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1.	Hess, Timo, et al. (författare) Dissecting the genetic heterogeneity of gastric cancer 2023 Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92 Tidskriftsartikel (refereegranskat)abstract Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
2.	Brown, Richard J. P., et al. (författare) Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice 2020 Ingår i: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 6:45 Tidskriftsartikel (refereegranskat)abstract Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous Cd302 expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.
3.	Falk, Martin, et al. (författare) Parallelized Agent-based Simulation on CPU and Graphics Hardware for Spatial and Stochastic Models in Biology 2011 Ingår i: Proceedings of the 9th International Conference on Computational Methods in Systems Biology, CMSB'112011. - New York, NY, USA : ACM Press. - 9781450308175 ; , s. 73-82 Konferensbidrag (refereegranskat)abstract The complexity of biological systems is enormous, even when considering a single cell where a multitude of highly parallel and intertwined processes take place on the molecular level. This paper focuses on the parallel simulation of signal transduction processes within a cell carried out solely on the graphics processing unit (GPU). Each signaling molecule is represented by an agent performing a discretetime continuous-space random walk to model its diffusion through the cell. Since the interactions and reactions between the agents can be competitive and are interdependent, we propose spatial partitioning for the reaction detection to overcome the data dependencies in the parallel execution of reactions. In addition, we present a simple way to simulate the Michaelis-Menten kinetics in our particle-based method using a per-particle delay. We apply this agent-based simulation to model signal transduction in the MAPK (Mitogen-Activated Protein Kinase) cascade both with and without cytoskeletal filaments. Finally, we compare the speed-up of our GPU simulation with a parallelized CPU version resulting in a twelvefold speedup.
4.	Kositzki, Ramona, et al. (författare) Electronic and molecular structure relations in diiron compounds mimicking the [FeFe]-hydrogenase active site studied by X-ray spectroscopy and quantum chemistry 2017 Ingår i: Dalton Transactions. - : ROYAL SOC CHEMISTRY. - 1477-9226 .- 1477-9234. ; 46:37, s. 12544-12557 Tidskriftsartikel (refereegranskat)abstract Synthetic diiron compounds of the general formula Fe-2(mu-S2R)(CO)(n)(L)(6-n) (R = alkyl or aromatic groups; L = CN- or phosphines) are versatile models for the active-site cofactor of hydrogen turnover in [FeFe]-hydrogenases. A series of 18 diiron compounds, containing mostly a dithiolate bridge and terminal ligands of increasing complexity, was characterized by X-ray absorption and emission spectroscopy in combination with density functional theory. Fe K-edge absorption and K beta main-line emission spectra revealed the varying geometry and the low-spin state of the Fe(I) centers. Good agreement between experimental and calculated core-to-valence-excitation absorption and radiative valence-to-core-decay emission spectra revealed correlations between spectroscopic and structural features and provided access to the electronic configuration. Four main effects on the diiron core were identified, which were preferentially related to variation either of the dithiolate or of the terminal ligands. Alteration of the dithiolate bridge affected mainly the Fe-Fe bond strength, while more potent donor substitution and ligand field asymmetrization changed the metal charge and valence level localization. In contrast, cyanide ligation altered all relevant properties and, in particular, the frontier molecular orbital energies of the diiron core. Mutual benchmarking of experimental and theoretical parameters provides guidelines to verify the electronic properties of related diiron compounds.
5.	Proceedings of the 10th International Symposium on Superalloy 718 and Derivatives 2023 Samlingsverk (redaktörskap) (refereegranskat)
6.	Ajob, Leith, et al. (författare) ABC om Wernickes encefalopati : [Wernicke encephalopathy] 2017 Ingår i: Läkartidningen. - : Läkartidningen förlag AB. - 0023-7205 .- 1652-7518. ; 114 Tidskriftsartikel (refereegranskat)
7.	Ayob, Leith, et al. (författare) ABC om Wernickes encefalopati 2022 Ingår i: Psykoser och andra psykosliknande tillstånd. - Stockholm : Läkartidningen Förlag AB. - 9789198509830 ; , s. 86-93 Bokkapitel (övrigt vetenskapligt/konstnärligt)
8.	Baqué, Mickael, et al. (författare) Biosignature stability in space enables their use for life detection on Mars 2022 Ingår i: Science Advances. - : NLM (Medline). - 2375-2548. ; 8:36 Tidskriftsartikel (refereegranskat)abstract Two rover missions to Mars aim to detect biomolecules as a sign of extinct or extant life with, among other instruments, Raman spectrometers. However, there are many unknowns about the stability of Raman-detectable biomolecules in the martian environment, clouding the interpretation of the results. To quantify Raman-detectable biomolecule stability, we exposed seven biomolecules for 469 days to a simulated martian environment outside the International Space Station. Ultraviolet radiation (UVR) strongly changed the Raman spectra signals, but only minor change was observed when samples were shielded from UVR. These findings provide support for Mars mission operations searching for biosignatures in the subsurface. This experiment demonstrates the detectability of biomolecules by Raman spectroscopy in Mars regolith analogs after space exposure and lays the groundwork for a consolidated space-proven database of spectroscopy biosignatures in targeted environments.
9.	Beyler, Maryline, et al. (författare) Pentacoordinate iron complexes as functional models of the distal iron in [FeFe] hydrogenases 2011 Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 47:42, s. 11662-11664 Tidskriftsartikel (refereegranskat)abstract Mononuclear pentacoordinate iron complexes with a free coordination site were prepared as mimics of the distal Fe (Fe(d)) in the active site of [FeFe] hydrogenases. The complexes catalyze the electrochemical reduction of protons at mild overpotential.
10.	Forssén, B., et al. (författare) Lithium use among psychiatric patients – a risk factor for hypernatremia? 2018 Ingår i: Journal of Psychosomatic Research. - : Elsevier. - 0022-3999 .- 1879-1360. ; 109, s. 103-103 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Aims: Hypernatremia is a serious condition that can potentially become life threatening. It is known, but not well-studied, that lithium can induce nephrogenic diabetes insipidus and thereby increase the risk for hypernatremia. In this study, we tested the hypothesis that lithium was a risk factor for hypernatremia in patients with severe affective disorders. Methods: A retrospective study of hypernatremia episodes in all patients aged 18 years or over in the county of Norrbotten who received treatment with lithium or any other mood stabilizing medication during 1997-2013. We identified all episodes of hypernatremia during this period and compared the patients using lithium with those who did not. Results: We identified a total of 204 hypernatremia episodes in 185 patients. For all the 204 episodes, infection (37%) was the dominating cause. Harmful use of substances including alcohol came second. Lithium was only identified as a cause for hypernatremia in 1 % of all the episodes. In patients aged 65 years or less, harmful use of substances including alcohol was the most common cause. Infection was the dominating cause in patients >65 years. There was no significant difference in hypernatremia episodes between lithium users and non-lithium users. Patients who had suffered episodes of hyponatremia or died of these were significantly older. Conclusion: Lithium does not increase the risk of hypernatremia in patients with severe affective disorder compared to patients who do not use lithium. However, in some patients using lithium, severe episodes of hypernatremia can still occur. Thus, clinicians need to remain vigilant. There is a need for more research concerning other risk factors that may contribute to hypernatremia in patients with severe affective disorder.
11.	Fransson, Filip, et al. (författare) Kidney function in patients with bipolar disorder with and without lithium treatment compared with the general population in northern Sweden : results from the LiSIE and MONICA cohorts 2022 Ingår i: Lancet psychiatry. - : Elsevier. - 2215-0374 .- 2215-0366. ; 9:10, s. 804-814 Tidskriftsartikel (refereegranskat)abstract Background: The clinical relevance of lithium nephropathy is subject to debate. Kidney function decreases with age and comorbidities, and this decline might lead to attribution bias when erroneously ascribed to lithium. We aimed to investigate whether patients with bipolar or schizoaffective disorder had faster decline in estimated glomerular filtration rate (eGFR) compared with the general population, whether observed differences in the steepness of the decline were attributable to lithium, and whether such changes depended on the length of lithium exposure.Methods: In this cross-sectional cohort study, we used clinical data from the Lithium–Study into Effects and Side-effects (LiSIE) retrospective cohort study, which included patients with bipolar disorder or schizoaffective disorder whose medical records were reviewed up to Dec 31, 2017, and the WHO Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, covering a representative sample of the general population in northern Sweden aged 25–74 years. The primary outcome was the age-associated decline of creatinine-based eGFR, assessed using linear regression. We adjusted for sex and grouped for different lengths of lithium exposure (never or <1 year, 1–5 years, >5–10 years, and >10 years). For patients with moderate-to-severe kidney disease we identified the underlying nephropathy in the case records.Findings: From LiSIE, we included 785 patients (498 [63%] female and 287 [37%] male), with a mean age of 49·8 years (SD 13·2; range 25–74). From MONICA, we included 1549 individuals (800 [52%] female and 749 [48%] male), with a mean age of 51·9 years (13·8; 25–74). No ethnicity data were collected. Adjusted for duration of lithium exposure, eGFR declined by 0·57 mL/min/1·73 m2/year (95% CI 0·50–0·63) in patients with bipolar disorder or schizoaffective disorder and by 0·57 mL/min/1·73 m2/year (0·53–0·61) in the reference population. Lithium added 0·54 mL/min/1·73 m2 (0·43–0·64) per year of treatment (p<0·0001). After more than 10 years on lithium, decline was significantly steeper than in all other groups including the reference population (p<0·0001). Lithium nephropathy was judged to be the commonest cause of moderate-to-severe chronic kidney disease, but comorbidities played a role. The effect of lithium on eGFR showed a high degree of inter-individual variation.Interpretation: Steeper eGFR decline in patients with bipolar disorder or schizoaffective disorder can be attributed to lithium, but the trajectory of kidney function decline varies widely. Comorbidities affecting kidneys should be treated assertively as one possible means to affect the trajectory. In patients with a fast trajectory, a trade-off is required between continuing lithium to treat mental health problems and discontinuing lithium for the sake of renal health.Funding: Norrbotten County Research and Learning Fund Sweden, Visare Norr (Northern County Councils Regional Federation Fund), Swedish Kidney Foundation (Njurfonden), Swedish Kidney Association (Njurförbundet), Norrbotten section.Translation: For the Swedish translation of the Summary see Supplementary Materials section.
12.	Fransson, Filip, et al. (författare) Renal function after discontinuation of chronic lithium treatment : findings from the LiSIE retrospective cohort study 2020 Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 35, s. 592-592 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
13.	Gardner, James M, 1982-, et al. (författare) Light-Driven Electron Transfer between a Photosensitizer and a Proton-Reducing Catalyst Co-adsorbed to NiO 2012 Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 134:47, s. 19322-19325 Tidskriftsartikel (refereegranskat)abstract While intermolecular hole-hopping along the surface of semiconductors is known, there are no previous examples of electron-hopping between molecules on a surface. Herein, we present the first evidence of electron transfer from the photoreduced sensitizer Coumarin-343 (C343) to complex 1, both bound on the surface of NiO. In solution, 1 has been shown to be a mononuclear Fe-based proton-reducing catalyst. The reduction of 1 is reversible and occurs within 50 ns after excitation of C343. Interfacial recombination between the reduced 1(-) and NiO hole occurs on a 100 µs time scale by non-exponential kinetics. The observed process is the first essential step in the photosensitized generation of H2 from a molecular catalyst in the absence of a sacrificial donor reagent.
14.	Goto, Junko, et al. (författare) Myocardial markers are highly altered by higher rates of fluid removal during hemodialysis 2024 Ingår i: Hemodialysis International. - : John Wiley & Sons. - 1492-7535 .- 1542-4758. ; 28:1, s. 17-23 Tidskriftsartikel (refereegranskat)abstract Introduction: Although hemodialysis is lifesaving in patients with kidney failure extensive interdialytic weight gain (IDWG) between dialyses worsens the prognosis. We recently showed a strong correlation between IDWG and predialytic values of cardiac markers. The aim of the present study was to evaluate if the cardiac markers N-terminal pro-B-type natriuretic peptide (proBNP) and troponin T were influenced by IDWG and speed of fluid removal (ultrafiltration-rate).Methods: Twenty hemodialysis patients performed in total 60 hemodialysis (three each). Predialytic values of proBNP and troponin T and changes from predialysis to 180 min hemodialysis (180–0 min) were compared with the IDWG calculated in percent of body weight. The ultrafiltration-rate was adjusted (UF-rateadj) to IDWG: (100 × weight gain between dialysis [kg])/(estimated body dry weight [kg] × length of hemodialysis session [hours]).Results: UF-rateadj correlated (Spearman) with (1) predialytic values of IDWG (r = 0.983, p < 0.001), proBNP (r = 0.443, p < 0.001), and troponin T (r = 0.296, p = 0.025); and (2) differences in proBNP180–0min (r = 0.572, p < 0.001) and troponin T180–0min (r = 0.400, p = 0.002). UF-ratesadj above a breakpoint of 0.60 caused more release of proBNP180–0min (p = 0.027). Remaining variables in multiple regression analysis with ProBNP180–0min as dependent factor were predialytic proBNP (p < 0.001) and the ultrafiltration-rate (p < 0.001).Conclusion: Higher UF-rateadj during dialysis was correlated to increased levels of cardiac markers. Data support a UF-rateadj lower than 0.6 to limit such increase. Further studies may confirm if limited fluid intake and a lower UF-rateadj should be recommended to prevent cardiac injury during dialysis.
15.	Gunnerlind, Oscar, et al. (författare) Alcohol consumption under lockdown measures during the COVID-19 pandemic in three Nordic countries 2024 Ingår i: International Journal of Social Psychiatry. - : Sage Publications. - 0020-7640 .- 1741-2854. ; 70:1, s. 48-58 Tidskriftsartikel (refereegranskat)abstract Background: At the beginning of the COVID-19 pandemic, concerns arose about a possible rise in alcohol consumption. Early surveys, however, more commonly pointed towards a decrease of alcohol use. But studies based on self-reports may underestimate alcohol use. They also depend on the population sampled. Because of border closures and gastronomy restrictions, countries with centralised alcohol sales provided a unique opportunity to study total domestic consumption during the pandemic without influence of private import or reliance on self-reports.Aims: We examined the correlation between alcohol sales and national COVID-19 restrictions in three such countries, Finland, Norway and Sweden.Method: We conducted this study as a mirror image study, comparing alcohol sales during the first 2 years of the COVID-19 pandemic with the two preceding years. We explored hours of daylight/season as potential confounders.Results: We found no relevant change in alcohol sales during the pandemic years for Finland or Sweden. For Norway, there was a level-change in sales, which could be explained by decreased imports. Sales followed a seasonal pattern. In all three countries, the initial pandemic increase in alcohol sales coincided with an underlying annually recurring seasonal variation.Conclusions: The COVID-19 pandemic had less of an impact on alcohol consumption in the three Nordic countries than could intuitively be expected. The increase of alcohol sales at the beginning of the COVID-19 pandemic coincided with a seasonal rise following a pre-pandemic pattern. Therefore, caution should be exercised with drawing conclusions from data with a short time perspective to avoid attribution bias.
16.	Haas, Brian J., et al. (författare) De novo transcript sequence reconstruction from RNA-seq using the Trinity platform for reference generation and analysis 2013 Ingår i: Nature Protocols. - : Springer Science and Business Media LLC. - 1754-2189 .- 1750-2799. ; 8:8, s. 1494-1512 Tidskriftsartikel (refereegranskat)abstract De novo assembly of RNA-seq data enables researchers to study transcriptomes without the need for a genome sequence; this approach can be usefully applied, for instance, in research on 'non-model organisms' of ecological and evolutionary importance, cancer samples or the microbiome. In this protocol we describe the use of the Trinity platform for de novo transcriptome assembly from RNA-seq data in non-model organisms. We also present Trinity-supported companion utilities for downstream applications, including RSEM for transcript abundance estimation, R/Bioconductor packages for identifying differentially expressed transcripts across samples and approaches to identify protein-coding genes. In the procedure, we provide a workflow for genome-independent transcriptome analysis leveraging the Trinity platform. The software, documentation and demonstrations are freely available from http://trinityrnaseq.sourceforge.net. The run time of this protocol is highly dependent on the size and complexity of data to be analyzed. The example data set analyzed in the procedure detailed herein can be processed in less than 5 h.
17.	Jaeger, Michael, et al. (författare) Tridentate pi-extended carbanionic donor sets for RuII polypyridyl-type photosensitizer 2017 Ingår i: Abstracts of Papers of the American Chemical Society. - : AMER CHEMICAL SOC. - 0065-7727. ; 254 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
18.	Karnahl, Michael, et al. (författare) Mixed-valence [(FeFeII)-Fe-I] hydrogenase active site model complexes stabilized by a bidentate carborane bis-phosphine ligand 2012 Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 41:40, s. 12468-12477 Tidskriftsartikel (refereegranskat)abstract A series of [FeFe]-hydrogenase active site analogues, with the general formula [Fe-2(dt)(CO)(4)(BC)] 1-3 (dt = dithiolate, pdt = propyl-1,3-dt (1), bdt = benzene-1,2-dt (2), edt = ethyl-1,2-dt (3); BC = 1,2-bisdiphenylphosphine-1,2-o-carborane), has been prepared and structurally characterized. While the electrochemical reductions of 1-3 are largely invariant to the different nature of their dt bridges, the oxidations differ by more than 120 mV in between the series. Remarkably, all three compounds are reversibly oxidized, with complex 1 that contains the most electron-donating pdt ligand at the mildest potential of -0.09 V vs. Fc/Fc(+). The one-electron oxidized state 1(ox) is stable for several minutes and was spectroscopically characterized by FTIR and EPR. EPR spectroscopy provided evidence that in the mixed-valence [(FeFeII)-Fe-I] state most of the spin density is located on the iron with the BC-ligand. This is monitored through the strong P-31 hyperfine coupling of the phenyl groups of the BC ligand, while further delocalization into the o-carborane unit is negligible.
19.	Karnahl, Michael, et al. (författare) Structural and spectroscopic characterization of tetranuclear iron complexes containing a (P2N2Ph)-N-R bridge 2012 Ingår i: Journal of coordination chemistry (Print). - : Informa UK Limited. - 0095-8972 .- 1029-0389 .- 1026-7441. ; 65:15, s. 2713-2723 Tidskriftsartikel (refereegranskat)abstract A pair of tetranuclear iron complexes consisting of two Fe-2(Cl(2)bdt)(CO)(5) subunits (Cl(2)bdt = 3,6-dicholorobenzene-1,2-dithiolate) bridged by different cyclic 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligands were prepared and structurally characterized. In the solid state, the P2N2 ligands adopt a boat conformation, which results in rather short distances between the two Fe-2(Cl(2)bdt)(CO)(5) clusters that promotes electronic communication across the diphosphine ligand.
20.	Leidel, Nils, et al. (författare) Electronic Structure of an [FeFe] Hydrogenase Model Complex in Solution Revealed by X-ray Absorption Spectroscopy Using Narrow-Band Emission Detection 2012 Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 134:34, s. 14142-14157 Tidskriftsartikel (refereegranskat)abstract High-resolution X-ray absorption spectroscopy with narrow-band X-ray emission detection, supported by density functional theory calculations (XAES-DFT), was used to study a model complex, ([Fe-2(mu-adt)(CO)(4)(PMe3)(2)] (1, adt = S-CH2-(NCH2Ph)-CH2-S), of the [FeFe] hydrogenase active site. For 1 in powder material (1(powder)), in MeCN solution (1'), and in its three protonated states (1H, 1Hy, 1HHy; H denotes protonation at the adt-N and Hy protonation of the Fe-Fe bond to form a bridging metal hydride), relations between the molecular structures and the electronic configurations were determined. EXAFS analysis and DFT geometry optimization suggested prevailing rotational isomers in MeCN, which were similar to the crystal structure or exhibited rotation of the (CO) ligands at Fe1 (1(CO), 1Hy(CO)) and in addition of the phenyl ring (1H(CO,ph), 1HHy(CO,ph)), leading to an elongated solvent-exposed Fe-Fe bond. Isomer formation, adt-N protonation, and hydride binding caused spectral changes of core-to-valence (pre-edge of the Fe K-shell absorption) and of valence-to-core (K beta(2,5) emission) electronic transitions, and of K alpha RIXS data, which were quantitatively reproduced by DFT. The study reveals (1) the composition of molecular orbitals, for example, with dominant Fe-d character, showing variations in symmetry and apparent oxidation state at the two Fe ions and a drop in MO energies by similar to 1 eV upon each protonation step, (2) the HOMO-LUMO energy gaps, of similar to 2.3 eV for 1(powder) and similar to 2.0 eV for 1', and (3) the splitting between iron d(z(2)) and d(x(2-)y(2)) levels of similar to 0.5 eV for the nonhydride and similar to 0.9 eV for the hydride states. Good correlations of reduction potentials to LUMO energies and oxidation potentials to HOMO energies were obtained. Two routes of facilitated bridging hydride binding thereby are suggested, involving ligand rotation at Fe1 for 1Hy(CO) or adt-N protonation for 1HHy(CO,ph). XAES-DFT thus enables verification of the effects of ligand substitutions in solution for guided improvement of [FeFe] catalysts.
21.	Leidel, Nils, et al. (författare) Site-Selective X-ray Spectroscopy on an Asymmetric Model Complex of the [FeFe] Hydrogenase Active Site 2012 Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 51:8, s. 4546-4559 Tidskriftsartikel (refereegranskat)abstract The active site for hydrogen production in [FeFe] hydrogenase comprises a diiron unit. Bioinorganic chemistry has modeled important features of this center, aiming at mechanistic understanding and the development of novel catalysts. However, new assays are required for analyzing the effects of ligand variations at the metal ions. By high-resolution X-ray absorption spectroscopy with narrow-band X-ray emission detection (XAS/XES = XAES) and density functional theory (DFT), we studied an asymmetrically coordinated [FeFe] model complex, [(CO)(3)Fe(I)1-(bdtCl(2))-Fe-2(I)(CO)(Ph2P-CH2-NCH3-CH2-PPh2)] (1, bdt = benzene-1,2-dithiolate), in comparison to iron-carbonyl references. K beta emission spectra (K beta(1,3), K beta') revealed the absence of unpaired spins and the low-spin character for both Fe ions in 1. In a series of low-spin iron compounds, the K beta(1,3) energy did not reflect the formal iron oxidation state, but it decreases with increasing ligand field strength due to shorter iron-ligand bonds, following the spectrochemical series. The intensity of the valence-to-core transitions (K beta(2,5)) decreases for increasing Fe-ligand bond length, certain emission peaks allow counting of Fe-CO bonds, and even molecular orbitals (MOs) located on the metal-bridging bdt group of 1 contribute to the spectra. As deduced from 3d -> 1s emission and 1s -> 3d absorption spectra and supported by DFT, the HOMO-LUMO gap of 1 is about 2.8 eV. K beta-detected XANES spectra in agreement with DFT revealed considerable electronic asymmetry in 1; the energies and occupancies of Fe-d dominated MOs resemble a square-pyramidal F(0) for Fe1 and an octahedral Fe(II) for Fe2. EXAFS spectra for various K beta emission energies showed considerable site-selectivity; approximate structural parameters similar to the crystal structure could be determined for the two individual iron atoms of 1 in powder samples. These results suggest that metal site- and spin-selective XAES on [FeFe] hydrogenase protein and active site models may provide a powerful tool to study intermediates under reaction conditions.
22.	Lieber, Ingrid, 1990- (författare) Affective disorders and their treatments : implications for thyroid function 2023 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract BackgroundThe relationship between affective disorders, mood-stabilisers and thyroid dysfunction is complex and poorly understood. Symptoms of thyroid dysfunction can overlap with symptoms of affective disorder, destabilise mood, and impact physical health. Subjective symptoms and biochemical abnormalities may not always match, especially when changes in thyroid function are only mild. Therefore, diagnosis and treatment of both hypothyroidism and hyperthyroidism in individuals with affective disorders remain complex. For lithium, a first-line treatment for bipolar disorder, an impact on thyroid function was first described in 1968. Since that time, it has become evident that lithium is much more frequently associated with hypothyroidism than hyperthyroidism. But even for lithium, many aspects of how associated thyroid dysfunction should be handled remain unclear. Aims The overall aim of this thesis was, in five studies, to examine aspects of the diagnosis and treatment of thyroid dysfunction in individuals with affective disorders, with a particular focus on lithium. The individual aims of the five studies were todetermine if lithium-associated hypothyroidism was reversible in individuals who had discontinued lithium.identify patterns and trends in thyroid hormone replacement therapy prescribed for individuals with bipolar or schizoaffective disorder.assess whether elevated thyroxine concentrations (hyperthyroxinaemia) were a risk factor for lithium intoxication caused by a change in tubular renal function.examine the incidence rate and aetiology of lithium-associated hyperthyroidism in individuals with bipolar or schizoaffective disorder.explore the attitudes of practising clinicians towards the diagnosis and treatment of subclinical hypothyroidism in individuals with or without affective disorder or anxiety.MethodsStudies 1–4 were part of the LiSIE (Lithium - Study into Effects and Side Effects) retrospective cohort study. LiSIE compares the effects and adverse effects of lithium treatment and other mood stabilisers in the Norrbotten Region and the Region of Västerbotten over a time period of up to 21 years between 1997–2017. For our studies, we used data from the Norrbotten Region only. Study 5 used a three-round modified Delphi consensus-building process. Study 5 was conducted with clinicians from three specialties, general practice, endocrinology and psychiatry, from two countries with similar health care systems, Sweden and the UK. ResultsStudy 1: Of 1340 potentially eligible individuals with lithium treatment, 90 individuals (who had developed hypothyroidism while treated with lithium and later discontinued lithium), were included. Of these, 27% had overt hypothyroidism at the start of thyroid hormone replacement therapy. Of the 85 individuals available for follow-up, 41% stopped thyroid hormone replacement therapy after lithium discontinuation. Only six individuals reinstated thyroid hormone replacement therapy subsequently. Only one had overt hypothyroidism.Study 2: Of 1564 potentially eligible individuals with bipolar or schizoaffective disorder, 291 (27%) had received thyroid hormone replacement therapy at some point during the 21-year review period. In 41% of cases, thyroid hormone replacement therapy was started for subclinical hypothyroidism. At the start of thyroid hormone replacement therapy, the median thyroid stimulating hormone (TSH) concentration was 6.0 (IQR 4.0) mIU/L. The median free serum thyroxine (fT4) was 11.8 (IQR 3.9) pmol/L. The median TSH concentration at the start of thyroid hormone replacement therapy decreased annually by 0.10 mIU/L, being significantly higher in individuals treated with lithium than in individuals treated with other mood stabilisers.Study 3: Of 1562 potentially eligible individuals with bipolar or schizoaffective disorder, 53 individuals had experienced a total of 65 episodes of unintentional lithium intoxication during the review period. In nine episodes, there was elevated fT4 at the time of lithium intoxication, corresponding to an incidence of 1.3 episodes/1000 person-years. For all nine episodes of unintentional lithium intoxication, we could identify alternative explanations that were more plausible than hyperthyroxinaemia. Study 4: In 1562 individuals with bipolar disorder or schizoaffective disorder, we identified 16 episodes of hyperthyroidism, corresponding to an incidence rate of 0.9 episodes/1000 person-years. Individuals who had concurrently been exposed to lithium, had an incidence rate of 1.3 episodes/1000 person-years. Individuals who had been previously exposed to lithium had an incidence rate of 0.8/1000 person-years. Individuals who had never been exposed to lithium (lithium naïve) had a 0.5/1000 person-years incidence rate. There were no significant differences in the risk ratios for individuals with concurrent or previous exposure compared to lithium-naïve individuals, neither for hyperthyroidism overall, nor for thyrotoxicosis or thyroiditis. Study 5: For the expert panel, 60 clinicians; 20 general practitioners, 20 endocrinologists and 20 psychiatrists were recruited. Fifty-three (88%) participants completed all three rounds. The participants reached a consensus on five of the 26 practice statements. The participants agreed that (a) repeated testing was required for the diagnosis of subclinical hypothyroidism, (b) antibody screening should usually occur, and (c and d) antibody screening would strengthen the indication for thyroid hormone replacement therapy in both individuals with and without affective disorder or anxiety. The participants disagreed with (e) requiring a TSH threshold of ≥ 20 mIU/L before starting thyroid hormone replacement therapy.ConclusionsStudy 1: In most cases, lithium-associated hypothyroidism appears reversible. Therefore, thyroid hormone replacement therapy could be discontinued more often once lithium is stopped. Study 2: In most cases, thyroid hormone replacement therapy was started with mild or absent thyroid function changes. The TSH level at which thyroid hormone replacement therapy was initiated decreased over time. When starting thyroid hormone replacement therapy for subclinical hypothyroidism in people with bipolar or schizoaffective disorder, clinicians must carefully weigh the benefits and risks.Study 3: Lithium intoxication with simultaneously elevated fT4 is uncommon. A direct causal link between elevated fT4 and altered tubular renal function remains elusive. An increased frequency of routine thyroid function tests is unlikely to decrease the risk of lithium intoxication. Study 4: Lithium-associated hyperthyroidism is uncommon. The risk of hyperthyroidism does not differ significantly between lithium-exposed and lithium-naïve individuals.Study 5: Attitudes toward diagnosing and treating subclinical hypothyroidism remain diverse. A threshold of an TSH of at least 20 mIU/L for thyroid hormone replacement therapy start, suggested in a previously published guideline, was deemed too high. As the evidence regarding diagnosis and treatment of subclinical hypothyroidism remains limited, future guidelines should consider the views of a broad range of practising clinicians to increase their clinical acceptability and usefulness.
23.	Lieber, Ingrid, et al. (författare) Elevated Thyroxine Concentration and Lithium Intoxication - An Analysis Based on the LiSIE Retrospective Cohort Study 2022 Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 11:11 Tidskriftsartikel (refereegranskat)abstract (1) Background: It has been suggested that hyperthyroxinaemia is a risk factor for lithium intoxication by altering tubular renal function. (2) Methods: We determined the relevance of hyperthyroxinaemia as a risk factor for lithium intoxication in patients with bipolar or schizoaffective disorder in the framework of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. Of 1562 patients included in the study, 897 patients had been exposed to lithium at any time between 1997 and 2017 with 6684 person-years of observation. (3) Results: There were 65 episodes of unintentional lithium intoxication in 53 patients. There were nine episodes with hyperthyroxinaemia at the time of lithium intoxication, yielding an incidence of 1.3 episodes/1000 person-years. For all nine episodes, we could identify alternative, more plausible, explanations for the observed lithium intoxications. (4) Conclusions: We conclude that hyperthyroxinaemia-associated unintentional lithium intoxication is an uncommon event. A direct causal link between hyperthyroxinaemia and altered tubular renal function remains elusive. Increasing the frequency of routine thyroid function tests seems unlikely to decrease the risk of lithium intoxication.
24.	Lieber, Ingrid, et al. (författare) Incidence of hyperthyroidism in patients with bipolar or schizoaffective disorder with or without lithium : 21-year follow-up from the LiSIE retrospective cohort study 2023 Ingår i: Therapeutic Advances in Psychopharmacology. - : Sage Publications. - 2045-1253 .- 2045-1261. ; 13 Tidskriftsartikel (refereegranskat)abstract Background: Lithium-associated hyperthyroidism is much rarer than lithium-associated hypothyroidism. Yet, it may be of substantial clinical significance for affected individuals. For instance, lithium-associated hyperthyroidism could destabilise mood, mimic manic episodes and impact physical health. Only few studies have explored incidence rates of lithium-associated hyperthyroidism. Even fewer studies have compared incidence rates according to lithium exposure history.Objectives: To determine the impact of lithium treatment on the incidence rate of hyperthyroidism in patients with bipolar or schizoaffective disorder and assess its aetiology.Design: This study is part of the LiSIE (Lithium - Study into Effects and Side Effects) retrospective cohort study.Methods: Between 1997 and 2017, patients in the Swedish region of Norrbotten with a diagnosis of bipolar or schizoaffective disorder were screened for all episodes of overt hyperthyroidism in form of thyrotoxicosis or thyroiditis. Incidence rates of episodes of hyperthyroidism per 1000 person-years (PY) were compared in relation to lithium exposure; concurrent, previous, or no exposure ever (lithium-naïve patients).Results: In 1562 patients, we identified 16 episodes of hyperthyroidism corresponding to an incidence rate of 0.88 episodes per 1000 PY. Ninety-four percent of episodes had occurred in women. Patients who had concurrently been exposed to lithium, had an incidence rate of 1.35 episodes per 1000 PY. Patients who had previously been exposed to lithium had an incidence rate of 0.79 per 1000 PY. Patients who had never been exposed to lithium had an incidence rate of 0.47 per 1000 PY. There were no significant differences in the risk ratios for patients with concurrent or previous exposure compared with lithium-naïve patients, neither for hyperthyroidism overall, thyrotoxicosis, or thyroiditis.Conclusion: Lithium-associated hyperthyroidism seems uncommon. The risk of hyperthyroidism does not seem significantly higher in patients with current or previous lithium exposure than in lithium-naïve patients.
25.	Lieber, Ingrid, et al. (författare) Lithium-associated hypothyroidism : Reversible after lithium discontinuation? 2021 Ingår i: European psychiatry. - : Cambridge University Press. - 0924-9338 .- 1778-3585. ; 64:S1, s. S76-S76 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract The association between lithium and thyroid dysfunction has long been known. Yet it is not known whether lithium-associated hypothyroidism is reversible, once lithium treatment has been stopped.ObjectivesTo determine whether lithium-associated hypothyroidism was reversible in patients who subsequently discontinued lithium.MethodsRetrospective cohort study in the Swedish region of Norrbotten into the effects and side- effects of lithium treatment and other drugs for relapse prevention (LiSIE). For this particular study, we reviewed medical records between 1997 and 2015 of patients treated with lithium.ResultsOf 1340 patients screened, we identified 90 patients with lithium-associated hypothyroidism who subsequently discontinued lithium. Of these, 27% had overt hypothyroidism at the time when thyroid replacement therapy was initiated. The mean delay from lithium start to thyroid replacement therapy start was 2.3 (SD 4.7) years. Fifty percent received thyroid replacement therapy within 10 months of starting lithium. Of 85 patients available for follow up, 35 (41%) stopped thyroid replacement therapy after lithium discontinuation. Six patients reinstated thyroid replacement therapy subsequently. Only one of these had overt hypothyroidism, occurring 13 days after stopping lithium and 11 days after stopping thyroid replacement therapy.ConclusionsLithium-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 discontinuation of thyroid replacement therapy if at all.DisclosureMO: scient adv. board member Astra Zeneca Sweden; UW: educ. activities Norrbotten Region: Astra Zeneca, Eli Lilly, Janssen, Novartis, Otsuka/Lundbeck, Servier, Shire and Sunovion. All others: none.
26.	Lieber, Ingrid, et al. (författare) Lithium-associated hypothyroidism and potential for reversibility after lithium discontinuation : findings from the LiSIE retrospective cohort study 2020 Ingår i: Journal of Psychopharmacology. - : Sage Publications. - 0269-8811 .- 1461-7285. ; 34:3, s. 293-303 Tidskriftsartikel (refereegranskat)abstract 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.
27.	Lieber, Ingrid, et al. (författare) Patterns of thyroid hormone prescription in patients with bipolar or schizoaffective disorder : Findings from the lisie retrospective cohort study 2021 Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:21 Tidskriftsartikel (refereegranskat)abstract The prescription of thyroid hormone replacement therapy (THRT) has increased in the general population; the thyroid stimulating hormone (TSH) threshold to initiate THRT has decreased. It remains unclear whether a similar trend has occurred in patients with bipolar disorder (BD). In this work we explore patterns and trends of prescribing THRT in patients with BD or schizoaffective disorder (SZD) with an observational study and time‐trend analysis in the framework of the LiSIE (Lithium—Study into Effects and Side Effects) retrospective cohort study. In most patients, THRT was initiated for subclinical hypothyroidism. The median TSH at which THRT was started was 6.0 (IQR 4.0) mIU/L and the median free serum thyroxine (fT4) at which THRT was started was 11.8 (IQR 3.9) pmol/L. The median TSH concentration at the start of THRT decreased annually with 0.10 mIU/L (p = 0.047) and was higher in patients treated with lithium than in patients treated with other mood stabilisers (p = 0.02). In conclusion, THRT was typically initiated in the context of mild or absent alterations of thyroid function tests with a decreasing TSH threshold. As THRT is rarely reversed once initiated, clinicians need to weigh up potential benefits and risks when prescribing THRT for subclinical hypothyroidism in patients with BD or SZD.
28.	Lieber, Ingrid, et al. (författare) Treating subclinical hypothyroidism in individuals with or without mental health problems – a Delphi based expert consensus study in two countries 2023 Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. Tidskriftsartikel (refereegranskat)abstract Background: Subclinical hypothyroidism (SCH) is a common endocrine problem with prevalence estimates between 4% and 20%. Symptoms are often non-specific but can substantially affect well-being leading to repeated medical consultations. The effect of thyroid hormone replacement therapy (THRT) in patients with SCH remains uncertain. Current guidelines, limited by the lack of high-quality evidence, have been controversial with limited adherence in clinical practice.Methods: Three-round modified Delphi method to establish consensus regarding diagnosis and treatment of individuals with SCH with and without affective disorder or anxiety, conducted with clinicians from three specialties, general practice, endocrinology and psychiatry, and two countries, Sweden and the United Kingdom.Results: Sixty clinicians, 20 per specialty, were recruited. Fifty-three (88%) participants completed all three rounds. The participants reached consensus on five of the 26 practice statements that (a) repeated testing was required for the diagnosis of subclinical hypothyroidism, (b) antibody screening should usually occur, and (c and d) antibody screening would strengthen the indication for thyroid hormone replacement therapy in both individuals with or without affective disorder or anxiety. The participants disagreed with (e) a requirement of a TSH threshold ≥ 20 mIU/L for thyroid hormone replacement therapy start. Psychiatrists and GPs but not endocrinologists, agreed that there was a frequent discrepancy between laboratory results and clinical symptoms, and disagreed that testing for thyroid dysfunction was overused in patients presenting with depression or anxiety, or fatigue.Conclusions: In many aspects, attitudes toward diagnosing and treating SCH remain diverse. The inability of our Delphi panel to achieve consensus on most items and the disagreement with a TSH ≥ 20 mIU/L threshold for treatment suggest that the concept of SCH may need rethinking with a better understanding of the hypothalamic-pituitary-thyroid physiology. Given that the scientific evidence is currently not conclusive, guidelines in this area should not be taken as definitive.
29.	Lund, Peter A., et al. (författare) Understanding How Microorganisms Respond to Acid pH Is Central to Their Control and Successful Exploitation 2020 Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 11 Tidskriftsartikel (refereegranskat)abstract Microbes from the three domains of life,Bacteria,Archaea, andEukarya, share the need to sense and respond to changes in the external and internal concentrations of protons. When the proton concentration is high, acidic conditions prevail and cells must respond appropriately to ensure that macromolecules and metabolic processes are sufficiently protected to sustain life. While, we have learned much in recent decades about the mechanisms that microbes use to cope with acid, including the unique challenges presented by organic acids, there is still much to be gained from developing a deeper understanding of the effects and responses to acid in microbes. In this perspective article, we survey the key molecular mechanisms known to be important for microbial survival during acid stress and discuss how this knowledge might be relevant to microbe-based applications and processes that are consequential for humans. We discuss the research approaches that have been taken to investigate the problem and highlight promising new avenues. We discuss the influence of acid on pathogens during the course of infections and highlight the potential of using organic acids in treatments for some types of infection. We explore the influence of acid stress on photosynthetic microbes, and on biotechnological and industrial processes, including those needed to produce organic acids. We highlight the importance of understanding acid stress in controlling spoilage and pathogenic microbes in the food chain. Finally, we invite colleagues with an interest in microbial responses to low pH to participate in the EU-funded COST Action network called EuroMicropH and contribute to a comprehensive database of literature on this topic that we are making publicly available.
30.	Löscher, Simone, et al. (författare) Facilitated hydride binding in an Fe-Fe hydrogenase active-site biomimic revealed by X-ray absorption spectroscopy and DFT calculations 2007 Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 46:26, s. 11094-11105 Tidskriftsartikel (refereegranskat)abstract Iron-only hydrogenases are high-efficiency biocatalysts for the synthesis and cleavage of molecular hydrogen. Their active site is a diiron center, which carries CO and CN ligands. Remarkably, the two iron atoms likely are connected by a non-protein azadithiolate (adt = S-CH2-NH-CH2-S). To dwell on the role of the adt in H-2 catalysis, a specific biomimetic diiron compound, 1 = [Fe-2(mu-adt-CH2-Ph)(CO)(4)(PMe3)(2)], with unprecedented positive reduction potential, has been synthesized and crystallized previously. It comprises two protonation sites, the N-benzyl-adt nitrogen that can hold a proton (H) and the Fe-Fe bond that will formally carry a hydride (Hy). We investigated changes in the solution structure of 1 in its four different protonation states (1', [1H](+), [1HHy](2+), and [1Hy](+)) by X-ray absorption spectroscopy at the iron K-edge. EXAFS reveals that already protonation at the adt nitrogen atom causes a change of the ligand geometry involving a significant lengthening of the Fe-Fe distance and CO and PMe3 repositioning, respectively, thereby facilitating the subsequent binding of a bridging hydride. Hydride binding clearly is discernible in the XANES spectra of [1HHy](2+) and [1Hy](+). DIFT calculations are in excellent agreement with the experimentally derived structural parameters and provide complementary insights into the electronic structure of the four protonation states. In the iron-only hydrogenases, protonation of the putative adt ligand may cause the bridging CO to move to a terminal position, thereby preparing the active site for hydride binding en route to H2 formation.
31.	Malmström, Rickard E., et al. (författare) Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs 2013 Ingår i: Frontiers in Pharmacology. - : FRONTIERS RESEARCH FOUNDATION. - 1663-9812. ; 4 Tidskriftsartikel (refereegranskat)abstract Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
32.	Mansouri, Larry, et al. (författare) Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma 2016 Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 128:23, s. 2666-2670 Tidskriftsartikel (refereegranskat)abstract We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
33.	Nishida, Jun, et al. (författare) Structural dynamics inside a functionalized metal-organic framework probed by ultrafast 2D IR spectroscopy 2014 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:52, s. 18442-18447 Tidskriftsartikel (refereegranskat)abstract The structural elasticity of metal-organic frameworks (MOFs) is a key property for their functionality. Here, we show that 2D IR spectroscopy with pulse-shaping techniques can probe the ultrafast structural fluctuations of MOFs. 2D IR data, obtained from a vibrational probe attached to the linkers of UiO-66 MOF in low concentration, revealed that the structural fluctuations have time constants of 7 and 670 ps with no solvent. Filling the MOF pores with dimethylformamide (DMF) slows the structural fluctuations by reducing the ability of the MOF to undergo deformations, and the dynamics of the DMF molecules are also greatly restricted. Methodology advances were required to remove the severe light scattering caused by the macroscopic-sizedMOF particles, eliminate interfering oscillatory components from the 2D IR data, and address Forster vibrational excitation transfer.
34.	Nuding, Sabine, et al. (författare) Gastric Antimicrobial Peptides Fail to Eradicate Helicobacter pylori Infection Due to Selective Induction and Resistance 2013 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:9 Tidskriftsartikel (refereegranskat)abstract Background: Although antimicrobial peptides protect mucus and mucosa from bacteria, Helicobacter pylori is able to colonize the gastric mucus. To clarify in which extend Helicobacter escapes the antimicrobial defense, we systematically assessed susceptibility and expression levels of different antimicrobial host factors in gastric mucosa with and without H. pylori infection.Materials and Methods: We investigated the expression levels of HBD1 (gene name DEFB1), HBD2 (DEFB4A), HBD3 (DEFB103A), HBD4 (DEFB104A), LL37 (CAMP) and elafin (PI3) by real time PCR in gastric biopsy samples in a total of 20 controls versus 12 patients colonized with H. pylori. Immunostaining was performed for HBD2 and HBD3. We assessed antimicrobial susceptibility by flow cytometry, growth on blood agar, radial diffusion assay and electron microscopy.Results: H. pylori infection was associated with increased gastric levels of the inducible defensin HBD2 and of the antiprotease elafin, whereas the expression levels of the constitutive defensin HBD1, inducible HBD3 and LL37 remained unchanged. HBD4 was not expressed in significant levels in gastric mucosa. H. pylori strains were resistant to the defensins HBD1 as well as to elafin, and strain specific minimally susceptible to HBD2, whereas HBD3 and LL37 killed all H. pylori strains effectively. We demonstrated the binding of HBD2 and LL37 on the surface of H. pylori cells. Comparing the antibacterial activity of extracts from H. pylori negative and positive biopsies, we found only a minimal killing against H. pylori that was not increased by the induction of HBD2 in H. pylori positive samples.Conclusion: These data support the hypothesis that gastric H. pylori evades the host defense shield to allow colonization.
35.	Orthaber, Andreas, et al. (författare) Coordination and conformational isomers in mononuclear iron complexes with pertinence to the [FeFe] hydrogenase active site 2014 Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 43:11, s. 4537-4549 Tidskriftsartikel (refereegranskat)abstract A series of six mononuclear iron complexes of the type [Fe(X-bdt)((P2N2Ph)-N-R)(CO)] ((P2N2Ph)-N-R = 1,5-diaza-3,7-diphosphaoctane, bdt = benzenedithiolate with X = H, Cl-2 or Me and R = Ph, Bn, Cyc or tert-Bu) was prepared. This new class of penta-coordinate iron complexes contains a free coordination site and a pendant base as essential structural features of the [FeFe]-hydrogenase active site. The bidentate nature of the (P2N2Ph)-N-R ligands was found to be crucial for the preferential formation of coordinatively unsaturated penta-coordinate complexes, which is supported by first principle calculations. IR-spectroscopic data suggest the presence of coordination isomers around the metal center, as well as multiple possible conformers of the (P2N2Ph)-N-R ligand. This finding is further corroborated by X-ray crystallographic and computational studies. P-31{H-1}-NMR- and IR-spectroscopic as well as electrochemical measurements show that the electronic properties of the complexes are strongly, and independently, influenced by the P-substituents at the (P2N2Ph)-N-R ligand as well as by modifications of the bdt bridge. These results illustrate the advantages of this modular platform, which allows independent and selective tuning through site specific modifications. Potential catalytic intermediates, namely singly reduced and protonated complexes, have been further investigated by spectroscopic methods and exhibit remarkable stability. Finally, their general capacity for electro-catalytic reduction of protons to molecular hydrogen was verified.
36.	Ott, Michael, et al. (författare) A Mixed Presentation of Serotonin Syndrome Versus Neuroleptic Malignant Syndrome in a 12-Year-Old Boy 2019 Ingår i: Pediatric emergency care. - : Lippincott Williams & Wilkins. - 0749-5161 .- 1535-1815. ; 35:5, s. E98-E98 Tidskriftsartikel (refereegranskat)
37.	Ott, Michael, et al. (författare) Comment on Liu et al. Hemodialysis treatment for patients with lithium poisoning. Int. J. Environ. Res. Public health 2022, 19, 10044 2023 Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 20:10 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
38.	Ott, Michael, et al. (författare) Comment on the serotonin toxidrome : shortfalls of current diagnostic criteria for related syndromes 2022 Ingår i: Clinical Toxicology. - : Taylor & Francis Group. - 1556-3650 .- 1556-9519. ; 60:9, s. 1079-1081 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
39.	Ott, Michael, 1970-, et al. (författare) Lithium intoxication : Incidence, clinical course and renal function - a population-based retrospective cohort study 2016 Ingår i: Journal of Psychopharmacology. - : SAGE Publications. - 0269-8811 .- 1461-7285. ; 30:10, s. 1008-1019 Tidskriftsartikel (refereegranskat)abstract When prescribing lithium, the risk of toxicity remains a concern. In this study, we examined a cohort of patients exposed to lithium between 1997 and 2013. The aims of this study were to determine the frequency of lithium intoxication and to evaluate the clinical course and changes in renal function. Of 1340 patients, 96 had experienced at least one episode of lithium levels ⩾1.5 mmol/L, yielding an incidence of 0.01 per patient-year. Seventy-seven patients available for review had experienced 91 episodes, of whom 34% required intensive care and 13% were treated with haemodialysis. There were no fatalities. Acute kidney injury occurred, but renal function at baseline was not different to renal function after the episode. Renal impairment was often associated with co-morbidities and other factors. Both intermittent and continuous-venovenous haemodialysis were used, but the clearance of continuous-venovenous haemodialysis can be too low in cases where large amounts of lithium have been ingested. Saline and forced diuresis have been used and are safe. Lithium intoxication seems rare and can be safely managed in most cases. Physicians should not withhold lithium for fear of intoxication in patients who benefit from it. Yet, physicians should have a low threshold to screen for toxicity.
40.	Ott, Michael, et al. (författare) Lithium treatment, nephrogenic diabetes insipidus and the risk of hypernatraemia : a retrospective cohort study 2019 Ingår i: Therapeutic Advances in Psychopharmacology. - : Sage Publications. - 2045-1253 .- 2045-1261. ; 9 Tidskriftsartikel (refereegranskat)abstract Background: Hypernatraemia is a serious condition that can potentially become life threatening. It is known that lithium is associated with polyuria and nephrogenic diabetes insipidus, risk factors for hypernatraemia. In this study, we tested the hypothesis that lithium treatment was a risk factor for hypernatraemia.Methods: We performed a retrospective cohort study in the Swedish region of Norrbotten into the effects and potential adverse effects of lithium treatment and other mood stabilizers (LiSIE). For this particular study, we included all patients who had experienced at least one episode with a sodium concentration > 150 mmol/L between 1997 and 2013. Medical records were reviewed regarding past or current lithium exposure, diabetes insipidus and other potential risk factors for hypernatraemia.Results: Of 2463 patients included, 185 (7.5%) had experienced 204 episodes of hypernatraemia within the 17-year review period. In patients 65 years or older, infections dominated as the cause with 51%. In patients younger than 65 years, intoxications, particularly with alcohol, dominated as the cause with 35%. In the whole sample, dehydration accounted for 12% of episodes, 25% of which in the context of suspected or confirmed nephrogenic diabetes insipidus. Of all episodes, 25% resulted in death, with infection being the most common cause of death in 62% of cases.Conclusions: In our sample, infections and harmful use of substances including alcohol were the most common causes of hypernatraemia. Both current and past use of lithium also led to episodes of hypernatraemia, when associated with nephrogenic diabetes insipidus. Clinicians should remain vigilant, have a low threshold for checking sodium concentrations and consider even risk factors for hypernatraemia beyond lithium.
41.	Ott, Michael, et al. (författare) Management of severe arterial hypertension associated with serotonin syndrome : a case report analysis based on systematic review techniques 2019 Ingår i: Therapeutic Advances in Psychopharmacology. - : Sage Publications. - 2045-1253 .- 2045-1261. ; 9, s. 1-32 Forskningsöversikt (refereegranskat)abstract Serotonin syndrome is thought to arise from serotonin excess. In many cases, symptoms are mild and self-limiting. But serotonin syndrome can become life threatening, when neuromuscular hyperexcitability spins out of control. Uncontainable neuromuscular hyperexcitability may lead to cardiovascular complications, linked to extreme changes in blood pressure. Currently, there is little guidance on how to control blood pressure in hyperserotonergic states. We report a case with treatment-resistant arterial hypertension, followed by a clinical review (using systematic review principles and techniques) of the available evidence from case reports published between 2004 and 2016 to identify measures to control arterial hypertension associated with serotonin syndrome. We conclude that classic antihypertensives may not be effective for the treatment of severe hypertension associated with serotonin syndrome. Benzodiazepines may lower blood pressure. Patients with severe hypertension not responding to benzodiazepines may benefit from cyproheptadine, propofol or both. In severe cases, higher cyproheptadine doses than currently recommended may be necessary.
42.	Ott, Michael, et al. (författare) Metformin-associated lactic acidosis may be treatable with thiamine 2024 Ingår i: Medical Hypotheses. - : Elsevier. - 0306-9877 .- 1532-2777. ; 189 Tidskriftsartikel (refereegranskat)abstract Metformin is a biguanide antidiabetic and a first-line therapy for type-2 diabetes mellitus. It is highly effective, cheap, and easily available since taken in tablet form. Metformin-associated lactic acidosis (MALA) is a serious adverse event with high mortality. It is currently treated with bicarbonate and haemodialysis. The mechanism by which metformin can precipitate lactic acidosis remains subject to debate. Lactic acidosis has also been reported in thiamine (vitamin B1) deficiency. Thiamine deficiency results in a switch from aerobic to anaerobic metabolism with accumulation of lactate. MALA and thiamine-associated lactic acidosis are usually considered separate entities. Both, thiamine and metformin are competitive substrates of the organ cation and thiamine transporters. This way, metformin could cause thiamine deficiency in liver cells. We hypothesize that MALA may be treatable with thiamine. High-dose intravenous thiamine treatment is used routinely for the treatment of Wernicke's encephalopathy and is regarded as safe. Thiamine has been reported to have improved MALA in four cases, who had been refractory to haemodialysis. Thiamine is widely available, easy to administer, and cheap. Thiamine could already be given while waiting for dialysis. Above all, thiamine could prove life-saving in the treatment of MALA in clinical settings in which dialysis is not available.
43.	Ott, Michael, et al. (författare) Prognosis and outcome of severe lithium poisoning : authors' reply 2017 Ingår i: Journal of Psychopharmacology. - : Sage Publications. - 0269-8811 .- 1461-7285. ; 31:9, s. 1275-1277 Tidskriftsartikel (refereegranskat)
44.	Ott, Michael, et al. (författare) Wernicke's encephalopathy - from basic science to clinical practice. Part 1 : understanding the role of thiamine 2020 Ingår i: Therapeutic Advances in Psychopharmacology. - : Sage Publications. - 2045-1253 .- 2045-1261. ; 10 Forskningsöversikt (refereegranskat)abstract Wernicke's encephalopathy (WE) is an acute neuropsychiatric state. Untreated, WE can lead to coma or death, or progress to Korsakoff syndrome (KS) - a dementia characterized by irreversible loss of anterograde memory. Thiamine (vitamin B1) deficiency lies at the heart of this condition. Yet, our understanding of thiamine regarding prophylaxis and treatment of WE remains limited. This may contribute to the current undertreatment of WE in clinical practice. The overall aim of this review is to identify the best strategies for prophylaxis and treatment of WE in regard to (a) dose of thiamine, (b) mode of administration, (c) timing of switch from one mode of administration to another, (d) duration of administration, and (e) use of magnesium along thiamine as an essential cofactor. Evidence from randomized controlled trials and other intervention studies is virtually absent. Therefore, we have to resort to basic science for proof of principle instead. Here, we present the first part of our clinical review, in which we explore the physiology of thiamine and the pathophysiology of thiamine deficiency. We first explore both of these in their historical context. We then review the pharmacodynamics and pharmacokinetics of thiamine, exploring the roles of the six currently known thiamine compounds, their transporters, and target enzymes. We also explore the significance of magnesium as a cofactor in thiamine-facilitated enzymatic reactions and thiamine transport. In the second (forthcoming) part of this review, we will use the findings of the current review to make evidence-based inferences about strategies for prophylaxis and treatment of WE.
45.	Parada, Giovanny A., et al. (författare) Tuning the Electronics of Bis(tridentate)ruthenium(II) Complexes with Long-Lived Excited States : Modifications to the Ligand Skeleton beyond Classical Electron Donor or Electron Withdrawing Group Decorations 2013 Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 52:9, s. 5128-5137 Tidskriftsartikel (refereegranskat)abstract A series of homoleptic bis(tridentate) [Ru-(L)(2)](2+) (1, 3) and heteroleptic [Ru(L)(dqp)](2+) complexes (2, 4) [L = dqxp (1, 2) or dNinp (3, 4); dqxp = 2,6-di(quinoxalin-5-yl)pyridine, dNinp = 2,6-di(N-7-azaindol-1-yl)pyridine, dqp = 2,6-di(quinolin-8-yl)pyridine) was prepared and in the case of 2 and 4 structurally characterized. The presence of dqxp and dNinp in 1-4 result in anodically shifted oxidation potentials of the Ru3+/2+ couple compared to that of the archetypical [Ru(dqp)(2)](2+) (5), most pronounced for [Ru(dqxp)(2)](2+) (1) with a shift of +470 mV. These experimental findings are corroborated by DFT calculations, which show contributions to the complexes' HOMOs by the polypyridine ligands, thereby stabilizing the HOMOs and impeding electron extraction. Complex 3 exhibits an unusual electronic absorption spectrum with its lowest energy maximum at 382 nm. TD-DFT calculations suggest that this high-energy transition is caused by a localization of the LUMO on the central pyridine fragments of the dNinp ligands in 3, leaving the lateral azaindole units merely spectator fragments. The opposite is the case in 1, where the LUMO experiences large stabilization by the lateral quinorralines. Owing to the differences in LUMO energies, the complexes' reduction potentials differ by about 900 mV [E-1/2(1(2+/1+)) = -1.17 V, E-c,E-p(3(2+/1+)) = -2.06 V vs Fc(+/0)]. As complexes 1-4 exhibit similar excited state energies of around 1.80 V, the variations of the lateral heterocycles allow the tuning of the complexes' excited state oxidation strengths over a range of 900 mV. Complex 1 is the strongest excited state oxidant of the series, exceeding even [Ru(bpy)(3)](2+) by more than 200 mV. At room temperature, complex 3 is nonemissive, whereas complexes 1, 2, and 4 exhibit excited state lifetimes of 255, 120, and 1570 ns, respectively. The excited state lifetimes are thus somewhat shortened compared to that of 5 (3000 ns) but still acceptable to qualify the complexes as photosensitizers in light-induced charge-transfer schemes, especially for those that require high oxidative power.
46.	Pujari-Palmer, Michael, et al. (författare) Pyrophosphate Stimulates Differentiation, Matrix Gene Expression and Alkaline Phosphatase Activity in Osteoblasts 2016 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10 Tidskriftsartikel (refereegranskat)abstract Pyrophosphate is a potent mitogen, capable of stimulating proliferation in multiple cell types, and a critical participant in bone mineralization. Pyrophosphate can also affect the resorption rate and bioactivity of orthopedic ceramics. The present study investigated whether calcium pyrophosphate affected proliferation, differentiation and gene expression in early (MC3T3 pre-osteoblast) and late stage (SAOS-2 osteosarcoma) osteoblasts. Pyrophosphate stimulated peak alkaline phosphatase activity by 50% and 150% at 100 mu M and 0.1 mu M in MC3T3, and by 40% in SAOS-2. The expression of differentiation markers collagen 1 (COL1), alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN) were increased by an average of 1.5, 2, 2 and 3 fold, by high concentrations of sodium pyrophosphate (100 mu M) after 7 days of exposure in MC3T3. COX-2 and ANK expression did not differ significantly from controls in either treatment group. Though both high and low concentrations of pyrophosphate stimulate ALP activity, only high concentrations (100 mu M) stimulated osteogenic gene expression. Pyrophosphate did not affect proliferation in either cell type. The results of this study confirm that chronic exposure to pyrophosphate exerts a physiological effect upon osteoblast differentiation and ALP activity, specifically by stimulating osteoblast differentiation markers and extracellular matrix gene expression.
47.	Pujari-Palmer, Michael, et al. (författare) Rebamipide Delivered by Brushite Cement Enhances Osteoblast and Macrophage Proliferation 2015 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5 Tidskriftsartikel (refereegranskat)abstract Many of the bioactive agents capable of stimulating osseous regeneration, such as bone morphogenetic protein-2 (BMP-2) or prostaglandin E2 (PGE2), are limited by rapid degradation, a short bioactive half-life at the target site in vivo, or are prohibitively expensive to obtain in large quantities. Rebamipide, an amino acid modified hydroxylquinoline, can alter the expression of key mediators of bone anabolism, cyclo-oxygenase 2 (COX-2), BMP-2 and vascular endothelial growth factor (VEGF), in diverse cell types such as mucosal and endothelial cells or chondrocytes. The present study investigates whether Rebamipide enhances proliferation and differentiation of osteoblasts when delivered from brushite cement. The reactive oxygen species (ROS) quenching ability of Rebampide was tested in macrophages as a measure of bioactivity following drug release incubation times, up to 14 days. Rebamipide release from brushite occurrs via non-fickian diffusion, with a rapid linear release of 9.70%+/- 0.37% of drug per day for the first 5 days, and an average of 0.5%-1% per day thereafter for 30 days. Rebamipide slows the initial and final cement setting time by up to 3 and 1 minute, respectively, but does not significantly reduce the mechanical strength below 4% (weight percentage). Pre-osteoblast proliferation increases by 24% upon exposure to 0.4uM Rebamipide, and by up to 73% when Rebamipide is delivered via brushite cement. Low doses of Rebamipide do not adversely affect peak alkaline phosphatase activity in differentiating pre-osteoblasts. Rebamipide weakly stimulates proliferation in macrophages at low concentrations (118 +/- 7.4% at 1uM), and quenches ROS by 40-60%. This is the first investigation of Rebamipide in osteoblasts.
48.	Pujari-Palmer, Michael, 1978- (författare) The biological and physical performance of high strength dicalcium phosphate cement in physiologically relevant models 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The chemical properties of calcium phosphate cements (CPCs) are very similar to the mineral phase of bone. CPCs are, consequently, very effective substrates (scaffolds) for tissue engineering; bone and stem cells attach readily, and can proliferate and differentiate to form new bone tissue. Unlike other CPCs that may remain largely unchanged in the body for years, such as hydroxyapatite, dicalcium phosphates are remodelled by the body and rapidly converted to new bone. Unfortunately, the dicalcium phosphates are also typically too weak to support load bearing in the human body. Our laboratory has recently developed a novel, high strength brushite CPC, (hsCPC), which can reach 10-50 fold higher failure strength than many commercially available CPCs. The aim of this thesis was to investigate the physical, chemical and biological performance of hsCPCs in physiologically relevant model of drug release, load bearing, osteoconductivity, and as a scaffold for bone tissue engineering.Multiple CPCs were compared in a model of screw augmentation to determine whether the physical properties of the cement, such as bulk strength and porosity, affected orthopedic screw holding strength. In an in vitro model of bone regeneration stem cells were grown on macroporous scaffolds that were fabricated from hsCPC. Drug releasing scaffolds were fabricated to examine whether the low porosity of hsCPC impeded drug release during a 4 week incubation period. The biological activity of an incorporated drug, Rebamipide, was examined after acute and chronic incubation periods. In the drug release study it was noted that the biological response to hsCPC was significantly better than tissue culture grade polystyrene, even in groups without drug. The mechanism underlying this biological response was further investigated by testing the effect of pyrophosphate, a common cement additive, on bone cell proliferation and differentiation. This thesis concludes that a high strength cement can produce significant improvement in screw augmentation strength, if there is sufficient cortical bone near the augmentation site. The hsCPC is also cytocompatible, and can support bone and stem cell proliferation and differentiation. hsCPC scaffolds stimulated osteogenic gene expression comparable to native bone scaffolds. hsCPC scaffolds are also capable of delivering drug for up to 4 weeks, in vitro. Finally, a cement additive, pyrophosphate, stimulated differentiation, but not proliferation of bone cells.
49.	Pujari-Palmer, Shiuli, et al. (författare) Incorporation and delivery of an organoselenium antioxidant from a brushite cement 2017 Ingår i: Materials letters (General ed.). - : Elsevier BV. - 0167-577X .- 1873-4979. ; 197, s. 115-119 Tidskriftsartikel (refereegranskat)abstract An inflammatory reaction occurs following biomaterial implantation in the body, which produce toxic byproducts such as reactive oxygen species (ROS). Although ROS is required to clear the wound, excessive ROS can damage the tissue around the implant site, eventually leading to implant failure. One approach to control the inflammatory response is to incorporate an antioxidant into the biomaterial in order to scavenge ROS produced by activated phagocytes. In the present study, an organoselenium antioxidative compound was incorporated into a brushite cement, with the goal of scavenging ROS generated from activated primary human mononuclear leukocytes (MNCs), in vitro. The effect of the antioxidant on the physical properties of brushite cement, and its release from the cement were investigated via compressive strength, setting time, phase composition, and UV spectroscopy analysis. The physical properties of brushite remained unchanged following incorporation of the antioxidant. The antioxidant was slowly released from the cement, following a non-Fickian transport mechanism, with approximately 60% of the loaded antioxidant released over five days. The released antioxidant was then tested for its ability to scavenge ROS released by MNCs using the luminol amplified chemiluminescence assay. The results show that antioxidative released at both early stages (24 h) and late stages (120 h) retained its scavenging capacity and effectively reduced ROS production. These results indicate that brushite cements loaded with organoselenium compounds can modulate ROS production after implantation and potentially modulate the inflammatory response to improve device integration.
50.	Pujari-Palmer, Shiuli, et al. (författare) Reduced oxidative stress in primary human cells by antioxidant released from nanoporous alumina 2016 Ingår i: Journal of Biomedical Materials Research. Part B - Applied biomaterials. - : Wiley. - 1552-4973 .- 1552-4981. ; 104:3, s. 568-575 Tidskriftsartikel (refereegranskat)abstract Nanoporous alumina elicits different inflammatory responses dependent on pore size, such as increased complement activation and reactive oxygen species (ROS) production, on 200 versus 20 nm pores. In this study, we attempt to further modulate inflammatory cell response by loading nanoporous alumina membranes (20, 100, and 200 nm pores), with an antioxidant, Trolox, for controlled drug release. For mononuclear cells (MNC) no difference in cell response, due to pore size, was seen when cultured on nonloaded membranes. However, when exposed to membranes loaded with Trolox, 100 uM was enough to quench ROS by more than 95% for all pore sizes. Polymorphonuclear cells (PMNC) produced significantly more ROS when exposed to 20 versus 100 nm pores. For Trolox loaded membranes, this trend reversed, due to slower release of antioxidant from the 20 nm pores. Furthermore, Trolox exhibited a unique effect on PMNCs that has not previously been reported: It delayed the production of ROS in a manner distinct from antioxidant activity. The present study confirms that nanoporous alumina is a suitable vehicle for drug delivery, and that Trolox can successfully modulate the inflammatory response of both MNC and PMNCs.

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