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  • 1. Elmroth, K.
    et al.
    Nygren, Jonas
    Södertörns högskola, Avdelning Naturvetenskap. Karolinska Institute.
    Mårtensson, S.
    Ismail, I. H.
    Hammarsten, O.
    Cleavage of cellular DNA by calicheamicin γ12003Inngår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 2, nr 4, s. 363-374Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is assumed that the efficient antitumor activity of calicheamicin γ1 is mediated by its ability to introduce DNA double-strand breaks in cellular DNA. To test this assumption we have compared calicheamicin γ1-mediated cleavage of cellular DNA and purified plasmid DNA. Cleavage of purified plasmid DNA was not inhibited by excess tRNA or protein indicating that calicheamicin γ1 specifically targets DNA. Cleavage of plasmid DNA was not affected by incubation temperature. In contrast, cleavage of cellular DNA was 45-fold less efficient at 0°C as compared to 37° due to poor cell permeability at low temperatures. The ratio of DNA double-strand breaks (DSB) to single-stranded breaks (SSB) in cellular DNA was 1:3, close to the 1:2 ratio observed when calicheamicin γ1 cleaved purified plasmid DNA. DNA strand breaks introduced by calicheamicin γ1 were evenly distributed in the cell population as measured by the comet assay. Calicheamicin γ1-induced DSBs were repaired slowly but completely and resulted in high levels of H2AX phosphorylation and efficient cell cycle arrest. In addition, the DSB-repair deficient cell line Mo59J was hyper sensitive to calicheamicin γ. The data indicate that DSBs is the crucial damage after calicheamicin γ1 and that calicheamicin γ1-induced DSBs are recognized normally. The high DSB:SSB ratio, specificity for DNA and the even damage distribution makes calicheamicin γ1 a superior drug for studies of the DSB-response and emphasizes its usefulness in treatment of malignant disease.

  • 2.
    Gustafsson, Kerstin
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Miljövetenskap. Södertörns högskola, Institutionen för livsvetenskaper, Biologi.
    Blidberg, Eva
    Elfgren, Irene Karlsson
    Hellström, Anna
    Kylin, Henrik
    Gorokhova, Elena
    Direct and indirect effects of the fungicide azoxystrobin in outdoor rackish water microcosms2010Inngår i: Ecotoxicology, ISSN 0963-9292, E-ISSN 1573-3017, Vol. 19, nr 2, s. 431-444Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effects of the strobilurin fungicide azoxystrobin were studied in rackish water microcosms, with natural plankton communities and ediment. Two experiments were conducted: Experiment 1 (nominal conc. 0, 5 and 60 mu g/L, 24-L outdoor microcosms for 21 days) and a second, ollow-up, Experiment 2 (nominal conc. 0, 3, 7.5, 15 mu g/L, 4-L indoor icrocosms for 12 days). The microcosms represent a simplified brackish ater community found in shallow semi-enclosed coastal areas in gricultural districts in the Baltic Sea region. Measured water oncentrations of the fungicide (Experiment 1) were, on average, 83 and 2% of nominal concentrations directly after application, and 25 and 30% fter 21 days, for the low and high dose treatments, respectively, orresponding to mean DT50-values of 15.1 and 25.8 days, for low and igh dose treatments, respectively. In Experiment 1, direct toxic ffects on calanoid copepods at both test concentrations were observed. imilarly, in Experiment 2, the copepod abundance was significantly educed at all tested concentrations. There were also significant econdary effects on zooplankton and phytoplankton community structure, tanding stocks and primary production. Very few ecotoxicological tudies have investigated effects of plant protection products on Baltic rganisms in general and effects on community structure and function pecifically. Our results show that azoxystrobin is toxic to brackish ater copepods at considerably lower concentrations than previously eported from single species tests on freshwater crustaceans, and that irect toxic effects on this ecologically important group may lead to ascade effects altering lower food webs and ecosystem functioning.

  • 3.
    Jaensson, Alia
    Södertörns högskola, Institutionen för livsvetenskaper, Biologi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Pheromonal Mediated Behaviour and Endocrine Responses in Salmonids: The impact of Cypermethrin, Copper, and Glyphosate2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The effects of cypermethrin, copper and glyphosate on the endocrine system and subsequent response to female pheromones were investigated in mature male brown trout (Salmo trutta) parr.  Responses measured were the amount of strippable milt, blood plasma levels of both an androgen (11-ketotestosterone (11-KT)) and a progestin (17α,20β-dihydroxy-4-pregnen-3-one (17,20b-P)), and behavioural changes. This was done in a two phased investigation where parr were exposed to one of the following via ambient water: 1) 0.1 or 1.0 μg L-1 cypermethrin, 2) 10 or 100 μg L-1 copper (Cu2+), or 3) 150 μg L-1 glyphosate for a 96 hour period.  Phase one was a priming experiment exposing parr to a treatment followed by priming with PGF or ovarian fluid (OVF). Atlantic salmon (Salmo salar) parr were, also exposed to glyphosate during phase I. The second phase was centered on behavioural observations.  Exposed parr were placed in a 35,000 L stream aquarium together with two ovulated females and four anadromous males. After the experiments a blood sample was taken, milt volumes measured and testes weighed.  The plasma was analyzed for 11-KT and 17,20b-P concentrations using radioimmunoassay (RIA).

    Results from phase I-priming: 1.0 μg L-1 cypermethrin exposure lowered 17,20b-P and 11-KT; Copper exposure lowered milt volumes; glyphosate exposure lowered 11-KT in salmon and raised 17,20b-P in trout.  Results from phase II-behaviour: 1.0 μg L-1 cypermethrin exposure lowered 11-KT, milt and spawning behaviour; copper exposure lowered spawning behaviour and raised 11-KT; Glyphosate exposure lowered 11KT; continuous cypermethrin exposure raised 17,20b-P, 11-KT and gave a tendency towards increased aggression. It is concluded that low concentration exposure to the compounds examined can induce negative effects on male salmonid endocrine systems, either through a disruption in the olfactory system or through a direct effect.

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  • 4.
    Josephson, Maria
    Södertörns högskola, Institutionen för historia och samtidsstudier, Idéhistoria.
    Lex THX: Historien om Sveriges största medicinska konflikt och den märkvärdiga veterinären som skapade den2022Bok (Annet vitenskapelig)
    Abstract [sv]

    Berättelsen om veterinärmedicinaren Elis Sandberg och kalvthymusextraktet THX är en unik och dramatisk svensk medicinhistoria. Den spänner över nästan fyra decennier, befinner sig i olika bryt- och brännpunkter och sätter förstoringsglaset på avgörande frågor i samhällsutvecklingen. Det handlar om synen på patienten, om lidande och död, men också om konflikterna mellan alternativmedicin och evidens, stad och landsbygd, allmänhet och etablissemang. Det är en berättelse om Sveriges väg in i moderniteten.

    Den första THX-patienten, en grannes ko, tillfrisknade snabbt och gjorde Elis Sandberg övertygad om att han hade löst cancerns gåta. Från 1950-talet och framåt fick mellan 50 000 och 150 000 människor injektioner med extraktet. Hela tiden i konflikt med den svenska medicinalstyrelsen och stora delar av läkarkåren. Som mest fanns 25 THX-kliniker spridda över Sverige och Sandberg var en rikskändis.

    Det här är utan konkurrens vår största medicinska konflikt genom tiderna och den kom att påverka svensk sjukvård i grunden. En veterinärmedicinare från Småland banade väg för en ny syn på den sjuka människan i Sverige.

  • 5.
    Krantz-Frid, Madelene
    Södertörns högskola, Institutionen för livsvetenskaper.
    Ecotoxicological effects from three antifouling paints on the red macroalga Ceramium tenuicorne.2009Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Antifouling paints are applied on vessels to prevent growth of fouling organisms such hasbarnacles. Presently, there are a number of different paints available on the Swedish marketwith different strategies and active substances. The paints might work by either continuouslyreleasing biocides or physically by peeling off or provide an easily cleansed surface whereorganisms cannot attach. The physically working paints do not need to register an activesubstance since its purpose is not to affect living organisms by a chemical or biological modeof action. In this study, two commercially available paints, the copper-based Fabi 3959(International Paint Ltd) and physically eroding, biocide-free labelled Mille Light (HempelFärg AB) were compared to Hard Racing superior, containing copper and the forbiddensubstance Tributyltin. Fabi International is only allowed to be used on the Swedish west coastdue to 6% added as active substance while the biocide-free Mille Light is eligible for eastcoast usage. The toxic effect from respective paint was investigated by assembling a growthinhibition test with the red macro alga Ceramium tenuicorne. The results show that all thestudied paints had a negative effect on growth and therefore leaked substances inconcentrations high enough to be harmful to the alga. The toxic response differed with theeffect on growth being in the following order, Hard racing superior>Fabi >Mille Light.Implications regarding the current legalization involving biocide-free labelled antifoulingpaints are discussed.

    Fulltekst (pdf)
    FULLTEXT02
  • 6.
    Lindström, Jonna
    Södertörns högskola, Institutionen för livsvetenskaper.
    Dietary intake estimations of brominated flame retardants for Swedish children2008Independent thesis Advanced level (degree of Magister), 20 poäng / 30 hpOppgave
    Abstract [en]

    The dietary intake of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) have been estimated for Swedish children. A dietary survey performed in 2003, including 4, 8-9 and 11-12 year olds, and concentrations in individual food items were combined. The food included in the study was mainly of animal origin, consisting of fish and shellfish, dairy products, meat products, eggs, animal and vegetable fats and fats from miscellaneous food products. The medium-bound intake of PBDEs (9 congeners) were estimated to 23.0 ng/day, 30.9 ng/day and 27.7 ng/day for 4, 8-9 and 11-12 years olds respectively. The corresponding estimations for HBCD were 7.94 ng/day 10.7 ng/day and 9.46 ng/day for 4, 8-9 and 11-12 years olds respectively. These results show a higher daily intake for 8-9 year olds compared with the other age groups. However, when estimating the daily intake per kg bw, the intake decreases with age. BDE-47 contributed the most to the total intake of PBDEs, with approximately 40%. The food group contributing the most to the intake of PBDEs and HBCD was fish and shellfish, of which non-Baltic fatty fish was the largest contributor. There were no considerable differences between boys and girls in any of the aspects examined. The result from this study show a lower intake of PBDEs and HBCD in Swedish children compared with children in other studies made in Europe and the United States.

    Fulltekst (pdf)
    FULLTEXT01
  • 7.
    Löfmark, Sonja
    et al.
    Södertörns högskola, Institutionen för kemi, biologi, geografi och miljövetenskap. Karolinska Institutet.
    Fang, Hong
    Karolinska Institutet.
    Hedberg, Maria
    Karolinska Institutet.
    Edlund, Charlotta
    Södertörns högskola, Institutionen för kemi, biologi, geografi och miljövetenskap. Karolinska Institutet.
    Inducible metronidazole resistance and nim genes in clinical Bacteroides fragilis group isolates2005Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 49, nr 3, s. 1253-1256Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nitroimidazole resistance (nim) genes were detected in 2% of 1,502 clinical Bacteroides fragilis group strains isolated from 19 European countries, and a novel nim gene was identified. High metronidazole resistance could be induced in nim-positive strains, which emphasizes the importance of acknowledging metronidazole resistance in the clinical setting.

  • 8.
    Löfmark, Sonja
    et al.
    Karolinska Institute.
    Jernberg, Cecilia
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Jansson, Janet K.
    Swedish University of Agricultural Sciences.
    Edlund, Charlotta
    Karolinska Institute / Medical Products Agency.
    Clindamycin-induced enrichment and long-term persistence of resistant Bacteroides spp. and resistance genes2006Inngår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 58, nr 6, s. 1160-1167Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The aim was to study the long-term consequences of 1 week clindamycin administration regarding selection and persistence of resistance, resistance determinants and diversity of the Bacteroides spp. in the intestinal microflora. Methods: A total of 1306 Bacteroides isolates were collected from constitutively cultured faecal samples during a 2 year period from eight healthy volunteers. The strains were identified by biochemical and genotyping methods. MIC values were determined by the agar dilution method and presence of resistance genes was screened by real-time PCR. Results: Ecological changes in the intestinal microflora persisting up to 24 months were recorded after a 7 day clindamycin administration to four healthy volunteers. Compared to a control group, not exposed to clindamycin, an enrichment and stabilization of resistant Bacteroides strains and resistance determinants were discovered up to 2 years after clindamycin exposure. Conclusions: The results indicate that even a short-term antibiotic administration can cause long-term alterations in the commensal microbiota of individual subjects, detectable 2 years after dosing. The recorded selection and persistence of resistant strains and resistance genes, illustrates the importance of increasing our knowledge of the role of the abundant intestinal microbial community as a reservoir for spread of resistance.

  • 9.
    Pettersson, Sara
    Södertörns högskola, Institutionen för livsvetenskaper.
    Development of siRNA against the CYP1A1 gene for trap of endogenous Ah-receptor ligand2006Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    The aryl hydrocarbon receptor (Ah-receptor) is a member of the bHLH-PAS protein family. The Ah-receptor is a ligand dependent transcription factor, which activates a wide range of genes, most notably the xenobiotica metabolising genes, CYP1A1 and CYP1A2. The biological function of the Ah-receptor is still unknown and an endogenous ligand has yet not been identified. A possible Ah-receptor ligand is 6-formylindolo[3,2-b]carbazole (FICZ). FICZ has a high affinity for the Ah-receptor and is rapidly metabolised by CYP1A1, CYP1A2 and aldehydeoxidase (AOX). To try to trap FICZ or other possible endogenous Ah-receptor ligands, the metabolising enzymes CYP1A1, CYP1A2 and AOX were blocked. This was achieved through chemical blockage of CYP1A1 and CYP1A2 by ellepticin and through silencing with siRNA directed against CYP1A1 and CYP1A2. Successful blockage would be seen as an increase in Ah-receptor dependent XRE-luciferase activity. Chemical blockage of AOX with tungstate did not affect FICZ-dependent XRE-luciferase activation which could indicate that HepG2 cells lack AOX. The chemical blockage of CYP1A1 and CYP1A2 with ellepticin modified the XRE-luciferase response, but did not completely block Ah-receptor activation. In addition it is possible that ellepticin is a ligand for the Ah-receptor. The blockage of CYP1A1 by siRNA was successful; a silencing of CYP1A1 mRNA by at least 50 percent was detected. However due to lack of time it was not tested if the blockage of CYP1A1 and CYP1A2 was sufficient to trap Ah-receptor ligands.

    Fulltekst (pdf)
    FULLTEXT01
  • 10.
    Schenk, Linda
    Södertörns högskola, Institutionen för livsvetenskaper. KTH, Filosofi.
    Setting occupational exposure limits: Practices and outcomes of toxicological risk assessment2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Occupational Exposure Limits (OELs) are used as an important regulatory instrument to protect workers’ health from adverse effects of chemical exposures. The main objective of this thesis is to study risk assessment practices in the setting of OEL in order to produce knowledge that will help improve the consistency and transparency of OELs.

    For the purpose of paper I a database of OELs for a total of 1341 substances was compiled. Of these, only 25 substances have OELs from all 18 included organisations while more than one third of the substances are only regulated by one organisation alone. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland.

    In paper II six EU member states’ OELs are compared to the European Commission’s OELs. Also within Europe there is a large difference concerning the average level of OELs (35%). The average level of lists tends to decrease over time, although there are exceptions to this. There are also indications that the exposure limits of EU member states are converging towards the European Commission’s OELs.

    The work presented in paper III identifies steps in the risk assessment that could account for the large differences in OELs for 14 different substances. Differences in the identification of the critical effect could explain the different level of the OELs for half of the substances. But the age of the data review could not account for all the differences in data selection, only one fifth of the documents referred to all available key studies. Also the evaluation of the key studies varied significantly.

    The aim of paper IV was to investigate how the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Commission uses assessment factors when proposing health-based indicative OELs. For only one third of the investigated OELs were explicit assessment factors given. On average the safety margin of the recommendations was 2.1 higher when an explicit assessment factor had been used. It is recommended that the SCOEL develop and adhere to a more articulate framework on the use of assessment factors.

    Paper V focuses on the Derived No-Effect Levels (DNELs) which are to be calculated under the new European Union REACH legislation. It is a comparison of the safety margins of 88 SCOEL recommendations with those of the corresponding worker-DNELs, derived according to the default approach as described in the REACH guidance document. Overall, the REACH safety margins were approximately six times higher than those derived from the SCOEL documentations but varied widely with REACH/SCOEL safety margin ratios ranging by two orders of magnitude, from 0.3 to 58.

  • 11.
    Schenk, Linda
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper. KTH.
    Hansson, Sven Ove
    Ruden, Christina
    Södertörns högskola, Institutionen för livsvetenskaper. KTH.
    Gilek, Michael
    Södertörns högskola, Institutionen för livsvetenskaper.
    Are occupational exposure limits becoming more alike within the European Union?2008Inngår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 28, nr 7, s. 858-866Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The occupational exposure limits (OELs) established by seven different national regulatory agencies of EU member states are compared with those of the European Commission (EC). The comparison concerned: (1) what chemicals have been selected, (2) the average level of exposure limits for all chemicals, and (3) the similarity between the OELs of different EU member states and the OELs recommended by the European Commission. The average level of the exposure limits has declined during the past 10 years in four of the live countries in our study for which historical data were available to us. Poland has not changed its level noticeably and Germany has increased it. Since the first list of indicative OELs was established by the EC, a few of the EU exposure limits have been lowered. The similarity index indicates that the exposure limits of EU member states are converging towards the European Commission's recommended OELs. Still, the average level of OELs differs between organizations - the Estonian OELs are on average 35% higher than the Polish OELs.

  • 12.
    Schenk, Linda
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper. KTH.
    Hansson, Sven Ove
    Ruden, Christina
    Södertörns högskola, Institutionen för livsvetenskaper. KTH.
    Gilek, Michael
    Södertörns högskola, Institutionen för livsvetenskaper.
    Occupational exposure limits: A comparative study2008Inngår i: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 50, nr 2, s. 261-270Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Occupational exposure limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In this study we compared the OELs established by 18 different organisations or national regulatory agencies. The OELs were compared with respect to: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. Our database contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one-third of the substances are only regulated by one organisation. The average level of the exposure limits has declined during the past 10 years for 6 of the 8 organisations in our study for which historical data were available; it has increased for Poland and remained nearly unchanged for Sweden. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. The scientific or policy-related motivations for these differences remain to be analysed.

  • 13.
    Schenk, Linda
    et al.
    KTH, Filosofi.
    Johanson, Gunnar
    Institute of Environmental Medicine, Karolinska Institutet.
    Use of Uncertainty Factors by the SCOEL in their derivation of health-based Occupational Exposure Limits2010Inngår i: Critical reviews in toxicology, ISSN 1040-8444, E-ISSN 1547-6898, Vol. 40, nr 9, s. 791-798Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to investigate how the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Commission uses uncertainty factors when proposing health-based indicative occupational exposure limit values (IOELVs). In total, 75 IOELVs in 62 summary documents published from 1991 to 2003 were analyzed. For 31 of the IOELVs, no explicit uncertainty factor (EUF) was stated. For these, we calculated an implicit safety margin (ISM) as the ratio between the point of departure (POD, derived from the NOAEL or LOAEL of the critical effect) and the proposed IOELV. We further analysed whether date of recommendation, type of critical effect, nature of POD or amount of available data influenced the magnitude of the EUFs and ISMs. The ISMs varied little (range 1-5), while the EUFs showed more variability (range 1-50). The EUFs remained unaffected over time and the ISMs decreased slightly. Significant differences in the magnitude of the EUFs, but not ISMs, were found between critical effects, however, contrary to expected the average EUFs and ISMs for irritation were similar to those for more severe systemic effects. The nature of the POD affected the ISMs and EUFs only slightly and less than expected. Both EUFs and ISMs showed a weak but significant negative correlation with the amount of available toxicological data, measured as the number of relevant publications in PubMed, whereas SCOEL statements on data sufficiency had no influence. Overall, the most striking difference was that between EUFs and ISMs, the former being on average 2.1 times higher.

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