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  • 1.
    Arner, P.
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.
    Bernard, S.
    Univ Lyon, CNRS, UMR5208, Inst Camille Jordan, Villeurbanne, France.
    Appelsved, L.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Fu, K. -Y
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, D. P.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Thorell, A.
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden;Karolinska Inst, Ersta Hosp, Dept Surg, Stockholm, Sweden.
    Ryden, M.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.
    Spalding, K. L.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden;Integrated Cardio Metab Ctr, Dept Med, Stockholm, Sweden.
    Adipose lipid turnover and long-term changes in body weight2019In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, no 9, p. 1385-1389Article in journal (Refereed)
    Abstract [en]

    The worldwide obesity epidemic(1) makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates(2,3). Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived C-14 in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.

  • 2. Arner, Peter
    et al.
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Liebl, Jakob
    Steier, Peter
    Buchholz, Bruce A.
    Eriksson, Mats
    Arner, Erik
    Hauner, Hans
    Skurk, Thomas
    Ryden, Mikael
    Frayn, Keith N.
    Spalding, Kirsty L.
    Dynamics of human adipose lipid turnover in health and metabolic disease2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 478, no 7367, p. 110-113Article in journal (Refereed)
    Abstract [en]

    Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes(1). Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring (14)C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.

  • 3. Bergmann, Olaf
    et al.
    Zdunek, Sofia
    Felker, Anastasia
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Alkass, Kanar
    Bernard, Samuel
    Sjostrom, Staffan L.
    Szewczykowska, Mirosawa
    Jackowska, Teresa
    dos Remedios, Cris
    Malm, Torsten
    Andrae, Michaela
    Jashari, Ramadan
    Nyengaard, Jens R.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Jovinge, Stefan
    Druid, Henrik
    Frisen, Jonas
    Dynamics of Cell Generation and Turnover in the Human Heart2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 161, no 7, p. 1566-1575Article in journal (Refereed)
    Abstract [en]

    The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived C-14 revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart.

  • 4.
    Eilers, Gerriet
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Persson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Gustavsson, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Ryderfors, Linus
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Mukhtar, Emad
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    The Radiocarbon Intracavity Optogalvanic Spectroscopy Setup at Uppsala2013In: Radiocarbon, ISSN 0033-8222, E-ISSN 1945-5755, Vol. 55, no 3-4, p. 237-250Article in journal (Refereed)
    Abstract [en]

    Accelerator mass spectrometry (AMS) is by far the predominant technology deployed for radiocarbon tracer studies. Applications are widespread from archaeology to biological, environmental, and pharmaceutical sciences. In spite of its excellent performance, AMS is expensive and complicated to operate. Consequently, alternative detection techniques for 14C are of great interest, with the vision of a compact, user-friendly, and inexpensive analytical method. Here, we report on the use of intracavity optogalvanic spectroscopy (ICOGS) for measurements of the 14C/12C ratio. This new detection technique was developed by Murnick et al. (2008). In the infrared (IR) region, CO2 molecules have strong absorption coefficients. The IR-absorption lines are narrow in line width and shifted for different carbon isotopes. These properties can potentially be exploited to detect 14CO2, 13CO2, or 12CO2 molecules unambiguously. In ICOGS, the sample is in the form of CO2 gas, eliminating the graphitization step that h is required in most AMS labs. The status of the ICOGS setup in Uppsala is presented. The system is operational but not yet fully developed. Data are presented for initial results that illustrate the dependence of the optogalvanic signal on various parameters, such as background and plasma-induced changes in the sample gas composition.

  • 5.
    Ernst, Aurélie
    et al.
    Karolinska Institut.
    Alkass, Kanar
    Karolinska Institut.
    Bernard, Samuel
    University of Lyon, Villeurbanne, France.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Perl, Shira
    NHLBI, NIH, Bethesda, Maryland, USA.
    Tisdale, John
    NHLBI, NIH, Bethesda, Maryland, USA.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Druid, Henrik
    Karolinska Institut.
    Frisén, Jonas
    Karolinska Institut.
    Neurogenesis in the Striatum of the Adult Human Brain2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 156, no 5, p. 1072-1083Article in journal (Refereed)
    Abstract [en]

    Neurons are added throughout life in the hippocampus and olfactory bulb in most mammals, although humans represent an exception without detectable olfactory bulb neurogenesis. Nevertheless, neuroblasts are generated in the lateral ventricle wall in humans, the neurogenic niche for olfactory bulb neurons in other mammals. We show that, in humans, new neurons integrate adjacent to this neurogenic niche, in the striatum. The neuronal turnover in the striatum appears restricted to interneurons and we show that postnatally generated striatal neurons are preferentially depleted in Huntington’s disease. This demonstrates a unique pattern of neurogenesis in the adult human brain.  

  • 6.
    Forsgård, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Accelerator mass spectrometry in the attomolar concentration range for C-14-labeled biologically active compounds in complex matrixes2010In: Journal of Analytical Atomic Spectrometry, ISSN 0267-9477, E-ISSN 1364-5544, Vol. 25, no 1, p. 74-78Article in journal (Refereed)
    Abstract [en]

    Accelerator mass spectrometry (AMS) is an ultra-sensitive analytical method suitable for detection of sub-nanomolar concentrations of labeled biological substances such as pharmaceutical drugs in body fluids. A limiting factor in extending the concentration measurements to the sub-picomolar range is the natural C-14 content in living tissues. This can be circumvented by separating the labeled drug from the tissue matrix with, for example, liquid chromatography. The analysis of drugs and their metabolites or endogenous compounds in biological fluids by liquid chromatography is usually complicated and the sample preparation step remains the most serious problem both with regard to losses and degradation of the analyte, and also automation of the analysis. In this article a method for detection and quantification of extremely low concentrations of C-14-labeled biomolecules in biological fluids by AMS is described. The use of a column switched chromatographic system incorporating a restricted-access media (RAM) column allowed the direct injection of untreated human plasma samples, which reduces the total time of analysis and makes automation of the sample preparation step possible. As the separated total drug amount is in the attogram to femtogram region, it is not possible to use a standard AMS sample preparation method, where mg sizes are required. We have utilized a sensitive carbon carrier method where a C-14-deficient compound is added to the HPLC fractions and the composite sample is prepared and analysed by AMS. The method shows remarkable sensitivity, low background values and good linearity, allowing the detection and quantification of a pharmaceutical drug in human plasma in the low femtomolar and down to the attomolar concentration range.

  • 7.
    Huttner, Hagen B.
    et al.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden; Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Bergmann, Olaf
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden; Tech Univ Dresden, DFG Ctr Regenerat Therapies Dresden, Dresden, Germany.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    El Cheikh, Raouf
    Aix Marseille Univ, Inserm S 911, CRO2, SMARTc Pharmacokinet Unit, Marseille, France.
    Nakamura, Makoto
    Univ Hosp Hannover, Dept Neurosurg, Hannover, Germany.
    Tortora, Angelo
    Univ Hosp Hannover, Dept Neurosurg, Hannover, Germany.
    Heinke, Paula
    Tech Univ Dresden, DFG Ctr Regenerat Therapies Dresden, Dresden, Germany.
    Coras, Roland
    Univ Hosp Erlangen, Dept Neuropathol, Erlangen, Germany.
    Englund, Elisabet
    Univ Hosp Lund, Dept Pathol, Lund, Sweden.
    Eyuepoglu, Ilker Y.
    Univ Hosp Erlangen, Dept Neurosurg, Erlangen, Germany.
    Kuramatsu, Joji B.
    Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Roeder, Sebastian S.
    Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Kloska, Stephan P.
    Univ Hosp Erlangen, Dept Neuroradiol, Erlangen, Germany.
    Muehlen, Iris
    Univ Hosp Erlangen, Dept Neuroradiol, Erlangen, Germany.
    Doerfler, Arnd
    Univ Hosp Erlangen, Dept Neuroradiol, Erlangen, Germany.
    Schwab, Stefan
    Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics. Uppsala Univ, Dept Phys & Astron, Div Ion Phys, Uppsala, Sweden..
    Bernard, Samuel
    Univ Lyon, CNRS, UMR 5208, Inst Camille Jordan, Villeurbanne, France.
    Frisen, Jonas
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Meningioma growth dynamics assessed by radiocarbon retrospective birth dating2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 27, p. 176-181Article in journal (Refereed)
    Abstract [en]

    It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n = 6 with meningothelial and n = 6 with fibrous subtype, as well as n = 2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1 ± 6.5 years, whereas atypical WHO grade II meningiomas originated 1.5 ± 0.1 years prior to surgery (p < 0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.

  • 8. Huttner, Hagen B
    et al.
    Bergmann, Olaf
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Rácz, Attila
    Tatarishvili, Jemal
    Lindgren, Emma
    Csonka, Tamás
    Csiba, László
    Hortobágyi, Tibor
    Méhes, Gábor
    Englund, Elisabet
    Solnestam, Beata Werne
    Zdunek, Sofia
    Scharenberg, Christian
    Ström, Lena
    Ståhl, Patrik
    Sigurgeirsson, Benjamin
    Dahl, Andreas
    Schwab, Stefan
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Bernard, Samuel
    Kokaia, Zaal
    Lindvall, Olle
    Lundeberg, Joakim
    Frisén, Jonas
    The age and genomic integrity of neurons after cortical stroke in humans2014In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 17, no 6, p. 801-803Article in journal (Refereed)
    Abstract [en]

    It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.

  • 9. Hägg, Sara
    et al.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Noori, Peri
    Lundström, Jesper
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Takolander, Rabbe
    Konrad, Peter
    Rosfors, Stefan
    Ruusalepp, Arno
    Skogsberg, Josefin
    Tegner, Jesper
    Björkegren, Johan
    Carotid Plaque Age Is a Feature of Plaque Stability Inversely Related to Levels of Plasma Insulin2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, p. e18248-Article in journal (Refereed)
    Abstract [en]

    Background: The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric C-14-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques. Methodology/Principal Finding: The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for C-14 content by accelerator mass spectrometry. The average plaque age (i.e. formation time) was 9.6+/-3.3 years. All but two plaques had formed within 5-15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p=0.0014). Most plaques were echo-lucent rather than echo-rich (2.2460.97, range 1-5). However, plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages (67.8+/-12.4 vs. 50.4+/-6.2, p=0.00005; 57.6+/-26.1 vs. 39.8+/-25.7, p<0.0005, respectively), less collagen (45.3+/-6.1 vs. 51.1+/-9.8, p<0.05), and fewer smooth muscle cells (130+/-31 vs. 141+/-21, p<0.05) than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation. Conclusions/Significance: Our results show, for the first time, that plaque age, as judge by relative incorporation of C-14, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.

  • 10. Landsverk, Ole J. B.
    et al.
    Snir, Omri
    Casado, Raquel Bartolome
    Richter, Lisa
    Mold, Jeff E.
    Reu, Pedro
    Horneland, Rune
    Paulsen, Vemund
    Yaqub, Sheraz
    Aandahl, Einar Martin
    Oyen, Ole M.
    Thorarensen, Hildur Sif
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Frisen, Jonas
    Sollid, Ludvig M.
    Baekkevold, Espen S.
    Jahnsen, Frode L.
    Antibody-secreting plasma cells persist for decades in human intestine2017In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, no 2, p. 309-317Article in journal (Refereed)
    Abstract [en]

    Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19(+) PC subset was dynamically exchanged, whereas of two CD19(-) PC subsets, CD45(+) PCs exhibited little and CD45(-) PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45(-) PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19(-) PC subsets support selection and maintenance of protective PCs for life in human intestine.

  • 11.
    Persson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Berglund, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Thornell, Greger
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    State of the art Intracavity Optogalvanic Spectroscopy at Uppsala University2013Conference paper (Refereed)
    Abstract [en]

    About five years ago, the first reports of a novel and ultrasensitive method for ro-vibrational spectroscopy of isotope ratios were published [1-3]. The method was called intracavity optogalvanic spectroscopy (ICOGS), and claimed a sensitivity and limit-of-detection (LOD) for detection of radiocarbon in the 10-15range. Applied to measuring the isotopic composition of carbon samples, ICOGS utilizes the narrow linewidth ro-vibrational absorption lines of CO2 in the long-wavelength IR spectrum, typically between 10 - 13 µm [4]. These absorption lines are strongly dependent on the isotopic composition of the CO2 molecule, where a 14CO2 line typically is separated by several hundred linewidths form the nearest 12CO2 and 13CO2 lines. In order to facilitate unambiguous detection of radiocarbon, which is typically 1010-1012 times less abundant than the isotopes 12C and 13C, the sample is moved inside the laser cavity of a 14CO2 laser. This intracavity approach has been claimed to increase the sensitivity of the detection by almost seven orders of magnitude as compared to traditional ‘extracavity’ optogalvanic spectroscopy [3]. However, despite the methodical and thorough efforts of at least five research groups worldwide, the exceptional claims regarding the sensitivity and LOD of ICOGS have not been possible to confirm.

          As the first research group to properly repeat the original experiments, we recently reported [5] serious deficiencies in the reproducibility of the original results [1-3]. We found that ICOGS in its original embodiment suffers from considerable problems with the stability and reproducibility of the optogalvanic signal, and that these uncertainties, together with mix-ups and mistakes, likely are the explanation for the extraordinary sensitivity in the original reports. An example of the irreproducibility of the original results can be seen in Fig. 1 (a) where the shape of the P20 line of 14C16O2 with different 14C concentrations is shown. As can be seen, the previously reported Voight profile-like line shape, indicating resonant absorption [3], was not found for 14C concentrations in the 10-13 ‒10-11 range, but only for samples with much higher 14C concentration. The problems with stability and reproducibility can be traced back to instabilities in the plasma source, in which the sample is partially ionized in order to extract the optogalvanic signal. The plasma sources currently used in ICOGS are based on 30 years old technology and suffer from problems with both electromagnetic interference and reproducibility in terms of the discharge conditions (pressure, temperature, etc.).

          In order to overcome these problems, we aim to deploy a completely novel kind of plasma source, based on a stripline split-ring resonator (SSRR), for ICOGS, Fig. 1 (b). We have recently published a report on the applicability of such a plasma source for ordinary optogalvanic spectroscopy [6], and now intend to optimize it for ICOGS. Based on its intrinsic properties, an SSRR could not only improve the stability of the signal, but also reduce the non-resonant background in the spectrum, and facilitate analysis of smaller samples. The latter is due to its extremely small size, with an analyzed volume in the order of 10 µl, Fig. 1 (c). In this report, we summarize our criticism towards the original publications on ICOGS, and report on the latest development regarding our efforts in the deployment of the SSRR plasma source.

  • 12.
    Persson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Berglund, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Thornell, Greger
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Stripline split-ring resonator with integrated optogalvanic sample cell2014In: Laser Physics Letters, ISSN 1612-2011, Vol. 11, no 4, p. 045701-Article in journal (Refereed)
    Abstract [en]

    Intracavity optogalvanic spectroscopy (ICOGS) has been proposed as a method for unambiguous detection of rare isotopes. Of particular interest is 14C, where detection of extremely low concentrations in the 1:1015 range (14C:12C), is of interest in, e.g., radiocarbon dating and pharmaceutical sciences. However, recent reports show that ICOGS suffers from substantial problems with reproducibility. To qualify ICOGS as an analytical method, more stable and reliable plasma generation and signal detection are needed. In our proposed setup, critical parameters have been improved. We have utilized a stripline split-ring resonator microwave-induced microplasma source to excite and sustain the plasma. Such a microplasma source offers several advantages over conventional ICOGS plasma sources. For example, the stripline split-ring resonator concept employs separated plasma generation and signal detection, which enables sensitive detection at stable plasma conditions. The concept also permits in situ observation of the discharge conditions, which was found to improve reproducibility. Unique to the stripline split-ring resonator microplasma source of in this study, is that the optogalvanic sample cell has been embedded in the device itself. This integration enabled improved temperature control and more stable and accurate signal detection. Significant improvements are demonstrated, including reproducibility, signal-to-noise ratio and precision.

  • 13.
    Persson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Eilers, Gerriet
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Ryderfors, Linus
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Mukhtar, Emad
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Evaluation of Intracavity Optogalvanic Spectroscopy for Radiocarbon Measurements2013In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 85ASAP, no 14, p. 6790-6798Article in journal (Refereed)
    Abstract [en]

    Ever since the first publication of intracavity optogalvanic spectroscopy (ICOGS) in 2008, this novel technique for measuring the 14C/12C ratio in carbon dioxide has rendered considerable attention. As a result, there are currently at least five different research groups pursuing research on ICOGS. With a claimed limit of detection of 10–15 (14C/12C), i.e., in the same order as accelerator mass spectroscopy, achieved with a relatively inexpensive and uncomplicated table-top system, ICOGS has major scientific and commercial implications. However, during the past 5 years, no research group has been able to reproduce these results or present additional proof for ICOGS’s capability of unambiguous 14C detection, including the authors of the original publication. Starting in 2010, our group has set up a state-of-the-art ICOGS laboratory and has investigated the basic methodology of ICOGS in general and tried to reproduce the reported experiments in particular. We have not been able to reproduce the reported results concerning the optogalvanic signals dependence on14C concentration and wavelength and, ultimately, not seen any evidence of the capability of ICOGS to unambiguously detect 14C at all. Instead, we have found indications that the reported results can be products of measurement uncertainties and mistakes. Furthermore, our results strongly indicate that the reported limit of detection is likely to be overestimated by at least 2 orders of magnitude, based on the results presented in the original publication. Hence, we conclude that the original reports on ICOGS cannot be confirmed and therefore must be in error.

  • 14.
    Persson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Comment on “Intracavity OptoGalvanic Spectroscopy Not Suitable for Ambient Level Radiocarbon Detection"2016In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 8, p. 4578-4579Article in journal (Refereed)
    Abstract [en]

    Every new discovery must undergo thorough scientific scrutiny before being recognized. One important step in the process is confirmation by independent experiments. The case at hand is intracavity optogalvanic spectroscopy (ICOGS), which was first published by Murnick et al. in 2008, and claimed to have the potential to revolutionize rare-isotope measurements in general and those of radiocarbon in particular. Since then, no data has been reported in any shape or form to support it. On the contrary, in spite of extensive efforts at five different sites around the world – apart from Murnick’s group at Rutgers University, Professor Meijer’s group at the Energy and Sustainability Research Institute Groningen at University of Groningen, Professor Lackner’s group at the Department of Earth and Environmental Engineering at Columbia University, our group at the Department of Physics and Astronomy at Uppsala University, and the company Planetary Emission Management Inc. – the original data still remains unconfirmed, and a number of publications have seriously questioned the scientific validity of the original report.

  • 15.
    Persson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Intracavity optogalvanic spectroscopy: Is there any evidence of a radiocarbon signal?2015In: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, ISSN 0168-583X, E-ISSN 1872-9584, Vol. 361, p. 8-12Article in journal (Refereed)
    Abstract [en]

    In 2008, the first report of an ultrasensitive method for ro-vibrational spectrometry of radiocarbon dioxide was published. The method, called intracavity optogalvanic spectroscopy (ICOGS), claimed a sensitivity and limit-of-detection comparable to accelerator mass spectroscopy. ICOGS was claimed to utilize the isotope-dependent ro-vibrational absorption lines of carbon dioxide in the infrared spectrum. In order to facilitate unambiguous detection of radiocarbon, the sample was placed inside the cavity of a radiocarbon dioxide laser. This intracavity approach was claimed to increase the sensitivity by seven orders of magnitude compared with traditional optogalvanic methods. However, despite the methodical and thorough efforts of several research groups worldwide, these claims have not been possible to reproduce. Instead, we have previously reported serious deviations from the original results, where we found that ICOGS suffers from considerable problems with the stability and reproducibility of the optogalvanic signal, and that misinterpretations of these uncertainties likely are the explanation for the claimed sensitivity in the first reports. Having identified the stability and reproducibility of the detection as major concerns, we decided to improve the setup by with state-of-the-art plasma source technology. Deploying a custom-made stripline split-ring resonator optogalvanic detector, we have now investigated the applicability of ICOGS to radiocarbon detection even further. Measurements have been made with a wide range of parameters including different gas mixtures at various pressures and wavelengths. We have also conducted measurements with gas flowing through the sample cell to investigate the effect of plasma induced decomposition of the sample. Still, we have seen no indications of a significant radiocarbon signal in a concentration range between 0.29 Modern and 9.7 Modern, i.e., the range of interest to the radiocarbon community. Hence, our conclusions after four years of working in this field, is that ICOGS is not a viable method for radiocarbon detection. 

  • 16. Reu, Pedro
    et al.
    Khosravi, Azadeh
    Bernard, Samuel
    Mold, Jeff E.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Alkass, Kanar
    Perl, Shira
    Tisdale, John
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Druid, Henrik
    Frisen, Jonas
    The Lifespan and Turnover of Microglia in the Human Brain2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 4, p. 779-784Article in journal (Refereed)
    Abstract [en]

    The hematopoietic system seeds the CNS with microglial progenitor cells during the fetal period, but the subsequent cell generation dynamics and maintenance of this population have been poorly understood. We report that microglia, unlike most other hematopoietic lineages, renew slowly at a median rate of 28% per year, and some microglia last for more than two decades. Furthermore, we find no evidence for the existence of a substantial population of quiescent long-lived cells, meaning that the microglia population in the human brain is sustained by continuous slow turnover throughout adult life.

  • 17. Reu, Pedro
    et al.
    Mold, Jeff
    Michaelsson, Jakob
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Frisen, Jonas
    Human T cell lifespan2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, p. P1284-Article in journal (Other academic)
  • 18.
    Sadiq, Muhammad Waqas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Forsgård, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Morphine brain pharmacokinetics at very low concentrations studied with Accelerator Mass Spectrometry and Liquid Chromatography-tandem Mass Spectrometry2011In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 39, no 2, p. 174-179Article in journal (Refereed)
    Abstract [en]

    Morphine has been predicted to show nonlinear blood-brain barrier (BBB) transport at lower concentrations. Present study investigated the possibility of separating active influx of morphine from its efflux by using very low morphine concentrations, and to compare AMS with LC-MS/MS as method for analysing microdialysis samples. A 10-min bolus infusion of morphine, followed by a constant-rate infusion, was given to male rats (n=6) to achieve high (250 ng.ml(-1)), medium (50 ng.ml(-1)) and low (10 ng.ml(-1)) steady-state plasma concentrations (C(ss)). An additional rat received infusions to achieve low (10 ng.ml(-1)), very low (2 ng.ml(-1)) and ultra low (0.4 ng.ml(-1)) concentrations. Unbound morphine concentrations from brain extracellular fluid and blood were sampled with microdialysis and analysed by LC-MS/MS and AMS. The average K(p,uu) for the low and medium steady-state levels were 0.22±0.08 and 0.21±0.05, when measured with AMS (NS; p=0.5). For the medium and high steady-state levels, K(p,uu) values were 0.24±0.05 and 0.26±0.05, measured with LC-MS/MS (NS; p=0.2). For the low, very low and ultra low levels, K(p,uu) values were 0.16±0.01, 0.16±0.02 and 0.18±0.03, respectively, measured with AMS. The medium-concentration K(p,uu) values were, on average, 16% lower with AMS than with LC-MS/MS. There were no significant changes in K(p,uu) over a 625-fold concentration range (0.4-250 ng.ml(-1)). It was not possible to separate active uptake transport from active efflux using these low concentrations. The two analytical methods provided indistinguishable results for blood plasma concentrations, but differed by up to 38% for microdialysis samples; however, this did not affect our conclusions.

  • 19.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Ekblom, Jonas
    Sabetsky, Vladimir
    Håkansson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Accelerator mass spectrometry offers new opportunities for microdosing of peptide and protein pharmaceuticals2010In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 24, no 10, p. 1481-1489Article in journal (Refereed)
    Abstract [en]

    Accelerator Mass Spectrometry (AMS) is an ultra-sensitive analytical method which has been instrumental in developing microdosing as a strategic tool in early drug development. Considerable data is available for AMS microdosing using typical pharmaceutical drugs with a molecular weight of a few hundred Daltons. The so-called biopharmaceuticals such as proteins offer interesting possibilities as drug candidates; however, experimental data for protein microdosing and AMS is scarce. The analysis of proteins in conjunction with early drug development and microdosing is overviewed and three case studies are presented on the topic. In the first case study AMS experimental data is presented, for the measured concentration of orally administered recombinant insulin in the blood stream of laboratory rabbits. Case study 2 concerns minimum sample size requirements. AMS samples normally require about 1 mg of carbon (10 mu L of blood) which makes AMS analysis unsuitable in some applications due to the limited availability of samples such as human biopsies or DNA from specific cells. Experimental results are presented where the sample size requirements have been reduced by about two orders of magnitude. The third case study concerns low concentration studies. It is generally accepted that protein pharmaceuticals may be potentially more hazardous than smaller molecules because of immunological reactions. Therefore, future first-in-man microdosing studies might require even lower exposure concentrations than is feasible today, in order to increase the safety margin. This issue is discussed based on the current available analytical capabilities.

  • 20.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Forsgard, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Possnert, Goran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Accelerator mass spectrometry of small biological samples2008In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 22, no 23, p. 3928-3934Article in journal (Refereed)
    Abstract [en]

    Accelerator mass spectrometry (AMS) is an ultra-sensitive technique for isotopic ratio measurements. In the biomedical field, AMS can be used to measure femtomolar concentrations of labeled drugs in body fluids, with direct applications in early drug development such as Microdosing. Likewise, the regenerative properties of cells which are of fundamental significance in stem-cell research can be determined with an accuracy of a few years by AMS analysis of human DNA. However, AMS nominally requires about 1 mg of carbon per sample which is not always available when dealing with specific body substances such as localized, organ-specific DNA samples. Consequently, it is of analytical interest to develop methods for the routine analysis of small samples in the range of a few tens of mu g. We have used a 5 MV Pelletron tandem accelerator to study small biological samples using AMS. Different methods are presented and compared. A 12 C-carrier sample preparation method is described which is potentially more sensitive and less susceptible to contamination than the standard procedures.

  • 21.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Forsgard, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Biological AMS at Uppsala University: Status report2010In: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, ISSN 0168-583X, E-ISSN 1872-9584, Vol. 268, no 7-8, p. 884-886Article in journal (Refereed)
    Abstract [en]

    In January 2007 a new research program was initiated at Uppsala University focusing on the biological applications of AMS. We have used a 5 MV Pelletron Tandem accelerator to study biological samples. With Microdosing applications in mind, a variety of measurements have been performed on human blood, plasma and urine that have been labeled with a C-14-labeled pharmaceutical drug covering a concentration range, spanning 3 orders of magnitude. Furthermore, by studying small sample amounts and low concentrations, we have demonstrated sensitivity in the hundred zeptomole range for a small pharmaceutical substance in human blood. Another application of interest, based on the enhanced C-14 activity from the cold war bomb-peak, is dating of DNA molecules providing fundamental data for the regenerative medicine and stem cell research community. We show data on a sensitive carrier method for measuring the isotopic ratio of small biological sample in the few mu gC range.

  • 22.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Forsgård, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    FemtoMolar measurements using accelerator mass spectrometry2009In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 23, no 5, p. 557-563Article in journal (Refereed)
    Abstract [en]

    Accelerator mass spectrometry (AMS) is an ultra-sensitive analytical  method suitable for the detection of sub-nM concentrations of labeled   biological substances such as pharmaceutical drugs in body fluids. A  limiting factor in extending the concentration measurements to the   sub-pM range is the natural C-14 content in living tissues. This was  circumvented by separating the labeled drug from the tissue matrix,  using standard high-performance liquid chromatography (HPLC)   procedures. As the separated total drug amount is in the few fg range,  it is not possible to use a standard AMS sample preparation method,  where mg sizes are required. We have utilized a sensitive carbon carrier method where a C-14-deficient compound is added to the HPLC fractions and the composite sample is prepared and analyzed by AMS.   Using 50 mu L human blood plasma aliquots, we have demonstrated concentration measurements below 20 JFM, containing sub-amol amounts of   the labeled drug. The method has the immediate potential of operating in the sub-fM region.

  • 23.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Håkansson, Karl
    Höglund, Urban
    Grahn-Westin, Annika
    Nilsson, Sten
    Márquez, Marcela
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Holmberg, Anders R.
    Application of accelerator mass spectrometry to macromolecules: preclinical pharmacokinetic studies on a polybisphosphonate2011In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 25, no 17, p. 2453-2458Article in journal (Refereed)
    Abstract [en]

    Data on the use of accelerator mass spectrometry (AMS) in conjunction with in vivo studies of macromolecular drugs are scarce. The present study shows the versatility of this technique when investigating the pharmacokinetics (PK) of a macromolecular drug candidate, a polybisphosphonate conjugate (ODX). The aforementioned is a polymer (molecular weight similar to 30 kDa) constituting a carbohydrate backbone with covalently linked ligands (aldendronate and aminoguanidine) and is intended for treatment of osteoporosis and the therapy of bone metastasis from prostate cancer. The conjugate is prepared through partial oxidation of the carbohydrate and sequential coupling of the ligands by reductive amination. (14)C was incorporated in the conjugate by means of coupling a commercially available (14)C-lysine in the conjugation sequence. Fifteen rats were injected intravenously with (14)C-labelled ODX (150 mu g, 14 Bq/rat) and blood samples were collected at 1, 2, 4, 6, and 24 h post-injection (3 rats/time point). Liver, spleen and kidney samples were collected at 4 and 24 h post-injection. Blood from each time point (triplicate) were collected for AMS measurement determining the isotopic ratio ((14)C/(12)C) and consequently the drug concentration in blood. ODX showed a transient presence in blood circulation; 93% of the total dose was cleared from the circulation within 1 h. The half-life after 1 h was estimated to be about 3 h; 0.7% of the administered (14)C dose of ODX remained in circulation after 24 h. The major (14)C accumulation was in the liver, the spleen and the kidneys indicating the probable route of metabolism and excretion. This study demonstrates the versatility of AMS for pharmacological in vivo studies of macromolecules. Labelling with (14)C is relatively simple, inexpensive and the method requires minimal radioactivity, eliminating the need for radioprotection precautions in contrast to methods using scintillation counting.

  • 24.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Håkansson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Accelerator mass spectrometry of ultra-small samples with applications in the biosciences2013In: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, ISSN 0168-583X, E-ISSN 1872-9584, Vol. 294, p. 97-103Article in journal (Refereed)
    Abstract [en]

    An overview is presented covering the biological accelerator mass spectrometry activities at Uppsala University. The research utilizes the Uppsala University Tandem laboratory facilities, including a 5 MV Pelletron tandem accelerator and two stable isotope ratio mass spectrometers. In addition, a dedicated sample preparation laboratory for biological samples with natural activity is in use, as well as another laboratory specifically for C-14-labeled samples. A variety of ongoing projects are described and presented. Examples are: (1) Ultra-small sample AMS. We routinely analyze samples with masses in the 5-10 mu g C range. Data is presented regarding the sample preparation method, (2) bomb peak biological dating of ultra-small samples. A long term project is presented where purified and cell-specific DNA from various part of the human body including the heart and the brain are analyzed with the aim of extracting regeneration rate of the various human cells, (3) biological dating of various human biopsies, including atherosclerosis related plaques is presented. The average built up time of the surgically removed human carotid plaques have been measured and correlated to various data including the level of insulin in the human blood, and (4) In addition to standard microdosing type measurements using small pharmaceutical drugs, pre-clinical pharmacokinetic data from a macromolecular drug candidate are discussed.

  • 25.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Håkansson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Small sample Accelerator Mass Spectrometry for biomedical applications2015In: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, ISSN 0168-583X, E-ISSN 1872-9584, Vol. 361, p. 43-47Article in journal (Refereed)
    Abstract [en]

    The Accelerator Mass Spectrometry activities at Uppsala University include a group dedicated to the biomedical applications, involving natural level samples, as well as C-14-labeled substances requiring separate handling and preparation. For most applications sufficient sample amounts are available but many applications are limited to samples sizes in the mu g-range. We have developed a preparation procedure for small samples biomedical applications, where a few mu g C can be analyzed, albeit with compromised precision. The latest results for the small sample AMS method are shown and some of the biomedical activities at our laboratory are presented.

  • 26.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Håkansson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Wacker, L.
    ETH, Ion Phys, Otto Stern Weg 5, CH-8093 Zurich, Switzerland..
    Synal, H-A
    ETH, Ion Phys, Otto Stern Weg 5, CH-8093 Zurich, Switzerland..
    Performance report for the low energy compact radiocarbon accelerator mass spectrometer at Uppsala University2016Conference paper (Refereed)
    Abstract [en]

    A range of ion beam analysis activities are ongoing at Uppsala University, including Accelerator Mass Spectrometry (AMS). Various isotopes are used for AMS but the isotope with the widest variety of applications is radiocarbon. Up until recently, only the 5 MV Pelletron tandem accelerator had been used at our site for radiocarbon AMS, ordinarily using 12 MeV C-14,13,12(3+) ions. Recently a new radiocarbon AMS system, the Green-MICADAS, developed at the ion physics group at ETH Zurich, was installed. The system has a number of outstanding features which will be described. The system operates at a terminal voltage of 175 kV and uses helium stripper gas, extracting singly charged carbon ions. The low- and high energy mass spectrometers in the system are stigmatic dipole permanent magnets (0.42 and 0.97 T) requiring no electrical power nor cooling water. The system measures both the C-14/C-12 and the C-13/C-12 ratios on-line. Performance of the system is presented for both standard mg samples as well as mu g-sized samples.

  • 27.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Håkansson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Life science application utilizing radiocarbon tracing2013In: Radiocarbon, ISSN 0033-8222, E-ISSN 1945-5755, Vol. 55, no 2-3, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Radiocarbon-based accelerator mass spectrometry (AMS) facilities at Uppsala University include a measurement center for archaeological applications and a separate entity dedicated to life science research. This paper addresses the latter, with the intention of giving a brief description of the biomedical activities at our laboratory, as well as presenting new data. The ultra-small sample preparation method, which can be used down to a few µg C samples, is outlined and complemented with new results. Furthermore, it is shown that the average secondary ion current performance for small samples can be improved by increasing the distance between the cathode surface and the pressed graphite surface. Finally, data is presented for a new application: Amyloidoses are a group of diseases where the conformational changes in specific proteins’ structure lead to the formation of extracellular deposits that spread and increase in mass and eventually may lead to total organ failure and death. The formation timeframe is unknown and yet it is an important clue for the elucidation of the mechanism. We present results on bomb-peak dating of 4 different types of purified amyloid proteins from human postmortem heart and spleen samples. The data indicates that the average measured age of the carbon originating from the systemic amyloid types studied here correspond to a few years before the death of the subject. This suggests that a major part of the fibril formation takes place during the last few years before death, rather than as an accumulation of amyloid deposits over decades.

  • 28.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Håkansson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Possnert, Possnert
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Life science applications utilizing radiocarbon tracing2013In: Radiocarbon, ISSN 0033-8222, E-ISSN 1945-5755, Vol. 55, no 2-3, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Radiocarbon-based accelerator mass spectrometry (AMS) facilities at Uppsala University include a measurement center for archaeological applications and a separate entity dedicated to life science research. This paper addresses the latter, with the intention of giving a brief description of the biomedical activities at our laboratory, as well as presenting new data. The ultra-small sample preparation method, which can be used down to a few μg C samples, is outlined and complemented with new results. Furthermore, it is shown that the average secondary ion current performance for small samples can be improved by increasing the distance between the cathode surface and the pressed graphite surface. Finally, data is presented for a new application: Amyloidoses are a group of diseases where the conformational changes in specific proteins’ structure lead to the formation of extracellular deposits that spread and increase in mass and eventually may lead to total organ failure and death. The formation timeframe is unknown and yet it is an important clue for the elucidation of the mechanism. We present results on bomb-peak dating of 4 different types of purified amyloid proteins from human postmortem heart and spleen samples. The data indicates that the average measured age of the carbon originating from the systemic amyloid types studied here correspond to a few years before the death of the subject. This suggests that a major part of the fibril formation takes place during the last few years before death, rather than as an accumulation of amyloid deposits over decades.

  • 29.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Bryhni, H
    Palminger-Hallén, I
    Ståhle, Lars
    Biological Accelerator Mass Spectrometry at Uppsala University2009In: Applied Radiation and Isotopes, ISSN 0969-8043, E-ISSN 1872-9800, Vol. 67, no 3, p. 495-499Article in journal (Refereed)
    Abstract [en]

    A new research programme for the biological applications of accelerator   mass spectrometry has been initiated at Uppsala University and the   first results are presented. A C-14-labelled pharmaceutical substance   has been dissolved in human blood, plasma and urine and diluted over 3   orders of magnitude. The measured drug concentrations were found to be   in good agreement with the predicted values. Furthermore, the effect of   the sample preparation background contribution has been studied as the   sample amount was varied down to sub-mu l sizes.

  • 30.
    Salehpour, Mehran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Bryhni, Heige
    Subattomole sensitivity in biological accelerator mass spectrometry2008In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 80, no 10, p. 3515-3521Article in journal (Refereed)
    Abstract [en]

    The Uppsala University 5 MV Pelletron tandem accelerator has been used to study C-14-labeled biological samples utilizing accelerator mass spectrometry (ANIS) technology. We have adapted a sample preparation method for small biological samples down to a few tens of micrograms of carbon, involving among others, miniaturizing of the graphitization reactor. Standard AMS requires about 1 mg of carbon with a limit of quantitation of about 10 amol. Results are presented for a range of small sample sizes with concentrations down to below 1 pM of a pharmaceutical substance in human blood. It is shown that C-14-labeled molecular markers can be routinely measured from the femtomole range down to a few hundred zepto-mole (10(-21) mol), without the use of any additional separation methods.

  • 31.
    Spalding, Kirsty L.
    et al.
    Karolinska Inst, Dept Mol & Cell Biol, SE-17177 Stockholm, Sweden.;Karolinska Inst, Metab Unit, SE-17176 Stockholm, Sweden.;Karolinska Inst, Karolinska Univ Hosp, KI AZ Integrated Cardio Metab Ctr, Dept Med, SE-17176 Stockholm, Sweden..
    Bernard, Samuel
    Univ Lyon, Inst Camille Jordan, F-69622 Villeurbanne, France..
    Näslund, Erik
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, SE-18288 Stockholm, Sweden..
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Appelsved, Lena
    Karolinska Inst, Dept Mol & Cell Biol, SE-17177 Stockholm, Sweden..
    Fu, Keng-Yeh
    Karolinska Inst, Dept Mol & Cell Biol, SE-17177 Stockholm, Sweden..
    Alkass, Kanar
    Karolinska Inst, Dept Mol & Cell Biol, SE-17177 Stockholm, Sweden..
    Druid, Henrik
    Karolinska Inst, Dept Oncol Pathol, SE-17177 Stockholm, Sweden.;Natl Board Forens Med, Dept Forens Med, SE-11120 Stockholm, Sweden..
    Thorell, Anders
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, SE-18288 Stockholm, Sweden.;Karolinska Inst, Ersta Hosp, Dept Surg, SE-11691 Stockholm, Sweden..
    Rydén, Mikael
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, SE-14186 Stockholm, Sweden..
    Arner, Peter
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, SE-14186 Stockholm, Sweden..
    Impact of fat mass and distribution on lipid turnover in human adipose tissue2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15253Article in journal (Refereed)
    Abstract [en]

    Differences in white adipose tissue (WAT) lipid turnover between the visceral (vWAT) and subcutaneous (sWAT) depots may cause metabolic complications in obesity. Here we compare triglyceride age and, thereby, triglyceride turnover in vWAT and sWAT biopsies from 346 individuals and find that subcutaneous triglyceride age and storage capacity are increased in overweight or obese individuals. Visceral triglyceride age is only increased in excessively obese individuals and associated with a lower lipid removal capacity. Thus, although triglyceride storage capacity in sWAT is higher than in vWAT, the former plateaus at substantially lower levels of excess WAT mass than vWAT. In individuals with central or visceral obesity, lipid turnover is selectively increased in vWAT. Obese individuals classified as 'metabolically unhealthy' (according to ATPIII criteria) who have small subcutaneous adipocytes exhibit reduced triglyceride turnover. We conclude that excess WAT results in depot-specific differences in lipid turnover and increased turnover in vWAT and/or decreased turnover in sWAT may result in metabolic complications of overweight or obesity.

  • 32. Spalding, Kl
    et al.
    Bergmann, O.
    Alkass, K.
    Buchholz, B.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Liebl, J.
    Steier, P.
    Kutschera, W.
    Bernard, S.
    Druid, H.
    Frisen, J.
    Radiocarbon analysis of neurogenesis in the adult human brain2013In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no S1, p. S117-S117Article in journal (Other academic)
  • 33. Spaulding, Kirsty
    et al.
    Bergmann, Olaf
    Alkass, Kanar
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Huttner, Hagen
    Boström, Emil
    Westerlund, Isabelle
    Vial, Céline
    Buchholz, Bruce
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Mash, Deborah
    Druid, Henrik
    Frisén, Jonas
    Dynamics of Hippocampal Neurogenesis in Adult Humans2013In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 153, no 6, p. 1219-1227Article in journal (Refereed)
    Abstract [en]

    Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have func- tional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear- bomb-test-derived 14C in genomic DNA, and we present an integrated model of the cell turnover dy- namics. We found that a large subpopulation of hip- pocampal neurons constituting one-third of the neu- rons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neu- rons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neuro- genesis may contribute to human brain function.

  • 34.
    Yeung, Maggie S. Y.
    et al.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Djelloul, Mehdi
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Steiner, Embla
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Bernard, Samuel
    Univ Lyon, CNRS, UMR 5208, Inst Camille Jordan, Villeurbanne, France.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Possnert, Göran
    Brundin, Lou
    Karolinska Inst, Karolinska Univ Hosp, Div Neurol, Dept Clin Neurosci, Stockholm, Sweden.
    Frisen, Jonas
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Dynamics of oligodendrocyte generation in multiple sclerosis2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 566, no 7745, p. 538-+Article in journal (Refereed)
    Abstract [en]

    Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths(1). Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process(2-4). Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans(5-9), it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of C-14 derived from nuclear testing in genomic DNA(10), we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques-thinly myelinated lesions that are thought to represent remyelinated areas-were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.

  • 35.
    Yeung, Maggie
    et al.
    Karolinska Insitutet, CMB.
    Sofia, Zdunek
    Karolinska Insitutet, CMB.
    Bergmann, Olaf
    Karolinska Insitutet, CMB.
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Alkass, Kanar
    Perl, Shira
    Tisdale, John
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Brundin, Lou
    Druid, Henrik
    Karolinska Insitutet, CMB.
    Frisén, Jonas
    Karolinska Insitutet, CMB.
    Dynamics of Oligodendrocyte Generation and Myelination in the Human Brain2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 4, p. 766-774Article in journal (Refereed)
    Abstract [en]

    The myelination of axons by oligodendrocytes has been suggested to be modulated by experience, which could mediate neural plasticity by optimizing the performance of the circuitry. We have assessed the dynamics of oligodendrocyte generation and myelination in the human brain. The number of oligodendrocytes in the corpus callosum is established in childhood and remains stable after that. Analysis of the integration of nuclear bomb test-derived 14C revealed that myelin is exchanged at a high rate, whereas the oligodendrocyte population in white matter is remarkably stable in humans, with an annual exchange of 1/300 oligodendrocytes. We conclude that oligodendrocyte turnover contributes minimally to myelin remodeling in human white matter and that this instead may be carried out by mature oligodendrocytes, which may facilitate rapid neural plasticity.

1 - 35 of 35
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