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  • 1.
    A Hulten, Maj
    et al.
    University Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands England .
    Patel, Suketu
    University Warwick, Department Biol Science, Coventry CV4 7AL, W Midlands England .
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Iwarsson, Erik
    Karolinska University Hospital, Karolinska Institute, Department Mol Med and Surg, Clin Genet Unit, S-17176 Stockholm, Sweden .
    On the origin of the maternal age effect in trisomy 21 Down syndrome: the Oocyte Mosaicism Selection model2010In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990, Vol. 139, no 1, p. 1-9Article, review/survey (Refereed)
    Abstract [en]

    We have recently documented that trisomy 21 mosaicism is common in human foetal ovaries. On the basis of this observation we propose that the maternal age effect in Down syndrome (DS) is caused by the differential behaviour of trisomy 21 in relation to disomy 21 oocytes during development from foetal life until ovulation in adulthood. in particular, we suggest that trisomy 21 oocytes, lagging behind those that are disomic, may escape the timed pruning of the seven million in foetal life to the 300-400 finally selected for ovulation. The net effect of this preferential elimination will be an accumulation of trisomy 21 oocytes in the ovarian reserve of older women. We here highlight the implications of this Oocyte Mosaicism Selection (OMS) model with respect to the prevalent view that the maternal age effect is complex, dependent on many different biological and environmental factors. We examine conclusions drawn from recent large-scale studies in families, tracing DNA markers along the length of chromosome 21q between parents and DS children, in comparison to the OMS model. We conclude that these family linkage data are equally compatible with the maternal age effect originating from the accumulation of trisomy 21 oocytes with advancing maternal age. One relatively straightforward way to get to grips with what is actually going on in this regard would be to compare incidence of trisomy 21 oocytes (and their pairing configurations) in foetal ovaries with that in oocytes at the meiosis I stage from adult women.

  • 2.
    Andersson, Patiyan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kolaric, Aleksandra
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Departments of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Departments of Urology, Örebro University Hospital, Örebro, Sweden..
    Andrén, Ove
    Departments of Urology, Örebro University Hospital, Örebro, Sweden..
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Karlsson, Mats G
    Departments of Pathology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arraysManuscript (Other academic)
    Abstract [en]

    The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

  • 3.
    Björk, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Lenner, Liselotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Persson, Birgitta
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Conjugated polythiophene probes target lysosome-related acidic vacuoles in cultured primary cells2007In: Molecular and Cellular Probes, ISSN 0890-8508, Vol. 21, no 5-6, p. 329-337Article in journal (Refereed)
    Abstract [en]

    Conformation-sensitive optical probes for studying biological processes and structures are of great interest. The present work shows for the first time that conjugated polyelectrolyte (CPE) probes can be used for specific targeting of chromatin, nuclear and cytoplasmatic vesicles, and cytoskeletal components in a complex system of cultured cells. One of the probes could also be used for vital staining of live cells. When bound to different entities, the polythiophene derivative probes emitted light with different colors due to the unique spectral properties of these conformation sensitive probes. The physical pre-requisites for binding could also be exploited for characterization of the target. Unexpectedly, lysosome-related acidic vacuoles were targeted in cultured primary cells by both anionic, cationic, and zwitter-ionic polythiophene derivatives. Pre-treatment with Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase, caused redistribution of the staining. The targeting of lysosome-related acidic vesicles could not be demonstrated in transformed cells (melanoma, neuroblastoma, and prostate cancer cell lines), indicating a difference in the localization, structure, accessibility, or quantity of the target in cultured normal cells as compared with the malignant cell lines. The chemical nature of the conjugated polyelectrolyte complex in the cytoplasmatic vacuoles remains elusive.

  • 4.
    Björnsson, Bergthor
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Winbladh, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Trulsson, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gullstrand, Per
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Remote or Conventional Ischemic Preconditioning -Local Liver Metabolism in Rats Studied with Microdialysis2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 176, no 1, p. 55-62Article in journal (Refereed)
    Abstract [en]

    Background. Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. Material and Methods. Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceeded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. Results. Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC = 759 (84) mu M] and the IRI = 732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. Conclusions. IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.

  • 5.
    Bojmar, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ellegard, Sander
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 84815-Article in journal (Refereed)
    Abstract [en]

    The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

  • 6.
    Cauvi, DM
    et al.
    The Scripps Institute, La Jolla, CA, USA.
    Pollard, KM
    The Scripps Institute, La Jolla, CA, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Autoimmune models2010In: Comprehensive Toxicology / [ed] Charlene A. McQueen, Oxford: Academic Press , 2010, 2, p. 413-438Chapter in book (Other academic)
    Abstract [en]

    Toxicology is the study of the nature and actions of chemicals on biological systems. In more primitive times, it really was the study of poisons. However, in the early 1500s, it was apparent to Paracelsus that "the dose differentiates a poison and a remedy". Clearly, the two most important tenets of toxicology were established during that time. The level of exposure (dose) and the duration of exposure (time) will determine the degree and nature of a toxicological response.

  • 7.
    Cederbrant, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    The Primary Lymphocyte Culture in the Diagnosis of Drug- and Metal-Induced Allergy2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Drugs and metals are examples of xenobiotics that can induce hypersensitivity in humans. These adverse reactions are classified as allergy if repeated exposure leads to the same type of clinical manifestation. Together with the clinical history, the skin test is the most commonly used test for the diagnosis of allergic disease. However, in vivo testing per se has drawbacks such as the risk of potentiation of the allergy or even sensitisation to a given test substance. For this reason in vitro testing is an attractive diagnostic alternative since it does not involve any exposure of the test subject to the allergen.

    The lymphocyte transformation test (LTT) has been used to complement the diagnosis of allergy to drugs and metals for more than thirty years. The principle behind this test is to show the presence of allergen-specific memory lymphocytes in peripheral blood, which is a sine qua non of a true allergy. LTT reveals the proliferation of such cells by showing DNA synthesis as the uptake of 3H-thymidine in primary PBMC (peripheral blood mononuclear cell) cultures treated with the allergen. However, LIT has not yet been generally accepted as a stand-alone test in the diagnosis of allergy. One reason for this is that different chemical properties of the allergens may lead to either false positive or false negative LTT responses.

    In the present study we investigated allergy to the drug bacampicillin and to the metals Au, Pd, Ni and Hg. Three different protocols for LTT: LIT in micro cultures (LTT-micro), LTT in macro cultures (LTT-macro) and memory lymphocyte immunostimulation assay (MELISA) were compared using a skin test or clinical history as reference methods. LTI showed a sensitivity of 87% and a specificity of 90% when used in the diagnosis of allergy to bacampicillin. When allergy to Au, Pd, Ni and Hg was investigated, the sensitivity was 33- 95% and the specificity 0-79%. There were no significant differences between the test protocols, except that MELISA showed a significantly higher specificity than LTT-micro and LTT-macro when Hg2+ was used as antigen. Even so, this specificity was only 70%, which would result in 30 of 100 healthy subjects receiving a false diagnosis of Hg allergy when using the MELISA protocol. Ni2+ also induced high numbers of false-positive LTI responses, 77-85% patch-test negative subjects showed positive results to these metals. However, group comparisons showed a significantly higher proliferation intensity in allergic than in nonallergic groups for all allergens except Hg2+. Furthermore, only 56% of patients with verified allergy to mercury showed a positive MELISA, a sensitivity that is unacceptably low.

    Following these findings, we investigated whether other endpoints than DNA synthesis could be used to discriminate allergic from healthy subjects, using primary PBMC cultures with Hg2+ or Ni2+ as a model system. Analysis of the T-cell receptor Vß profiles of lymphoblasts induced by these metal ions showed individual patterns, and there was no difference between healthy and allergic groups. However, the fraction of CD4+/Vß2+ cells correlated significantly with the proliferation intensity induced by Hg2+ in patients with a verified Hg allergy but not in non-allergic controls. Interestingly, such a correlation was not seen with CD8+/Nß2+ cells. This indicates that Hg2+ does not function as a superantigen, since classical superantigens also stimulate CD8+ lymphocytes. When Ni2+ was used as antigen we found significantly higher IL-10 production in allergic than in non-allergic subjects, despite no significant difference in proliferation intensity between these two groups.

    In conclusion, the LTT test is useful for the diagnosis of allergy to bacampicillin. Regarding Au, Pd and Ni the LIT has low validity and can only be used to discriminate groups of allergic from non-allergic individuals. LTT with Hg2+ and Ni2+ is not useful for the diagnosis of allergy to these metals since a high fraction of non-allergic individuals show positive results, irrespective of the test protocol used. This thesis calls for further studies on the usefulness of in vitro IL-10 production for the diagnosis of Ni allergy as well as on the specificity of in vitro induced CD4+N~2+ lymphoblasts from Hg allergic subjects.

    List of papers
    1. Characterization of primary recall in vitro lymphocyte responses to bacampicillin in allergic subjects
    Open this publication in new window or tab >>Characterization of primary recall in vitro lymphocyte responses to bacampicillin in allergic subjects
    2000 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 30, no 10, p. 1450-1459Article in journal (Refereed) Published
    Abstract [en]

    Background

    Antigen-specific cell lines or clones are often used as models of drug-specific allergy. However, cloning procedures are time consuming, and the repeated antigen stimulation cycles as well as the addition of various growth enhancers may affect the in vivo relevance of these systems.

    Objective

    Using bacampicillin-allergic subjects, we wanted to investigate the applicability of primary recall in vitro lymphocyte responses to characterize type I and type IV allergy. The sensitivity and specificity of LTT (Lymphocyte transformation test), when used as an in vitro diagnostic tool, were also assessed.

    Methods

    A total of 39 patients with symptoms of type I (rhinitis) or type IV (allergic contact dermatitis, ACD) allergy following occupational exposure to bacampicillin, were included. Ten individuals without penicillin allergy or occupational exposure to bacampicillin served as controls. All subjects were LTT tested. Four patients with rhinitis and two patients with ACD were available for studying the immunophenotype and the TCR-Vβ repertoire of bacampicillin induced lymphoblasts as well as the cytokine profiles and expression of the activation markers CD23 and CD134 in primary PBMC cultures.

    Results

    LTT was positive in 87% and at least one of the skin tests was positive in 85% of the patients with allergic symptoms. 69% of the patients with type I allergies were patch test-positive. Results from LTT and skin test correlated in 87% of the cases. The combined sensitivity of LTT and skin tests was 92%. The specificity of LTT was 90% in healthy controls. Bacampicillin induced lymphoblasts were mainly CD4 + in both ACD and rhinitis patients. The TCR-Vβ profiles of the predominant CD4 + lymphoblasts were heterogeneous with individual skewing towards Vβ2, Vβ3, Vβ5.1 and/or Vβ14. An increased expression of IFNγ was detected in bacampicillin treated PBMC cultures from the ACD but not from rhinitis patients. IL-5 was detected in bacampicillin exposed PBMC cultures from all patients but not from healthy controls. This Th2 environment could also be verified by CD23 and CD134 expression.

    Conclusion

    LTT and skin tests are equally sensitive in identifying bacampicillin allergic subjects. When the two tests are combined, the sensitivity increases. The patch test is useful not only for detection of type IV but also for the identification of type I allergies. When using primary PBMC cultures, IFNγ is the most suitable cytokine to discriminate between type I and type IV allergy. IL-5 can possibly be used as a general marker for bacampicillin induced allergy. Thus, primary cell cultures may be considered as an alternative to T-cell lines or clones for the study of drug induced allergy.

    Keywords
    activation markers, allergic contact dermatitis, bacampicillin, cytokines, flow cytometry, human lymphocytes, lymphocyte transformation test, rhinitis, skin test, T-cell receptor Vβ
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25872 (URN)10.1046/j.1365-2222.2000.00905.x (DOI)10309 (Local ID)10309 (Archive number)10309 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    2. In vitro Lymphocyte Proliferation as Compared to Patch Test Using Gold, Palladium and Nickel
    Open this publication in new window or tab >>In vitro Lymphocyte Proliferation as Compared to Patch Test Using Gold, Palladium and Nickel
    1997 (English)In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 112, no 3, p. 212-217Article in journal (Refereed) Published
    Abstract [en]

    Background: A conventional lymphocyte transformation test (LTT) was compared to the commercially available MELISA® (memory lymphocyte immuno-stimulation assay), a lymphoproliferative assay that has been suggested to be a valuable instrument for the diagnosis of metal allergy. Sensitivity and specificity of the two assays were calculated using a patch test as a reference method.

    Methods: 34 patients were patch-tested for gold sodium thiosulfate, palladium chloride and nickel sulfate, and the lymphocyte proliferation to these metals was tested in vitro using mononuclear cells from peripheral blood.

    Results: No significant differences regarding sensitivity and specificity were found between MELISA and conventional LTT. The sensitivity varied between 55 and 95% and the specificity between 17 and 79%.

    Conclusions: The low specificity of the two in vitro assays suggests that they are not useful for diagnosis of contact allergy to the metals gold, palladium and nickel, since a large number of false-positive results will be obtained.

    Keywords
    Lymphocytes human, Skin test, Metals
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79573 (URN)10.1159/000237456 (DOI)
    Available from: 2012-08-09 Created: 2012-08-09 Last updated: 2017-12-07Bibliographically approved
    3. IL-10 production in primary PBMC cultures: an in vitro marker for nickel allergy?
    Open this publication in new window or tab >>IL-10 production in primary PBMC cultures: an in vitro marker for nickel allergy?
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Nickel (Ni) is one of the most known contact allergens and at present, patch test and clinical history constitute the two cornerstones in the diagnostic procedure. Since the patch test is inherited with in vivo provocation and subjective interpretation of the test result, a non-invasive in vitro method with objective interpretation of the test result has long been searched for. Unfortunately, in vitro diagnosis of Ni- allergy is hampered by the fact that Ni2+ is able to trigger in vitro proliferative responses in lymphocytes from both Ni-allergic and non-allergic subjects. This constitutes a problem when LTT (lymphocyte transformation test), the most frequently used in vitro test as a complement in the diagnosis of contact allergy, is considered for Ni allergy. However, other parameters in the in vitro response might be more useful. In this study, Ni2+-stimulated primary PBMC-cultures derived from Ni-allergic and non-allergic subjects were assessed for IFN-γ, IL-4, IL-10 and IL-17. Also, Ni2+ induced lymphoblasts from such cultures were characterized by their immunophenotype and T-cell receptor Vß-affiliation.

    We found a significantly higher release of IL-10 in Ni2+ treated cultures from allergic than from non-allergic subjects. The Ni2+-induced lymphoblasts from both groups were predominantly CD4+. Two of the allergic patients (n=5) showed a skewing towards TCR-Vß17, a Vß family earlier associated with Ni-allergy. A significant increase in CD134 and CD23 expression indicated that Ni2+ activates B-cells in vitro. In conclusion, IL-10 seems to be a promising marker for Ni-allergy using primary PBMC cultures. Further, flow cytometric screening of Ni2+ induced lymphoblasts can detect expanded TCR-Vß families that may be used for preparation of Ni-specific T cell clones.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79574 (URN)
    Available from: 2012-08-09 Created: 2012-08-09 Last updated: 2012-08-09Bibliographically approved
    4. In vitro Lymphoproliferative Assays with HgCl2 Cannot Identify Patients with Systemic Symptoms Attributed to Dental Amalgam
    Open this publication in new window or tab >>In vitro Lymphoproliferative Assays with HgCl2 Cannot Identify Patients with Systemic Symptoms Attributed to Dental Amalgam
    Show others...
    1999 (English)In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 78, no 8, p. 1450-1458Article in journal (Refereed) Published
    Abstract [en]

    Dental amalgam is suspected, by some exposed individuals, to cause various systemic psychological, sensory, and neurological symptoms. Since not all amalgam-bearers experience such reactions, an individual characteristic—for example, a susceptible immune system—might explain these conditions. In vitro lymphocyte proliferation is a valuable tool in the diagnosis of allergy. With HgCl2 as the antigen, however, the test is hampered, because Hg2+ can cause unspecific lymphocyte proliferation, optimal at 1.4 to 9.5 μg HgCl2/mL. Recently, the use of suboptimal HgCl2 concentrations (≤ 0.5 μg/mL) has been suggested to circumvent these problems. The main aim of this study was to investigate whether patients with systemic symptoms alleged to result from the presence of dental amalgam differ from healthy controls, with reference to in vitro lymphoproliferative responses to HgCl2 ≤ 0.5 μg/mL. Three different test protocols—lymphocyte transformation test (LTT) in micro- and macro-cultures, and the memory lymphocyte immunostimulation assay (MELISA®)—were used. Other immune parameters—such as a standard patch test for dental materials, the number of T- and B-lymphocytes, monocytes, granulocytes, and NK cells in peripheral blood, allergic symptoms, and predisposition-were also investigated. Twenty-three amalgam patients, 30 healthy blood donors with amalgam, ten healthy subjects without amalgam, and nine patients with oral lichen planus (OLP) adjacent to dental amalgam and a positive patch test to Hg0 were tested. None of the investigated immune parameters revealed any significant differences between amalgam patients and controls. The sensitivity of in vitro lymphocyte proliferation ranged from 33 to 67%, with the OLP patients as a positive control group, and the specificity from 0 to 70% for healthy controls with a negative patch test to Hg°. Thus, despite the use of HgCl2 ≤ 0.5 μg/mL, a high frequency of positive results was obtained among healthy subjects with or without dental amalgam. Consequently, in vitro lymphocyte proliferation with HgCl2 cannot be used as an objective marker for mercury allergy in dental amalgam-bearers.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25875 (URN)10.1177/00220345990780081101 (DOI)10312 (Local ID)10312 (Archive number)10312 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    5. Characterization of mercuric mercury (Hg2+)-induced lymphoblasts from patients with mercury allergy and from healthy subjects
    Open this publication in new window or tab >>Characterization of mercuric mercury (Hg2+)-induced lymphoblasts from patients with mercury allergy and from healthy subjects
    2000 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 121, no 1, p. 23-30Article in journal (Refereed) Published
    Abstract [en]

    Hg2+ induces lymphocyte proliferation when added to cell cultures from both healthy and mercury-allergic subjects. Consequently, when measuring DNA synthesis a possible Hg2+-specific response, resulting from proliferating memory cells, cannot be discriminated from a non-allergic response. The mechanism behind this non-allergic response is unknown but a superantigenic effect of Hg2+ has been suggested. In this study, five mercury-allergic patients, with oral lichen planus (OLP) lesions adjacent to dental amalgam and a positive patch test to Hg0, and five healthy subjects without amalgam were examined. The immunophenotype and the T cell receptor Vβ (TCR Vβ) repertoire of Hg2+-induced lymphoblasts as well as the expression of the lymphocyte activation markers CD23 and CD134 were analysed for possible differences between healthy and allergic subjects. The mechanism of Hg2+-induced proliferation was examined by comparing the TCR Vβ expression of Hg- and staphylococcal enterotoxin B (SEB)-activated lymphoblasts, the latter used as a positive superantigen control. It was not possible to discriminate between mercury-allergic and healthy subjects using the immunophenotype or the TCR Vβ profile of the Hg2+-induced lymphoblasts or the expression of CD23 and CD134. However, Hg2+-induced CD4+ lymphoblasts showed a skewing towards Vβ2. This relative increase in Vβ2 was only detected in the CD4+ but not in the CD8+ lymphoblast population. In conclusion, Hg2+ induced a proliferation-dependent skewing towards CD4+ but not CD8+ lymphocytes expressing Vβ2. In this respect Hg2+ differs from the classical bacterial superantigen SEB, which also stimulates unique TCR Vβ families among CD8+ cells.

    Keywords
    Hg allergy, oral lichen planus, human lymphocytes, in vitro
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25873 (URN)10.1046/j.1365-2249.2000.01268.x (DOI)10310 (Local ID)10310 (Archive number)10310 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 8.
    Cederbrant, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Andersson, C.
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    Andersson, T.
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    Marcusson-Ståhl, Maritha
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    IL-10 production in primary PBMC cultures: an in vitro marker for nickel allergy?Manuscript (preprint) (Other academic)
    Abstract [en]

    Nickel (Ni) is one of the most known contact allergens and at present, patch test and clinical history constitute the two cornerstones in the diagnostic procedure. Since the patch test is inherited with in vivo provocation and subjective interpretation of the test result, a non-invasive in vitro method with objective interpretation of the test result has long been searched for. Unfortunately, in vitro diagnosis of Ni- allergy is hampered by the fact that Ni2+ is able to trigger in vitro proliferative responses in lymphocytes from both Ni-allergic and non-allergic subjects. This constitutes a problem when LTT (lymphocyte transformation test), the most frequently used in vitro test as a complement in the diagnosis of contact allergy, is considered for Ni allergy. However, other parameters in the in vitro response might be more useful. In this study, Ni2+-stimulated primary PBMC-cultures derived from Ni-allergic and non-allergic subjects were assessed for IFN-γ, IL-4, IL-10 and IL-17. Also, Ni2+ induced lymphoblasts from such cultures were characterized by their immunophenotype and T-cell receptor Vß-affiliation.

    We found a significantly higher release of IL-10 in Ni2+ treated cultures from allergic than from non-allergic subjects. The Ni2+-induced lymphoblasts from both groups were predominantly CD4+. Two of the allergic patients (n=5) showed a skewing towards TCR-Vß17, a Vß family earlier associated with Ni-allergy. A significant increase in CD134 and CD23 expression indicated that Ni2+ activates B-cells in vitro. In conclusion, IL-10 seems to be a promising marker for Ni-allergy using primary PBMC cultures. Further, flow cytometric screening of Ni2+ induced lymphoblasts can detect expanded TCR-Vß families that may be used for preparation of Ni-specific T cell clones.

  • 9.
    Christiansen Clifford, Jenny
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Färm, Gunilla
    Department of Dermatology, University Hospital, 701 85 Örebro, Sweden.
    Eid-Forest, Ruth
    Department of Dermatology, University Hospital, 701 85 Örebro, Sweden.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Dermatology and Venerology UHL.
    Cederbrant, Karin
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology.
    Interferon-gamma secreted from peripheral blood mononuclear cells as a possible diagnostic marker for allergic contact dermatitis to gold2006In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 55, no 2, p. 101-112Article in journal (Refereed)
    Abstract [en]

    10% of patch-tested patients have a positive reaction to gold. Most lack clinical symptoms, but allergic contact dermatitis (ACD) to gold is increasing. In this study, 77 dermatological outpatients were divided into 3 groups depending on epicutaneous patch test outcomes: a group positive to gold (EPI+), a group negative to gold (EPI-), and a group with irritant reactions to gold (EPI-IR). Lymphocytes were stimulated in vitro with gold sodium thiosulfate. Proliferation was assessed using the lymphocyte transformation test (LTT), and cytokine secretion was assessed using a multibead array (Luminex; Linco Research Inc., St. Charles, MO, USA), in order to evaluate whether an in vitro method with high diagnostic accuracy could be devised. The EPI+ group showed a significantly increased secretion of interferon (IFN)-gamma, interleukin (IL)-2, and IL-13 and also showed a significantly higher stimulation indexes for LTT, compared to the other 2 subject groups. Sensitivity and specificity were calculated for all methods individually and combined, but IFN-gamma assessment alone was the most accurate method for identifying ACD to gold, with sensitivity and specificity of 81.8% and 82.1%, respectively. This method also identified 87.5% of the EPI-IR subjects as non-allergic. Therefore, assessment of secretion of IFN-gamma should be a valuable complement to patch test for diagnosing gold allergy.

  • 10.
    Clifford, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Gold allergy: In vitro studies using peripheralblood mononuclear cells2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Positive patch test reactions to gold are commonly seen in dermatology clinics, but it is veryunusual for the patients to actually have any clinical symptoms. It is also common with irritantreactions that are not linked to adaptive immunity. Therefore, a deeper understanding of themechanisms underlying allergic contact dermatitis (ACD) reaction, and the search for acomplementing diagnostic tool, is important.

    In paper I we included three subject groups; one with morphologically positive patch testreactions to gold sodium thiosulphate (GSTS, the gold salt used in patch testing), one withnegative patch tests, and one with irritant reactions to gold. Blood samples were collected andexamined regarding the proliferation rate and which cytokines were secreted after culturingwith GSTS. We saw that the cultured lymphocytes from the allergic donors proliferated at asignificantly higher rate than the two other subject groups, and that the cells secreted cytokinesof both Th1 (Interferon (IFN) -g and Interleukin (IL) -2) and Th2 (IL-13 and IL-10) types. Theallergic donors secreted significantly higher levels of IFN-g, IL-2 and IL-13 than the two othersubject groups. Both the negative and irritant subject groups showed suppressed levels of thecytokines as compared with the unstimulated cultures, demonstrating the immunosuppressingeffects of gold.

    We also examined whether any of the analyzed markers, alone or combined, could be usedas an aid for diagnosing ACD to gold. We found that the IFN-g assay yielded the highestsensitivity (81.8 %) and specificity (82.1 %), and also identified 87.5 % of the irritant group asnon-allergic.

    In paper II we decided to investigate what cell types and subsets that reacted to the goldstimulation. We analyzed proliferation rate and expression of CD45RA, CD45R0, cutaneouslymphocyte-associated antigen (CLA) and the chemokine receptors CXCR3, CCR4 andCCR10. Similar to what has previously been published about nickel (Ni) allergy, the cells fromthe gold-allergic subjects that reacted to the GSTS stimulation expressedCD3+CD4+CD45R0+CLA+. However, contrary to findings in studies on Ni-reactive cells, wesaw no differences between allergic and non-allergic subjects regarding any of the chemokine receptors studied.

    In conclusion, we found that analysis of IFN-g might be a useful complement to patchtesting, possibly of interest in avoiding the need for repeated tests to rule out irritant reactions.We also saw that the cells that proliferated in response to gold were memory T-cells expressingCD4 and CLA, the marker for skin-homing. However, these cells did not express elevatedlevels of any of the chemokine receptors analyzed, showing that there are both similarities anddifferences between the mechanisms for Ni allergy and gold allergy.

    List of papers
    1. Interferon-gamma secreted from peripheral blood mononuclear cells as a possible diagnostic marker for allergic contact dermatitis to gold
    Open this publication in new window or tab >>Interferon-gamma secreted from peripheral blood mononuclear cells as a possible diagnostic marker for allergic contact dermatitis to gold
    Show others...
    2006 (English)In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 55, no 2, p. 101-112Article in journal (Refereed) Published
    Abstract [en]

    10% of patch-tested patients have a positive reaction to gold. Most lack clinical symptoms, but allergic contact dermatitis (ACD) to gold is increasing. In this study, 77 dermatological outpatients were divided into 3 groups depending on epicutaneous patch test outcomes: a group positive to gold (EPI+), a group negative to gold (EPI-), and a group with irritant reactions to gold (EPI-IR). Lymphocytes were stimulated in vitro with gold sodium thiosulfate. Proliferation was assessed using the lymphocyte transformation test (LTT), and cytokine secretion was assessed using a multibead array (Luminex; Linco Research Inc., St. Charles, MO, USA), in order to evaluate whether an in vitro method with high diagnostic accuracy could be devised. The EPI+ group showed a significantly increased secretion of interferon (IFN)-gamma, interleukin (IL)-2, and IL-13 and also showed a significantly higher stimulation indexes for LTT, compared to the other 2 subject groups. Sensitivity and specificity were calculated for all methods individually and combined, but IFN-gamma assessment alone was the most accurate method for identifying ACD to gold, with sensitivity and specificity of 81.8% and 82.1%, respectively. This method also identified 87.5% of the EPI-IR subjects as non-allergic. Therefore, assessment of secretion of IFN-gamma should be a valuable complement to patch test for diagnosing gold allergy.

    Keywords
    Allergic contact dermatitis, cytokines, gold, interferon-γ, lymphocyte transformation test, multibead assay
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20564 (URN)10.1111/j.1600-0536.2006.00908.x (DOI)16930235 (PubMedID)
    Available from: 2009-09-14 Created: 2009-09-14 Last updated: 2017-12-13Bibliographically approved
    2. T-cells expressing CD4, CD45RO and CLA from gold-allergic but not healthy subjects react to gold sodium thiosufate in vitro
    Open this publication in new window or tab >>T-cells expressing CD4, CD45RO and CLA from gold-allergic but not healthy subjects react to gold sodium thiosufate in vitro
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Patch test positivity to gold is common in western societies, but in contrast to nickel (Ni) allergy it is uncommon that the patch test positive patient shows any clinical symptoms. In this study we investigated cytotoxic effects of gold sodium thiosulphate (GSTS) on peripheral blood mononuclear cells (PBMC), including different T-cell subsets. We also separated lymphocytes from allergic and non-allergic subjects into CD45RA and CD45R0 cell fractions. We also expressed CLA. The fraction of analyzed the effects of GSTS using lymphocyte transformation test, propidium iodide staining and flow cytometry to determine lymphocyte memory status, expression of chemokine receptors and cutaneous lymphocyte-associated antigen (CLA), and compared the results to what has previously been reported on Ni allergy. We found that only the cells from the allergic subjects proliferated in the lymphocyte transformation test (LTT), and in the CD45R0 fraction there was a dose-dependent increase in the fraction of CD3/CD4 cells. Similar to Ni-allergy, these CD3/CD4/CD45R0 cells also expressed CLA. The fraction of CD3/CD8 in the CD45R0 enriched fraction decreased with GSTS exposure. In contrast to Ni allergy, however, we found no differences between the allergic and non-allergic subjects regarding the chemokine receptors CCR4, CXCR3 and CCR10.

    Keywords
    contact dermatitis t-cell CD45RA CD45R0 CLA gold
    National Category
    Dermatology and Venereal Diseases
    Identifiers
    urn:nbn:se:liu:diva-19965 (URN)
    Available from: 2009-09-14 Created: 2009-08-21 Last updated: 2010-01-14Bibliographically approved
  • 11.
    Clifford, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Dermatology and Venerology UHL.
    Karin, Cederbrant
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    T-cells expressing CD4, CD45RO and CLA from gold-allergic but not healthy subjects react to gold sodium thiosufate in vitroManuscript (preprint) (Other academic)
    Abstract [en]

    Patch test positivity to gold is common in western societies, but in contrast to nickel (Ni) allergy it is uncommon that the patch test positive patient shows any clinical symptoms. In this study we investigated cytotoxic effects of gold sodium thiosulphate (GSTS) on peripheral blood mononuclear cells (PBMC), including different T-cell subsets. We also separated lymphocytes from allergic and non-allergic subjects into CD45RA and CD45R0 cell fractions. We also expressed CLA. The fraction of analyzed the effects of GSTS using lymphocyte transformation test, propidium iodide staining and flow cytometry to determine lymphocyte memory status, expression of chemokine receptors and cutaneous lymphocyte-associated antigen (CLA), and compared the results to what has previously been reported on Ni allergy. We found that only the cells from the allergic subjects proliferated in the lymphocyte transformation test (LTT), and in the CD45R0 fraction there was a dose-dependent increase in the fraction of CD3/CD4 cells. Similar to Ni-allergy, these CD3/CD4/CD45R0 cells also expressed CLA. The fraction of CD3/CD8 in the CD45R0 enriched fraction decreased with GSTS exposure. In contrast to Ni allergy, however, we found no differences between the allergic and non-allergic subjects regarding the chemokine receptors CCR4, CXCR3 and CCR10.

  • 12.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L.
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression2008Article in journal (Other academic)
    Abstract [en]

    Objective: The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD.

    Methods: One hundred and twenty-nine patients with biopsy proven NAFLD were included in a long-term histological follow-up study. Clinical and histological course were compared between NASH, “borderline NASH”, and “not NASH” patients. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up.

    Results: Eighty-eight patients accepted re-evaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend towards higher baseline NAS was seen in patients (n = 7) that developed end-stage liver disease (3.1 ± 0.9 vs. 2.4 ± 1.0; P = 0.062). Baseline NAS was significantly higher in patients with progressive fibrosis (2.9 ± 0.9 vs. 2.2 ± 0.9; P = 0.017), and NAS was independently associated with significant fibrosis progression tested in a multivariate analysis (P = 0.023). However, 18% of patients without NASH progressed significantly in fibrosis stage.

    Conclusion: Although the NAS is independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS-score groups.

  • 13.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.2007In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 1, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins.

    Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up.

    Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage.

    Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.

  • 14.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden;.
    Thorelius, Lars
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Long-term follow-up of patients with NAFLD and elevated liver enzymes.2006In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 44, no 4, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

  • 15.
    Ekstrand, Jimmy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nielsen, Jesper B
    University South Denmark.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Zalups, Rudolfs K
    Mercer University.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mercury toxicokinetics-dependency on strain and gender2010In: TOXICOLOGY AND APPLIED PHARMACOLOGY, ISSN 0041-008X, Vol. 243, no 3, p. 283-291Article in journal (Refereed)
    Abstract [en]

    Mercury (Hg) exposure from dental amalgam fillings and thimerosal in vaccines is not a major health hazard, but adverse health effects cannot be ruled out in a small and more susceptible part of the exposed population. Individual differences in toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.SW and B10.S mice and their F1- and F2-hybrids were given HgCl2 with 2.0 mg Hg/L drinking water and traces of Hg-203. Whole-body retention (WBR) was monitored until steady state after 5 weeks, when the organ Hg content was assessed. Despite similar Hg intake, A.SW males attained a 20-30% significantly higher WBR and 2- to 5-fold higher total renal Hg retention/concentration than A.SW females and B10.S mice. A selective renal Hg accumulation but of lower magnitude was seen also in B10.S males compared with females. Differences in WBR and organ Hg accumulation are therefore regulated by non-H-2 genes and gender. Lymph nodes lacked the strain- and gender-dependent Hg accumulation profile of kidney, liver and spleen. After 15 days without Hg A.SW mice showed a 4-fold higher WBR and liver Hg concentration, but 11-fold higher renal Hg concentration, showing the key role for the kidneys in explaining the slower Hg elimination in A.SW mice. The trait causing higher mercury accumulation was not dominantly inherited in the F1 hybrids. F2 mice showed a large inter-individual variation in Hg accumulation, showing that multiple genetic factors influence the Hg toxicokinetics in the mouse. The genetically heterogeneous human population may therefore show a large variation in mercury toxicokinetics.

  • 16.
    Elander, Nils
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Uematsu, Satoshi
    Department of Host Defense, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
    Akira, Shizuo
    Department of Host Defense, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 372, no 1, p. 249-253Article in journal (Refereed)
    Abstract [en]

    The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. © 2008 Elsevier Inc. All rights reserved.

  • 17.
    Falck, Anna-Karin
    et al.
    Lund University, Sweden .
    Bendahl, Par-Ola
    Lund University, Sweden .
    Chebil, Gunilla
    Lund University, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ferno, Marten
    Lund University, Sweden .
    Ryden, Lisa
    Lund University, Sweden .
    Biomarker expression and St Gallen molecular subtype classification in primary tumours, synchronous lymph node metastases and asynchronous relapses in primary breast cancer patients with 10 years follow-up2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 140, no 1, p. 93-104Article in journal (Refereed)
    Abstract [en]

    Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classification in primary breast tumours, synchronous lymph node metastases and asynchronous relapses and relate the results to 10-year breast cancer mortality (BCM). Tissue microarrays were constructed from archived tissue blocks of primary tumours (N = 524), synchronous lymph node metastases (N = 147) and asynchronous relapses (N = 36). The samples were evaluated by two independent pathologists according to oestrogen receptor (ER), progesterone receptor (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and in situ hybridisation. The expression of biomarkers and molecular subtypes in the primary tumour was compared with that in the synchronous lymph node metastases and relapses, and related to 10-year BCM. Discordances were found between primary tumours and relapses (ER: p = 0.006, PR: p = 0.04, Ki67: p = 0.02, HER2: p = 0.02, St Gallen subtypes: p = 0.07) but not between primary tumours and metastatic lymph node. Prognostic information was gained by the molecular subtype classification in primary tumours and nodal metastases; triple negative subtype had the highest BCM compared with the luminal A subtype (primary tumours: HR 4.0; 95 % CI 2.0-8.2, p andlt; 0.001, lymph node metastases: HR 3.5; 95 % CI 1.3-9.7, p = 0.02). When a shift in subtype inherence between primary tumour and metastatic lymph node was identified, the prognosis seemed to follow the subtype of the lymph node. Molecular profiles are not stable throughout tumour progression in breast cancer. Prognostic information for individual patients appears to be available from the analysis of biomarker expression in synchronous metastatic lymph nodes. The study supports biomarker analysis also in asynchronous relapses.

  • 18.
    Fernö, Mårten
    et al.
    Lunds universitet.
    Haglund, Monica
    Universitetssjukhuset MAS, Malmö.
    Bendahl, Pär-Ola
    Lunds universitet.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Rydén, Lisa
    Universitetssjukhuset i Lund.
    Analys av HER2 i bröstcancer kvalitetssäkrad. Viktig behandlingsprediktiv och prognostisk faktor2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 32-33, p. 2181-2184Article in journal (Other academic)
    Abstract [sv]

    Human epidermal growth factor receptor 2 (HER2) är en tyrosinkinasreceptor som förekommer överuttryckt i ca 15– 20 procent av invasiv bröstcancer och medför ökad risk för återfall i sjukdomen.

    HER2-status kan bestämmas immunhistokemiskt på proteinnivå eller med fluorescent in situ-hybridisering (FISH), som påvisar antalet genkopior. Analysen bör ingå vid rutindiagnostik av bröstcancer.

    Svenska HER2-analysgruppen utförde under 2005 och 2006 en reproducerbarhetsstudie av HER2-status genom att distribuera elva bröstcancerfall till patologlaboratorier i Sverige som rutinmässigt utför HER2-analyser.

    Resultaten visar att reproducerbarheten av HER2-status var god (2005) respektive mycket god (2006) för immunhistokemi och mycket god för FISH vid båda undersökningstillfällena.

  • 19.
    Franzén, Lennart E
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bodin, Lennart
    Unit of Biostatistics and Epidemiology, Clinical Research Centre, University Hospital, Örebro, Sweden.
    Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.2005In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 18, no 7, p. 912-916Article in journal (Refereed)
    Abstract [en]

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.

  • 20.
    Fryland, Linda
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Tobias
    Department of Molecular Biology, Umeå University, Umeå, Sweden.
    Bergström, Sven
    Department of Molecular Biology, Umeå University, Umeå, Sweden.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
    Mapping of T-cell subsets in relation to disease course in experimental Borrelia burgdorferi infection2012Manuscript (preprint) (Other academic)
    Abstract [en]

    Resolution of Lyme borreliosis has previously been shown to be associated with a strong initial Th1 response, followed by a subsequent Th2 response,  shutting off inflammation. We mapped markers for Th1, Th2, Th17, cytotoxic and T regulatory subsets in a murine model, where the outcome of Borrelia (B.) burgdorferi sensu stricto (s.s.) infection was altered by immune-deviation towards Th2 by exposure to a subtoxic dose of mercury. Twenty-one B. burgdorferi s.s.-infected (Bb), 21 immune-deviated B. burgdorferi s.s.-infected (BbId), and seven control C3H/HeN mice were sacrificed on days 15, 28 and 43 post-infection (p.i.) with B. burgdorferi s.s. BbId mice had increased joint swelling compared with Bb at the height of the disease (28 p.i.), and also showed a trend for increased spirochaetal load that became significant on day 43 p.i. BbId had an increased histopathology score on day 28 p.i. compared with both earlier and later time points. mRNA expression of IL-4 (p=0.018), IL-10 (p=0.018) and EBI-3 (p=0.009) decreased in Bb mice, but not in BbId, over the course of infection. A trend for higher expression of IL-12p40 mRNA in Bb mice compared with BbId was seen late in the disease course, while BbId showed trends for higher levels of Foxp3 and GM-CSF. At the protein level, BbId showed decreased levels of CXCL9 compared to the Bb group on day 15 p.i (p=0.007). Bb mice showed increases of CXCL9 and CXCL10 at all time points compared with day 0 p.i. (p≤0.014), whereas BbId mice showed an initial decrease in both chemokines at day 15 p.i. compared with day 0 (p≤0.008). In conclusion, both the clinical signs of infection and the trends for increased expression of pro-inflammatory GM-CSF and T-regulatory marker Foxp3 in BbId mice suggested ongoing inflammation. Although our findings support the need for a strong Th1 response followed by anti-inflammatory response for optimal resolution, the anti-inflammatory response seems to be more complex than only dampening the inflammation by a Th1-antagonistic Th2 response.

  • 21.
    Gabriela Sitaru, Ana
    et al.
    Medical University of Lubeck.
    Sesarman, Alina
    Medical University of Lubeck.
    Mihai, Sidonia
    Medical University of Lubeck.
    Chiriac, Mircea T
    Medical University of Lubeck.
    Zillikens, Detlef
    Medical University of Lubeck.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Solbach, Werner
    Medical University of Lubeck.
    Sitaru, Cassian
    University of Freiburg.
    T Cells Are Required for the Production of Blister-Inducing Autoantibodies in Experimental Epidermolysis Bullosa Acquisita2010In: JOURNAL OF IMMUNOLOGY, ISSN 0022-1767, Vol. 184, no 3, p. 1596-1603Article in journal (Refereed)
    Abstract [en]

    Epidermolysis bullosa acquisita is a prototypical organ-specific autoimmune disease caused by autoantibodies against type VII collagen of the dermal-epidermal junction. Although mechanisms of autoantibody-induced blister formation were extensively characterized, the initiation of autoantibody production in autoimmune blistering diseases is still poorly defined. In the current study, we addressed the role of T cells for the production of blister-inducing autoantibodies in mice immunized with type VII collagen. To detect autoreactive type VII collagen-specific T cells, lymph node cells from immunized SJL mice were stimulated in vitro with recombinant Ag, and their proliferation was measured by radioactive thymidine incorporation and flow cytometry analysis of CFSE-labeled cells. Interestingly, using synthetic peptides of the immunogen, partly different T and B cell epitopes in mice immunized with type VII collagen were demonstrated. In contrast to wild-type mice, immunization with type VII collagen of SJL athymic nude mice lacking T cells did not induce an autoimmune response and blistering phenotype. Importantly, SJL nude mice repleted with T cells from immunized wild-type mice showed a robust and durable autoantibody production resulting in subepidermal blistering disease in the recipients. Our present results demonstrate that T cells are required for the initiation of autoimmunity against type VII collagen in experimental epidermolysis bullosa acquisita and provide a basis for developing T cell-directed immunomodulatory strategies for this and related autoimmune diseases.

  • 22.
    Gati, Istvan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine.
    Landtblom, Anne-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Letter: Bent Spine Syndrome: A Phenotype of Dysferlinopathy or a Symptomatic DYSF Gene Mutation Carrier2012In: European Neurology, ISSN 0014-3022, E-ISSN 1421-9913, Vol. 67, no 5, p. 300-302Article in journal (Other academic)
    Abstract [en]

    n/a

  • 23.
    Gati, Istvan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Lindehammar, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Neurophysiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Neurophysiology UHL.
    Lindvall, B
    University Örebro, Örebro, Sweden .
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Landtblom, Anne-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland, Department of Medical Specialist.
    SENSORY ATAXIC NEUROPATHY WITH DYSARTHRIA/DYSPHAGIA AND OPHTHALMOPLEGIA (SANDO) - CASE HISTORIES in EUROPEAN JOURNAL OF NEUROLOGY, vol 18, issue SI, pp 282-2822011In: EUROPEAN JOURNAL OF NEUROLOGY, Wiley-Blackwell , 2011, Vol. 18, no SI, p. 282-282Conference paper (Refereed)
    Abstract [en]

    n/a

  • 24.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Effect of thimerosal on the murine immune system: especially induction of systemic autoimmunity2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The organic mercury compound ethylmercurithiosalicylate (thimerosal), an antiseptic and a preservative, has recently raised public health concern due to its presence in vaccines globally. Thimerosal dissociates in the body to thiosalicylate and ethyl mercury (EtHg), which is partly converted to inorganic mercuric mercury (Hg2+). The immunosuppressive, immunostimulatory, and de novo autoimmunogen effect of thimerosal in mice, as well as the accelerating/aggravating effect on spontaneous systemic autoimmunity including dose-response aspects were the subject of this thesis.

    Thimerosal perorally (590 μg Hg/kg body weight (bw)/day) to genetically susceptible (H-2s) mice caused immunosuppression during the first week with reduction of the total number of splenocytes, T- and B-cells. The suppression lasted 2 weeks for CD4+ cells, but was superseded by a strong immunostimulation/proliferation including T- as well as B-cells, and polyclonal B-cell activation (PBA). Antinuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin (AFA) appeared after 10 days, followed by renal mesangial and systemic vessel wall immune-complex (IC) deposits. The Lowest Observed Adverse Effect Level (LOAEL) was in the order AFA = glomerular and splenic vessel wall deposits < hyperimmunoglobulinemia < PBA. The LOAEL for AFA was 118 μg Hg/kg bw/day. The LOAEL for the different parameters of this thimerosal-induced systemic autoimmune condition (HgIA) was 3-11-fold higher compared with HgIA induced by HgCl2. The thimerosal-induced HgIA shared with HgCl2 a significant dose-response relationship, and requirement for: T-cells, the costimulatory factor CD28, the IFN-γ/IFN-γ-receptor pathway,but not IL-4. The mRNA expression in lymph nodes of IL-2, IFN-γ, IL-4, and IL-15 was significantly increased but not delayed compared with HgCl2.

    Treatment with the ubiquitous organic Hg compound methyl Hg using equimolar doses of Hg (533 μg Hg/kg bw/day) caused a transient immunosuppression, followed by a weak immunostimulation and AFA. The IgG AFA isotypes induced by the organic Hg compounds MeHg and EtHg were stable and dominated by a Th1-like pattern over a broad time- and dose range. Treatment with inorganic HgCl2 caused a dose- and time-dependent pattern of IgG AFA isotypes. Low doses favored a Th1-like pattern, a high dose a balanced or Th2-like pattern. Middle-range doses showed initially a Th1-like pattern which gradually evolved into a balanced or Th2-like pattern. The qualitative difference in IgG AFA isotypes between organic and inorganic Hg may be due to differences in activation and/or suppression of T-helper cell subsets or factors influencing the Th1/Th2-function. Speciation of the renal Hg2+ concentration and comparison with the threshold dose for induction of AFA by HgCl2 showed that even with the lowest doses of thimerosal and MeHg used in this thesis, the AFA response might from a dose threshold point of view have been caused by conversion of the organic Hg species to Hg2+.

    Primary treatment with inorganic Hg (HgCl2) accelerates/aggravates murine systemic autoimmunity, both spontaneous (genetic) and induced by other means. This capacity was assessed for thimerosal over a broad dose range using the (NZB X NZW)F1 hybrid mouse model. Significantly increased antinuclear antibodies (ANA) was seen after 4-7 weeks treatment (LOAEL 147 μg Hg/kg bw/day), and the response was dose-dependent up to 13 weeks. Renal mesangial and systemic vessel walls deposits similar to those in de novo HgIA were present after 7 weeks treatment. Twenty-two to 25 weeks treatment with thimerosal caused, in a dose-dependent fashion (LOAEL 295 μg Hg/kg bw/day), relocalization of the spontaneously developing glomerular IC deposits from the capillary vessel walls to the mesangium, which attenuated histological kidney damage and proteinuria, and increased survival. Thimerosal caused systemic vessel wall IC-deposits over a broad dose range: the Low Observed Adverse Effect Level (LOAEL) for renal and splenic vessel wall IC deposits was 18 and 9 μg Hg/kg bw/day, respectively. The No Observed Adverse Effect Level (NOAEL) could not be determined for the latter, since deposits were present even with the lowest dose used.

    Thimerosal causes in genetically susceptible mice an initial, transient immunosuppression which is superseded by a strong immunostimulation and systemic autoimmunity, sharing many characteristics with the HgIA induced by inorganic HgCl2. The IgG AFA isotype pattern is however qualitatively different, and the threshold dose substantially higher. In contrast, long-term treatment with thimerosal induces systemic vessel wall IC-deposits also using doses below those needed to induce HgIA de novo in H-2s mice.

    List of papers
    1. Dose-response study of thimerosal-induced murine systemic autoimmunity
    Open this publication in new window or tab >>Dose-response study of thimerosal-induced murine systemic autoimmunity
    2004 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 194, no 2, p. 169-179Article in journal (Refereed) Published
    Abstract [en]

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury.

    A.SW mice were exposed to 1.25–40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose–response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.

    Keywords
    Thimerosal, Ethylmercury, Mice, Autoimmunity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13815 (URN)10.1016/j.taap.2003.09.006 (DOI)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2009-08-18
    2. Immunosuppressive and autoimmune effects of thimerosal in mice
    Open this publication in new window or tab >>Immunosuppressive and autoimmune effects of thimerosal in mice
    Show others...
    2005 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 204, no 2, p. 109-121Article in journal (Refereed) Published
    Abstract [en]

    The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2s) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 μg Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-γ mRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment with increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-1-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2s strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (t1), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2s mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell co-stimulatory molecule CD28 (B10.S–CD28−/−), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2s strains with targeted mutations, we found that IFN-γ and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 81 μg Hg/g. EtHg made up 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.

    Keywords
    Thimerosal; Ethylmercury; Mice; Immunosuppression; Autoimmunity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13816 (URN)10.1016/j.taap.2004.08.019 (DOI)
    Available from: 2006-04-21 Created: 2006-04-21
    3. The autoimmunogen effect of the organic mercury species methyl mercury and ethyl mercury
    Open this publication in new window or tab >>The autoimmunogen effect of the organic mercury species methyl mercury and ethyl mercury
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13817 (URN)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2010-01-13
    4. Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury)
    Open this publication in new window or tab >>Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury)
    2006 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 214, no 1, p. 43-54Article in journal (Refereed) Published
    Abstract [en]

    Inorganic mercury may aggravate murine systemic autoimmune diseases which are either spontaneous (genetically determined) or induced by non-genetic mechanisms. Organic mercury species, the dominating form of mercury exposure in the human population, have not been examined in this respect. Therefore, ethyl mercury in the form of thimerosal, a preservative recently debated as a possible health hazard when present in vaccines, was administered in a dose of 0.156–5 mg/L drinking water to female (NZB × NZW)F1 (ZBWF1) mice. These mice develop an age-dependent spontaneous systemic autoimmune disease with high mortality primarily due to immune-complex (IC) glomerulonephritis. Five mg thimerosal/L drinking water (295 μg Hg/kg body weight (bw)/day) for 7 weeks induced glomerular, mesangial and systemic vessel wall IC deposits and antinuclear antibodies (ANA) which were not present in the untreated controls. After 22–25 weeks, the higher doses of thimerosal had shifted the localization of the spontaneously developing renal glomerular IC deposits from the capillary wall position seen in controls to the mesangium. The altered localization was associated with less severe histological kidney damage, less proteinuria, and reduced mortality. The effect was dose-dependent, lower doses having no effect compared with the untreated controls. A different effect of thimerosal treatment was induction of renal and splenic vessel walls IC deposits. Renal vessel wall deposits occurred at a dose of 0.313–5 mg thimerosal/L (18–295 μg Hg/kg bw/day), while splenic vessel wall deposits developed also in mice given the lowest dose of thimerosal, 0.156 mg/L (9 μg Hg/kg bw/day). The latter dose is 3- and 15-fold lower than the dose of Hg required to induce vessel wall IC deposits in genetically susceptible H-2s mice by HgCl2 and thimerosal, respectively. Further studies on the exact conditions needed for induction of systemic IC deposits by low-dose organic mercurials in autoimmune-prone individuals, as well as the potential effect of these deposits on the vessel walls, are warranted.

    Keywords
    Thimerosal; Mice; Autoimmunity; Immune-complex; (NZB × NZW)F1 mice
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13818 (URN)10.1016/j.taap.2005.12.004 (DOI)
    Available from: 2006-04-21 Created: 2006-04-21
  • 25.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury)2006In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 214, no 1, p. 43-54Article in journal (Refereed)
    Abstract [en]

    Inorganic mercury may aggravate murine systemic autoimmune diseases which are either spontaneous (genetically determined) or induced by non-genetic mechanisms. Organic mercury species, the dominating form of mercury exposure in the human population, have not been examined in this respect. Therefore, ethyl mercury in the form of thimerosal, a preservative recently debated as a possible health hazard when present in vaccines, was administered in a dose of 0.156–5 mg/L drinking water to female (NZB × NZW)F1 (ZBWF1) mice. These mice develop an age-dependent spontaneous systemic autoimmune disease with high mortality primarily due to immune-complex (IC) glomerulonephritis. Five mg thimerosal/L drinking water (295 μg Hg/kg body weight (bw)/day) for 7 weeks induced glomerular, mesangial and systemic vessel wall IC deposits and antinuclear antibodies (ANA) which were not present in the untreated controls. After 22–25 weeks, the higher doses of thimerosal had shifted the localization of the spontaneously developing renal glomerular IC deposits from the capillary wall position seen in controls to the mesangium. The altered localization was associated with less severe histological kidney damage, less proteinuria, and reduced mortality. The effect was dose-dependent, lower doses having no effect compared with the untreated controls. A different effect of thimerosal treatment was induction of renal and splenic vessel walls IC deposits. Renal vessel wall deposits occurred at a dose of 0.313–5 mg thimerosal/L (18–295 μg Hg/kg bw/day), while splenic vessel wall deposits developed also in mice given the lowest dose of thimerosal, 0.156 mg/L (9 μg Hg/kg bw/day). The latter dose is 3- and 15-fold lower than the dose of Hg required to induce vessel wall IC deposits in genetically susceptible H-2s mice by HgCl2 and thimerosal, respectively. Further studies on the exact conditions needed for induction of systemic IC deposits by low-dose organic mercurials in autoimmune-prone individuals, as well as the potential effect of these deposits on the vessel walls, are warranted.

  • 26.
    Havarinasab, Said
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology .
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Organic mercury compounds and autoimmunity2005In: Autoimmunity Reviews, ISSN 1568-9972, E-ISSN 1873-0183, Vol. 4, no 5, p. 270-275Article, review/survey (Refereed)
    Abstract [en]

    Based on in vitro studies and short-term in vivo studies, all mercurials were for a long time considered as prototypic immunosuppressive substances. Recent studies have confirmed that organic mercurials such as methyl mercury (MeHg) and ethyl mercury (EtHg) are much more potent immunosuppressors than inorganic mercury (Hg). However, Hg interacts with the immune system in the presence of a susceptible genotype to cause immunostimulation, antinucleolar antibodies targeting fibrillarin, and systemic immune-complex (IC) deposits, a syndrome called Hg-induced autoimmunity (HgIA). Recent studies in mice with a susceptible genotype has revealed that the immunosuppressive effect of MeHg and EtHg will within 1-3 weeks be superseded by immunostimulation causing an HgIA-like syndrome. At equimolar doses of Hg, MeHg has the weakest immunostimulating, autoimmunogen, and IC-inducing effect, while the effect of thimerosal is similar to that of inorganic mercury. The immunosuppression is caused by the organic mercurials per se. Since they undergo rapid transformation to inorganic Hg, studies are being undertaken to delineate the importance of the organic substances per se and the newly formed inorganic Hg for induction of autoimmunity. © 2004 Elsevier B.V. All rights reserved.

  • 27.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Björn, Erik
    Department of Chemistry, Analytical Chemistry, Umeå University, Umeå, Sweden.
    Pollard, K.M.
    Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Immunosuppressive and autoimmune effects of thimerosal in mice2005In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 204, no 2, p. 109-121Article in journal (Refereed)
    Abstract [en]

    The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2s) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 μg Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-γ mRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment with increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-1-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2s strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (t1), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2s mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell co-stimulatory molecule CD28 (B10.S–CD28−/−), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2s strains with targeted mutations, we found that IFN-γ and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 81 μg Hg/g. EtHg made up 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.

  • 28.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Lambertsson, Lars
    Department of Chemistry, Analytical Chemistry, Umeå University, Umeå, Sweden.
    Qvarnström, Johanna
    Department of Chemistry, Analytical Chemistry, Umeå University, Umeå, Sweden.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Dose-response study of thimerosal-induced murine systemic autoimmunity2004In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 194, no 2, p. 169-179Article in journal (Refereed)
    Abstract [en]

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury.

    A.SW mice were exposed to 1.25–40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose–response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.

  • 29.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Pollard, K M
    Scripps Research Institute.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Gold- and silver-induced murine autoimmunity - requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 3, p. 567-576Article in journal (Refereed)
    Abstract [en]

    Treatment with gold in the form of aurothiomaleate, silver or mercury (Hg) in genetically susceptible mouse strains (H-2(s) ) induces a systemic autoimmune condition characterized by anti-nuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin, as well as lymphoproliferation and systemic immune-complex (IC) deposits. In this study we have examined the effect of single-gene deletions for interferon (IFN)-gamma, interleukin (IL)-4, IL-6 or CD28 in B10.S (H-2(s) ) mice on heavy metal-induced autoimmunity. Targeting of the genes for IFN-gamma, IL-6 or CD28 abrogated the development of both anti-fibrillarin antibodies (AFA) and IC deposits using a modest dose of Hg (130 mu g Hg/kg body weight/day). Deletion of IL-4 severely reduced the IgG1 AFA induced by all three metals, left the total IgG AFA response intact, but abrogated the Hg-induced systemic IC deposits. In conclusion, intact IFN-gamma and CD28 genes are necessary for induction of AFA with all three metals and systemic IC deposits using Hg, while lack of IL-4 distinctly skews the metal-induced AFA response towards T helper type 1. In a previous study using a higher dose of Hg (415 mu g Hg/kg body weight/day), IC deposits were preserved in IL-4(-/-) and IL-6(-/-) mice, and also AFA in the latter mice. Therefore, the attenuated autoimmunity following loss of IL-4 and IL-6 is dose-dependent, as higher doses of Hg are able to override the attenuation observed using lower doses.

  • 30.
    Hulten, M A.
    et al.
    University of Warwick, England .
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Iwarsson, E
    Karolinska Institute, Sweden .
    Uppal, P
    Imperial Coll School Med, England .
    Vorsanova, S G.
    Rosmedtechnol, Russia .
    Yurov, Y B.
    Rosmedtechnol, Russia .
    Iourov, I Y.
    Rosmedtechnol, Russia .
    Trisomy 21 Mosaicism: We May All Have a Touch of Down Syndrome2013In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 139, no 3, p. 189-192Article in journal (Refereed)
    Abstract [en]

    Ever increasing sophistication in the application of new analytical technology has revealed that our genomes are much more fluid than was contemplated only a few years ago. More specifically, this concerns interindividual variation in copy number (CNV) of structural chromosome aberrations, i.e. microdeletions and microduplications. It is important to recognize that in this context, we still lack basic knowledge on the impact of the CNV in normal cells from individual tissues, including that of whole chromosomes (aneuploidy). Here, we highlight this challenge by the example of the very first chromosome aberration identified in the human genome, i.e. an extra chromosome 21 (trisomy 21, T21), which is causative of Down syndrome (DS). We consider it likely that most, if not all, of us are T21 mosaics, i.e. everyone carries some cells with an extra chromosome 21, in some tissues. In other words, we may all have a touch of DS. We further propose that the occurrence of such tissue-specific T21 mosaicism may have important ramifications for the understanding of the pathogenesis, prognosis and treatment of medical problems shared between people with DS and those in the general non-DS population.

  • 31.
    Hulten, Maj A.
    et al.
    Warwick Medical School, University of Warwick, UK.
    Patel, Suketu D.
    Department of Biological Sciences, University of Warwick, UK.
    Westgren, Magnus
    Department of Obstetrics and Gynecology, Karolinska Institutet, Sweden.
    Papadogiannakis, Nikos
    Department of Pathology, Karolinska Institutet, Sweden.
    Jonsson, Anna Maria
    Department of Obstetrics and Gynecology, Karolinska Institutet, Sweden.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Iwarsson, Erik
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden.
    On the paternal origin of trisomy 21 Down syndrome2010In: Molecular Cytogenetics, ISSN 1755-8166, E-ISSN 1755-8166, Vol. 3, p. 4-Article in journal (Refereed)
    Abstract [en]

    Background: Down syndrome (DS), characterized by an extra free chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 originates from the mother in more than 90% of cases, the incidence increases with maternal age and there is a high recurrence in young women. In a previous report we have presented data to indicate that maternal trisomy 21 (T21) ovarian mosaicism might provide the major causative factor underlying these patterns of DS inheritance. One important outstanding question concerns the reason why the extra chromosome 21 in DS rarely originates from the father, i.e. in less than 10% of T21 DS cases. We here report data indicating that one reason for this parental sex difference is a very much lower degree of fetal testicular in comparison to ovarian T21 mosaicism. Results: We used fluorescence in situ hybridisation (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in fetal testicular cell nuclei from four male fetuses, following termination of pregnancy for a non-medical/social reason at gestational age 14-19 weeks. The cells studied were selected on the basis of their morphology alone, pending immunological specification of the relevant cell types. We could not detect any indication of testicular T21 mosaicism in any of these four male fetuses, when analysing at least 2000 cells per case (range 2038-3971, total 11.842). This result is highly statistically significant (p < 0.001) in comparison to the average of 0.54% ovarian T21 mosaicism (range 0.20-0.88%) that we identified in eight female fetuses analysing a total of 12.634 cells, as documented in a previous report in this journal. Conclusion: Based on these observations we suggest that there is a significant sex difference in degrees of fetal germ line T21 mosaicism. Thus, it would appear that most female fetuses are T21 ovarian mosaics, while in sharp contrast most male fetuses may be either very low grade T21 testicular mosaics or they may be non-mosaics. We further propose that this sex difference in germ line T21 mosaicism may explain the much less frequent paternal origin of T21 DS than maternal. The mechanisms underlying the DS cases, where the extra chromosome 21 does originate from the father, remains unknown and further studies in this respect are required.

  • 32.
    Hulten, Maj Anita
    et al.
    University of Warwick, England Karolinska Institute, Sweden .
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Westgren, Magnus
    Karolinska Institute, Sweden .
    Jonsson, Anna Maria
    Karolinska Institute, Sweden .
    Papadogiannakis, Nikos
    Karolinska Institute, Sweden .
    Iwarsson, Erik
    Karolinska Institute, Sweden .
    Letter: Comment on "Origin of trisomy: no evidence to support the ovarian mosaicism theory"2012In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 32, no 12, p. 1221-1221Article in journal (Other academic)
    Abstract [en]

    n/a

  • 33.
    Hultén, Maj A
    et al.
    University of Warwick.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Nordgren, Ann
    Karolinska Institute.
    Iwarsson, Erik
    Karolinska Institute.
    Germinal and Somatic Trisomy 21 Mosaicism: How Common is it, What are the Implications for Individual Carriers and How Does it Come About?2010In: CURRENT GENOMICS, ISSN 1389-2029, Vol. 11, no 6, p. 409-419Article in journal (Refereed)
    Abstract [en]

    It is well known that varying degrees of mosaicism for Trisomy 21, primarily a combination of normal and Trisomy 21 cells within individual tissues, may exist in the human population. This involves both Trisomy 21 mosaicism occurring in the germ line and Trisomy 21 mosaicism documented in different somatic tissues, or indeed a combination of both in the same subjects. Information on the incidence of Trisomy 21 mosaicism in different tissue samples from people with clinical features of Down syndrome as well as in the general population is, however, still limited. One of the main reasons for this lack of detailed knowledge is the technological problem of its identification, where in particular low grade/cryptic Trisomy 21 mosaicism, i.e. occurring in less than 3-5% of the respective tissues, can only be ascertained by fluorescence in situ hybridization (FISH) methods on large cell populations from the different tissue samples. In this review we summarize current knowledge in this field with special reference to the question on the likely incidence of germinal and somatic Trisomy 21 mosaicism in the general population and its mechanisms of origin. We also highlight the reproductive and clinical implications of this type of aneuploidy mosaicism for individual carriers. We conclude that the risk of begetting a child with Trisomy 21 Down syndrome most likely is related to the incidence of Trisomy 21 cells in the germ line of any carrier parent. The clinical implications for individual carriers may likewise be dependent on the incidence of Trisomy 21 in the relevant somatic tissues. Remarkably, for example, there are indications that Trisomy 21 mosaicism will predispose carriers to conditions such as childhood leukemia and Alzheimers Disease but there is on the other hand a possibility that the risk of solid cancers may be substantially reduced.

  • 34.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Interleukin-10 in murine mercury-induced systemic autoimmunity2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 3, p. 422-431Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.

    The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.

    The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.

  • 35.
    Jonasson, Jon
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Monstein, Hans-Jurg
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Molecular Biological Techniques.
    Commentary: Classification, identification and subtyping of bacteria based on pyrosequencing and signature matching of 16S rDNA fragments APMIS 110, 263-270: Commentary2007In: APMIS: Acta pathologica, microbiologica et immunologica Scandinavica. Supplementum, ISSN 0903-465X, E-ISSN 1600-5503, Vol. 115, no 5, p. 678-679p. 678-679Article in journal (Other academic)
    Abstract [en]

    [No abstract available]

  • 36.
    Kissopoulou, Antheia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Next Generation Sequencing Analysis of Human Platelet PolyA plus mRNAs and rRNA-Depleted Total RNA2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 81809-Article in journal (Refereed)
    Abstract [en]

    Background: Platelets are small anucleate cells circulating in the blood vessels where they play a key role in hemostasis and thrombosis. Here, we compared platelet RNA-Seq results obtained from polyA+ mRNA and rRNA-depleted total RNA. Materials and Methods: We used purified, CD45 depleted, human blood platelets collected by apheresis from three male and one female healthy blood donors. The Illumina HiSeq 2000 platform was employed to sequence cDNA converted either from oligo(dT) isolated polyA+ RNA or from rRNA-depleted total RNA. The reads were aligned to the GRCh37 reference assembly with the TopHat/Cufflinks alignment package using Ensembl annotations. A de novo assembly of the platelet transcriptome using the Trinity software package and RSEM was also performed. The bioinformatic tools HTSeq and DESeq from Bioconductor were employed for further statistical analyses of read counts. Results: Consistent with previous findings our data suggests that mitochondrially expressed genes comprise a substantial fraction of the platelet transcriptome. We also identified high transcript levels for protein coding genes related to the cytoskeleton function, chemokine signaling, cell adhesion, aggregation, as well as receptor interaction between cells. Certain transcripts were particularly abundant in platelets compared with other cell and tissue types represented by RNA-Seq data from the Illumina Human Body Map 2.0 project. Irrespective of the different library preparation and sequencing protocols, there was good agreement between samples from the 4 individuals. Eighteen differentially expressed genes were identified in the two sexes at 10% false discovery rate using DESeq. Conclusion: The present data suggests that platelets may have a unique transcriptome profile characterized by a relative over-expression of mitochondrially encoded genes and also of genomic transcripts related to the cytoskeleton function, chemokine signaling and surface components compared with other cell and tissue types. The in vivo functional significance of the non-mitochondrial transcripts remains to be shown.

  • 37.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Blechschmidt, Cristiane
    Charite, Germany .
    Nogalska, Anna
    University of So Calif, CA USA .
    Prokop, Stefan
    Charite, Germany .
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    King Engel, W
    University of So Calif, CA USA .
    Askanas, Valerie
    University of So Calif, CA USA .
    Heppner, Frank L.
    Charite, Germany .
    Nilsson, K Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Luminescent Conjugated Oligothiophenes for Sensitive Fluorescent Assignment of Protein Inclusion Bodies2013In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 5, p. 607-616Article in journal (Refereed)
    Abstract [en]

    Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.

  • 38. Kolak, M.
    et al.
    Karpati, F.
    Stockholm Cystic Fibrosis Centre, Huddinge University Hospital, Stockholm, Sweden.
    Monstein, Hans-Jurg
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Molecular Biological Techniques.
    Jonasson, Jon
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Molecular typing of the bacterial flora in sputum of cystic fibrosis patients2003In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 293, no 4, p. 309-317Article in journal (Refereed)
    Abstract [en]

    Despite recent advances in therapy, lower airway infections remain the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Bacterial colonisation of the lower airways in CF is limited to a few bacterial species, commonly Staphylococcus aureus, Pseudomonas aeruginosa and Haemophilus influenzae. Burkholderia cepacia colonisation is much rarer, but it has been thought to be associated with more advanced lung disease and increased mortality. A rapid characterisation of the bacterial flora in sputum of CF patients is of great importance for proper treatment. The aim of this study was to establish bacterial profiles and to identify pathogenic bacteria in respiratory specimens by means of molecular methods including temporal temperature gradient gel electrophoresis (TTGE) and DNA sequencing of PCR amplicons derived from 16S rDNA variable V3 and V6 regions. Sputa of 13 CF patients (7 males/6 females, age 19-59 years) collected at the Stockholm CF centre were analysed. TTGE revealed the presence of complex bacterial profiles in all samples. The V3 and V6 PCR amplicons were cloned and sequenced by real-time DNA PyrosequencingTM. DNA from Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa, respectively, was identified together with sequences from normal oral cavity flora. The results were in reasonable agreement with those obtained by conventional bacterial culture, considering that only known CF pathogens are included in routine reports. However, the methodology seems too elaborate to be introduced into daily routine.

  • 39. Liedberg, F
    et al.
    Andersson, H
    Bläckberg, M
    Chebil, G
    Davidsson, T
    Gudjonsson, S
    Jahnson, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Månsson, W
    Prospective study of transitional cell carcinoma in the prostatic urethra and prostate in the cystoprostatectomy specimen2007In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, no 4, p. 290-296Article in journal (Refereed)
    Abstract [en]

    Objectives. To prospectively evaluate the incidence of transitional cell carcinoma (TCC) in the prostatic urethra and prostate in the cystoprostatectomy specimen, investigate characteristics of bladder tumours in relation to the risk of involvement of the prostatic urethra and prostate and examine the sensitivity of preoperative loop biopsies from the prostatic urethra. Material and methods. Preoperatively, patients were investigated with cold cup biopsies from the bladder and transurethral loop biopsies from the bladder neck to the verumontanum. The prostate and bladder neck were submitted to sagittal whole-mount pathological analysis. Results. The incidence of TCC in the prostatic urethra and prostate in the cystoprostatectomy specimen was 29% (50/175 patients). Age, previous bacillus Calmette-Guérin treatment, carcinoma in situ (Cis) in the cold cup mapping biopsies and tumour grade were not associated with the risk of TCC in the prostatic urethra/prostate. Cis, multifocal Cis (≥2 locations) and tumour location in the trigone were significantly more common in cystectomy specimens with TCC in the prostatic urethra and prostate: 21/50 (42%) vs 32/125 (26%), p=0.045, 20/50 (40%) vs 27/125 (22%), p=0.023, and 20/50 (40%) vs 26/125 (21%), p=0.01, respectively. Preoperative resectional biopsies from the prostatic urethra in the 154 patients analysed identified 31/47 (66%) of patients with TCC in the prostatic urethra/prostate, with a specificity of 89%. The detection of stromal-invasive and non-stromal involvement was similar: 66% and 65%, respectively. Conclusions. The incidence of TCC in the prostatic urethra and prostate was 29% (50/175) in the cystoprostatectomy specimen. Preoperative biopsies from the prostatic urethra identified 66% of patients with such tumour growth. Our findings suggest that preoperative cold cup mapping biopsies of the bladder for detection of Cis add little extra information with regard to the risk of TCC in the prostatic urethra and prostate.

  • 40.
    Liedberg, Fredrik
    et al.
    Skåne University Hospital, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sundqvist, Pernilla
    Vaxjo County Hospital, Sweden .
    Very late prostate cancer local recurrence 23 years after radical prostatectomy2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 4, p. 304-305Article in journal (Refereed)
    Abstract [en]

    Recurrence after radical prostatectomy occurs most frequently during the first 5 years after surgery. Later recurrences have, however, been described. This report describes a case with local recurrence 23 years after radical prostatectomy.

  • 41.
    Lundmark, Katarzyna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Murphy, Charles L.
    Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
    Solomon, Alan
    Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
    Transmissibility of systemic amyloidosis by a prion-like mechanism2002In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 10, p. 6979-6984Article in journal (Refereed)
    Abstract [en]

    The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

  • 42.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Cederbrant, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Cytokines in induction of ANoA and hypergammaglobulinemia in mercury-induced autoimmunity: a lesson from Fc!RIII deficient miceManuscript (Other academic)
    Abstract [en]

    Xenobiotic agents such as metals, drugs, toxic oils and pristane can induce autoimmune diseases. Heavy metal induction of autoimmunity has been observed for mercury (Hg), silver and gold in mice. Mercury-induced autoimmunity (HgIA) in mice is characterised by lymphoproliferation, hypergammaglobulinemia, antinucleolar autoantibodies (ANoA) and immune complex deposits in the renal glomerular mesangium and systemically in vessel walls. HgIA is T-cell dependent, IFNγ is necessary for all manifestations of HgIA, and the activating Fc!RIII enhance development of ANoA. This study focused firstly on exploring the cytokine profile in the genetically susceptible DBA/1 (H-2q) wild type (wt) and DBA/1 FcγRIII-/- mice treated with 15 mg/l Hg, and secondly on the hypothesis that IFN-! producing NK cells are vital for induction of ANoA in the HgIA model. DBA/1 wt mice showed a significantly more marked Th1 profile compared to DBA/1 FcγRIII-/- mice following Hg treatment, whereas the total Th2 and Th17 profile increased in both DBA/1 wt and DBA/1 FcγRIII-/- mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in DBA/1 FcγRIII-/- mice compared with DBA/1 wt mice. However, we were unable to show that the increased Th1 profile in the DBA/1 wt mice was due to IFN-γsecretion from NK cells. Our findings suggest that the delayed ANoA induction in DBA/1 FcγRIII-/- mice is due to the attenuated Th1 profile. In addition the reduced expression of IL-21 in DBA/1 FcγRIII-/- mice might be responsible for the lack of serum IgG1 response in these mice.

  • 43.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex depositsManuscript (preprint) (Other academic)
    Abstract [en]

    Inorganic mercury (Hg) induces in susceptible mouse strains a T-cell dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, antinuclear antibodies, and immune-complex (IC) deposits in glomeruli and vessel walls. Activating Fcγ-receptors (FcγRs) are important for induction of HgIA. We have examined if activating FcγRs affect circulating immune complexes (CIC), the initial development of tissue IC deposits and their composition in HgIA. BALB/c mice with a targeted mutation for activating FcγRs and BALB/c mice without any mutation (wild type - wt - mice) were treated up to 35 days with Hg. Wild type mice showed a significant but modest increase of CIC from day 12 until day 18 and day 35 for IgG2a- and IgG1-containing CIC, respectively. Mercury-treated FcγR−/− mice showed significantly higher CIC levels than Hg-treated wt mice during the entire treatment time for IgG1-CIC, and after 26 and 35 days for IgG2a-CIC. Tissue IC deposits developed later in the FcγR−/− mice especially in the renal mesangium. After 35 days of Hg treatment the fraction of mice with and/or the amount of IgG1 and C3c deposits were significantly reduced in vessel walls and for IgG1 also in the renal mesangium compared with wt mice. We conclude that susceptible mice lacking activating FcγRs respond to an autoimmune stimulus with increased levels and altered quality of CIC compared with wt mice. It is likely that lack of FcγRs reduced elimination of CIC as indicated by delayed and significantly reduced IC deposits in the tissues of mice without activating receptors.

  • 44.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    The role of Fc-receptors in murine mercury-induced systemic autoimmunity2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 144, no 2, p. 309-318Article in journal (Refereed)
    Abstract [en]

    Inorganic mercury (Hg) in genetically susceptible mouse strains induces a T cell-dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, anti-nuclear antibodies (ANA) and systemic immune-complex (IC) deposits. The exact phenotypic expression of HgIA in different strains depends on H-2 and non-H-2 genes. Fc receptors (FcRs) are important in the development of many autoimmune diseases. In this study, the effect of targeted mutations for activating and inhibiting FcRs in the BALB/c model of HgIA was examined. Hg-treated BALB/c mice without mutation (wild-type, wt) showed heavy IC deposits in the renal glomerular mesangium, as well as in renal and splenic vessel walls. The renal mesangial IC deposits were severely reduced in Hg-treated BALB/c mice without the gamma-chain (lack of the activating receptors FcgammaRI, FcgammaRIII and FcinRI), but unchanged in mice lacking the inhibitory FcgammaRIIB. The Hg-induced vessel wall IC deposits present in wt mice were abolished and reduced in the FcRgamma and FcgammaRIIB strains, respectively. Hg-treated BALB/c wt mice and mice without the gamma-chain showed an increase in serum IgE, while the increase in IgG1 was attenuated in the latter strain. In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE. In conclusion, FcRs are important mainly for the induction of systmeic IC deposits in the HgIA model, but also affects serum IgG1 and IgE levels.

  • 45.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Kleinau, Sandra
    Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity2008In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 31, no 1, p. 22-29Article in journal (Refereed)
    Abstract [en]

    Fc-receptors for IgG (FcgammaR) link cellular and humoral immune responses, controlling the balance between activating and inhibitory immune responses, and are involved in autoimmune diseases. Mercury (Hg) induces an autoimmune condition in genetically (H-2(s,q,f)) susceptible mice characterized by lymphoproliferation, hypergammaglobulinemia and IgG antinucleolar antibodies (ANoA). Here we investigate the role of activating (FcgammaRI, FcgammaRIII) and inhibitory (FcgammaRIIb) Fc-receptors on mercury-induced autoimmunity (HgIA) using DBA/1 mice (H-2(q)) with targeted FcgammaR mutations and wild type (wt) mice. Mice deficient for the FcRgamma-chain or FcgammaRIII and treated with 15 mg/L HgCl(2) showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice. Female Hg-treated FcgammaRIIB(-/-) mice showed a significant increased of IgG2b ANoA development compared to wt mice. The total serum IgG1 response due to Hg was attenuated in FcRgamma(-/-) and FcgammaRIII(-/-) mice compared to wt mice. Hg-treated FcgammaRIIB(-/-) mice showed an increase of both serum IgG1 and IgE compared to wt mice. We conclude that FcgammaRIII is of importance for the rapidity and final strength of the ANoA response and the increase in serum IgG1 in HgIA, while lack of FcgammaRIIb increases the IgG2b ANoA response and the serum IgG1 and IgE response.

  • 46.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Mousavi, Seyed Ali
    Rikshospital University Hospital, Oslo.
    Berg, Trond
    University of Oslo.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Deficiency of Activating Fc gamma-Receptors Reduces Hepatic Clearance and Deposition of IC and Increases CIC Levels in Mercury-Induced Autoimmunity2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed)
    Abstract [en]

    Background: Inorganic mercury (Hg) induces a T-cell dependent, systemic autoimmune condition (HgIA) where activating Fc gamma-receptors (Fc gamma Rs) are important for the induction. In this study we examined the influence of activating Fc gamma Rs on circulating levels and organ localization of immune complexes (IC) in HgIA. Methods and Principal Findings: Mercury treated BALB/c wt mice showed a significant but modest increase of circulating IC (CIC) from day 12 until day 18 and day 35 for IgG2a- and IgG1- CIC, respectively. Mercury-treated mice lacking the transmembrane gamma-chain of activating Fc gamma Rs (FcR gamma(-/-)) had significantly higher CIC levels of both IgG1-CIC and IgG2a-CIC than wt mice during the treatment course. The hepatic uptake of preformed CIC was significantly more efficient in wt mice compared to Fc gamma R-/- mice, but also development of extrahepatic tissue IC deposits was delayed in FcR gamma(-/-) mice. After 35 days of Hg treatment the proportion of immune deposits, as well as the amounts was significantly reduced in vessel FcR gamma(-/-) mice compared to wt mice. Conclusions: We conclude that mice lacking functional activating Fc gamma Rs respond to Hg with increased levels and altered quality of CIC compared with wt mice. Lack of functional activating Fc gamma Rs delayed the elimination of CIC, but also significantly reduced extrahepatic tissue localization of CIC.

  • 47.
    Myhrinder, Anna Lanemo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Hellqvist, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Jansson, Mattias
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Nilsson, Kenneth
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Jonasson, Jon
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Rosén, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 8, p. 1769-1779Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

  • 48.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stage T1 Urinary Bladder Carcinoma: Investigation of A Population-Based Cohort2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Approximately 2 300 new cases of urinary bladder carcinoma (UBC) are diagnosed every year in Sweden. This type of cancer is characterized as a long-standing disease with a high risk of recurrence and progression from an indolent to a more aggressive course. UBC occurs in a non-muscle-invasive form (stages Ta and T1), which is treated mainly with local resection and BCG instillation, and a muscle-invasive form (stage ≥ T2), for which the treatment of choice is irradiation or cystectomy.

    The aim of the research underlying this thesis was to explore the factors involved in tumor development and progression, and to find prognostic markers for recurrence and progression in patients with primary stage T1 urothelial carcinoma of the bladder (UCB).

    Tumor tissue in archived paraffin blocks from patients diagnosed with that type of malignancy was used in the four studies that were conducted. This was a population-based project, because all of the patients had been reported to the cancer center in the Southeast Healthcare Region in Sweden from 1992 to 2001. The follow-up time was comparable long in the cases included and was intended to be at least 10 years.

    The hospital records were reviewed to gather information on clinical characteristics of the tumors, such as size and multiplicity, as well as treatment modalities, recurrence and/or progression, and eventual death from UBC. The original tumor slides were re-evaluated. These two initial activities yielded a study population comprising 211 well-characterized patients with primary T1 UCB. Some of the originally selected patients were excluded due to missing paraffin blocks or poor quality of the tumor material, the latter being particularly important in the genetic analyses conducted in the fourth study.

    Ordinary light microscopy was performed to evaluate specific tumor characteristics, such as lymphovascular tumor infiltration, and for T1 sub-staging. Immunohistochemistry was carried out to, among other things, analyze cell cycle regulators. Furthermore, pyrosequencing, single-strand conformation analysis (SSCA), and Sanger sequencing were conducted in the fourth study to assess mutations in the p53 gene and murine double minute 2 SNP309 promoter polymorphism. Statistical analyses to estimate the risk of tumor recurrence and progression were carried out in all four investigations.

    Conclusions: This population-based cohort of patients with well-characterized T1 tumors of the urinary bladder showed high rates of recurrence (80%) and progression (39%), and the aggressiveness is underlined by the fact that 32% died from the disease. Lymphovascular tumor infiltration and abnormal immunohistochemical staining for p16 were found to be associated with tumor progression, and in the future analysis of these parameters might be used in treatment decisions regarding T1 bladder tumors. No other clinical or pathological variable or cell cycle regulator was associated with progression, and none of the genetic analyses conducted in the current studies were helpful in predicting outcome or explaining the mechanisms of tumor development.

    List of papers
    1. HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder
    Open this publication in new window or tab >>HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder
    2012 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 2, p. 102-107Article in journal (Refereed) Published
    Abstract [en]

    Objective. The HER2 receptor is involved in pathways essential for cell proliferation, and is an important predictive and prognostic factor in breast cancer. HER2 probably plays a critical role in many types of cancer, including urothelial carcinoma of the bladder (UCB). Stage T1 UCB exhibits heterogeneous clinical behaviour, and the frequency of HER2 expression in such disease has not been thoroughly examined. The aim of this study was to use an immunohistochemical technique to evaluate the frequency of HER2 expression in a defined population-based cohort of patients registered as having primary stage T1 UCB. Material and methods. The initial study population comprised 285 patients registered as having primary stage T1 UCB. The original histological specimens were re-evaluated with regard to T stage and World Health Organization grade. Hospital records provided information on tumour size, multiplicity, possible presence of histologically proven recurrence and progression. The patients were followed for at least 5 years or until death. In tumours still considered stage T1 after re-evaluation, HER2 was investigated by immunohistochemistry of paraffin-embedded material and scored according to the guidelines used in breast cancer. Results. After histopathological re-evaluation, 201 patients were still T1 UCB and could be investigated regarding HER2 expression. HER2 overexpression was observed in 25 of those patients (12.4%). HER2 status was not significantly associated with recurrence or progression. Conclusions. HER2 was overexpressed in 12.4% of the present cohort of patients with primary stage T1 UCB. There was no significant association between tumour HER2 status and prognosis.

    Place, publisher, year, edition, pages
    Informa Healthcare, 2012
    Keywords
    HER2 overexpression, stage T1, urinary bladder carcinoma
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-76526 (URN)10.3109/00365599.2011.637955 (DOI)000301539200005 ()
    Available from: 2012-04-12 Created: 2012-04-11 Last updated: 2017-12-07
    2. Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours
    Open this publication in new window or tab >>Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours
    2013 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 47, no 3, p. 188-195Article in journal (Refereed) Published
    Abstract [en]

    Objective. Stage T1 urothelial carcinoma of the bladder (UCB) exhibits heterogeneous clinical behaviour, and the treatment is controversial. The aim of this study was to evaluate prognostic factors for UCB in a defined, population-based cohort comprising patients with a first time diagnosis of primary stage T1 UCB.

    Material and methods. The study population initially consisted of 285 patients with primary stage T1 UCB reported to the regional Bladder Cancer Registry in the Southeast Healthcare Region of Sweden from 1992 to 2001. The histological specimens were re-evaluated concerning stage, substaging of T1, World Health Organization (WHO) grade, lymphovascular invasion (LVI), tumour volume and total resected volume. Hospital records provided data on tumour size and multiplicity, occurrence of possible relapse and/or progression, death from UCB and whether treatment was given.

    Results. After re-evaluation, the study population comprised 211 patients. The median follow-up time was 60 months. LVI was a prognostic factor for UCB progression and recurrence. Tumour size larger than 30 mm and multiplicity increased the risk of recurrence. T1 substaging, tumour volume and total resected volume were not associated with recurrence or tumour progression.

    Conclusions. LVI is significantly correlated with progression and recurrence in patients with primary stage T1 UCB. Therefore, the presence of LVI should be evaluated in every new case of T1 UCB.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85012 (URN)10.3109/00365599.2012.719539 (DOI)000321415400004 ()
    Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
    3. Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer
    Open this publication in new window or tab >>Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer