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  • 351.
    Alving, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Basic aspects of exhaled nitric oxide2010In: European Respiratory Monograph, ISSN 1025-448X, E-ISSN 2075-6674, Vol. 49, p. 1-31Article, review/survey (Refereed)
    Abstract [en]

    Nitric oxide (NO) in orally exhaled air mainly originates fromthe respiratory epithelium. NO is produced by inducible NOsynthase (iNOS), which is regulated by signal transducer andactivator of transcription (STAT)-1 under the influence ofhomeostatic interferon-c. In patients with asthma, iNOSexpression is upregulated by interleukin (IL)-4 and IL-13 viathe activation of STAT-6 in the bronchial epithelium. Thus,exhaled NO primarily signals local T-helper cell type 2-driveninflammation in the bronchial mucosa. With these character-istics, exhaled NO will be a suitable marker for predicting theresponse to inhaled corticosteroids, and to monitor the anti-inflammatory effect.The methodology for measuring exhaled NO has beenstandardised based on international consensus. The determi-nants of exhaled NO levels are fairly well characterised, withthe most important being cigarette smoking, nitrate intake, airpollution, allergen sensitisation and exposure, along withheight, sex and age. A future development may be the estima-tion of peripheral airway inflammation by measuring exhaledNO at multiple exhalation flow rates.

  • 352.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.

    In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples.  These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.

    List of papers
    1. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
    Open this publication in new window or tab >>Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
    Show others...
    2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, p. 6809-6923Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    Keywords
    multiple myeloma; Polycomb; EZH2; H3K27me3; UNC1999
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-289186 (URN)10.18632/oncotarget.6843 (DOI)000376123100032 ()26755663 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), R01GM103893
    Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2019-04-14Bibliographically approved
    2. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
    Open this publication in new window or tab >>EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
    Show others...
    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, p. 10213-10224Article in journal (Refereed) Published
    Abstract [en]

    Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-312396 (URN)10.18632/oncotarget.14378 (DOI)000394181800106 ()28052011 (PubMedID)
    Available from: 2017-01-09 Created: 2017-01-09 Last updated: 2019-04-14Bibliographically approved
    3. The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Open this publication in new window or tab >>The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Show others...
    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103731-103743Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

    Keywords
    Multiple Myeloma, Epigenetics, Polycomb, BMI-1, PTC-209
    National Category
    Cancer and Oncology
    Research subject
    Medical Science; Molecular Medicine
    Identifiers
    urn:nbn:se:uu:diva-313562 (URN)10.18632/oncotarget.21909 (DOI)000419562500079 ()29262596 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2017-01-20 Created: 2017-01-20 Last updated: 2019-04-14Bibliographically approved
  • 353.
    Alzrigat, Mohammad
    et al.
    Univ Florida, Hlth Canc Ctr, Div Hematol & Oncol, Dept Med, Gainesville, FL 32610 USA.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Licht, Jonathan D.
    Univ Florida, Hlth Canc Ctr, Div Hematol & Oncol, Dept Med, Gainesville, FL 32610 USA.
    Targeting EZH2 in Multiple Myeloma-Multifaceted Anti-Tumor Activity2018In: EPIGENOMES, ISSN 2075-4655, Vol. 2, no 3, article id 16Article, review/survey (Refereed)
    Abstract [en]

    The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM.

  • 354.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg-Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Epigenetics in multiple myeloma: From mechanisms to therapy2018In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, p. 101-115Article, review/survey (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of antibody producing plasmablasts/plasma cells that resides within the bone marrow (BM). In addition to the well-established role of genetic lesions and tumor-microenvironment interactions in the development of MM, deregulated epigenetic mechanisms are emerging as important in MM pathogenesis. Recently, MM sequencing and expression projects have revealed that mutations and copy number variations as well as deregulation in the expression of epigenetic modifiers are characteristic features of MM. In the past decade, several studies have suggested epigenetic mechanisms via DNA methylation, histone modifications and non-coding RNAs as important contributing factors in MM with impacts on disease initiation, progression, clonal heterogeneity and response to treatment. Herein we review the present view and knowledge that has accumulated over the past decades on the role of epigenetics in MM, with focus on the interplay between epigenetic mechanisms and the potential use of epigenetic inhibitors as future treatment modalities for MM.

  • 355.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Majumder, Muntasir
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Ma, Anqi
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Jin, Jian
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Heckman, Caroline
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103731-103743Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

  • 356.
    Amandusson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Utredning av epileptiska anfall och misstänkt epilepsi: Anamnes och vittnesbeskrivning är avgörande för rätt diagnos2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, article id E47DArticle in journal (Refereed)
  • 357.
    Amandusson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Elf, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Grindlund, Margareta E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Punga, Anna R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Diagnostic Utility of Repetitive Nerve Stimulation in a Large Cohort of Patients With Myasthenia Gravis2017In: Journal of clinical neurophysiology, ISSN 0736-0258, E-ISSN 1537-1603, Vol. 34, no 5, p. 400-407Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Optimizing the diagnostic utility of repetitive nerve stimulation in myasthenia gravis (MG) may include tailoring the examination to clinical phenotype. Therefore, we analyzed all available repetitive nerve stimulation parameters in a large cohort of patients with confirmed MG diagnosis.

    METHODS: All repetitive nerve stimulation examinations at the Uppsala University Hospital rendering an MG diagnosis during 1996 to 2014 were analyzed. The deltoid, trapezius, anconeus, nasalis, abductor digiti quinti, and frontalis muscles were examined.

    RESULTS: Two hundred one patients with MG were diagnosed. Abnormal amplitude decrement was found in 54% of patients with ocular MG, 77% of patients with predominantly bulbar fatigue, and in 83% of patients with predominantly limb fatigue. The deltoid muscle had the highest sensitivity in all MG subtypes, with a mean of 77% sensitivity in all clinical subtypes, and the most pronounced decrement for amplitude (P = 0.0002) and area (P < 0.0001). Technical issues were rare.

    CONCLUSIONS: These data contribute to further optimization of repetitive nerve stimulation strategies regarding muscle selection and technical performance in the electrodiagnostic workup of MG.

  • 358.
    Amaral, Andre F. S.
    et al.
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Coton, Sonia
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Kato, Bernet
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Tan, Wan C.
    Univ British Columbia, Heart Lung Innovat Ctr, Vancouver, BC V5Z 1M9, Canada..
    Studnicka, Michael
    Paracelsus Med Univ, Dept Pulm Med, Salzburg, Austria..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gislason, Thorarinn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Reykjavik, Iceland..
    Mannino, David
    Univ Kentucky, Div Pulm Crit Care & Sleep Med, Lexington, KY USA..
    Bateman, Eric D.
    Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa..
    Buist, Sonia
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Burney, Peter G. J.
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Lung function defects in treated pulmonary tuberculosis patients2016In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 47, no 1, p. 352-353Article in journal (Refereed)
  • 359.
    Amaral, Andre F. S.
    et al.
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Coton, Sonia
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Kato, Bernet
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Tan, Wan C.
    Univ British Columbia, Heart Lung Innovat Ctr, Vancouver, BC V5Z 1M9, Canada..
    Studnicka, Michael
    Paracelsus Med Univ, Dept Pulm Med, Salzburg, Austria..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gislason, Thorarinn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Reykjavik, Iceland..
    Mannino, David
    Univ Kentucky, Div Pulm Crit Care & Sleep Med, Lexington, KY USA..
    Bateman, Eric D.
    Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa..
    Buist, Sonia
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Burney, Peter G. J.
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London SW3 6LR, England..
    Tuberculosis associates with both airflow obstruction and low lung function: BOLD results2015In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 46, no 4, p. 1104-1112Article in journal (Refereed)
    Abstract [en]

    In small studies and cases series, a history of tuberculosis has been associated with both airflow obstruction, which is characteristic of chronic obstructive pulmonary disease, and restrictive patterns on spirometry. The objective of the present study was to assess the association between a history of tuberculosis and airflow obstruction and spirometric abnormalities in adults. The study was performed in adults, aged 40 years and above, who took part in the multicentre, cross-sectional, general population-based Burden of Obstructive Lung Disease study, and had provided acceptable post-bronchodilator spirometry measurements and information on a history of tuberculosis. The associations between a history of tuberculosis and airflow obstruction and spirometric restriction were assessed within each participating centre, and estimates combined using meta-analysis. These estimates were stratified by high- and low/middle-income countries, according to gross national income. A self-reported history of tuberculosis was associated with airflow obstruction (adjusted odds ratio 2.51, 95% CI 1.83-3.42) and spirometric restriction (adjusted odds ratio 2.13, 95% CI 1.42-3.19). A history of tuberculosis was associated with both airflow obstruction and spirometric restriction, and should be considered as a potentially important cause of obstructive disease and low lung function, particularly where tuberculosis is common.

  • 360.
    Amaral, Andre F. S.
    et al.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Newson, Roger B.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England.;Univ London Imperial Coll Sci Technol & Med, Dept Primary Care & Publ Hlth, Sch Publ Hlth, London, England..
    Abramson, Michael J.
    Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia..
    Anto, Josep M.
    Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.;IMIM Hosp del Mar, Med Res Inst, Barcelona, Spain.;UPF, Barcelona, Spain.;CIBERESP, Madrid, Spain..
    Bono, Roberto
    Univ Turin, Dept Publ Hlth & Pediat, Turin, Italy..
    Corsico, Angelo G.
    Univ Pavia, Div Resp Dis, IRCCS Policlin San Matteo Fdn, Via Palestro 3, I-27100 Pavia, Italy..
    de Marco, Roberto
    Univ Verona, Unit Epidemiol & Med Stat, Dept Publ Hlth & Community Med, I-37100 Verona, Italy..
    Demoly, Pascal
    CHU Montpellier, Dept Pulmonol, Div Allergy, Arnaud de Villeneuve Hosp, Paris, France.;INSERM, EPAR Team, UMR S 1136, Paris, France..
    Forsberg, Bertil
    Umea Univ, Div Occupat & Environm Med, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gislason, Thorarinn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Natl Univ Hosp Iceland, Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Heinrich, Joachim
    Helmholtz Zentrum, Inst Epidemiol 1, Munich, Germany.;Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Inner City Clin, Univ Hosp Munich, Munich, Germany..
    Huerta, Ismael
    Dept Hlth Asturias, Directorate Gen Publ Hlth, Epidemiol Surveillance Sect, Oviedo, Spain..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Jogi, Rain
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Tartu Univ Hosp, Lung Clin, Tartu, Estonia..
    Kim, Jeong-Lim
    Univ Gothenburg, Dept Publich Hlth & Community Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Maldonado, Jose
    Univ Hosp Huelva, Unit Clin Management Pneumol & Allergy, Huelva, Spain..
    Rovira, Jesus Martinez-Moratalla
    Univ Hosp Albacete, Unit Pneumol, Albacete, Spain..
    Neukirch, Catherine
    INSERM, UMR1152, Paris, France.;Univ Paris 07, UMR1152, Paris, France..
    Nowak, Dennis
    Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Inner City Clin, Univ Hosp Munich, Munich, Germany.;German Ctr Lung Res, Munich, Germany..
    Pin, Isabelle
    CHU Grenoble, Pole Couple Enfants, Pediat, F-38043 Grenoble, France.;Inst Albert Bonniot, INSERM, U823, Grenoble, France.;Univ Grenoble 1, Grenoble, France..
    Probst-Hensch, Nicole
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland.;Univ Basel, Basel, Switzerland..
    Raherison-Semjen, Chantal
    Bordeaux Univ, Inst Publ Hlth & Epidemiol, INSERM, U897, Bordeaux, France..
    Svanes, Cecilie
    Univ Bergen, Ctr Int Hlth, Bergen, Norway.;Haukeland Hosp, Dept Occupat Med, N-5021 Bergen, Norway..
    Landa, Isabel Urrutia
    Galdakao Hosp, Dept Pneumol, Bizkaia, Spain..
    van Ree, Ronald
    Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Versteeg, Serge A.
    Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Weyler, Joost
    Univ Antwerp, Epidemiol & Social Med, B-2020 Antwerp, Belgium.;Univ Antwerp, StatUA Stat Ctr, B-2020 Antwerp, Belgium..
    Zock, Jan-Paul
    Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.;UPF, Barcelona, Spain.;CIBERESP, Madrid, Spain..
    Burney, Peter G. J.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Jarvis, Deborah L.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Changes in IgE sensitization and total IgE levels over 20 years of follow-up2016In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 137, no 6, p. 1788-1795Article in journal (Refereed)
    Abstract [en]

    Background: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. Objective: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. Methods: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. Results: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. Conclusion: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years.

  • 361. Amaral, Andre F. S.
    et al.
    Ramasamy, Adaikalavan
    Castro-Giner, Francesc
    Minelli, Cosetta
    Accordini, Simone
    Sorheim, Inga-Cecilie
    Pin, Isabelle
    Kogevinas, Manolis
    Jõgi, Rain
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Balding, David J.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Verlato, Giuseppe
    Olivieri, Mario
    Probst-Hensch, Nicole
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Zock, Jan-Paul
    Heinrich, Joachim
    Jarvis, Deborah L.
    Interaction between gas cooking and GSTM1 null genotype in bronchial responsiveness: results from the European Community Respiratory Health Survey2014In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 69, no 6, p. 558-564Article in journal (Refereed)
    Abstract [en]

    Background Increased bronchial responsiveness is characteristic of asthma. Gas cooking, which is a major indoor source of the highly oxidant nitrogen dioxide, has been associated with respiratory symptoms and reduced lung function. However, little is known about the effect of gas cooking on bronchial responsiveness and on how this relationship may be modified by variants in the genes GSTM1, GSTT1 and GSTP1, which influence antioxidant defences. Methods The study was performed in subjects with forced expiratory volume in one second at least 70% of predicted who took part in the multicentre European Community Respiratory Health Survey, had bronchial responsiveness assessed by methacholine challenge and had been genotyped for GSTM1, GSTT1 and GSTP1-rs1695. Information on the use of gas for cooking was obtained from interviewer-led questionnaires. Effect modification by genotype on the association between the use of gas for cooking and bronchial responsiveness was assessed within each participating country, and estimates combined using meta-analysis. Results Overall, gas cooking, as compared with cooking with electricity, was not associated with bronchial responsiveness (beta=-0.08, 95% CI -0.40 to 0.25, p=0.648). However, GSTM1 significantly modified this effect (beta for interaction=-0.75, 95% CI - 1.16 to -0.33, p=4x10(-4)), with GSTM1 null subjects showing more responsiveness if they cooked with gas. No effect modification by GSTT1 or GSTP1-rs1695 genotypes was observed. Conclusions Increased bronchial responsiveness was associated with gas cooking among subjects with the GSTM1 null genotype. This may reflect the oxidant effects on the bronchi of exposure to nitrogen dioxide.

  • 362.
    Amaral, Rita
    et al.
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Fonseca, Joao A.
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Univ Porto, Fac Med, MEDCIDS Dept Community Med Informat & Hlth Sci, Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Jacinto, Tiago
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Pereira, Ana M.
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Having concomitant asthma phenotypes is common and independently relates to poor lung function in NHANES 2007-20122018In: Clinical and Translational Allergy, ISSN 2045-7022, E-ISSN 2045-7022, Vol. 8, article id 13Article in journal (Refereed)
    Abstract [en]

    Background: Evidence for distinct asthma phenotypes and their overlap is becoming increasingly relevant to identify personalized and targeted therapeutic strategies. In this study, we aimed to describe the overlap of five commonly reported asthma phenotypes in US adults with current asthma and assess its association with asthma outcomes. Methods: Data from the National Health and Nutrition Examination Surveys (NHANES) 2007-2012 were used (n =30,442). Adults with current asthma were selected. Asthma phenotypes were: B-Eos-high [if blood eosinophils (B-Eos) >= 300/mm(3)]; FeNO-high (FeNO >= 35 ppb); B-Eos&FeNO-low (B-Eos < 150/mm(3) and FeNO < 20 ppb); asthma with obesity (AwObesity) (BMI >= 30 kg/m(2)); and asthma with concurrent COPD. Data were weighted for the US population and analyses were stratified by age (< 40 and >= 40 years old). Results: Of the 18,619 adults included, 1059 (5.6% [95% CI 5.1-5.9]) had current asthma. A substantial overlap was observed both in subjects aged < 40 years (44%) and >= 40 years (54%). The more prevalent specific overlaps in both age groups were AwObesity associated with either B-Eos-high (15 and 12%, respectively) or B-Eos&FeNO-low asthma (13 and 11%, respectively). About 14% of the current asthma patients were"non-classified". Regardless of phenotype classification, having concomitant phenotypes was significantly associated with (adjusted OR, 95% CI) >= 2 controller medications (2.03, 1.16-3.57), and FEV1 < LLN (3.21, 1.74-5.94), adjusted for confounding variables. Conclusions: A prevalent overlap of commonly reported asthma phenotypes was observed among asthma patients from the general population, with implications for objective asthma outcomes. A broader approach may be required to better characterize asthma patients and prevent poor asthma outcomes.

  • 363.
    Amaral, Rita
    et al.
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Pereira, Ana M.
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Jacinto, Tiago
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Fonseca, Joao A.
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal;Univ Porto, MEDCIDS Dept Community Med Informat & Hlth Sci, Fac Med, Porto, Portugal.
    Comparison of hypothesis- and data-driven asthma phenotypes in NHANES 2007-2012: the importance of comprehensive data availability2019In: Clinical and Translational Allergy, ISSN 2045-7022, E-ISSN 2045-7022, Vol. 9, article id 17Article in journal (Refereed)
    Abstract [en]

    Background

    Half of the adults with current asthma among the US National Health and Nutrition Examination Survey (NHANES) participants could be classified in more than one hypothesis-driven phenotype. A data-driven approach applied to the same subjects may allow a more useful classification compared to the hypothesis-driven one.

    Aim

    To compare previously defined hypothesis-driven with newly derived data-driven asthma phenotypes, identified by latent class analysis (LCA), in adults with current asthma from NHANES 2007-2012.

    Methods

    Adults (18years) with current asthma from the NHANES were included (n=1059). LCA included variables commonly used to subdivide asthma. LCA models were derived independently according to age groups: <40 and 40years old.

    Results

    Two data-driven phenotypes were identified among adults with current asthma, for both age groups. The proportions of the hypothesis-driven phenotypes were similar among the two data-driven phenotypes (p>0.05). Class A <40years (n=285; 75%) and Class A 40years (n=462; 73%), respectively, were characterized by a predominance of highly symptomatic asthma subjects with poor lung function, compared to Class B <40years (n=94; 25%) and Class B 40years (n=170; 27%). Inflammatory biomarkers, smoking status, presence of obesity and hay fever did not markedly differ between the phenotypes.

    Conclusion

    Both data- and hypothesis-driven approaches using clinical and physiological variables commonly used to characterize asthma are suboptimal to identify asthma phenotypes among adults from the general population. Further studies based on more comprehensive disease features are required to identify asthma phenotypes in population-based studies.

  • 364.
    Amarasinghe, H.
    et al.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Wojdacz, T.
    Aarhus Univ, Aarhus Inst Adv Studies, Aarhus, Denmark..
    Rose-Zerilli, M.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Beattie, A.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Forster, J.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Kadalayil, L.
    Univ Southampton, Genet Epidemiol & Bioinformat, Southampton, Hants, England..
    Blakemore, S.
    Univ Cologne, Dept Internal Med, Cologne, Germany..
    Parker, H.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Larrayoz, M.
    Univ Navarra, Div Hematooncol, Pamplona, Spain..
    Clifford, R.
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Else, M.
    Inst Canc Res, Div Mol Pathol, London, England..
    Cohen, D.
    Univ Leeds, Leeds Inst Clin Trials Res, Leeds, W Yorkshire, England..
    Steele, A.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Collins, A.
    Univ Southampton, Human Dev & Hlth, Southampton, Hants, England..
    Pettitt, A.
    Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England..
    Hillmen, P.
    St James Univ Hosp, Dept Haematol, Leeds, W Yorkshire, England..
    Plass, C.
    German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany..
    Catovsky, D.
    Inst Canc Res, Div Mol Pathol, London, England..
    Schuh, A.
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Oakes, C.
    Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA..
    Strefford, J.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Patients with a Memory-like DNA Methylation Signature exhibit long-term survival after first-line immuno-chemotherapy: Data from the UK CLL4, ARCTIC and ADMIRE trials2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, p. 29-29Article in journal (Other academic)
  • 365.
    Amaratunga, Chanaki
    et al.
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Andrianaranjaka, Voahangy Hanitriniaina
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar;Univ Antananarivo, Fac Sci, Antananarivo, Madagascar.
    Ashley, Elizabeth
    MOCRU, Yangon, Myanmar;Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.
    Bethell, Delia
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Bjorkman, Anders
    Karolinska Inst, Dept Mol Tumor & Cell Biol, Stockholm, Sweden.
    Bonnington, Craig A.
    Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Cooper, Roland A.
    Dominican Univ Calif, Dept Nat Sci & Math, San Rafael, CA USA.
    Dhorda, Mehul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Dondorp, Arjen
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand.
    Erhart, Annette
    ITM Antwerp, Dept Publ Hlth, Antwerp, Belgium;Inst Trop Med, MRC Unit Gambia, Fajara, Gambia;Inst Trop Med, MRC Unit Gambia, Fajara, Gambia.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Faiz, Abul
    Dev Care Fdn, Dhaka, Bangladesh.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Oxford Res Unit, Bangkok, Thailand.
    Fukuda, Mark M.
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Guerin, Philippe
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    van Huijsduijnen, Rob Hooft
    Med Malaria Venture, Geneva, Switzerland.
    Hien, Tran Tinh
    Hong, N. V.
    Natl Inst Malariol Parasitol & Entomol, Hanoi, Vietnam.
    Htut, Ye
    Dept Med Res, Yangon, Myanmar.
    Huang, Fang
    Chinese Ctr Dis Control & Prevent, Natl Inst Parasit Dis, Shanghai, Peoples R China.
    Humphreys, Georgina
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Imwong, Mallika
    Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Kennon, Kalynn
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Lin, Khin
    Dept Med Res, Pyin Oo Lwin Branch, Anesakhan, Myanmar.
    Lon, Chanthap
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mayxay, Mayfong
    Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, LOMWRU, Viangchan, Laos;Univ Hlth Sci, Minist Hlth, Fac Postgrad Studies, Viangchan, Laos;Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Mokuolu, Olugbenga
    Univ Ilorin, Coll Hlth Sci, Dept Paediat & Child Hlth, Ilorin, Nigeria;Univ Ilorin, Teaching Hosp, Ctr Malaria & Other Trop Dis Care, Ilorin, Nigeria.
    Morris, Ulrika
    Karolinska Inst, Dept Mol Tumor & Cell Biol, Stockholm, Sweden.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Amambua-Ngwa, Alfred
    Inst Trop Med, MRC Unit Gambia, Fajara, Gambia.
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria.
    Nosten, Francois
    Shoklo Malaria Res Unit, Mae Sot, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Onyamboko, Marie
    Mahidol Oxford Res Unit, Bangkok, Thailand;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO.
    Phyo, Aung Pyae
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Pukrittayakamee, Sasithon
    Mahidol Univ, Dept Clin Trop Med, Bangkok, Thailand;Royal Soc Thailand, Bangkok, Thailand.
    Randrianarivelojosia, Milijaona
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar;Univ Toliara, Fac Sci, Toliara, Madagascar.
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA;Univ Calif San Francisco, Div HIV Infect Dis & Global Med, San Francisco, CA 94143 USA.
    Saunders, David L.
    Armed Forces Res Inst Regenerat Med, Bangkok, Thailand;US Army Med Mat Dev Act, Ft Detrick, MD USA.
    Sibley, Carol Hopkins
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Spring, Michele D.
    Armed Forces Res Inst Med Sci, Dept Immunol & Med, Bangkok, Thailand.
    Sondo, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;CRUN, Ouaga, Burkina Faso.
    Sreng, Sokunthea
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia.
    Starzengruber, Peter
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria;Med Univ Vienna, Dept Lab Med, Div Clin Microbiol, Vienna, Austria.
    Stepniewska, Kasia
    Univ Oxford, Ctr Trop Med & Global Hlth, WWARN, Oxford, England.
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia.
    Takala-Harrison, Shannon
    Univ Maryland, Sch Med, Inst Global Hlth, Div Malaria Res, Baltimore, MD 21201 USA.
    Thriemer, Kamala
    Inst Trop Med, Antwerp, Belgium;Menzies Sch Hlth Res, Darwin, NT, Australia.
    Thuy-Nhien, Nguyen
    Tun, Kyaw Myo
    Myanmar Oxford Clin Res Unit, Yangon, Myanmar;Def Serv Med Acad, Yangon, Myanmar.
    White, Nicholas J.
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Woodrow, Charles
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments: a WWARN individual patient data meta-analysis2019In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 17, p. 1-20, article id 1Article in journal (Refereed)
    Abstract [en]

    Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa.

    Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site.

    Results: Both the pfk13 genotypes and the PC1/2 were available from 3250 (95%) patients (n=3012 from Asia (93%), n=238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC1/2 compared to the PC1/2 of wild type isolates (all p≤0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC1/2. None of the isolates from four countries in Africa showed a significant difference between the PC1/2 of parasites with or without pfk13 propeller region mutations.Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.

    Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

  • 366.
    Amark, Hanna
    et al.
    Karolinska Institute, Department of Clinical Science and Education, Unit of Obstetrics and Gynecology, Södersjukhuset, Stockholm, Sweden.
    Millde-Luthander, Charlotte
    Karolinska Institute, Department of Clinical Science and Education, Unit of Obstetrics and Gynecology, Södersjukhuset, Stockholm, Sweden.
    Ajne, Gunilla
    Department of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Högberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Pettersson, Hans
    Karolinska Institute, Department of Clinical Science and Education, Unit of Obstetrics and Gynecology, Södersjukhuset, Stockholm, Sweden.
    Wiklund, Ingela
    Department of Clinical Sciences, Division of Obstetrics and Gynecology, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.
    Grunewald, Charlotta
    Karolinska Institute, Department of Clinical Science and Education, Unit of Obstetrics and Gynecology, Södersjukhuset, Stockholm, Sweden.
    Single versus pairwise interpretation of cardiotochography, a comparative study from six Swedish delivery units2014In: Sexual & Reproductive HealthCare, ISSN 1877-5756, E-ISSN 1877-5764, Vol. 5, no 4, p. 195-198Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of the study was to evaluate whether interpreting CTG pairwise brings about a higher level of correctly classified CTG recordings in a non-selected population of midwives and physicians.

    STUDY DESIGN: A comparative study.

    SETTING: Five delivery units in Stockholm and one delivery unit in Uppsala, with 1589, 3740, 3908, 4539, 6438, and 7331 deliveries in 2011, respectively.

    SUBJECTS: 536 midwives and physicians classified one randomly selected CTG recording individually followed by a pairwise classification. The pairs consisted of two midwives (119 pairs) or one midwife and one physician (149 pairs), a total of 268 pairs.

    MAIN OUTCOME MEASURE: The proportion of individually correctly classified CTG recordings versus the proportion of pairwise correctly classified CTG recordings.

    RESULTS: The proportion of individually correctly classified CTG's was 75% and the proportion of pairwise correctly classified CTG's was 80% (difference 5%, p = 0.12).

    CONCLUSIONS: There was no statistically significant difference when CTG's were classified pairwise compared to individual classifications. The proportion of individually correctly classified CTG's was high (75%). There were differences in the proportion of correctly classified CTG recordings between the delivery units, indicating potential areas of improvement.

  • 367.
    Ambavane, Apoorva
    et al.
    Modeling and Simulation, Evidera, London, United Kingdom.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Giannitsis, Evangelos
    Medizinische Klinik III, University Heidelberg, Heidelberg, Germany .
    Roiz, Julie
    Modeling and Simulation, Evidera, London, United Kingdom .
    Mendivil, Joan
    Market Access, Roche Diagnostics International Ltd., Rotkreuz, Switzerland .
    Frankenstein, Lutz
    Department of Cardiology, Angiology, Pulmonology, University Hospital of Heidelberg, Heidelberg, Germany .
    Body, Richard
    Emergency Department, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom .
    Christ, Michael
    Department of Emergency and Critical Care Medicine, Paracelsus Medical University, Nuremberg General Hospital, Nuremberg, Germany .
    Bingisser, Roland
    Emergency Department, University of Basel, University Hospital, Basel, Switzerland .
    Alquezar, Aitor
    Servei de Urgencies. Hospital de Sant Pau, Barcelona, Spain .
    Mueller, Christian
    Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, Basel, Switzerland .
    Economic evaluation of the one-hour rule-out and rule-in algorithm for acute myocardial infarction using the high-sensitivity cardiac troponin T assay in the emergency department2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187662Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The 1-hour (h) algorithm triages patients presenting with suspected acute myocardial infarction (AMI) to the emergency department (ED) towards "rule-out," "rule-in," or "observation," depending on baseline and 1-h levels of high-sensitivity cardiac troponin (hs-cTn). The economic consequences of applying the accelerated 1-h algorithm are unknown.

    METHODS AND FINDINGS: We performed a post-hoc economic analysis in a large, diagnostic, multicenter study of hs-cTnT using central adjudication of the final diagnosis by two independent cardiologists. Length of stay (LoS), resource utilization (RU), and predicted diagnostic accuracy of the 1-h algorithm compared to standard of care (SoC) in the ED were estimated. The ED LoS, RU, and accuracy of the 1-h algorithm was compared to that achieved by the SoC at ED discharge. Expert opinion was sought to characterize clinical implementation of the 1-h algorithm, which required blood draws at ED presentation and 1h, after which "rule-in" patients were transferred for coronary angiography, "rule-out" patients underwent outpatient stress testing, and "observation" patients received SoC. Unit costs were for the United Kingdom, Switzerland, and Germany. The sensitivity and specificity for the 1-h algorithm were 87% and 96%, respectively, compared to 69% and 98% for SoC. The mean ED LoS for the 1-h algorithm was 4.3h-it was 6.5h for SoC, which is a reduction of 33%. The 1-h algorithm was associated with reductions in RU, driven largely by the shorter LoS in the ED for patients with a diagnosis other than AMI. The estimated total costs per patient were £2,480 for the 1-h algorithm compared to £4,561 for SoC, a reduction of up to 46%.

    CONCLUSIONS: The analysis shows that the use of 1-h algorithm is associated with reduction in overall AMI diagnostic costs, provided it is carefully implemented in clinical practice. These results need to be prospectively validated in the future.

  • 368.
    Amcoff, K.
    et al.
    Orebro Univ, Dept Gastroenterol, Fac Med & Hlth, Orebro, Sweden..
    Cao, Y.
    Univ Orebro, Sch Med Sci, Clin Epidemiol & Biostat, Orebro, Sweden..
    Zhulina, Y.
    Orebro Univ, Dept Gastroenterol, Fac Med & Hlth, Orebro, Sweden..
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Halfvarson, J.
    Orebro Univ, Dept Gastroenterol, Fac Med & Hlth, Orebro, Sweden..
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Prognostic significance of eosinophil granule proteins in inflammatory bowel disease2018In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, p. S181-S182Article in journal (Other academic)
  • 369.
    Amcoff, Karin
    et al.
    Univ Orebro, Fac Med & Hlth, Dept Gastroenterol, SE-70182 Orebro, Sweden..
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Magnuson, Anders
    Univ Orebro, Sch Med Sci, Clin Epidemiol & Biostat, Orebro, Sweden..
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Halfvarson, Jonas
    Univ Orebro, Fac Med & Hlth, Dept Gastroenterol, SE-70182 Orebro, Sweden..
    Clinical implications of assay specific differences in f-calprotectin when monitoring inflammatory bowel disease activity over time2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 3, p. 344-350Article in journal (Refereed)
    Abstract [en]

    Objective: With several faecal calprotectin (FC) assays on the market, it has been difficult to define a uniform threshold for discriminating between remission and active disease in patients with inflammatory bowel disease (IBD). We aimed to compare the results of different FC-assays in IBD patients, followed over time.Material and methods: IBD patients provided faecal samples and reported clinical activity every third month prospectively over a two year period. FC was measured with two ELISA - (Buhlmann and Immunodiagnostik) and one automated fluoroimmunoassay (Phadia).Results: In total, 13 patients provided 91 faecal samples. The median (IQR) concentration of FC was higher at active disease than at remission for all assays: Buhlmann 845 (1061-226) g/g versus 62 (224-39) g/g, Phadia 369 (975-122) g/g versus 11 (52-11) g/g, and Immundiagnostik 135 (302-69) g/g versus 8 (56-4) g/g. The Buhlmann assay produced the largest absolute difference but the corresponding relative difference seemed to be more pronounced when analysed by the Phadia - (ratio of means 8.5; 95% CI 3.3-21.9) or the Immundiagnostik assay (ratio of means 7.4; 95% CI 3.1-17.6) than by the Buhlmann assay (ratio of means 5.3; 95% CI 2.7-10.6). Consequently, the specificity for discriminating active disease from remission varied between assays (34-75%) when the cut-off 50g/g was used, whereas the differences in sensitivity were less pronounced.Conclusions: Cross-comparisons revealed overall poor agreement between the assays as well as differences in the dynamics of FC. These findings suggest that standardisation of the method is needed to implement FC as a disease monitoring tool at large-scale.

  • 370.
    Amid Hägg, Shadi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Emilsson, Össur Ingi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Franklin, Karl
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Nocturnal gastroesophageal reflux increases the risk of daytime sleepiness in women2019In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 53, p. 94-100Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Daytime sleepiness is common in women and has negative health effects. Nocturnal gastroesophageal reflux (nGER) and snoring are risk factors for daytime sleepiness, but the effect of their interaction remains unknown. The aim of this study was to examine how nGER and snoring combined affected daytime sleepiness and involuntary falling asleep in women.

    METHODS: A questionnaire was sent to randomly selected women in 2000 and 2010. Participants who answered questions regarding both nGER and snoring in both questionnaires were included (N = 4882). Daytime sleepiness was defined as severe or very severe problems with daytime sleepiness. Involuntary falling asleep was defined as sometimes, often or very often falling asleep involuntarily during the day. Respondents snoring loudly and disturbingly sometimes, often or very often were defined as snorers. Having nocturnal heartburn or acid reflux sometimes, often or very often was defined as having nGER.

    RESULTS: Daytime sleepiness was reported by 14% of the participants, involuntary falling asleep by 11%. After adjustment for age, smoking, physical activity, caffeine intake and alcohol dependency, increased odd ratios (ORs) for both daytime sleepiness (adjusted OR 4.2, 95% confidence interval (CI): 1.9-9.2) and involuntary falling asleep (adjusted OR 3.1, 95% CI: 1.5-6.4) were seen in women with the combination of nGER and snoring at both baseline and follow-up. The association with daytime sleepiness was also strong for those with only persistent nGER but not for those with only persistent snoring.

    CONCLUSION: Women with nGER were at increased risk of developing daytime sleepiness and snoring augmented this association. In addition, women with both nGER and snoring were also at increased risk of developing involuntary falling asleep.

  • 371.
    Amin, Kawa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Univ Sulaimani, Dept Microbiol Immunol, Sch Med, Fac Med Sci, Sulaimani, Iraq.
    Allergic Respiratory Inflammation and Remodeling2015In: Turkish Thoracic Journal, ISSN 1302-7808, Vol. 16, no 3, p. 133-140Article, review/survey (Refereed)
    Abstract [en]

    Asthma and rhinitis are inflammatory diseases of the respiratory tract. Respiratory inflammation of the adaptive and innate immune system is the focus of this review, and chronic inflammation is not limited to the respiratory tissue. The inflammatory response, which consists of phagocytes, eosinophils, mast cells, and lymphocytes, spreads along the respiratory tract, leading to tissue damage. Mast cells and eosinophils are commonly recognized for their detrimental role in allergic reactions on activation through the high- and low-affinity receptors for IgE FcεRI. These cells rapidly produce and secrete many of the mediators responsible for the typical symptoms of asthma and rhinitis. However, increasing amount of evidence demonstrate that mast cells and leukocytes have vital roles in host defense against pathogenesis. Histological methods are used to study leukocytes and receptor expression pattern in different respiratory tract compartments.

    The overall aim of this review was to understand the relationship between upper and lower respiratory tract inflammation and remodeling in patients with allergic and non-allergic asthma and rhinitis. In conclusion, this review discusses the relationship between the upper and lower airway in respiratory disease and focuses on the effect of respiratory processes on laryngeal inflammation, remodeling, function, and symptoms; however, they also have a central role in the initiation of the allergic immune response. Our findings suggest that there are differences that contribute to the development of immunopathological mechanisms of these clinically distinct forms of asthma, rhinitis, and chronic obstructive pulmonary disease.

  • 372.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Beillevaire, Didier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mahmoud, Elgaali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hammar, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mard, Per-Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Froman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Binding of Galanthus nivalis lectin to Chlamydia trachomatis and inhibition of in vitro infection1995In: APMIS: Acta pathologica, microbiologica et immunologica Scandinavica. Supplementum, ISSN 0903-465X, E-ISSN 1600-5503, ISSN 0903-4641, Vol. 103, no 10, p. 714-720, article id 8534430Article in journal (Refereed)
  • 373.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology. Dept. of Microbiology/Immunology, University of Sulaimani, Sulaimani, Iraq.
    Hurst, David S
    Roomans, Godfried M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sveus, Lahja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eosinophils and neutrophils in biopsies from the middle ear of atopic children with otitis media with effusion1999In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 48, no 12, p. 626-631, article id 10669113Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE AND DESIGN:

    The majority of patients with otitis media with effusion (OME) and atopy have been shown to have elevated levels of eosinophil cationic protein (ECP) in their middle ear fluid. The mechanism underlying these elevated levels of ECP is not clear. The purpose of this study was to investigate the feasibility of a quantitative determination of eosinophils and neutrophils in the middle ear lining by specific immunocytochemical markers, in order to study the extent of the involvement of these cells in patients with OME.

    METHODS:

    Bilateral middle ear biopsies from five children with persistent OME and atopy confirmed by in vitro testing were evaluated for the presence of eosinophils and neutrophils with monoclonal antibodies against specific granule proteins. Five subjects who had no signs of effusion or infection but were undergoing routine tympanoplasty for dry perforations served as controls. The biopsies were embedded in a plastic resin to improve the structural preservation of the target cells and to increase the resolution in the light microscope. Dual markers were used to determine which marker was better for eosinophils and neutrophils, respectively. The following markers were used: eosinophil cationic protein (EG2), and eosinophil peroxidase (EPO) for eosinophils and myeloperoxidase (MPO) and human neutrophil lipocalin (HNL) for neutrophils.

    RESULTS:

    Antibodies against EPO gave a more localized and intense staining than antibodies against EG2. Antibodies against HNL appear more specific to neutrophils than antibodies against MPO that also recognize monocytes. The number of cells was determined both in the tissue and in the mucus covering the epithelium. Eosinophils and neutrophils were present in the subepithelial connective tissue and in the mucus blanket in the middle ear of patients with OME in significantly higher number than in the control group. In general, there were more inflammatory cells in the mucus than in the tissue itself, but the number of inflammatory cells in the mucus showed a significant positive correlation with the number of inflammatory cells in the tissue. There was a significant positive correlation between the number of neutrophils and the number of eosinophils in the tissue as well as in the mucus, irrespective of which marker was used.

    CONCLUSION:

    The results of this study show the feasibility of using specific antibodies to identify eosinophils and neutrophils in the middle ear. The initial data suggest that atopic children with OME have higher numbers of such cells as compared to non-OME controls.

  • 374.
    Amini, Hashem
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fetal Anomalies: Surveillance and Diagnostic Accuracy of Ultrasound and Magnetic Resonance Imaging2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aims were to investigate the accuracy of ultrasound in diagnosis of structural fetal anomalies with special focus on false positive findings (I), to evaluate the additional value of second trimester fetal MRI on pregnancy management (II-III) and to estimate the ascertainment in the Swedish Birth Defects Registry and incidence of spina bifida and cleft lip/palate (IV).

    Retrospectively, 328 fetal autopsies were identified where pregnancies were terminated due to ultrasonographically diagnosed fetal anomalies. In 175 (53.4 %) cases ultrasound and fetal autopsy were identical, in 124 (37.8 %) ultrasound was almost correct, in 23 (7.0 %)  ultrasound diagnoses could not be verified, but fetal autopsy showed other anomalies with at least the same prognostic value and in six (1.8 %)  ultrasound diagnosis could not be verified and autopsy showed no or less severe anomalies (I).

    Prospectively, 29 pregnancies with CNS- (II) and 63 with non-CNS-anomalies (III) were included. In the CNS study MRI provided no additional information in 18 fetuses (62 %), additional information without changing the management in 8 (28 %) and additional information altering the pregnancy management in 3 (10%). In the non-CNS study the corresponding figures were 43 (68 %), 17 (27 %) and three (5 %), respectively. MRI in the second trimester might be a clinically valuable adjunct to ultrasound for the evaluation of CNS anomalies, especially when the ultrasound is inconclusive due to maternal obesity (II) and in non-CNS anomalies in cases of diaphragmatic hernia or oligohydramnios (III).

    In newborns, the ascertainments of birth defects are relatively high and assessable, but in pregnancy terminations they are lower or unknown. The incidence of newborns with spina bifida has decreased because of an increased rate of pregnancy terminations (>60%). There is room for improvement concerning the reporting of anomalies from terminated pregnancies (IV).

    List of papers
    1. Comparison of ultrasound and autopsy findings in pregnancies terminated due to fetal anomalies
    Open this publication in new window or tab >>Comparison of ultrasound and autopsy findings in pregnancies terminated due to fetal anomalies
    Show others...
    2006 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 85, no 10, p. 1208-1216Article in journal (Refereed) Published
    Abstract [en]

    Objective. To compare antenatal diagnoses with autopsy findings in pregnancies terminated after ultrasound detection of fetal anomalies. A second aim was to study the quality of antenatal fetal diagnosis over time. Design. Retrospective, multicenter study over two consecutive six-year periods in Uppsala and Stockholm. Setting. Cases were identified through fetal autopsy reports. Subjects. Three hundred and twenty-eight fetuses from pregnancies terminated between 1992 and 2003 because of ultrasonographically diagnosed anomalies. Main outcome measures. The findings at the last ultrasound examination were compared with the autopsy reports. Results. In 299 cases (91.2%) ultrasound findings either exactly matched or were essentially similar to the autopsy findings. In 23 cases (7%) ultrasound findings were not confirmed at autopsy, but the postnatal findings were at least as severe as the antenatal ones. In six cases (1.8%) termination was performed for an anomaly which proved to be less severe than was predicted by ultrasound. The number of such cases was the same in both six-year periods, while the total number of cases increased from 113 in the first to 215 in the second period. Fetal examination provided further diagnostic information in 47% of the cases. In 10% a syndrome was disclosed. Conclusion. Termination of pregnancy was not always based on a correct antenatal diagnosis. All fetuses but one from terminated pregnancies had evident anomalies. In six cases (1.8%) the decision to terminate was based on suboptimal prognostic and diagnostic information. Fetal autopsy by an experienced perinatal pathologist is essential to provide a definitive diagnosis.

    Keywords
    fetal anomaly, ultrasound, antenatal diagnosis, pregnancy termination, fetal autopsy
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-21374 (URN)10.1080/00016340600880886 (DOI)000241362200009 ()17068680 (PubMedID)
    Available from: 2008-06-28 Created: 2008-06-28 Last updated: 2017-12-08Bibliographically approved
    2. The Swedish Birth Defects Registry: ascertainment and incidence of spina bifida and cleft lip/palate
    Open this publication in new window or tab >>The Swedish Birth Defects Registry: ascertainment and incidence of spina bifida and cleft lip/palate
    2009 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 88, no 6, p. 654-659Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To assess the ascertainment of spina bifida and cleft lip/palate (CLP) in newborns and in fetuses from terminated pregnancies (ToPs) in the Swedish Birth Defects Registry (BDR) and to estimate the true incidences of these two anomalies. DESIGN: Retrospective register study. SETTING: Center for Epidemiology at the Swedish National Board of Health and Welfare, and Uppsala University Hospital. POPULATION: Newborns and fetuses from ToPs with spina bifida (1999-2004) and CLP (1999-2002) in Sweden. METHODS: Data from four registries/sources were used to estimate ascertainment in BDR and incidences of spina bifida and CLP. Main outcome measure: Ascertainment, under-ascertainment, and true incidence. RESULTS: For newborns, under-ascertainment of spina bifida and CLP were 6 and 13%, respectively, in BDR after record linkage with the Medical Birth Registry. Ascertainment of cleft palate increased when accompanied by cleft lip. The under-ascertainment of spina bifida in ToPs after 18 gestational weeks was 27%. Ascertainment of CLP in all ToPs and of spina bifida in ToPs before the 18th gestational week could not be estimated. The majority (109/155, 70%) of ToPs with spina bifida occurred before the 18th week. The estimated incidence of spina bifida per 10,000 births was 6.1 (2.4 newborns and 3.7 ToPs) and of CLP 20.1 (18.9 newborns and 1.2 ToPs). CONCLUSION: The ascertainments are relatively high for newborns in BDR, but lower or unknown for ToPs, which has an impact on the surveillance of spina bifida in view of the high proportion of ToPs.

    Keywords
    Birth defects registry, ascertainment, cleft lip/palate, spina bifida, termination of pregnancies
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-106006 (URN)10.1080/00016340902934696 (DOI)000267201800006 ()19412801 (PubMedID)
    Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2017-12-13Bibliographically approved
    3. The Clinical Impact of Fetal Magnetic Resonance Imaging on Management of CNS Anomalies in the Second Trimester of Pregnancy
    Open this publication in new window or tab >>The Clinical Impact of Fetal Magnetic Resonance Imaging on Management of CNS Anomalies in the Second Trimester of Pregnancy
    2010 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 89, no 12, p. 20p. 1571-1581Article in journal (Refereed) Published
    Abstract [en]

    Objectives: To evaluate the additional information of second trimester magnetic resonance imaging (MRI) compared to ultrasound in fetuses with identified or suspected CNS anomalies and to study the clinical impact of the information on pregnancy management.

    Design: Prospective study during 2004-2007. The fetal MRI examination was planned to be performed within three days after the ultrasound.

    Setting: Uppsala University hospital.    

    Subjects: Twenty-nine pregnant women where second trimester ultrasound identified or suspected fetal CNS anomalies.

    Main outcome measures: Evaluation of the additional information gained from MRI and the consequence it had on pregnancy management.

    Results: The mean interval between ultrasound and MRI was 1.6 days (range 0 –7). In 18 fetuses (62 %)  MRI verified the ultrasound diagnosis but provided no additional information, while in 8 (28 %) MRI gave additional information without changing the management. In 3 (10 %), MRI provided additional information that changed the management of the pregnancy. Two of these women were obese.

    Conclusions: Fetal MRI in the second trimester might be a clinically valuable adjunct to ultrasound for the evaluation of CNS anomalies, especially when ultrasound is inconclusive due to maternal obesity.

     

    Publisher
    p. 20
    Keywords
    CNS anomalies, Fetal MRI, Pregnancy management, Second trimester, Ultrasound
    National Category
    Medical and Health Sciences
    Research subject
    Obstetrics and Gynaecology; Medicine
    Identifiers
    urn:nbn:se:uu:diva-121487 (URN)10.3109/00016349.2010.526184 (DOI)000284318900012 ()21080900 (PubMedID)
    Available from: 2010-03-24 Created: 2010-03-24 Last updated: 2017-12-12Bibliographically approved
    4. The Clinical Impact of Fetal Magnetic Resonance Imaging on Management of Non-CNS Anomalies in the Second Trimester of Pregnancy
    Open this publication in new window or tab >>The Clinical Impact of Fetal Magnetic Resonance Imaging on Management of Non-CNS Anomalies in the Second Trimester of Pregnancy
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Objectives: To evaluate the additional information of second trimester MRI compared to ultrasound in fetuses with identified or suspected non-CNS anomalies and to study the clinical impact of the MRI information on pregnancy management.

    Methods: Sixty-three women were included, where the second trimester ultrasound identified or raised suspicion of fetal anomalies. Ultrasound was compared to MRI in relation to the final diagnosis, fetal autopsy if performed or postnatal diagnosis. The additional information of MRI and effect on pregnancy management was estimated in consensus.

    Results: The mean gestational age at the last ultrasound before MRI was 18+1 weeks (range 13+0-21+5). The mean interval between ultrasound and MRI was 2.6 days (range 0-15). In 42 (67 %) cases MRI was performed within three days. All MRI examinations were assessable. In 43 (68 %) fetuses MRI provided no additional information, in 17 (27 %) MRI added information without changing the management and in three (5 %) MRI provided additional information which changed the management. These three cases had all oligohydramnios. In all six cases of diaphragmatic hernia MRI provided additional information.

    Conclusions: Fetal MRI of non-CNS anomalies is feasible in the second trimester and gives additional information in nearly a third of cases. It may provide a clinically valuable adjunct to ultrasound especially in cases of diaphragmatic hernia or oligohydramnios.

    Keywords
    Fetal MRI, non-CNS anomalies, second trimester, ultrasound, pregnancy management, antenatal diagnosis
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-121500 (URN)
    Available from: 2010-03-24 Created: 2010-03-24 Last updated: 2010-03-24
  • 375.
    Amini, Hashem
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    The Clinical Impact of Fetal Magnetic Resonance Imaging on Management of Non-CNS Anomalies in the Second Trimester of PregnancyManuscript (preprint) (Other academic)
    Abstract [en]

    Objectives: To evaluate the additional information of second trimester MRI compared to ultrasound in fetuses with identified or suspected non-CNS anomalies and to study the clinical impact of the MRI information on pregnancy management.

    Methods: Sixty-three women were included, where the second trimester ultrasound identified or raised suspicion of fetal anomalies. Ultrasound was compared to MRI in relation to the final diagnosis, fetal autopsy if performed or postnatal diagnosis. The additional information of MRI and effect on pregnancy management was estimated in consensus.

    Results: The mean gestational age at the last ultrasound before MRI was 18+1 weeks (range 13+0-21+5). The mean interval between ultrasound and MRI was 2.6 days (range 0-15). In 42 (67 %) cases MRI was performed within three days. All MRI examinations were assessable. In 43 (68 %) fetuses MRI provided no additional information, in 17 (27 %) MRI added information without changing the management and in three (5 %) MRI provided additional information which changed the management. These three cases had all oligohydramnios. In all six cases of diaphragmatic hernia MRI provided additional information.

    Conclusions: Fetal MRI of non-CNS anomalies is feasible in the second trimester and gives additional information in nearly a third of cases. It may provide a clinically valuable adjunct to ultrasound especially in cases of diaphragmatic hernia or oligohydramnios.

  • 376.
    Amini, Rose-Marie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hodgkin Lymphoma: Studies of Advanced Stages, Relapses and the Relation to Non-Hodgkin Lymphomas2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The relationship between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is not entirely elucidated and a clonal relation may be present more often than previously believed. Mechanisms of tumour progression and resistance to therapy are poorly understood.

    Between 1974 and 1994 all individuals in Sweden with both HL and NHL were identified. Thirty-two cases were studied using clinical, histopathological and immunohistochemical methods. The second lymphoma often appeared in an aggressive clinical form and a significant correlation between the expression of p53 and LMP-1 in the first and second lymphoma was demonstrated.

    The treatment outcome for 307 patients with advanced stages of HL, in an unselected population was in accordance with the treatment results of large centres world-wide. Some patients were successfully selected for a shorter chemotherapy-regimen without inferior treatment results.

    In 124 patients with relapse, the survival of those primarily treated with radiotherapy according to the National guidelines was in accordance with the survival of patients of initially advanced stages. A worse outcome was found for those who received both chemotherapy and radiotherapy initially, probably because of a higher frequency of bulky disease in this group.

    Immunohistochemical analysis of the tumour suppressor protein p53 and retinoblastoma protein (Rb) of paired samples at diagnosis and at relapse in 81 patients did not reveal any specific staining pattern affecting survival.

    A novel B-cell line (U-2932) was established from a patient with a diffuse large B-cell lymphoma previously treated for advanced stage and subsequent relapses of HL. An identical rearranged IgH gene was demonstrated in tumour cells from the patient and in U-2932. A p53 point mutation was detected and over-expression of the p53 protein was found. A complex karyotype with high-level amplifications of the chromosomal regions 18q21 and 3q27, i.e. the loci for bcl-2 and bcl-6 were demonstrated.

    List of papers
    1. Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients
    Open this publication in new window or tab >>Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients
    1997 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, no 4, p. 510-516Article in journal (Refereed) Published
    Abstract [en]

    The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89775 (URN)10.1002/(SICI)1097-0215(19970516)71:4<510::AID-IJC2>3.0.CO;2-X (DOI)9178801 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2017-12-14Bibliographically approved
    2. Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience
    Open this publication in new window or tab >>Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience
    Show others...
    2000 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 65, no 6, p. 379-389Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Despite improved treatment results achieved in Hodgkin's disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB-IVB) of HD in younger patients in an unselected population-based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post-CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected.

    PATIENTS AND METHODS: Between 1985-92, 307 patients between 17-59 yr of age (median 36) were diagnosed with HD in stages IIB-IVB in 5/6 health care regions in Sweden. Median follow-up time was 7.8 yr (1.3-13). Retrospectively, laboratory parameters were collected.

    RESULTS: In total, 267 (87%) patients had a complete response (CR). The overall and disease-free 10-yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT + RT. In univariate analyses survival was affected by age, stage IVB, bone-marrow involvement, B-symptoms, S-LDH, S-Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant.

    CONCLUSIONS: The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89776 (URN)10.1034/j.1600-0609.2000.065006379.x (DOI)11168495 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2017-12-14Bibliographically approved
    3. A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma
    Open this publication in new window or tab >>A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma
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    2002 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 68, no 4, p. 225-232Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Our aims were to evaluate the response to salvage treatment in relation to initial treatment and to evaluate prognostic factors at the time of relapse in an unselected population of relapsing patients with Hodgkin's lymphoma (HL).

    PATIENTS AND METHODS:

    In total, 124 patients younger than 60 yr of age with initial diagnosis of HL in Sweden relapsed between 1985 and 1995.

    RESULTS:

    Fifty-eight patients relapsed after initial treatment with radiotherapy (RT) only, 62 after combination chemotherapy (CT), of whom 30 had received additional involved-field RT, and four after a short course of CT followed by extended-field RT. For 37 patients among the 58 relapsers after initial RT treated according to the recommendations of the National guidelines, the 5-yr Hodgkin-specific survival (HLS) was 85%, overall survival (OS) 73% and event-free survival (EFS) 62%, which is not inferior to survival in patients with primarily advanced stages. It was poorer in the 21 patients who initially had received RT only, even though they had been recommended for more extensive treatment. For patients initially treated with a full course (6-8 cycles) of CT the 5-yr HLS was 60%, OS 58% and EFS 22%. Bulky disease and age at diagnosis strongly affected survival in a multivariate analysis.

    CONCLUSIONS:

    Patients initially treated with RT who relapse have a favourable outcome, provided they have been treated according to the recommendations of the guidelines at the time of diagnosis. Initially bulky disease and, as a consequence, additional RT as part of the initial treatment negatively affect survival at relapse in patients initially treated with a full course of CT.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89777 (URN)10.1034/j.1600-0609.2002.01565.x (DOI)12071938 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2017-12-14Bibliographically approved
    4. Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival
    Open this publication in new window or tab >>Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival
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    2002 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 6, p. 1253-1260Article in journal (Refereed) Published
    Abstract [en]

    Patients with relapsing Hodgkin's lymphoma (HL) have a rather poor prognosis and mechanisms that lead to resistance to therapy are poorly understood. Our aims were to investigate the immunohistochemical staining patterns of Rb (retinoblastoma protein) and the p53 tumour suppressor protein in HL at initial presentation and at relapse in order to elucidate a possible role in disease progression and resistance to therapy. Further to evaluate the presence and prognostic importance of Epstein-Barr virus (EBV) and anaplastic lymphoma kinase (ALK). Eighty-one cases of relapsing HL were reexamined histopathologically and immunostained for the expression of p53, Rb, ALK and CD30. EBV was detected with LMP-1 stainings and in situ hybridisation for EBER. Clinical data were extracted from the Swedish National Health Care Programme for HL. Median follow-up time was six years (range 0-12) from the date of relapse. The majority of cases were positive for p53 and Rb both at presentation and at relapse, though to a different extent. Both an increase and a decrease in the proportion of stained tumour cells were observed. None of our cases was ALK-positive and 44% were EBV-positive. No specific staining pattern was directly correlated to survival. In 12 patients a switch in HL subtype from diagnosis to relapse was observed and the five-year Hodgkin-specific survival (HLS) was statistically significantly inferior, 37 vs 81% (p = 0.002), in those patients. We found a significant relation between the expression of p53 and EBV at diagnosis and relapse, indicating a clonal relationship. We were unable to find any specific staining pattern of p53 or Rb, affecting survival.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89778 (URN)10.1080/10428190290026303 (DOI)12152993 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2017-12-14Bibliographically approved
    5. A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
    Open this publication in new window or tab >>A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
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    2002 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 11, p. 2179-2189Article in journal (Refereed) Published
    Abstract [en]

    Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89779 (URN)10.1080/1042819021000032917 (DOI)12533045 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2017-12-14Bibliographically approved
  • 377.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Laszlo, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafsson, Kristin Ayoola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Lokon Pharma, AB,Uppsala, Sweden.
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 316Article in journal (Refereed)
    Abstract [en]

    Background: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome. Methods: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome. Results: The percentage of CD3-positive T-cells was lower (p=0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p=0.2) nor the T-cell/monocyte ratio (p=0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7(+)/CD3(-)/CD56(bright)/CD16(dim/-)) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p=0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p=0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p=0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p=0.04). Conclusions: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

  • 378.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    [Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research].2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id EMDHArticle in journal (Refereed)
    Abstract [sv]

    Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research Core needle biopsies (CNBs) are widely used in clinical diagnostic labs to aid in the diagnosis of malignant lymphomas and in latter years their use is increasing. CNBs provide a rapid method for obtaining tumour material and may be beneficial when the affected lymph nodes are located deep in the abdominal cavity or mediastinum and surgical excisional biopsies may be difficult to perform. However, according to the Swedish Haematopathology Quality and Standardization Committee, CNBs are insufficient for lymphoma diagnostic purposes and the guidelines state that material from surgical excisional biopsies are mandatory in order to obtain a robust histopathological evaluation of the lymph node architecture, cellular composition and growth pattern. Surgical excision biopsies also ensure that adequate material is available if additional molecular analyses should be required and also to facilitate future research.

  • 379.
    Amir, Ferdaus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Användning av inhalatorer vid astma och KOL på Karolinska universitetssjukhusets Lung Allergi klinik2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion Dagens farmakologisk behandling av astma- och KOL, som till största delen består av inhalationsterapi, är generellt effektiva. Inhalationstekniken till ordinerad behandling är däremot väldigt bristfällig, vilket leder till att många patienter misslyckas med att uppnå sin behandlings mål. Flera decennier har gått sedan den första inhalatorn infördes, men än idag är felaktig användning av inhalatorer ett stort hinder för att uppnå en optimal sjukdomsbehandling. Syfte Huvudsyftet med denna studie var att undersöka hur väl patienter med KOL eller astma använder sina inhalatorer på Karolinska Universitetssjukhusets lungmottagning. Material En observationell tvärsnittsstudie av totalt 63 patienter (81 inhalatorer) med KOL eller astma som genomgår behandling med Turbuhaler, Handihaler, Easyhaler, Diskus eller Breezhaler. Data samlades in med hjälp av en enkätundersökning och observation av inhalationstekniken. Inkorrekt inhalationsteknik definierades som ett eller flera stegfel i samband med inhalationen. Resultat Turbuhaler (50 %) som var den vanligaste inhalatorn på Karolinska Universitetssjukhuset var även den som till största del användes inkorrekt (83%). I 77 % av fallen sedd till de observerade inhalatorerna gjordes minst ett felsteg. De vanligaste felen vid handhavandet av inhalatorer var att inte hålla inhalatorn upprätt vid framvridning av en dos, att inte hålla andan efter inhalation samt att patienten inte andades ut ordentlig före inandning. Konklusion Majoriteten av patienter som använde en inhalator gjorde minst ett misstag vid inhalationen. Korrekt utbildning om inhalatorns användning och ett visuellt feedback-system som visar när en korrekt inhalation har skett behövs för att förbättra kontrollen av astma och KOL. 

  • 380. Amirian, E Susan
    et al.
    Armstrong, Georgina N
    Zhou, Renke
    Lau, Ching C
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill S
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L
    Merrell, Ryan T
    Wrensch, Margaret R
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I
    Scheurer, Michael E
    Aldape, Kenneth
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Brännström, Thomas
    Broholm, Helle
    Collins, Peter
    Giannini, Caterina
    Rosenblum, Marc
    Tihan, Tarik
    Melin, Beatrice S
    Bondy, Melissa L
    The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium2016In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 183, no 2, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

  • 381.
    Ammoun, Sylwia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Orexin Receptors in Recombinant CHO Cells: Signaling to Short- and Long-Term Cell Responses2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recently discovered neuropeptides orexins (orexin-A and -B) act as endogenous ligands for G-protein-coupled receptors called OX1 and OX2 receptors. Our previous studies have established model systems for investigation of the pharmacology and signaling of these receptors in recombinant CHO cells. OX1 receptor-expressing CHO cells were mainly utilized in this thesis.

    Orexin-A and -B activate both OX1 and OX2 receptors. However, orexin-B is less potent in activating OX1 receptors than orexin-A, whereas the peptides are equipotent on OX2 receptors. We have performed mutagenesis on orexin-A to investigate the basis for this selectivity. We show that OX2 receptor is generally less affected by the mutations and thus OX2 receptor appears to have less strict requirements for ligand binding, likely explaining the lack of difference in affinity/potency between orexin-A and orexin-B on OX2 receptor.

    The other studies focus on orexin receptor signaling. OX1 receptors are shown to regulate adenylyl cyclase both in positive and negative manner, activate different MAP-kinases (ERK1/2 and p38) and induce cell death after long-lasting stimulation. Adenylyl cyclase regulation occurs likely through three different G-protein families, Gi, Gs and Gq. For ERK1/2, several downstream pathways, such as Ras, Src, PI3-kinase and protein kinase C (PKC) are implicated. OX1 receptor-mediated activation of ERK is suggested to be cytoprotective whereas p38 MAP-kinase induces programmed cell death.

    Three particularly interesting findings were made. Firstly, novel PKC δ (delta) is suggested to regulate adenylyl cyclase, whereas conventional and atypical PKCs are involved in activation of ERK. Secondly, adenylyl cyclase and ERK activation is fully dependent on extracellular Ca2+. Further experiments suggest that the previously discovered receptor-operated Ca2+ influx is not affecting the downstream effectors of orexin receptors but that it instead enables orexin receptors to couple to several signal cascades. Thirdly, upon inhibition of caspases, classical mediators of programmed cell death, OX1 receptor-mediated cell death is not reversed, but instead the pathways to death are altered so de novo gene transcription is no longer required for cell death.

    List of papers
    1. Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
    Open this publication in new window or tab >>Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
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    2003 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 305, no 2, p. 507-514Article in journal (Refereed) Published
    Abstract [en]

    In this study, we have compared the abilities of orexin-A and orexin-B and variants of orexin-A to activate different Ca(2+) responses (influx and release) in human OX(1) and OX(2) receptor- expressing Chinese hamster ovary cells. Responses mediated by activation of both receptor subtypes with either orexin-A or -B were primarily dependent on extracellular Ca(2+), suggesting similar activation of Ca(2+) influx as we have previously shown for orexin-A and OX(1) receptors. Amino acid-wise truncation of orexin-A reduced its ability to activate OX(1) and OX(2) receptors, but the response mediated by the OX(2) receptor was more resistant to truncation than the response mediated by the OX(1) receptor. We also performed a sequential replacement of amino acids 14 to 26 with alanine in the truncated orexin-A variant orexin-A(14-33). Replacement of the same amino acids produced a fall in the potency for each receptor subtype, but the reduction was less prominent for the OX(2) receptor. The most marked reduction was produced by the replacement of Leu20, Asp25, and His26 with alanine. Interestingly, extracellular Ca(2+) dependence of responses to some of the mutated peptides was different from those of orexin-A and -B. The mutagenesis also suggests that although the determinants required from orexin-A for binding to and activation of the receptor are highly conserved between the orexin receptor subtypes, the OX(2) receptor requires fewer determinants. This might in part explain why orexin-B has the affinity and potency equal to orexin-A for this subtype, although it has 10- to 100-fold lower affinity and potency for the OX(1) receptor.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93307 (URN)10.1124/jpet.102.048025 (DOI)12606634 (PubMedID)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
    2. OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms
    Open this publication in new window or tab >>OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms
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    2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 8, p. 6570-6579Article in journal (Refereed) Published
    Abstract [en]

    In this study, the mechanism of OX(1) orexin receptors to regulate adenylyl cyclase activity when recombinantly expressed in Chinese hamster ovary cells was investigated. In intact cells, stimulation with orexin-A led to two responses, a weak (21%), high potency (EC(50) approximately 1 nm) inhibition and a strong (4-fold), low potency (EC(50) = approximately 300 nm) stimulation. The inhibition was reversed by pertussis toxin, suggesting the involvement of G(i/o) proteins. Orexin-B was, surprisingly, almost equally as potent as orexin-A in elevating cAMP (pEC(50) = approximately 500 nm). cAMP elevation was not caused by Ca(2+) elevation or by Gbetagamma. In contrast, it relied in part on a novel protein kinase C (PKC) isoform, PKCdelta, as determined using pharmacological inhibitors. Yet, PKC stimulation alone only very weakly stimulated cAMP production (1.1-fold). In the presence of G(s) activity, orexins still elevated cAMP; however, the potencies were greatly increased (EC(50) of orexin-A = approximately 10 nm and EC(50) of orexin-B = approximately 100 nm), and the response was fully dependent on PKCdelta. In permeabilized cells, only a PKC-independent low potency component was seen. This component was sensitive to anti-Galpha(s) antibodies. We conclude that OX(1) receptors stimulate adenylyl cyclase via a low potency G(s) coupling and a high potency phospholipase C --> PKC coupling. The former or some exogenous G activation is essentially required for the PKC to significantly activate adenylyl cyclase. The results also suggest that orexin-B-activated OX(1) receptors couple to G(s) almost as efficiently as the orexin-A-activated receptors, in contrast to Ca(2+) elevation and phospholipase C activation, for which orexin-A is 10-fold more potent.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93308 (URN)10.1074/jbc.M407397200 (DOI)15611118 (PubMedID)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
    3. OX1 orexin receptors activate extracellular signal-regulated kinase in Chinese hamster ovary cells via multiple mechanisms: the role of Ca2+ influx in OX1 receptor signaling
    Open this publication in new window or tab >>OX1 orexin receptors activate extracellular signal-regulated kinase in Chinese hamster ovary cells via multiple mechanisms: the role of Ca2+ influx in OX1 receptor signaling
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    2006 (English)In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 20, no 1, p. 80-99Article in journal (Refereed) Published
    Abstract [en]

    Activation of OX1 orexin receptors heterologously expressedin Chinese hamster ovary (CHO) cells led to a rapid, strong,and long-lasting increase in ERK phosphorylation (activation).Dissection of the signal pathways to ERK using multiple inhibitorsand dominant-negative constructs indicated involvement of Ras,protein kinase C, phosphoinositide-3-kinase, and Src. Most interestingly,Ca2+ influx appeared central for the ERK response in CHO cells,and the same was indicated in recombinant neuro-2a cells andcultured rat striatal neurons. Detailed investigations in CHOcells showed that inhibition of the receptor- and store-operatedCa2+ influx pathways could fully attenuate the response, whereasinhibition of the store-operated Ca2+ influx pathway alone orthe Ca2+ release was ineffective. If the receptor-operated pathwaywas blocked, an exogenously activated store-operated pathwaycould take its place and restore the coupling of OX1 receptorsto ERK. Further experiments suggested that Ca2+ influx, as such,may not be required for ERK phosphorylation, but that Ca2+,elevated via influx, acts as a switch enabling OX1 receptorsto couple to cascades leading to ERK phosphorylation, cAMP elevation,and phospholipase C activation. In conclusion, the data suggestthat the primary coupling of orexin receptors to Ca2+ influxallows them to couple to other signal pathways; in the absenceof coupling to Ca2+ influx, orexin receptors can act as signalintegrators by taking advantage of other Ca2+ influx pathways.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93309 (URN)10.1210/me.2004-0389 (DOI)16141359 (PubMedID)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
    4. G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase
    Open this publication in new window or tab >>G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase
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    2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, p. 834-842Article in journal (Refereed) Published
    Abstract [en]

    We have investigated the signaling of OX1 receptors to cell death using Chinese hamster ovary cells as a model system. OX1 receptor stimulation with orexin-A caused a delayed cell death independently of cytosolic Ca2+ elevation. The classical mitogen-activated protein kinase (MAPK) pathways, ERK and p38, were strongly activated by orexin-A. p38 was essential for induction of cell death, whereas the ERK pathway appeared protective. A pathway often implicated in the p38-mediated cell death, activation of p53, did not mediate the cell death, as there was no stabilization of p53 or increase in p53-dependent transcriptional activity, and dominant-negative p53 constructs did not inhibit cell demise. Under basal conditions, orexin-A-induced cell death was associated with compact chromatin condensation and it required de novo gene transcription and protein synthesis, the classical hallmarks of programmed (apoptotic) cell death. However, though the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (Z-VAD-fmk) fully inhibited the caspase activity, it did not rescue the cells from orexin-A-induced death. In the presence of Z-VAD-fmk, orexin-A-induced cell death was still dependent on p38 and de novo protein synthesis, but it no longer required gene transcription. Thus, caspase inhibition causes activation of alternative, gene transcription-independent death pathway. In summary, the present study points out mechanisms for orexin receptor-mediated cell death and adds to our general understanding of the role of G-protein-coupled receptor signaling in cell death by suggesting a pathway from G-protein-coupled receptors to cell death via p38 mitogen-/stress-activated protein kinase independent of p53 and caspase activation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93310 (URN)10.1074/jbc.M508603200 (DOI)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
  • 382.
    Amoroso, Vito
    et al.
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    Pavel, Marianne
    Friedrich Alexander Univ Erlangen Nurnberg, Div Endocrinol, Dept Med, D-91012 Erlangen, Germany.
    Claps, Melanie
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    Roca, Elisa
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    Ravanelli, Marco
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Radiol Unit, I-25123 Brescia, Italy.
    Maroldi, Roberto
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Radiol Unit, I-25123 Brescia, Italy.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Berruti, Alfredo
    Univ Brescia, ASST Spedali Civili, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth,Med Oncol Unit, I-25123 Brescia, Italy.
    IFN-alpha in advanced well-differentiated neuroendocrine tumors: the neglected drug?2018In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 14, no 10, p. 897-899Article in journal (Other academic)
  • 383.
    An, Feng-Wei
    et al.
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Yuan, Hu
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Guo, Weiwei
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Hou, Zhao-Hui
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Cai, Jian-Ming
    Chinese Peoples Liberat Army Gen Hosp, Dept Radiol, Beijing, Peoples R China.
    Luo, Chun-Cai
    Chinese Peoples Liberat Army Gen Hosp, Dept Radiol, Beijing, Peoples R China.
    Yu, Ning
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Jiang, Qing-Qing
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Cheng, Wei
    Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol & Head Neck Surg, Beijing, Peoples R China;Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Yang, Shi-Ming
    Chinese PLA Med Sch, Key Lab Hearing Impairment Sci, Minist Educ, Key Lab Hearing Impairment Prevent & Treatment Be, Beijing, Peoples R China.
    Establishment of a Large Animal Model for Eustachian Tube Functional Study in Miniature Pigs2019In: Anatomical Record Part A-discoveries in Molecular Cellular and Evolutionary Biology, ISSN 1552-4884, E-ISSN 1932-8494, Vol. 302, no 6, p. 1024-1038Article in journal (Refereed)
    Abstract [en]

    This study was performed to investigate whether miniature pigs are a suitable animal model for studies of the Eustachian tube (ET). Sixteen Chinese experimental miniature pigs were used in this investigation. Ten animals were used for anatomical and morphometric analyses to obtain qualitative and quantitative information regarding the ET. Three animals were used for histological analysis to determine the fine structure of ET cross-sections. Three animals were used to investigate the feasibility of balloon dilation of the Eustachian tube (BDET). The anatomical study indicated that the pharyngeal orifice and tympanic orifice of the miniature pig ET are located at the posterior end of the nasal lateral wall and anterior wall of the middle ear cavity, respectively. The cartilaginous tube was seen to pass through the whole length of the ET, the length of the cartilaginous part of the ET and the diameter of the isthmus were similar between humans and miniature pigs. The inclination of the ET in miniature pigs was larger than that in humans. The gross histology seemed to be slightly different between miniature pig and human, but the fine structures were essentially the same in both species. BDET experiments verified that the miniature pig model is suitable as a model for clinical operations. The miniature pig ET corresponds very well to that of humans. In addition, the miniature pig ET is suitable as a model for clinical operations. Therefore, the miniature pig is a valid animal model for ET study. 

  • 384.
    An, Hongbin
    et al.
    HUST, Sch Mech Sci & Engn, Wuhan 430074, Hubei, Peoples R China.
    Chen, Liangzhou
    HUST, Sch Mech Sci & Engn, Wuhan 430074, Hubei, Peoples R China.
    Liu, Xiaojun
    HUST, Sch Mech Sci & Engn, Wuhan 430074, Hubei, Peoples R China.
    Zhao, Bin
    HUST, Sch Mech Sci & Engn, Wuhan 430074, Hubei, Peoples R China.
    Zhang, Hong
    HUST, Tongji Med Coll, Tongji Hosp, Dept Ophthalmol, Wuhan 430074, Hubei, Peoples R China.
    Wu, Zhigang
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology. HUST, Sch Mech Sci & Engn, Wuhan 430074, Hubei, Peoples R China.
    Microfluidic contact lenses for unpowered, continuous and non-invasive intraocular pressure monitoring2019In: Sensors and Actuators A-Physical, ISSN 0924-4247, E-ISSN 1873-3069, Vol. 295, p. 177-187Article in journal (Refereed)
    Abstract [en]

    Intraocular pressure (IOP) is a crucial physiological indicator of the visual system and play a key role in the diagnosis and treatment of glaucoma. However, the current handheld single measurement tools for IOP sensing cannot meet the future demands for glaucoma management. Thus, here we present the microfluidic contact lens sensors that could provide unpowered, continuous and non-invasive IOP monitoring. The microfluidic contact lens is comprised of a sensing layer of the micropatterned soft-elastomer and a hard plastic reference layer. The devices use the annular sensing chamber filled with the dyed liquid and a sensing microchannel as the IOP transducer. Resulting from the volume variance of the sensing chamber and caused by the deformation of the sensing layer under pressure, the IOP signal is detected as the displacement change of the dyed liquid's interface in the sensing channel, and in which, the displacement change can be optically observed by using the smart-phone camera. Based on the silicone rubber model eyeball, the sensing mechanism of the devices with different design parameters (the position of the sensing chambers and the dimension of the sensing channels) are explored by using the theoretical analyses and experimental investigations. The characteristics of these microfluidic contact lens sensors are tested, in which, the maximum sensitivity of the device (with the sensing chamber of 8.5 mm in diameter and the sensing channel of 100 x 40 um in size) can be achieved to 0.708 mm/mmHg in a working range of 0 (4) over tilde0 mmHg. Also, cyclical tests were conducted and indicated that the devices had a good reversibility and Long-term stability. Furthermore, the device (with the sensing chamber of 5.0 mm in diameter and the sensing channel of 150 x 40 urn in size) was test on the porcine eyes ex vivo, showing a sensitivity of 0.2832 mm/mmHg in a range of 8 (3) over tilde2 mmHg and, the device had a good reproducibility to its IOP change. This work provides a promising approach for unpowered, continuous and non-invasive monitoring of IOP.

  • 385.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hyöty, Heikki
    University of Tampere, School of Medicine, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetesManuscript (preprint) (Other academic)
    Abstract [en]

    Hypothesis: Fulminant Type 1 diabetes is a unique subtype of T1D, mostly reported in the Japanese population, which is characterized by extensive beta cell death already at onset, often without any insulitis. Enterovirus (EV) infections are associated with the etiology of both fulminant and conventional T1D. However the causative mechanism is not known for any of these diseases. EVs capability to cause lytic vs non-lytic infection in explanted human islets may have implications on the pathogenesis of these two types of T1D.

    Aim: To study the effect of infection of explanted human pancreatic islets with lytic (CBV-1) and non-lytic (CBV-4) Coxsackie B virus strains on cytopathic effect/islet disintegration and to what extent genes involved in viral sensing, antiviral defense and encoding of islet auto-antigens are affected by the viral replication. Also, to compare these findings with the findings reported in fulminant and conventional T1D.

    Methods: Degree of cytopathic effect/islet disintegration was studied and viral replication was measured. Genes involved in viral sensing (NOD2, TLR7 and TLR4), antiviral pathways (OAS2, MX1, PKR, and IRF7), genes coding for known islet auto antigens (GAD65, ZNT8) and the islet hormones, insulin and glucagon, were studied. Mock-infected explanted islet served as controls.

    Results: All CBV strains replicated in the explanted islets but only the CBV-1 strains caused cytopathic effect/islet cell disintegration. Infection with all CBV strains resulted in the induction of genes encoding OAS2 and MX1. In contrast, mRNA expression levels of the gene encoding insulin was reduced. The gene encoding PKR was induced by one of the lytic strains (CBV-1-11) and also by the non-lytic CBV4 strain, while the mRNA expression levels of genes encoding glucagon, NOD2, TLR7, TLR4, MCL1, GAD65 and ZNT8 were not significantly affected.

  • 386.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Richardson, Sarah J.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Oberste, M. Steven
    Centers for Disease Control and Prevention, Atlanta, Georgia.
    Sioofy-Khojine, Amir-Babak
    School of Medicine, University of Tampere, Tampere, Finland.
    Hyoty, Heikki
    School of Medicine, University of Tampere, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Morgan, Noel G.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway2014In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, p. 1402-1411Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1. Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFN beta, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFN beta, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential beta-cell tropism of the virus.

  • 387.
    Analatos, Apostolos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden; Nykoping Hosp, Dept Surg, Nykoping, Sweden.
    Lindblad, Mats
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Rouvelas, Ioannis
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Elbe, Peter
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Lundell, Lars
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Nilsson, Magnus
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Tsekrekos, Andrianos
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Tsai, Jon A.
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden; Karolinska Inst, Dept Clin Intervent & Technol CLINTEC, Div Surg, Stockholm, Sweden.
    Evaluation of resection of the gastroesophageal junction and jejunal interposition (Merendino procedure) as a rescue procedure in patients with a failed redo antireflux procedure. A single-center experience2018In: BMC Surgery, ISSN 1471-2482, E-ISSN 1471-2482, Vol. 18, article id 70Article in journal (Refereed)
    Abstract [en]

    Background: Primary antireflux surgery has high success rates but 5 to 20% of patients undergoing antireflux operations can experience recurrent reflux and dysphagia, requiring reoperation. Different surgical approaches after failed fundoplication have been described in the literature. The aim of this study was to evaluate resection of the gastroesophageal junction with jejunal interposition (Merendino procedure) as a rescue procedure after failed fundoplication.

    Methods: All patients who underwent a Merendino procedure at the Karolinska University Hospital between 2004 and 2012 after a failed antireflux fundoplication were identified. Data regarding previous surgical history, preoperative workup, postoperative complications, subsequent investigations and re-interventions were collected retrospectively. The follow-up also included questionnaires regarding quality of life, gastrointestinal function and the dumping syndrome.

    Results: Twelve patients had a Merendino reconstruction. Ten patients had undergone at least two previous fundoplications, of which one patient had four such procedures. The main indication for surgery was epigastric and radiating back pain, with or without dysphagia. Postoperative complications occurred in 8/12 patients (67%). During a median follow-up of 35 months (range 20-61), four (25%) patients had an additional redo procedure with conversion to a Roux-en-Y esophagojejunostomy within 12 months, mainly due to obstructive symptoms that could not be managed conservatively or with endoscopic techniques. Questionnaires scores were generally poor in all dimensions.

    Conclusions: In our experience, the Merendino procedure seems to be an unsuitable surgical option for patients who require an alternative surgical reconstruction due to a failed fundoplication. However, the small number of patients included in this study as well as the small number of participants who completed the postoperative workout limits this study.

  • 388.
    Anandavadivelan, Poorna
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Surg Care Sci, Stockholm, Sweden.
    Wikman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Johar, Asif
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Surg Care Sci, Stockholm, Sweden.
    Lagergren, Pernilla
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Surg Care Sci, Stockholm, Sweden.
    Profiles of patient and tumour characteristics in relation to health-related quality of life after oesophageal cancer surgery2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0196187Article in journal (Refereed)
    Abstract [en]

    Strong deterioration in health-related quality of life (HRQOL) is a major concern in a sub-group of long-term oesophageal cancer survivors. This study aimed to identify potential clustering of patients and tumour variables that predicts such deterioration. Patient and tumour variables were collected in a prospective cohort of patients who underwent surgery for oesophageal cancer in Sweden 2001–2005. Latent cluster analysis identified statistically significant clustering of these variables. Multivariable logistic regression adjusted for age, BMI, tumour stage and marital status was used to determine odds ratios (ORs) with 95% confidence intervals (CIs) between patient profiles and HRQOL at 3 and 5 years from surgery. Among 155 included patients at 3 years, three patient profiles were identified: 1) ‘reference profile’ (males, younger age, employed, upper secondary education, co-habitating, urban dwellers, adenocarcinoma and advanced tumour stage) (n = 47;30%), 2) ‘adenocarcinoma profile’ (middle age, unemployed/retired, males, low education, co-habitating, adenocarcinoma, advanced tumour stage, tumour in lower oesophagus/cardia, and co-morbidities (n = 79;51%), and 3) ‘squamous-cell carcinoma profile’ (unemployed/retired, middle-age, males, low BMI, urban dwellers, squamous-cell carcinoma, tumour in upper/middle oesophagus (n = 29;19%). These profiles did not differ regarding most HRQOL measures. Exceptions were the squamous-cell carcinoma profile, reporting more constipation (OR = 5.69; 95%CI: 1.34–24.28) and trouble swallowing saliva (OR = 4.87; 95%CI: 1.04–22.78) and the adenocarcinoma profile reporting more dyspnoea (OR = 2.60; 95%CI: 1.00–6.77) and constipation (OR = 3.31; 95%CI: 1.00–10.97) compared to the reference profile. Three distinct patient profiles were identified but these could not explain the substantial deterioration in HRQOL observed in the sub-sample of survivors.

  • 389.
    Anastasopoulou, Stavroula
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Eriksson, Mats A.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Heyman, Mats
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Wang, Chen
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Niinimäki, Riitta
    Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland;Univ Oulu, PEDEGO Res Unit, Oulu, Finland.
    Mikkel, Sirje
    Univ Tartu, Dept Hematol & Oncol, Tartu, Estonia.
    Vaitkeviciene, Goda E.
    Vilnius Univ Hosp Santaros Klin, Childrens Hosp, Vilnius, Lithuania;Vilnius Univ, Vilnius, Lithuania.
    Johannsdottir, Inga Maria
    Oslo Univ Hosp, Dept Pediat Hematol Oncol, Oslo, Norway.
    Myrberg, Ida Hed
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Jonsson, Olafur Gisli
    Univ Iceland, Dept Pediat, Reykjavik, Iceland.
    Als-Nielsen, Bodil
    Rigshosp, Univ Hosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark.
    Schmiegelow, Kjeld
    Rigshosp, Univ Hosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark.
    Banerjee, Joanna
    Univ Helsinki, Childrens Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Harila-Saari, Arja H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Ranta, Susanna
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease2019In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 66, no 5, article id e27594Article in journal (Refereed)
    Abstract [en]

    Background: Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL).

    Procedure: Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records.

    Results: The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1-2.5) and at one year 3.7% (95% CI, 2.9-4.9). Older age (hazard ratios [HR] for each one-year increase in age 1.1; 95% CI, 1.0-1.2, P = 0.001) and T-cell immunophenotype (HR, 2.9; 95% CI, 1.6-5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios [OR] = 2.8; 95% CI, 1.2-6.5, P = 0.015) was associated with early PRES and high-risk block treatment (HR = 2.63; 95% CI, 1.1-6.4, P = 0.033) with late PRES. At follow-up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties.

    Conclusion: PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long-term morbidity. Older age, T-cell leukemia, CNS involvement and high-risk block treatment are risk factors for PRES.

  • 390. Anclair, M
    et al.
    Hovén, E
    Lannering, B
    Boman, K K
    Parental fears following their child's brain tumor diagnosis and treatment2009In: Journal of Pediatric Oncology Nursing, ISSN 1043-4542, E-ISSN 1532-8457, Vol. 26, no 2, p. 68-74Article in journal (Refereed)
    Abstract [en]

    The objective of this study is to portray the illness-related threats experienced by parents of children after the diagnosis of central nervous system (CNS) tumor. Parents were asked to rate the extent to which they experienced a set of specific fears related to their child's brain tumor and its treatment. Outcomes for parents of CNS tumor patients (n = 82) were compared with those of reference parents of patients treated for acute lymphoblastic leukemia (n = 208). The fears about an illness recurrence and the late effects of treatment were most prominent among parents of CNS tumor patients. For 7 out of 11 kinds of fear, parents of CNS tumor patients expressed a stronger fear than the reference group. More than a quarter of the parents of children treated for CNS tumors feared a complete decline of the child. Parents of CNS tumor patients experience relatively heightened cancer related fears in several domains. The fear of devastating consequences felt by one fourth of parents signals the need of individualized psychological support and information at diagnosis and follow-up to facilitate parental coping with the posttreatment situation.

  • 391.
    Andell, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Tomson, Torbjorn
    Carlsson, Sofia
    Hellebro, Eva
    Andersson, Tomas
    Adelow, Cecilia
    Amark, Per
    The incidence of unprovoked seizures and occurrence of neurodevelopmental comorbidities in children at the time of their first epileptic seizure and during the subsequent six months2015In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 113, p. 140-150Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the incidence of unprovoked seizures in children and the prevalence of related neurodevelopmental comorbidities at the time of the presumed first seizure and six months thereafter. Methods: The medical records of all children (0-18 years of age) seeking medical attention as the result of a first unprovoked seizure between September 1, 2001 and December 31, 2006, and registered in the population-based Stockholm Incidence Registry of Epilepsy (SIRE) were reviewed. Neurodevelopmental comorbidities were evaluated on the basis of the medical records from this first visit and from other healthcare during the following six months. Results: The incidence of unprovoked seizures was between 30 and 204/100,000 person years (n=766) in the different age groups. It was highest among the youngest children and lowest among the 18-year-olds with small gender differences. The most common neurodevelopment comorbidities were developmental delay (22%, CI: 19-25%), speech/language and learning difficulties (23%, CI: 20-26%) and intellectual disability (16%, CI: 13-18%). The types of neurodevelopmental comorbidity varied by age at the time of seizure onset, with cerebral palsy being more common among the 0-5-year-olds, attention deficits among the 6-16-year-olds, and autism and psychiatric diagnosis among the older children. An associated neurodevelopmental comorbidity was more common among those experiencing recurrent than single seizures during follow-up six months from the index seizure (42% versus 66%). In 68% (CI: 64-71%) of the children there was no known or suspected neurodevelopmental comorbidity. Conclusion: The incidence of unprovoked, non-febrile seizures among 0-18-year-olds included in the SIRE was 67/100,000 person-years. Neurodevelopmental comorbidities were common already at the time of onset of the seizure disorder, indicating that neither seizure treatment nor seizures were the underlying cause of other neurodevelopmental symptoms in these patients during the period studied.

  • 392. Andell, P.
    et al.
    Erlinge, D.
    Smith, J. G.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Koul, S.
    The effect of beta-blockers on mortality in COPD patients after myocardial infarction: A Swedish nation-wide observational study2014In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, p. 686-687Article in journal (Refereed)
  • 393.
    Andell, P.
    et al.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    Karlsson, S.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    Mohammad, M.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    Gotberg, M.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jensen, J.
    Capio St Goran Hosp, Stockholm, Sweden..
    Frobert, O.
    Orebro Univ Hosp, Orebro, Sweden..
    Angeras, O.
    Sahlgrens Acad, Gothenburg, Sweden..
    Nilsson, J.
    Umea Univ Hosp, Umea, Sweden..
    Omerovic, E.
    Sahlgrens Acad, Gothenburg, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Persson, J.
    Danderyd Hosp, Stockholm, Sweden..
    Koul, S.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    Erlinge, D.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    Intravascular ultrasound guidance is associated with lower mortality in patients undergoing stenting for unprotected left main coronary artery lesions compared to angiography-guided stent implantation2016Conference paper (Refereed)
  • 394. Andell, Pontus
    et al.
    Erlinge, David
    Smith, J. Gustav
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Koul, Sasha
    beta-Blocker Use and Mortality in COPD Patients After Myocardial Infarction: A Swedish Nationwide Observational Study2015In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 4, no 4, article id e001611Article in journal (Refereed)
    Abstract [en]

    Background-Patients with myocardial infarction (MI) and concomitant chronic obstructive pulmonary disease (COPD) constitute a high-risk group with increased mortality. beta-Blocker therapy has been shown to reduce mortality, prevent arrhythmias, and delay heart failure development after an MI in broad populations. However, the effect of beta-blockers in COPD patients is less well established and they may also be less treated due to fear of adverse reactions. We investigated beta-blocker prescription at discharge in patients with COPD after MI. ethods and Results-Patients hospitalized for MI between 2005 and 2010 were identified from the nationwide Swedish SWEDEHEART registry. Patients with COPD who were alive and discharged after an MI were selected as the study population. In this cohort, patients who were discharged with beta-blockers were compared to patients not discharged with beta-blockers. The primary end point was all-cause mortality. A total of 4858 patients were included, of which 4086 (84.1%) were discharged with a beta-blocker while 772 (15.9%) were not. After adjusting for potential confounders including baseline characteristics, comorbidities, and in-hospital characteristics, patients discharged with a beta-blocker had lower all-cause mortality (hazard ratio 0.87, 95% CI 0.78 to 0.98) during the total follow-up time (maximum 7.2 years). In the subgroup of patients with a history of heart failure, the corresponding hazard ratio was 0.77 (95% CI 0.63 to 0.95). Conclusions-Patients with COPD discharged with beta-blockers after an MI had a lower all-cause mortality compared to patients not prescribed beta-blockers. The results indicate that MI patients with COPD may benefit from beta-blockers.

  • 395.
    Andell, Pontus
    et al.
    Lund Univ, Dept Cardiol, Clin Sci, S-22185 Lund, Sweden..
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cannon, Christopher P.
    Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA.;Harvard Clin Res Inst, Boston, MA USA..
    Cyr, Derek D.
    Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA..
    Himmelmann, Anders
    AstraZeneca Res & Dev, Molndal, Sweden..
    Husted, Steen
    Hosp Unit West, Dept Med, Herning Holstebro, Denmark..
    Keltai, Matyas
    Semmelweis Univ, Hungarian Inst Cardiol, H-1085 Budapest, Hungary..
    Koul, Sasha
    Lund Univ, Dept Cardiol, Clin Sci, S-22185 Lund, Sweden..
    Santoso, Anwar
    Univ Indonesia, Natl Cardiovasc Ctr, Harapan Kita Hosp, Dept Cardiol,Vasc Med,Fac Med, Jakarta, Indonesia. INSERM, U1148, Paris, France. Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75877 Paris, France. Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. Royal Brompton Hosp, ICMS, NHLI Imperial Coll, London SW3 6LY, England..
    Steg, Gabriel
    Storey, Robert F.
    Univ Sheffield, Dept Cardiovasc Sci, Sheffield S10 2TN, S Yorkshire, England..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Erlinge, David
    Lund Univ, Dept Cardiol, Clin Sci, S-22185 Lund, Sweden..
    Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and Chronic Obstructive Pulmonary Disease: An Analysis From the Platelet Inhibition and Patient Outcomes (PLATO) Trial2015In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 4, no 10, article id e002490Article in journal (Refereed)
    Abstract [en]

    Background-Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients. Methods and Results-In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1-year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO-defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non-COPD patients (HR=1.85). No COPD status-by-treatment interactions were found, showing consistency with the main trial results. Conclusions-In this post-hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit-risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD.

  • 396.
    Andell, Pontus
    et al.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Karlsson, Sofia
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Mohammad, Moman A.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Gotberg, Matthias
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jensen, Jens
    Karolinska Inst, Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.;Capio St Gorans Sjukhus, Unit Med, Stockholm, Sweden..
    Frobert, Ole
    Orebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Angeras, Oskar
    Sahlgrens Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.;Univ Gothenburg, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Nilsson, Johan
    Umea Univ Hosp, Heart Ctr, Dept Cardiol, Umea, Sweden..
    Omerovic, Elmir
    Sahlgrens Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.;Univ Gothenburg, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Persson, Jonas
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden..
    Koul, Sasha
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Erlinge, David
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden..
    Intravascular Ultrasound Guidance Is Associated With Better Outcome in Patients Undergoing Unprotected Left Main Coronary Artery Stenting Compared With Angiography Guidance Alone2017In: Circulation. Cardiovascular Interventions, ISSN 1941-7640, E-ISSN 1941-7632, Vol. 10, no 5, article id e004813Article in journal (Refereed)
    Abstract [en]

    Background: Small observational studies have indicated better outcome with intravascular ultrasound (IVUS) guidance when performing unprotected left main coronary artery (LMCA) percutaneous coronary intervention (PCI), but the overall picture remains inconclusive and warrants further investigation. We studied the impact of IVUS guidance on outcome in patients undergoing unprotected LMCA PCI in a Swedish nationwide observational study.

    Methods and Results: Patients who underwent unprotected LMCA PCI between 2005 and 2014 because of stable coronary artery disease or acute coronary syndrome were included from the nationwide SCAAR (Swedish Coronary Angiography and Angioplasty Registry). Of 2468 patients, IVUS guidance was used in 621 (25.2%). The IVUS group was younger (median age, 70 versus 75 years) and had fewer comorbidities but more complex lesions. IVUS was associated with larger stent diameters (median, 4 mm versus 3.5 mm). After adjusting for potential confounders, IVUS was associated with significantly lower occurrence of the primary composite end point of all-cause mortality, restenosis, or definite stent thrombosis (hazard ratio, 0.65; 95% confidence interval, 0.50-0.84) and all-cause mortality alone (hazard ratio, 0.62; 95% confidence interval, 0.47-0.82). In 340 propensity score-matched pairs, IVUS was also associated with significantly lower occurrence of the primary end point (hazard ratio, 0.54; 95% confidence interval, 0.37-0.80).

    Conclusions: IVUS was associated with an independent and significant outcome benefit when performing unprotected LMCA PCI. Potential mediators of this benefit include larger and more appropriately sized stents, perhaps translating into lower risk of subsequent stent thrombosis. Although residual confounding cannot be ruled out, our findings indicate a possible hazard when performing unprotected LMCA PCI without IVUS guidance.

  • 397. Andell, Pontus
    et al.
    Koul, Sasha
    Martinsson, Andreas
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jernberg, Tomas
    Smith, J Gustav
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Erlinge, David
    Impact of chronic obstructive pulmonary disease on morbidity and mortality after myocardial infarction2014In: Open heart, E-ISSN 2053-3624, Vol. 1, no 1, p. e000002-Article in journal (Refereed)
    Abstract [en]

    AIM:

    To gain a better understanding of the impact of chronic obstructive pulmonary disease (COPD) on long-term mortality in patients with myocardial infarction (MI) and identify areas where the clinical care for these patients may be improved.

    METHODS:

    Patients hospitalised for MI between 2005 and 2010 were identified from the nationwide Swedish SWEDEHEART registry. Patients with MI and a prior COPD hospital discharge diagnosis were compared to patients with MI without a prior COPD hospital discharge diagnosis for the primary endpoint of all-cause mortality at 1 year after MI. Secondary endpoints included rates of reinfarction, new-onset stroke, new-onset bleeding and new-onset heart failure at 1 year.

    RESULTS:

    A total of 81 191 MI patients were included, of which 4867 (6%) had a COPD hospital discharge diagnosis at baseline. Patients with COPD showed a significantly higher unadjusted 1-year mortality (24.6 vs 13.8%) as well as a higher rate of reinfarction, new-onset bleeding and new-onset heart failure post-MI. After adjustment for potential confounders, including comorbidities and treatment, the patients with COPD still showed a significantly higher 1-year mortality (HR 1.14, 95% CI 1.07 to 1.21) as well as a higher rate of new-onset heart failure (HR 1.35, 95% CI 1.24 to 1.47), whereas no significant association between COPD and myocardial reinfarction or new-onset bleeding remained.

    CONCLUSIONS:

    In this nationwide contemporary study, patients with COPD frequently had an atypical presentation, less often underwent revascularisation and less often received guideline-recommended secondary preventive medications of established benefit. Prior COPD was associated with a higher 1-year mortality and a higher risk of subsequent new-onset heart failure after MI. The association seems to be mainly explained by differences in background characteristics, comorbidities and treatment, although a minor part might be explained by COPD in itself. Improved in-hospital MI treatment and post-MI secondary prevention according to the guidelines may lower the mortality in this high-risk population.

  • 398.
    Andell, Pontus
    et al.
    Lund Univ, Dept Cardiol, Clin Sci, S-22185 Lund, Sweden.;Skane Univ Hosp, S-22185 Lund, Sweden..
    Sjogren, Johan
    Skane Univ Hosp, S-22185 Lund, Sweden.;Lund Univ, Dept Cardiothorac Surg, Clin Sci, Lund, Sweden..
    Batra, Gorav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Szummer, Karolina
    Dept Med, Huddinge, Sweden.;Karolinska Inst, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Koul, Sasha
    Lund Univ, Dept Cardiol, Clin Sci, S-22185 Lund, Sweden.;Skane Univ Hosp, S-22185 Lund, Sweden..
    Outcome of patients with chronic obstructive pulmonary disease and severe coronary artery disease who had a coronary artery bypass graft or a percutaneous coronary intervention2017In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 52, no 5, p. 930-936Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) who also have acute coronary syndromes are a high-risk population with a high mortality rate. Little is known about these patients following coronary artery bypass grafting (CABG). METHODS: Patients presenting with acute coronary syndromes between 2006 and 2014 with an angiogram showing 3-vessel disease or left main coronary artery involvement who were treated with CABG or percutaneous coronary intervention (PCI) only were included from the nationwide SWEDEHEART registry. Patients were stratified according to COPD status and compared with regard to outcome. The primary end-point was the 5-year mortality rate; secondary outcomes were the 30-day mortality rate and in-hospital complications after CABG. RESULTS: We identified 6985 patients in the population who had CABG (COPD prevalence = 8.0%) and 14 209 who had PCI only (COPD = 8.2%). Patients with COPD were older and had more comorbidities than patients without COPD. The 5-year mortality rate was nearly doubled in patients with COPD versus patients without COPD (CABG: 27.2% vs 14.5%, P < 0.001; PCI only: 50.1% vs 29.1%, P < 0.001). After adjusting for age, sex and comorbidities, patients with COPD in both CABG-treated [hazard ratio = 1.52 (1.25-1.86), P < 0.001] and PCI-treated populations still had a significantly higher 5-year mortality rate. COPD was also independently associated with significantly more postoperative infections in need of antibiotics [odds ratio = 1.48 (1.07-2.04), P = 0.017] and pneumonia [odds ratio = 2.21 (1.39-3.52), P = 0.001]. CONCLUSIONS: Patients with COPD presenting with acute coronary syndromes and severe coronary artery disease are a high-risk population following CABG or PCI only, with higher risk of long-term and short-term death and postoperative infections. Preventive measures, including careful monitoring for signs of infection and prompt antibiotic treatment when indicated, should be considered.

  • 399.
    Ander, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Grönqvist, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Cernvall, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Engvall, Gunn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hedström, Mariann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lyhagen, Johan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Mattsson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Development of health-related quality of life and symptoms of anxiety and depression among persons diagnosed with cancer during adolescence: a 10-year follow-up study2016In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 25, no 5, p. 582-589Article in journal (Refereed)
    Abstract [en]

    Objective: The main aim was to investigate the development of health-related quality of life (HRQOL) and symptoms of anxiety and depression in a cohort diagnosed with cancer during adolescence from shortly after up to 10 years after diagnosis.

    Methods: Participants (n = 61) completed the SF-36 and the HADS shortly; six, 12, and 18 months; and two, three, four, and 10 years (n = 28) after diagnosis. Polynomial change trajectories were used to model development.

    Results: Polynomial change trajectories showed an initial increase which abated over time into a decrease which abated over time for the SF-36 subscales Mental Health and Vitality; an initial decline which abated over time into an increase for HADS anxiety; and an initial decline which abated over time into an increase which abated over time for HADS depression. The SF-36 mental component summary showed no change from two to 10 years after diagnosis whereas the SF-36 physical component summary showed an increase from two years after diagnosis which declined over time. Ten years after diagnosis 29% reported possible anxiety.

    Conclusions: Development of HRQOL and symptoms of anxiety and depression appears to be nonlinear among persons diagnosed with cancer during adolescence. Well into permanent survivorship an increase in symptoms of anxiety is shown and approximately a third of the participants report possible anxiety. The findings indicate the need for: studies designed to pinpoint the times of highest psychological risk, clinical follow-up focusing on psychological problems, and development of effective psychological interventions for survivors of adolescent cancer

  • 400.
    Ander, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Norberg, Annika Lindahl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ljotsson, Brjann
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Identification of Cancer-related Psychological Suffering Experienced by Young People Diagnosed with Cancer During Adolescence and Development of a Psychological Treatment to Reduce This Suffering2015Conference paper (Refereed)
567891011 351 - 400 of 13972
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