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  • 151.
    Hamberg, Anna-Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Pharmacogenetics-based warfarin dosing in children2014Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 15, nr 3, s. 361-374Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Clinical factors, demographic variables and variations in two genes, CYP2C9 and VKORC1, have been shown to contribute to the variability in warfarin dose requirements among adult patients. Less is known about their relative importance for dose variability in children. A few small studies have been reported, but the results have been conflicting, especially regarding the impact of genotypes. In this article, we critically review published pharmacogenetic-based prediction models for warfarin dosing in children, and present results from a head-to-head comparison of predictive performance in a distinct cohort of warfarin-treated children. Finally we discuss what properties a prediction model should have, and what knowledge gaps need to be filled, to improve warfarin therapy in children of all ages.

  • 152.
    Hamberg, Anna-Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Friberg, Lena E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Biss, Tina T
    Kamali, Farhad
    Jonsson, E Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Characterising variability in warfarin dose requirements in children using modelling and simulation2013Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 78, nr 1, s. 158-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation.

    METHODS: Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimise a published adult pharmacometric warfarin model for use in children.

    RESULTS: Genotype effects in children were found to be comparable to what has been reported for adults, with CYP2C9 explaining up to a 4-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a 2-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a 3-fold difference in dose for a 4-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children.

    CONCLUSIONS: The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting warfarin dose variability in children. With this new knowledge more individualised dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.

  • 153.
    Hansson, Lars-Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Althaus, Harald
    Blirup-Jensen, Sören
    Grubb, Anders
    The first harmonization step on cystatin C, with the aim to introduce the first ERM-DA471/IFCC cystatin C calibrator and one worldwide company-independent EGFR equation2011Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 49, nr s1, s. s557-s557Artikkel i tidsskrift (Fagfellevurdert)
  • 154. Hansson Petersen, Camilla A
    et al.
    Alikhani, Nyosha
    Behbahani, Homira
    Wiehager, Birgitta
    Pavlov, Pavel F
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Leinonen, Ville
    Ito, Akira
    Winblad, Bengt
    Glaser, Elzbieta
    Ankarcrona, Maria
    The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.2008Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 35, s. 13145-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Abeta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Abeta, a peptide considered to be of major significance in Alzheimer's disease.

  • 155.
    Hasni, Muhammad Sharif
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Yakimchuk, Konstantin
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Guan, Jiyu
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Linderoth, Johan
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Estrogen receptor beta 1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker2017Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, nr 2, s. 418-427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor beta (ER beta) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ER beta 1 expression analysis in primary DLBCL's by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERb1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERb1 is an interesting future therapeutic target for treatment of DLBCL, and that ERb1 expression can be used as a prognostic marker.

  • 156.
    Hedeland, Ylva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi. Uppsala University Hospital, Uppsala, Sweden.
    Gustafsson, Christina M
    Uppsala University Hospital, Uppsala, Sweden.
    Touza, Zinah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi. Uppsala University Hospital, Uppsala, Sweden.
    Hemolysis interference in 10 coagulation assays on an instrument with viscosity-based, chromogenic, and turbidimetric clot detection2020Inngår i: International Journal of Laboratory Hematology, ISSN 1751-5521, E-ISSN 1751-553XArtikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Hemolysate in plasma samples from patients may cause misleading results in coagulation assays. Even though modern coagulation instruments often are equipped with modules that can detect hemolysis, icterus, and lipemia (HIL), studies that report the influence of these interferences are still limited. The present paper focuses on the influence of hemolysis on 10 coagulation assays.

    METHODS: Artificial hemolysis was created by freezing/thawing, and the hemolysates generated were added to pools of patient plasma. Pathological and normal levels were pooled separately. These spiked samples were analyzed on a STA R Max 2 instrument. The coagulation assays evaluated utilize clot, chromogenic, or immunoturbidimetric detection.

    RESULTS: Four of the evaluated assays were not influenced by hemolysis: fibrinogen, von Willebrand factor antigen, activated partial thromboplastin time, and factor VIII. Interestingly, normal and slightly elevated prothrombin time (INR < 2.0) was insensitive to hemolysis, whereas samples with a high INR (≥2.0) exhibited falsely high readings. The assays for antithrombin and fibrin D-dimer displayed an intermediate sensitivity to hemolysis. The most sensitive assay turned out to be anti-Xa, followed by protein C and protein S. For the anti-Xa assay, the results are decreased by 10% already at 0.5 g/L hemoglobin.

    CONCLUSION: The present study shows that hemolysis affects several of commonly used coagulation assays. Since the sensitivity for hemolysis is dependent on the brand of the assay as well as the instrument and principle of measurement, it is necessary to evaluate the influence of each specific combination.

    Fulltekst (pdf)
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  • 157.
    Hellbacher, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hjorton, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Knight, Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Malignant lymphoma in granulomatosis with polyangiitis: subtypes, clinical characteristics and prognosis2019Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, nr 11, s. 1655-1659Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Several autoimmune and inflammatory conditions, such as rheumatoid arthritis (RA) and primary Sjögrens’s syndrome (pSS), have repeatedly been linked to an increased risk of malignant lymphoma [1,2]. Certain inflammatory conditions are also associated with the development of specific lymphoma subtypes such as mucosa-associated lymphoid tissue (MALT) lymphoma in pSS and diffuse large B-cell lymphoma (DLBCL) in RA. The underlying mechanisms behind this association remain unclear. The highly increased risk of developing MALT lymphoma of the parotid gland in pSS indicates that local inflammatory processes can promote lymphoma development at the site of chronic inflammation [3]. In RA, an association between disease severity and risk of lymphoma has been shown.

    Granulomatosis with polyangiitis (GPA), formerly Wegener’s granulomatosis, is a systemic small vessel vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and characterized by granulomatous inflammation and necrotizing vasculitis of the airways and kidneys but possibly affecting any organ system. An increased risk of lymphoma in patients with GPA has been reported in several epidemiological studies [4,5]. However, very little is known about risk factors for lymphoma development in this group, possible relation to disease severity, treatment and lymphoma subtypes or the prognosis for the lymphomas. This is the first published study on GPA and lymphoma, giving detailed information on the GPA characteristics and possible risk factors for lymphoma and also lymphoma subtypes treatment and survival.

  • 158.
    Hellgren, K.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Smedby, K. E.
    Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden..
    Askling, J.
    Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden..
    Rheumatoid Arthritis and Risk of Malignant Lymphoma - Is the risk still increased?2017Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, nr 4, s. 700-708Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas with a strong correlation with RA disease severity. Given the changes in RA therapy over recent decades, we aimed at assessing whether lymphoma risk remains increased, and if so, to explore risk predictors and lymphoma subtypes.

    METHODS: We identified 12,656 incident RA patients from the Swedish Rheumatology Register 1997-2012 including information on therapy and inflammatory activity during the first year following diagnosis. Each patient was matched to 10 population comparator subjects. Through linkage to the Swedish Cancer Register, lymphomas including subtypes were identified. We assessed Hazard ratios (HRs) using Cox regression.

    RESULTS: Overall, the HR of lymphoma was increased, 1.6, 95% confidence interval [CI] 1.2-2.1. Taking RA duration into account, risks did not appear to have declined over successive calendar years of RA diagnosis. Neither use of methotrexate the 1(st) year following RA diagnosis nor ever use of TNF inhibitors (HR=0.9; 95% CI 0.4-1.9) increased lymphoma risk. Use of oral corticosteroids the 1(st) year following RA diagnosis was associated with a reduced risk (HR=0.6; 95% CI 0.5 -0.9). Inflammatory activity during the 1(st) year following RA diagnosis did not predict future lymphoma risk. Chronic lymphocytic lymphoma occurred less, and Hodgkin lymphoma more frequently than expected compared to the general population.

    CONCLUSION: The average lymphoma risk in recently diagnosed RA is of similar magnitude as that reported from historical cohorts. Standard anti-rheumatic treatment including TNF inhibitors did not predict future lymphoma risk. Distribution of lymphoma subtypes warrants further investigation.

  • 159.
    Hellström, Jussi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Romanos Zapata, Romina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ortiz-Nieto, Francisco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Evaluation of the INTERPRET decision-support system: can it improve the diagnostic value of magnetic resonance spectroscopy of the brain?2019Inngår i: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 61, nr 1, s. 43-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: We evaluated in a clinical setting the INTERPRET decision-support system (DSS), a software generated to aid in MRS analysis to achieve a specific diagnosis for brain lesions.

    Methods: The material consisted of 100 examinations of focal intracranial lesions with confirmed diagnoses. MRS was obtained at 1.5 T using TE 20–30 ms. Data were processed with the LCModel for conventional analysis. The INTERPRET DSS 3.1. was used to obtain specific diagnoses. MRI and MRS were reviewed by one interpreter. DSS analysis was made by another interpreter, in 80 cases by two interpreters. The diagnoses were compared with the definitive diagnoses. For comparisons between DSS, conventional MRS analysis, and MRI, the diagnoses were categorised: high-grade tumour, low-grade tumour, non-neoplastic lesion.

    Results: Interobserver agreement in choosing the diagnosis from the INTERPRET database was 75%. The diagnosis was correct in 38/100 cases, incorrect in 57 cases. No good match was found in 5/100 cases. The diagnostic category was correct with DSS/conventional MRS/MRI in 67/58/52 cases, indeterminate in 5/8/20 cases, incorrect in 28/34/28 cases. Results with DSS were not significantly better than with conventional MRS analysis. All definitive diagnoses did not exist in the INTERPRET database. In the 61 adult patients with the diagnosis included in the database, DSS/conventional MRS/MRI yielded a correct diagnosis category in 48/32/29 cases (DSS vs conventional MRS: p = 0.002, DSS vs MRI: p = 0.0004).

    Conclusion: Use of the INTERPRET DSS did not improve MRS categorisation of the lesions in the unselected clinical cases. In adult patients with lesions existing in the INTERPRET database, DSS improved the results, which indicates the potential of this software with an extended database.

    Fulltekst (pdf)
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  • 160.
    Hellström, Jussi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Romanos Zapata, Romina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ortiz-Nieto, Francisco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    The value of magnetic resonance spectroscopy as a supplement to MRI of the brain in a clinical setting2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 11, artikkel-id e0207336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: There are different opinions of the clinical value of MRS of the brain. In selected materials MRS has demonstrated good results for characterisation of both neoplastic and non-neoplastic lesions. The aim of this study was to evaluate the supplemental value of MR spectroscopy (MRS) in a clinical setting.

    MATERIAL AND METHODS: MRI and MRS were re-evaluated in 208 cases with a clinically indicated MRS (cases with uncertain or insufficient information on MRI) and a confirmed diagnosis. Both single voxel spectroscopy (SVS) and chemical shift imaging (CSI) were performed in 105 cases, only SVS or CSI in 54 and 49 cases, respectively. Diagnoses were grouped into categories: non-neoplastic disease, low-grade tumour, and high-grade tumour. The clinical value of MRS was considered very beneficial if it provided the correct category or location when MRI did not, beneficial if it ruled out suspected diseases or was more specific than MRI, inconsequential if it provided the same level of information, or misleading if it provided less or incorrect information.

    RESULTS: There were 70 non-neoplastic lesions, 43 low-grade tumours, and 95 high-grade tumours. For MRI, the category was correct in 130 cases (62%), indeterminate in 39 cases (19%), and incorrect in 39 cases (19%). Supplemented with MRS, 134 cases (64%) were correct, 23 cases (11%) indeterminate, and 51 (25%) incorrect. Additional information from MRS was beneficial or very beneficial in 31 cases (15%) and misleading in 36 cases (17%).

    CONCLUSION: In most cases MRS did not add to the diagnostic value of MRI. In selected cases, MRS may be a valuable supplement to MRI.

    Fulltekst (pdf)
    fulltext
  • 161.
    Helmersson, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Boija, Elisabet Eriksson
    External Qual Assessment Clin Lab Investigat Equa, Uppsala, Sweden.
    Nordin, Gunnar
    External Qual Assessment Clin Lab Investigat Equa, Uppsala, Sweden.
    Lower creatinine concentration values and lower inter-laboratory variation among Swedish hospital laboratories in 2014 compared to 1996: results from the Equalis external quality assessment program2019Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 57, nr 6, s. 838-844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Creatinine measurement for estimation of glomerular filtration rate (GFR) is a frequently used laboratory test. Differences in analytic creatinine methods have caused large inter-laboratory variation. International and national standardization efforts have been made in the last decade.

    Methods:

    This study describes the results of the standardization efforts in Sweden by summarizing data for creatinine concentration in blood plasma in the Equalis quality assessment program during 1996-2014.

    Results:

    Non-compensated Jaffe methods dominated in 1996-2001 (91 of 103 laboratories; 90%) and were then gradually replaced by either compensated Jaffe methods or enzymatic creatinine methods. In 2014 a majority of Swedish hospital laboratories (139 of 159; 87%) used enzymatic methods. The reported mean creatinine value by the Swedish laboratories was about 10 mu mol/L higher than the isotope dilution mass spectrometry (IDMS) assured reference value in 2003, but consistent with the reference value from 2009 to 2014. The inter-laboratory CV was 7%-9% for creatinine values until 2007, and thereafter gradually decreased to about 4%-5% in 2014.

    Conclusions:

    The introduction of enzymatic methods in Swedish laboratories has contributed to achieving a low inter-laboratory variation. Also, the reported values are lower for enzymatic methods compared to Jaffe methods, and the values obtained with enzymatic methods were consistent with IDMS certified values established at reference laboratories. Thus, many Swedish hospital laboratories reported 10 mu mol/L lower, and more true, creatinine concentrations in 2012 than in 2003, which may cause bias in longitudinal studies.

  • 162.
    Helmersson, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Reference values for 34 frequently used laboratory tests in 80-year-old men and women2016Inngår i: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 92, s. 97-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Reference values are usually based on blood samples from healthy individuals in the age range 20-50 years. Most patients seeking health care are older than this reference population. Many reference intervals are age dependent and there is thus a need to have appropriate reference intervals also for elderly individuals.

    METHODS: We analyzed a group of frequently used laboratory tests in an 80-year-old population (n=531, 266 females and 265 males). The 2.5th and 97.5th percentiles for these markers were calculated according to the International Federation of Clinical Chemistry guidelines on the statistical treatment of reference values.

    RESULTS: Reference values are reported for serum alanine transaminase (ALT), albumin, alkaline phosphatase, pancreatic amylase, apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 ratio, aspartate aminotransferase (AST), AST/ALT ratio, bilirubin, calcium, calprotectin, cholesterol, HDL-cholesterol, creatinine kinase (CK), creatinine, creatinine estimated GFR, C-reactive protein, cystatin C, cystatin C estimated GFR, gamma-glutamyltransferase (GGT), iron, iron saturation, lactate dehydrogenase (LDH), magnesium, phosphate, transferrin, triglycerides, urate, urea, zinc, hemoglobin, platelet count and white blood cell count. The upper reference limit for creatinine and urea was significantly increased while the lower limit for iron and albumin was decreased in this elderly population in comparison with the population in the Nordic Reference Interval Project (NORIP).

    CONCLUSIONS: Reference values calculated from the whole population and a subpopulation without cardiovascular disease showed strong concordance. Several of the reference interval limits were outside the 90% confidence interval of NORIP.

  • 163.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Hansson, Lars-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    The age related association is more pronounced for cystatin C estimated GFR than for creatinine estimated GFR in primary care patients2013Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 46, nr 16-17, s. 1761-1763Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    There is an age associated change in GFR but this association may be influenced by the method used. The aims of the present study were to assess the association between age and cystatin C and creatinine based glomerular filtration rate estimates in primary care patients, and to determine the proportion of patients with clinically important renal impairment.

    Materials and methods

    1552 samples with simultaneous requests for creatinine and cystatin C from 1552 primary care patients in the county of Uppsala, Sweden were analysed. MDRD, CKD-EPI and cystatin C equations were used to calculate glomerular filtration rate (GFR) and the associations between GFR and age were explored.

    Results

    The yearly change in cystatin C estimated GFR was 1.24 mL/min/1.73 m2 while the corresponding decline for creatinine estimated GFR was 0.76 mL/min/1.73 m2 for MDRD and 0.99 mL/min/1.73 m2 for CKD-EPI.

    Conclusions

    The age related association with GFR estimates is smaller for creatinine estimates than for cystatin C estimates. This leads to differences in the number of patients with reduced eGFR detected with the three estimates and the patient treatment will depend on the estimate used. This is not coherent with a good patient care and we thus need to develop new eGFR equations with better agreement between the estimates.

  • 164.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Havelka, Aleksandra Mandic
    Karolinska Univ Hosp, Dept Clin Chem, Stockholm, Sweden.
    Xu, Xiao Yan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    The Roche Immunoturbidimetric Albumin Method on Cobas c 501 Gives Higher Values Than the Abbott and Roche BCP Methods When Analyzing Patient Plasma Samples2016Inngår i: Journal of clinical laboratory analysis (Print), ISSN 0887-8013, E-ISSN 1098-2825, Vol. 30, nr 5, s. 677-681Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Serum/plasma albumin is an important and widely used laboratory marker and it is important that we measure albumin correctly without bias. We had indications that the immunoturbidimetric method on Cobas c 501 and the bromocresol purple (BCP) method on Architect 16000 differed, so we decided to study these methods more closely.

    METHOD: A total of 1,951 patient requests with albumin measured with both the Architect BCP and Cobas immunoturbidimetric methods were extracted from the laboratory system. A comparison with fresh plasma samples was also performed that included immunoturbidimetric and BCP methods on Cobas c 501 and analysis of the international protein calibrator ERM-DA470k/IFCC.

    RESULTS: The median difference between the Abbott BCP and Roche immunoturbidimetric methods was 3.3 g/l and the Roche method overestimated ERM-DA470k/IFCC by 2.2 g/l. The Roche immunoturbidimetric method gave higher values than the Roche BCP method: y = 1.111x - 0.739, R² = 0.971.

    CONCLUSION: The Roche immunoturbidimetric albumin method gives clearly higher values than the Abbott and Roche BCP methods when analyzing fresh patient samples. The differences between the two methods were similar at normal and low albumin levels.

  • 165.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Karlsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Fredricsson, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Gastroenterologi/hepatologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Evaluation of the Alere D-dimer test for point of care testing2014Inngår i: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 38, nr 2, s. 250-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The primary care regularly sees patients that have symptoms that could be due to thromboembolic diseases. It would be valuable to be able to rule out deep venous thrombosis or pulmonary embolism using Wells score and a negative D-dimer testing already at the primary care unit. This requires a validated D-dimer assay suitable for primary care use. We compared D-dimer results obtained with the new point of care analyzer Alere Triage(®) and the central hospital laboratory STA-R Evolution analyzer from the same patient samples (n = 102). We also calculated the total coefficient of variation (CV) for the Alere method. The two methods showed a good linear correlation (R(2) = 0.977) and a slope of 0.975. CV for the Alere D-dimer method was well below 10 %. The study shows that the Alere D-dimer assay and the central laboratory standard assay show similar results. We suggest that the Alere D-dimer assay could be used in primary care in combination with Wells score to reduce referrals to the emergency unit.

  • 166.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Association of Test Results for 33 Frequently Used Laboratory Tests with Body Mass Index (BMI)2020Inngår i: CLINICAL AND EXPERIMENTAL INVESTIGATIONS, Vol. 1, nr 1, s. 2-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Once considered a problem only for high-income countries, obesity rates are now rising worldwide. When evaluating test results from obese patients it is important to be aware of the effect of obesity on individual laboratory test results. The aim of the present study was to study the association between body mass index (BMI) and a group of frequently requested laboratory tests to evaluate which of these analytes that are affected by BMI. We analyzed the association between body mass index (BMI) and Alanine aminotransaminase (ALT), Albumin, Alkaline phosphatase, Pancreatic amylase, Apolipoprotein A1, Apolipoprotein B, Apolipoprotein B/Apolipoprotein A1 ratio, Aspartate aminotransferase (AST), AST/ALT ratio, Bilirubin, Calcium, Calprotectin, Cholesterol, HDL-cholesterol, Creatinine kinase (CK), Creatinine, C-reactive protein, Cystatin C, Gamma-glutamyl transferase (GGT), Iron, Iron saturation, Lactate dehydrogenase (LDH), Magnesium, Phosphate, Transferrin, Triglycerides, Urate, Urea, Zink, Hemoglobin, Platelet count and White blood cell count in an 80-year old population (n=531, 266 females and 265 males). There were significant Spearman rank associations between BMI and laboratory test results for several of the studied markers in both females and males. The strongest associations with BMI were noted for ALT, Apolipoprotein A1, HDL-cholesterol, Hemoglobin, CRP, Cystatin C, Triglycerides and Urate. In conclusion, several of the most frequently used laboratory markers are significantly associated with BMI. To be able to correctly interpret a test result it is important to be aware of the effects of BMI on the test results.

  • 167.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Carlsson, Axel C.
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden; Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Family Med, Huddinge, Sweden.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Urinary KIM-1, but not urinary cystatin C, should be corrected for urinary creatinine2016Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 49, nr 15, s. 1164-1166Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: The interest for tubular damage markers such as urinary cystatin C (U-CystC) and kidney injury molecule-1 (U-KIM-1) grows, especially for the diagnosis of acute kidney injury. The trend to measure proteins in spot urine samples instead of 24-h urine collections calls for adjustment of urine dilution with urinary creatinine (UCr). However, it is not known whether UCr adjustment provides a more true value of basal U-CystC and U-KIM-1 levels than absolute values.

    DESIGN & METHODS: This study examines the rationale for UCr correction for U-CystC and U-KIM-1 by exploring the linear relations between U-CystC and U-KIM-1 and UCr, respectively, and the biological day to day variation of absolute concentrations and UCr adjusted values of the two biomarkers.

    RESULTS: Both U-CystC and U-KIM-1 concentrations correlated positively with UCr (R=0.37, P<0.001 and R=0.62, P<0.001, respectively) in 378 participants in a community cohort, which indicated a rationale for adjustment with UCr. However, U-CystC/Cr ratio associated negatively with UCr (R=- 0.31, P<0.001), which could indicate a certain amount of 'over-adjustment'. Morning urine collected for 10 consecutive days from 13 healthy volunteers showed a biological day to day variation of 82% for U-CystC, 75% for U-cystC/Cr ratio, 70% for U-KIM-1 and 46% for U-KIM-1/Cr ratio.

    CONCLUSIONS: This study supports the use of U-KIM-1/Cr ratio in clinical population studies. Data supporting the use of U-CysC/U-Cr ratio were less convincing and the possible confounding of UCr has to be acknowledged in clinical settings.

  • 168.
    Henein, Michael Y.
    et al.
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Suhr, Ole B.
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Arvidsson, Sandra
    Umea Univ, Ctr Heart, Clin Physiol, Umea, Sweden.
    Pilebro, Björn
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hörnsten, Rolf
    Umea Univ, Ctr Heart, Clin Physiol, Umea, Sweden.
    Lindqvist, Per
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Reduced left atrial myocardial deformation irrespective of cavity size: a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis2018Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, nr 1, s. 46-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Cardiac amyloidosis (CA) is a myocardial disease and commonly under-diagnosed condition. In CA patients, atrial fibrillation might occur in the absence of left atrial (LA) enlargement.

    Objectives: The aim of this study is to assess LA size and function, and its relationship with atrial arrhythmia in patients with hereditary transthyretin amyloidosis (ATTR).

    Methods: Forty-six patients with confirmed ATTR amyloidosis on abdominal biopsy were studied. Assessment with 2D echocardiography and 2D strain showed 31 patients had increased LV wall thickness (LVWT) (septal thickness >12mm), and 15 had normal LVWT. In addition to conventional measurements, LV and LA global longitudinal strain (GLS%) and strain rate (SR) were obtained. Western blot analysis was done to assess fibril type. ATTR patients with increased LVWT were compared with 23 patients with hypertrophic cardiomyopathy (HCM) and 31 healthy controls. ATTR amyloidosis patients also underwent 24hour Holter monitoring to determine the presence of atrial arrhythmia.

    Results: Atrial deformation during atrial systole was reduced in ATTR amyloidosis patients with increased LVWT independent of LA size and in contrast to HCM. Twenty of the ATTR amyloidosis patients (54%) had ECG evidence of significant atrial arrhythmic events. LA strain rate, during atrial systole, was the only independent predictor of atrial arrhythmia (=3.28, p=.012).

    Conclusion: In ATTR cardiomyopathy with increased LVWT, LA myocardial function is abnormal, irrespective of atrial cavity size. Reduced LA myocardial SR during atrial systole, irrespective of cavity volume, E/e and LV deformation, is also a strong predictor for atrial arrhythmic events.

    Fulltekst (pdf)
    fulltext
  • 169. Hesstvedt, Liv
    et al.
    Arendrup, Maiken C
    Poikonen, Eira
    Klingpor, Lena
    Friman, Vanda
    Nordøy, Ingvild
    Differences in epidemiology of candidaemia in the Nordic countries - what is to blame?2017Inngår i: Mycoses (Berlin), ISSN 0933-7407, E-ISSN 1439-0507, Vol. 60, nr 1, s. 11-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    National data from Denmark, Finland, Norway and Sweden demonstrate remarkable differences in candidaemia epidemiology. Only Denmark has reported a high incidence of 10 per 100 000 inhabitants and a species shift towards increased C. glabrata candidaemias. The reasons for this development remain unclear. The aim of this study was to explore possible contributing factors for the differences in Candida epidemiology in the Nordic countries. We used public data from 2011 from Denmark, Finland, Norway and Sweden on epidemiology, demographics, health facilities, predisposing risk factors, consumption of antimicrobial drugs and fungicides in agricultural industry. Only the prevalence of haematological malignancies (P < 0.001) was significantly higher in Denmark compared to the other Nordic countries. The antibacterial drug use of metronidazole, piperacillin-tazobactam, ciprofloxacin, colistin and carbapenems, and antifungal use of fluconazole in humans (P < 0.001), were significantly higher in Denmark compared to the other Nordic countries (all P < 0.001). Our findings suggest haematological malignancy, the use of certain antibacterial drugs and azoles in humans as possible contributing factors for the differences in Candida epidemiology. However, our results should be interpreted with caution due to the lack of long-term, case-specific data. Further studies are needed.

  • 170. Hjalgrim, Henrik
    et al.
    Rostgaard, Klaus
    Johnson, Paul C. D.
    Lake, Annette
    Shield, Lesley
    Little, Ann-Margaret
    Ekström-Smedby, Karin
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Hamilton-Dutoit, Stephen
    Kane, Eleanor
    Taylor, G. Malcolm
    McConnachie, Alex
    Ryder, Lars P.
    Andersen, Paal Skytt
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Chang, Ellen T.
    Alexander, Freda E.
    Melbye, Mads
    Jarrett, Ruth F.
    HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma2010Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 14, s. 6400-6405Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.

  • 171.
    Hjort, Marcus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Eggers, Kai M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lindhagen, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Agewall, Stefan
    Univ Oslo, Inst Clin Sci, Oslo Univ Hosp, Oslo, Norway.
    Brolin, Elin B.
    Soder Sjukhuset, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Collste, Olov
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Daniel, Maria
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Ekenbäck, Christina
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Frick, Mats
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Henareh, Loghman
    Karolinska Univ Hosp, Dept Med, Heart & Vasc Theme, Stockholm, Sweden.
    Hofman-Bang, Claes
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Malmqvist, Karin
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Spaak, Jonas
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Sörensson, Peder
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Y-Hassan, Shams
    Karolinska Univ Hosp, Dept Med, Heart & Vasc Theme, Stockholm, Sweden.
    Tornvall, Per
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Lindahl, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries2019Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 65, nr 8, s. 1023-1030Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD).

    METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age-and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses.

    RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-kappa-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls.

    CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts. 

  • 172.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ginman, Beatrice
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Expression of PD-1 and PD-L1 increase in consecutive biopsies in patients with classical Hodgkin lymphoma2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 9, artikkel-id e0204870Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High expression of programmed death receptor 1 (PD-1) and its ligand (PD-L1) by leukocytes in primary classical Hodgkin lymphoma (cHL) is associated with inferior outcome. However, it is unclear how expression varies during disease progression, and in the event of relapse. Our aim was to study PD-1 and PD-L1 in consecutive biopsies from untreated and treated cHL patients. We screened pathology registries from 3500 cHL patients. Eleven patients had a diagnostic cHL biopsy and a previous benign lymph node biopsy reclassified as cHL when reviewed and designated as the untreated. Thirty patients had a primary and a relapse biopsy, designated as the treated. Biopsies were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells. In the untreated, none of the markers were statistically significantly different when biopsies 1 and 2 were compared. In the treated, 19, 22, and 18 of 30 cases had increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ tumor cells, respectively, and were all statistically significantly increased when primary and relapse biopsies were compared. PD-1 and PD-L1 most likely increase due to primary treatment with chemotherapy and radiotherapy, which could have implications regarding treatment with PD-1 inhibitors.

    Fulltekst (pdf)
    fulltext
  • 173.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ginman, Beatrice
    Molin, Daniel
    Enblad, Gunilla
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Glimelius, Ingrid
    Precursor cells and implications of a T-cell inflamed immune response in the pre-malignant setting in Hodgkin lymphoma.2019Inngår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, artikkel-id S0171-2985(19)30248-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The etiology of classical Hodgkin lymphoma (cHL) is largely unknown. High serum CD30-levels are associated with increased risk of cHL. Epstein-Barr virus (EBV) is detectable in the tumor cells in 1/3 of cHL cases in the Western world. The PD-1 pathway (T-cell inflamed immune response) might contribute to the pathogenesis by enabling pre-malignant CD30+ or EBV + cells to evade immune surveillance. We aimed to investigate if high infiltrations of CD30+, PD-1+, PD-L1+ and EBV + cells in benign lymph nodes from patients that later develop cHL (cases) (n = 15) were associated with risk of cHL compared to controls (n = 45) with benign lymph nodes from patients that did not develop cHL. Pathology registries including 3500 cH L patients were screened. Lymph nodes were stained with immunohistochemistry and in situ hybridization and the risk for cHL calculated with logistic regression. High CD30-expression by B- and T-cells was associated with a decreased risk of cHL [(OR = 0.10, 95 % CI:0.03-0.39) and (OR = 0.13, 95 % CI:0.01-0.71), respectively], which remained significant for CD30 + B-cells (OR = 0.15, 95 % CI:0.03-0.60) in multivariate analyses. Amount of PD-1+, PD-L1+ and EBV + cells were not statistically significantly associated with risk of cHL. However, the amount of PD-L1+ leukocytes tended to be higher in cases later developing cHL (OR = 2.84, 95 % CI:0.61-12.61). High proportions of potential precursors to cHL, i.e. CD30 + B-cells in benign lymph nodes are not associated with an increased risk of cHL, while a tendency for a T-cell inflamed immune response, i.e. abundant PD-L1+ cells, was observed in biopsies taken prior to the cHL diagnosis.

  • 174.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kamper, Peter
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Smedby, Karin Ekstrom
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ludvigsen, Maja
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Mortensen, Julie
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hamilton-Dutoit, Stephen
    Aarhus Univ Hosp, Inst Pathol, Aarhus, Denmark..
    d'Amore, Francesco
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome2017Inngår i: Blood Advances, ISSN 2473-9529, Vol. 1, nr 18, s. 1427-1439Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1(+) (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1(+) (HR 5 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 x 10(9)/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 x 10(9)/L, sex, and country). A high proportion of PD-L1(+) leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1(+) and PD-L1(+) leukocytes in the tumor microenvironment.

  • 175.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Rostgaard, Klaus
    Ekström-Smedby, Karin
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Loskog, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    de Nully Brown, Peter
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hjalgrim, Henrik
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome2018Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, nr 1, s. 88-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The classical Hodgkin lymphoma (cHL) tumor microenvironment shows anongoing inflammatory response consisting of varying degrees of infiltrating eosinophils,mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.

    Methods: Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.

    Results: The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barrvirus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.

    Conclusions: Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

    Fulltekst (pdf)
    fulltext
  • 176.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rostgaard, Klaus
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Chang, Ellen T.
    Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA.;Exponent Inc, Hlth Sci, Menlo Pk, CA USA..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brown, Peter de Nully
    Rigshosp, Dept Haematol, DK-2100 Copenhagen, Denmark..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Melbye, Mads
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma2015Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 182, nr 7, s. 624-632Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

  • 177.
    Horie, Masafumi
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan;RIKEN, Ctr Life Sci Technol, DGT, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa, Japan.
    Miyashita, Naoya
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mikami, Yu
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Lab Med Reg Skane, Pathol, Lund, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan.
    An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer2018Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, nr 2, s. 154-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.

  • 178. Horne, B D
    et al.
    Lenzini, P A
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Jorgensen, A L
    Kimmel, S E
    Ridker, P M
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Anderson, J L
    Pirmohamed, M
    Limdi, N A
    Pendleton, R C
    McMillin, G A
    Burmester, J K
    Kurnik, D
    Stein, C M
    Caldwell, M D
    Eby, C S
    Rane, A
    Lindh, J D
    Shin, J-G
    Kim, H-S
    Angchaisuksiri, P
    Glynn, R J
    Kronquist, K E
    Carlquist, J F
    Grice, G R
    Barrack, R L
    Li, J
    Gage, B F
    Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy2012Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 107, nr 2, s. 232-240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.

  • 179.
    Hotz, A.
    et al.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Fagerberg, C.
    Odense Univ Hosp, Dept Clin Genet, Odense, Denmark..
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Bygum, A.
    Odense Univ Hosp, Dept Dermatol, Odense, Denmark.;Odense Univ Hosp, Allergy Ctr, Odense, Denmark..
    Törmä, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Rauschendorf, M-A
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Zhang, Hanqian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Heinz, L.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany.;Univ Freiburg, Fac Biol, Freiburg, Germany..
    Bourrat, E.
    Hop St Louis, Ctr Reference Genodermatoses, Paris, France..
    Hausser, I.
    Univ Hosp Heidelberg, Inst Pathol, Heidelberg, Germany..
    Vestergaard, V.
    Odense Univ Hosp, Dept Clin Pathol, Odense, Denmark..
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Zimmer, A. D.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Fischer, J.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis2018Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 178, nr 3, s. E207-E209Artikkel i tidsskrift (Annet vitenskapelig)
  • 180. Husby, Simon
    et al.
    Ralfkiaer, Ulrik
    Garde, Christian
    Zandi, Roza
    Ek, Sara
    Kolstad, Arne
    Jerkeman, Mats
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Raety, Riikka
    Pedersen, Lone B.
    Pedersen, Anja
    Ehinger, Mats
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Karjalainen-Lindsberg, Marja-Liisa
    Delabie, Jan
    Clasen-Linde, Erik
    Brown, Peter
    Cowland, Jack B.
    Workman, Christopher T.
    Geisler, Christian H.
    Gronbaek, Kirsten
    miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, nr 17, s. 2669-2677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2trial (screening cohort). Prognosticmi RNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.

  • 181.
    Hårdstedt, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning Dalarna.
    Lindblom, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Hong, Jaan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    A novel model for studies of blood-mediated long-term responses to cellular transplants2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 1, s. 28-39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims

    Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h.

    Methods

    Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability.

    Results

    Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen.

    Conclusion

    A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.

  • 182.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B).  In this thesis, the clinical importance of the two types of amyloid fibrils was investigated.

    We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients.

    The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development.

    By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations.

    In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.

    Delarbeid
    1. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
    Åpne denne publikasjonen i ny fane eller vindu >>Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
    Vise andre…
    2008 (engelsk)Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, nr 2, s. 253-61Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

    Emneord
    amyloid, transthyretin, fibril, familial, heart, phenotype, age of onset
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-103613 (URN)10.1002/path.2411 (DOI)000259510000015 ()18729067 (PubMedID)
    Tilgjengelig fra: 2009-05-20 Laget: 2009-05-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients
    Åpne denne publikasjonen i ny fane eller vindu >>Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients
    Vise andre…
    2009 (engelsk)Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 379, nr 4, s. 846-850Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Familial ATTR amyloidosis is caused by point mutations in the transthyretin gene. The clinical manifestations are highly varied but polyneuropathy and/or cardiomyopathy are generally the main symptoms. The amyloid fibrils can either be composed of only intact ATTR molecules or intact together with fragmented ATTR species. As plasma TTR is almost exclusively synthesized in the liver, liver transplantation is performed in order to eliminate the mutant plasma TTR. The procedure has shown best results among patients with the V30M mutation, while a rapid continued cardiac deposition of wild-type (wt) TTR has been seen for many other mutations. In this paper we investigated the proportion of wtATTR in two TTRT60A patients that underwent liver transplantation; one patient died 3 weeks after surgery, the other patient survived for 12 months. As the role of fragmented TTR species in the pathogenesis is far from understood, we investigated the proportion of wt in these species separately to the full-length molecules, which has not been done before in transplanted patients. The results show a higher proportion of wtTTR in the 12-months-surviving patient than the 3-weeks-surviving patient, but interestingly this difference in wt proportion is mainly seen among the full-length, and not the fragmented, molecules.

    Emneord
    Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, ATTRT60A, Liver transplantation, Fibril, Cardiomyopathy, Wild-type
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-103620 (URN)10.1016/j.bbrc.2008.12.095 (DOI)000263336700009 ()19118530 (PubMedID)
    Tilgjengelig fra: 2009-05-20 Laget: 2009-05-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
    Åpne denne publikasjonen i ny fane eller vindu >>Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
    2011 (engelsk)Inngår i: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 89, nr 2, s. 171-180Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated.

    Emneord
    Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, Liver transplantation, Wild-type
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-150732 (URN)10.1007/s00109-010-0695-1 (DOI)000288363300008 ()21107516 (PubMedID)
    Tilgjengelig fra: 2011-04-05 Laget: 2011-04-05 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    4. Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
    Åpne denne publikasjonen i ny fane eller vindu >>Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement.

    The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy.

    Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits.

    This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.

    Emneord
    amyloid, transthyretin, familial amyloidotic polyneuropathy, non-TTRV30M, TTRV30M, cardiomyopathy, fibril composition
    HSV kategori
    Forskningsprogram
    Biokemi; Biologi med inriktning mot molekylärbiologi; Biomedicinsk laboratorievetenskap; Experimentell patologi; Medicinsk biokemi; Molekylärbiologi; Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-160979 (URN)
    Tilgjengelig fra: 2011-11-27 Laget: 2011-11-03 Sist oppdatert: 2018-01-12
    Fulltekst (pdf)
    fulltext
  • 183.
    Ihse, Elisabet
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Rapezzi, Claudio
    Cardiovascular Dept, University of Bologna, Italy.
    Merlini, Giampaolo
    Amyloid Research and Treatment Center, Scientific Institute Policlinico San Matteo, University of Pavia, Italy.
    Benson, Merrill D
    Dept of Pathology and Laboratory Medicine, Indiana University School of Medicine and Roudebush VA medical Center, Indianapolis, IN, USA.
    Ando, Yukio
    Dept of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
    Suhr, Ole B
    Dept of Public Health and Clinical Medicine, Umeå University.
    Leone, Ornella
    Pathology Department, S.Orsola-Malpighi Hospital, Bologna, Italy.
    Lorenzini, Massimiliano
    Cardiovascular Dept, University of Bologna, Italy.
    Quarta, Candida Cristina
    Cardiovascular Dept, University of Bologna, Italy.
    Obici, Laura
    Amyloid Research and Treatment Center, Scientific Institute Policlinico San Matteo, University of Pavia, Italy.
    Lavatelli, Francesca
    Amyloid Research and Treatment Center, Scientific Institute Policlinico San Matteo, University of Pavia, Italy.
    Liepnieks, Juris
    Dept of Pathology and Laboratory Medicine, Indiana University School of Medicine and Roudebush VA medical Center, Indianapolis, IN, USA.
    Ohshima, Toshinori
    Dept of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.
    Jono, Hirofumi
    Dept of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosisManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement.

    The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy.

    Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits.

    This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.

  • 184. Isfoss, Björn L
    et al.
    Majak, Bernard
    Busch, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Braathen, Geir J
    Diagnosis of intraurothelial neoplasia: Interobserver variation and the value of individual histopathologic attributes2011Inngår i: Analytical and Quantitative Cytology and Histology, ISSN 0884-6812, Vol. 33, nr 2, s. 75-81Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To determine interobserver variation in histopathologic diagnosis of carcinoma in situ (CIS) and dysplasia (collectively intraurothelial neoplasia [IUN]) of the bladder and identify histomorphologic features important for diagnosis.

    STUDY DESIGN:

    A total of 272 consecutive bladder tissue samples were re-evaluated blindly by two general pathologists and one uropathologist for IUN. Discrepancies were resolved jointly. Fifteen histopathologic attributes were evaluated for prediction of diagnosis. Followup revealed recurrence and progression rates for each diagnostic category.

    RESULTS:

    Thirty-six percent of specimens contained no evaluable flat mucosa; 51% percent of specimens from papillary urothelial neoplasia (PUN) cases showed CIS. General pathologists detected 56-69% of CIS and 8-42% of dysplasia. Histopathologic features most predictive for CIS were nuclear size, variation in nuclear shape, loss of maturation, loss of polarity, and architectural disorder. None of these individually or in combination exceeded general pathologists' diagnostic accuracy. IUN was not predictive of recurrence or progress.

    CONCLUSION:

    Using material mostly consisting of flat mucosa gratuitously provided in PUN resection specimens, IUN carries no prognostic value. General histopathologists detect IUN poorly to moderately, and the five most discriminatory histomorphologic features are insufficient for diagnosis. Interobserver agreement for dysplasia is dismal. Absent flat mucosa in PUN resections predicts recurrence.

  • 185. Isfoss, Björn L
    et al.
    Majak, Bernard
    Busch, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Braathen, Geir J
    Simplification of grading papillary urothelial neoplasia using a reduced set of diagnostic features2011Inngår i: Analytical and Quantitative Cytology and Histology, ISSN 0884-6812, Vol. 33, nr 2, s. 68-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To determine whether a reduced set of the histopathologic features used in internationally accepted classifications is capable of accurately grading papillary urothelial neoplasms (PUN).

    STUDY DESIGN:

    All surgical specimens from urinary bladders received during a 2-year period were reexamined by an expert uropathologist for assessing the accuracy of original nonexpert PUN grading and staging. Thirteen histopathologic features entailing 32 attributes were evaluated with regard to prediction of expert grade. Patients were followed for 35-59 months (mean, 47).

    RESULTS:

    A total of 88 PUN specimens could be analyzed completely including follow-up specimens. Agreement between original and expert grade was 71% for low-grade and 87% for high-grade PUN, with overall kappa = 0.53. The histomorphologic features most predictive of expert grade were architectural disorder, variability of nuclear enlargement, and absence of umbrella cells. Neither individual histomorphologic attributes nor their combinations were as predictive of expert pathologist grade as original diagnoses.

    CONCLUSION:

    Improvements in PUN grading and prognostication are not likely to be accomplished by only reducing the number of histomorphologic features currently recommended by the World Health Organization and International Society of Urological Pathology.

  • 186.
    Jabs, Verena
    et al.
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Edlund, Karolina
    Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Koenig, Helena
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Grinberg, Marianna
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Madjar, Katrin
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Ekman, Simon
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Bergkvist, Michael
    Gavle Cent Hosp, Dept Oncol, Gavle, Sweden..
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Reg Canc Ctr Uppsala Orebro, Uppsala, Sweden.;Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Ickstadt, Katja
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hengstler, Jan G.
    Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikkel-id e0187246Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-small cell lung cancer (NSCLC) represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes), high correlations, with a correlation coefficient >0.7, were obtained only in a subset of 301 genes (1.6%), including KRAS, EGFR and MDM2. Higher correlation coefficients were associated with higher copy number and expression levels. Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression. Among the highly correlating genes, GO groups associated with posttranslational protein modifications were particularly frequent, including ubiquitination and neddylation. In a meta-analysis including 1,779 patients we found that survival associated genes were overrepresented among highly correlating genes (61 of the 301 highly correlating genes, FDR adjusted p<0.05). Among them are the chaperone CCT2, the core complex protein NUP107 and the ubiquitination and neddylation associated protein CAND1. In conclusion, in a comprehensive analysis we described a distinct set of highly correlating genes. These genes were found to be overrepresented among survival-associated genes based on gene expression in a large collection of publicly available datasets.

    Fulltekst (pdf)
    fulltext
  • 187.
    Jansson, Desiree S.
    et al.
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Bröjer, Caroline
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, Uppsala, Sweden..
    Neimanis, Aleksija
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, Uppsala, Sweden..
    Mörner, Torsten
    Natl Vet Inst SVA, Dept Dis Control & Epidemiol, Uppsala, Sweden..
    Murphy, Charles L.
    Univ Tennessee, Med Ctr, Dept Med, Knoxville, TN USA..
    Otman, Faruk
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Post mortem findings and their relation to AA amyloidosis in free-ranging Herring gulls (Larus argentatus)2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 3, artikkel-id e0193265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since the late 1990s, high mortality and declining populations have been reported among sea birds including Herring gulls ( Larus argentatus) from the Baltic Sea area in Northern Europe. Repeated BoNT type C/D botulism outbreaks have occurred, but it remains unclear whether this is the sole and primary cause of mortality. Thiamine deficiency has also been suggested as a causal or contributing factor. With this study, we aimed to investigate gross and microscopic pathology in Herring gulls from affected breeding sites in Sweden in search of contributing diseases. Herring gulls from Iceland served as controls. Necropsies and histopathology were performed on 75 birds, of which 12 showed signs of disease at the time of necropsy. Parasites of various classes and tissues were commonly observed independent of host age, e.g. oesophageal capillariosis and nematode infection in the proventriculus and gizzard with severe inflammation, air sac larid pentastomes and bursal trematodiasis in pre-fledglings. Gross and microscopic findings are described. Notably, amyloidosis was diagnosed in 93 and 33% of the adult birds from Sweden and Iceland, respectively ( p<0.001), with more pronounced deposits in Swedish birds ( p<0.001). Gastrointestinal deposits were observed in the walls of arteries or arterioles, and occasionally in villi near the mucosal surface. Amyloid was identified within the intestinal lumen in one severely affected gull suggesting the possibility of oral seeding and the existence of a primed state as previously described in some mammals and chickens. This could speculatively explain the high occurrence and previously reported rapid onset of amyloidosis upon inflammation or captivity in Herring gulls. Amyloid-induced malabsorbtion is also a possibility. The Herring gull SAA/AA protein sequence was shown to be highly conserved but differed at the N-terminus from other avian species.

  • 188. Jardin, Fabrice
    et al.
    Pujals, Anais
    Pelletier, Laura
    Bohers, Elodie
    Camus, Vincent
    Mareschal, Sylvain
    Dubois, Sydney
    Sola, Brigitte
    Ochmann, Marlène
    Lemonnier, François
    Viailly, Pierre-Julien
    Bertrand, Philippe
    Maingonnat, Catherine
    Traverse-Glehen, Alexandra
    Gaulard, Philippe
    Damotte, Diane
    Delarue, Richard
    Haioun, Corinne
    Argueta, Christian
    Landesman, Yosef
    Salles, Gilles
    Jais, Jean-Philippe
    Figeac, Martin
    Copie-Bergman, Christiane
    Molina, Thierry Jo
    Picquenot, Jean Michel
    Cornic, Marie
    Fest, Thierry
    Milpied, Noel
    Lemasle, Emilie
    Stamatoullas, Aspasia
    Moeller, Peter
    Dyer, Martin J S
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bastard, Christian
    Tilly, Hervé
    Leroy, Karen
    Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.2016Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 91, nr 9, s. 923-30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.

    Fulltekst (pdf)
    fulltext
  • 189.
    Jiang, Yiwen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Olofsson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, nr 4, s. 977-990Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

    Fulltekst (pdf)
    fulltext
  • 190. Jin, J-P
    et al.
    Bloch, Robert J
    Huang, Xupei
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Muscle contractility and cell motility2012Inngår i: Journal of Biomedicine and Biotechnology, ISSN 1110-7243, E-ISSN 1110-7251, nr Article ID 257812Artikkel i tidsskrift (Fagfellevurdert)
  • 191. Johnson, JA
    et al.
    Caudle, KE
    Gong, L
    Whirl-Carrillo, M
    Stein, CM
    Scott, SA
    Lee, MT
    Gage, BF
    Kimmel, SE
    Perera, MA
    Anderson, JL
    Pirmohamed, M
    Klein, TE
    Limdi, NA
    Cavallari, LH
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update2017Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, nr 3, s. 397-404Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

    Fulltekst (pdf)
    fulltext
  • 192.
    Jonsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Reference interval for urinary catecholamines and methylated catecholamines analysed using HPLC2012Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Catecholamines are stress hormones that are produced and released by a rare tumor called pheochromocytoma. This tumor can cause hypertension which if undiagnosed and untreated leads to death. Since good therapy is available, it is important to find the tumor in time. The most common way to diagnose the tumor is measurement of the biochemical markers; catecholamines and their metabolites, methylated catecholamines.

    After observation that almost all normetanephrine results for women were higher than the upper reference limit and therefore pathological, the accuracy of the present reference intervals was questioned. Therefore new reference intervals for both urinary catecholamines and methylated catecholamines were developed by analysis of 46 samples using HPLC. Creatinine was analysed in acidified urine in order to see if the results became the same as when analysed in non-acidified urine.

    Urinary catecholamines and methylated catecholamines were analysed using HPLC. Comparison between measurement of creatinine in acidified urine and non-acidified urine with an enzymatic method was performed using Architect ci 8200, Abbott.

    As suspected, there was a difference between the present and new intervals. Therefore the new intervals will be used for future diagnosis. There was no difference between the two treatments of creatinine samples wherefore it can be measured in both.In conclusion reference intervals determind in this study will be used and it was shown that creatinine can be measured in acidified urine.

    Fulltekst (pdf)
    Annas examensarbete
  • 193. Jonsson, M
    et al.
    Hansson, L-O
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Grubb, Anders
    Plasmaproteiner, inflammation och amyloidos2018Inngår i: Laurells klinisk kemi i praktisk medicin. / [ed] Theodorsson E. ; Berggren Söderlund, M., Lund: Studentlitteratur AB, 2018, 10, s. 87-130Kapittel i bok, del av antologi (Fagfellevurdert)
  • 194.
    Kaden, Rene
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi. National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden.
    Ferrari, Sevinc
    National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden.
    Jinnerot, Tomas
    National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden.
    Lindberg, Martina
    National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden; National Food Agency, Uppsala, Sweden.
    Wahab, Tara
    Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Public Health Agency of Sweden Solna, Sweden..
    Lavander, Moa
    Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden; National Food Agency, Uppsala, Sweden..
    Brucella abortus: determination of survival times and evaluation of methods for detection in several matrices2018Inngår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 18, artikkel-id 259Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Brucella abortus is a highly pathogenic zoonotic agent, tempting for the development of a rapid diagnostic method to enable adequate treatment and prevent further spread. Enrichment of the bacteria is often used as a first step in diagnostics to increase the bacterial number above the detection limit of the real-time PCR. The enrichment of Brucella spp. takes at least 3 days, which might be avoidable if sensitive PCR methods can be used. Since many matrices contain PCR inhibitors, the limit of detection (LOD) must be determined for each separate matrix. Another aim of this study was the determination of survival of Brucella abortus in the analyzed matrices. METHODS: The LOD for the detection of B. abortus in 14 matrices, relevant for human medicine, veterinary medicine and food and feed safety, was determined to evaluate the need of a pre-enrichment step prior to real-time PCR. The survival of B. abortus in the spiked matrices was tested by plate count in a 7-day interval for 132 days. RESULTS: The limit of detection for B. abortus in most matrices was in the range of 10(3)-10(4) CFU/g for cultivation and 10(4)-10(5) CFU/g for direct real-time PCR. The survival time of B. abortus was less than 21 days in apple puree and stomach content and 28 days in water while B. abortus remained viable at day 132 in milk, blood, spinach and minced meat. CONCLUSIONS: A direct PCR analysis without enrichment of bacteria saves at least 3 days. However, the limit of detection between direct PCR and plate count differs in a 10 fold range. We conclude that this lower sensitivity is acceptable in most cases especially if quick analysis are required.

    Fulltekst (pdf)
    fulltext
  • 195. Kankel, Jennifer
    et al.
    Obreja, Otilia
    Kleggetveit, Inge Petter
    Schmidt, Roland
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Jørum, Ellen
    Schmelz, Martin
    Namer, Barbara
    Differential effects of low dose lidocaine on C-fiber classes in humans2012Inngår i: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 13, nr 12, s. 1232-1241Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nonselective sodium channel blocker lidocaine is widely used as a local anesthetic but also systemically for treatment of postoperative and neuropathic pain. Voltage-gated sodium channels are crucial for action potential generation and conduction, and their availability controls the amount of activity-dependent conduction velocity slowing. This important axonal property, as assessed by microneurography, is used to differentiate human mechanoinsensitive (silent) nociceptors from the classical polymodal nociceptors. In the current study, microneurography was used to assess axonal properties of the 2 main nociceptor classes in humans, before and after intradermal injection of lidocaine .1% or control saline solution in the receptive field. In mechanosensitive nociceptors, lidocaine reduced baseline conduction velocity and turned activity-dependent slowing into speeding of conduction. In contrast, mechanoinsensitive fibers were not affected in their baseline conduction velocity or their activity-dependent slowing, but probability of conduction block with repetitive stimulation increased. Recovery cycles showed reduced hyperpolarization in all C-fiber classes after lidocaine injections. These results support our hypothesis that sodium channel subtypes are differentially expressed in the 2 nociceptor classes of mechanosensitive C-fibers (CMs) and mechanoinsensitive C-fibers (CMis).

    Perspective: This study reveals that microneurography can be used to assess pharmacologicaleffects on single C-fibers directly in humans. 

  • 196.
    Karakatsanis, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Bergkvist, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Abdsaleh, S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Simplifying Logistics and Avoiding the Unnecessary in Patients with Breast Cancer Undergoing Sentinel Node Biopsy. A Prospective Feasibility Trial of the Preoperative Injection of Super Paramagnetic Iron Oxide Nanoparticles2018Inngår i: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 107, nr 2, s. 130-137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Sentinel node is routinely localized with the intraoperative use of a radioactive tracer, involving challenging logistics. Super paramagnetic iron oxide nanoparticle is a non-radioactive tracer with comparable performance that could allow for preoperative localization, would simplify the procedure, and possibly be of value in axillary mapping before neoadjuvant treatment. The current trial aimed to determine the a priori hypothesis that the injection of super paramagnetic iron oxide nanoparticles in the preoperative period for the localization of the sentinel node is feasible.

    METHODS: This is a prospective feasibility trial, conducted from 9 September 2014 to 22 October 2014 at Uppsala University Hospital. In all, 12 consecutive patients with primary breast cancer planned for resection of the primary and sentinel node biopsy were recruited. Super paramagnetic iron oxide nanoparticles were injected in the preoperative visit in the outpatient clinic. The radioactive tracer (99mTc) and the blue dye were injected perioperatively in standard fashion. A volunteer was injected with super paramagnetic iron oxide nanoparticles to follow the decline in the magnetic signal in the sentinel node over time. The primary outcome was successful sentinel node detection.

    RESULTS: Super paramagnetic iron oxide nanoparticles' detection after preoperative injection (3-15 days) was successful in all cases (100%). In the volunteer, axillary signal was presented for 4 weeks. No adverse effects were noted. Conclusion and relevance: Preoperative super paramagnetic iron oxide nanoparticles' injection is feasible and leads to successful detection of the sentinel node. That may lead to simplified logistics as well as the identification, sampling, and marking of the sentinel node in patients planned for neoadjuvant treatment.

  • 197. Karamanakos, Petros N.
    et al.
    Jaaskelainen, Juha E.
    Alafuzoff, Irina
    Department of Clinical Pathology, University Hospital, Kuopio, Finland.
    Pirinen, Elina
    Vanninen, Ritva
    Silvennoinen, Sanna
    Sankilampi, Ulla
    Immonen, Arto
    Malignant giant cell tumor in the posterior fossa of a neonate: case report2010Inngår i: Journal of Neurosurgery: Pediatrics, ISSN 1933-0707, E-ISSN 1933-0715, Vol. 5, nr 3, s. 277-282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Giant cell tumors (GCTs) of the bone are rare, usually benign but locally aggressive neoplasms that primarily occur in the epiphyses of long bones. They seldom develop in the cranium; when they do, they involve principally the sphenoid and temporal bones. These tumors usually affect young adults, and few reports in children have been published. Primary malignant GCTs of the skull are even more uncommon. The 3 published cases all involved adults over 40 years of age. Herein, the authors present a case of a highly aggressive primary malignant GCT of the posterior fossa in a 5-week old preterm infant. One month after the gross-total resection of the tumor found in the bone, the infant's condition rapidly deteriorated and she died. Magnetic resonance imaging and postmortem examination revealed a tumor larger than it had been before the operation, with expansion toward the brain. To the best of the authors' knowledge, this is the youngest patient reported with a primary malignant GCT of the skull, and actually the first case in a pediatric patient. In addition, the extremely high growth rate of the tumor in the postoperative period renders this case the most aggressive primary malignant GCT of the cranium described so far.

  • 198.
    Karawajczyk, Malgorzata
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Point-of-care instruments need to offer high levels of accuracy2017Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, nr 10, artikkel-id 1707Artikkel i tidsskrift (Annet vitenskapelig)
  • 199.
    Karlsson, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Veerla, Srinivas
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jönsson, Mats
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Reuterswärd, Christel
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Skane Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden..
    Staaf, Johan
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 8, s. 1257-1267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.

    Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.

    Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.

    Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.

    Fulltekst (pdf)
    fulltext
  • 200.
    Karlsson, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Cirenajwis, Helena
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Ericson-Lindquist, Kajsa
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22185 Lund, Sweden;Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22185 Lund, Sweden;Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Reuterswärd, Christel
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Jonsson, Mats
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Ortiz-Villalon, Cristian
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden.
    Hussein, Aziz
    Sahlgrens Univ Hosp, Dept Pathol & Cytol, Gothenburg, Sweden.
    Bergman, Bengt
    Sahlgrens Univ Hosp, Dept Resp Med, Gothenburg, Sweden.
    Vikström, Anders
    Univ Hosp Linkoping, Dept Pulm Med, Linkoping, Sweden.
    Monsef, Nastaran
    Linkoping Univ, Dept Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Karolinska Inst, Dept Med Solna & CMM, Resp Med Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Karolinska Inst, Dept Med Solna & CMM, Resp Med Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    de Petris, Luigi
    Karolinska Univ Hosp, Thorac Oncol Unit, Stockholm, Sweden;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Patthey, Annika
    Umea Univ Hosp, Dept Pathol, SE-90185 Umea, Sweden.
    Behndig, Annelie F.
    Umea Univ, Div Med, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden.
    Johansson, Mikael
    Umea Univ, Dept Radiat Sci, Oncol, SE-90185 Umea, Sweden.
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden;Skane Univ Hosp, Dept Resp Med & Allergol, SE-22185 Lund, Sweden.
    Staaf, Johan
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 5207Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

    Fulltekst (pdf)
    FULLTEXT01
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