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  • 101.
    Chibani, Zohra
    et al.
    Univ Sfax, Tunisia.
    Abid, Imen Zone
    Univ Sfax, Tunisia.
    Molbaek, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Feki, Jamel
    Univ Sfax, Tunisia.
    Hmani-Aifa, Mounira
    Univ Sfax, Tunisia.
    Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families2019In: Clinical and Experimental Ophthalmology, ISSN 1442-6404, E-ISSN 1442-9071Article in journal (Refereed)
    Abstract [en]

    Background

    Epidemiological studies of hereditary eye diseases allowed us to identify two Tunisian families suffering from macular dystrophies: Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The purpose of the current study was to investigate the clinical characteristics and the underlying genetics of these two forms of macular dystrophy.

    Methods

    Complete ophthalmic examination was performed including optical coherence tomography, electroretinography, electrooculography and autofluoresence imaging in all patients. Genomic DNA was extracted from peripheral blood collected from patients and family members.

    Results

    Sanger sequencing of all exons of the BEST1 gene in both families identified two new mutations: a missense mutation c.C91A [p.L31 M] at the N‐terminal transmembrane domain within the ARB family and a nonsense mutation C1550G (p.S517X) in the C‐terminal domain segregating in the BVMD family.

    Conclusions

    Several mutations of the BEST1 gene have been reported which are responsible for numerous ocular pathologies. To the best of our knowledge, it is the first time we report mutations in this gene in Tunisian families presenting different forms of macular dystrophy. Our report also expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

  • 102.
    Chow, Joyce A
    et al.
    RISE Interactive Institute, Norrköping, Sweden.
    Törnros, Martin E
    Interaktiva Rum Sverige, Gothenburg, Sweden.
    Waltersson, Marie
    Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Richard, Helen
    Region Östergötland, Center for Diagnostics, Clinical pathology.
    Kusoffsky, Madeleine
    RISE Interactive Institute, Norrköping, Sweden.
    Lundström, Claes
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Sectra AB, Linköping, Sweden.
    Kurti, Arianit
    RISE Interactive Institute, Norrköping, Sweden.
    A Design Study Investigating Augmented Reality and Photograph Annotation in a Digitalized Grossing Workstation2017In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 8, no 31Article in journal (Refereed)
    Abstract [en]

    Context: Within digital pathology, digitalization of the grossing procedure has been relatively underexplored in comparison to digitalization of pathology slides. 

    Aims: Our investigation focuses on the interaction design of an augmented reality gross pathology workstation and refining the interface so that information and visualizations are easily recorded and displayed in a thoughtful view. 

    Settings and Design: The work in this project occurred in two phases: the first phase focused on implementation of an augmented reality grossing workstation prototype while the second phase focused on the implementation of an incremental prototype in parallel with a deeper design study. 

    Subjects and Methods: Our research institute focused on an experimental and “designerly” approach to create a digital gross pathology prototype as opposed to focusing on developing a system for immediate clinical deployment. 

    Statistical Analysis Used: Evaluation has not been limited to user tests and interviews, but rather key insights were uncovered through design methods such as “rapid ethnography” and “conversation with materials”. 

    Results: We developed an augmented reality enhanced digital grossing station prototype to assist pathology technicians in capturing data during examination. The prototype uses a magnetically tracked scalpel to annotate planned cuts and dimensions onto photographs taken of the work surface. This article focuses on the use of qualitative design methods to evaluate and refine the prototype. Our aims were to build on the strengths of the prototype's technology, improve the ergonomics of the digital/physical workstation by considering numerous alternative design directions, and to consider the effects of digitalization on personnel and the pathology diagnostics information flow from a wider perspective. A proposed interface design allows the pathology technician to place images in relation to its orientation, annotate directly on the image, and create linked information. 

    Conclusions: The augmented reality magnetically tracked scalpel reduces tool switching though limitations in today's augmented reality technology fall short of creating an ideal immersive workflow by requiring the use of a monitor. While this technology catches up, we recommend focusing efforts on enabling the easy creation of layered, complex reports, linking, and viewing information across systems. Reflecting upon our results, we argue for digitalization to focus not only on how to record increasing amounts of data but also how these data can be accessed in a more thoughtful way that draws upon the expertise and creativity of pathology professionals using the systems.

  • 103.
    Chowdhury, Manish
    et al.
    KTH, School of Technology and Health, Sweden.
    Klintström, Benjamin
    Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH, School of Technology and Health, Sweden.
    Klintström, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. KTH, School of Technology and Health, Sweden.
    Moreno, Rodrigo
    KTH, School of Technology and Health, Sweden.
    Granulometry-Based Trabecular Bone Segmentation2017In: Image Analysis - 20th Scandinavian Conference on Image Analysis, SCIA 2017, Proceedings / [ed] Sharma P., Bianchi F., Springer, 2017, Vol. 10270, p. 100-108Conference paper (Refereed)
    Abstract [en]

    The accuracy of the analyses for studying the three dimensionaltrabecular bone microstructure rely on the quality of the segmentationbetween trabecular bone and bone marrow. Such segmentationis challenging for images from computed tomography modalities thatcan be used in vivo due to their low contrast and resolution. For thispurpose, we propose in this paper a granulometry-based segmentationmethod. In a first step, the trabecular thickness is estimated by usingthe granulometry in gray scale, which is generated by applying the openingmorphological operation with ball-shaped structuring elements ofdifferent diameters. This process mimics the traditional sphere-fittingmethod used for estimating trabecular thickness in segmented images.The residual obtained after computing the granulometry is comparedto the original gray scale value in order to obtain a measurement ofhow likely a voxel belongs to trabecular bone. A threshold is applied toobtain the final segmentation. Six histomorphometric parameters werecomputed on 14 segmented bone specimens imaged with cone-beam computedtomography (CBCT), considering micro-computed tomography(micro-CT) as the ground truth. Otsu’s thresholding and AutomatedRegion Growing (ARG) segmentation methods were used for comparison.For three parameters (Tb.N, Tb.Th and BV/TV), the proposedsegmentation algorithm yielded the highest correlations with micro-CT,while for the remaining three (Tb.Nd, Tb.Tm and Tb.Sp), its performancewas comparable to ARG. The method also yielded the strongestaverage correlation (0.89). When Tb.Th was computed directly fromthe gray scale images, the correlation was superior to the binary-basedmethods. The results suggest that the proposed algorithm can be usedfor studying trabecular bone in vivo through CBCT.

  • 104.
    Christensen, Michael
    et al.
    Aarhus Univ, Denmark.
    Schiffer, Tomas A.
    Uppsala Univ, Sweden.
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Norrköping/Finspång.
    Palmelund Krag, Soren
    Aarhus Univ Hosp, Denmark.
    Norregaard, Rikke
    Aarhus Univ, Denmark.
    Palm, Fredrik
    Uppsala Univ, Sweden.
    Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-22019In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 35, no 2, article id e3091Article in journal (Refereed)
    Abstract [en]

    Background The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis. Methods Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance. Results Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats. Conclusions Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.

  • 105.
    Christofer Juhlin, C.
    et al.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA; Karolinska Institute, Sweden.
    Stenman, Adam
    Karolinska Institute, Sweden.
    Haglund, Felix
    Karolinska Institute, Sweden.
    Clark, Victoria E.
    Yale University, CT 06520 USA.
    Brown, Taylor C.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Baranoski, Jacob
    Yale University, CT 06520 USA.
    Bilguvar, Kaya
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Goh, Gerald
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Svahn, Fredrika
    Karolinska Institute, Sweden.
    Rubinstein, Jill C.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Caramuta, Stefano
    Karolinska Institute, Sweden.
    Yasuno, Katsuhito
    Yale University, CT 06520 USA.
    Guenel, Murat
    Yale University, CT 06520 USA.
    Backdahl, Martin
    Karolinska Institute, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Prasad, Manju L.
    Yale University, CT 06520 USA.
    Korah, Reju
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Lifton, Richard P.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA; Yale Centre Mendelian Genom, CT USA.
    Carling, Tobias
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene2015In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 9, p. 542-554Article in journal (Refereed)
    Abstract [en]

    As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.

  • 106.
    Cibis, Merih
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Left Atrial 4D Blood Flow Dynamics and Hemostasis following Electrical Cardioversion of Atrial Fibrillation2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 1052Article in journal (Refereed)
    Abstract [en]

    Background: Electrical cardioversion in patients with atrial fibrillation is followed by a transiently impaired atrial mechanical function, termed atrial stunning. During atrial stunning, a retained risk of left atrial thrombus formation exists, which may be attributed to abnormal left atrial blood flow patterns. 4D Flow cardiovascular magnetic resonance (CMR) enables blood flow assessment from the entire three-dimensional atrial volume throughout the cardiac cycle. We sought to investigate left atrial 4D blood flow patterns and hemostasis during left atrial stunning and after left atrial mechanical function was restored. Methods: 4D Flow and morphological CMR data as well as blood samples were collected in fourteen patients at two time-points: 2-3 h (Time-1) and 4 weeks (Time-2) following cardioversion. The volume of blood stasis and duration of blood stasis were calculated. In addition, hemostasis markers were analyzed. Results: From Time-1 to Time-2: Heart rate decreased (61 +/- 7 vs. 56 +/- 8 bpm, p = 0.01); Maximum change in left atrial volume increased (8 +/- 4 vs. 22 +/- 15%, p = 0.009); The duration of stasis (68 +/- 11 vs. 57 +/- 8%, p = 0.002) and the volume of stasis (14 +/- 9 vs. 9 +/- 7%, p = 0.04) decreased; Thrombin-antithrombin complex (TAT) decreased (5.2 +/- 3.3 vs. 3.3 +/- 2.2it.g/L, p = 0.008). A significant correlation was found between TAT and the volume of stasis (r(2) = 0.69, p amp;lt; 0.001) at Time-1 and between TAT and the duration of stasis (r(2) = 0.34, p = 0.04) at Time-2. Conclusion: In this longitudinal study, left atrial multidimensional blood flow was altered and blood stasis was elevated during left atrial stunning compared to the restored left atrial mechanical function. The coagulability of blood was also elevated during atrial stunning. The association between blood stasis and hypercoagulability proposes that assessment of left atrial 4D flow can add to the pathophysiological understanding of thrombus formation during atrial fibrillation related atrial stunning.

  • 107.
    Claesson, Kjersti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Counting the platelets: a robust and sensitive quantification method for thrombus formation2016In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 115, no 6, p. 1178-1190Article in journal (Refereed)
    Abstract [en]

    Flow chambers are common tools used for studying thrombus formation in vitro. However, the use of such devices is not standardised and there is a large diversity among the flow chamber systems currently used, and also in the methods used for quantifying the thrombus development. It was the study objective to evaluate a new method for analysis and quantification of platelet thrombus formation that can facilitate comparison of results between research groups. Whole blood was drawn over a collagen patch in commercial Ibid or in-house constructed PDMS flow chambers. Five percent of the platelets were fluorescently labelled and z-stack time-lapse images were captured during thrombus formation. Images were processed in a Python script in which the number of platelets and their respective x-, y- and z-positions were obtained. For comparison with existing methods the platelets were also labelled and quantified using fluorescence intensity and thrombus volume estimations by confocal microscopy. The presented method was found less sensitive to microscope and image adjustments and provides more details on thrombus development dynamics than the methods for measuring fluorescence intensity and thrombus volume estimation. The platelet count method produced comparable results with commercial and PDMS flow chambers, and could also obtain information regarding the stability of each detected platelet in the thrombus. In conclusion, quantification of thrombus formation by platelet count is a sensitive and robust method that enables measurement of platelet accumulation and platelet stability in an absolute scale that could be used for comparisons between research groups.

  • 108.
    Clarke, Emily L.
    et al.
    Univ Leeds, England; Leeds Teaching Hosp NHS Trust, England.
    Revie, Craig
    FFEI Ltd, England.
    Brettle, David
    Leeds Teaching Hosp NHS Trust, England.
    Shires, Michael
    Univ Leeds, England.
    Jackson, Peter
    Leeds Teaching Hosp NHS Trust, England.
    Cochrane, Ravinder
    FFEI Ltd, England.
    Wilson, Robert
    FFEI Ltd, England.
    Mello-Thoms, Claudia
    Univ Sydney, Australia.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Clinical pathology. Univ Leeds, England; Leeds Teaching Hosp NHS Trust, England.
    Development of a novel tissue-mimicking color calibration slide for digital microscopy2018In: Color Research and Application, ISSN 0361-2317, E-ISSN 1520-6378, Vol. 43, no 2, p. 184-197Article in journal (Refereed)
    Abstract [en]

    Digital microscopy produces high resolution digital images of pathology slides. Because no acceptable and effective control of color reproduction exists in this domain, there is significant variability in color reproduction of whole slide images. Guidance from international bodies and regulators highlights the need for color standardization. To address this issue, we systematically measured and analyzed the spectra of histopathological stains. This information was used to design a unique color calibration slide utilizing real stains and a tissue-like substrate, which can be stained to produce the same spectral response as tissue. By closely mimicking the colors in stained tissue, our target can provide more accurate color representation than film-based targets, whilst avoiding the known limitations of using actual tissue. The application of the color calibration slide in the clinical setting was assessed by conducting a pilot user-evaluation experiment with promising results. With the imminent integration of digital pathology into the routine work of the diagnostic pathologist, it is hoped that this color calibration slide will help provide a universal color standard for digital microscopy thereby ensuring better and safer healthcare delivery.

  • 109.
    Coenen, Adriaan
    et al.
    Erasmus Univ, Netherlands.
    Kim, Young-Hak
    Univ Ulsan, South Korea.
    Kruk, Mariusz
    Inst Cardiol, Poland.
    Tesche, Christian
    Med Univ South Carolina, SC 29425 USA.
    De Geer, Jakob
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Kurata, Akira
    Ehime Univ, Japan.
    Lubbers, Marisa L.
    Erasmus Univ, Netherlands.
    Daemen, Joost
    Erasmus Univ, Netherlands.
    Itu, Lucian
    Siemens SRL, Romania.
    Rapaka, Saikiran
    Siemens Healthcare, NJ USA.
    Sharma, Puneet
    Siemens Healthcare, NJ USA.
    Schwemmer, Chris
    Siemens Healthcare GmbH, Germany.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Schoepf, U. Joseph
    Med Univ South Carolina, SC 29425 USA.
    Kepka, Cezary
    Inst Cardiol, Poland.
    Yang, Dong Hyun
    Univ Ulsan, South Korea.
    Nieman, Koen
    Erasmus Univ, Netherlands; Stanford Univ, CA 94305 USA.
    Diagnostic Accuracy of a Machine-Learning Approach to Coronary Computed Tomographic Angiography-Based Fractional Flow Reserve Result From the MACHINE Consortium2018In: Circulation Cardiovascular Imaging, ISSN 1941-9651, E-ISSN 1942-0080, Vol. 11, no 6, article id e007217Article in journal (Refereed)
    Abstract [en]

    Background: Coronary computed tomographic angiography (CTA) is a reliable modality to detect coronary artery disease. However, CTA generally overestimates stenosis severity compared with invasive angiography, and angiographic stenosis does not necessarily imply hemodynamic relevance when fractional flow reserve (FFR) is used as reference. CTA-based FFR (CT-FFR), using computational fluid dynamics (CFD), improves the correlation with invasive FFR results but is computationally demanding. More recently, a new machine-learning (ML) CT-FFR algorithm has been developed based on a deep learning model, which can be performed on a regular workstation. In this large multicenter cohort, the diagnostic performance ML-based CT-FFR was compared with CTA and CFD-based CT-FFR for detection of functionally obstructive coronary artery disease. Methods and Results: At 5 centers in Europe, Asia, and the United States, 351 patients, including 525 vessels with invasive FFR comparison, were included. ML-based and CFD-based CT-FFR were performed on the CTA data, and diagnostic performance was evaluated using invasive FFR as reference. Correlation between ML-based and CFD-based CT-FFR was excellent (R=0.997). ML-based (area under curve, 0.84) and CFD-based CT-FFR (0.84) outperformed visual CTA (0.69; Pamp;lt;0.0001). On a per-vessel basis, diagnostic accuracy improved from 58% (95% confidence interval, 54%-63%) by CTA to 78% (75%-82%) by ML-based CT-FFR. The per-patient accuracy improved from 71% (66%-76%) by CTA to 85% (81%-89%) by adding ML-based CT-FFR as 62 of 85 (73%) false-positive CTA results could be correctly reclassified by adding ML-based CT-FFR. Conclusions: On-site CT-FFR based on ML improves the performance of CTA by correctly reclassifying hemodynamically nonsignificant stenosis and performs equally well as CFD-based CT-FFR.

  • 110.
    Coleman, Jamie J.
    et al.
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; City Hosp, England.
    Samer, Caroline
    Geneva Univ Hosp HUG, Switzerland.
    Zeitlinger, Markus
    Med Univ Vienna, Austria.
    van Agtmael, Michiel
    Univ Amsterdam, Netherlands.
    Rongen, Gerard A.
    Radboudumc, Netherlands.
    Marquet, Pierre
    Univ Limoges, France.
    Simon, Tabassome
    Pierre and Marie Curie Univ, France.
    Singer, Donald
    11 Chandos St, England.
    Manolopoulos, Vangelis G.
    Democritus Univ Thrace, Greece.
    Böttiger, Ylva
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    The European Association for Clinical Pharmacology and Therapeutics25years young and going strong2019In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 75, no 6, p. 743-750Article in journal (Refereed)
    Abstract [en]

    Clinical pharmacology as a scientific discipline and medical specialty was unarguably born in the twentieth century. Whilst pharmacologythe science behind the treatment of diseasehad been in evolution since at least medieval times, the clinical discipline of pharmacology has had a more recent genesis and rather insidious evolution. During the 1900s, there were some clear father (parent) figures of clinical pharmacology in Europe that emerged and were responsible for the development of the specialty in this continent. This was a time when there were parallel developments in geographically dispersed academic departments (around the globe), during an age of excitement in drug discovery and clinical application of new therapeutic agents. It was the meeting of minds of some of these progenitors of the specialty that led to the development of the European Association for Clinical Pharmacology and Therapeutics (EACPT) 25years ago arising from a working party supported by the World Health Organization in Europe. The EACPT now includes all major national organizations for clinical pharmacology in Europe, representing over 4000 individual professionals interested in clinical pharmacology and therapeutics. The EACPT has a major interest in promoting the safe use of medicines across Europe and internationally and has supported these aims since 1995, through biennial international scientific congresses and summer schools with delegates and presenters from around the world as well as various working group activities. In this article, the current executive committee members of EACPT recall this history, describe the evolution of the association over the last quarter of a century, and provide an update on the activities and ambitions of the association today.

  • 111.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Sweden.
    Sundberg, Erik
    Umeå University, Sweden.
    Ahlm, Clas
    Umeå University, Sweden.
    Hultdin, Johan
    Umeå University, Sweden.
    Baudin, Maria
    Umeå University, Sweden.
    Larsson, Johanna
    Umeå University, Sweden.
    Dunne, Eimear
    Royal Coll Surgeons Ireland, Ireland.
    Kenny, Dermot
    Royal Coll Surgeons Ireland, Ireland.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Sofie
    Umeå University, Sweden.
    Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

  • 112.
    Cordeddu, Viviana
    et al.
    Ist Super Sanita, Italy; University of G dAnnunzio, Italy.
    Yin, Jiani C.
    University of Toronto, Canada; University of Toronto, Canada.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Medicine and Health Sciences.
    Virtanen, Carl
    University of Toronto, Canada; University of Toronto, Canada.
    Drunat, Severine
    Hop Robert Debre, France.
    Lepri, Francesca
    Bambino Gesu Pediat Hospital, Italy.
    De Luca, Alessandro
    Casa Sollievo Sofferenza Hospital, Italy.
    Rossi, Cesare
    St Orsola Marcello Malpighi Hospital, Italy.
    Ciolfi, Andrea
    Ist Super Sanita, Italy.
    Pugh, Trevor J.
    University of Toronto, Canada; University of Toronto, Canada.
    Bruselles, Alessandro
    Ist Super Sanita, Italy.
    Priest, James R.
    Stanford University, CA 94305 USA; Stanford University, CA 94305 USA.
    Pennacchio, Len A.
    University of Calif Berkeley, CA 94720 USA; US Department Energy Joint Genome Institute, CA 94598 USA.
    Lu, Zhibin
    University of Toronto, Canada; University of Toronto, Canada.
    Danesh, Arnavaz
    University of Toronto, Canada; University of Toronto, Canada.
    Quevedo, Rene
    University of Toronto, Canada; University of Toronto, Canada.
    Hamid, Alaa
    University of Toronto, Canada; University of Toronto, Canada.
    Martinelli, Simone
    Ist Super Sanita, Italy.
    Pantaleoni, Francesca
    Ist Super Sanita, Italy.
    Gnazzo, Maria
    Bambino Gesu Pediat Hospital, Italy.
    Daniele, Paola
    Casa Sollievo Sofferenza Hospital, Italy.
    Lissewski, Christina
    Otto von Guericke University, Germany.
    Bocchinfuso, Gianfranco
    University of Roma Tor Vergata, Italy.
    Stella, Lorenzo
    University of Roma Tor Vergata, Italy.
    Odent, Sylvie
    Hop SUD, France.
    Philip, Nicole
    Hop Enfants la Timone, France.
    Faivre, Laurence
    Hop Enfants, France.
    Vlckova, Marketa
    Charles University of Prague, Czech Republic; University Hospital Motol, Czech Republic.
    Seemanova, Eva
    Charles University of Prague, Czech Republic; University Hospital Motol, Czech Republic.
    Digilio, Cristina
    Bambino Gesu Pediat Hospital, Italy.
    Zenker, Martin
    Otto von Guericke University, Germany.
    Zampino, Giuseppe
    University of Cattolica Sacro Cuore, Italy.
    Verloes, Alain
    Hop Robert Debre, France.
    Dallapiccola, Bruno
    Bambino Gesu Pediat Hospital, Italy.
    Roberts, Amy E.
    Boston Childrens Hospital, MA 02115 USA; Boston Childrens Hospital, MA 02115 USA.
    Cave, Helene
    Hop Robert Debre, France; University of Paris Diderot, France.
    Gelb, Bruce D.
    Icahn School Medical Mt Sinai, NY 10029 USA; Icahn School Medical Mt Sinai, NY 10029 USA; Icahn School Medical Mt Sinai, NY 10029 USA.
    Neel, Benjamin G.
    University of Toronto, Canada; University of Toronto, Canada; NYU, NY 10016 USA.
    Tartaglia, Marco
    Ist Super Sanita, Italy; Bambino Gesu Pediat Hospital, Italy.
    Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 11, p. 1080-1087Article in journal (Refereed)
    Abstract [en]

    The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

  • 113.
    Couch, Fergus J.
    et al.
    Mayo Clin, MN 55905 USA; Mayo Clin, MN 55905 USA.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Mendoza-Fandino, Gustavo A.
    University of S Florida, FL 33612 USA.
    Nord, Silje
    Radiumhosp, Norway.
    Lilyquist, Janna
    Mayo Clin, MN 55905 USA.
    Olswold, Curtis
    Mayo Clin, MN 55905 USA.
    Hallberg, Emily
    Mayo Clin, MN 55905 USA.
    Agata, Simona
    IRCCS, Italy.
    Ahsan, Habibul
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    Ambrosone, Christine
    Roswell Pk Cancer Institute, NY 14263 USA.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Lars
    Institute Qual and Efficiency Health Care IQWiG, Germany.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Blank, Stephanie V.
    NYU, NY 10016 USA.
    Blomqvist, Carl
    University of Helsinki, Finland; University of Helsinki, Finland.
    Bogdanova, Natalia V.
    Hannover Medical Sch, Germany.
    Bojesen, Stig E.
    Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; National Centre Tumor Disease NCT, Germany.
    Burwinkel, Barbara
    Heidelberg University, Germany.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Caldes, Trinidad
    IdISSC, Spain.
    Caligo, Maria A.
    University of Pisa, Italy; University Hospital Pisa, Italy.
    Canzian, Federico
    German Cancer Research Centre, Germany.
    Carpenter, Jane
    University of Sydney, Australia.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Chanock, Stephen J.
    NCI, MD 20850 USA.
    Chung, Wendy K.
    Columbia University, NY 10032 USA; Columbia University, NY 10032 USA.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cox, Angela
    University of Sheffield, England.
    Cross, Simon S.
    University of Sheffield, England.
    Cunningham, Julie M.
    Mayo Clin, MN 55905 USA.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    de la Hoya, Miguel
    IdISSC, Spain.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall dHebron, Spain; University of Autonoma Barcelona, Spain.
    Ding, Yuan C.
    City Hope National Medical Centre, CA 91010 USA.
    Dolcetti, Riccardo
    CRO Aviano National Cancer Institute, Italy.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    dos-Santos-Silva, Isabel
    University of London London School Hyg and Trop Med, England.
    Dumont, Martine
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Dunning, Alison M.
    University of Cambridge, England.
    Eccles, Diana M.
    University of Southampton, England.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ekici, Arif B.
    University of Erlangen Nurnberg, Germany; Comprehens Cancer Centre EMN, Germany.
    Eliassen, Heather
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Ellis, Steve
    University of Cambridge, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany.
    Figueroa, Jonine
    NCI, MD 20850 USA.
    Flesch-Janys, Dieter
    University of Clin Hamburg Eppendorf, Germany; University of Clin Hamburg Eppendorf, Germany.
    Foersti, Asta
    German Cancer Research Centre, Germany; Lund University, Sweden.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Friebel, Tara
    University of Philadelphia, PA 19104 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gabrielson, Marike
    Karolinska Institute, Sweden.
    Gammon, Marilie D.
    University of N Carolina, NC 27599 USA.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90095 USA; Jonsson Comprehens Cancer Centre, CA 90095 USA.
    Gapstur, Susan M.
    Amer Cancer Soc, GA 30303 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Gaudet, Mia M.
    Amer Cancer Soc, GA 30303 USA.
    Gayther, Simon A.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Gerdes, Anne-Marie
    Copenhagen University Hospital, Denmark.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Godwin, Andrew K.
    University of Kansas, KS 66205 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre CNIO, Spain.
    Greene, Mark H.
    NCI, MD 20850 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Gunter, Marc
    University of London Imperial Coll Science Technology and Med, England.
    Haeberle, Lothar
    University of Erlangen Nurnberg, Germany.
    Haiman, Christopher A.
    University of So Calif, CA 90033 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Hart, Steven
    Mayo Clin, MN 55905 USA.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heikkinen, Tuomas
    Heidelberg University, Germany; University of Helsinki, Finland.
    Henderson, Brian E.
    University of So Calif, CA 90033 USA.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hooning, Maartje J.
    Erasmus University, Netherlands.
    Hoover, Robert N.
    NCI, MD 20850 USA.
    Hopper, John L.
    University of Melbourne, Australia.
    Humphreys, Keith
    Karolinska Institute, Sweden.
    Hunter, David J.
    Harvard University, MA 02115 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Oncology Research Institute, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20007 USA.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    James, Paul
    Peter MacCallum Cancer Centre, Australia; University of Melbourne, Australia.
    Janavicius, Ramunas
    State Research Institute, Lithuania.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Jones, Michael
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kar, Siddhartha
    University of Cambridge, England.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland; University of Helsinki, Finland.
    Khaw, Kay-Tee
    University of Cambridge, England.
    Kibriya, Muhammad G.
    University of Chicago, IL 60637 USA.
    Knight, Julia A.
    Mt Sinai Hospital, Canada.
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Germany.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Kosma, Veli-Matti
    University of Eastern Finland, Finland.
    Kristensen, Vessela
    Radiumhosp, Norway.
    Kwong, Ava
    Hong Kong Hereditary Breast Cancer Family Registry, Peoples R China; University of Hong Kong, Peoples R China.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium.
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain.
    Lee, Eunjung
    University of So Calif, CA 90032 USA.
    Le Marchand, Loic
    University of Cancer Centre, HI 96813 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Lindor, Noralane
    Mayo Clin, AZ 85259 USA.
    Lindstrom, Sara
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Liu, Jianjun
    Genome Institute Singapore, Singapore.
    Long, Jirong
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mai, Phuong L.
    NCI, MD 20850 USA.
    Makalic, Enes
    University of Melbourne, Australia.
    Malone, Kathleen E.
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98195 USA.
    Mannermaa, Arto
    University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Margolin, Sara
    Karolinska University Hospital, Sweden.
    Marme, Frederik
    Heidelberg University, Germany.
    Martens, John W. M.
    Erasmus MC Cancer Institute, Netherlands.
    McGuffog, Lesley
    University of Cambridge, England.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Miller, Austin
    Roswell Pk Cancer Institute, NY 14263 USA.
    Milne, Roger L.
    Cancer Council Victoria, Australia.
    Miron, Penelope
    Case Western Reserve University, OH 44106 USA.
    Montagna, Marco
    IRCCS, Italy.
    Mazoyer, Sylvie
    University of Lyon, France.
    Mulligan, Anna M.
    University of Health Network, Canada; University of Toronto, Canada.
    Muranen, Taru A.
    Heidelberg University, Germany; University of Helsinki, Finland.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nordestgaard, Borge G.
    Copenhagen University Hospital, Denmark.
    Nussbaum, Robert L.
    Invitae Corp, CA 94107 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Mayo Clin, MN 55905 USA.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain.
    Park, Sue K.
    Seoul National University, South Korea; Seoul National University, South Korea.
    Peeters, Petra H.
    University of Medical Centre, Netherlands; University of London Imperial Coll Science Technology and Med, England.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Peterlongo, Paolo
    Fdn Ist FIRC Oncology Mol, Italy.
    Peto, Julian
    University of London London School Hyg and Trop Med, England.
    Phelan, Catherine M.
    University of S Florida, FL 33612 USA.
    Pilarski, Robert
    Ohio State University, OH 43210 USA.
    Poppe, Bruce
    University of Ghent, Belgium.
    Pylkaes, Katri
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Rahman, Nazneen
    Institute Cancer Research, England.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Rappaport, Christine
    Medical University of Vienna, Austria.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel; B Rappaport Fac Med, Israel.
    Richardson, Andrea
    Johns Hopkins University, MD 21205 USA.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Romieu, Isabelle
    Int Agency Research Canc, France.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Rutgers, Emiel J.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Sanchez, Maria-Jose
    University of Granada, Spain; CIBER Epidemiol and Salud Public CIBERESP, Spain.
    Santella, Regina M.
    Columbia University, NY 10032 USA.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schmidt, Daniel F.
    University of Melbourne, Australia.
    Schmidt, Marjanka K.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Schumacher, Fredrick
    University of So Calif, CA 90033 USA.
    Scott, Rodney
    John Hunter Hospital, Australia.
    Senter, Leigha
    Ohio State University, OH 43210 USA.
    Sharma, Priyanka
    University of Kansas, KS 66205 USA.
    Simard, Jacques
    University of Laval, Canada.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    University of Lyon, France; Hospital Civils Lyon, France.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa
    University of Melbourne, Australia.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France.
    Swerdlow, Anthony
    Institute Cancer Research, England.
    Szabo, Csilla I.
    NHGRI, MD 20892 USA.
    Tamimi, Rulla
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Tapper, William
    University of Southampton, England.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo-Hwang
    Cancer Research Initiat Fdn, Malaysia; University of Malaya, Malaysia.
    Terry, Mary B.
    Columbia University, NY 10032 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Thompson, Deborah
    University of Cambridge, England.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Toland, Amanda E.
    Ohio State University, OH 43210 USA.
    Tollenaar, Robert A. E. M.
    Leiden University, Netherlands.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Truong, Therese
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Tsimiklis, Helen
    University of Melbourne, Australia.
    Teule, Alex
    IDIBELL Catalan Institute Oncol, Spain.
    Tumino, Rosario
    Civ MP Arezzo Hospital, Italy; Civ MP Arezzo Hospital, Italy.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Turnbull, Clare
    Institute Cancer Research, England.
    Ursin, Giski
    Institute Populat Based Cancer Research, Norway.
    van Deurzen, Carolien H. M.
    Erasmus University, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Wang, Zhaoming
    NCI, MD 20877 USA.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weiderpass, Elisabete
    Karolinska Institute, Sweden; Institute Populat Based Cancer Research, Norway; University of Tromso, Norway; Folkhalsan Research Centre, Finland.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Whittemore, Alice
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital, Belgium.
    Winqvist, Robert
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Yang, Xiaohong R.
    NCI, MD 20892 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yao, Song
    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
    Pilar Zamora, M.
    Hospital University of La Paz, Spain.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Kraft, Peter
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55905 USA.
    Slager, Susan
    Mayo Clin, MN 55905 USA.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Pharoah, Paul D. P.
    University of Cambridge, England.
    Monteiro, Alvaro A. N.
    University of S Florida, FL 33612 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20850 USA.
    Easton, Douglas F.
    University of Cambridge, England.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, no 11375, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  • 114.
    Crisci, Elisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Rondahl, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Bergström, Tomas
    University of Gothenburg, Gothenburg, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Eriksson, Kristina
    University of Gothenburg, Gothenburg, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Complement opsonization promotes HSV-2 infection of human dendritic cells2016In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed)
    Abstract [en]

    Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

    IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

  • 115.
    Daferera, Niki
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kumar Kumawat, Ashok
    University of Örebro, Sweden.
    Hultgren-Hornquist, Elisabeth
    University of Örebro, Sweden.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Faculty of Medicine and Health Sciences.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Fecal stream diversion and mucosal cytokine levels in collagenous colitis: A case report2015In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, no 19, p. 6065-6071Article in journal (Refereed)
    Abstract [en]

    In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a 46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs: loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin (IL)-1 beta, IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-gamma, IL-4, IL-5, IL-10 and IL-13 were all higher during active disease and decreased to non-detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction, the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in collagenous colitis.

  • 116.
    Daghighi, Abtin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tropp, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Klarbring, Anders
    Linköping University, Department of Management and Engineering, Solid Mechanics. Linköping University, Faculty of Science & Engineering.
    Correction: F.E.M. Stress-Investigation of Scolios Apex2018In: Open Biomedical Engineering Journal, ISSN 1874-1207, E-ISSN 1874-1207, Vol. 12, p. 51-71Article in journal (Refereed)
  • 117.
    Daghighi, Abtin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tropp, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Spinal Surgery.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Klarbring, Anders
    Linköping University, Department of Management and Engineering, Solid Mechanics. Linköping University, Faculty of Science & Engineering.
    F.E.M. Stress-Investigation of Scolios Apex2018In: Open Biomedical Engineering Journal, ISSN 1874-1207, E-ISSN 1874-1207, Vol. 12, p. 51-71Article in journal (Refereed)
    Abstract [en]

    In scoliosis, kypholordos and wedge properties of the vertebrae should be involved in determining how stress is distributed in the vertebral column. The impact is logically expected to be maximal at the apex.

  • 118.
    Dahl, Sara
    et al.
    Karolinska Inst, Sweden.
    Kristoffersen Wiberg, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Fahnehjelm, Kristina Tear
    Karolinska Inst, Sweden; St Erik Eye Hosp, Sweden; Univ Gothenburg, Sweden.
    Savendahl, Lars
    Karolinska Inst, Sweden.
    Wickstrom, Ronny
    Karolinska Inst, Sweden.
    High prevalence of pituitary hormone deficiency in both unilateral and bilateral optic nerve hypoplasia2019In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, no 9, p. 1677-1685Article in journal (Refereed)
    Abstract [en]

    Aim This study examined the prevalence of neurological impairment and pituitary hormone deficiency (PHD) in patients with unilateral and bilateral optic nerve hypoplasia (ONH). Methods A population-based cross-sectional cohort study of 65 patients (51% female) with ONH was conducted in Stockholm. Of these were 35 bilateral and 30 unilateral. The patients were below 20 years of age, living in Stockholm in December 2009 and found through database searching. The median age at the analysis of the results in January 2018 was 16.1 years (range 8.1-27.5 years). Neurological assessments and blood sampling were conducted, neuroradiology was reviewed and growth curves were analysed. Diagnoses of PHDs were based on clinical and biochemical evidence of hormone deficiency. Results Neurological impairments were identified in 47% of the patients and impairments in gross and fine motor function were more prevalent in bilateral ONH (p amp;lt; 0.001). In addition, 9% had cerebral palsy and 14% had epilepsy. The prevalence of PHD was 29 and 19% had multiple PHD. Conclusion Children with ONH had a high risk of neurological impairment, especially in bilateral disease. Both unilateral and bilateral ONH signified an increased prevalence of PHD and all these children should be endocrinologically followed up until completed puberty.

  • 119.
    Dahlrot, R. H.
    et al.
    Odense Univ Hosp, Denmark.
    Dowsett, J.
    Odense Univ Hosp, Denmark.
    Fosmark, S.
    Odense Univ Hosp, Denmark.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Henriksson, R.
    Umea Univ, Sweden; Reg Canc Ctr Stockholm Gotland, Sweden.
    Boldt, H.
    Odense Univ Hosp, Denmark.
    de Stricker, K.
    Odense Univ Hosp, Denmark.
    Sorensen, M. D.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Poulsen, H. S.
    Rigshosp, Denmark.
    Lysiak, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Business support and Development, Regional Cancer Center.
    Hansen, S.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Kristensen, B. W.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis2018In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 44, no 2, p. 172-184Article in journal (Refereed)
    Abstract [en]

    Aims: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status. Methods: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population-based Region of Southern Denmark (RSD)cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM-patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules. Results: When divided at the median, patients with low expression of MGMT protein (AF-low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS-cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF-low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF-low had the best outcome; median OS 23.1 and 20.0 months, respectively. Conclusion: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour-specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.

  • 120.
    Danielsson, Olof
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lindvall, Björn
    University Hospital Örebro, Sweden.
    Hallert, Claes
    Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Increased prevalence of celiac disease in idiopathic inflammatory myopathies2017In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 7, no 10, article id e00803Article in journal (Refereed)
    Abstract [en]

    ObjectivesIdiopathic inflammatory myopathies (IIM) are often associated with other immune-mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of ostergotland, Sweden. Material and MethodsWe reviewed medical records and analyzed sera from 106 patients, fulfilling pathological criteria of inflammatory myopathy, for the presence of IgA antibodies against endomysium and gliadin. Antibody-positive patients were offered further investigation with small bowel biopsy or investigation for the presence of antibodies against antitissue transglutaminase (t-TG). The patients were classified according to Bohan and Peter or Griggs criteria. The presence of celiac disease, systemic inflammatory, and malignant diseases was documented. ResultsFour of 88 patients classified as IIM (4.5%) had biopsy-confirmed celiac disease, which is higher than the prevalence in the general population, detected with a similar screening procedure (0.53%). Thirty-three patients (38%) had a systemic inflammatory disease and five (5.7%) a malignancy. The incidence of confirmed IIM in the county of ostergotland was 7.3 per million/year. ConclusionsThe results highlight the high frequency of associated inflammatory and malignant diseases and confirm an increased prevalence of celiac disease in IIM.

  • 121.
    Darras, Kathryn E.
    et al.
    Univ British Columbia, Canada; Maastricht Univ, Netherlands.
    de Bruin, Anique B. H.
    Maastricht Univ, Netherlands.
    Nicolaou, Savvas
    Univ British Columbia, Canada.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    van Merrienboer, Jeroen
    Maastricht Univ, Netherlands.
    Forster, Bruce B.
    Univ British Columbia, Canada.
    Is there a superior simulator for human anatomy education? How virtual dissection can overcome the anatomic and pedagogic limitations of cadaveric dissection2018In: Medical teacher, ISSN 0142-159X, E-ISSN 1466-187X, Vol. 40, no 7, p. 752-753Article in journal (Refereed)
    Abstract [en]

    Educators must select the best tools to teach anatomy to future physicians and traditionally, cadavers have always been considered the "gold standard" simulator for living anatomy. However, new advances in technology and radiology have created new teaching tools, such as virtual dissection, which provide students with new learning opportunities. Virtual dissection is a novel way of studying human anatomy through patient computed tomography (CT) scans. Through touchscreen technology, students can work together in groups to "virtually dissect" the CT scans to better understand complex anatomic relationships. This article presents the anatomic and pedagogic limitations of cadaveric dissection and explains what virtual dissection is and how this new technology may be used to overcome these limitations.

  • 122.
    Davidson, Thomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Lindelof, Ann
    Region Östergötland, Local Health Care Services in East Östergötland.
    Wallen, Torbjorn
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping. Vastervik Hospital, Sweden.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hallert, Claes
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland.
    Point-of-care monitoring of warfarin treatment in community dwelling elderly - A randomised controlled study2015In: Journal of Telemedicine and Telecare, ISSN 1357-633X, E-ISSN 1758-1109, Vol. 21, no 5, p. 298-301Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to assess clinical effectiveness and costs of launching point-of-care monitoring of warfarin treatment in community dwelling frail elderly patients. A prospective multicentre controlled randomised study over 12 months comparing a point-of-care strategy with usual monitoring routines was carried out in primary healthcare centres and anticoagulation clinics in southeast Sweden. The subjects were community dwelling elderly across rural southeast Sweden on chronic warfarin treatment. Main outcome measures were time in therapeutic range (TTR), rate of treatment-related adverse events and costs. The study comprised 103 elderly people (61% women) mean age 86 yrs (range 75-98) treated with warfarin for median 9 yrs (range 1-18). Patients randomised to start point-of-care monitoring (n = 55) showed 75.9% in TTR before trial vs. 72.6% during trial (ns). The patients randomised to continue on usual monitoring routines (n = 48) showed 75.2% in TTR prior to trial vs. 72.9% during trial (ns). The point-of-care monitoring showed potential savings of SEK 624 per patient annually (based partly on effects that were not statistically significant). The study shows that point-of-care monitoring of warfarin treatment in community dwelling elderly in rural areas is as effective as usual monitoring routines and that it may offer savings to society.

  • 123.
    Davidsson, Anette
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Georgiopoulos, Charalampos
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dizdar (Dizdar Segrell), Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Granerus, Göran
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Zachrisson, Helene
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Comparison between visual assessment of dopaminergic degeneration pattern and semi-quantitative ratio calculations in patients with Parkinsons disease and Atypical Parkinsonian syndromes using DaTSCAN (R) SPECT2014In: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 28, no 9, p. 851-859Article in journal (Refereed)
    Abstract [en]

    Objective To verify if I-123-FP-CIT, DaTSCAN (R) can differentiate early stages of Parkinsons disease (PD) as well as patients with Atypical Parkinsonian syndromes (APS) from manifest Parkinsons disease. Methods 128 consecutive patients were investigated with I-123-FP-CIT SPECT during a 4-year period. All patients were diagnosed according to the established consensus criteria for diagnosis of PD (n = 53) and APS (n = 19). Remaining patients were grouped early PD (before onset of L-DOPA medication), (n = 20), vascular PD (n = 6), and non-PD syndromes (n = 30) and SWEDD (n = 1). SPECT images were analyzed visually according to a predefined ranking scale of dopaminergic nerve cell degeneration, distinguishing a posterior-anterior degeneration pattern (egg shape) from a more global and severe degeneration pattern (burst striatum). Striatum uptake ratios were quantitatively analyzed with the 3D software, EXINI. Results In the group of APS patients, the burst striatum pattern was most frequent and found in 61 % (11/18 patients). In PD patients, the egg shape pattern was dominating, especially in early PD where it was present in 95 % (19/20 patients). The positive predictive value for the egg shape pattern to diagnose PD was 92 % in this material (APS and all PD patients) and the specificity 90 % for the burst striatum pattern to exclude APS. The uptake ratios were reduced in both PD and APS patients and closely related to the image ranking. Conclusion In this study, we found that in more than half of the patients it was possible to differentiate between PD and APS by visual interpretation only. Similar results were obtained using semi-quantitative uptake ratios. Combining visual assessment with uptake ratios did not add to the discriminating power of DaTSCAN (R) SPECT in this material.

  • 124.
    Davidsson, Anette
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Georgiopoulos, Charalampos
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dizdar Segrell, Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Granerus, Göran
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Zachrisson, Helene
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Comparison between visual assessment of dopaminergic degeneration pattern and semi-quantitative ratio calculations in patients with Parkinson's disease and Atypical Parkinsonian snydromes using DaTSCAN SPECT2014Conference paper (Other academic)
    Abstract [en]

    Background: Parkinson's disease (PD) is a degenerative disorder characterized by the progressive degeneration of dopamine-containing cells in substantia nigra, and it is the second most common neurodegenerative disorder worldwide. It can be difficult to differentiate between idiopathic PD and Atypical Parkinsonian syndromes (APS). In a high percentage of APS patients, the right diagnosis is not established even during late stages of the disease. Currently there is no specific test to verify PD, especially in the early stages of the disease.

    The aim was to verify if 123I-FP-CIT, DaTSCAN ® can differentiate early stages of Parkinson's disease as well as patients with Atypical Parkinsonian syndromes from manifest Parkinson's disease.

    Materials and methods: 121 consecutive patients were investigated with 123I-FP-CIT SPECT, during a four year period. All patients were diagnosed according to the established consensus criteria for diagnosis of Parkinson's disease (PD), (n=53), Atypical Parkinsonian syndromes (APS) (n=18). Remaining patients were grouped early PD (before onset the of L-dopa medication), (n=20), and non-PD syndromes (n=30). SPECT images were analysed visually according to a predefined ranking scale of dopaminergic degeneration, distinguishing a posterior-anterior degeneration pattern (egg shape) to a more global and severe degeneration pattern (burst striatum). Striatum ratios were quantitatively analysed with the 3D software, EXINI.

    Results: In the group of APS patients the burst striatum pattern was most frequent and found in 61% (11/18 patients). In PD patients the egg shape pattern was dominating, especially in early PD where it was present in 95% (19/20 patients). The sensitivity of burst striatum degeneration pattern was 61% (95%-CI 36-83%), specificity 90% (95%-CI 81-96%). The sensitivity of egg shape pattern was 74% (95%-CI 62-84%), specificity 90% (95%-CI 47-90%). The uptake ratios were reduced in both PD and APS patients and closely related to the image pattern. The lowest putamen/caudate ratio was found in early PD.

    Conclusion: In this study we found that in more than half of the patients it was possible to differentiate between PD and APS by visual interpretation only. Similar results were obtained using semi-quantitative uptake ratios, but combining visual assessment with uptake ratios did not add to the discriminating power of DATSCAN ® SPECT in this material

    References: Kahraman D, Eggers C, Schicha H, Timmermann L, Schmidt M. Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson's disease. J Neurol. 2012;259:251-60

  • 125.
    de Geer, Jakob
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Coenen, Adriaan
    Erasmus MC, Netherlands.
    Kim, Young-Hak
    Univ Ulsan, South Korea.
    Kruk, Mariusz
    Inst Cardiol, Poland; Inst Cardiol, Poland.
    Tesche, Christian
    Med Univ South Carolina, SC 29425 USA.
    Schoepf, U. Joseph
    Med Univ South Carolina, SC 29425 USA.
    Kepka, Cezary
    Inst Cardiol, Poland; Inst Cardiol, Poland.
    Yang, Dong Hyun
    Univ Ulsan, South Korea.
    Nieman, Koen
    Erasmus MC, Netherlands; Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Effect of Tube Voltage on Diagnostic Performance of Fractional Flow Reserve Derived From Coronary CT Angiography With Machine Learning: Results From the MACHINE Registry2019In: American Journal of Roentgenology, ISSN 0361-803X, E-ISSN 1546-3141, Vol. 213, no 2, p. 325-331Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE. Coronary CT angiography (CCTA)-based methods allow noninvasive estimation of fractional flow reserve (cFFR), recently through use of a machine learning (ML) algorithm (cFFR(ML)). However, attenuation values vary according to the tube voltage used, and it has not been shown whether this significantly affects the diagnostic performance of cFFR and cFFR(ML). Therefore, the purpose of this study is to retrospectively evaluate the effect of tube voltage on the diagnostic performance of cFFR(ML). MATERIALS AND METHODS. A total of 525 coronary vessels in 351 patients identified in the MACHINE consortium registry were evaluated in terms of invasively measured FFR and cFFR(ML). CCTA examinations were performed with a tube voltage of 80, 100, or 120 kVp. For each tube voltage value, correlation (assessed by Spearman rank correlation coefficient), agreement (evaluated by intraclass correlation coefficient and Bland-Altman plot analysis), and diagnostic performance (based on ROC AUC value, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the cFFR(ML) in terms of detection of significant stenosis were calculated. RESULTS. For tube voltages of 80, 100, and 120 kVp, the Spearman correlation coefficient for cFFR(ML) in relation to the invasively measured FFR value was rho = 0.684, rho = 0.622, and rho = 0.669, respectively (p amp;lt; 0.001 for all). The corresponding intraclass correlation coefficient was 0.78, 0.76, and 0.77, respectively (p amp;lt; 0.001 for all). Sensitivity was 100.0%, 73.5%, and 85.0%, and specificity was 76.2%, 79.0%, and 72.8% for tube voltages of 80, 100, and 120 kVp, respectively. The ROC AUC value was 0.90, 0.82, and 0.80 for 80, 100, and 120 kVp, respectively (p amp;lt; 0.001 for all). CONCLUSION. CCTA-derived cFFR(ML) is a robust method, and its performance does not vary significantly between examinations performed using tube voltages of 100 kVp and 120 kVp. However, because of rapid advancements in CT and postprocessing technology, further research is needed.

  • 126.
    De Geer, Jakob
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Sandstedt, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Björkholm, Anders
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Alfredsson, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Janzon, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Software-based on-site estimation of fractional flow reserve using standard coronary CT angiography data.2016In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 57, no 10, p. 1186-1192Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The significance of a coronary stenosis can be determined by measuring the fractional flow reserve (FFR) during invasive coronary angiography. Recently, methods have been developed which claim to be able to estimate FFR using image data from standard coronary computed tomography angiography (CCTA) exams.

    PURPOSE: To evaluate the accuracy of non-invasively computed fractional flow reserve (cFFR) from CCTA.

    MATERIAL AND METHODS: A total of 23 vessels in 21 patients who had undergone both CCTA and invasive angiography with FFR measurement were evaluated using a cFFR software prototype. The cFFR results were compared to the invasively obtained FFR values. Correlation was calculated using Spearman's rank correlation, and agreement using intraclass correlation coefficient (ICC). Sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for significant stenosis (defined as both FFR ≤0.80 and FFR ≤0.75) were calculated.

    RESULTS: The mean cFFR value for the whole group was 0.81 and the corresponding mean invFFR value was 0.84. The cFFR sensitivity for significant stenosis (FFR ≤0.80/0.75) on a per-lesion basis was 0.83/0.80, specificity was 0.76/0.89, and accuracy 0.78/0.87. The positive predictive value was 0.56/0.67 and the negative predictive value was 0.93/0.94. The Spearman rank correlation coefficient was ρ = 0.77 (P < 0.001) and ICC = 0.73 (P < 0.001).

    CONCLUSION: This particular CCTA-based cFFR software prototype allows for a rapid, non-invasive on-site evaluation of cFFR. The results are encouraging and cFFR may in the future be of help in the triage to invasive coronary angiography.

  • 127.
    Dellgren, Linus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases. inkoping, Sweden.
    Claesson, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Högdahl, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Forsberg, Jon
    Not Found:Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; Linkoping Univ, Dept Urol, Linkoping, Sweden.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Phenotypic screening for quinolone resistance in Escherichia coli2019In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 38, no 9, p. 1765-1771Article in journal (Refereed)
    Abstract [en]

    Recent studies show that rectal colonization with low-level ciprofloxacin-resistant Escherichia coli (ciprofloxacin minimal inhibitory concentration (MIC) above the epidemiological cutoff point, but below the clinical breakpoint for resistance), i.e., in the range amp;gt; 0.06-0.5 mg/L is an independent risk factor for febrile urinary tract infection after transrectal ultrasound-guided biopsy (TRUS-B) of the prostate, adding to the other risk posed by established ciprofloxacin resistance in E. coli (MIC amp;gt; 0.5 mg/L) as currently defined. We aimed to identify the quinolone that by disk diffusion best discriminates phenotypic wild-type isolates (ciprofloxacin MIC amp;lt;= 0.06 mg/L) of E. coli from isolates with acquired resistance, and to determine the resistance genotype of each isolate. The susceptibility of 108 E. coli isolates was evaluated by ciprofloxacin, levofloxacin, moxifloxacin, nalidixic acid, and pefloxacin disk diffusion and correlated to ciprofloxacin MIC (broth microdilution) using EUCAST methodology. Genotypic resistance was identified by PCR and DNA sequencing. The specificity was 100% for all quinolone disks. Sensitivity varied substantially, as follows: ciprofloxacin 59%, levofloxacin 46%, moxifloxacin 59%, nalidixic acid 97%, and pefloxacin 97%. We suggest that in situations where low-level quinolone resistance might be of importance, such as when screening for quinolone resistance in fecal samples pre-TRUS-B, a pefloxacin (S amp;gt;= 24 mm) or nalidixic acid (S amp;gt;= 19 mm) disk, or a combination of the two, should be used. In a setting where plasmid-mediated resistance is prevalent, pefloxacin might perform better than nalidixic acid.

  • 128.
    Dessauvagie, Benjamin F.
    et al.
    Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England; Fiona Stanley Hosp, Australia; Univ Western Australia, Australia; Univ Western Australia, Australia.
    Lee, Andrew H. S.
    Nottingham Univ Hosp NHS Trust, England.
    Meehan, Katie
    Univ Western Australia, Australia; Univ Western Australia, Australia.
    Nijhawan, Anju
    Leeds Teaching Hosp NHS Trust, England.
    Tan, Puay Hoon
    Singapore Gen Hosp, Singapore.
    Thomas, Jeremy
    Western Gen Hosp, Scotland.
    Tie, Bibiana
    Fiona Stanley Hosp, Australia.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    Umar, Seemeen
    Leeds Teaching Hosp NHS Trust, England.
    Hanby, Andrew M.
    Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    Millican-Slater, Rebecca
    Leeds Teaching Hosp NHS Trust, England.
    Interobserver variation in the diagnosis of fibroepithelial lesions of the breast: a multicentre audit by digital pathology2018In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 71, no 8, p. 672-679Article in journal (Refereed)
    Abstract [en]

    Aim Fibroepithelial lesions (FELs) of the breast span a morphological continuum including lesions where distinction between cellular fibroadenoma (FA) and benign phyllodes tumour (PT) is difficult. The distinction is clinically important with FAs managed conservatively while equivocal lesions and PTs are managed with surgery. We sought to audit core biopsy diagnoses of equivocal FELs by digital pathology and to investigate whether digital point counting is useful in clarifying FEL diagnoses. Method Scanned slide images from cores and subsequent excisions of 69 equivocal FELs were examined in a multicentre audit by eight pathologists to determine the agreement and accuracy of core needle biopsy (CNB) diagnoses and by digital point counting of stromal cellularity and expansion to determine if classification could be improved. Results Interobserver variation was high on CNB with a unanimous diagnosis from all pathologists in only eight cases of FA, diagnoses of both FA and PT on the same CNB in 15 and a weak mean kappa agreement between pathologists (k=0.36). Moderate agreement was observed on CNBs among breast specialists (k=0.44) and on excision samples (k=0.49). Up to 23% of lesions confidently diagnosed as FA on CNB were PT on excision and up to 30% of lesions confidently diagnosed as PT on CNB were FA on excision. Digital point counting did not aid in the classification of FELs. Conclusion Accurate and reproducible diagnosis of equivocal FELs is difficult, particularly on CNB, resulting in poor interobserver agreement and suboptimal accuracy. Given the diagnostic difficulty, and surgical implications, equivocal FELs should be reported in consultation with experienced breast pathologists as a small number of benign FAs can be selected out from equivocal lesions.

  • 129.
    Devito, Claudia
    et al.
    Swedish Inst Infect Dis Control, Sweden; HD Dept Clin Virol, Sweden.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ohlin, Mats
    Lund Univ, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Broliden, Kristina
    Karolinska Inst, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed)
    Abstract [en]

    The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

  • 130.
    Dock, Hua
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats2015In: TRANSLATIONAL STROKE RESEARCH, ISSN 1868-4483, Vol. 6, no 4, p. 296-300Article in journal (Refereed)
    Abstract [en]

    5-Aza-deoxycytidine (5-aza-dC) confers neuroprotection in ischemic mice by inhibiting DNA methylation. Zebularine is another DNA methylation inhibitor, less toxic and more stable in aqueous solutions and, therefore more biologically suitable. We investigated Zebularines effects on brain ischemia in a rat middle cerebral artery occlusion (MCAo) model in order to elucidate its therapeutic potential. Male Wistar wild-type (WT) rats were randomly allocated to three treatment groups, vehicle, Zebularine 100 mu g, and Zebularine 500 mu g. Saline (10 mu L) or Zebularine (10 mu L) was administered intracerebroventricularly 20 min before 45-min occlusion of the middle cerebral artery. Reperfusion was allowed after 45-min occlusion, and the rats were sacrificed at 24-h reperfusion. The brains were removed, sliced, and stained with 2 % 2,3,5-triphenyltetrazolium chloride (TTC) before measuring infarct size. Zebularine (500 mu g) reduced infarct volumes significantly (p less than 0.05) by 61 % from 20.7 +/- 4.2 % in the vehicle treated to 8.1 +/- 1.6 % in the Zebularine treated. Zebularine (100 mu g) also reduced infarct volumes dramatically by 55 to 9.4 +/- 1.2 %. The mechanisms behind this neuroprotection is not yet known, but the results agree with previous studies and support the notion that Zebularine-induced inhibition of DNA methyltransferase ameliorates ischemic brain injury in rats.

  • 131.
    Domert, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sackmann, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Severinsson, Emelie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Gothenburg, Sweden.
    Bergstrom, Joakim
    Uppsala University, Sweden.
    Ingelsson, Martin
    Uppsala University, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes2016In: PLOS ONE, ISSN 1932-6203, Vol. 11, no 12, article id e0168700Article in journal (Refereed)
    Abstract [en]

    Parkinsons disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

  • 132.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Genetics of primary hyperaldosteronism2016In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 23, no 10, p. R437-R454Article, review/survey (Refereed)
    Abstract [en]

    Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

  • 133.
    Edvardsson, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång, Primary Health Care in Finspång.
    Sund-Levander, Märtha
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Grodzinsky, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Rättsmedicinalverket, Linköping, Sweden.
    Clinical use of conventional reference intervals in the frail elderly2015In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 21, no 2, p. 229-235Article in journal (Refereed)
    Abstract [en]

    Rationale, aims and objectives

    Reference intervals provided by the laboratory are commonly established by measuring samples from apparently healthy subjects in the ages 18–65 years, excluding elderly individuals with chronic diseases and medication. The aim of our study was to establish whether current reference intervals for immune parameters and chemical biomarkers are valid for older individuals including those with chronic diseases, so-called frail elderly.

    Methods

    Data from our cohort of 138 non-infected nursing home residents (NHR), mean age 86.8 years, range 80–98, were compared with raw data, as basis for the development of reference intervals, obtained from reference populations, like blood donors (IgA, IgG, IgM, C3 and C4) and from the Nordic Reference Interval Project (NORIP) (alanine aminotransferase, albumin, aspartate aminotransferase, creatinine, gamma-glutamyl transferase, lactate dehydrogenase, phosphate, sodium and urea). Immune parameters were measured by nephelometry and in NORIP the measurements were performed by means of different routine methods, in more than 100 laboratories.

    Results

    Only nine individuals (7%) of NHR were found to be free from chronic disease. C3, C4 (P < 0.001) and IgG levels (P < 0.05) were higher, while IgM levels (P < 0.001) were lower in NHR compared with reference blood donors. Levels of alanine aminotransferase, phosphate (P < 0.001), albumin (P < 0.05) and sodium (P < 0.01) were lower while creatinine and urea levels were higher (P < 0.001) in NHR compared with NORIP subjects.

    Conclusion

    Comparing laboratory results from elderly people with conventional reference intervals can be misleading or even dangerous, as normal conditions may appear pathological, or vice versa and thus lead to unnecessary or even harmful treatment.

  • 134.
    Edvardsson, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång.
    Sund-Levander, Märtha
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Milberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Advanced Home Care in Norrköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Elevated levels of CRP and IL-8 are related to reduce survival time: 1-year follow-up measurements of different analytes in frail elderly nursing home residents2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 5, p. 288-292Article in journal (Refereed)
    Abstract [en]

    There are only few studies with specific focus on predictors of survival in nursing home residents (NHRs). The aim was to study whether 1-year changes in complete blood count (including hemoglobin, red blood cells, erythrocyte volume fraction, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cells count and platelet count), C-reactive protein and interleukin-1 beta (IL-1 beta), IL-1Ra, IL-6, IL-8 and IL-10, are associated with 8-year survival in elderly NHRs, aged amp;gt;= 80 years. Complete blood count, C-reactive protein and interleukins were measured at baseline, after 6 and 12 months from 167 NHRs aged 80-101 years, mean age 88 +/- 4.5 years, 75% of whom were women. Dates of death were collected from the National Death Register 8 years after baseline. Levels of hemoglobin, red blood cells and mean corpuscular hemoglobin concentration were lower after 1-year, but higher for mean corpuscular volume and IL-1 beta, compared to baseline or 6 month follow-up. In the Cox regression model with a time-dependent covariate, raised levels of C-reactive protein and IL-8 were associated with reduced survival time. Elevated levels of C-reactive protein and IL-8 during 1-year follow-up were related to reduce lengths of survival in elderly NHRs.

  • 135.
    Ehlersson, Gustaf
    et al.
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Hellmark, Bengt
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Svartström, Olov
    Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Stenmark, Bianca
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Soderquist, Bo
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Phenotypic characterisation of coagulase-negative staphylococci isolated from blood cultures in newborn infants, with a special focus on Staphylococcus capitis2017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 10, p. 1576-1582Article in journal (Refereed)
    Abstract [en]

    Aim: This Swedish study determined which species of coagulase-negative staphylococci (CoNS) were found in neonatal blood cultures and whether they included Staphylococcus capitis clones with decreased susceptibility to vancomycin. Methods: CoNS isolates (n = 332) from neonatal blood cultures collected at orebro University Hospital during 1987-2014 were identified to species level with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). The antibiotic susceptibility pattern of S. capitis isolates was determined by the disc diffusion test and Etest, and the presence of heterogeneous glycopeptide-intermediate S. capitis (hGISC) was evaluated. Results: Staphylococcus epidermidis (67.4%), Staphylococcus haemolyticus (10.5%) and S. capitis (9.6%) were the most common CoNS species. Of the S. capitis isolates, 75% were methicillin-resistant and 44% were multidrug-resistant. No isolate showed decreased susceptibility to vancomycin, but at least 59% displayed the hGISC phenotype. Staphylococcus capitis isolates related to the strain CR01 displaying pulsotype NRCS-A were found. Conclusion: Staphylococcus epidermidis, S. haemolyticus and S. capitis were the predominant species detected in neonatal blood cultures by MALDI-TOF MS. The number of episodes caused by S. capitis increased during the study period, but no isolates with decreased susceptibility to vancomycin were identified. However, S. capitis isolates related to the strain CR01 displaying pulsotype NRCS-A were found.

  • 136.
    Ehsan Saffari, Seyed
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Sabzevar University of Medical Science, Iran.
    Love, Askell
    Lund University, Sweden; Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Smedby, Örjan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    Regression models for analyzing radiological visual grading studies - an empirical comparison2015In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 15, no 49Article in journal (Refereed)
    Abstract [en]

    Background: For optimizing and evaluating image quality in medical imaging, one can use visual grading experiments, where observers rate some aspect of image quality on an ordinal scale. To analyze the grading data, several regression methods are available, and this study aimed at empirically comparing such techniques, in particular when including random effects in the models, which is appropriate for observers and patients. Methods: Data were taken from a previous study where 6 observers graded or ranked in 40 patients the image quality of four imaging protocols, differing in radiation dose and image reconstruction method. The models tested included linear regression, the proportional odds model for ordinal logistic regression, the partial proportional odds model, the stereotype logistic regression model and rank-order logistic regression (for ranking data). In the first two models, random effects as well as fixed effects could be included; in the remaining three, only fixed effects. Results: In general, the goodness of fit (AIC and McFaddens Pseudo R-2) showed small differences between the models with fixed effects only. For the mixed-effects models, higher AIC and lower Pseudo R-2 was obtained, which may be related to the different number of parameters in these models. The estimated potential for dose reduction by new image reconstruction methods varied only slightly between models. Conclusions: The authors suggest that the most suitable approach may be to use ordinal logistic regression, which can handle ordinal data and random effects appropriately.

  • 137.
    Ekholm, Maria
    et al.
    Lund University, Sweden; Ryhov County Hospital, Sweden.
    Grabau, Dorthe
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Bendahl, Par-Ola
    Lund University, Sweden.
    Bergh, Jonas
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Elmberger, Goran
    University of Örebro, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Russo, Leila
    University of Milan, Italy.
    Viale, Giuseppe
    University of Milan, Italy.
    Ferno, Marten
    Lund University, Sweden.
    Highly reproducible results of breast cancer biomarkers when analysed in accordance with national guidelines - a Swedish survey with central re-assessment2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 7, p. 1040-1048Article in journal (Refereed)
    Abstract [en]

    Background. Biomarkers are crucial for decisions regarding adjuvant therapy in primary breast cancer, and their correct assessment is therefore of the utmost importance. Aims. To investigate the concordance between Swedish pathology departments and a reference laboratory, for routine analysis of oestrogen receptor (ER), progesterone receptor (PR), Ki67, and human epidermal growth factor receptor 2 (HER2), alone, and in combination (St Gallen subtypes). Methods. This survey included 27 of the 28 pathology laboratories in Sweden, covering 98% of cases of primary breast cancer surgery in Sweden. Paraffin-embedded tumour blocks (n = 270) were collected and sent to the central reference laboratory, together with the originally stained slides, for re-analysis. The primary evaluations were previously performed according to national Swedish guidelines, without any knowledge of the subsequent central assessment. Results. The agreement for ER, PR, and Ki67 was 99% [kappa value (kappa) = 0.95], 95% (kappa = 0.85), and 85% (kappa = 0.70), respectively. The agreement for HER2 (0/1 + vs. 2+/3+) was 85% (kappa = 0.64), but when equivocal tumours were further analysed with in situ hybridisation, only one discrepancy was observed. Discrepancies between results for ER and PR seem to be explained by analytical differences, whereas the interpretation of staining seems to be more critical for Ki67 and HER2 immunohistochemistry. The agreement between the results from the Swedish laboratories and the reference laboratory, based on the St Gallen subtypes, was 88% (kappa = 0.81). Conclusions. When applying national guidelines, highly reproducible results were obtained in routine assessment of breast cancer biomarkers, and the results of this study confirm the clinical utility of these markers for decisions regarding the treatment of primary breast cancer.

  • 138.
    Ekman, Bertil
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Wahlberg Topp, Jeanette
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Landberg, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Urine oligosaccharide pattern in patients with hyperprolactinaemia2015In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 32, no 8, p. 635-641Article in journal (Refereed)
    Abstract [en]

    Free milk-type oligosaccharides are produced during pregnancy and lactation and may have an impact on several cells in the immune system. Our aim was to investigate if patients with isolated hyperprolactinaemia, not related to pregnancy, also have increased synthesis and urinary excretion of milk-type oligosaccharides and to compare the excretion pattern with that found during pregnancy. Urine samples were collected as morning sample from 18 patients with hyperprolactinaemia, 13 healthy controls with normal prolactin levels and four pregnant women. After purification, lactose and free oligosaccharides were analysed and quantified by high-performance anion-exchange chromatography with pulsed amperometric detection. The identity of peaks was confirmed by exoglycosidase treatment and comparison with oligosaccharide standards. Prolactin was measured in serum collected between 09 and 11 a.m. by a standardized immunochemical method. Patients with hyperprolactinaemia had higher urinary excretion of lactose than normoprolactinemic controls and urinary lactose correlated positively to prolactin levels (r = 0.51, p less than 0.05). Increased levels of the fucosylated oligosaccharides 2-fucosyl lactose and lacto-di-fucotetraose were found in urine from three and two patients, respectively. The acidic oligosaccharide 3-sialyl lactose was found in high amount in urine from two patients with prolactin of greater than 10,000 mU/l. However, pregnant women in their third trimester had the highest concentration of all these oligosaccharides and excretion increased during pregnancy. This study is first to show that both lactose and certain fucosylated and sialylated milk-type oligosaccharides are increased in some patients with hyperprolactinaemia. It remains to elucidate the functional importance of these findings.

  • 139.
    Elawa, Sherif
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Mirdell, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    The microvascular response in the skin to topical application of methyl nicotinate: Effect of concentration and variation between skin sites2019In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 124, p. 54-60Article in journal (Refereed)
    Abstract [en]

    Background

    Methyl nicotinate (MN) induces a local cutaneous erythema in the skin and may be used as a local provocation in the assessment of microcirculation and skin viability. The aims were to measure the effects of increasing doses of MN, to find the concentration that yields the most reproducible effect from day to day and between sites, and to study the variation between skin sites.

    Methods

    Microvascular responses to topically applied MN at different concentrations were measured in 12 subjects on separate days and on contralateral sides, using laserspeckle contrast imaging (LSCI). MN effects were measured in four different body sites.

    Results

    At 20 mmol/L, the response to MN was most reproducible day-to-day and site-to-site, and resulted in a plateau response between 5 and 20 min after application.

    The skin region of the lower back had a lower perfusion value compared to the epigastric region (p = 0.007). When responses were compared to nearby, unprovoked areas, a significantly larger increase in perfusion was seen in the forearm, compared to all other anatomical sites (p < 0.03).

    Conclusion

    A concentration of 20 mmol/L MN generated the most reproducible microvascular response in the skin. The response varies between different body sites.

  • 140.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-12015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed)
    Abstract [en]

    Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

  • 141.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Khalid, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. King Khalid Univ, Saudi Arabia.
    Svanberg, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Holgersson, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thoren, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Wittgren, Mirja Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Shankar, Esaki M.
    Univ Malaya, Malaysia; Cent Univ Tamil Nadu, India.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed)
    Abstract [en]

    Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

  • 142.
    Elmasry, Moustafa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Mirdell, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Laser speckle contrast imaging in children with scalds: Its influence on timing of intervention, duration of healing and care, and costs2019In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 45, no 4, p. 798-804Article in journal (Refereed)
    Abstract [sv]

    Background

    Scalds are the most common type of burn injury in children, and the initial evaluation of burn depth is a problem. Early identification of deep dermal areas that need excision and grafting would save unnecessary visits and stays in hospital. Laser speckle contrast imaging (LSCI) shows promise for the evaluation of this type of burn. The aim of this study was to find out whether perfusion measured with LSCI has an influence on the decision for operation, duration of healing and care period, and costs, in children with scalds.

    Methods

    We studied a group of children with scalds whose wounds were evaluated with LSCI on day 3–4 after injury during the period 2012–2015. Regression (adjustment for percentage total body surface area burned (TBSA%), age, and sex) was used to analyse the significance of associations between degree of perfusion and clinical outcome.

    Results

    We studied 33 children with a mean TBSA% of 6.0 (95% CI 4.4–7.7)%. Lower perfusion values were associated with operation (area under the receiver-operating characteristic curve 0.86, 95% CI 0.73–1.00). The perfusion cut-off with 100% specificity for not undergoing an operation was ≥191 PU units (66.7% sensitivity and 72.7% accurately classified). Multivariable analyses showed that perfusion was independently associated with duration of healing and care period.

    Conclusion

    Lower perfusion values, as measured with LSCI, are associated with longer healing time and longer care period. By earlier identification of burns that will be operated, perfusion measurements may further decrease the duration of care of burns in children with scalds.

  • 143.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Ronnelid, Johan
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 5, p. 817-825Article in journal (Refereed)
    Abstract [en]

    Objective. Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. Methods. Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjogren syndrome (n = 54) served as controls. Results. CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fishers exact test revealed striking differences between methods regarding associations with certain disease phenotypes. Conclusion. CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.

  • 144.
    Eriksson, Anders
    et al.
    Umeå University, Sweden.
    Gustafsson, Torfinn
    Umeå University, Sweden.
    Hoistad, Malin
    Swedish Agency Health Technology Assessment and Assessment, Sweden; Karolinska Institute, Sweden.
    Hultcrantz, Monica
    Swedish Agency Health Technology Assessment and Assessment, Sweden; Karolinska Institute, Sweden.
    Jacobson, Stella
    Swedish Agency Health Technology Assessment and Assessment, Sweden.
    Mejare, Ingegerd
    Swedish Agency Health Technology Assessment and Assessment, Sweden.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Diagnostic accuracy of postmortem imaging vs autopsy-A systematic review2017In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 89, p. 249-269Article, review/survey (Refereed)
    Abstract [en]

    Background Postmortem imaging has been used for more than a century as a complement to medico-legal autopsies. The technique has also emerged as a possible alternative to compensate for the continuous decline in the number of clinical autopsies. To evaluate the diagnostic accuracy of postmortem imaging for various types of findings, we performed this systematic literature review. Data sources The literature search was performed in the databases PubMed, Embase and Cochrane Library through January 7, 2015. Relevant publications were assessed for risk of bias using the QUADAS tool and were classified as low, moderate or high risk of bias according to pre-defined criteria. Autopsy and/or histopathology were used as reference standard. Findings The search generated 2600 abstracts, of which 340 were assessed as possibly relevant and read in full-text. After further evaluation 71 studies were finally included, of which 49 were assessed as having high risk of bias and 22 as moderate risk of bias. Due to considerable heterogeneity - in populations, techniques, analyses and reporting - of included studies it was impossible to combine data to get a summary estimate of the diagnostic accuracy of the various findings. Individual studies indicate, however, that imaging techniques might be useful for determining organ weights, and that the techniques seem superior to autopsy for detecting gas Conclusions and Implications In general, based on the current scientific literature, it was not possible to determine the diagnostic accuracy of postmortem imaging and its usefulness in conjunction with, or as an alternative to autopsy. To correctly determine the usefulness of postmortem imaging, future studies need improved planning, improved methodological quality and larger materials, preferentially obtained from multi-center studies. (C) 2016 Published by Elsevier Ireland Ltd.

  • 145.
    Eriksson, D.
    et al.
    Karolinska Institute, Sweden; Metab and Diabet Karolinska University Hospital, Sweden.
    Bianchi, M.
    Uppsala University, Sweden.
    Landegren, N.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Nordin, J.
    Uppsala University, Sweden.
    Dalin, F.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Mathioudaki, A.
    Uppsala University, Sweden.
    Eriksson, G. N.
    Karolinska Institute, Sweden.
    Hultin-Rosenberg, L.
    Uppsala University, Sweden.
    Dahlqvist, J.
    Uppsala University, Sweden.
    Zetterqvist, H.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Karlsson, A.
    Uppsala University, Sweden.
    Hallgren, A.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Farias, F. H. G.
    Uppsala University, Sweden.
    Muren, E.
    Uppsala University, Sweden.
    Ahlgren, K. M.
    Uppsala University, Sweden.
    Lobell, A.
    Uppsala University, Sweden.
    Andersson, G.
    Swedish University of Agriculture Science, Sweden.
    Tandre, K.
    Uppsala University, Sweden.
    Dahlqvist, S. R.
    Umeå University, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rönnblom, L.
    Uppsala University, Sweden.
    Hulting, A. -L.
    Karolinska Institute, Sweden.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ekwall, O.
    University of Gothenburg, Sweden.
    Dahlqvist, P.
    Umeå University, Sweden.
    Meadows, J. R. S.
    Uppsala University, Sweden.
    Bensing, S.
    Metab and Diabet Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Lindblad-Toh, K.
    Uppsala University, Sweden; Broad Institute MIT and Harvard, MA USA.
    Kampe, O.
    Karolinska Institute, Sweden; Metab and Diabet Karolinska University Hospital, Sweden; Uppsala University, Sweden.
    Pielberg, G. R.
    Uppsala University, Sweden.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addisons disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed)
    Abstract [en]

    BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addisons disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addisons disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addisons disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addisons disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addisons disease, we have identified BACH2 as a major risk locus in Addisons disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

  • 146.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Landegren, Nils
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Dalin, Frida
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Skov, Jakob
    Karolinska Inst, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala Univ, Sweden.
    Mathioudaki, Argyri
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Hallgren, Asa
    Karolinska Inst, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Hulting, Anna-Lena
    Not Found:[Eriksson, Daniel; Landegren, Nils; Dalin, Frida; Hallgren, Asa; Kampe, Olle] Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; [Eriksson, Daniel; Bensing, Sophie; Kampe, Olle] Karolinska Univ Hosp, Dept Endocrinol Metab and Diabet, Stockholm, Sweden; [Bianchi, Matteo; Hultin-Rosenberg, Lina; Mathioudaki, Argyri; Nordin, Jessika; Meadows, Jennifer R. S.; Lindblad-Toh, Kerstin; Pielberg, Gerli Rosengren] Uppsala Univ, Dept Med Biochem and Microbiol, Sci Life Lab, Uppsala, Sweden; [Landegren, Nils; Dalin, Frida; Tandre, Karolina; Ronnblom, Lars] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden; [Skov, Jakob; Bensing, Sophie] Karolinska Inst, Dept Mol Med and Surg, Stockholm, Sweden; [Andersson, Goran] Swedish Univ Agr Sci, Dept Anim Breeding and Genet, Uppsala, Sweden; [Dahlqvist, Solbritt Rantapaa; Dahlqvist, Per] Umea Univ, Dept Publ Hlth and Clin Med, Umea, Sweden; [Soderkvist, Peter; Wahlberg, Jeanette] Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Endocrinol, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol and Inflammat Res, Gothenburg, Sweden; [Lindblad-Toh, Kerstin] Broad Inst MIT and Harvard, Cambridge, MA USA; [Kampe, Olle] KG Jebsen Ctr Autoimmune Dis, Bergen, Norway;.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT and Harvard, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Kampe, Olle
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; KG Jebsen Ctr Autoimmune Dis, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addisons disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addisons disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 147.
    Eriksson, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bornefall, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Villamil Giraldo, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Impact of high cholesterol in a Parkinsons disease model: Prevention of lysosomal leakage versus stimulation of alpha-synuclein aggregation2017In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 96, no 2, p. 99-109Article in journal (Refereed)
    Abstract [en]

    Parkinsons disease is characterized by accumulation of intraneuronal cytoplasmic inclusions, Lewy bodies, which mainly consist of aggregated alpha-synuclein. Controversies exist as to whether high blood cholesterol is a risk factor for the development of the disease and whether statin treatment could have a protective effect. Using a model system of BE(2)-M17 neuroblastoma cells treated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), we found that MPP+-induced cell death was accompanied by cholesterol accumulation in a lysosomal-like pattern in pre-apoptotic cells. To study the effects of lysosomal cholesterol accumulation, we increased lysosomal cholesterol through pre-treatment with U18666A and found delayed leakage of lysosomal contents into the cytosol, which reduced cell death. This suggests that increased lysosomal cholesterol is a stress response mechanism to protect lysosomal membrane integrity in response to early apoptotic stress. However, high cholesterol also stimulated the accumulation of alpha-synuclein. Treatment with the cholesterol-lowering drug lovastatin reduced MPP+-induced cell death by inhibiting the production of reactive oxygen species, but did not prevent lysosomal cholesterol increase nor affect alpha-synuclein accumulation. Our study indicates a dual role of high cholesterol in Parkinsons disease, in which it acts both as a protector against lysosomal membrane permeabilization and as a stimulator of alpha-synuclein accumulation. (C) 2017 Elsevier GmbH. All rights reserved.

  • 148.
    Eriksson, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Analysis of Lysosomal pH by Flow Cytometry Using FITC-Dextran Loaded Cells2017In: Lysosomes: Methods and Protocols / [ed] Karin Öllinger;Hanna Appelqvist, Humana Press, 2017, Vol. 1594, p. 179-189Chapter in book (Refereed)
    Abstract [en]

    The acidic environment of the lysosomal lumen provides an optimal milieu for the acid hydrolases and is also essential for fusion/fission of endo-lysosomal compartments and sorting of cargo. Evidence suggests that maintaining lysosomal acidity is essential to avoid disease. In this chapter, we describe a protocol for analyzing the lysosomal pH in cultured cells using the fluorescent probe fluorescein isothiocyanate (FITC)-dextran together with a dual-emission ratiometric technique suitable for flow cytometry. Fluorescence-labeled dextran is endocytosed and accumulated in the lysosomal compartment. FITC shows a pH-dependent variation in fluorescence when analyzed at maximum emission wavelength and no variation when analyzing at the isosbestic point, thereby the ratio can be used to determine the lysosomal pH. A standard curve is obtained by equilibrating intralysosomal pH with extracellular pH using the ionophore nigericin. The protocol also includes information regarding procedures to induce lysosomal alkalinization and lysosomal membrane permeabilization.

  • 149.
    Eriksson, Irene
    et al.
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Wettermark, Bjorn
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Persson, Marie
    Stockholm County Council, Sweden.
    Edström, Morgan
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Godman, Brian
    University of Liverpool, England; Karolinska University Hospital, Sweden; University of Strathclyde, Scotland.
    Lindhe, Anna
    Regional Vastra Gotaland, Sweden.
    Malmstrom, Rickard E.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Ramstrom, Helena
    Stockholm County Council, Sweden.
    von Eulerz, Mia
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bergkvist Christensen, Anna
    Regional Skåne, Sweden.
    The Early Awareness and Alert System in Sweden: History and Current Status2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 674Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Over the past decades, early awareness and alert (FAA) activities and systems have gained importance and become a key early health technology assessment (HTA) tool. While a pioneer in HTA, Sweden had no national level EAA activities until 2010. We describe the evolution and current status of the Swedish EAA System. Methods: This was a historical analysis based on the knowledge and experience of the authors supplemented by a targeted review of published and gray literature as well as documents relating to EM activities in Sweden. Key milestones and a description of the current state of the Swedish FAA System is presented. Results: Initiatives to establish a system for the identification and assessment of emerging health technologies in Sweden date back to the 1980s. In the 1990s, the Swedish Agency for HTA and Assessment of Social Services (SBU) supported the development of EuroScan as one of its founder members. In the mid-2000s, an independent regional initiative, driven by the Stockholm County Drug and Therapeutics Committee, resulted in the establishment of a regional horizon scanning function. By 2009, this work had expanded to a collaboration between the four biggest counties in Sweden. The following year it was further expanded to the national level and since then the Swedish EAA System has been carrying out identification, filtration and prioritization of new medicines, early assessment of the prioritized medicines, and dissemination of information. In 2015, the EAA System was incorporated into the Swedish national process for managed introduction and follow-up of new medicines. Outputs from the EAA System are now used to select new medicines for inclusion in this process. Conclusions: The Swedish FAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

  • 150.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Andersson, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Cassel, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Letter: Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 1, p. 80-83Article in journal (Other academic)
    Abstract [en]

    n/a

1234567 101 - 150 of 582
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