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- Kip, A E, et al.
(författare)
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Quantification of miltefosine in peripheral blood mononuclear cells by high-performance liquid chromatography-tandem mass spectrometry.
- 2015
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 998-999, s. 57-62
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Tidskriftsartikel (refereegranskat)abstract
- Phagocytes, the physiological compartment in which Leishmania parasites reside, are the main site of action of the drug miltefosine, but the intracellular pharmacokinetics of miltefosine remain unexplored. We developed a bioanalytical method to quantify miltefosine in human peripheral blood mononuclear cells (PBMCs), expanding from an existing high performance liquid chromatography-tandem mass spectrometry method for the quantification of miltefosine in plasma. The method introduced deuterated miltefosine as an internal standard. Miltefosine was extracted from PBMC pellets by addition of 62.5% methanol. Supernatant was collected, evaporated and reconstituted in plasma. Chromatographic separation was performed on a reversed phase C18 column and detection with a triple-quadrupole mass spectrometer. Miltefosine was quantified using plasma calibration standards ranging from 4 to 1000ng/mL. This method was validated with respect to its PBMC matrix effect, selectivity, recovery and stability. No matrix effect could be observed from the PBMC content (ranging from 0.17 to 26.3×10(6)PBMCs) reconstituted in plasma, as quality control samples were within 3.0% of the nominal concentration (precision less than 7.7%). At the lower limit of quantitation of 4 ng/mL plasma, corresponding to 0.12ng/10(6) PBMCs in a typical clinical sample, measured concentrations were within 8.6% of the nominal value. Recovery showed to be reproducible as adding additional pre-treatment steps did not increase the recovery with more than 9%. This method was successfully applied to measure intracellular miltefosine concentrations in PBMC samples from six cutaneous leishmaniasis patients up to one month post-treatment.
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| 4. |
- Kip, A E, et al.
(författare)
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Validation and clinical evaluation of a novel method to measure miltefosine in leishmaniasis patients using dried blood spot sample collection
- 2016
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 60:4, s. 2081-2089
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Tidskriftsartikel (refereegranskat)abstract
- To facilitate future pharmacokinetic studies of combination treatments against leishmaniasis in remote endemic regions, a simple and cheap sampling methodology was required for miltefosine quantification. The aim of this study was to validate a liquid chromatography-tandem mass spectrometry method to quantify miltefosine in dried blood spots (DBS) and to validate its use in Ethiopian visceral leishmaniasis (VL) patients. Since hematocrit (Ht) values are typically severely decreased in VL patients, regressing to normal during treatment, the method was evaluated over a range of clinically relevant Ht values.Miltefosine was extracted from DBS using a simple pre-treatment method with methanol, resulting in >97% recovery. The method was validated over a calibration range of 10-2,000 ng/mL and accuracy and precision were within ±11.2% and ≤7.0% (≤19.1% at LLOQ), respectively. The method was accurate and precise for blood spot volumes between 10-30 μL and for an Ht of 20-35%, though a linear effect of Ht on miltefosine quantification was observed in the bioanalytical validation. DBS samples were stable for at least 162 days at 37°C.Clinical validation of the method using paired DBS and plasma samples from 16 VL patients showed a median observed DBS:plasma miltefosine concentration ratio of 0.99, with good correlation (Pearson's r=0.946). Correcting for patient-specific Ht did not further improve the concordance between the sampling methods.This successfully validated method to quantify miltefosine in DBS was demonstrated to be a valid and practical alternative to venous blood sampling which can be applied in future miltefosine pharmacokinetic studies in leishmaniasis patients, without Ht-correction.
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| 5. |
- Liu, X. D., et al.
(författare)
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Origin and expansion of the world's most widespread pinniped: Range-wide population genomics of the harbour seal (Phoca vitulina)
- 2022
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Ingår i: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 31:6, s. 1682-1699
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Tidskriftsartikel (refereegranskat)abstract
- The harbour seal (Phoca vitulina) is the most widely distributed pinniped, occupying a wide variety of habitats and climatic zones across the Northern Hemisphere. Intriguingly, the harbour seal is also one of the most philopatric seals, raising questions as to how it colonized its current range. To shed light on the origin, remarkable range expansion, population structure and genetic diversity of this species, we used genotyping-by-sequencing to analyse similar to 13,500 biallelic single nucleotide polymorphisms from 286 individuals sampled from 22 localities across the species' range. Our results point to a Northeast Pacific origin of the harbour seal, colonization of the North Atlantic via the Canadian Arctic, and subsequent stepping-stone range expansions across the North Atlantic from North America to Europe, accompanied by a successive loss of genetic diversity. Our analyses further revealed a deep divergence between modern North Pacific and North Atlantic harbour seals, with finer-scale genetic structure at regional and local scales consistent with strong philopatry. The study provides new insights into the harbour seal's remarkable ability to colonize and adapt to a wide range of habitats. Furthermore, it has implications for current harbour seal subspecies delineations and highlights the need for international and national red lists and management plans to ensure the protection of genetically and demographically isolated populations.
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- Dorlo, Thomas P C, et al.
(författare)
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Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry.
- 2008
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 865:1-2, s. 55-62
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Tidskriftsartikel (refereegranskat)abstract
- A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of miltefosine is presented. A 250 microL human EDTA plasma aliquot was spiked with miltefosine and extracted by a solid-phase extraction method. Separation was performed on a Gemini C18 column (150 mm x 2.0 mm I.D., 5 microm) using an alkaline eluent. Detection was performed by positive ion electrospray ionization followed by triple-quadrupole mass spectrometry. The assay has been validated for miltefosine from 4 to 2000 ng/mL using 250 microL human EDTA plasma samples. Results from the validation demonstrate that miltefosine can be accurately and precisely quantified in human plasma. At the lowest level, the intra-assay precision was lower than 10.7%, the inter-assay precision was 10.6% and accuracies were between 95.1 and 109%. This assay is successfully used in a clinical pharmacokinetic study with miltefosine.
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| 7. |
- Hoffmann, J. Elis, et al.
(författare)
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Constraining the process of Eoarchean TTG formation in the Itsaq Gneiss Complex, southern West Greenland
- 2014
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 1385-013X .- 0012-821X. ; 388, s. 374-386
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Tidskriftsartikel (refereegranskat)abstract
- We present new major and trace element, high-precision high-field-strength-element, hafnium and neodymium isotope data for well preserved Eoarchean TTGs within the Itsaq Gneiss Complex (IGC) of southern West Greenland. These data are combined with thermodynamic model predictions of partial melting and fractional crystallization to gain new insights into continental crust formation in the Archean. Our results show that the observed compositional range of Eoarchean TTGs can be explained by a combination two processes: (1) 5-25% partial melting of amphibolite within thickened mafic crust and (2) subsequent fractional crystallization processes. The Eoarchean TTG suite of SW Greenland probably formed through mixing of melt batches that originally formed at different source depths between 10 and 14 kbar and ponded as plutons at mid-crustal levels. The trace element compositions of some TTGs point to subsequent fractional crystallization processes involving plagioclase, clinopyroxene, amphibole and garnet. Our model is consistent with recent studies proposing that the Eoarchean Itsaq Gneiss Complex TTGs from the IGC formed by re-working of mafic protocrust that stabilized as accreted juvenile crustal terranes in the Eoarchean. The model is also in good agreement with field observations from the area. (C) 2013 Elsevier B.V. All rights reserved.
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| 8. |
- Kip, A E, et al.
(författare)
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Volumetric absorptive microsampling (VAMS) as an alternative to conventional dried blood spots in the quantification of miltefosine in dried blood samples.
- 2017
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 135, s. 160-166
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Tidskriftsartikel (refereegranskat)abstract
- Miltefosine is an oral agent against the neglected tropical disease leishmaniasis, which is mostly endemic in resource-poor areas. Dried blood spot (DBS) sampling is an attractive alternative to plasma sampling for pharmacokinetic studies in these remote areas, but introduces additional variability in analyte quantification due to possible blood spot inhomogeneity and variability in blood spot volume and haematocrit values. Volumetric absorptive microsampling (VAMS) potentially overcomes a few of these issues as the VAMS device absorbs a fixed volume that is processed as a whole. We developed and validated an LC-MS/MS method for the quantification of miltefosine with this novel sampling technique with good performance in terms of linearity, selectivity, accuracy (bias within ±10.8%), precision (CV%≤11.9%), recovery, carry-over and matrix effect. VAMS samples were stable for at least one month at room temperature and 37°C. The impact of haematocrit on assay accuracy was reduced compared to conventional DBS sampling, but indicated a declining recovery with increased haematocrit due to haematocrit dependency in recovery from the sampling device. A clinical validation will be required to investigate whether VAMS is an appropriate and cost-effective alternative sampling method to conventional DBS sampling.
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| 9. |
- Naeraa, Tomas, et al.
(författare)
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A lower crustal mafic source for the ca. 2550 Ma Qorqut Granite Complex in southern West Greenland
- 2014
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Ingår i: Lithos. - : Elsevier BV. - 0024-4937 .- 1872-6143. ; 192, s. 291-304
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Tidskriftsartikel (refereegranskat)abstract
- The late Neoarchaean Qorqut Granite Complex is the youngest large igneous intrusion in the Nuuk region in southern West Greenland, where basement is primarily of Eoarchaean and Mesoarchaean age with a tonalite-trondhjemite-granodiorite (TTG) composition. The Qorqut granite is generally undeformed and it intruded during a prolonged period, starting at ca. 2730 Ma, characterised by crustal reworking, possibly related to syn- or post accretion tectonics or continental collision. We present major and trace element whole rock chemistry and combined U/Pb, Hf and O isotope data from zircon. We obtained a mean zircon U/Pb age of 2547 +/- 4 Ma (MSWD = 0.63). Initial sHf values range from - 12 to -18 requiring a long residence time and a rather homogeneous source. Sample averaged zircon delta O-18 values range from 6.1 +/- 0.2%. to 6.5 +/- 0.3/0.7%o best interpreted with a source region of mainly unweathered mantle derived igneous rocks. Compared to the regional TTG basement, the QGC is characterised by low CaO and Na2O and high K2O, LREE and Rb contents, and a stronger fractionated REE pattern with a negative Eu anomaly. We show that the homogeneous Hf isotope signature of the granite together with its low epsilon value and its pristine oxygen isotope composition are best explained with an Eoarchaean mafic source with a Lu-176/Hf-176 around 0.015-0.019. Trace element modelling confirms that a mafic source in REE and with an eclogitic residue and with plagioclase as a fractionating phase would generate appropriate melt compositions. Modelling requires residual rutile in the source which constrain the pressures to > ca. 13-18 kbar. Zirconium saturation temperatures suggest magma temperatures in the range 750-850 degrees C. The obtained P-T conditions suggest a lower crustal source region in a thickened crustal unit consistent with a post or late continental collisional setting. (C) 2014 Elsevier B.V. All rights reserved.
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| 10. |
- Naeraa, Tomas, et al.
(författare)
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Hafnium isotope evidence for a transition in the dynamics of continental growth 3.2Gyr ago
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 485:7400, s. 627-627
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Tidskriftsartikel (refereegranskat)abstract
- Earth's lithosphere probably experienced an evolution towards the modern plate tectonic regime, owing to secular changes in mantle temperature(1,2). Radiogenic isotope variations are interpreted as evidence for the declining rates of continental crustal growth over time(3-5), with some estimates suggesting that over 70% of the present continental crustal reservoir was extracted by the end of the Archaean eon(3,5). Patterns of crustal growth and reworking in rocks younger than three billion years (Gyr) are thought to reflect the assembly and break-up of supercontinents by Wilson cycle processes and mark an important change in lithosphere dynamics(6). In southern West Greenland numerous studies have, however, argued for subduction settings and crust growth by arc accretion back to 3.8 Gyr ago(7-9), suggesting that modern-day tectonic regimes operated during the formation of the earliest crustal rock record. Here we report in situ uranium-lead, hafnium and oxygen isotope data from zircons of basement rocks in southern West Greenland across the critical time period during which modern-like tectonic regimes could have initiated. Our data show pronounced differences in the hafnium isotope-time patterns across this interval, requiring changes in the characteristics of the magmatic protolith. The observations suggest that 3.9-3.5-Gyr-old rocks differentiated from a >3.9-Gyr-old source reservoir with a chondritic to slightly depleted hafnium isotope composition. In contrast, rocks formed after 3.2 Gyr ago register the first additions of juvenile depleted material (that is, new mantle-derived crust) since 3.9 Gyr ago, and are characterized by striking shifts in hafnium isotope ratios similar to those shown by Phanerozoic subduction-related orogens(10-12). These data suggest a transitional period 3.5-3.2 Gyr ago from an ancient (3.9-3.5 Gyr old) crustal evolutionary regime unlike that of modern plate tectonics to a geodynamic setting after 3.2 Gyr ago that involved juvenile crust generation by plate tectonic processes.
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