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  • 1.
    Benyamin, Gad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Frisk, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Arsenic is decreased in target organs during viral infection in mice2006In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 20, no 2, p. 121-126Article in journal (Refereed)
    Abstract [en]

    Arsenic (As), a potentially toxic trace element, has been shown to influence viral replication and resistance to microbial infection. However, the impact of infection on the normal As status in target organs involved in the disease process has not been studied to date. In the present study, As was measured through inductively coupled plasma mass spectrometry in the plasma, liver, spleen, kidney, heart, pancreas and brain at days 1 and 3 of coxsackievirus B3 infection in female Balb/c mice. The severity of the infection was assessed from clinical signs of disease. The infection changed plasma As in a biphasic pattern with a small increase (n.s.) at day 1 that turned into a decreasing trend (13%, p<0.05) by day 3. In the liver, spleen, heart, pancreas and kidney As was unchanged at day 1 but, at day 3, it had decreased by 71% (p<0.01), 64% (p<0.01), 55% (p<0.01), 63% (p<0.01) and 73% (p<0.01), respectively. In the brain, As went unchanged. The pathophysiological interpretation of these findings requires further research.

  • 2.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Frisk, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Molin, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hjelm, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Trace element balance is changed in infected organs during acute Chlamydophila pneumoniae infection in mice2008In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 21, no 2, p. 229-237Article in journal (Refereed)
    Abstract [en]

    Most infectious diseases are accompanied by changed levels of several trace elements in the blood. However, sequential changes in trace elements in tissues harbouring bacterial infections have not been studied. In the present study the respiratory pathogen Chlamydophila pneumoniae (C. pneumoniae), adapted to C57BL/6J mice, was used to study whether the balance of trace elements is changed in infected organs. Bacteria were quantitatively measured by real-time PCR in the blood, lungs, liver, aorta, and heart on days 2, 5, and 8 of the infection. Concentrations of 13 trace elements were measured in the liver, heart, and serum by inductively coupled plasma mass-spectrometry (ICP-MS). Infected mice developed expected clinical signs of disease and bacteria were found in lungs, liver, and heart on all days. The number of bacteria peaked on day 2 in the heart and on day 5 in the liver. The copper/zinc (Cu/Zn) ratio in serum increased as a response to the infection. Cu increased in the liver but did not change in the heart. Iron (Fe) in serum decreased progressively, whereas in the heart it tended to increase, and in the liver it progressively increased. C. pneumoniae may thus cause a changed trace element balance in target tissues of infection that may be pivotal for bacterial growth.

  • 3.
    Frisk, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Danersund, Antero
    Hudecek, Romuald
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Changed clinical chemistry pattern in blood after removal of dental amalgam and other metal alloys supported by antioxidant therapy2007In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 120, no 1-3, p. 163-170Article in journal (Refereed)
    Abstract [en]

    This study aimed to investigate a possible connection between removal of dental amalgam restorations supported by antioxidant therapy and indicative changes of clinical chemistry parameters. A group of 24 patients, referred for complaints related to amalgam restorations, underwent a removal of their amalgams. All patients were treated with antioxidants (vitamin B-complex, vitamin C, vitamin E, and sodium selenite). An age- and sex-matched control group of 22 individuals was also included. The mercury (Hg) and selenium (Se) concentration in plasma, Hg concentration in erythrocytes, and 17 clinical chemistry variables were examined in three groups: patients before amalgam removal (Before), patients after amalgam removal (After), and control individuals (Control). The Hg and Se values decreased (p < 0.05) in plasma, and the Hg concentration decreased (p < 0.05) in erythrocytes after amalgam removal. The variables serum lactate dehydrogenase (serum LDH) and serum sodium differed significantly both when comparing Control with Before (p < 0.01) and Before with After (p < 0.01). The variables white blood cell count (WBC), blood neutrophil count, blood eosinophil count, blood basophil count, blood lymphocyte count, blood monocyte count, serum potassium, and serum creatinine differed in the Before/After test (p < 0.05). Multivariate statistics (discriminant function analysis) could separate the groups Before and After with only one misclassification.

  • 4.
    Frisk, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Darnerud, Per Ola
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sequential trace element changes in serum and blood during a common viral infection in mice2007In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 21, no 1, p. 29-36Article in journal (Refereed)
    Abstract [en]

    When trace elements are used as diagnostic tools during disease, it is important to know whether the balance is changed in free or bound elements. Although acute infections are associated with changed trace element balance in serum/plasma, it is not known whether changes occur concomitantly in serum and blood. In the present study the human coxsackievirus B3 (CB3), here adapted to Balb/c mice, was used to study whether infection alters the normal physiological trace element balance in blood and serum. Virus was quantitatively measured in two target organs (pancreas and liver) of this infection by reverse transcription polymerase chain reaction (RT-PCR), showing high concentrations of virus proving ongoing infection. Concentrations of 14 elements were measured in whole blood and serum using inductively coupled plasma mass spectrometry (ICP-MS) on days 3, 6 and 9 of the infection. Free and total thyroxine were measured in serum to prove metabolic changes associated with the infection. The thyroxine decreased, while iron and the Cu/Zn ratio in serum increased as a response to the infection. No clear changes in these elements were observed in blood. Cd and Hg tended to decrease in serum but to increase in blood, indicating accumulation in blood cells. Moreover, Al showed a similar decreasing trend in both serum and blood. A correlation between serum and blood levels was observed at different time points of the disease for 9 of the elements. However, As was the only element indicating correlations between serum and blood during the entire course of the disease.

  • 5.
    Frisk, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Lindvall, Anders
    Hudecek, Romuald
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Decrease of trace elements in erythrocytes and plasma after removal of dental amalgam and other metal alloys2006In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 113, no 3, p. 247-259Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to determine the concentration changes of 13 elements in erythrocytes and plasma after the removal of dental amalgam and other metal alloys. Blood samples from 250 patients were collected, separated into erythrocytes and plasma, and analyzed by inductively coupled plasma-mass spectrometry. The 250 patients were divided into 3 groups (Negative, Zero, and Positive) depending on their estimation of quality of life in an earlier study. Magnesium in plasma, selenium and mercury in plasma, and erythrocytes showed decreased concentrations after amalgam removal in all groups (p < 0.05). Titanium in plasma, copper in plasma, and erythrocytes and zinc in plasma exhibited decreased concentrations after amalgam removal in the Negative and Positive groups (p < 0.05). Silver in plasma and gold in erythrocytes decreased in the Zero and Positive groups after amalgam removal (p < 0.05). Copper in erythrocytes and silver and gold in plasma showed higher concentrations after amalgam removal in the Negative compared to the Positive group (p < 0.05), suggesting that patients in the Negative group excrete metals slowly. Moreover, the cobalt levels in plasma were lowest in the Negative group and only this group showed a significant increase in vitamin B12 levels in blood after amalgam removal.

  • 6.
    Hylander, Lars D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Air and Water Science.
    Lindvall, Anders
    Uhrberg, Roland
    Gahnberg, Lars
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Mercury recovery in situ of four different dental amalgam separators2006In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 366, no 1, p. 320-336Article in journal (Refereed)
    Abstract [en]

    Amalgam separators are used to physically remove dental amalgam from waste water in dental clinics. They are thereby supposed to reduce mercury (Hg) emissions to the municipal waste water system to acceptable levels. We here present results from a comparative study in situ of three amalgam separators available on the market, all with a claimed efficiency of 99% according to Danish and ISO protocols, and using sedimentation as the principle of separation. We also present corresponding data for an investigational prototype of an improved separator. The obtained efficiency of the three commercial separators is far below what is stated by the manufacturer and by authorities assumed to be the efficiency in clinical conditions. They reduced Hg emissions by 79 - 91%, leaving an average Hg content in outgoing waste water of 1.5 mg L(-1). However, the prototype separator participating in this study retained 99.9% of the waste water Hg emissions, leaving an average Hg content in outgoing waste water of 0.004 mg L(-1). Physical restrictions prohibit sedimentary type separators to recover the Hg fractions causing the largest damages in wastewater treatment plants. This fraction is not considered in the ISO protocol for testing amalgam separators, which therefore needs to be revised. Abolishing the use of dental amalgam and cleaning the tubing systems is the most efficient long-term solution to reduce Hg emissions from dental clinics. Until then, Hg emissions originating from placing, polishing or removing existing amalgam fillings, should be counteracted by the use of low-emission amalgam separators, already on the market or presently being developed for use alone or together with sedimentary type amalgam separators.

  • 7.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Minqin, Ren
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Watt, Frank
    Iron and copper accumulation in the brain of coxsackievirus-infected mice exposed to cadmium2006In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 102, no 3, p. 308-313Article in journal (Refereed)
    Abstract [en]

    Cadmium (Cd) is a potentially toxic metal widely distributed in the environment and known to cause adverse health effects in humans. During coxsackievirus infection, the concentrations of essential and nonessential trace elements (e.g., iron (Fe), copper (Cu), and Cd) change in different target organs of the infection. Fe and Cu are recognized cofactors in host defence reactions, and Fe is known to be associated with certain pathological conditions of the brain. However, whether nonessential trace elements could influence the balance of essential trace elements in the brain is unknown. In this study the brain Fe, Cu, and Cd contents were measured through inductively coupled plasma mass spectrometry and their distributions determined by nuclear microscopy in the early phase (day 3) of coxsackievirus B3 (CB3) infection in nonexposed and in Cd-exposed female Balb/c mice. In CB3 infection the brain is a well-known target that has not been studied with regard to trace element balance. The brain concentration of Cu compared with that of noninfected control mice was increased by 9% (P < 0.05) in infected mice not exposed to Cd and by 10% (not significant) in infected Cd-exposed mice. A similar response was seen for Fe, which in infected Cd-exposed mice, compared to noninfected control mice, tended to increase by 16%. Cu showed an even tissue distribution, whereas Fe was distributed in focal deposits. Changes in Cd concentration in the brain of infected mice were less consistent but evenly distributed. Further studies are needed to define whether the accumulation and distribution of trace elements in the brain have an impact on brain function.

  • 8.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Minqin, Ren
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Watt, Frank
    Selenium and mercury are redistributed to the brain during viral infection in mice2005In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 108, no 1-3, p. 215-224Article in journal (Refereed)
    Abstract [en]

    As part of the general host response to coxsackievirus B3 (CB3) infection, the concentration of essential and nonessential trace elements changes in different target organs of the infection. Essential (e.g., Se) and nonessential (e.g., Hg) trace elements are known to interact and affect inflammatory tissue lesions induced by CB3 infection. However, it is unknown whether these changes involve the brain. In the present study, the brain Hg and Se contents were measured through inductively coupled plasma-mass spectrometry and their distribution investigated by means of nuclear microscopy in the early phase (d 3) of CB3 infection in normally fed female Balb/c mice. Because of the infection, the concentration of Hg (4.07 +/- 0.46 ng/g wet wt) and Se (340 +/- 16 ng/g wet wt) in the brain increased twofold for Hg (8.77 +/- 1.65 ng/g wet wt, p < 0.05) and by 36% for Se (461 +/- 150 ng/g wet wt, ns). Nuclear microscopy of brain sections from mice having elevated Se and Hg concentrations failed to find localized levels of the elements high enough to make detection possible, indicating approximately homogeneous tissue distribution. Although the pathophysiological interpretation of these findings requires further research, the increase of Hg in the brain during infection might have an influence on the pathogenesis of the disease.

  • 9.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Metal biology: aspects of beneficial effects2007In: Ambio, ISSN 0044-7447, E-ISSN 1654-7209, Vol. 36, no 1, p. 107-110Article in journal (Refereed)
  • 10.
    Molin, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Frisk, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Hjelm, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Arsenic trioxide influences viral replication in target organs of coxsackievirus B3-infected mice2010In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 12, no 12-13, p. 1027-1034Article in journal (Refereed)
    Abstract [en]

    New antiviral agents are urgently needed. Based on in vitro studies, arsenic trioxide (As2O3) seems to affect viral replication, although this has been studied only marginally in vivo. In this study the replication of coxsackievirus B3 (CVB3) was studied in Balb/c mice administered 1 mg As2O3/kg bw once daily during 7 days of infection and in Vero cells exposed for 3 or 5 days to 0.4, 2 or 4 µM As2O3. Viral RNA was measured by reverse-transcription PCR (RT-PCR) (in vitro and in vivo) and arsenic concentration was measured by inductively coupled plasma-mass spectrometry (ICP-MS) (in vivo). In vivo, As2O3 decreased viral RNA in the brain on days 3 (by 81%; p<0.05) and 7 (by 97%; p<0.01) and in the pancreas on day 7 (by 75%; p<0.05), two of the target organs of this infection. The results were confirmed in vitro, where As2O3 dose-dependently reduced viral RNA, with the effect being more pronounced in the surrounding culture medium than inside the infected cells, indicating an impaired virion release. Thus, As2O3 reduced CVB3 replication both in vitro and in vivo, indicating that As2O3 is a viable option in the pursuit of new therapeutic agents against viral infections.

  • 11. Yaqob, Amer
    et al.
    Danersund, Antero
    Stejskal, Vera
    Lindvall, Anders
    Hudecek, Romuald
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Metal-specific lymphocyte reactivity is downregulated after dental metal replacement2006In: Neuro - endocrinology letters, ISSN 0172-780X, Vol. 27, no 1-2, p. 189-197Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: This study was done to evaluate the results and clinical relevance of an optimized lymphocyte proliferation test, MELISA, for metal-induced inflammation in patients with CFS-like symptoms. The treatment of patients consisted of the replacement of incompatible dental materials (RID) together with supportive anti-oxidant therapy.

    DESIGN OF THE STUDY: 513 patients were tested by MELISA at the beginning of the study. Out of this group, 248 patients were available for follow-up MELISA after RID.

    METHODS: In MELISA, lymphocytes are isolated from the blood and cultivated with different metal salts in tissue culture medium containing 10% inactivated human AB+ serum or autologous serum. After 5 days, the presence of metal-reactive lymphocytes are measured by isotope labelling of newly formed DNA in growing lymphoblasts and evaluated by calculating the Stimulation Index.

    RESULTS: Nickel was the most common sensitizer, followed by inorganic mercury, thimerosal, lead, cadmium, palladium and gold. After RID treatment, a decrease of metal-specific lymphocyte responses in patients who reacted to metals at the beginning of the study could be observed. The cultivation of lymphocytes in autologous and homologous serum did not significantly affect the results. Simultaneous, the health status of patients improved as well.

    CONCLUSIONS: Replacement of incompatible dental materials resulted in down-regulation of metal-induced lymphocyte sensitivity in vitro, as well as in the improvement of health status of majority of patients with unspecific CFS-like symptoms.

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