| 1. |
- Asp, Vendela, et al.
(författare)
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CYTOTOXICITY AND DECREASED CORTICOSTERONE PRODUCTION IN ADRENOCORTICAL CELLS BY METHYLSULPHONATED DERIVATIVES OF p,p′-DDE
- 2007
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Konferensbidrag (refereegranskat)abstract
- 3-methylsulphonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo. The activated compound induces cell death in the adrenocortical zona fasciculata and decreases glucocorticoid production. We have in the present study reproduced both the cytotoxicity and the decreased hormone production in vitro using the mouse adrenocortical cell line Y-1. Cytotoxicity was inhibited by the CYP11-inhibitor etomidate, confirming that CYP11-dependent bioactivation takes place also in vitro. Moreover, 3-MeSO2-DDE decreased corticosterone production in a concentration-dependent manner both in cells that had been induced with forskolin and in non-induced cells. In addition, we have investigated the effects on cell viability and corticosterone production of three structurally related compounds. 2-MeSO2-DDE and 3,3′(bis)-MeSO2-DDE induced cytotoxicity, although to a lower degree than 3-MeSO2-DDE. In contrast, the parent compound p,p′-DDE was not cytotoxic, indicating that the methylsulphonyl moieties are required for biological activity. This study shows that by using the basic structures of 3-MeSO2-DDE in drug design we can easily screen for biologically active compounds in the development of new adrenocorticolytic drugs for adrenocortical cancer and Cushing’s syndrome. We consider the Y-1 and other adrenocortical cell lines to be useful tools in overcoming the gap between animal studies and estimation of potential therapeutic effects and/or risks in humans.
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| 2. |
- Asp, Vendela, et al.
(författare)
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Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
- 2009
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 83:4, s. 389-396
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Tidskriftsartikel (refereegranskat)abstract
- The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO2-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO2-DDE and, to a lesser extent, 3,3'(bis)-MeSO2-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO2-DDE nor p,p'-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO2-DDE is crucial for its biological activity. The adrenocortical toxicant o,p'-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO2-DDE inhibits CYP11B1 activity on the protein level.
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| 3. |
- Björk, Jonas, et al.
(författare)
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Prediction of relative glomerular filtration rate in adults: New improved equations based on Swedish Caucasians and standardized plasma-creatinine assays.
- 2007
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 67:7, s. 678-695
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate newly developed equations predicting relative glomerular filtration rate(GFR) in adult Swedish Caucasians and to compare with the Modification of Diet in Renal Disease(MDRD) and Mayo Clinic equations using enzymatic and zero-calibrated plasma creatinine assays. MATERIAL AND METHODS: GFR was measured with iohexol clearance adjusted to 1.73 m(2). One population sample (n=436/Lund) was used to derive an equation based on plasma-creatinine/age/gender, and a second with the addition of lean body mass (LBM). Both equations were validated in a separate sample (n=414/Malmö). The coefficients of the equations were eventually fine-tuned using all 850 patients and yielding Lund-Malmö equations without (LM) and with LBM-term (LM(LBM)).Their performance was compared with the MDRD(CC) (conventional creatinine calibration), MDRD(IDMS) (isotope dilution mass spectroscopy traceable calibration) and Mayo Clinic equations. RESULTS: The Lund equations performed similarly in both samples. In the combined set, the Mayo Clinic/MDRD(CC) resulted in +19.0/+10.2 % median bias, while bias for the other equations was < 10 %. LM(LBM) had the highest accuracy (86 % of estimates within 30 % of measured GFR), significantly (p < 0.001) better than for MDRD(IDMS) (80 %). In men with BMI < 20 kg/m(2), MDRD(IDMS)/LM had +46 %/+19 % median bias. MDRD(IDMS) also overestimated GFR by 22 %/14 % in men/women above 80 years of age. The LM(LBM) equation had < 10 % bias irrespective of BMI, age or GFR except for a 15 % negative bias at GFR > 90 mL/min/1.73 m(2). CONCLUSION: The newly developed Lund-Malmö equations for GFR estimation performed better than the MDRD(IDMS) and Mayo Clinic equations in a Swedish Caucasian sample. Inclusion of an LBM term improved performance markedly in certain subgroups.
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| 4. |
- Blirup, Soren, et al.
(författare)
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Standardization of Cystatin C: development of primary and secondary reference preparations.
- 2008
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 68:s241, s. 67-70
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Tidskriftsartikel (refereegranskat)abstract
- A Primary Reference Preparation has been produced using pure, recombinant, Cystatin C in a solvent of 0.1 mol/L KCl. Dry mass determination of the Primary Reference Preparation resulted in a Cystatin C concentration of 5.20 g/L. Agarose-electrophoresis and SDS-electrophoresis, as well as N-terminal sequencing, verified the purity, homogeneity and identity of Cystatin C in the Primary Reference Preparation. For the Secondary Reference Preparation, a serum pool was collected and stabilized. A pilot batch was made to verify the selected procedure and spiking with the pure, recombinant Cystatin C. The final Secondary Reference Preparation is now produced (4468 vials) and ready for value assignment and further characterization.
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| 5. |
- Brage, M, et al.
(författare)
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Different cysteine proteinases involved in bone resorption and osteoclast formation.
- 2005
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:6, s. 439-47
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Tidskriftsartikel (refereegranskat)abstract
- Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.
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| 6. |
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| 7. |
- Frohm, Jörgen, 1972, et al.
(författare)
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Levels of automation in manufacturing
- 2008
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Ingår i: Ergonomia - an International journal of ergonomics and human factors. - 0137-4990. ; 30:3, s. 29-
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this paper is to increase the general understanding of task allocation in semi-automated systems and to provide a systematic approach for changing the level of automation. The paper presents a literature review of definitions and taxonomies for levels of automation (LoA) across multiple scientific and industrial domains. A synthesizing concept is suggested, including a LoA definition and taxonomy aimed for application in the manufacturing domain. Results suggest that the level of automation should be divided into two separate variables, i.e. physical/mechanical LoA and cognitive/information-related LoA. Further, the idea is that LoA in a manufacturing context can be described and assessed using seven-step reference scales for both physical and cognitive LoA.
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| 8. |
- Frohm, Jörgen, et al.
(författare)
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The Industry's View on Automation in Manufacturing
- 2006
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Ingår i: Poster at the 9th IFAC Symposium on Automated Systems Based on Human Skill and Knowledge.
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Konferensbidrag (populärvet., debatt m.m.)abstract
- Many manufacturing companies in Europe are presently focusing on automation as a weapon for competition on a global market. This paper focuses on industry’s view of automation. The paper presents data on advantages and disadvantages of automation, based on one pilot study and one Delphi study in two rounds.
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| 9. |
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| 10. |
- Grubb, Anders, et al.
(författare)
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Simple Cystatin C-Based Prediction Equations for Glomerular Filtration Rate Compared with the Modification of Diet in Renal Disease Prediction Equation for Adults and the Schwartz and the Counahan-Barratt Prediction Equations for Children.
- 2005
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 51:8, s. 1420-1431
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Serum creatinine is the most commonly used marker for estimation of glomerular filtration rate (GFR). To compensate for its drawbacks as a GFR marker, several prediction equations including several parameters are being used, with the Modification of Diet in Renal Disease (MDRD), Schwartz, and Counahan-Barratt equations being the ones most widely accepted for estimation of relative GFR in mL x min(-1) x (1.73 m(2))(-1). The present study analyzes whether these GFR prediction equations for adults and children might be replaced by simple prediction equations based on plasma concentrations of cystatin C.METHODS: Data from 536 patients (0.3-93 years), consecutively referred for determination of GFR by an invasive gold standard procedure, were used for the analysis. Calculations of bias (median percentage of error), correlation (adjusted R(2)), and percentage of estimates within 30% and 50% of measured GFR were used in the comparisons.RESULTS: A cystatin C-based prediction equation using only concentration in mg/L and a prepubertal factor: GFR [mL x min(-1) x (1.73 m(2))(-1)] = 84.69 x cystatin C (mg/L)(-1.680) x 1.384 (if a child <14 years) assessed GFR equally well or better than the simplified MDRD, the Schwartz, and the Counahan-Barratt prediction equations for the adult (> or =18 years) and juvenile groups of the investigated cohort. Age did not influence the cystatin C-based prediction equation for adults, whereas gender did, but with a factor close to unity (0.948 for females).CONCLUSION: A GFR prediction equation based solely on cystatin C (in mg/L) and a prepubertal factor might replace the simplified MDRD prediction equation for adults and the Schwartz and Counahan-Barratt prediction equations for children.
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