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- Ittermann, T., et al.
(författare)
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Standardized Map of Iodine Status in Europe
- 2020
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 30:9
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Tidskriftsartikel (refereegranskat)abstract
- Background:Knowledge about the population's iodine status is important, because it allows adjustment of iodine supply and prevention of iodine deficiency. The validity and comparability of iodine-related population studies can be improved by standardization, which was one of the goals of the EUthyroid project. The aim of this study was to establish the first standardized map of iodine status in Europe by using standardized urinary iodine concentration (UIC) data. Materials and Methods:We established a gold-standard laboratory in Helsinki measuring UIC by inductively coupled plasma mass spectrometry. A total of 40 studies from 23 European countries provided 75 urine samples covering the whole range of concentrations. Conversion formulas for UIC derived from the gold-standard values were established by linear regression models and were used to postharmonize the studies by standardizing the UIC data of the individual studies. Results:In comparison with the EUthyroid gold-standard, mean UIC measurements were higher in 11 laboratories and lower in 10 laboratories. The mean differences ranged from -36.6% to 49.5%. Of the 40 postharmonized studies providing data for the standardization, 16 were conducted in schoolchildren, 13 in adults, and 11 in pregnant women. Median standardized UIC was <100 mu g/L in 1 out of 16 (6.3%) studies in schoolchildren, while in adults 7 out of 13 (53.8%) studies had a median standardized UIC <100 mu g/L. Seven out of 11 (63.6%) studies in pregnant women revealed a median UIC Conclusions:We demonstrate that iodine deficiency is still present in Europe, using standardized data from a large number of studies. Adults and pregnant women, particularly, are at risk for iodine deficiency, which calls for action. For instance, a more uniform European legislation on iodine fortification is warranted to ensure that noniodized salt is replaced by iodized salt more often. In addition, further efforts should be put on harmonizing iodine-related studies and iodine measurements to improve the validity and comparability of results.
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- Pridgeon, CS, et al.
(författare)
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Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.
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- Jukic, MM, et al.
(författare)
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Functional characterization of CYP2D7 gene variants
- 2018
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 19:12, s. 931-936
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Tidskriftsartikel (refereegranskat)abstract
- The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.
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- Milosavljević, Filip, et al.
(författare)
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The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
- 2023
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 49:1
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Tidskriftsartikel (refereegranskat)abstract
- Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
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- Rogoza, Radoslaw, et al.
(författare)
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Structure of Dark Triad Dirty Dozen Across Eight World Regions
- 2021
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Ingår i: Assessment (Odessa, Fla.). - : SAGE Publications. - 1073-1911 .- 1552-3489. ; 28:4, s. 1125-1135
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Tidskriftsartikel (refereegranskat)abstract
- The Dark Triad (i.e., narcissism, psychopathy, Machiavellianism) has garnered intense attention over the past 15 years. We examined the structure of these traits' measure-the Dark Triad Dirty Dozen (DTDD)-in a sample of 11,488 participants from three W.E.I.R.D. (i.e., North America, Oceania, Western Europe) and five non-W.E.I.R.D. (i.e., Asia, Middle East, non-Western Europe, South America, sub-Saharan Africa) world regions. The results confirmed the measurement invariance of the DTDD across participants' sex in all world regions, with men scoring higher than women on all traits (except for psychopathy in Asia, where the difference was not significant). We found evidence for metric (and partial scalar) measurement invariance within and between W.E.I.R.D. and non-W.E.I.R.D. world regions. The results generally support the structure of the DTDD.
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- Tedesco-Silva, Helio, et al.
(författare)
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Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants : An Analysis From the Randomized TRANSFORM Study
- 2019
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 103:9, s. 1953-1963
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail.METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids.RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA.CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.
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