apraiz Larrucea, Itxaso
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Development and application of a proteomic approach to the assessment of pollution in the marine environment2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today, assessment of the health of coastal waters is recognized as being important for both the conservation of nature and well-being of humans. Anthropogenic pollution has been the focus of extensive research for some time and a variety of programs for the monitoring and assessment of environmental pollution have been developed. Determination of the levels of pollution in sensitive ‘sentinels’ such as mussels, allows monitoring of these levels in a given area over a prolonged period of time. Furthermore, the biological effects of pollution are reflected in a series of biomarkers, none of which provides a general picture of the sentinel’s state of health and all of which are individually specific for certain pollutants and influenced by both biotic and abiotic factors.

    In an attempt to improve biomonitoring of marine pollution, we have developed two proteomic approaches here. In the first portion of the thesis, a proteomic analysis was performed on peroxisomes isolated from mussels exposed either to one of three model anthropogenic pollutants, or two different types of crude oil, or from mussels exposed to the Prestige oil spill. Application of two-dimensional electrophoresis (2-DE) provided protein expression signatures (PES) for exposure to these different pollutants.Furthermore, several individual protein components of these PES could be putatively identified.

    In the second portion of this work, such analysis of subproteomes was developed further in order to improve the applicability of this approach to biomonitoring. A simple fractionation procedure in combination with liquid chromatography and 2-DE provided samples from mussels residing in different regions of a pollution gradient around the harbor of Gothenburg, as well as from mussels exposed to two types of fuel oil similar to that of the Prestige that were suitable for environmental proteomics. In addition, we constructed a model for this approach that can be cross-validated in the future and applied to assess sources of fuel oil pollution in connection with biomonitoring programs.

  • 6. Arbesu Valdivia, Alejandro
    et al.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Romero Batista, Yamilet
    Kumar, Saroj
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Characterization of recombinant antibodies for cancer therapy by infrared spectroscopy2013In: Biologicals (Print), ISSN 1045-1056, E-ISSN 1095-8320, Vol. 41, no 2, p. 104-110Article in journal (Refereed)
    Abstract [en]

    Fourier transform infrared (FTIR) spectroscopy was used to study the structure of the recombinant antibodies 1E10, anti-CD20 and hR3, which are used as anti-cancer therapeutic drugs. We tested their sensitivity against different conditions and treatments such as pH, temperature, freeze-thaw cycles and drying, which are relevant for the practical usefulness of the drugs. All antibodies were stable against moderate temperature increases (up to 50 degrees C) and pH changes (range 5-9). 1E10 was sensitive to extreme pH values (pH 3 and 12), whereas hR3 was most sensitive to temperature (at and above 60 degrees C). We did not observe any significant changes upon freeze-thaw and drying treatments. The secondary structure content of all three antibodies was estimated to be similar to that of IgG with similar to 64% beta-sheet, 0% alpha-helix and similar to 36% other structure. (C) 2012 The International Alliance for Biological Standardization.

  • 7.
    Asgard, Rikard
    et al.
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Golkar, Siv Osterman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hellman, Bjorn
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Czene, Stefan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool2013In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 637-644Article in journal (Refereed)
    Abstract [en]

    The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

  • 8.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm University.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, Stina
    Lund University.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5YManuscript (preprint) (Other academic)
  • 9.
    Axelsson, Viktoria
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holback, Sofia
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sjögren, Maria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gustafsson, Helena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.2006In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 345, no 3, p. 1068-74Article in journal (Refereed)
    Abstract [en]

    In this study, a significant increase by 50% in intracellular free calcium concentration ([Ca(2+)](i)) was observed in differentiated human neuroblastoma (SH-SY5Y) cells after exposure to 0.25microM of the fungal metabolite gliotoxin for 72h. Further, the involvement of caspases and calpains was demonstrated to underlie the gliotoxin-induced cytotoxic and neurite degenerative effects. The caspase inhibitor Z-VAD-fmk almost completely reduced the neurite degeneration from 40% degeneration of neurites to 5% as compared to control. Inhibition of calpains with calpeptin significantly attenuated gliotoxin-induced cytotoxicity, determined as reduction in total cellular protein content, from 43% to 14% as compared to control cells. Western blot analyses of alphaII-spectrin breakdown fragments confirmed activity of the proteases, and that alphaII-spectrin was cleaved by caspases in gliotoxin-exposed cells. These results show that calpains and caspases have a role in the toxicity of gliotoxin in differentiated SH-SY5Y cells and that the process may be Ca(2+)-mediated.

  • 10. Bal-Price, Anna
    et al.
    Crofton, Kevin M.
    Sachana, Magdalini
    Shafer, Timothy J.
    Behl, Mamta
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Hargreaves, Alan
    Landesmann, Brigitte
    Lein, Pamela J.
    Louisse, Jochem
    Monnet-Tschudi, Florianne
    Paini, Alicia
    Rolaki, Alexandra
    Schrattenholz, Andre
    Sunol, Cristina
    van Thriel, Christoph
    Whelan, Maurice
    Fritsche, Ellen
    Putative adverse outcome pathways relevant to neurotoxicity2015In: Critical reviews in toxicology, ISSN 1040-8444, E-ISSN 1547-6898, Vol. 45, no 1, p. 83-91Article, review/survey (Refereed)
    Abstract [en]

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways.

  • 11. Bassyouni, Fatma A.
    et al.
    Saleh, Tamer S.
    ElHefnawi, Mahmoud M.
    Abd El-Moez, Sherein I.
    El-Senousy, Waled M.
    Abdel-Rehim, Mohamed E.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Synthesis, pharmacological activity evaluation and molecular modeling of new polynuclear heterocyclic compounds containing benzimidazole derivatives2012In: Archives of pharmacal research, ISSN 0253-6269, E-ISSN 1976-3786, Vol. 35, no 12, p. 2063-2075Article in journal (Refereed)
    Abstract [en]

    Novel heterocyclic compounds containing benzimidazole derivatives were synthesized from 2-(1Hbenzimidazol-2-yl) acetonitrile (1) and arylhydrazononitrile derivative 2 was obtained via coupling of 1 with 4-methyl phenyldiazonium salt, which was then reacted with hydroxylamine hydrochloride to give amidooxime derivative 3. This product was cyclized into the corresponding oxadiazole derivative 4 upon reflux in acetic anhydride. Compound 4 was refluxed in DMF in the presence of triethylamine to give the corresponding 5-(1H-benzimidazol-2-yl)-2-p-tolyl-2H-1,2,3-triazol-4-amine 6. Treatment of compound 6 with ethyl chloroformate afforded 2,6-dihydro-2-(4-methylphenyl)-1,2,3-triazolo[4aEuro(3),5aEuro(3)-4',5']pyrimido[1,6-a]benzimidazole-5(4H)-one (8). 1,2-bis(2-cyanomethyl-1H-benzimidazol-1-yl)ethane-1,2-dione (10) was synthesized via the condensation reaction of 2-(1H-benzimidazol-2-yl) acetonitrile (1) and diethyloxalate. The reactivity of compound 10 towards some diamine reagents was studied. The in vitro antimicrobial activity of the synthesized compounds was investigated against several pathogenic bacterial strains such as Escherichia coli O157, Salmonella typhimurium, E. coli O119, S. paratyphi, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes and Bacillus cereus. The results of MIC revealed that compounds 12a-c showed the most effective antimicrobial activity against tested strains. On the other hand, compounds 12a, b exhibited high activity against rotavirus Wa strain while compounds 12b, c exhibited high activity against adenovirus type 7. In silico target prediction, docking and validation of the compounds 12a-c were performed. The dialkylglycine decarboxylase bacterial enzyme was predicted as a potential bacterial target receptor using pharmacophorebased correspondence with previous leads; giving the highest normalized scores and a high correlation docking score with mean inhibition concentrations. A novel binding mechanism was predicted after docking using the MOE software and its validation.

  • 12. Batistuzzo, S.
    et al.
    Galvão, M. O.
    Duarte, E. S.
    Hoelzemann, J. J.
    Menezes Filho, J.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Dreij, K.
    PAH exposure and relationship between buccal micronucleus cytome assay and urinary 1-hydroxypyrene levels among cashew nut roasting workers2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, p. S223-S224Article in journal (Refereed)
    Abstract [en]

    The present study conducted the first assessment of the occupational risk associated to artisanal cashew nut roasting by the use of exposure and effect biomarkers, as well as the characterization and dispersion analysis of the released particulate matter (PM). The PM concentrations in the exposed area were higher than in the non-exposed area. Furthermore, in the control area yielded a higher prevalence of coarse particles, while in the exposed area was observed fine particles. The morphological analysis showed a wide variety of particles. Biomass burning tracers K, Cl, S and Ca were the major inorganic compounds and polycyclic aromatic hydrocarbons (PAHs) with mutagenic and carcinogenic potential, such as benzo[a]pyrene, benzo[b]fluoranthene, benzo[a]anthracene, benzo[j]fluoranthene and indeno[1,2,3-c,d]pyrene were the most abundant PAHs. In addition, atmospheric modeling analysis suggest that these particles can reach regions higher than 40 kilometers. Occupational PAH exposure was confirmed by increases in 1-OHP levels in cashew nut workers. The frequencies of BMCyt biomarkers of genotoxic (micronuclei and nuclear bud) and cytotoxic (pyknosis, karyolysis, karyorrhexis and condensed chromatin) were higher in the exposed group (p < 0.0001) compared with the control group. The influence of factors such as age on the micronucleus was evidenced and a correlation between 1-OHP and MN was observed. It was the first study to found a correlation between these types of biomarkers. The uses of exposure and effect biomarkers were therefore efficient in assessing the occupational risk associated with artisanal cashew nut roasting and the high rates of PM2.5 are considered a potential contributor to this effect.

  • 13. Bell, J. Simon
    et al.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wimmer, Barbara C.
    Wiese, Michael D.
    Multidose drug dispensing and optimising drug use in older people2013In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 42, no 5, p. 556-558Article in journal (Refereed)
  • 14. Benfenati, E.
    et al.
    Golbamaki, A.
    Raitano, G.
    Roncaglioni, A.
    Manganelli, S.
    Lemke, F.
    Norinder, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Swetox, Sweden.
    Lo Piparo, Elena
    Honma, M.
    Manganaro, A.
    Gini, G.
    A large comparison of integrated SAR/QSAR models of the Ames test for mutagenicity($)2018In: SAR and QSAR in environmental research (Print), ISSN 1062-936X, E-ISSN 1029-046X, Vol. 29, no 8, p. 591-611Article in journal (Refereed)
    Abstract [en]

    Results from the Ames test are the first outcome considered to assess the possible mutagenicity of substances. Many QSAR models and structural alerts are available to predict this endpoint. From a regulatory point of view, the recommendation from international authorities is to consider the predictions of more than one model and to combine results in order to develop conclusions about the mutagenicity risk posed by chemicals. However, the results of those models are often conflicting, and the existing inconsistency in the predictions requires intelligent strategies to integrate them. In our study, we evaluated different strategies for combining results of models for Ames mutagenicity, starting from a set of 10 diverse individual models, each built on a dataset of around 6000 compounds. The novelty of our study is that we collected a much larger set of about 18,000 compounds and used the new data to build a family of integrated models. These integrations used probabilistic approaches, decision theory, machine learning, and voting strategies in the integration scheme. Results are discussed considering balanced or conservative perspectives, regarding the possible uses for different purposes, including screening of large collection of substances for prioritization.

  • 15. Bennett, Alexander
    et al.
    Gnjidic, Danijela
    Gillett, Mark
    Carroll, Peter
    Matthews, Slade
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Hilmer, Sarah
    Prevalence and Impact of Fall-Risk-Increasing Drugs, Polypharmacy, and Drug-Drug Interactions in Robust Versus Frail Hospitalised Falls Patients: A Prospective Cohort Study2014In: Drugs & Aging, ISSN 1170-229X, E-ISSN 1179-1969, Vol. 31, no 3, p. 225-232Article in journal (Refereed)
    Abstract [en]

    Background Several measures of medication exposure are associated with adverse outcomes in older people. Exposure to and the clinical outcomes of these measures in robust versus frail older inpatients are not known. Objective In older robust and frail patients admitted to hospital after a fall, we investigated the prevalence and clinical impact of fall-risk-increasing drugs (FRIDs), total number of medications, and drug-drug interactions (DDIs). Methods Patients >= 60 years of age admitted with a fall to a tertiary referral teaching hospital in Sydney were recruited and frailty was assessed. Data were collected at admission, discharge, and 2 months after admission. Results A total of 204 patients were recruited (mean age 80.5 +/- 8.3 years), with 101 robust and 103 frail. On admission, compared with the robust, frail participants had significantly higher mean +/- SD number of FRIDs (frail 3.4 +/- 2.2 vs. robust 1.6 +/- 1.5, P < 0.0001), total number of medications (9.8 +/- 4.3 vs. 4.4 +/- 3.3, P < 0.0001), and DDI exposure (35 vs. 5 %, P = 0.001). Number of FRIDs on discharge was significantly associated with recurrent falls [odds ratio (OR) 1.7 (95 % confidence interval [CI] 1.3-2.1)], which were most likely to occur with 1.5 FRIDs in the frail and 2.5 FRIDs in the robust. Number of medications on discharge was also associated with recurrent falls [OR 1.2 (1.0-1.3)], but DDIs were not. Conclusion Exposure to FRIDs and other measures of high-risk medication exposures is common in older people admitted with falls, especially the frail. Number of FRIDs and to a lesser extent total number of medicines at discharge were associated with recurrent falls.

  • 16.
    Bergander, Linda
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Formation and metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole - a light-induced Ah-receptor ligand2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aryl hydrocarbon receptor (AhR) is a ligand dependent transcription factor ubiquitously expressed in mammalian cells. It is a genetically ancient protein mostly known for binding the extremely toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Binding to the AhR explains the variety of toxic responses of TCDD as well as the induction of several drug metabolizing enzymes. Induction of cytochrome P4501A1 (CYP1A1) is the most well characterized of the AhR regulated responses. The physiological functions of AhR and the endogenous ligand(s) for the receptor are under investigation but are not yet unraveled.

    Several tryptophan (TRP) derived indol-containing compounds have been reported to possess AhR affinity/CYP1A1 inducing capacity and TRP mediates CYP1A1 induction by UV light. The TRP photoproduct, 6-formylindolo[3,2-b]carbazole (FICZ) has the highest AhR affinity described so far and it causes a rapid and transient induction of the CYP1A1 gene in human cells. A number of reports on constitutive CYP1A1 activity in cultured cells is therefore most likely explained by the presence of TRP-derived AhR ligands in cell culture media.

    The aims of the studies were to investigate the impact of FICZ and FICZ metabolism on CYP1A1 gene regulation, to explore the metabolic fate of FICZ and to identify whether normal laboratory light could lead to formation of FICZ and thereby contribute to earlier observed CYP1A1 inducing effects by cell culture media.

    Metabolic studies using fractions of Aroclor-induced and non-induced rat liver and human liver as well as heterologously expressed enzymes revealed that FICZ can be efficiently metabolized by the CYP enzymes 1A1 and 1A2 and by an unknown cytosolic enzyme, to a number of hydroxylated and other oxidized metabolites. All of the hitherto identified 11 hydroxylated metabolites of FICZ are prone to conjugation reactions by glucuronosyltranferases and sulfotransferases. The metabolites formed by human enzymes are primarily sulfated. Thus, the sulfated metabolites of FICZ will be crucial in the future analyzes of FICZ formation in vivo. FICZ was identified to be formed, not only by UV illumination, but also by normal laboratory light. The constitutive CYP1A1 activity was significantly induced through the formation of several TRP related photoproducts in light-exposed medium. One of these photoproducts was identified as FICZ. Thus, the TRP photoproduct, FICZ, fits into a model in which FICZ auto-regulates the expression of induced enzymes. It is hypothesized that FICZ might function as a chemical messenger that activates AhR in response to light and might be one of several possible endogenous AhR ligands.

  • 17.
    Beronius, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Hanberg, Annika
    Zilliacus, Johanna
    Rudén, Christina
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Bridging the gap between academic research and regulatory health risk assessment of Endocrine Disrupting Chemicals2014In: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 19, p. 99-104Article in journal (Refereed)
    Abstract [en]

    Regulatory risk assessment is traditionally based primarily on toxicity studies conducted according to standardized and internationally validated test guidelines. However, health risk assessment of endocrine disrupting chemicals (EDCs) is argued to rely on the efficient integration of findings from academic research. The aim of this review was to provide an overview of current developments to facilitate the use of academic research in regulatory risk assessment of chemicals and how certain aspects of study design and reporting are particularly important for the risk assessment process. By bridging the gap between academic research and regulatory health risk assessment of EDCs, scientific uncertainty in risk assessment conclusions can be reduced, allowing for better targeted policy decisions for chemical risk reduction.

  • 18. Beronius, Anna
    et al.
    Johansson, Niklas
    Rudén, Christina
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Hanberg, Annika
    The influence of study design and sex-differences on results from developmental neurotoxicity studies of bisphenol A, implications for toxicity testing2013In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 311, no 1-2, p. 13-26Article in journal (Refereed)
    Abstract [en]

    Developmental neurotoxicity (DNT) of bisphenol A (BPA) has been investigated in a large number of studies. However, there are discrepancies in the results reported between the studies. The aim of this study was to identify and analyze factors that may contribute to these differences and to assess whether there are sex-differences in the sensitivity of certain endpoints or tests used in DNT-studies. Forty-four DNT studies of BPA were identified from the open literature. Details about study design and results from each study, as well as the criteria for DNT testing according to the standardized OECD test guideline (TG) 426, were collected in a database. This enabled systematic and detailed comparisons between studies as well as to the criteria and recommendations stated in TG 426. Multivariate analyses were also used to investigate how different factors of the study design contributed to differences in study results. The analyses showed behavioral effects were often observed for endpoints that are not required according to OECD TG 426, such as anxiety-related, social and sexual behaviors, especially at very low doses and in female offspring. On the other hand relatively few studies observed any effects on motor activity, which is commonly used in screening for neurotoxic effects in regulatory testing. However, varied and to some extent seemingly contradictory results have been reported in these studies, especially for endpoints related to motor activity and anxiety and exploration. Many studies were also poorly reported, limiting these analyses. No strong conclusions could be drawn from the multivariate analyses. A few factors of study design, such as the size of the dose and number of dose levels used and the use of litter or individual pup as statistical unit seemed to have some influence on study results. In conclusion, this analysis suggests that DNT-studies conducted according to the standardized OECD TG 426 may overlook sensitive effects of BPA, and possibly other potential endocrine disruptors, especially in female offspring.

  • 19.
    Beronius, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM). Karolinska Institute, Sweden.
    Molander, Linda
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Rudén, Christina
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Hanberg, Annika
    Facilitating the use of non-standard in vivo studies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting2014In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 34, no 6, p. 607-617Article in journal (Refereed)
    Abstract [en]

    To improve data availability in health risk assessment of chemicals and fill information gaps there is a need to facilitate the use of non-standard toxicity studies, i.e. studies not conducted according to any standardized toxicity test guidelines. The purpose of this work was to propose criteria and guidance for the evaluation of reliability and relevance of non-standard in vivo studies, which could be used to facilitate systematic and transparent evaluation of such studies for health risk assessment. Another aim was to propose user friendly guidance for reporting of non-standard studies intended to promote an improvement in reporting of studies that could be of use in risk assessment. Requirements and recommendations for the design and execution of in vivo toxicity studies were identified from The Organisation for Economic Co-operation and Development (OECD) test guidelines, and served as basis for the data evaluation criteria and reporting guidelines. Feedback was also collected from experts within the field of toxicity testing and risk assessment and used to construct a two-tiered framework for study evaluation, as well as refine the reporting guidelines. The proposed framework emphasizes the importance of study relevance and an important aspect is to not completely dismiss studies from health risk assessment based on very strict criteria for reliability. The suggested reporting guidelines provide researchers with a tool to fulfill reporting requirements as stated by regulatory agencies. Together, these resources provide an approach to include all relevant data that may fill information gaps and reduce scientific uncertainty in health risk assessment conclusions, and subsequently also in chemical policy decisions.

  • 20. Björk, Christel
    et al.
    Nenonen, Hannah
    Giwercman, Aleksander
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Rylander, Lars
    Giwercman, Yvonne Lundberg
    Persistent organic pollutants have dose and CAG repeat length dependent effects on androgen receptor activity in vitro2011In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 32, p. 293-297Article in journal (Refereed)
    Abstract [en]

    Recently, the effect of exposure to persistent organic pollutants (POPS) on sperm concentration was only seen in men with a short androgen receptor (AR) gene CAG repeat. In order to investigate whether these effects could be observed also in vitro, we tested the impact of 2,2’,4,4’,5,5’-hexachlorobiphenyl (CB-153) and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (4,4’-DDE) on 5 alpha-dihydrotestosterone activated ARs containing 16,22 and 28 CAG repeats, respectively. Single exposure to 4,4’-DDE had the most pronounced effect on the AR activity containing 16 CAG repeats, whereas 28 CAG was the most sensitive variant when a mixture of the two compounds was added. Thus, our in vitro results have confirmed the in vivo data indicating a CAG repeat length dependent effect of endocrine disrupters on the AR activity.

  • 21. Bolelli, K.
    et al.
    Musdal, Yaman
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Aki-Yalcin, E.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yalcin, I.
    Synthesis and activity mechanism of some novel 2-substituted benzothiazoles as hGSTP1-1 enzyme inhibitors2017In: SAR and QSAR in environmental research (Print), ISSN 1062-936X, E-ISSN 1029-046X, Vol. 28, no 11, p. 927-940Article in journal (Refereed)
    Abstract [en]

    Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of human tumours and is involved in the development of resistance to several anticancer drugs. So, it has become an important target in cancer treatment. In this study, 12 benzothiazole derivatives were synthesized and screened for their in vitro inhibitory activity for hGSTP1-1. Among these compounds, two of them (compounds #2 and #5) have been found to be the leads when compared with the reference drug etoposide. In order to analyse the structure-activity relationships (SARs) and to investigate the binding side interactions of the observed lead compounds, a HipHop pharmacophore model was generated and the molecular docking studies were performed by using CDocker method. In conclusion, it is observed that the lead compounds #2 and #5 possessed inhibitory activity on the hGSTP1-1 by binding to the H-site as a substrate in which the para position of the phenyl ring of the benzamide moiety on the benzothiazole ring is important. Substitution at this position with a hydrophobic group that reduces the electron density at the phenyl ring is required for the interaction with the H side active residue Tyr108.

  • 22. Borg, D.
    et al.
    Bogdanska, J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Nobel, S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Håkansson, H.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    DePierre, J. W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Halldin, K.
    Bergstrom, U.
    Tissue distribution of S-35-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 4, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to S-35-PFOS (12 5 mg/kg) we determined the distribution in dams fetuses (GD18 and GD20) and pups (postnatal day 1 PND1) employing whole-body autoradiography and liquid scintillation counting In dams levels were highest in liver and lungs After placental transfer S-35-PFOS was present on GD18 at 2-3 times higher levels in lungs liver and kidneys than in maternal blood In PND1 pups levels in lungs were significantly higher than in GD18 fetuses A heterogeneous distribution of S-35-PFOS was observed in brains of fetuses and pups with levels higher than in maternal brain This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.

  • 23. Brandli, Rahel C.
    et al.
    Breedveld, Gijsbert D.
    Cornelissen, Gerard
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Tributyltin Sorption to Marine Sedimentary Black Carbon and to Amended Activated Carbon2009In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 28, no 3, p. 503-508Article in journal (Refereed)
    Abstract [en]

    Under marine conditions, tributyltin (TBT) is speciated mainly as an uncharged hydroxyl complex (TBTOH) that is expected to have a similar fate to hydrophobic organic contaminants. Earlier studies indicated that for the later compounds, sorption to black carbon (BC) can be more than two orders of magnitude stronger than sorption to organic carbon, notably at low and environmentally relevant concentrations. The aim of the present study was to investigate the sorption strength of spiked TBT to a sediment and its BC isolate. It was observed that carbon-normalized sorption coefficients were in the same range for the sediment total organic carbon (TOC) and for its BC (log K-TOC 5.05 L/kg(TOC) and log K BC 5.09 L/kg(BC), respectively). This indicates that TBT does not sorb as strongly to BC as other hydrophobic organic contaminants. Activated carbon (AC), a strong man-made sorbent, has the potential to be used for in situ remediation of contaminated sediments and soils, in particular for polycyclic aromatic hydrocarbons and polychlorinated biphenyls. In the present study, both granular and powdered AC were found to strongly sorb TBT under marine conditions, with a log sorption coefficient of 6.8 L/kg(carbon). Tributyl- and dibutyltin concentrations in the pore water of a natively contaminated sediment were reduced by more than 70% on addition of 2% of powdered AC, whereas granular AC did not show a similar reduction. The results indicate that powdered AC might be a feasible remediation agent for sediments contaminated by organotins.

  • 24. Brooks, Steven J.
    et al.
    Harman, Christopher
    Grung, Merete
    Farmen, Eivind
    Ruus, Anders
    Vingen, Sjur
    Godal, Brit F.
    Barsiene, Janina
    Andreikenaite, Laura
    Skarpheoinsdottir, Halldora
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Liewenborg, Birgitta
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Sundt, Rolf C.
    Water Column Monitoring of the Biological Effects of Produced Water from the Ekofisk Offshore Oil Installation from 2006 to 20092011In: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 74, no 7-9, p. 582-604Article in journal (Refereed)
    Abstract [en]

    The Norwegian water column monitoring program investigates the biological effects of offshore oil and gas activities in Norwegian waters. In three separate surveys in 2006, 2008, and 2009, bioaccumulation and biomarker responses were measured in mussels (Mytilus edulis) and Atlantic cod (Gadus morhua) held in cages at known distances from the produced water (PW) discharge at the Ekofisk oil field. Identical monitoring studies performed in all three years have allowed the biological effects and bioaccumulation data to be compared, and in addition, enabled the potential environmental benefits of a PW treatment system (CTour), implemented in 2008, to be evaluated. The results of the 2009 survey showed that caged animals were exposed to low levels of PW components, with highest tissue concentrations in mussels located closest to the PW discharge. Mussels located approximately 1-2 km away demonstrated only background concentrations of target compounds. Concentrations of polycyclic aromatic hydrocarbons (PAH) and alkyl phenol (AP) metabolites in the bile of caged cod were elevated at stations 200-250 m from the discharge. There was also a signal of exposure relative to discharge for the biomarkers CYP1A in fish and micronuclei in mussels. All other fish and mussel biomarkers showed no significant exposure effects in 2009. The mussel bioaccumulation data in 2009 indicated a lower exposure to the PW effluent than seen previously in 2008 and 2006, resulting in an associated general improvement in the health of the caged mussels. This was due to the reduction in overall discharge of PW components (measured as oil in water) into the area in 2009 compared to previous years as a result of the improved PW treatment system.

  • 25.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Osterman Golkar, Siv
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Characterization of a Hemoglobin Adduct from Ethyl Vinyl Ketone Detected in Human Blood Samples2015In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 11, p. 2120-2129Article in journal (Refereed)
    Abstract [en]

    Electrophiles have the ability to form adducts to nudeophilic sites in proteins and DNA. Internal exposure to such compounds thus constitutes a risk for toxic effects. Screening of adducts using mass spectrometric methods by adductomic approaches offers possibilities to detect unknown electrophiles present in tissues. Previously, we employed untargeted adductomics to detect 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood. This article describes the characterization of one of these adducts, which was identified as the adduct from ethyl vinyl ketone (EVK). The mean adduct level was 40 +/- 12 pmol/g Hb in 12 human blood samples; adduct levels from acrylamide (AA) and methyl vinyl ketone (MVK) were quantified for comparison. Using L-valine p-nitroanilide (Val-pNA), introduced as a model of the N-terminal valine, the rate of formation of the EVK adduct was studied, and the rate constant determined to 200 M(-1)h(-1) at 37 degrees C. In blood, the reaction rate was too fast to be feasibly measured, EVK showing a half-life <1 min. Parallel experiments with AA and MVK showed that the two vinyl ketones react approximately 2 x 10(3) times faster than AA. The EVK-Hb adduct was found to be unstable, with a half-life of 7.6 h. From the mean adduct level measured in human blood, a daily dose (area under the concentration-time-curve, AUC) of 7 nMh EVK was estimated. The AUC of AA from intake via food is about 20 times higher. EVK is naturally present in a wide range of foods and is also used as a food additive. Most probably, naturally formed EVK is a major source to observed adducts. Evaluation of available toxicological data and information on occurrence of EVK indicate that further studies of EVK are motivated. This study illustrates a quantitative strategy in the initial evaluation of the significance of an adduct detected through adduct screening.

  • 26.
    Caster, Ola
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
    Conforti, Anita
    Viola, Ermelinda
    Edwards, I. Ralph
    Methylprednisolone-induced hepatotoxicity: experiences from global adverse drug reaction surveillance2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 4, p. 501-503Article in journal (Refereed)
  • 27.
    Caster, Ola
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre (UMC), Sweden.
    Edwards, I. Ralph
    Comparative Quantitative Benefit-Risk Assessment of High- and Low-Dose Methylprednisolone in Multiple Sclerosis Relapse Management2014In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 23, p. 238-238Article in journal (Other academic)
  • 28.
    Caster, Ola
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre (UMC), Sweden.
    Juhlin, Kristina
    Watson, Sarah
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre (UMC), Sweden.
    A Paradigm Shift for Screening Individual Case Reports: Accounting for Quality and Content2014In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 23, p. 37-37Article in journal (Other academic)
  • 29. Cattaneo, Alberto Maria
    et al.
    Gonzalez, Francisco
    Bengtsson, Jonas M.
    Stockholm University, Faculty of Science, Department of Zoology.
    Corey, Elizabeth A.
    Jacquin-Joly, Emmanuelle
    Montagné, Nicolas
    Salvagnin, Umberto
    Walker, William B.
    Witzgall, Peter
    Anfora, Gianfranco
    Bobkov, Yuriy V.
    Candidate pheromone receptors of codling moth Cydia pomonella respond to pheromones and kairomones2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 41105Article in journal (Refereed)
    Abstract [en]

    Olfaction plays a dominant role in the mate-finding and host selection behaviours of the codling moth (Cydia pomonella), an important pest of apple, pear and walnut orchards worldwide. Antennal transcriptome analysis revealed a number of abundantly expressed genes related to the moth olfactory system, including those encoding the olfactory receptors (ORs) CpomOR1, CpomOR3 and CpomOR6a, which belong to the pheromone receptor (PR) lineage, and the co-receptor (CpomOrco). Using heterologous expression, in both Drosophila olfactory sensory neurones and in human embryonic kidney cells, together with electrophysiological recordings and calcium imaging, we characterize the basic physiological and pharmacological properties of these receptors and demonstrate that they form functional ionotropic receptor channels. Both the homomeric CpomOrco and heteromeric CpomOrco + OR complexes can be activated by the common Orco agonists VUAA1 and VUAA3, as well as inhibited by the common Orco antagonists amiloride derivatives. CpomOR3 responds to the plant volatile compound pear ester ethyl-(E, Z)-2,4-decadienoate, while CpomOR6a responds to the strong pheromone antagonist codlemone acetate (E, E)-8,10-dodecadien-1-yl acetate. These findings represent important breakthroughs in the deorphanization of codling moth pheromone receptors, as well as more broadly into insect ecology and evolution and, consequently, for the development of sustainable pest control strategies based on manipulating chemosensory communication.

  • 30.
    Chen, Yao
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sjölinder, Mikael
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Wang, Xiao
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Altenbacher, Georg
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hagner, Matthias
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Berglund, Pernilla
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gao, Yumin
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lu, Ting
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Thyroid hormone enhances nitric oxide mediated bacterial clearance and promotes survival after meningococcal infection2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, article id e41445Article in journal (Refereed)
    Abstract [en]

    Euthyroid sick syndrome characterized by reduced levels of thyroid hormones (THs) is observed in patients with meningococcal shock. It has been found that the level of THs reflects disease severity and is predictive for mortality. The present study was conducted to investigate the impact of THs on host defense during meningococcal infection. We found that supplementation of thyroxine to mice infected with Neisseria meningitidis enhanced bacterial clearance, attenuated the inflammatory responses and promoted survival. In vitro studies with macrophages revealed that THs enhanced bacteria-cell interaction and intracellular killing of meningococci by stimulating inducible nitric oxide synthase (iNos)-mediated NO production. TH treatment did not activate expression of TH receptors in macrophages. Instead, the observed TH-directed actions were mediated through nongenomic pathways involving the protein kinases PI3K and ERK1/2 and initiated at the membrane receptor integrin alpha v beta 3. Inhibition of nongenomic TH signaling prevented iNos induction, NO production and subsequent intracellular bacterial killing by macrophages. These data demonstrate a beneficial role of THs in macrophage-mediated N. meningitidis clearance. TH replacement might be a novel option to control meningococcal septicemia.

  • 31. Clemedson, Cecilia
    et al.
    Nordin-Andersson, Marika
    Bjerregaard, Henning F.
    Clausen, Jørgen
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gustafsson, Helena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Hansson, Ulrika
    Isomaa, Boris
    Jørgensen, Carsten
    Kolman, Ada
    Kotova, Natalia
    Krause, Gunter
    Kristen, Udo
    Kurppa, Kalle
    Romert, Lennart
    Scheers, Ellen
    Development of an in vitro test battery for the estimation of acute human systemic toxicity: An outline of the EDIT project. Evaluation-guided Development of New In Vitro Test Batteries2002In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 30, no 3, p. 313-321Article in journal (Refereed)
    Abstract [en]

    The aim of the Evaluation-guided Development of new In Vitro Test Batteries (EDIT) multicentre programme is to establish and validate in vitro tests relevant to toxicokinetics and for organ-specific toxicity, to be incorporated into optimal test batteries for the estimation of human acute systemic toxicity. The scientific basis of EDIT is the good prediction of human acute toxicity obtained with three human cell line tests (R(2) = 0.77), in the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. However, the results from the MEIC study indicated that at least two other types of in vitro test ought to be added to the existing test battery to improve the prediction of human acute systemic toxicity - to determine key kinetic events (such as biotransformation and passage through biological barriers), and to predict crucial organ-specific mechanisms not covered by the tests in the MEIC battery. The EDIT programme will be a case-by-case project, but the establishment and validation of new tests will be carried through by a common, step-wise procedure. The Scientific Committee of the EDIT programme defines the need for a specific set of toxicity or toxicokinetic data. Laboratories are then invited to perform the defined tests in order to provide the "missing" data for the EDIT reference chemicals. The results obtained will be evaluated against the MEMO (the MEIC Monograph programme) database, i.e. against human acute systemic lethal and toxicity data. The aim of the round-table discussions at the 19th Scandinavian Society for Cell Toxicology (SSCT) workshop, held in Ringsted, Denmark on 6-9 September 2001, was to identify which tests are the most important for inclusion in the MEIC battery, i.e. which types of tests the EDIT programme should focus on. It was proposed that it is important to include in vitro methods for various kinetic events, such as biotransformation, absorption in the gut, passage across the blood-brain barrier, distribution volumes, protein binding, and renal clearance/accumulation. Models for target organ toxicity were also discussed. Because several of the outlier chemicals (paracetamol, digoxin, malathion, nicotine, paraquat, atropine and potassium cyanide) in the MEIC in vivo-in vitro evaluation have a neurotoxic potential, it was proposed that the development within the EDIT target organ programme should initially be focused on the nervous system.

  • 32. Danielsson, Bengt
    et al.
    Collin, Julius
    Jonasdottir Bergman, Gudrun
    Borg, Natalia
    Salmi, Peter
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). National Board of Health and Welfare, Stockholm.
    Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study2016In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 81, no 4, p. 773-783Article in journal (Refereed)
    Abstract [en]

    AimThe aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. MethodsA matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n=286092) and matched controls (n=1430460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds () and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. ResultsUse of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. ConclusionThe CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.

  • 33.
    Daryanavard, Seyed
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Jeppsson-Dadoun, Amin
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Andersson, Lars I.
    Hashemi, Mahdi
    Colmsjö, Anders
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Abdel-Rehim, Mohamed
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Molecularly imprinted polymer in microextraction by packed sorbent for the simultaneous determination of local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine in plasma and urine samples2013In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 27, no 11, p. 1418-1488Article in journal (Refereed)
    Abstract [en]

    This study presents the use of molecularly imprinted polymer (MIP) as packing material for microextraction by packed syringe (MEPS) to achieve higher extraction selectivity. Pentycaine was used as template for MIP. Development and validation of the determination of lidocaine, ropivacaine, mepivacaine and bupivacaine in human plasma and urine samples utilizing MIP-MEPS and liquid chromatography–tandem mass spectrometry (LC-MS/MS) were carried out. The MEPS MIP-cartridge could be used for 100 extractions before it was discarded. The extraction recovery ranged from 60 to 80%. The correlation coefficients values were >0.999 for all assays using lidocaine, ropivacaine, mepivacaine and bupivacaine in the calibration range 5–2000 nmol/L. The accuracy of the studied compounds, given as a percentage variation from the nominal concentration values, ranged from -4.9 to 8.4% using plasma and urine samples. The between-batch precision, given as the relative standard deviation, at three different concentrations (quality control samples) was ranged from −4.7 to 14.0% and from 1.8 to 12.7% in plasma and urine, respectively. The lower limit of quantification and limit of detection of the studied substances were 5.0 and 1.0 nm, respectively

  • 34. Duarte-Salles, Talita
    et al.
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Granum, Berit
    Gutzkow, Kristine B.
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Mendez, Michelle A.
    Brunborg, Gunnar
    Brantsaeter, Anne Lise
    Meltzer, Helle Margrete
    Alexander, Jan
    Haugen, Margaretha
    Dietary Acrylamide Intake during Pregnancy and Fetal Growth-Results from the Norwegian Mother and Child Cohort Study (MoBa)2013In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, no 3, p. 374-379Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Acrylamide has shown developmental and reproductive toxicity in animals, as well as neurotoxic effects in humans with occupational exposures. Because it is widespread in food and can pass through the human placenta, concerns have been raised about potential developmental effects of dietary exposures in humans. OBJECTIVES: We assessed associations of prenatal exposure to dietary acrylamide with small for gestational age (SGA) and birth weight. METHODS: This study included 50,651 women in the Norwegian Mother and Child Cohort Study (MoBa). Acrylamide exposure assessment was based on intake estimates obtained from a food frequency questionnaire (FFQ), which were compared with hemoglobin (Hb) adduct measurements reflecting acrylamide exposure in a subset of samples (n = 79). Data on infant birth weight and gestational age were obtained from the Medical Birth Registry of Norway. Multivariable regression was used to estimate associations between prenatal acrylamide and birth outcomes. RESULTS: Acrylamide intake during pregnancy was negatively associated with fetal growth. When women in the highest quartile of acrylamide intake were compared with women in the lowest quartile, the multivariable-adjusted odds ratio (OR) for SGA was 1.11 (95% CI: 1.02, 1.21) and the coefficient for birth weight was -25.7 g (95% CI: -35.9, -15.4). Results were similar after excluding mothers who smoked during pregnancy. Maternal acrylamide-and glycidamide-Hb adduct levels were correlated with estimated dietary acrylamide intakes (Spearman correlations = 0.24; 95% CI: 0.02, 0.44; and 0.48; 95% CI: 0.29, 0.63, respectively). CONCLUSIONS: Lowering dietary acrylamide intake during pregnancy may improve fetal growth.

  • 35.
    Eklund, Britta
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Hansson, Tomas
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bengtsson, Henrik
    Eriksson Wiklund, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Pollutant Concentrations and Toxic Effects on the Red Alga Ceramium tenuicorne of Sediments from Natural Harbors and Small Boat Harbors on the West Coast of Sweden2016In: Archives of Environmental Contamination and Toxicology, ISSN 0090-4341, E-ISSN 1432-0703, Vol. 70, no 3, p. 583-594Article in journal (Refereed)
    Abstract [en]

    This investigation set out to analyze the toxicity of surface sediments in a number of natural harbors and small boat harbors on the west coast of Sweden. This was done with the growth inhibition method with Ceramium tenuicorne. Also, concentrations of copper (Cu), lead (Pb), zinc (Zn), irgarol, organotin compounds, and polycyclic aromatic hydrocarbons (PAHs) in the sediments were analyzed. The small boat harbors were heavily polluted by Cu, Zn, butyltins, and PAHs, and to a lesser extent by Pb. The Cu, Pb, Zn, and butyltins probably originated from their past and/or present use in antifouling paints, whereas the PAHs probably had multiple sources, including boat motor exhausts. The measured toxicity of the sediment was generally related to their Cu, Zn, and butyltin content, although other toxic substances than those analyzed here probably contributed to the toxicity in some of the harbors. The natural harbor sediments contained less pollutants and were less toxic than the small boat harbor sediments. Nevertheless, our data indicate that the boating pressure today may be high enough to produce toxic effects even in natural harbors in pristine areas. The strongest relationship between toxicity and the major pollutants was obtained when the sediment toxicity was expressed as gram wet weight per liter compared with gram dry weight per liter and gram total organic carbon per liter. Hence, for pollutants that can be elutriated with natural sea water, sediment toxicity expressed as gram wet weight per liter appears preferable.

  • 36.
    EL Andaloussi, Samir
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Johansson, Henrik
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundberg, Pontus
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Cell-penetrating short interfering RNAs and decoy oligonucleotides2007In: Handbook of cell-penetrating peptides / [ed] Ülo Langel, Boca Ranton: CRC Press, 2007, 2, p. 375-386Chapter in book (Refereed)
  • 37. El-Seedi, Hesham R.
    et al.
    Gomaa, Mohamed
    Salem, Mousa Maali
    Benchoula, Khaled
    Keshk, Hager M.
    Yosri, Nermeen
    Ayesh, Ahmed
    Asker, Ahmed M.
    Soliman, Kawther
    Hamza, Zeinab
    Mansour, Hager M.
    Elkhateeb, Ahmed
    Khalifa, Shaden A. M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska University Hospital, Sweden.
    CYTOTOXIC EFFECTS OF THE RED SEA SOFT CORAL SARCOPHYTON TROCHELIOPHORUM2016In: Acta Poloniae Pharmaceutica, ISSN 0001-6837, Vol. 73, no 6, p. 1587-1592Article in journal (Refereed)
    Abstract [en]

    The present study describes the in vitro cytotoxic effects of soft coral (Sarcophyton trocheliophorum). Soft corals of genus Sarcophyton were reported to contain compounds that arc active against brine shrimp and promote paclitaxel cytotoxicity in the human colon cancer Caco-2 cell line. The a-hexane extract of the soft coral Sarcophyton trocheliophorum induced significant dose-dependent toxicity (LC50 96.7 ppm) compared with ethyl acetate (LC50 120 ppm). We reported the most active cytotoxic level to be correspondence to LC50 values of 20.2, 59.2 ppm and 18.9 and 26 ppm. Accordingly, bio-assay guided fractionation was conducted to identify the bioactive compounds. Arachidonic acid. eicosapentaenoic acid and docosahexaenoic acid were characterized based on GC-MS analyses. Our results demonstrate the value of marine products as a natural source of medicinally interesting cytotoxic compounds.

  • 38. Engström, Karin
    et al.
    Wojdacz, Tomasz K.
    Marabita, Francesco
    Ewels, Philip
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kaller, Max
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Prezza, Nicola
    Gruselius, Joel
    Vahter, Marie
    Broberg, Karin
    Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women2017In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 5, p. 2067-2078Article in journal (Refereed)
    Abstract [en]

    Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 mu g/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate < 0.05) between the exposure groups. Key genes regulating the immune system, such as tumor necrosis factor alpha and interferon gamma, as well as genes related to the NF-kappa-beta complex, were significantly downregulated in the high-arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (> 80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.

  • 39. Ertan-Bolelli, Tugba
    et al.
    Bolelli, Kayhan
    Musdal, Yaman
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yildiz, Ilkay
    Aki-Yalcin, Esin
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yalcin, Ismail
    Design and synthesis of 2-substituted-5-(4-trifluoromethylphenyl-sulphonamido)benzoxazole derivatives as human GST P1-1 inhibitors2018In: Artificial Cells, Nanomedicine, and Biotechnology, ISSN 2169-1401, Vol. 46, no 3, p. 510-517Article in journal (Refereed)
    Abstract [en]

    The glutathione transferases (GSTs) are a family of widely distributed Phase II detoxification enzymes. GST P1-1 is frequently overexpressed in rat and human tumours. It is suggested that overexpression of hGST P1-1 by human tumor cells may play a role in resistance to cancer chemotherapy. Hence, hGST P1-1 can be a promising target for cancer treatment. In this study, new hGST P1-1 inhibitors, 2-(4-substitutedphenyl/benzyl)-5-(4-trifluoromethylphenylsulphonamido) benzoxazole derivatives (Va-Vk) have been designed and synthesized. Surprisingly, in vitro hGST P1-1 enzyme inhibition studies demonstrated that all of the tested compounds except Vj had better activity than the reference drug EA and it is also correlated with the docking results. Additionally we compared the interactions with hGST P1-1 enzyme of newly synthesized compound Vh (bearing CF3 group) and previously synthesized compound 5f (bearing NO2 group). According to the docking results, compound Vh bound to the hGST P1-1 enzyme with a higher affinity compared to 5f. Therefore, we can consider that these data make a sense and can explain its higher activity. The compounds that obtained from this research could be used as scaffolds in design of new potent hGST P1-1 inhibitors useful in the treatment of the resistance of cancer chemotherapy.

  • 40. Esbjörner, Elin K.
    et al.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nordén, Bengt
    Membrane Interactions of Cell-Penetrating Peptides2007In: Handbook of Cell-Penetrating Peptides / [ed] Ülo Langel, Boca Raton: CRC Press, 2007, 2, p. 109-137Chapter in book (Refereed)
  • 41. Faassen, Elisabeth J.
    et al.
    Antoniou, Maria G.
    Beekman-Lukassen, Wendy
    Blahova, Lucie
    Chernova, Ekaterina
    Christophoridis, Christophoros
    Combes, Audrey
    Edwards, Christine
    Fastner, Jutta
    Harmsen, Joop
    Hiskia, Anastasia
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Kaloudis, Triantafyllos
    Lopicic, Srdjan
    Lürling, Miquel
    Mazur-Marzec, Hanna
    Meriluoto, Jussi
    Porojan, Cristina
    Viner-Mozzini, Yehudit
    Zguna, Nadezda
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    A Collaborative Evaluation of LC-MS/MS Based Methods for BMAA Analysis: Soluble Bound BMAA Found to Be an Important Fraction2016In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, no 3, article id 45Article in journal (Refereed)
    Abstract [en]

    Exposure to beta-N-methylamino-l-alanine (BMAA) might be linked to the incidence of amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. Analytical chemistry plays a crucial role in determining human BMAA exposure and the associated health risk, but the performance of various analytical methods currently employed is rarely compared. A CYANOCOST initiated workshop was organized aimed at training scientists in BMAA analysis, creating mutual understanding and paving the way towards interlaboratory comparison exercises. During this workshop, we tested different methods (extraction followed by derivatization and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis, or directly followed by LC-MS/MS analysis) for trueness and intermediate precision. We adapted three workup methods for the underivatized analysis of animal, brain and cyanobacterial samples. Based on recovery of the internal standard D(3)BMAA, the underivatized methods were accurate (mean recovery 80%) and precise (mean relative standard deviation 10%), except for the cyanobacterium Leptolyngbya. However, total BMAA concentrations in the positive controls (cycad seeds) showed higher variation (relative standard deviation 21%-32%), implying that D(3)BMAA was not a good indicator for the release of BMAA from bound forms. Significant losses occurred during workup for the derivatized method, resulting in low recovery (<10%). Most BMAA was found in a trichloroacetic acid soluble, bound form and we recommend including this fraction during analysis.

  • 42.
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Läkemedel och Äldre2014In: Enligt ordination: om bättre läkemedelsanvändning / [ed] Nilsson J Lars G, Lund: Studentlitteratur AB, 2014, 2, p. 51-72Chapter in book (Other academic)
  • 43.
    Fastbom, Johan
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    National Indicators for Quality of Drug Therapy in Older Persons: the Swedish Experience from the First 10 Years2015In: Drugs & Aging, ISSN 1170-229X, E-ISSN 1179-1969, Vol. 32, no 3, p. 189-199Article, review/survey (Refereed)
    Abstract [en]

    Inappropriate drug use is an important health problem in elderly persons. Beginning with the Beers' criteria in the early 1990s, explicit criteria have been extensively used to measure and improve quality of drug use in older people. This article describes the Swedish indicators for quality of drug therapy in the elderly, introduced in 2004 and updated in 2010. These indicators were designed to be applied to people aged 75 years and over, regardless of residence and other characteristics. The indicators are divided into drug specific, covering choice, indication and dosage of drugs, polypharmacy, drug-drug interactions (DDIs), drug use in decreased renal function and in some symptoms; and diagnosis specific, covering the rational, irrational and hazardous drug use in common disorders in elderly people. During the 10 years since introduction, the Swedish indicators have several applications. They form the basis for recommendations for drug therapy in older people, are implemented in prescribing supports and drug utilisation reviews, are used in national benchmarking of the quality of Swedish healthcare and have contributed to initiatives from pensioner organisations. The indicators have also been used in several pharmacoepidemiological studies. Since 2005, there have been signs of improvement of the quality of drug prescribing to elderly persons in Sweden. For example, the prescribing of drugs that should be avoided in older persons decreased by 36 % between 2006 and 2012 in persons aged 80 years and older. Similarly, drug combinations that may cause DDIs decreased by 26 % and antipsychotics by 41 %. The indicators have likely contributed to this.

  • 44. Fereshtehnejad, Seyed-Mohammad
    et al.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Eriksdotter, Maria
    Anti-Dementia Drugs and Co-Medication Among Patients with Alzheimer's Disease Investigating Real-World Drug Use in Clinical Practice Using the Swedish Dementia Quality Registry (SveDem)2014In: Drugs & Aging, ISSN 1170-229X, E-ISSN 1179-1969, Vol. 31, no 3, p. 215-224Article in journal (Refereed)
    Abstract [en]

    Background There is a substantial risk of drug-interactions, adverse events, and inappropriate drug use (IDU) among frail Alzheimer's disease (AD) patients; however, there are few studies about co-medication and IDU in clinical settings. Objectives To investigate anti-dementia drugs, associated characteristics of cholinesterase inhibitors (ChEIs) and NMDA antagonists, co-medication, and IDU in a large population of outpatients with mild AD. Methods In this cross-sectional analysis of medication characteristics, we analyzed data from the Swedish Dementia Quality Registry (SveDem) on 5,907 newly diagnosed AD patients who were registered in memory clinics. SveDem is a national quality registry in Sweden, which was established in 2007 to evaluate and improve dementia healthcare. Comparisons were performed concerning co-medications, use of >= 3 psychotropic drugs (IDU) and polypharmacy (>= 5 drugs) based on anti-dementia treatment (ChEIs or NMDA antagonists). Information on baseline characteristics such as age, sex, living conditions, cognitive evaluation based on the Mini-Mental State Examination (MMSE) score, and diagnostic work-up was also evaluated. Results The majority of the AD patients were in the mild stage of the disease. Overall, 4,342 (75.4 %) patients received any ChEI, 438 (7.6 %) used an NMDA antagonist and 74 (1.3 %) patients were treated with both. However, 907 (15.7 %) patients were not treated with any anti-dementia drug. While polypharmacy was seen in 33.5 % of patients, only 2.6 % concurrently used >= 3 psychotropic medications. Patients on ChEIs were significantly younger, had a higher MMSE score and were treated with a smaller number of medications (a proxy for overall co-morbidity). Co-medication with antipsychotics [3.3 vs. 7.6 %; adjusted odds ratio (OR) 0.55 (95 % CI 0.38-0.79)] and anxiolytics [5.8 vs. 10.9 %; adjusted OR 0.62 (95 % CI 0.46-0.84)] was significantly lower in the ChEI+ group than in those with no anti-dementia treatment. Conclusion Patients taking ChEIs were treated with less antipsychotics and anxiolytics than those not taking ChEIs. More research is warranted to elucidate whether use of ChEIs in clinical practice can reduce the need for psychotropic drugs in AD patients.

  • 45. Forreryd, Andy
    et al.
    Norinder, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Karolinska Institutet, Sweden.
    Lindberg, Tim
    Lindstedt, Malin
    Predicting skin sensitizers with confidence - Using conformal prediction to determine applicability domain of GARD2018In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 48, p. 179-187Article in journal (Refereed)
    Abstract [en]

    GARD - Genomic Allergen Rapid Detection is a cell based alternative to animal testing for identification of skin sensitizers. The assay is based on a biomarker signature comprising 200 genes measured in an in vitro model of dendritic cells following chemical stimulations, and consistently reports predictive performances similar to 90% for classification of external test sets. Within the field of in vitro skin sensitization testing, definition of applicability domain is often neglected by test developers, and assays are often considered applicable across the entire chemical space. This study complements previous assessments of model performance with an estimate of confidence in individual classifications, as well as a statistically valid determination of the applicability domain for the GARD assay. Conformal prediction was implemented into current GARD protocols, and a large external test dataset (n = 70) was classified at a confidence level of 85%, to generate a valid model with a balanced accuracy of 88%, with none of the tested chemical reactivity domains identified as outside the applicability domain of the assay. In conclusion, results presented in this study complement previously reported predictive performances of GARD with a statistically valid assessment of uncertainty in each individual prediction, thus allowing for classification of skin sensitizers with confidence.

  • 46.
    Forsby, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Norman, Kimberly G.
    EL Andaloussi-Lilja, Johanna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Walczak, Vincent
    Curren, Rodger
    Martin, Katharine
    Tierney, Neena K.
    Using Novel In Vitro NociOcular Assay Based on TRPV1 Channel Activation for Prediction of Eye Sting Potential of Baby Shampoos2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 129, no 2, p. 325-331Article in journal (Refereed)
    Abstract [en]

    The transient receptor potential vanilloid type 1 (TRPV1) channel is one of the most well-characterized pain-inducing receptors. The purpose of this study was to predict human eye stinging of 19 baby bath and shampoo formulations by studying TRPV1 activity, as measured by increase in intracellular free Ca2+. The NociOcular test, a novel recombinant neuronal in vitro model with high expression of functional TRPV1 channels, was used to test formulations containing a variety of surfactants, preservatives, and fragrances. TRPV1-specific Ca2+ influx was abolished when the TRPV1 channel antagonist capsazepine was applied to the cells prior to shampoo samples. The positive control, an adult shampoo that contains cocamide monoethanolamine (CMEA), a known stinging ingredient, was the most active sample tested in the NociOcular test. The negative control, a marketed baby shampoo, was negative in the NociOcular and human tests. Seven of the formulations induced stinging in the human test, and of those six were positive in the NociOcular test. Twelve formulations were classified as nonstinging in the human test, and of those ten were negative in the NociOcular test. There was no correlation between the clinical stinging results for the baby formulations and the data generated from other in vitro eye irritation assays (cytosensor microphysiometer, neutral red uptake, EpiOcular, transepithelial permeability). Our data support that the TRPV1 channel is a principal mediator of eye-stinging sensation induced by baby bath and shampoo formulations and that the NociOcular test may be a valuable in vitro tool to predict human eye stinging sensation.

  • 47.
    Fotouhi, Asal
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cornella, Nicola
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ramezani, Mehrafarin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Investigation of micronucleus induction in MTH1 knockdown cells exposed to UVA, UVB or UVC2015In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 793, no SI, p. 161-165Article in journal (Refereed)
    Abstract [en]

    The longer wave parts of UVR can increase the production of reactive oxygen species (ROS) which can oxidize nucleotides in the DNA or in the nucleotide pool leading to mutations. Oxidized bases in the DNA are repaired mainly by the DNA base excision repair system and incorporation of oxidized nucleotides into newly synthesized DNA can be prevented by the enzyme MTH1. Here we hypothesize that the formation of several oxidized base damages (from pool and DNA) in close proximity, would cause a high number of base excision repair events, leading to DNA double strand breaks (DSB) and therefore giving rise to cytogenetic damage. If this hypothesis is true, cells with low levels of MTH1 will show higher cytogenetic damage after the longer wave parts of UVR. We analyzed micronuclei induction (MN) as an endpoint for cytogenetic damage in the human lymphoblastoid cell line, TK6, with a normal and a reduced level of MTH1 exposed to UVR. The results indicate a higher level of micronuclei at all incubation times after exposure to the longer wave parts of UVR. There is no significant difference between wildtype and MTH1-knockdown TK6 cells, indicating that MTH1 has no protective role in UVR-induced cytogenetic damage. This indicates that DSBs induced by UV arise from damage forms by direct interaction of UV or ROS with the DNA rather than through oxidation of dNTP.

  • 48. Ganyu, Anita
    et al.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Good, Liam
    Microbial membrane-penetrating peptides and their application2007In: Handbook of cell-penetrating peptides / [ed] Ülo Langel, Boca Raton: CRC Press, 2007, 2, p. 515-533Chapter in book (Refereed)
  • 49.
    Garcia-Bennett, Alfonso
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Feiler, Adam
    Mesoporous ASD: Fundamentals2014In: Amorphous Solid Dispersions: Theory and Practice / [ed] Shah, N; Sandhu, H; Choi, DS; Chokshi, H; Malick, AW, New York: Springer, 2014, p. 637-663Chapter in book (Refereed)
    Abstract [en]

    Mesoporous silica materials are having an impact in traditional pharmaceutical applications and nanomedicine. As excipients, they are allowing the enhancement of poorly soluble drugs with significant improvements in solubility for a large variety of type II drug compounds. Synthetic and structural versatility allows to truly design both mesopore structure and mesopore size with great precision promising to allow for a library of standard materials that can deliver tailored pharmacokinetic release profiles. In this chapter, we highlight some of the important developments in the field of mesoporous materials focusing on early synthetic aspects as well as later functionalisation strategies. The characterisation methods that are employed commonly and may be used to facilitate production and quality assessment are also discussed. Finally, we update the reader with some brief examples of how these non-toxic and biocompatible vehicles are entering pharmaceutical applications.

  • 50. George, Riham F.
    et al.
    Ismail, Nasser S. M.
    Stawinski, Jacek
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Girgis, Adel S.
    Design, synthesis and QSAR studies of dispiroindole derivatives as new antiproliferative agents2013In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 68, p. 339-351Article in journal (Refereed)
    Abstract [en]

    A variety of 4'-ary1-3-(arylmethylidene)-1 ''-[(cyclic-amino)methylene]-1'-methyl-dispiro[cyclohexane-1,3'-pyrrolidine-2',3 ''-[3H]indole]-2,2 ''(1H)-diones 4a-u were prepared via reaction of 2E,6E-bis(arylidene)-1-cyclohexanones 1a-i with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2a-c and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 liver, HELA cervical and PD prostate cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin. QSAR studies revealed good predictive and statistically significant 3 descriptor models (r(2) = 0.903-0.812, r(adjusted)(2) = 0.855-0.672, r(prediction)(2) = 0.773-0.605).

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