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- Ahlin, Gustav, et al.
(author)
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Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
- 2008
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:19, s. 5932-5942
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Journal article (peer-reviewed)abstract
- The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
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- Ahlstrand, Elisabeth, et al.
(author)
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Erfarna lärares engagemang : livsberättelser som retrospektiv reflektion
- 2008. - 1
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In: Läraren i blickpunkten<em> </em>. - Stockholm : Lärarförbundets Förlag. - 9789197659895 - 9197659894 ; , s. 189-205
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Book chapter (other academic/artistic)abstract
- Lärares arbete är komplext och kan beskrivas på olika sätt beroende på vilken utgångspunkt man väljer. I takt med att det ställs allt högre krav på lärare att utgå från en vetenskaplig bas i arbetet, behövs också fler redskap och begrepp för att förstå och förklara läraryrket. Hur ser arbetsprocesserna ut? Vad formar yrket? Vilka insatser kan göras för att förbättra verksamheten? Den här antologin presenterar femton sätt att se på lärares liv och arbete med hjälp av olika teoretiska perspektiv.Boken vänder sig till lärare och blivande lärare samt till alla som är intresserade av kunskapsutvecklingen kring lärares arbete.
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- Alling, Christer, et al.
(author)
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Anionic glycerophospholipids in platelets from alcoholics
- 1986
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In: Drug and Alcohol Dependence. - : Elsevier BV. - 1879-0046 .- 0376-8716. ; 16:4, s. 309-320
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Journal article (peer-reviewed)abstract
- Studies on ethanol-exposed animals have revealed changes in anionic phospholipids in brain membranes. The intention of this study was to investigate whether there was a similar effect on man. Assuming platelets to be an adequate model for CNS synaptosomes, concentration and fatty acid composition of anionic phospholipids, phosphatidylserine (PS) and phosphatidylositol (PI) in the platelet membrane from alcoholics after a debauche period were examined and compared to controls. Ethanol effects on neutral lipids were also analysed in order to obtain a comprehensive view. No quantitative difference was found in anionic phospholipids between alcoholics and controls. Fatty acid composition of individual phospholipids revealed significant changes which were more obvious in neutral phospholipids than in anionic. Oleic acid was increased and linoleic and arachidonic acids were decreased. After 1 week of detoxification, the abnormalities did not decrease, on the contrary they increased and total phospholipid concentration per platelet was significantly higher than in controls. It is concluded that the ethanol toxicity on bone marrow hampers the use of platelets as a model for synaptosomes but that the observed lipid abnormalities might play a major role in the impairment of platelet function in alcoholics.
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- Andersson, Lena, 1965-
(author)
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Quartz in Swedish iron foundries : exposure and cancer risk
- 2012
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Doctoral thesis (other academic/artistic)abstract
- The aims of the studies underlying this thesis were to assess the exposure to quartz in Swedish iron foundries and to determine the cancer morbidity for Swedish foundry workers. A cohort of 3,045 foundry workers and a final measurement database of 2,333 number of samples was established.The exposure measurements showed high levels of respirable quartz, in particular for fettlers and furnace and ladle repair workers with individual 8 hr TWA (GM=0.041 and 0.052 mg/m3; range 0.004-2.1 and 0.0098-0.83 mg/m3). In our database, the quartz concentrations as 8hr TWAs of current and historical data varied between 0.0018 and 4.9 mg/m3, averaging 0.083 mg/m3, with the highest exposures for fettlers (0.087 mg/m3) and furnace and ladle repair workers (0.42 mg/m3). The exposure for workers using respirators assuming full effect when used were assessed quantitatively, revealing workers with actual exposure exceeding the occupational exposure limits.Overall cancer morbidity was not increased, but the incidence of lung cancer was significantly elevated (SIR 1.61; 95 % CI 1.20-2.12). In the cohort study, significant associations between lung cancer and cumulative quartz exposure were detected for quartz doses of 1-2 mg/m3 * year (SIR 2.88; 95 % CI 1.44-5.16) and >2 mg/m3 * year (SIR 1.68; 95 % CI 1.07- 2.52). These findings were not confirmed in the case-control analysis.The agreement between the estimated exposure in our early historical model and the development model showed a regression coefficient of 2.42, implying an underestimation of the historical exposure when using the development model data. The corresponding comparison between the development and the validation model based on our survey data showed a B of 0.31, implying an overestimation of present exposures when using data from the validation model.The main conclusions of the thesis are that certain foundry workers are still exposed to high levels of quartz, and the overall excess lung cancer could not be confirmed in the exposure-response analysis.
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- Balk, Lennart, et al.
(author)
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Widespread episodic thiamine deficiency in Northern Hemisphere wildlife
- 2016
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Many wildlife populations are declining at rates higher than can be explained by known threats to biodiversity. Recently, thiamine (vitamin B-1) deficiency has emerged as a possible contributing cause. Here, thiamine status was systematically investigated in three animal classes: bivalves, ray-finned fishes, and birds. Thiamine diphosphate is required as a cofactor in at least five life-sustaining enzymes that are required for basic cellular metabolism. Analysis of different phosphorylated forms of thiamine, as well as of activities and amount of holoenzyme and apoenzyme forms of thiaminedependent enzymes, revealed episodically occurring thiamine deficiency in all three animal classes. These biochemical effects were also linked to secondary effects on growth, condition, liver size, blood chemistry and composition, histopathology, swimming behaviour and endurance, parasite infestation, and reproduction. It is unlikely that the thiamine deficiency is caused by impaired phosphorylation within the cells. Rather, the results point towards insufficient amounts of thiamine in the food. By investigating a large geographic area, by extending the focus from lethal to sublethal thiamine deficiency, and by linking biochemical alterations to secondary effects, we demonstrate that the problem of thiamine deficiency is considerably more widespread and severe than previously reported.
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| 9. |
- Berg, Tove, et al.
(author)
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Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects.
- 2014
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In: Pharmacology research & perspectives. - : Wiley. - 2052-1707. ; 2:4, s. e00054-
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Journal article (peer-reviewed)abstract
- This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters.
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- Björ, Ove, 1967-
(author)
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Strategies for assessing health risks from two occupational cohorts within the domain of northern Sweden
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Background: Studies based on a cohort design requires access to both subject-specific and period-specific information. In order to conduct an occupational cohort study, access to exposure information and the possibility and permission to link information on outcomes from other registers are generally necessary. The analysis phase is also aggravated by its added complexity because of the longitudinal dimension of the cohort’s data.This thesis aims at increasing the knowledge on hazards from work on fatalities and cancer within the domain of cohort studies on miners and metal refiners and to study the complexity of the analysis by discussing and suggesting analytical strategies.Methods: The study population for this thesis consisted of a cohort of 2264 blue-collar aluminium smelter workers (paper I) and a cohort of 13000 blue-collar iron-ore miners (papers II-IV), both followed for over 50 years. The outcomes were collected from the Swedish Cause of Death Register and the Swedish Cancer Register. The primary methods of analysis were either Standardized Morbidity Ratios (SMR) or internal comparisons based on Cox or Poisson regression modeling. In paper IV, a g-estimation based on an accelerated failure-time model was performed to estimate the survival ratio.Results: The results from paper I suggested that working as a blue-collar worker metal refiner was associated with increased rates of incidental lung cancer. Elevated rates among short term workers were observed for several outcomes. Paper I also showed that the choice of reference population when calculating SMR could influence the conclusions of the results. In paper II, several outcomes were elevated among the miners compared to the reference population from northern Sweden. However, no outcome except lung cancer was associated with cumulative employment time. The most recurrent pattern of the results was the negative association between cumulative employment time underground and several outcomes. The results from paper III showed that cumulative employment time working outdoors was associated with increased rates of cerebrovascular disease mortality. However, employment with heavy physical workloads did not explain the previously observed decreasing rates in the selected groups of outcomes. The adjustment for the healthy worker survivor effect by g-estimation in paper IV suggested that exposure from respirable dust was associated with elevated mortality risks that could not be observed with standard analytical methods.Conclusion: Our studies found several rates from the cohorts that were elevated compared to external refererence populations but also that long term employments generally were associated with decreasing rates. Furthermore, incidental lung cancer rates was found elevated for the metal refiners. Among the miners, mortality rates of cerebrovascular diseases depended on if work was performed outdoor (higher rates) or underground (lower rates). Methodologically, this thesis has discussed different analytical strategies for handling confounding in occupational cohort studies. Paper IV showed that the healthy worker survivor effect could be adjusted for by performing g-estimation.
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