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  • 151.
    Langrish, Jeremy P.
    et al.
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Watts, Simon J.
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Hunter, Amanda J.
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Shah, Anoop S. V.
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Bosson, Jenny A
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Barath, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lundbäck, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Cassee, Flemming R.
    National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands .
    Donaldson, Ken
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Newby, David E.
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Mills, Nicholas L.
    University of Edinburgh, University/BHF Centre for Cardiovascular Science, Edinburgh, United Kingdom.
    Controlled exposures to air pollutants and risk of cardiac arrhythmia2014Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, nr 7, s. 747-753Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Epidemiological studies have reported associations between air pollution exposure and increases in cardiovascular morbidity and mortality. Exposure to air pollutants can influence cardiac autonomic tone and reduce heart rate variability, and may increase the risk of cardiac arrhythmias, particularly in susceptible patient groups. OBJECTIVES: We investigated the incidence of cardiac arrhythmias during and after controlled exposure to air pollutants in healthy volunteers and patients with coronary heart disease. METHODS: We analyzed data from 13 double-blind randomized crossover studies including 282 participants (140 healthy volunteers and 142 patients with stable coronary heart disease) from whom continuous electrocardiograms were available. The incidence of cardiac arrhythmias was recorded for each exposure and study population. RESULTS: There were no increases in any cardiac arrhythmia during or after exposure to dilute diesel exhaust, wood smoke, ozone, concentrated ambient particles, engineered carbon nanoparticles, or high ambient levels of air pollution in either healthy volunteers or patients with coronary heart disease. CONCLUSIONS: Acute controlled exposure to air pollutants did not increase the short-term risk of arrhythmia in participants. Research employing these techniques remains crucial in identifying the important pathophysiological pathways involved in the adverse effects of air pollution, and is vital to inform environmental and public health policy decisions.

  • 152. Langworth, Sven
    et al.
    Bodlund, Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Ågren, Hans
    Efficacy and tolerability of reboxetine compared with citalopram: a double-blind study in patients with major depressive disorder2006Ingår i: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 26, nr 2, s. 121-127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to compare efficacy and tolerability of the selective noradrenalin reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram, in the treatment of major depressive disorder (MDD). In total, 357 outpatients with MDD were randomized to treatment with reboxetine 8-10 mg or citalopram 20-40 mg per day during 24 weeks. Primary end-point was change from baseline in the Hamilton Depression Rating Scale (HAM-D, 21 items). Sexual function/dysfunction was measured by the Sexual Function scale (SF). Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores: reboxetine with -21.4 and citalopram with -22.1 points (NS). LOCF analysis showed a greater reduction of the HAM-D scores with citaloprarn compared with reboxetine (- 19.6 vs. - 17.8; P = 0.034). The response rate was 90.3% for reboxetine and 92.7% for citalopram (NS). The most common side effect in the reboxetine group was dry mouth, and in the citalopram group sexual dysfunction. At week 24, anorgasmia was reported by 5.9% of the sexually active women in the reboxetine group vs 39% in the citalopram group. The dropout number was 91 in the reboxetine group, and 54 in the citaloprarn group. To summarize, both treatments gave a satisfactory antidepressant effect. The side effect profile differed between the groups, with a notably high prevalence of sexual dysfunctions in the citalopram group. The high number of dropouts in the reboxetine group, is considered as a result of the non-titration starting dose of 8 mg reboxetine per day, which gave a high incidence of early side-effects.

  • 153.
    Larsson, D G Joakim
    et al.
    Department of Neuroscience and Physiology, the Sahlgrenska Academy at University of Göteborg, Box 434, SE-405 30 Göteborg, Sweden.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Transparency throughout the production chain: a way to reduce pollution from the manufacturing of pharmaceuticals?2009Ingår i: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 53, nr 3, s. 161-163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent findings have shown that wastewater from bulk drug production can be a source of very high environmental concentrations of drugs in certain locations. The release of active ingredients is often not specifically regulated, and thus rapid initiatives from the industries themselves are warranted. Possible ways to stimulate action include changes in local and international regulations, including the implementation of appropriate environmental standards within existing industry guidelines as well as demands from prescribers and consumers of medicines. The lack of readily available information regarding the origin of drugs and the environmental impact of the production, however, prevents consumers from making informed decisions. Here, we investigated the origin of active pharmaceutical ingredients (APIs) in 242 selected products on the Swedish market. By comparing registers from Sweden and India we found that the APIs in 71 products (31%) originated from Indian manufacturers sending their waste to a treatment plant where unprecedented amount of environmental pollution with broad spectrum antibiotics and other drugs recently has been documented. We propose that increased transparency throughout the production chain would be one of several important steps to reducing pollution from the manufacturing of drugs.

  • 154.
    Larsson, Jan
    et al.
    Umeå universitet. Department of Pharmacology, Umeå University, S-901 87 Umeå, Sweden.
    Koskinen, Lars-Owe D.
    Department of Neurosurgery, University Hospital, S-901 85 Umeå, Sweden; Division of Biomedicine, Department of NBC Defence, National Defence Research Establishment, S-901 82 Umeå, Sweden.
    Wahlström, Göran
    Umeå universitet.
    Effects of TRH and atropine on induction and duration of anesthesia with propofol in rats.1996Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 17, nr 2, s. 293-297Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effects of IV TRH pretreatment on induction of anesthesia with propofol or pentobarbital were investigated in rats. The effects of IV TRH, administered after induction, on duration of propofol anesthesia and the interaction with atropine were also studied. The doses of propofol or pentobarbital were not influenced by TRH. TRH reduced duration of anesthesia after propofol, with higher brain concentrations of propofol at recovery. Atropine did not block this effect, but given alone prolonged duration of anesthesia. It is concluded that TRH shortens the duration of propofol anesthesia, probably due to a pharmacodynamic effect and not to a pharmacokinetic interaction.

  • 155.
    Larsson, Malin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van den Berg, Martin
    Brenerova, Petra
    van Duursen, Majorie B. M.
    van Ede, Karin I.
    Lohr, Christiane
    Luecke-Johansson, Sandra
    Machala, Miroslav
    Neser, Sylke
    Pencikova, Katerina
    Poellinger, Lorenz
    Schrenk, Dieter
    Strapacova, Simona
    Vondracek, Jan
    Andersson, Patrik L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Consensus Toxicity Factors for Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls Combining in Silico Models and, Extensive in Vitro Screening of AhR-Mediated Effects in Human and Rodent Cells2015Ingår i: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, nr 4, s. 641-650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.

  • 156.
    Leffler, Per
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin. Division CBRN–Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Brännäs, Eva
    Department of Aquaculture, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Ragnvaldsson, Daniel
    Division CBRN–Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Wingfors, Håkan
    Division CBRN–Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Berglind, Rune
    Division CBRN–Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Toxicity and accumulation of trinitrotoluene (TNT) and its metabolites in atlantic salmon alevins exposed to an industrially polluted water2014Ingår i: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 77, nr 19, s. 1183-1191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A pond in an industrial area in Sweden was selected to study adverse effects on salmon alevins from 2,4,6-trinitrotoluene (TNT)-contaminated water. Chemical screening revealed heavy contamination of TNT and its degradation products, 2-amino-4,6-dinitrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT), ranging from 0.05 to 230 g/kg in the sediment (dry weight) within the water system. Pond water contained 3 mg/L TNT. A dilution series of pond water mixed with tap water revealed increased death frequency in alevins down to fivefold dilution (approximate 0.4 mg TNT/L). Uptake was concentration dependent, reaching 7, 9, and 22 μg/g tissue for TNT, 2-ADNT, and 4-ADNT at the highest test concentration. A time-dependent uptake of TNT and its degradation products was found at a water concentration of 0.08 mg TNT/L. Degradation products of TNT showed a more efficient uptake compared to native TNT, and accumulation of 4-ADNT was more pronounced during the late phase of the 40-d exposure study. Bioconcentration factors (BCF) (0.34, 52, and 134 ml/g for TNT, 2-ADNT, and 4-ADNT, respectively) demonstrated a significant uptake of the metabolite 4-ADNT in alevin tissue. Disturbed physiological conditions and delayed development in alevins were not studied, but may not be excluded even at 125-fold diluted pond water (0.016 mg TNT/L). BCF data indicated that bioaccumulation of TNT metabolites need to be considered in TNT chronic toxicity. Fish species and age differences in the accumulation of TNT metabolites need to be further studied.

  • 157. Lei, Li-Jian
    et al.
    Chen, Liang
    Jin, Tai-Yi
    Nordberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Chang, Xiu-Li
    Estimation of benchmark dose for pancreatic damage in cadmium-exposed smelters2007Ingår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 97, nr 1, s. 189-195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to estimate the benchmark dose (BMD) for pancreas dysfunction caused by cadmium (Cd) exposure in smelters. Smelter workers who had been exposed to Cd for more than 1 year and matching nonoccupationally exposed subjects were asked to participate in this study. Urinary cadmium (UCd) was used as a biomarker for exposure, serum insulin and amylase were used as biomarkers for pancreatic effects. In this study, serum insulin and amylase were lower in the smelter workers than in the nonoccupationally exposed subjects. A significant dose-response relationship with UCd was displayed. BMI)s in terms of urinary Cd corrected for creatinine were calculated by use of BMDS (version 1.3.2). The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. It was found that the BMDL10 for serum insulin and serum amylase was 3.7 and 5.3 mu g/g Cr, respectively. Compared to the BMDL for renal damage caused by Cd exposure, identified by the effect biomarkers urinary beta(2)-microglobulin, urinary N-acetyl-beta-glucosaminidase, and urinary albumin (UALB), it was shown that BMDL10 for serum insulin is the lowest among all values and UALB gave the highest value (5.8 mu g/g Cr). This study indicates that Cd exposure can result in pancreatic dysfunction and the effect appears at lower urinary Cd level than renal dysfunction. The endocrine function of the pancreas was affected at lower urinary levels of Cd, compared to the exocrine function, which was seen at higher urinary levels of Cd than those giving rise to renal tubular dysfunction.

  • 158.
    Lei, Yang
    et al.
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Guanghui, Zhao
    Hong Hui Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
    Xi, Wang
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Yingting, Wang
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Xialu, Lin
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Fangfang, Yu
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Goldring, Mary
    Hospital for Special Surgery, Weill Cornell Medical College, New York, USA.
    Xiong, Guo
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, Shaanxi, P.R. China.
    Cellular responses to T-2 toxin and/or deoxynivalenol that induce cartilage damage are not specific to chondrocytes2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, nr 1, s. 2231-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The relationship between T-2 toxin and deoxynivalenol (DON) and the risk of Kashin-Beck disease is still controversial since it is poorly known about their selectivity in cartilage damage. We aimed to compare the cytotoxicity of T-2 toxin and DON on cell lines representative of cell types encountered in vivo, including human chondrocytes (C28/I2), human hepatic epithelial cells (L-02) and human tubular epithelial cells (HK-2). In addition, we determined the distribution of T-2 toxin and DON in Sprague-Dawley (SD) rats after a single dose exposure. T-2 toxin or DON decreased proliferation in a time- and concentration-dependent manner and their combination showed a similar antagonistic effect in C28/I2, L-02 and HK-2 cells. Moreover, we observed cell cycle arrest and apoptosis, associated with increased oxidative stress and decline in mitochondrial membrane potential induced by T-2 toxin and/or DON. In vivo study showed that T-2 toxin and DON did not accumulate preferentially in the knee joint compared to liver and kidney after an acute exposure in SD rats. These results suggest that T-2 toxin and/or DON inhibit proliferation and induce apoptosis through a possible mechanism involving reactive oxygen species-mediated mitochondrial pathway that is not specific for chondrocytes in vitro or joint tissues in vivo.

  • 159. Lemke, Bruno
    et al.
    Kjellström, Tord
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Calculating workplace WBGT from meteorological data: a tool for climate change assessment2012Ingår i: Industrial Health, ISSN 0019-8366, E-ISSN 1880-8026, Vol. 50, nr 4, s. 267-278Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The WBGT heat stress index has been well tested under a variety of climatic conditions and quantitative links have been established between WBGT and the work-rest cycles needed to prevent heat stress effects at the workplace. While there are more specific methods based on individual physiological measurements to determine heat strain in an individual worker, the WBGT index is used in international and national standards to specify workplace heat stress risks. In order to assess time trends of occupational heat exposure at population level, weather station records or climate modelling are the most widely available data sources. The prescribed method to measure WBGT requires special equipment which is not used at weather stations. We compared published methods to calculate outdoor and indoor WBGT from standard climate data, such as air temperature, dew point temperature, wind speed and solar radiation. Specific criteria for recommending a method were developed and original measurements were used to evaluate the different methods. We recommend the method of Liljegren et al. (2008) for calculating outdoor WBGT and the method by Bernard etal. (1999) for indoor WBGT when estimating climate change impacts on occupational heat stress at a population level.

  • 160.
    Lennestål, Roland
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Lakso, Hans-Åke
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Nilsson, Mats
    Mjörndal, Tom
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Urine monitoring of diazepam abuse: new intake or not?2008Ingår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 32, nr 6, s. 402-407Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Testing for drugs-of-abuse in urine is requested for multiple reasons, including legal and workplace policies. Two cases were studied in which there was a suspicion that the patients continued to abuse diazepam, because of repeatedly positive urine samples. In these cases, diazepam metabolites were measured in urine samples by gas or liquid chromatography coupled to mass spectrometry. The concentrations of diazepam metabolites were subsequently creatinine correlated. Very long elimination times were found in the described cases. None of them had in fact ingested diazepam again during the study period. By the use of pharmacogenetic typing, one of the subjects was found to have a slow metabolism for CYP2C9 as well as for CYP2C19. In the second case, there was a possible drug interaction between diazepam and zolpidem.

  • 161.
    Lennestål, Roland
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Otterblad Olausson, Petra
    Källén, Bengt
    Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants2009Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 65, nr 6, s. 615-625Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose To investigate the association between maternal use of antihypertensives in early pregnancy and delivery outcome, notably infant congenital malformations.

    Methods A cohort study of 1,418 women who had used antihypertensive drugs in early pregnancy but had no diabetes diagnosis were identified from the Swedish Medical Birth Register.

    Results There was an excess risk for placental abruption, caesarean section, delivery induction, and post-delivery hemorrhage in women taking hypertensives. Infants were more often than expected born preterm, were small for gestational age, and had an excess of various neonatal symptoms. Cardiovascular defects occurred with an adjusted odds ratio of 2.59 (95% CI 1.92-3.51). The results were similar when the woman had used ACE inhibitors or other antihypertensives, notably beta blockers. Stillbirth rate was increased (risk ratio 1.87, 95% CI 1.02-3.02), again without any clear drug specificity.

    Conclusions There seems to be little drug specificity in the association between maternal use of antihypertensives and an increased risk for infant cardiovascular defects.

  • 162.
    Lerner, Ulf H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Mellström, Dan
    Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Behandlingsprinciper för olika läkemedel vid osteoporos: skelettet i käkar och annorstädes, del 52012Ingår i: Tandläkartidningen, ISSN 0039-6982, Vol. 104, nr 11, s. 64-79Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Osteoporos drabbar många individer i hela världen. Från att ha varit en sjukdom utan farmakologisk behandling har ett flertal läkemedel nu utvecklats och fler är på väg. Här beskrivs behandlingsprinciperna för de läkemedel som i dag används vid osteoporos.

  • 163.
    Lieber, Ingrid
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Sunderby Research Unit, Luleå, Sweden.
    Ott, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Öhlund, Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Lundqvist, Robert
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Sunderby Research Unit, Luleå, Sweden.
    Sandlund, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Werneke, Ursula
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Sunderby Research Unit, Luleå, Sweden.
    Lithium-associated hypothyroidism and potential for reversibility after lithium discontinuation: Findings from the LiSIE retrospective cohort study2019Ingår i: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, artikel-id UNSP 0269881119882858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The association between lithium and thyroid dysfunction has long been known. However, it remains unknown if lithium-associated hypothyroidism is reversible once lithium treatment has been stopped.

    Aims: To determine whether lithium-associated hypothyroidism was reversible in patients who subsequently discontinued lithium.

    Methods: A retrospective cohort study in the Swedish region of Norrbotten into the effects and side- effects of lithium treatment and other drugs for relapse prevention (Lithium – Study into Effects and Side Effects). For this particular study, we reviewed medical records between 1997 and 2015 of patients with lithium-associated hypothyroidism who had discontinued lithium.

    Results: Of 1340 patients screened, 90 were included. Of these, 27% had overt hypothyroidism at the start of thyroid replacement therapy. The mean delay from starting lithium to starting thyroid replacement therapy was 2.3 years (SD 4.7). In total, 50% of patients received thyroid replacement therapy within 10 months of starting lithium. Of 85 patients available for follow-up, 41% stopped thyroid replacement therapy after lithium discontinuation. Only six patients reinstated thyroid replacement therapy subsequently. Of these, only one had overt hypothyroidism.

    Conclusions: Lithium-associated hypothyroidism seems reversible in most patients once lithium has been discontinued. In such cases, thyroid replacement therapy discontinuation could be attempted much more often than currently done. Based on the limited evidence of our study, we can expect hypothyroidism to recur early after thyroid replacement therapy discontinuation, if at all.

  • 164. Lilienthal, Hellmuth
    et al.
    Heikkinen, Paivi
    Andersson, Patrik L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van der Ven, Leo T. M.
    Viluksela, Matti
    Dopamine-dependent behavior in adult rats after perinatal exposure to purity-controlled polychlorinated biphenyl congeners (PCB52 and PCB180)2014Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 224, nr 1, s. 32-39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Since knowledge about toxic effects of non-dioxinlike (NDL) PCBs is fragmentary, regulatory panels have concluded that risk assessment of these congeners is hampered or impossible. As the dopaminergic system is one of the main targets in PCB-related neurotoxic effects after developmental exposure, we selected catalepsy induced by the dopamine receptor blocker haloperidol to characterize effects of the NDL congeners PCB52 and PCB180 in adult offspring from exposed rat dams. Rat dams were treated with PCB congeners by gavage using six dose levels (total doses: PCB52 - 0, 30, 100, 300, 1000 or 3000 mg/kg body wt.; PCB180 - 0, 10, 30, 100, 300, or 1000 mg/kg body wt.) to allow benchmark dose analysis of the results. Testing of adult offspring (starting at 180 days of age) for catalepsy induced by injection with haloperidol revealed slightly prolonged latencies to movement onset in female offspring exposed to PCB52. Exposure to PCB180 resulted in more pronounced effects, with generally reduced latencies in male offspring. These results indicate reduced dopaminergic activity after PCB52 exposure, whereas the outcome for PCB180 may be related to increased extracellular dopamine as reported in the literature. Benchmark dose analyses revealed that both PCB congeners exerted effects mainly at moderate exposure levels. Together, these results underline the importance of effects on the dopaminergic system as indicated by studies in human females after occupational PCB exposure.

  • 165.
    Lilienthal, Hellmuth
    et al.
    Center of Toxicology, IPA – Institute for Prevention and Occupational Medicine, German Social Accident Insurance, Ruhr University of Bochum, 44789 Bochum, Germany.
    Heikkinen, Päivi
    Department of Environmental Health, THL – National Institute for Health and Welfare, 70701 Kuopio, Finland.
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van der Ven, Leo T M
    Laboratory for Health Protection Research, RIVM - National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands.
    Viluksela, Matti
    Department of Environmental Health, THL – National Institute for Health and Welfare, 70701 Kuopio, Finland.
    Auditory effects of developmental exposure to purity-controlled Polychlorinated Biphenyls (PCB52 and PCB180) in rats2011Ingår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 122, nr 1, s. 100-111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are still present in the environment, with ongoing exposure in humans, including babies nursed by their mothers. Whereas toxicity of dioxin-like PCBs is well described, less systematic knowledge is available for non-dioxin-like PCBs (NDL-PCBs) which do not act via the Ah receptor. This study compared effects of developmental exposure to two ultrapure NDL-PCB congeners (PCB52 and PCB180) on auditory function in rats, using the brainstem auditory evoked potential (BAEP). Pregnant rats received repeated oral doses of PCB52 (total dose - 0, 30, 100, 300, 1000, or 3000 mg/kg body weight) or of PCB180 (total dose - 0, 10, 30, 100, 300, or 1000 mg/kg). BAEPs were recorded in adult male and female offspring after stimulation with clicks or pure tones in the frequency range from 0.5 kHz to 16 kHz. Significant elevation of BAEP thresholds were detected in the low-frequency range after developmental exposure to PCB52. Calculation of benchmark doses revealed lowest values in the frequency range of 0.5 - 2 kHz. Effects were more pronounced in male compared to female offspring. Latencies of waves II and IV were prolonged in exposed males, while only wave IV was affected in females. PCB180 increased thresholds only at few conditions and only in female offspring. These results confirm that developmental exposure to ultrapure NDL-PCBs affects auditory function, but different congeners exhibit differences in potencies.

  • 166. Lillienberg, Linnea
    et al.
    Andersson, Eva M.
    Järvholm, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Toren, Kjell
    Respiratory Symptoms and Exposure-Response Relations in Workers exposed to Metalworking Fluid Aerosols2010Ingår i: Annals of Occupational Hygiene, ISSN 0003-4878, E-ISSN 1475-3162, Vol. 54, nr 4, s. 403-411Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the study was to identify specific health risks and exposure-response relationships associated with exposure to metalworking fluid (MWF) aerosols. In a cross-sectional study of machine workers exposed to MWF aerosols in five companies in Sweden, a self-administered questionnaire about health symptoms, work tasks, and exposure situations was sent out to 2294 employees, 1632 exposed and 662 referents. Referents were office workers and metal workers not working with MWFs. In four of the companies, there were recent measurements of personal exposure to MWF aerosols. Log-binomial regression models were used to estimate prevalence ratios with 95% confidence intervals for different health outcomes in relation to different variables of exposure. The response rate after two reminders was 67% resulting in 1048 (923 male, 125 female) workers exposed to MWF aerosols and 451 (374 male, 77 female) referents. The study indicates that metal workers in Sweden currently exposed to a mean value of MWF aerosols of 0.4 mg m(-3) have a significantly higher prevalence of wheeze, chronic bronchitis, chronic rhinitis, and eye irritation compared to the referents. At a mean exposure of 0.4 mg m(-3), a level below the Swedish 8-h exposure limit value of 1 mg m(-3), machine operators showed increased prevalence of symptoms in eyes and airways. Thus, the current exposure limit value does not seem to protect the workers from such symptoms.

  • 167.
    Lin, Xialu
    et al.
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Shao, Wanzhen
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Yu, Fangfang
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Xing, Ke
    Xi'an Hong Hui Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Liu, Huan
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Zhang, Feng'e
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Goldring, Mary B.
    Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA.
    Lammi, Mikko J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Guo, Xiong
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
    Individual and combined toxicity of T-2 toxin and deoxynivalenol on human C-28/I2 and rat primary chondrocytes2019Ingår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 39, nr 2, s. 343-353, artikel-id 30251759Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Deoxynivalenol (DON) and T-2 toxin are prevalent mycotoxin contaminants in the food and feed stuffs worldwide, with non-negligible co-contamination and co-exposure conditions. Meanwhile, they are considerable risk factors for Kashin-Beck disease, a chronic endemic osteochondropathy. The aim of this study was to investigate the individual and combined cytotoxicity of DON and T-2 toxin on proliferating human C-28/I2 and newborn rat primary costal chondrocytes by MTT assay. Four molar concentration combination ratios of DON and T-2 toxin were used, 1:1 for R1 mixture, 10:1 for R10, 100:1 for R100 and 1000:1 for R1000. The toxicological interactions were quantified by the MixLow method. DON, T-2 toxin, and their mixtures all showed a clear dose-dependent toxicity for chondrocytes. The cytotoxicity of T-2 toxin was 285-fold higher than DON was in human chondrocytes, and 22-fold higher in the rat chondrocytes. The combination of DON and T-2 toxin was significantly synergistic at middle and high level concentrations of R10 mixtures in rat chondrocytes, but significantly antagonistic at the low concentrations of R100 mixtures in both cells and at the middle concentrations of R1000 mixtures in rat chondrocytes. These results indicated that the combined toxicity was influenced by the cell sensitivity for toxins, the difference between the combination ratio and equitoxic ratio, the concentrations and other factors.

  • 168. Linnér, Love
    et al.
    Schiöler, Helena
    Samuelsson, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Milsom, Ian
    Nilsson, Fredrik
    Low persistence of anticholinergic drug use in Sweden2011Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, nr 5, s. 535-536Artikel i tidskrift (Refereegranskat)
  • 169. Lohr, C
    et al.
    Neser, S
    Andresen, K
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schrenk, D
    Whole genome microarray analysis of the effects of TCDD and PCB 153 in human hepatic cell models2012Ingår i: Naunyn-Schmiedeberg's Archives of Pharmacology, ISSN 0028-1298, E-ISSN 1432-1912, Vol. 385, nr Suppl 1, s. 54-54Artikel i tidskrift (Refereegranskat)
  • 170. Lundin, Cecilia
    et al.
    Malmborg, Agota
    Slezak, Julia
    Danielsson, Kristina Gemzell
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bengtsdotter, Hanna
    Marions, Lena
    Lindh, Ingela
    Theodorsson, Elvar
    Hammar, Mats
    Sundstrom-Poromaa, Inger
    Sexual function and combined oral contraceptives: a randomised, placebo-controlled trial2018Ingår i: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 7, nr 11, s. 1208-1216Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The effect of combined oral contraceptives (COCs) on female sexuality has long been a matter of discussion, but placebo-controlled studies are lacking. Thus, the aim of the present study was to investigate if an oestradiol-containing COC influences sexual function.

    Design: Investigator-initiated, randomised, double-blinded, placebo-controlled clinical trial where 202 healthy women were randomised to a combined oral contraceptive (1.5 mg oestradiol and 2.5 mg nomegestrol acetate) or placebo for three treatment cycles.

    Methods: Sexual function at baseline and during the last week of the final treatment cycle was evaluated by the McCoy Female Sexuality Questionnaire. Serum and hair testosterone levels were assessed at the same time points.

    Results: Compared to placebo, COC use was associated with a small decrease in sexual interest (COC median change score: -2.0; interquartile range (IQR): -5.0 to 0.5 vs placebo: -1.0; IQR: -3.0 to 2.0, P=0.019), which remained following adjustment for change in self-rated depressive symptoms (B= -0.80 +/- 0.30, Wald =7.08, P=0.008). However, the proportion of women who reported a clinically relevant deterioration in sexual interest did not differ between COC or placebo users (COC 18 (22.2%) vs placebo 16 (17.8%), P=0.47). Change in other measured aspects of sexual function as well as total score of sexual function did not differ between the two treatments.

    Conclusions: This study suggests that use of oestradiol-based COCs is associated with reduced sexual interest. However, the changes are minute, and probably not of clinical relevance.

  • 171.
    Löfgren, Magnus
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap, Obstetrik och gynekologi.
    Behavioral effects of female sex steroid hormones : models of PMS and PMDD in Wistar rats2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABAA receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors.

    Aims The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids.

    Methods In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA).

    Results In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior.

    Conclusions It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats.

  • 172.
    Löfgren, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Johansson, Inga-Maj
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Meyerson, Bengt
    Department of Neuroscience, Division of Pharmacology, P.O. Box 593, BMC, SE-751 24 Uppsala, Sweden.
    Turkmen, Sahruh
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Withdrawal effects from progesterone and estradiol relate to individual risk-taking and explorative behavior in female rats2009Ingår i: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 96, nr 1, s. 91-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Withdrawal from progesterone and estradiol has been used as an animal model of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). In the clinical population individual sensitivity to sex steroid hormones, personality and heredity influence PMS/PMDD. Understanding the phenotypic risk factors of PMS/PMDD and drug development requires an animal model which incorporates individual steroid sensitivity. The main objective of this study was to investigate whether the individual trait of risk-taking and exploration influence the severity of PEWD in female rats. Thirty-two female Wistar rats in their diestrus phase were tested in the open field (OF) and divided into high responders (HR) and low responders (LR). Injections were given i.p. twice daily for 6 days, either 5 mg/kg progesterone combined with 10 microg/kg 17beta-estradiol, or vehicle (sesame oil). After a 24-hour withdrawal the animals were tested in the elevated plus maze (EPM). Blood samples for CORT analysis were collected after both behavioral tests. The HR rats withdrawn from progesterone and estradiol, spent less time on the EPM open arms and had lower CORT levels than the HR controls. The LR group showed no differences in EPM behavior and CORT levels during PEWD. The controls showed a stable trait of risk-taking and exploration, indicated by behavioral and CORT level correlations between the OF and EPM tests. These findings show that female rats with the trait of risk-taking and explorative behavior (HR) are more affected by PEWD.

  • 173.
    Löfgren, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Johansson, Inga-Maj
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Strömberg, Jessica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Meyerson, Bengt
    Department of Neuroscience, Division of Pharmacology, Box 593, BMC, SE-751 24 Uppsala, Sweden..
    Bäcktröm, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Chronic subordination stress augments combined progesterone and estradiol withdrawal behaviorManuskript (Övrigt vetenskapligt)
    Abstract [en]

    Exposure to stress is a risk factor for developing pre-menstrual syndrome (PMS) and pre-menstrual dysphoric disorder (PMDD), and stress enhances the anxiogenic effect of female sex steroids in animals. This study examines the interaction between chronic subordination stress and withdrawal from progesterone (P4) and estradiol (E2) (PEWD) in producing behaviors analogous to anxiety and irritability in rats. At the start of the experiment, male Wistar rats were housed in triads consisting of one younger rat (~35 days) and two older rats (~50 days). The housing condition was aimed at producing chronic subordination stress in the younger animals. Chronic subordination stress was assessed by the elevated plus maze (EPM) and by corticosterone (CORT) analysis. A triad of three 35-day-old rats was used as age control. Social rank within the triads was determined using a food competition test (FCT) and the tube test (TT). The younger rats (subordinate) and the dominant rats were assigned to 10 days of treatment with 5 mg/kg progesterone combined with 10 µg/kg 17β estradiol. Twenty-four hours after the last injection, the subordinate and dominant animals were tested in the open-field test (OFT) and in the intruder test (IT). The IT consists of a 10-minute exposure to 3 unfamiliar rats. Chronic subordination stress reduced EPM open-arm time and altered the CORT response. It also made the subordinate animals more vulnerable to PEWD. The effects were increased locomotion in the OFT, increased defensive burying, and increased social anxiety in the intruder test (IT). Dominant animals did not react to PEWD. Thus, chronic subordination stress augments PEWD.

  • 174.
    Lövheim, Hugo
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Karlsson, Stig
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Gustafson, Yngve
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    The use of central nervous system drugs and analgesics among very old people with and without dementia2008Ingår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 17, nr 9, s. 912-918Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Old people in general, and particularly those with dementia, are more sensitive to adverse drug effects than younger people. Despite this, the use of central nervous system (CNS) drugs among old people is common. The aim of the present study was to compare the use of central nervous system drugs and analgesics among people aged 85 years or older, with and without dementia. METHODS: One half of all people aged 85 years old and all those aged 90, 95 and above in Umeå, Sweden and Vaasa and Mustasaari, Finland, were asked to participate in this part of the GERDA/Umeå 85+ study. Both those living in their own homes and those in institutions were included. Trained investigators performed structured interviews and assessments. Medication data were obtained from the participants and medical records. Dementia disorders were diagnosed according to DSM-IV. RESULTS: Dementia was diagnosed in 247/546 participants (45.2%). A higher proportion of the participants with dementia used paracetamol (50.6% compared to 21.4%, p < 0.001), antipsychotics (22.3% and 2.7%, p < 0.001), antidepressants (33.6% and 11.4%, p < 0.001) and anxiolytics (19.0% and 8.0%, p < 0.001). There were no differences in the use of opioid analgesics, anticonvulsants and hypnotics. CONCLUSIONS: The use of CNS drugs and analgesics was common among this population of very old people. Furthermore, the prescription of CNS drugs was more common among people with dementia. The use of antipsychotics in people with dementia should arouse particular concern, because of the high risk of severe adverse events and the limited evidence of positive effects.

  • 175. Magnusson, Beatrice M.
    et al.
    Koskinen, Lars-Owe D.
    National Defense Research Establishment, Department of NBC Defence, Division of Biomedicine and Department of Neurosurgery, University Hospital of Northern Sween, Umeå, Sweden .
    Effects of topical application of capsaicin to human skin: a comparison of effects evaluated by visual assessment, sensation registration, skin blood flow and cutaneous impedance measurements.1996Ingår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 76, nr 2, s. 129-132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new non-invasive device, which enables local measurements of electrical impedance, has been used to evaluate the degree of irritation in human skin. The results have been compared with visual scoring, sensations and laser Doppler flowmetry. Capsaicin (50 microliters 1% solution) and control solutions (50 microliters 50% ethanol) were applied in a chamber for 30 min on the volar forearm of 7 volunteers. Values were recorded before application and during the total test period of 4.5 h. Sensations like sting/prick, burn and pain were produced by this treatment, and the flare response was observed. Using the non-invasive laser Doppler flow technique to measure blood flow in human skin, we have shown that topical application of capsaicin abolishes the vasodilator response to local heat provocation (40 degrees C). There was close agreement among values obtained using visual assessments, sensations and laser Doppler flowmetry. Results obtained using electrical impedance measurements were not consistent with the other three methods.

  • 176. Magnusson, Beatrice M.
    et al.
    Runn, Per
    Koskinen, Lars-Owe D.
    National Defense Research Establishment, Department of NBC Defence, Division of Biomedicine and Department of Neurosurgery, University Hospital of Northern Sween, Umeå, Sweden.
    Terpene-enhanced transdermal permeation of water and ethanol in human epidermis.1997Ingår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 77, nr 4, s. 264-267Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The study was performed to investigate the effect of penetration enhancers on the stratum corneum barrier. Epidermal membranes were prepared from freeze-stored (-70 degrees C) Caucasian breast skin and mounted in a flow-through diffusion cell. The validity of the freeze storage procedure was verified by measurement of [3H]-water penetration. The effect of the cyclic terpene, carveol, on the transdermal penetration of water and ethanol was studied in vitro. Control ethanol and water penetration measured with a donor solution of 50% ethanol/PBS (w/w) was 1.9+/-0.2 and 3.6+/-0.5 x 10(-3) cm/h. The addition of 3% carveol to the donor solution increased the permeation of ethanol and water after 4 h to 8.3+/-1.1 and 12.5+/-1.9 x 10(-3) cm/h, respectively. In a separate experiment, terpinen-4-ol and alpha-terpineol were also tested, in addition to carveol, for effect on tritium flux. No significant difference in maximum tritium flux was obtained between the three terpenes studied. The maximum increase in permeability coefficients of carveol, terpinen-4-ol and alpha-terpineol was 10.6, 8.7 and 10.9, respectively.

  • 177. Mansoor, M Azam
    et al.
    Stea, Tonje Holte
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Reine, Andreas
    Early biochemical and hematological response to intramuscular cyanocobalamin therapy in vitamin B-12-deficient patients2013Ingår i: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 62, nr 4, s. 347-353Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Data on early biochemical and hematological responses to cobalamin therapy in vitamin B-12-deficient patients are scarce. Therefore, we investigated whether cobalamin injections would include prompt biochemical and hematological responses in vitamin B-12-deficient patients.

    Subjects and Methods: Seven female patients (mean age: 69.4 years, range: 61-78) with a mean serum cobalamin level of 104 +/- 38 pmol/l mean +/- SD and 7 male patients (mean age: 67.0 years, range: 53-78) with a mean serum cobalamin level of 84 +/- 40 (+/- SD) participated in the study. They were administered 1 mg i.m. cyanocobalamin per week for 3 weeks. Blood samples were collected before and 1, 3, 7, 14 and 21 days after cobalamin injection. The concentrations of plasma aminothiols and serum methylmalonic acid (MMA) were measured with high-performance liquid chromatography and gas chromatography/mass spectrometry, respectively, and hematological parameters were determined with a hematological analyzer.

    Results: Already 1 day after intramuscular Cobalamin injections, the concentrations of serum vitamin B-12 and plasma total cysteine were significantly increased while the concentrations of serum folate, plasma total homocysteine and serum MMA were decreased. Mean cell volume was also significantly decreased first after 14 days of therapy.

    Conclusion: Intramuscular cobalamin administration causes swift and significant changes in plasma aminothiols, whereas the first change in hematological parameters was detected only after 14 days. Copyright (C) 2013 S. Karger AG, Basel

  • 178.
    Marwaha, Sania
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Uvell, Hanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Salin, Olli
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lindgren, Anders E. G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Silver, Jim
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gylfe, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis2014Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, nr 5, s. 2968-2971Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

  • 179.
    Mattsson, Sofia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Sjöström, Hans-Erik
    Umeå universitet, Umeå universitetsbibliotek (UB), Universitetspedagogik och lärandestöd (UPL).
    Englund, Claire
    Umeå universitet, Umeå universitetsbibliotek (UB), Universitetspedagogik och lärandestöd (UPL).
    Using a Virtual Tablet Machine to Improve Student Understanding of the Complex Processes Involved in Tablet Manufacturing2016Ingår i: American Journal of Pharmaceutical Education, ISSN 0002-9459, E-ISSN 1553-6467, Vol. 80, nr 5, artikel-id 87Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. To develop and implement a virtual tablet machine simulation to aid distance students' understanding of the processes involved in tablet production.

    Design. A tablet simulation was created enabling students to study the effects different parameters have on the properties of the tablet. Once results were generated, students interpreted and explained them on the basis of current theory.

    Assessment. The simulation was evaluated using written questionnaires and focus group interviews. Students appreciated the exercise and considered it to be motivational. Students commented that they found the simulation, together with the online seminar and the writing of the report, was beneficial for their learning process.

    Conclusion. According to students' perceptions, the use of the tablet simulation contributed to their understanding of the compaction process.

  • 180.
    Mattsson, Sofia
    et al.
    Umeå universitet, Humanistiska fakulteten, Universitetspedagogiskt centrum (UPC). Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Sjöström, Hans-Erik
    Umeå universitet, Humanistiska fakulteten, Universitetspedagogiskt centrum (UPC).
    Lampe Persson, Jonas
    Umeå universitet, Humanistiska fakulteten, Universitetspedagogiskt centrum (UPC).
    Englund, Claire
    Umeå universitet, Humanistiska fakulteten, Universitetspedagogiskt centrum (UPC).
    Use of a virtual tablet machine in pharmaceutical education2012Ingår i: NGL 2012 Next Generation Learning Conference Falun: Book of Abstracts, 2012Konferensbidrag (Refereegranskat)
    Abstract [en]

    One of the pedagogical problems frequently faced by distance students, particularly on web-based vocational programmes, is the lack of opportunity to train practical elements in the course. This presentation describes a project to provide a technological solution to this problem and also to enhance distance students’ understanding of the processes involved in tablet production by means of a virtual tablet machine. The web-based Master of Science in Pharmacy Programme at Umeå University includes the course Drug Formulation. One of the expected learning outcomes of the course is to understand and explain relationships between composition, compaction process and properties of tablets. In order to facilitate this, a tablet simulation (virtual tablet machine) was created. Simulations can be successfully used in education to illustrate rather complex relationships during a limited time frame and they are also ideal in distance education since they do not require access to expensive laboratory facilities and can be carried out by the student at any time and place. A web-based tablet simulation was created enabling the students to choose different compositions, compaction pressures and compaction speeds in order to observe which effect these parameters have on the properties of the tablet produced. The simulation is performed and the results are displayed in the form of graphs. Once the results have been generated the students then interpret and explain the results on the basis of current theory using a Wiki. During the course the students also manufacture tablets in real life; the tablet simulation therefore also serves as preparation for these practical experiments. After the simulation had been carried out it was evaluated by the students in the form of a written questionnaire and a focus group interview. The students found the tablet simulation easy to use, motivational and considered the simulation to have contributed to their understanding of the compaction process. The students also considered the simulation to be a good theoretical preparation for the practical experiments. Some operational problems were reported, for example difficulties in changing the compaction pressure and the presentation of the results may also be improved. In conclusion, we found that the use of the tablet simulation, in combination with practical experiments and assignments, improved the student’s understanding of the compaction process and provided a suitable technological solution to a pedagogical problem in a web-based Pharmaceutical Science Programme. The project would like to thank “Flexible education at Umeå University” for financial support.

  • 181.
    McCallum, Erin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Cerveny, Daniel
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brodin, Tomas
    Slow-Release Implants for Manipulating Contaminant Exposures in Aquatic Wildlife: A New Tool for Field Ecotoxicology2019Ingår i: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 53, nr 14, s. 8282-8290Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Field-based ecotoxicology studies are invaluable for uncovering the effects of contaminants of emerging concern (CECs) on aquatic organisms. However, large-scale exposures are still very rare due to prohibitive costs, the availability of replicated habitats, and the potential for exposure to cause lasting damage to the environment. Here, we evaluated the viability of internal slow-release implants as an alternative method for manipulating CEC exposures in aquatic wildlife using two fat-based carriers (coconut oil and vegetable shortening). We treated roach (Rutilus rutilus) with implants containing a high (50 mu g/g), low (25 mu g/g), or control (0 mu g/g) concentration of the behavior-modifying pharmaceutical oxazepam. We then measured oxazepam uptake in four tissues (plasma, muscle, liver, and the brain) over 1 month. The two carriers released oxazepam differently: coconut oil was the superior implant type because it delivered a more consistent dose across time, while vegetable shortening released oxazepam rapidly at the start of the exposure period. For both carriers and treatments, the brain and liver contained the most oxazepam. Overall, the method is a promising technique for controlled manipulations of pharmaceuticals in fish, and we have provided some of the first data on the suitability and contaminant release kinetics from different implant types.

  • 182.
    McCallum, Erin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Sundelin, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Alanärä, Anders
    Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Klaminder, Jonatan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Hellström, Gustav
    Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Brodin, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Investigating tissue bioconcentration and the behavioural effects of two pharmaceutical pollutants on sea trout (Salmo trutta) in the laboratory and field2019Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 207, s. 170-178Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pharmaceuticals entering aquatic ecosystems via wastewater effluents are of increasing concern for wild animals. Because some pharmaceuticals are designed to modulate human behaviour, measuring the impacts of exposure to pharmaceuticals on fish behaviour has become a valuable endpoint. While laboratory studies have shown that pharmaceuticals can affect fish behaviour, there is a lack of understanding if behaviour is similarly affected in natural environments. Here, we exposed sea trout (Salmo trutta) smolts to two concentrations of two pharmaceutical pollutants often detected in surface waters: temazepam (a benzodiazepine, anxiolytic) or irbesartan (an angiotensin II receptor blocker, anti-hypertensive). We tested the hypothesis that changes to behavioural traits (anxiety and activity) measured in laboratory trials following exposure are predictive of behaviour in the natural environment (downstream migration). Measures of anxiety and activity in the laboratory assay did not vary with temazepam treatment, but temazepam-exposed fish began migrating faster in the field. Activity in the laboratory assay did predict overall migration speed in the field. In contrast to temazepam, we found that irbesartan exposure did not affect behaviour in the laboratory, field, or the relationship between the two end-points. However, irbesartan was also not readily taken up into fish tissue (i.e. below detection levels in the muscle tissue), while temazepam bioconcentrated (bioconcentration factor 7.68) rapidly (t(1/2) < 24 h). Our findings add to a growing literature showing that benzodiazepine pollutants can modulate fish behaviour and that laboratory assays may be less sensitive at detecting the effects of pollutants compared to measuring effects in natural settings. Therefore, we underscore the importance of measuring behavioural effects in the natural environment.

  • 183. Miletic, Hrvoje
    et al.
    Niclou, Simone P
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. NorLux Neuro-Oncology Laboratory, CRP-Santé, Luxembourg.
    Bjerkvig, Rolf
    Anti-VEGF therapies for malignant glioma: treatment effects and escape mechanisms2009Ingår i: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, Vol. 13, nr 4, s. 455-468Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Background: Glioblastoma multiforme (GBM) has a very poor prognosis and novel treatment strategies are urgently needed. GBM appears to be an optimal target for anti-angiogenic therapy as the tumour shows a high degree of endothelial cell proliferation and pro-angiogenic growth factor expression. Objective: To examine the role of angiogenic factors (particularly VEGF) in glioma and whether inhibition of these factors can be used as a treatment.

    Methods: A review of relevant literature.

    Results/conclusions: Anti-angiogenic therapy has fulfilled the proof of concept in glioma animal models. In glioma patients, the efficacy of anti-angiogenic mono-therapies initially has been disappointing. However recent clinical trials combining bevacizumab, an anti-VEGF antibody, with chemotherapy reported very encouraging response rates. Although randomized phase III clinical trials with anti-angiogenic molecules are not yet available for GBM patients, this treatment regimen is already applied off protocol in several clinical centers. It should be kept in mind though that tumours can develop escape mechanisms. In particular invasive cells, which migrate away from the highly vascularized tumour core, are not targeted by anti-angiogenic therapies. In our opinion, the future of anti-angiogenic therapy will rely on a combination strategy including chemotherapy and drugs that target invasive glioma cells.

  • 184.
    Moodie, Lindon W. K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sepcic, Kristina
    Turk, Tom
    Frangez, Robert
    Svenson, Johan
    Natural cholinesterase inhibitors from marine organisms2019Ingår i: Natural product reports (Print), ISSN 0265-0568, E-ISSN 1460-4752, Vol. 36, nr 8, s. 1053-1092Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Inhibition of cholinesterases is a common approach for the management of several disease states. Most notably, cholinesterase inhibitors are used to alleviate the symptoms of neurological disorders like dementia and Alzheimer's disease and treat myasthenia gravis and glaucoma. Historically, most drugs of natural origin have been isolated from terrestrial sources and inhibitors of cholinesterases are no exception. However, the last 50 years have seen a rise in the quantity of marine natural products with close to 25 000 reported in the scientific literature. A number of marine natural products with potent cholinesterase inhibitory properties have also been reported; isolated from a variety of marine sources from algae to ascidians. Representing a diverse range of structural classes, these compounds provide inspirational leads that could aid the development of therapeutics. The current paper aims to, for the first time, comprehensively summarize the literature pertaining to cholinesterase inhibitors derived from marine sources, including the first papers published in 1974 up to 2018. The review does not report bioactive extracts, only isolated compounds, and a specific focus lies on compounds with reported doseresponse data. In vivo and mechanistic data is included for compounds where this is reported. In total 185 marine cholinesterase inhibitors and selected analogs have been identified and reported and some of the compounds display inhibitory activities comparable or superior to cholinesterase inhibitors in clinical use.

  • 185. Morgan, Ruth A.
    et al.
    Beck, Katharina R.
    Nixon, Mark
    Homer, Natalie Z. M.
    Crawford, Andrew A.
    Melchers, Diana
    Houtman, René
    Meijer, Onno C.
    Stomby, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Anderson, Anna J.
    Upreti, Rita
    Stimson, Roland H.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Michoel, Tom
    Cohain, Ariella
    Ruusalepp, Arno
    Schadt, Eric E.
    Björkegren, Johan L. M.
    Andrew, Ruth
    Kenyon, Christopher J.
    Hadoke, Patrick W. F.
    Odermatt, Alex
    Keen, John A.
    Walker, Brian R.
    Carbonyl reductase 1 catalyzes 20 beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 10633Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH-dependent production of 20 beta-dihydrocortisol (20 beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20 beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.

  • 186. Mudway, Ian S
    et al.
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Frew, Anthony J
    Kelly, Frank J
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Vitamin supplementation does not protect against symptoms in ozone-responsive subjects2006Ingår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 40, nr 10, s. 1702-1712Artikel i tidskrift (Refereegranskat)
  • 187. Naslund, Johanna
    et al.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Asker, Noomi
    Ekman, Elisabet
    Larsson, D. G. Joakim
    Norrgren, Leif
    Diclofenac affects kidney histology in the three-spined stickleback (Gasterosteus aculeatus) at low mu g/L concentrations2017Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 189, s. 87-96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diclofenac, a commonly used non-steroidal anti-inflammatory drug, is considered for regulation under the European water framework directive. This is because effects on fish have been reported at concentrations around those regularly found in treated sewage effluents (similar to 1 mu g/L). However, a recent publication reports no effects on fish at 320 mu g/L. In this study, three-spined sticklebacks (Gasterosteus aculeatus) were exposed to 0, 4.6, 22, 82 and 271 mu g/L diclofenac in flow-through systems for 28 days using triplicate aquaria per concentration. At the highest concentration, significant mortalities were observed already after 21 days (no mortalities found up to 22 mu g/L). Histological analysis revealed a significant increase in the proportion of renal hematopoietic tissue (renal hematopoietic hyperplasia) after 28 days at the lowest concentration and at all higher concentrations, following a clear dose-response pattern. Skin ulcerations of the jaw were noted by macroscopic observations, primarily at the two highest concentrations. No histological changes were observed in the liver. There was an increase in the relative hepatic mRNA levels of c7 (complement component 7), a gene involved in the innate immune system, at 22 mu g/L and at all higher concentrations, again following a clear dose-response. The bio-concentration factor was stable across concentrations, but lower than reported for rainbow trout, suggesting lower internal exposure to the drug in the stickleback. In conclusion, this study demonstrates that diclofenac causes histological changes in the three-spined stickleback at low mu g/L concentrations, which cause concern for fish populations exposed to treated sewage effluents.

  • 188. Neser, S
    et al.
    Lohr, C
    van Ede, KI
    Andresen, K
    van Duursen, MBM
    van den Berg, M
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schrenk, D
    Gene regulating effects in mouse liver subsequent to treatment with selected dioxin-like compounds and PCB 153 using whole genome microarray analysis2012Ingår i: Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikogie e.V.: Abstract of the 78th Annual Meeting March 19-22, 2012, Dresden, Germany, Springer, 2012, Vol. 385, nr Suppl 1, s. 62-63Konferensbidrag (Övrigt vetenskapligt)
  • 189.
    Niklasson, Bertil
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Mammalian brain acetylcholinesterase: a study of its solubilization, purification, molecular state and interactions with cholinergic ligands including an endogenous modulator1981Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Membrane bound AChE from calf brain caudate nucleus was solubilized by use of ion-free media in presence of 10~ M EDTA and 10“5M tetracaine. The irreversible release of AChE was more effectively inhibited by divalent ions compared to monovalent ions added to the medium. EDTA appears to chelate divalent ions released from the tissue while tetracaine competes with the same ions at the membrane. The tetracaine effect is restricted to the procaine series of local anesthetics. Small amounts of soluble AChE are present in the cytosol fraction.

    In fresh preparations most of the enzyme appeared in a form having a molecular weight of 80.000 daltons as determined by gel filtration. The enzyme seems to be released in this form. It is proposed that this form represents the monomer form of the enzyme. In solution the AChE aggregates seemingly together with a factor that is released from the membrane in amounts stafchio- metric to the enzyme. By treatment with DEAE-Sephadex the enzyme preparation can be made non-aggregating. A highly purified nonaggregating monomeric AChE Specific activity 17150 micromoles acetylthiocholine hydrolyzed per minute at 27° C per mg protein) was obtained by affinity chromatography.

    Some anomalous binding phenomena was observed during the affinity chromatographic purification. The main observation was that edrophonium eluted crude enzyme preparation adsorbed to the affinity gel in a biphasic manner. It was found that in the crude preparation there is present besides unspecific material competing with the enzyme for the affinity gels a factor that increases the affinity of AChE to certain cholinergic ligands. Since the enzyme could be titrated by the factor it seems to have a very high affinity to the enzyme and the biphasic elution curve is explained by the presence of free as well as factor- bound enzyme in the preparation. In search for compounds having a similar effect it was found that fluoride ion too increased the affinity of AChE to the same ligands as the factor.

    The affinity of edrophonium to the site defined by the binding of AChE to MTA-CH (65x10“5m) is lower than that defined by the enzyme inhibitory constant (1.8xlO“7M). As an explanation of this finding it is proposed that the substrate induces a conformation having high affinity to edrophonium, a conformation that has a comparatively low relaxation rate. Thus acetylcholinesterase may be added to the list of enzymes that have hystere- tic properties.

  • 190.
    Nilsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Cannabinoids as neuroprotective agents: a mechanistic study2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Glucose and oxygen supply to the brain is critical for its proper function and when it is restricted as during a stroke, neurons and glial cells quickly become necrotic leading to structural damage as well as functional impairment and even death. To date there are few effective therapies that inhibit the neurodegenerative process and improves the outcome for the affected individual. One possible target is the cannabinoid system. Cannabinoid receptor agonists reduce ischemic volume, endogenous cannabinoid levels are elevated during neurodegenerative insults and mice devoid of the central cannabinoid receptor are more seriously affected by experimental stroke than wild type mice. The cannabinoids are also ascribed anti-inflammatory properties and post ischemic inflammation has been proposed to contribute to the evolution of the ischemic damage. In this thesis mechanisms that can contribute to cannabinoid neuroprotection have been studied. In papers I and II the chick was used as a model species, since preparation of embryonic primary neuronal cultures from chick is relatively simple and time efficient compared to rodent primary cultures. Both adult and embryonic chick brain membranes contain functional CB1 receptors and in the cultures they are coupled to inhibition of cAMP production. In embryonic primary cultures, neurons were not protected from glutamate toxicity by preincubation with CB receptor agonists suggesting that postsynaptic cannabinoid mediated neuroprotection is not effective in this system. The effect of cannabinoid agonists on neutrophil chemotaxis and transmigration was investigated in paper III. The CB1/CB2 agonist WIN 55,212-2 inhibited TNF-α-induced transmigration across ECV304 cell monolayers. The effect of WIN 55,212-2 on this process which was mediated by a reduction of IL-8 release from the ECV304 cells rather than a direct effect upon the migratory response to IL-8 was not possible to abolish with CB1 or CB2 agonists suggesting a mechanism distinct from the cannabinoid receptors is operative. In paper IV the photothrombotic ring stroke model was evaluated to determine if it is suitable in intervention studies targeting the cannabinoid system. Three major endpoints were of interest, ischemic volume, neutrophil infiltration and CB1 receptor function. Consistent with previous studies the ischemic volume peaked at 48 hours after irradiation. Neutrophil infiltration was quantified using a myeloperoxidase activity assay. The assay revealed an increase in myeloperoxidase activity 48 hours after irradiation, albeit at a modest level. The function of the CB1 receptor was assessed by radioligand binding and there was no change in either total binding or functional G-protein coupling following photothrombosis. Taken together these results indicate that it is feasible to undertake cannabinoid intervention studies in this model.

  • 191.
    Nilsson, Olov
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Hellqvist, Hedvig
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Investigation of brain endothelial cell lines as models of the blood-brain barrier2012Ingår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 253, nr 1-2, s. 39-39Artikel i tidskrift (Övrigt vetenskapligt)
  • 192. Niziolek-Kierecka, Magdalena
    et al.
    Dreij, Kristian
    Lundstedt, Staffan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stenius, Ulla
    γH2AX, pChk1, and Wip1 as Potential Markers of Persistent DNA Damage Derived from Dibenzo[a,l]pyrene and PAH-Containing Extracts from Contaminated Soils2012Ingår i: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 25, nr 4, s. 862-872Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polycyclic aromatic hydrocarbons (PAHs) are formed during incomplete combustion of organic material and are ubiquitous environmental contaminants. High levels of PAHs are commonly found in soils at industrial sites, thereby constituting a risk for humans and the environment. However, this risk is often difficult to estimate due to the complexity of the contamination. In the present study we investigated the cellular DNA damage response induced by extracts of PAH-contaminated soils collected at various industrial sites in Sweden. The results show that interactions of PAHs in the soil extracts caused activation of DNA damage signaling consistent with persistent DNA damage. Signaling in HepG2 cells exposed to soil PAH extracts corresponding to 1 µM benzo[a]pyrene was similar to that of 0.1 µM dibenzo[a,l]pyrene, a highly carcinogenic PAH known to produce persistent DNA damage. The response involved prolonged activation of DNA damage marker (H2AX), check point kinase (Chk1), and phosphatases (Wip1). Furthermore, blocking DNA damage signaling using specific inhibitors and siRNA showed the important role of signaling through Chk1 for the level of DNA damage. We conclude that the combination of prolonged Chk1 phosphorylation and induced expression of Wip1 might serve as potential markers for persistent DNA damage induced by complex mixtures of environmental PAHs. Discrepancies between mRNA and protein levels of Wip1 in response to soil extracts, in parallel with increased microRNA (miR)-16 levels, suggest a role of miR-16 in the regulation of DNA damage signaling in response to PAHs. Taken together, our data indicate that PAH extracts induce irreparable DNA-damage and that this is consistent with the prolonged activation of DNA-damage signaling.

  • 193.
    Norberg, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Biomedicinsk laboratorievetenskap.
    Utveckling av LC-MS metod för kvantitativ analys av metadon och dess huvudmetabolit EDDP i urin2014Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 194.
    Nordberg, Gunnar F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Fowler, Bruce A.
    Risk Assessment2007Ingår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. 281-301Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Risk assessment for metallic substances usually follows the generally accepted framework format for risk assessment for all toxic substances, which involves (1) exposure assessment, (2) hazard identification, (3) assessment of dose-response relationships, and (4) risk characterization. The importance of risk communication is also addressed. Risk assessment/risk communication is of particular relevance for metals and metalloids, because all living organisms are exposed to these elements, and metals such as lead, cadmium, and mercury and the metalloid arsenic have been responsible for many human poisonings and even deaths. It is, hence, imperative that readers of this handbook have a firm perspective on the exposure levels of metallic substances that produce adverse health effects and the various risk assessment approaches that have been used and are evolving to protect the health and well-being of living organisms. Biomonitoring approaches, identification of toxic metallic species for hazard identification, dose-effect relationships, construction of dose-response curves, and the development of benchmark doses for various metallic species are discussed in relation to protecting sensitive subpopulations, because not all individuals within a general population are at equal risk for toxicity. Risk characterization using modern biomarkers that are capable of detecting early cellular effects to low-dose exposures to metallic substances will play an increasingly important role in assessing risk from exposure to this class of toxic substances on an individual or mixture basis. The issue of metal/metalloid-induced carcinogenesis is of ever increasing importance, because many of the elements associated with this cellular outcome produce a number of early cellular effects, including formation of reactive oxygen species (ROS) and apoptosis. Finally, the issue of risk communication/risk management is of great importance, because these issues are critical to addressing the health concerns of exposed populations and the practical, ethical, and financial issues related to reducing hazardous exposures to metallic substances.

  • 195.
    Nordberg, Gunnar F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Fowler, Bruce ANordberg, Monica
    Handbook on the toxicology of metals2015Samlingsverk (redaktörskap) (Refereegranskat)
  • 196.
    Nordberg, Gunnar F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Fowler, Bruce A.
    Nordberg, Monica
    Preface2007Ingår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. V-VKapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 197.
    Nordberg, Gunnar F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Fowler, Bruce ANordberg, MonicaFriberg, Lars T
    Handbook on the toxicology of metals2007Samlingsverk (redaktörskap) (Övrigt vetenskapligt)
    Abstract [en]

    Handbook of the Toxicology of Metals is the standard reference work for physicians, toxicologists and engineers in the field of environmental and occupational health. This new edition is a comprehensive review of the effects on biological systems from metallic elements and their compounds. An entirely new structure and illustrations represent the vast array of advancements made since the last edition. Special emphasis has been placed on the toxic effects in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-to-date reference provides easy access to a broad range of basic toxicological data and also gives a general introduction to the toxicology of metallic compounds.

  • 198.
    Nordberg, Gunnar F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Fowler, Bruce A.
    Nordberg, Monica
    Friberg, Lars T.
    Introduction-General Considerations and International Perspectives2007Ingår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. 1-9Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    This introductory chapter is composed of two parts. The first section is a brief history of the science of the toxicology of metals by the late Dr. Lars Friberg. He delineates the early realization of the need for international cooperation and consensus that have guided seminal studies related to environmental and occupational toxicology. In this spirit, he initiated work on the first edition of the Handbook of Toxicology of Metals that included contributors from around the world. The second section takes up some current concerns related to the toxicology of metals. It highlights such concerns in relation to the current status of the scientific understanding to date of the metals included and discussed fully in the chapters of the Handbook. Furthermore, it draws attention to future directions in generating new knowledge to fill gaps in the continued quest to assemble the knowledge base necessary for the protection of human health from adverse consequences related to exposure to metals.

  • 199.
    Nordberg, Gunnar F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Gerhardsson, Lars
    Broberg, Karin
    Mumtaz, Moiz
    Ruiz, Patricia
    Fowler, Bruce A.
    Interactions in Metal Toxicology2007Ingår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. 117-145Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Human exposures to metals and metalloids such as arsenic frequently occur as mixtures, and hence it is important to consider interactions among these elements in terms of both mechanisms of action and for risk assessment purposes. Interactions among these elements may produce additive, synergistic/potentiative, or antagonistic effects that may be manifested as direct cellular toxicity (necrosis or apoptosis) or carcinogenicity. Dose-response relationships may further be influenced by constitutive factors such as age, sex, and the expression of specific proteins. The roles of molecular factors regulated by specific genes (so called gene-environment interactions) for the expression of metal toxicity are known only to a limited extent for most metals. However, for chronic beryllium disease causing fibrosis of the lung, it has been shown that beryllium sensitization, a prerequisite for developing the disease, depends on an antigen-specific immune response occurring predominantly among persons with a specific HLA-DBP1 genotype. Some gene-environment interactions in terms of genetic polymorphisms have been demonstrated such as those involving ALAD and arsenic methyl transferases, but the importance of these observations for development of human diseases has not been fully explored. Mechanisms of importance for interactions and the development of toxicity are the expression of metal-binding proteins (metallothioneins or lead-binding proteins). In many cases, direct primary data on interactions among toxic or essential elements are lacking, and so innovative derivative methods such as the binary weight of evidence (BINWOE) method have been used to predict potential interactions among groups of metals and metalloids. At present, there is much to be learned about interactions among both toxic and essential elements, but this is clearly a critical area of research.

  • 200.
    Nordberg, Gunnar F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Nogawa, Koji
    Friberg, Lars T.
    Nordberg, Monica
    Cadmium2007Ingår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. 445-486Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Cadmium (Cd) is chemically similar to zinc; it occurs naturally with zinc and lead in sulfide ores. Elevated concentrations in air, water, and soil may occur close to industrial emission sources, particularly those of nonferrous mining and metal refining industries. Cadmium metal has been used as an anticorrosive, electroplated onto steel, and Cd compounds are used as pigments, often in plastics. Cadmium and its compounds are also used in electric batteries, electronic components, and nuclear reactors. Because some of the applications of Cd can be performed by other less-toxic materials, the use of Cd has, therefore, been restricted by law in some countries. The absorption of Cd compounds through the skin is negligible. Between 10 and 50% of inhaled Cd will be absorbed, with the degree of absorption being greater for smaller particles and fumes than for larger dust particles. Humans absorb 5-10% of ingested Cd. A low intake of calcium, zinc, or iron increases the degree of absorption; for example, in iron-deficient individuals, the gastrointestinal absorption rate may be as high as 20%. Cadmium is transported in plasma when bound to metallothionein-a low-molecular-weight protein and/or to certain high-molecular-weight proteins. The accumulation of Cd occurs in many tissues, with particularly long half-lives (10-30 years) having been reported for Cd in muscle, kidney, and liver tissue. Cadmium stimulates metallothionein production in the same manner as other bivalent metals, such as zinc, copper, and mercury. Metallothionein-bound Cd in plasma is filtered through the renal glomeruli and reabsorbed in the tubuli, where the metal ion is released after lysosomal degradation of the protein. The unbound Cd stimulates the production of new metallothionein, which binds the Cd in the renal tubular cells. When not all of this new Cd is bound, toxic effects occur, possibly because of the interference of Cd with zinc-dependent enzymes and/or membrane function. The average amount of Cd ingested in most European and North American countries is approximately 1020 mu g/day. The corresponding average urinary excretion is approximately 0.5-1.0 mu g/day. Most of the Cd in blood is located in the cells. The average blood concentration is approximately 0.5-1.0 mu g/L in nonsmokers; it is twice as high in smokers because of Cd absorption from cigarette smoke. Concentrations of 10-20 mu g/kg are usually found in the kidney cortex of nonsmokers in European countries. Although the intake of Cd through food has been higher in Japan than in Europe, and the reported tissue levels are correspondingly higher, the food intake of Cd has decreased in Japan during the last few decades. Ingestion of highly contaminated food or drink results in acute gastrointestinal effects with concomitant diarrhea and vomiting. Acute inhalation of Cd in air-for example, from soldering or welding fumes-may lead to severe chemical pneumonitis. Long-term exposure to low air levels may lead to chronic obstructive lung disease and possibly lung cancer. Long-term excessive exposure from the air or food leads to renal tubular dysfunction. The first sign of damage is a low-molecular-weight proteinuria. This condition is the critical effect of such exposure to Cd and is used in quantitative risk assessment. Long-term exposure from food, often combined with other means of delivery, may also lead to disturbance of calcium metabolism, osteoporosis, and osteomalacia, mainly among postmenopausal women. A disease exhibiting these features-called Itai-Itai disease-occurred in the 1950s in Cd-polluted areas of Japan; 124 cases were diagnosed up to 1970, and decreasing numbers of clinical cases have been diagnosed later, with 66 cases during the period between 1970 and 2006. In animals exposed to Cd through injection, inhalation, or oral exposure, cancer may develop at the injection site, in the lungs and prostate, or in other organs. Although some epidemiological studies have found an increase in the rates of cancer of the lungs and prostate, other studies have not demonstrated such effects. Cadmium is classified as a human carcinogen (Group 1) by the International Agency for Research on Cancer. Exposure to Cd in the air at concentrations of 5-10 mu g/m(3) during a working life of 45 years may give rise to renal tubular dysfunction in a small proportion of exposed workers. At approximately 100 mu g/m(3), signs of chronic obstructive lung disease may develop even after exposure for a shorter duration. After a lifetime of exposure from food at an average intake of approximately 200 mu g/day, renal effects have been observed at age 50. There is considerable individual variation in the sensitivity of these renal effects. It has been suggested that such effects can be avoided if renal cortex levels are kept <50 mu g/kg and urine levels <2.5 mu g/g CR. Recent reports of low, but statistically significant, increases at even lower levels of urinary Cd are, however, noteworthy. Such increases are observed in the general population, particularly among people with diabetes. There is no specific treatment for Cd poisoning. When there are signs of osteomalacia, large doses of vitamin D should be given. Because of the long half-life of Cd in the kidneys, which are the critical organs and the irreversibility of the critical effect, primary prevention is essential. Prevention can be assisted through environmental and biological monitoring. The extensive literature on the toxicological and environmental aspects of Cd has been reviewed in detail by Friberg et al. (1974, 1985, 1986a), Tsuchiya (1978), Nriagu (1980, 1981), the WHO/IPCS (1992), the IARC (1993), Jarup et al. (1998c), the ATSDR (1999), Nordberg and Nordberg (2002), the EU (2003), Satarug and Moore (2004), and the WHO/FAO (2003, 2005).

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