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  • 151.
    Falck, A. K.
    et al.
    Clin Science Lund, Sweden; Hospital Helsingborg, Sweden.
    Rome, A.
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Ferno, M.
    Clin Science Lund, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Chebil, G.
    Unilabs Pathol Unit, Sweden.
    Bendahl, P. O.
    Clin Science Lund, Sweden.
    Ryden, L.
    Clin Science Lund, Sweden; Skåne University Hospital, Sweden.
    St Gallen molecular subtypes in screening-detected and symptomatic breast cancer in a prospective cohort with long-term follow-up2016In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 103, no 5, p. 513-523Article in journal (Refereed)
    Abstract [en]

    Background: Diagnosis by screening mammography is considered an independent positive prognostic factor, although the data are not fully in agreement. The aim of the study was to explore whether the mode of detection (screening-detected versus symptomatic) adds prognostic information to the St Gallen molecular subtypes of primary breast cancer, in terms of 10-year cumulative breast cancer mortality (BCM). Methods: A prospective cohort of patients with primary breast cancer, who had regularly been invited to screening mammography, were included. Tissue microarrays were constructed from primary tumours and lymph node metastases, and evaluated by two independent pathologists. Primary tumours and lymph node metastases were classified into St Gallen molecular subtypes. Cause of death was retrieved from the Central Statistics Office. Results: A total of 434 patients with primary breast cancer were included in the study. Some 370primary tumours and 111 lymph node metastases were classified into St Gallen molecular subtypes. The luminal A-like subtype was more common among the screening-detected primary tumours (P=0.035) and corresponding lymph node metastases (P=0.114) than among symptomatic cancers. Patients with screening-detected tumours had a lower BCM (P=0.017), and for those diagnosed with luminal A-like tumours the 10-year cumulative BCM was 3 per cent. For patients with luminal A-like lymph node metastases, there was no BCM. In a stepwise multivariable analysis, the prognostic information yielded by screening detection was hampered by stage and tumour biology. Conclusion: The prognosis was excellent for patients within the screening programme who were diagnosed with a luminal A-like primary tumour and/or lymph node metastases. Stage, molecular pathology and mode of detection help to define patients at low risk of death from breast cancer.

  • 152.
    Falk, Magnus
    et al.
    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 West Östergötland, Research & Development Unit in Local Health Care.
    Sjödahl, Rune
    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. Region Östergötland, Center for Health and Developmental Care, Patient Safety.
    Wiréhn, Ann-Britt
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis.
    Lagerfelt, Marie
    Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Woisetschläger, Mischa
    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.
    Ahlström, Ulla
    Vårdcentralen Kungsgatan Linköping, Sweden Region Östergötland, Sweden.
    Myrelid, Pär
    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.
    Modifierad brittisk modell kortade ledtid till datortomografi av kolon2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112Article in journal (Refereed)
    Abstract [en]

    The British national Institute for Health and Care Excellence (NICE) has presented guidelines based on signs and symptoms which should raise a suspicion of colorectal cancer. A slightly modified version of these guidelines, adapted to Swedish conditions, named Swedish NICE (sNICE) criteria, was implemented at eight primary care centres. By following the sNICE criteria, cases with higher degree of suspicion of colorectal cancer were advised for computer tomography (CT) of the colon, whereas cases of low degree of suspicion were advised for the considerably less time and patient demanding CT of the abdomen. For patients with isolated anal symptoms without presence of sNICE criteria, active expectancy for six weeks was recommended, followed by renewed consideration. Results showed that the ratio between CT colon and CT abdomen was reduced from 2.2 to 1.1 after introduction of the sNICE criteria. Also, the proportion of patients undergoing CT colon within two weeks from admittance was increased from 3 to 25 %. We conclude that the sNICE criteria may be a useful supportive tool for the primary care physician.

  • 153.
    Fardell, Camilla
    et al.
    Univ Gothenburg, Sweden.
    Zettergren, Anna
    Univ Gothenburg, Sweden.
    Ran, Caroline
    Karolinska Inst, Sweden.
    Belin, Andrea Carmine
    Karolinska Inst, Sweden.
    Ekman, Agneta
    Univ Gothenburg, Sweden.
    Sydow, Olof
    Karolinska Univ Hosp, Sweden.
    Backman, Lars
    Karolinska Inst, Sweden.
    Holmberg, Bjorn
    Univ Gothenburg, Sweden.
    Dizdar Segrell, Nil
    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.
    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.
    Nissbrandt, Hans
    Univ Gothenburg, Sweden.
    S100B polymorphisms are associated with age of onset of Parkinsons disease2018In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 19, article id 42Article in journal (Refereed)
    Abstract [en]

    Background: In this study we investigated the association between SNPs in the S100B gene and Parkinsons disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar (R) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3-UTR of the S100B gene, was strongly associated with age of onset of PD.

  • 154.
    Faresjö, Åshild
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jullander, Miriam
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Götmalm, Sara
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Higher perceived stress and poorer health reflected in elevated cortisol concentrtions measured in extracts of hair from middle-aged healthy women2014In: BMC Psychology, ISSN 2050-7283, Vol. 2, no 30, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Background

    The prevalence of mental strain and stress has increased in modern societies, resulting in increased public health problems. Stress can be measured either by biomarkers or by self-reports. A new biomarker that measures long-term biological stress is cortisol measured in timed hair extracts. Hair grows at approximately 1 cm per month, and retrospectively reflects average stress levels. However, the plausible relationship between perceived stress and self-reported health and this novel biomarker is yet not firmly established. The objective of this study was to investigate the possible relationship between perceived stress, self-reported health, and cortisol in hair extracts in healthy middle-aged women from two different occupations.

    Method

    A cross-sectional study was conducted in 112 middle-aged women working as nurses or librarians in a county in southeast Sweden. The women were invited to fill in a questionnaire covering stress, health, and life situation. The questionnaire included questions on health and disease symptoms, the Perceived Stress Scale (PSS), and the Hospital Anxiety and Depression (HAD) scale. A piece of hair was cut from the vertex posterior area of the head an analysed by a competitive radioimmunoassay method.

    Results

    Middle-aged women who reported high perceived stress (p = 0.031) or lower health (p = 0.029), or had signs of depressiveness (p = 0.016) had significantly higher cortisol concentrations adjusted for age. There were no significant differences in cortisol in hair concentrations or perceived stress between nurses and librarians. Two women with extremely high cortisol concentrations were considered as outliers, but during the interview at follow-up they reported experiences of serious life events in their work or social life during the retrospective time of the sample taken for cortisol measurement.

    Conclusions

    Higher cortisol concentrations measured in the hair of healthy and working middle-aged women were associated with higher perceived stress and generally poorer health and with depressiveness. These findings lend support to the general applicability of cortisol measured in hair extracts as a biomarker in population-based epidemiological studies.

  • 155.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Stjernstrom, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ansell, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Garvin, Stina
    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.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck2015In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 31, p. 64-72Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q XRCC1 R399Q and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. (C) 2015 Elsevier B.V. All rights reserved.

  • 156.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    University of Gothenburg, Gothenburg, Sweden .
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of 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 Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, p. 3818-3824Article in journal (Refereed)
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

  • 157.
    Fernlund, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Lund University, Sweden.
    Wålinder Österberg, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mikael
    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.
    Jansson, Kjell
    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.
    Gunnarsson, Cecilia
    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. Region Östergötland, Center for Business support and Development.
    Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death2017In: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 38, no 6, p. 1262-1268Article in journal (Refereed)
    Abstract [en]

    Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G amp;gt; A(p.Arg173Gln)] and BAG3 [BAG3 c.785C amp;gt; T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.

  • 158.
    Folkesson, Maggie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Sadowska, Natalia
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Carlhäll, Carl-Johan
    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).
    Länne, Toste
    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 Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models2016In: Biology Open, ISSN 2046-6390, Vol. 5, no 7, p. 970-978Article in journal (Refereed)
    Abstract [en]

    Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

  • 159.
    Forsberg, Daniel
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra AB, Linköping, Sweden.
    Lindblom, Maria
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Quick, Petter
    Linköping University, Department of Medical and Health 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).
    Gauffin, Håkan
    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 Orthopaedics in Linköping.
    Quantitative analysis of the patellofemoral motion pattern using semi-automatic processing of 4D CT data2016In: International Journal of Computer Assisted Radiology and Surgery, ISSN 1861-6410, E-ISSN 1861-6429, Vol. 11, no 9, p. 1731-1741Article in journal (Refereed)
    Abstract [en]

    To present a semi-automatic method with minimal user interaction for quantitative analysis of the patellofemoral motion pattern. 4D CT data capturing the patellofemoral motion pattern of a continuous flexion and extension were collected for five patients prone to patellar luxation both pre- and post-surgically. For the proposed method, an observer would place landmarks in a single 3D volume, which then are automatically propagated to the other volumes in a time sequence. From the landmarks in each volume, the measures patellar displacement, patellar tilt and angle between femur and tibia were computed. Evaluation of the observer variability showed the proposed semi-automatic method to be favorable over a fully manual counterpart, with an observer variability of approximately 1.5 for the angle between femur and tibia, 1.5 mm for the patellar displacement, and 4.0-5.0 for the patellar tilt. The proposed method showed that surgery reduced the patellar displacement and tilt at maximum extension with approximately 10-15 mm and 15-20 for three patients but with less evident differences for two of the patients. A semi-automatic method suitable for quantification of the patellofemoral motion pattern as captured by 4D CT data has been presented. Its observer variability is on par with that of other methods but with the distinct advantage to support continuous motions during the image acquisition.

  • 160.
    Forsberg, Daniel
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra, Linköping, Sweden.
    Monsef, Nastaran
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Evaluating Cell Nuclei Segmentation for Use on Whole-Slide Images in Lung Cytology2014In: 2014 22nd International Conference on Pattern Recognition (ICPR), IEEE Computer Society, 2014, p. 3380-3385Conference paper (Refereed)
    Abstract [en]

    This paper presents results from an evaluation of three previously presented methods for segmentation of cell nuclei in lung cytology samples scanned by whole-slide scanners. Whole-slide images from seven cases of endobronchial ultrasound-guided transbronchial needle aspiration samples were used for extracting a number of regions of interest, in which approximately 2700 cell nuclei were manually segmented to form the ground truth. The segmented cells included benign bronchial epithelium, lymphocytes, granulocytes, histiocytes and malignant epithelial cells. The best results were obtained with a method based upon adaptive thresholding and an added step of clustering for distinguishing between cytoplasm and cell nuclei. This method achieved a mean DICE-score of 0.81 and a sensitivity and specificity of 0.88 and 0.81 respectively. In addition, this method was by far the fastest method, with a mean processing time of 7.8 s per image (2048 x 2048 pixels per image). By further improvements, such as lowering the false positive rate and using parallel computing hardware, this method has the potential to form the first building block in a system for computerized screening of whole-slide images in lung cytology.

  • 161.
    Forsgren, Mikael
    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 Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Markus
    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).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    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).
    Norén, Bengt
    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).
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Ekstedt, Mattias
    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 Gastroentorology.
    Kechagias, Stergios
    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 Gastroentorology.
    Lundberg, Peter
    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, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort2019In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, PLOS COMPUTATIONAL BIOLOGY, Vol. 15, no 6, article id e1007157Article in journal (Refereed)
    Abstract [en]

    Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.

    Author summary

    Being able to accurately and reliably estimate liver function is important when monitoring the progression of patients with liver disease, as well as when identifying drug-induced liver injury during drug development. A promising method for quantifying liver function is to use magnetic resonance imaging combined with gadoxetate. Gadoxetate is a liver-specific contrast agent, which is taken up by the hepatocytes and excreted into the bile. We have previously developed a mechanistic model for gadoxetate dynamics using averaged data from healthy volunteers. In this work, we extended our model with a non-linear mixed-effects modeling framework to give patient-specific estimates of the gadoxetate transport-rates. We validated the model by recruiting 100 patients with liver disease, covering a range of severity and etiologies. All patients underwent an MRI-examination and provided both blood and liver biopsies. Our validated model provides a new and deeper look into how the mechanisms of liver function varies across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate.

  • 162.
    Forsgren, Mikael
    et al.
    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 Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Wolfram MathCore AB, Linköping, Sweden.
    Norén, Bengt
    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 Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Kihlberg, Johan
    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 Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dahlqvist Leinhard, Olof
    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 Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Lundberg, Peter
    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 Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Comparing hepatic 2D and 3D magnetic resonance elastography methods in a clinical setting – Initial experiences2015In: European Journal of Radiology Open, E-ISSN 2352-0477, Vol. 2, p. 66-70Article in journal (Refereed)
    Abstract [en]

    Purpose

    Continuous monitoring of liver fibrosis progression in patients is not feasible with the current diagnostic golden standard (needle biopsy). Recently, magnetic resonance elastography (MRE) has emerged as a promising method for such continuous monitoring. Since there are different MRE methods that could be used in a clinical setting there is a need to investigate whether measurements produced by these MRE methods are comparable. Hence, the purpose of this pilot study was to evaluate whether the measurements of the viscoelastic properties produced by 2D (stiffness) and 3D (elasticity and ‘Gabs,Elastic’) MRE are comparable.

    Materials and methods

    Seven patients with diffuse or suspect diffuse liver disease were examined in the same day with the two MRE methods. 2D MRE was performed using an acoustic passive transducer, with a 1.5 T GE 450 W MR system. 3D MRE was performed using an electromagnetic active transducer, with a 1.5 T Philips Achieva MR system. Finally, mean viscoelastic values were extracted from the same anatomical region for both methods by an experienced radiologist.

    Results

    Stiffness correlated well with the elasticity, R2 = 0.96 (P < 0.001; slope = 1.08, intercept = 0.61 kPa), as well as with ‘Gabs,ElasticR2 = 0.96 (P < 0.001; slope = 0.95, intercept = 0.28 kPa).

    Conclusion

    This pilot study shows that different MRE methods can produce comparable measurements of the viscoelastic properties of the liver. The existence of such comparable measurements is important, both from a clinical as well as a research perspective, since it allows for equipment-independent monitoring of disease progression.

  • 163.
    Forslin, Y.
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Martola, J.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bergendal, A.
    Karolinska Inst, Sweden.
    Fredrikson, S.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, 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.
    Granberg, T.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gadolinium Retention in the Brain: An MRI Relaxometry Study of Linear and Macrocyclic Gadolinium-Based Contrast Agents in Multiple Sclerosis2019In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 40, no 8, p. 1265-1273Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Brain gadolinium retention is consistently reported for linear gadolinium-based contrast agents, while the results for macrocyclics are contradictory and potential clinical manifestations remain controversial. Furthermore, most previous studies are based on conventional T1-weighted MR imaging. We therefore aimed to quantitatively investigate longitudinal and transversal relaxation in the brain in relation to previous gadolinium-based contrast agent administration and explore associations with disability in multiple sclerosis. MATERIALS AND METHODS: Eighty-five patients with MS and 21 healthy controls underwent longitudinal and transverse relaxation rate (R-1 and R-2) relaxometry. Patients were divided into linear, mixed, and macrocyclic groups based on previous gadolinium-based contrast agent administration. Neuropsychological testing was performed in 53 patients. The dentate nucleus, globus pallidus, caudate nucleus, and thalamus were manually segmented. Repeatability measures were also performed. RESULTS: The relaxometry was robust (2.0% scan-rescan difference) and detected higher R-1 (dentate nucleus, globus pallidus, caudate nucleus, thalamus) and R-2 (globus pallidus, caudate nucleus) in patients receiving linear gadolinium-based contrast agents compared with controls. The number of linear gadolinium-based contrast agent administrations was associated with higher R-1 and R-2 in all regions (except R-2 in the thalamus). No similar differences and associations were found for the macrocyclic group. Higher relaxation was associated with lower information-processing speed (dentate nucleus, thalamus) and verbal fluency (caudate nucleus, thalamus). No associations were found with physical disability or fatigue. CONCLUSIONS: Previous linear, but not macrocyclic, gadolinium-based contrast agent administration is associated with higher relaxation rates in a dose-dependent manner. Higher relaxation in some regions is associated with cognitive impairment but not physical disability or fatigue in MS. The findings should be interpreted with care but encourage studies into gadolinium retention and cognition.

  • 164.
    Fotouhi, Omid
    et al.
    German Cancer Consortium (DKTK) partner site Freiburg, German Cancer Research Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, Germany.
    Zedenius, Jan
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Höög, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Juhlin, Carl Christofer
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Regional differences in somatostatin receptor 2 (SSTR2) immunoreactivity is coupled to level of bowel invasion in small intestinal neuroendocrine tumors2018In: Neuro - endocrinology letters, ISSN 0172-780X, Vol. 39, no 4, p. 305-309Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Somatostatin receptor (SSTR) expression constitutes a pivotal cornerstone for accurate radiological detection and medical treatment of small intestinal neuroendocrine tumors (SI-NETs), and the development of somatostatin analogues for these purposes have revolutionized the clinical work-up. Previous assessments of SSTR isoform expression in SI-NETs have found correlations to overall prognosis and treatment response, however these analyses usually report overall tumoral immunoreactivity, and little is reported regarding histo-regional differences in expressional patterns.

    METHODS: Thirty-seven primary SI-NETs (WHO grade I, n=32 and WHO grade II, n=5) were collected and assessed for SSTR2 immunohistochemistry. Samples were stratified with regards to histological level of bowel infiltration and spread (mucosal region, muscularis propria region, subserosal region) and each of these tumoral regions was separately scored by SSTR2 staining localization (membrane, cytoplasmic), overall staining intensity and local staining differences within each region.

    RESULTS: SSTR2 immunoreactivity was progressively weaker as the tumor cells advanced through the small intestinal layers. This was exemplified by a reduction in the amount of tumor samples with strong SSTR2 expression in the deeper histological levels of the section; 56% of tumors displayed strong SSTR2 expression in the mucosal region, as compared to 29% and 30% of tumors within muscularis propria and subserosal layers, respectively.

    CONCLUSIONS: This observation indicates a down-regulation of SSTR2 expression as the tumors progress through the intestinal wall, which might signify underlying biological processes of importance for SI-NET invasion behavior.

  • 165.
    Fransson, Sven Göran
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Editorial Material: Tuberculosis: a medical evergreen in ACTA RADIOLOGICA, vol 56, issue 5, pp 515-5162015In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 56, no 5, p. 515-516Article in journal (Other academic)
    Abstract [en]

    n/a

  • 166.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Pihl, Liselotte
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Khan, Nadeem
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Norrköping/Finspång. Linköping University, Faculty of Medicine and Health Sciences.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice2016In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 310, no 9, p. F807-F809Article in journal (Refereed)
    Abstract [en]

    Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease in order to be the causal mechanism. In order to establish if hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared to normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined in order to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia three days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

  • 167.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lotfi, Kourosh
    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.
    Fomichov, Victoria
    Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Juliusson, G.
    Lund University, Sweden; Lund University, Sweden.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Frequent and long-term follow-up of health-related quality of life following allogeneic haematopoietic stem cell transplantation2015In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 24, no 6, p. 898-910Article in journal (Refereed)
    Abstract [en]

    Health-related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n=18) or reduced intensity conditioning (RIC, n=76). HRQL was assessed with the EORTC QLQ C-30 during the inpatient period as well as during the following 3years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1year for HRQL to return to the baseline level. The only function that improved significantly 3years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease experienced reduced HRQL. These results provide a clinically useful overview of patients HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow-ups during the first year after HSCT to improve preventive or supportive interventions.

  • 168.
    Fuellhase, Claudius
    et al.
    University of Rostock, Germany; University of Munich, Germany.
    Schreiber, Andrea
    University of Munich, Germany; University of Munich, Germany.
    Giese, Armin
    University of Munich, Germany.
    Schmidt, Michael
    University of Munich, Germany.
    Montorsi, Francesco
    University of Milan, Italy; University of Vita San Raffaele, Italy.
    Gratzke, Christian
    University of Munich, Germany.
    La Croce, Giovanni
    University of Milan, Italy; Lund University, Sweden.
    Castiglione, Fabio
    University of Vita San Raffaele, Italy; Lund University, Sweden.
    Stief, Christian
    University of Munich, Germany.
    Hedlund, Petter
    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. University of Milan, Italy.
    Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats2016In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 35, no 4, p. 464-470Article in journal (Refereed)
    Abstract [en]

    AimsTo test if urodynamic effects from systemic Fatty Acid Amide Hydrolase (FAAH) inhibition involve sacral spinal cannabinoid type 1 (CB1) or type 2 (CB2) receptors. MethodsMale rats with or without partial urethral obstruction were used for cystometry or immunohistochemistry. Urodynamic effects of intravenous (IV) 0.3mg/kg Oleoyl Ethyl Amide (OEtA; FAAH inhibitor), and intrathecal (IT) 5g rimonabant (CB1 antagonist) or 5g SR144528 (CB2 antagonist) were studied in awake rats. ResultsAfter administration of rimonabant or SR144528, non-obstructed rats with normal bladder function developed bladder overactivity (BO), which was counteracted by OEtA. OEtA also counteracted BO in obstructed rats. SR144528 did not affect bladder function in obstructed rats but counteracted the urodynamic effects of OEtA. Surprisingly, rimonabant (and AM251, another CB1 antagonist) reduced BO in obstructed rats, whereafter OEtA produced no additional urodynamic effects. CB1 expression increased in the sacral spinal cord of obstructed rats whereas no changes were observed for CB2 or FAAH. ConclusionsUrodynamic effects of systemic FAAH inhibition involve activities at spinal neuronal CB1 and CB2 receptors in normal and obstructed rats. Endogenous spinal CB receptor ligands seem to regulate normal micturition and BO. Altered spinal CB receptor functions may be involved in the pathogenesis of obstruction-induced BO. Neurourol. Urodynam. 35:464-470, 2016. (c) 2015 Wiley Periodicals, Inc.

  • 169.
    Fyrberg, Anna
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Lotfi, Kourosh
    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.
    NUCLEOSIDE ANALOG ACTIVITY IN MALIGNANT MELANOMA CELL LINES2015In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 34, no 9, p. 639-649Article in journal (Refereed)
    Abstract [en]

    Mitochondrial deoxyguanosine kinase (dGK), is an enzyme responsible for activation of nucleoside analogs (NAs) to phosphorylated compounds which exert profound cytotoxicity, especially in hematological malignancies. Screening malignant melanoma cell lines against NAs revealed high sensitivity to several of them. This was believed to be due to the high levels of dGK expression in these cells. Downregulation of dGK in the melanoma cell line RaH5 using siRNA did not cause resistance to NAs as expected, but instead cells became more sensitive. This was probably partly due to the increased activity of another mitochondrial enzyme, thymidine kinase 2, seen in transfected cells.

  • 170.
    Garvin, Peter
    et al.
    Linköping University, Department of Medical and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Evalill
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    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.
    Kristenson, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    The joint subclinical elevation of CRP and IL-6 is associated with lower health-related quality of life in comparison with no elevation or elevation of only one of the biomarkers2016In: Quality of Life Research, ISSN 0962-9343, E-ISSN 1573-2649, Vol. 25, no 1, p. 213-221Article in journal (Refereed)
    Abstract [en]

    Measures of health-related quality of life (HRQoL), like the Short Form (SF)-36, have been suggested to correlate with inflammatory biomarkers. It is, however, unclear whether a joint measure of two inflammatory biomarkers would bring additional information in comparison with evaluation of one inflammatory biomarker. To evaluate associations between SF-36 and low-grade inflammation in a Swedish population, with emphasis on a combined measure of C-reactive protein (CRP) and interleukin-6 (IL-6) as a proxy for low-grade inflammation. In a randomly selected sample of a middle-aged Swedish general population (n = 905; aged 45-69 years, 50 % women), relations between SF-36 parameters and the biomarkers were tested. Regression and correlation analyses were adjusted for sex, age, presence of disease, lifestyle, and psychological factors. After adjustment for sex and age, HRQoL was significantly lower in the group with a joint elevation of CRP and IL-6 in comparison with either the group with no elevation or the groups showing elevation of one of the two biomarkers. Also after full adjustments, the combined measure of elevated CRP and IL-6, with few exceptions, was associated with significantly lower HRQoL in comparison with elevations in one of them, difference ranging from 4 (Mental Health scale) to 18 scale steps (Role-Physical scale). This study confirms that there is a relationship between HRQoL and low-grade inflammation. In particular, SF-36 scores are significantly lower in a group with joint elevation of IL-6 and CRP, in comparison with elevation of either one of them.

  • 171.
    Garvin, Stina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Oda, Husam
    Cty Hosp Ryhov, Sweden; Umea Univ, Sweden.
    Arnesson, Lars-Gunnar
    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.
    Lindström, Annelie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shabo, Ivan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery2018In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 144, no 7, p. 1253-1263Article in journal (Refereed)
    Abstract [en]

    Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance. Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy gamma-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival. CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells. Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

  • 172.
    Gawel, Danuta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Serra-Musach, Jordi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lilja, Sandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Aagesen, Jesper
    Reg Jonkoping Cty, Sweden.
    Arenas, Alex
    Univ Rovira and Virgili, Spain.
    Asking, Bengt
    Reg Jonkoping Cty, Sweden.
    Bengner, Malin
    Reg Jonkoping Cty, Sweden.
    Bjorkander, Janne
    Reg Jonkoping Cty, Sweden.
    Biggs, Sophie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Hjortswang, Henrik
    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 Gastroentorology.
    Karlsson, Jan-Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Köpsén, Mattias
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Jung Lee, Eun Jung
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Yonsei Univ, South Korea.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Xinxiu
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Martinez, David
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Matussek, Andreas
    Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Schafer, Samuel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Sonmez, Ceylan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Stjernman, Henrik
    Reg Jonkoping Cty, Sweden.
    Tjärnberg, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Wu, Simon
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Åkesson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Shalek, Alex K.
    MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA.
    Stenmarker, Margaretha
    Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases2019In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 11, article id 47Article in journal (Refereed)
    Abstract [en]

    Background

    Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs.

    Methods

    The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs.

    Results

    We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model.

    Conclusions

    Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.

  • 173.
    Geessink, Oscar G. F.
    et al.
    Radboud Univ Nijmegen, Netherlands; Radboud Univ Nijmegen, Netherlands; Lab Pathol East Netherlands LabPON, Netherlands.
    Baidoshvili, Alexi
    Lab Pathol East Netherlands LabPON, Netherlands.
    Klaase, Joost M.
    Medisch Spectrum Twente, Netherlands.
    Bejnordi, Babak Ehteshami
    Radboud Univ Nijmegen, Netherlands.
    Litjens, Geert J. S.
    Radboud Univ Nijmegen, Netherlands.
    van Pelt, Gabi W.
    Leiden Univ, Netherlands.
    Mesker, Wilma E.
    Leiden Univ, Netherlands.
    Nagtegaal, Iris D.
    Radboud Univ Nijmegen, Netherlands.
    Ciompi, Francesco
    Radboud Univ Nijmegen, Netherlands.
    van der Laak, Jeroen
    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, Clinical pathology. Radboud Univ Nijmegen, Netherlands.
    Computer aided quantification of intratumoral stroma yields an independent prognosticator in rectal cancer2019In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 42, no 3, p. 331-341Article in journal (Refereed)
    Abstract [en]

    PurposeTumor-stroma ratio (TSR) serves as an independent prognostic factor in colorectal cancer and other solid malignancies. The recent introduction of digital pathology in routine tissue diagnostics holds opportunities for automated TSR analysis. We investigated the potential of computer-aided quantification of intratumoral stroma in rectal cancer whole-slide images.MethodsHistological slides from 129 rectal adenocarcinoma patients were analyzed by two experts who selected a suitable stroma hot-spot and visually assessed TSR. A semi-automatic method based on deep learning was trained to segment all relevant tissue types in rectal cancer histology and subsequently applied to the hot-spots provided by the experts. Patients were assigned to a stroma-high or stroma-low group by both TSR methods (visual and automated). This allowed for prognostic comparison between the two methods in terms of disease-specific and disease-free survival times.ResultsWith stroma-low as baseline, automated TSR was found to be prognostic independent of age, gender, pT-stage, lymph node status, tumor grade, and whether adjuvant therapy was given, both for disease-specific survival (hazard ratio=2.48 (95% confidence interval 1.29-4.78)) and for disease-free survival (hazard ratio=2.05 (95% confidence interval 1.11-3.78)). Visually assessed TSR did not serve as an independent prognostic factor in multivariate analysis.ConclusionsThis work shows that TSR is an independent prognosticator in rectal cancer when assessed automatically in user-provided stroma hot-spots. The deep learning-based technology presented here may be a significant aid to pathologists in routine diagnostics.

  • 174.
    Georgiopoulos, Charalampos
    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.
    Imaging Studies of Olfaction in Health and Parkinsonism2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Olfactory loss is a common non-motor symptom of Parkinson’s disease (PD), often preceding the cardinal motor symptoms of the disease. The aim of this thesis was to: (a) evaluate whether olfactory examination can increase diagnostic accuracy, and (b) study the structural and functional neural basis of olfactory dysfunction in PD with different applications of Magnetic Resonance Imaging (MRI).

    Paper I was a comparison of the diagnostic accuracy between a simple smell identification test and DaTSCAN Single Photon Emission Computerized Tomography (SPECT), a nuclear medicine tomographic imaging technique that is commonly used in patients with suspected parkinsonism. The results indicate that smell test is inferior to DaTSCAN SPECT, but the combination of these two methods can lead to improved diagnostic accuracy.

    Paper II showed that diffusion MRI could detect discrete microstructural changes in the white matter of brain areas that participate in higher order olfactory neurotransmission, whereas MRI with Magnetization Transfer contrast could not.

    Paper III was a methodological study on how two different acquisition parameters can affect the activation pattern of olfactory brain areas, as observed with functional MRI (fMRI). The results indicate that brief olfactory stimulation and fast sampling rate should be preferred on olfactory fMRI studies.

    Paper IV used olfactory fMRI and resting-state fMRI in order to elucidate potentially altered activation patterns and functional connectivity within olfactory brain areas, between PD patients and healthy controls. Olfactory fMRI showed that olfactory impairment in PD is associated with significantly lower recruitment of the olfactory network. Resting-state fMRI did not detect any significant changes in the functional connectivity within the olfactory network of PD patients.

    In conclusion, the included studies provide evidence of: (a) disease-related structural and functional changes in olfactory brain areas, and (b) beneficial addition of olfactory tests in the clinical work-up of patients with parkinsonism.

    List of papers
    1. The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes
    Open this publication in new window or tab >>The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes
    Show others...
    2015 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 262, no 9, p. 2154-2163Article in journal (Refereed) Published
    Abstract [en]

    The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinsons disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand I-123-FP-CIT (DaTSCAN (R)) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75 %) had visually predominant dopamine depletion in putamen, while most APS patients (56 %) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.

    Place, publisher, year, edition, pages
    Springer Berlin/Heidelberg, 2015
    Keywords
    Parkinsons disease; Atypical parkinsonism; Parkinsonian syndromes; Olfaction; I-123-FP-CIT SPECT
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-122669 (URN)10.1007/s00415-015-7830-4 (DOI)000363035400018 ()26122543 (PubMedID)
    Note

    Funding Agencies|Ostergotland County Council (ALF); Swedish Parkinsons Foundation

    Available from: 2015-11-16 Created: 2015-11-13 Last updated: 2019-03-05Bibliographically approved
    2. Olfactory Impairment in Parkinsons Disease Studied with Diffusion Tensor and Magnetization Transfer Imaging
    Open this publication in new window or tab >>Olfactory Impairment in Parkinsons Disease Studied with Diffusion Tensor and Magnetization Transfer Imaging
    Show others...
    2017 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 2, p. 301-311Article in journal (Refereed) Published
    Abstract [en]

    Background: Olfactory impairment is an early manifestation of Parkinsons disease (PD). Diffusion Tensor Imaging (DTI) and Magnetization Transfer (MT) are two imaging techniques that allow noninvasive detection of microstructural changes in the cerebral white matter. Objective: To assess white matter alterations associated with olfactory impairment in PD, using a binary imaging approach with DTI and MT. Methods: 22 PD patients and 13 healthy controls were examined with DTI, MT and an odor discrimination test. DTI data were first analyzed with tract-based spatial statistics (TBSS) in order to detect differences in fractional anisotropy, mean, radial and axial diffusivity between PD patients and controls. Voxelwise randomized permutation was employed for the MT analysis, after spatial and intensity normalization. Additionally, ROI analysis was performed on both the DTI and MT data, focused on the white matter adjacent to olfactory brain regions. Results: Whole brain voxelwise analysis revealed decreased axial diffusivity in the left uncinate fasciculus and the white matter adjacent to the left olfactory sulcus of PD patients. ROI analysis demonstrated decreased axial diffusivity in the right orbitofrontal cortex, as well as decreased mean diffusivity and axial diffusivity in the white matter of the left entorhinal cortex of PD patients. There were no significant differences regarding fractional anisotropy, radial diffusivity or MT between patients and controls. Conclusions: ROI analysis of DTI could detect microstructural changes in the white matter adjacent to olfactory areas in PD patients, whereas MT imaging could not.

    Place, publisher, year, edition, pages
    IOS PRESS, 2017
    Keywords
    Parkinson disease; smell; diffusion tensor imaging; magnetization transfer contrast imaging
    National Category
    Neurology
    Identifiers
    urn:nbn:se:liu:diva-138300 (URN)10.3233/JPD-161060 (DOI)000401801600010 ()28482644 (PubMedID)
    Note

    Funding Agencies|Swedish Parkinson Foundation; Linkoping University Hospital Research Fund; ALF Grants from Region Ostergotland

    Available from: 2017-06-13 Created: 2017-06-13 Last updated: 2019-03-05
    3. Olfactory fMRI: Implications of Stimulation Length and Repetition Time
    Open this publication in new window or tab >>Olfactory fMRI: Implications of Stimulation Length and Repetition Time
    Show others...
    2018 (English)In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 43, no 6, p. 389-398Article in journal (Refereed) Published
    Abstract [en]

    Studying olfaction with functional magnetic resonance imaging (fMRI) poses various methodological challenges. This study aimed to investigate the effects of stimulation length and repetition time (TR) on the activation pattern of 4 olfactory brain regions: the anterior and the posterior piriform cortex, the orbitofrontal cortex, and the insula. Twenty-two healthy participants with normal olfaction were examined with fMRI, with 2 stimulation lengths (6 s and 15 s) and 2 TRs (0.901 s and 1.34 s). Data were analyzed using General Linear Model (GLM), Tensorial Independent Component Analysis (TICA), and by plotting the event-related time course of brain activation in the 4 olfactory regions of interest. The statistical analysis of the time courses revealed that short TR was associated with more pronounced signal increase and short stimulation was associated with shorter time to peak signal. Additionally, both long stimulation and short TR were associated with oscillatory time courses, whereas both short stimulation and short TR resulted in more typical time courses. GLM analysis showed that the combination of short stimulation and short TR could result in visually larger activation within these olfactory areas. TICA validated that the tested paradigm was spatially and temporally associated with a functionally connected network that included all 4 olfactory regions. In conclusion, the combination of short stimulation and short TR is associated with higher signal increase and shorter time to peak, making it more amenable to standard GLM-type analyses than long stimulation and long TR, and it should, thus, be preferable for olfactory fMRI.

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS, 2018
    Keywords
    fMRI; olfaction; smell; repetition time
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-149862 (URN)10.1093/chemse/bjy025 (DOI)000438293600001 ()29726890 (PubMedID)
    Note

    Funding Agencies|Swedish Parkinson Foundation, Linkoping University Hospital Research Fund; ALF Grants from Region Ostergotland

    Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2019-04-17
  • 175.
    Georgiopoulos, Charalampos
    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.
    Davidsson, Anette
    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.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Larsson, Elna-Marie
    Uppsala University, Sweden.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dizdar (Dizdar Segrell), Nil
    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.
    The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes2015In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 262, no 9, p. 2154-2163Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinsons disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand I-123-FP-CIT (DaTSCAN (R)) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75 %) had visually predominant dopamine depletion in putamen, while most APS patients (56 %) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.

  • 176.
    Georgiopoulos, Charalampos
    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.
    Davidsson, Anette
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Granerus, Göran
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Dizdar (Dizdar Segrell), Nil
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    DaTSCAN SPECT EVALUATION OF PATIENTS WITH MOVEMENT DISORDERS2011In: EUROPEAN JOURNAL OF NEUROLOGY, Wiley-Blackwell, 2011, Vol. 18 (Suppl. 2), no SI, p. 567-567, article id P2617Conference paper (Other academic)
    Abstract [en]

    Introduction: Molecular imaging with DaTSCAN SPECTis widely used as a diagnostic tool in patients with movementdisorders in the form of Parkinson's Disease (PD),Parkinson-plus syndromes and Tremor. In the present studythe potency of DATScan SPECT to detect degeneration inthe basal ganglia in early stages of PD, before the onset ofmedication, is evaluated. In addition the efficacy ofDaTSCAN for differential diagnosis between patients withidiopathic PD and patients with Parkinson-plus syndromesis examined.

    Methodology: Participants: 21 patients with PD in earlystages, before the onset of medication, 20 patients withidiopathic PD and 6 patients with Parkinson-plussyndromes. 15 participants with normal results ofDaTSCAN SPECT and a clinical diagnosis different fromPD or Parkinson-plus were used as control.

    DaTSCAN SPECT: In the present study the quantificationof Striatum Occipital/Occipital and the Xeleris workstation(GE) were used.

    Results: The quantification for patients with idiopathic PD(1.185±0.05687) was significantly lower (p<0.0001) fromthe control (2.369±0.1258) and significantly lower (p<0.05)from that of patients in early stages of PD, before the onsetof medication (1.359±0.05324). There was no significantdifference between the idiopathic PD and Parkinson-plussyndromes (1.103±0.2442).

    Conclusion: DaTSCAN SPECT can detect efficiently earlydegeneration in the basal ganglia before the onset ofmedication is needed. Its efficacy for the differentialdiagnosis between idiopathic PD and Parkinson-plussyndromes is questioned. The combination of imaging andclinical examination is mandatory for a certain diagnosis.

  • 177.
    Georgiopoulos, Charalampos
    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.
    Warntjes, Marcel Jan Bertus
    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). SyntheticMR AB, Linkoping, Sweden.
    Dizdar Segrell, Nil
    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.
    Zachrisson, Helene
    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).
    Engström, Maria
    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).
    Haller, Sven
    Affidea CDRC Centre Diagnost Radiol Carouge SA, Switzerland; Uppsala University, Sweden.
    Larsson, Elna-Marie
    Uppsala University, Sweden.
    Olfactory Impairment in Parkinsons Disease Studied with Diffusion Tensor and Magnetization Transfer Imaging2017In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 2, p. 301-311Article in journal (Refereed)
    Abstract [en]

    Background: Olfactory impairment is an early manifestation of Parkinsons disease (PD). Diffusion Tensor Imaging (DTI) and Magnetization Transfer (MT) are two imaging techniques that allow noninvasive detection of microstructural changes in the cerebral white matter. Objective: To assess white matter alterations associated with olfactory impairment in PD, using a binary imaging approach with DTI and MT. Methods: 22 PD patients and 13 healthy controls were examined with DTI, MT and an odor discrimination test. DTI data were first analyzed with tract-based spatial statistics (TBSS) in order to detect differences in fractional anisotropy, mean, radial and axial diffusivity between PD patients and controls. Voxelwise randomized permutation was employed for the MT analysis, after spatial and intensity normalization. Additionally, ROI analysis was performed on both the DTI and MT data, focused on the white matter adjacent to olfactory brain regions. Results: Whole brain voxelwise analysis revealed decreased axial diffusivity in the left uncinate fasciculus and the white matter adjacent to the left olfactory sulcus of PD patients. ROI analysis demonstrated decreased axial diffusivity in the right orbitofrontal cortex, as well as decreased mean diffusivity and axial diffusivity in the white matter of the left entorhinal cortex of PD patients. There were no significant differences regarding fractional anisotropy, radial diffusivity or MT between patients and controls. Conclusions: ROI analysis of DTI could detect microstructural changes in the white matter adjacent to olfactory areas in PD patients, whereas MT imaging could not.

  • 178.
    Georgiopoulos, Charalampos
    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).
    Witt, Suzanne Tyson
    Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Haller, Sven
    Affidea CDRC Ctr Diagnost Radiol Carouge SA, Switzerland; Uppsala Univ, Sweden.
    Dizdar Segrell, Nil
    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.
    Zachrisson, Helene
    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.
    Engström, Maria
    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).
    Larsson, Elna-Marie
    Uppsala Univ, Sweden.
    Olfactory fMRI: Implications of Stimulation Length and Repetition Time2018In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 43, no 6, p. 389-398Article in journal (Refereed)
    Abstract [en]

    Studying olfaction with functional magnetic resonance imaging (fMRI) poses various methodological challenges. This study aimed to investigate the effects of stimulation length and repetition time (TR) on the activation pattern of 4 olfactory brain regions: the anterior and the posterior piriform cortex, the orbitofrontal cortex, and the insula. Twenty-two healthy participants with normal olfaction were examined with fMRI, with 2 stimulation lengths (6 s and 15 s) and 2 TRs (0.901 s and 1.34 s). Data were analyzed using General Linear Model (GLM), Tensorial Independent Component Analysis (TICA), and by plotting the event-related time course of brain activation in the 4 olfactory regions of interest. The statistical analysis of the time courses revealed that short TR was associated with more pronounced signal increase and short stimulation was associated with shorter time to peak signal. Additionally, both long stimulation and short TR were associated with oscillatory time courses, whereas both short stimulation and short TR resulted in more typical time courses. GLM analysis showed that the combination of short stimulation and short TR could result in visually larger activation within these olfactory areas. TICA validated that the tested paradigm was spatially and temporally associated with a functionally connected network that included all 4 olfactory regions. In conclusion, the combination of short stimulation and short TR is associated with higher signal increase and shorter time to peak, making it more amenable to standard GLM-type analyses than long stimulation and long TR, and it should, thus, be preferable for olfactory fMRI.

  • 179.
    Giambini, Hugo
    et al.
    Mayo Clin, MN 55905 USA.
    Hatta, Taku
    Mayo Clin, MN USA.
    Gorny, Krzysztof R.
    Mayo Clin, MN USA.
    Widholm, Per
    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. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Karlsson, Anette
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Adkins, Mark C.
    Mayo Clin, MN USA.
    Zhao, Chunfeng
    Mayo Clin, MN 55905 USA; Mayo Clin, MN USA.
    An, Kai-Nan
    Mayo Clin, MN 55905 USA; Mayo Clin, MN USA.
    INTRAMUSCULAR FAT INFILTRATION EVALUATED BY MAGNETIC RESONANCE IMAGING PREDICTS THE EXTENSIBILITY OF THE SUPRASPINATUS MUSCLE2018In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 57, no 1, p. 129-135Article in journal (Refereed)
    Abstract [en]

    Introduction: Rotator cuff (RC) tears result in muscle atrophy and fat infiltration within the RC muscles. An estimation of muscle quality and deformation, or extensibility, is useful in selecting the most appropriate surgical procedure. We determined if noninvasive quantitative assessment of intramuscular fat using MRI could be used to predict extensibility of the supraspinatus muscle. Methods: Seventeen cadaveric shoulders were imaged to assess intramuscular fat infiltration. Extensibility and histological evaluations were then performed. Results: Quantitative fat infiltration positively correlated with histological findings and presented a positive correlation with muscle extensibility (r=0.69; P=0.002). Extensibility was not significantly different between shoulders graded with a higher fat content versus those with low fat when implementing qualitative methods. Discussion: A noninvasive prediction of whole-muscle extensibility may directly guide pre-operative planning to determine if the torn edge could efficiently cover the original footprint while aiding in postoperative evaluation of RC repair.

  • 180.
    Ginstman, Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Frisk, Jessica
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
    Carlsson, Björn
    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.
    Ärlemalm, A.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Hägg, Staffan
    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.
    Brynhildsen, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Plasma concentrations of etonogestrel in women using oral desogestrel before and after Roux-en-Y gastric bypass surgery: a pharmacokinetic study2019In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 126, no 4, p. 486-492Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate whether Roux‐en‐Y gastric bypass (RYGB) affects oral desogestrel (etonogestrel) pharmacokinetics.

    Design

    Single centre, open label, phase‐2 pharmacokinetic study.

    Setting

    University hospital of Linköping, Sweden.

    Population

    Fourteen women with planned RYGB surgery were included; nine women aged 18–45 years using 75 micrograms desogestrel completed the study.

    Methods

    Steady‐state etonogestrel pharmacokinetic (PK) parameters were measured on three occasions for each individual (at 8 ± 6 weeks before surgery, and at 12 ± 2 and 52 ± 2 weeks after surgery). Each patient served as her own control. On each occasion, serum samples were collected during a 24‐hour period and etonogestrel concentrations were determined with ultra‐performance liquid chromatography/tandem mass spectrometry.

    Main outcome measures

    Area under the plasma concentration time curve of etonogestrel (AUC0–24 hours).

    Results

    All women had significant postoperative weight loss. There were no significant differences in AUC0–24 hours, terminal half‐lives (t½), time to peak serum concentrations (Tmax), or apparent oral clearances of etonogestrel (CLoral) before and after gastric bypass surgery on any occasion. Peak serum concentrations (Cmax) increased after 52 ± 2 weeks compared with preoperative values (0.817 ng/ml versus 0.590 ng/ml, P = 0.024).

    Conclusion

    To our knowledge, this is the first study to investigate the effects on desogestrel pharmacokinetics after RYGB. This study did not reveal any clinically significant changes in etonogestrel pharmacokinetics, suggesting that oral desogestrel may be used by women after RYGB surgery. The sample size was limited, however, and therefore the results should be interpreted cautiously.

  • 181.
    Gjesing Welinder, Karen
    et al.
    Aalborg University, Denmark.
    Hansen, Rasmus
    Aalborg University, Denmark; .
    Toft Overgaard, Michael
    Aalborg University, Denmark.
    Brohus, Malene
    Aalborg University, Denmark.
    Sonderkaer, Mads
    Aalborg University, Denmark.
    von Bergen, Martin
    Aalborg University, Denmark; UFZ Helmholtz Centre Environm Research, Germany; UFZ Helmholtz Centre Environm Research, Germany.
    Rolle-Kampczyk, Ulrike
    UFZ Helmholtz Centre Environm Research, Germany.
    Otto, Wolfgang
    UFZ Helmholtz Centre Environm Research, Germany.
    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.
    Arinell, Karin
    University of Örebro, Sweden.
    Evans, Alina L.
    Hedmark University of Coll, Norway.
    Swenson, Jon E.
    Norwegian University of Life Science, Norway; Norwegian Institute Nat Research, Norway.
    Revsbech, Inge G.
    Aarhus University, Denmark.
    Frobert, Ole
    University of Örebro, Sweden.
    Biochemical Foundations of Health and Energy Conservation in Hibernating Free-ranging Subadult Brown Bear Ursus arctos2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 43, p. 22509-22523Article in journal (Refereed)
    Abstract [en]

    Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematological features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex hormone-binding globulin levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms as follows: (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 degrees C reduction in body temperature and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of a few key proteins. The comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation and have implications for our understanding of physiology in general.

  • 182.
    Gnosa, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Capodanno, Alessandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dahl Ejby Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Sun, Xiao-Feng
    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 Oncology.
    AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 81634-81644Article in journal (Refereed)
    Abstract [en]

    Background Radiotherapy is a well-established anti-cancer treatment. Although radiotherapy has been shown to significantly decrease the local relapse in rectal cancer patients, the rate of distant metastasis is still very high. Several studies have shown that radiation enhances migration and invasion both in vitro and in vivo. The aim of this study was to evaluate whether AEG-1 is involved in radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model.

    Materials and Methods We evaluated the involvement of AEG-1 in migration and invasion and radiation-enhanced migration and invasion by Boyden chamber assay in three colon cancer cell lines and respective AEG-1 knockdown cell lines. Furthermore, we injected the cells in zebrafish embryos and evaluated the amount of disseminated cells into the tail.

    Results Migration and invasion was decreased in all the AEG-1 knockdown cell lines. Furthermore, radiation enhanced migration and invasion, while AEG-1 knockdown could abolish this effect. The results from the zebrafish model confirmed the results obtained in vitro. MMP-9 secretion and expression were decreased in AEG-1 knockdown cells.

    Conclusion Our results demonstrate that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced migration and invasion. We speculate that this is done via the downregulation of the intrinsic or radiation-enhanced MMP-9 expression. The zebrafish model can be used to study early events in radiation-enhanced invasion.

  • 183.
    Gothlin Eremo, Anna
    et al.
    University of Örebro, Sweden.
    Tina, Elisabet
    Örebro University Hospital, Sweden.
    Wegman, Pia
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stål, Olle
    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 Oncology.
    Fransen, Karin
    University of Örebro, Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Wingren, Sten
    University of Örebro, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (Pless than0.0005), PgR-negativity (Pless than0.0005), tumor size greater than20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

  • 184.
    Govorov, Igor
    et al.
    Karolinska Inst, Sweden.
    Bremme, Katarina
    Karolinska Inst, 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.
    Holmstrom, Margareta
    Karolinska Univ, Sweden.
    Komlichenko, Eduard
    Almazov Natl Med Res Ctr, Russia.
    Chaireti, Roza
    Karolinska Inst, Sweden.
    Mints, Miriam
    Karolinska Inst, Sweden.
    Thrombin generation during a regular menstrual cycle in women with von Willebrand disease2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17467Article in journal (Refereed)
    Abstract [en]

    Fluctuations of the sex steroids during the menstrual cycle might significantly influence hemostasis. This association, derived from a number of the observations on healthy women, is yet to be described in females affected by bleeding disorders. The aim of the current study was to assess the changes in hemostatic variables in women with vWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with healthy controls. The study group included 12 vWD-affected females with regular menstrual cycle, with none of them being prescribed any hormonal treatment. The control group consisted of 102 healthy females, matched for age and BMI. Within the vWD group FVIII and FX were both significantly higher during follicular phase than in luteal phase (p=0.013 and p=0.033 respectively). AT, FII, FVII and FX were higher in women with vWD, compared with controls during both phases of the menstrual cycle (pamp;lt;0.0005, pamp;lt;0.0005, p=0.001 and pamp;lt;0.0005). In women with vWD, lag time and time to peak were prolonged during both phases of the menstrual cycle(pamp;lt;0.0005), while peak thrombin concentration was reduced (p=0.003 and p=0.002 during follicular and luteal phase respectively) compared to healthy peers. Lower levels of FVIII and FX during luteal phase may predispose women to the development of the menorrhagia - common complication of vWD. Women with vWD need more time to reach the peak thrombin concentration, while the latter still remains less than in healthy women. Higher levels of AT in vWD-affected females, compared to controls, may also contribute to the existing bleeding tendency in this cohort.

  • 185.
    Grankvist, Kjell
    et al.
    Institutionen för medicinsk biovetenskap, Umeå universitet.
    Hammarsten, Ola
    Avdelningen för Laboratoriemedicin vid Institutionen för biomedicin, Göteborgs universitet.
    Maria, Berggren Söderlund
    Region Kronoberg, Klinisk kemi och transfusionsmedicin.
    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.
    Laboratoriernas verksamhet2018In: Laurells klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson, Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, p. 13-30Chapter in book (Other academic)
  • 186.
    Greaves, Ronda F
    et al.
    School of Health and Biomedical Sciences, RMIT University, Bundoora, Australia.
    Smith, Janet M
    Beastall, Graham
    Laboratory Medicine Consulting, Glasgow, UK.
    Florkowski, Chris
    Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
    Langman, Loralie
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States.
    Sheldon, Joanna
    Protein Reference Unit, St. George’s Hospital, London, UK.
    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.
    The IFCC Curriculum - phase 1.2018In: EJIFCC, ISSN 1650-3414, Vol. 29, no 1, p. 55-93Article in journal (Refereed)
  • 187.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Genetiska test för optimal dosering på väg att bli klinisk rutin2013In: Onkologi i Sverige, no 3, p. 36-40Article in journal (Other (popular science, discussion, etc.))
  • 188.
    Griekspoor, Petra
    et al.
    Linnaeus University, Sweden.
    Olsson Engvall, Eva
    National Vet Institute SVA, Sweden.
    Åkerlind, Britt
    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.
    Olsen, Bjorn
    Uppsala University, Sweden; Uppsala University, Sweden.
    Waldenstrom, Jonas
    Linnaeus University, Sweden.
    Genetic diversity and host associations in Campylobacter jejuni from human cases and broilers in 2000 and 20082015In: Veterinary Microbiology, ISSN 0378-1135, E-ISSN 1873-2542, Vol. 178, no 1-2, p. 94-98Article in journal (Refereed)
    Abstract [en]

    Campylobacter jejuni is an important food-borne pathogen, with a global distribution. It can colonize numerous host species, including both domestic and wild animals, but is particularly associated with birds (poultry and wild birds). For human campylobacteriosis, poultry products are deemed the most significant risk factor for acquiring infection. We conducted a genotyping and host attribution study of a large representative collection of C jejuni isolated from humans and broilers in Sweden in the years 2000 and 2008. In total 673 broiler and human isolates from 10 different abattoirs and 6 different hospitals were genotyped with multilocus sequence typing. Source attribution analyses confirmed the strong linkage between broiler C jejuni and domestic human cases, but also indicated a significant association to genotypes more commonly found in wild birds. Genotype distributions did not change dramatically between the two study years, suggesting a stable population of infecting bacteria. (C) 2015 Elsevier B.V. All rights reserved.

  • 189.
    Gréen, Anna
    et al.
    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.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden; Royal Institute Technology, Sweden; Science for Life Laboratory,{ School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Rehnberg, Malin
    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.
    Svensson, Anneli
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Gunnarsson, Cecilia
    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.
    Jonasson, Jon
    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.
    Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 1, p. 31-42Article in journal (Refereed)
    Abstract [en]

    The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TIN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with greater than99% of targeted nucleotides covered by greater than20x. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error causing motif Located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.90/0 to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to Loss of coverage.

  • 190.
    Gupta, Vikas
    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).
    Lantz, Jonas
    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).
    Henriksson, Lilian
    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.
    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. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    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).
    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).
    Automated three-dimensional tracking of the left ventricular myocardium in time-resolved and dose-modulated cardiac CT images using deformable image registration2018In: Journal of Cardiovascular Computed Tomography, ISSN 1934-5925, Vol. 12, no 2, p. 139-148Article in journal (Refereed)
    Abstract [en]

    Background Assessment of myocardial deformation from time-resolved cardiac computed tomography (4D CT) would augment the already available functional information from such an examination without incurring any additional costs. A deformable image registration (DIR) based approach is proposed to allow fast and automatic myocardial tracking in clinical 4D CT images.

    Methods Left ventricular myocardial tissue displacement through a cardiac cycle was tracked using a B-spline transformation based DIR. Gradient of such displacements allowed Lagrangian strain estimation with respect to end-diastole in clinical 4D CT data from ten subjects with suspected coronary artery disease. Dice similarity coefficient (DSC), point-to-curve error (PTC), and tracking error were used to assess the tracking accuracy. Wilcoxon signed rank test provided significance of tracking errors. Topology preservation was verified using Jacobian of the deformation. Reliability of estimated strains and torsion (normalized twist angle) was tested in subjects with normal function by comparing them with normal strain in the literature.

    Results Comparison with manual tracking showed high accuracy (DSC: 0.99± 0.05; PTC: 0.56mm± 0.47 mm) and resulted in determinant(Jacobian) > 0 for all subjects, indicating preservation of topology. Average radial (0.13 mm), angular (0.64) and longitudinal (0.10 mm) tracking errors for the entire cohort were not significant (p > 0.9). For patients with normal function, average strain [circumferential, radial, longitudinal] and peak torsion estimates were: [-23.5%, 31.1%, −17.2%] and 7.22°, respectively. These estimates were in conformity with the reported normal ranges in the existing literature.

    Conclusions Accurate wall deformation tracking and subsequent strain estimation are feasible with the proposed method using only routine time-resolved 3D cardiac CT.

  • 191.
    Gustafsson, Gabriel
    et al.
    Uppsala Univ, Sweden.
    Loov, Camilla
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Persson, Emma
    Uppsala Univ, Sweden.
    Lazaro, Diana F.
    Univ Med Ctr Gottingen, Germany.
    Takeda, Shuko
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Bergstrom, Joakim
    Uppsala Univ, Sweden.
    Erlandsson, Anna
    Uppsala Univ, Sweden.
    Sehlin, Dag
    Uppsala Univ, Sweden.
    Balaj, Leonora
    Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Gyorgy, Bence
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Outeiro, Tiago F.
    Univ Med Ctr Gottingen, Germany; Max Planck Inst Expt Med, Germany; Newcastle Univ, England.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hyman, Bradley T.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Ingelsson, Martin
    Uppsala Univ, Sweden; Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells2018In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed)
    Abstract [en]

    In Parkinsons disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular -synuclein (-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of -syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of -syn can influence the distribution and secretion of -syn in human neuroblastoma cells. Different -syn variants, including -syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted -syn, 0.1-2% was associated with vesicles. The major part of EV -syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For -syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT -syn. Moreover, such EV-associated -syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T -syn displayed an increased association with EVs. Taken together, our data suggest that -syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful -syn species and thereby contribute to the pathology in -synucleinopathies.

  • 192.
    Gustafsson, Håkan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Biomedical Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    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.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Norwegian University of Science and Technology, Norway.
    Kolbun, Natallia
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jonson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    de Muinck, Ebo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Visualization of oxidative stress in ex vivo biopsies using electron paramagnetic resonance imaging2015In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 73, no 4, p. 1682-1691Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study was to develop an X-Band electron paramagnetic resonance imaging protocol for visualization of oxidative stress in biopsies.

    METHODS: The developed electron paramagnetic resonance imaging protocol was based on spin trapping with the cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. Computer software was developed for deconvolution and back-projection of the EPR image. A phantom containing radicals of known spatial characteristic was used for evaluation of the developed protocol. As a demonstration of the technique electron paramagnetic resonance imaging of oxidative stress was performed in six sections of atherosclerotic plaques. Histopathological analyses were performed on adjoining sections.

    RESULTS: The developed computer software for deconvolution and back-projection of the EPR images could accurately reproduce the shape of a phantom of known spatial distribution of radicals. The developed protocol could successfully be used to image oxidative stress in six sections of the three ex vivo atherosclerotic plaques.

    CONCLUSIONS: We have shown that oxidative stress can be imaged using a combination of spin trapping with the cyclic hydroxylamine spin probe cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. A thorough and systematic evaluation on different types of biopsies must be performed in the future to validate the proposed technique. Magn Reson Med, 2014.

  • 193.
    Gustafsson, Håkan
    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 Norrköping/Finspång. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Kale, Ajay
    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 Otorhinolaryngology in Linköping.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. The Skandion Clinic, Uppsala, Sweden.
    Lund, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Chemical Physics. Linköping University, Faculty of Science & Engineering.
    Edqvist, Per-Henrik
    Uppsala University, Uppsala, Sweden.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    EPR oximetry of cetuximab-treated head-and-neck tumours in a mouse model2017In: Cell Biochemistry and Biophysics, ISSN 1085-9195, E-ISSN 1559-0283, Vol. 75, no 3-4, p. 299-309Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) tumours are associated with high mortality despite advances in therapy. The monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of advanced HNSCC. However, only a subset of HNSC patients receiving cetuximab actually responds to treatment, underlining the need for a means to tailor treatments of individual patients. The aim of the present study was to investigate the effect of cetuximab treatment on tumour growth, on tumour partial oxygen pressure as measured by LiPc electron paramagnetic resonance oximetry and on the expression of proteins involved in tumour growth, metabolism and hypoxia. Two HNSCC cell lines, UT-SCC-2 and UT-SCC-14, were used to generate xenografts on female BALB/c (nu/nu) nude mice. Mice with xenografts were given three injections of intraperitoneal cetuximab or phosphate-buffered saline, and the tumour volume was recorded continuously. After treatment the tumour partial oxygen pressure was measured by LiPc electron paramagnetic resonance oximetry and the expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Ki-67, MCT1, MCT4, GLUT1, CAIX and HIF-1α were investigated by immunohistochemistry. In xenografts from both cell lines (UT-SCC-2 and UT-SCC-14) cetuximab had effect on the tumour volume but the effect was more pronounced on UT-SCC-14 xenografts. A higher tumour oxygenation was measured in cetuximab-treated tumours from both cell lines compared to untreated controls. Immunocytochemical staining after cetuximab treatment shows a significantly decreased expression of EGFR, pEGFR, Ki67, CAIX and nuclear HIF-1α in UT-SCC-14 tumours compared to untreated controls. MCT1 and GLUT1 were significantly decreased in tumours from both cell lines but more pronounced in UT-SCC-14 tumours. Taken together, our results show that cetuximab treatment decreases the tumour growth and increases the tumour partial oxygen pressure of HNSCC xenografts. Furthermore we found a potential connection between the partial oxygen pressure of the tumours and the expression of proteins involved in tumour growth, metabolism and hypoxia.

  • 194.
    Gustafsson, Mika
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Alfredsson, Lars
    Karolinska Institute, Sweden.
    Baranzini, Sergio
    University of Calif San Francisco, CA, USA.
    Bjorkander, Janne
    County Council Jonköping, Sweden.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hellberg, Sandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Kockum, Ingrid
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden.
    Konstantinell, Aelita
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Arctic University of Norway, Norway.
    Lahesmaa, Riita
    University of Turku, Finland; Abo Akad University, Finland.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Liljenström, H. Robert I.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Mattson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Matussek, Andreas
    County Council Jonköping, Sweden.
    Mellergård, Johan
    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.
    Mendez, Melissa
    University of Peruana Cayetano Heredia, Peru.
    Olsson, Tomas
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden.
    Pujana, Miguel A.
    Catalan Institute Oncol, Spain.
    Rasool, Omid
    University of Turku, Finland; Abo Akad University, Finland.
    Serra-Musach, Jordi
    Catalan Institute Oncol, Spain.
    Stenmarker, Margaretha
    County Council Jonköping, Sweden.
    Tripathi, Subhash
    University of Turku, Finland; Abo Akad University, Finland.
    Viitala, Miro
    University of Turku, Finland; Abo Akad University, Finland.
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases2015In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 313, article id 313ra178Article in journal (Refereed)
    Abstract [en]

    Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

  • 195.
    Gustavsson, O.
    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, Department of Clinical Microbiology. Innlandet Hospital Trust, Norway.
    Johansson, A. V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Monstein, Hans-Jurg
    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.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bredberg, A.
    Innlandet Hospital Trust, Norway; Lund University, Sweden.
    A wide spectrum of fastidious and ampicillin-susceptible bacteria dominate in animal-caused wounds2016In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, no 8, p. 1315-1321Article in journal (Refereed)
    Abstract [en]

    The main purpose of this study was to assess the actual occurrence of Gram-negative oxidase-positive bacteria (GNOP) in human wounds caused by animals, mostly cat and dog bites and scratches, and with signs of infection. We report a prospective series of 92 wound samples. Routine culturing was combined with a procedure optimised for fastidious GNOP. All GNOP isolates were identified by 16S rDNA sequencing to the species level. We observed a more prominent role of GNOP, including at least 30 species mostly in the families Flavobacteriaceae, Neisseriaceae and Pasteurellaceae, and less of Staphylococcus aureus and streptococci. The antibiotic susceptibility pattern was investigated, as GNOP are associated with sudden onset of serious infections, making an early decision on antibiotic treatment vital. All GNOP isolates judged to be clinically relevant displayed susceptibility to ampicillin and meropenem, but resistance to oxacillin, clindamycin and gentamicin was frequent. Our findings emphasise the need to cover GNOP as recommended in guidelines, and not only common wound pathogens, when treating an animal-caused wound.

  • 196.
    Gyllemark, Paula
    et al.
    Department of Infectious Diseases, Region Jönköping County, Jönköping, Sweden.
    Forsberg, Pia
    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.
    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.
    Henningsson, Anna J.
    Clinical Microbiology, Division of Medical Services, Jönköping, Region Jönköping County, Sweden.
    Intrathecal Th17- and B cell-associated cytokine and chemokine responses in relation to clinical outcome in Lyme neuroborreliosis: a large retrospective study.2017In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: B cell immunity, including the chemokine CXCL13, has an established role in Lyme neuroborreliosis, and also, T helper (Th) 17 immunity, including IL-17A, has recently been implicated.

    METHODS: We analysed a set of cytokines and chemokines associated with B cell and Th17 immunity in cerebrospinal fluid and serum from clinically well-characterized patients with definite Lyme neuroborreliosis (group 1, n = 49), defined by both cerebrospinal fluid pleocytosis and Borrelia-specific antibodies in cerebrospinal fluid and from two groups with possible Lyme neuroborreliosis, showing either pleocytosis (group 2, n = 14) or Borrelia-specific antibodies in cerebrospinal fluid (group 3, n = 14). A non-Lyme neuroborreliosis reference group consisted of 88 patients lacking pleocytosis and Borrelia-specific antibodies in serum and cerebrospinal fluid.

    RESULTS: Cerebrospinal fluid levels of B cell-associated markers (CXCL13, APRIL and BAFF) were significantly elevated in groups 1, 2 and 3 compared with the reference group, except for BAFF, which was not elevated in group 3. Regarding Th17-associated markers (IL-17A, CXCL1 and CCL20), CCL20 in cerebrospinal fluid was significantly elevated in groups 1, 2 and 3 compared with the reference group, while IL-17A and CXCL1 were elevated in group 1. Patients with time of recovery <3 months had lower cerebrospinal fluid levels of IL-17A, APRIL and BAFF compared to patients with recovery >3 months.

    CONCLUSIONS: By using a set of markers in addition to CXCL13 and IL-17A, we confirm that B cell- and Th17-associated immune responses are involved in Lyme neuroborreliosis pathogenesis with different patterns in subgroups. Furthermore, IL-17A, APRIL and BAFF may be associated with time to recovery after treatment.

  • 197.
    Gyllensten, Hanna
    et al.
    Nordic School Public Health NHV, Sweden; University of Gothenburg, Sweden; Karolinska Institute, Sweden.
    Jönsson, Anna K
    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.
    Hakkarainen, Katja M.
    Nordic School Public Health NHV, Sweden; EPID Research, Finland.
    Svensson, Staffan
    Narhalsan Hjallbo Medical Centre, Finland.
    Hägg, Staffan
    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. Jonköping County Council, Sweden.
    Rehnberg, Clas
    Karolinska Institute, Sweden.
    Comparing Methods for Estimating Direct Costs of Adverse Drug Events2017In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 10, p. 1299-1310Article in journal (Refereed)
    Abstract [en]

    Objectives: To estimate how direct health care costs resulting from adverse drug events (ADEs) and cost distribution are affected by methodological decisions regarding identification of ADEs, assigning relevant resource use to ADEs, and estimating costs for the assigned resources. Methods: ADEs were identified from medical records and diagnostic codes for a random sample of 4970 Swedish adults during a 3-month study period in 2008 and were assessed for causality. Results were compared for five cost evaluation methods, including different methods for identifying ADEs, assigning resource use to ADEs, and for estimating costs for the assigned resources (resource use method, proportion of registered cost method, unit cost method, diagnostic code method, and main diagnosis method). Different levels of causality for ADEs and ADEs contribution to health care resource use were considered. Results: Using the five methods, the maximum estimated overall direct health care costs resulting from ADEs ranged from Sk10,000 (Sk = Swedish krona; similar to(sic)1,500 in 2016 values) using the diagnostic code method to more than Sk3,000,000 (similar to(sic)414,000) using the unit cost method in our study population. The most conservative definitions for ADEs contribution to health care resource use and the causality of ADEs resulted in average costs per patient ranging from Sk0 using the diagnostic code method to Sk4066 (similar to(sic)500) using the unit cost method. Conclusions: The estimated costs resulting from ADEs varied considerably depending on the methodological choices. The results indicate that costs for ADEs need to be identified through medical record review and by using detailed unit cost data. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

  • 198.
    Haage, Pernilla
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping Sweden.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping Sweden.
    Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.2016In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 119, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The analgesic drug tramadol and its metabolites are chiral compounds, with the (+)- and (-)-enantiomers showing different pharmacological and toxicological effects. This novel enantioselective method, based on LC-MS/MS in reversed phase mode, enabled measurement of the parent compound and its three main metabolites O-desmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol simultaneously. Whole blood samples of 0.5g were fortified with internal standards (tramadol-(13)C-D3 and O-desmethyl-cis-tramadol-D6) and extracted under basic conditions (pH 11) by liquid-liquid extraction. Chromatography was performed on a chiral alpha-1-acid glycoprotein (AGP) column preceded by an AGP guard column. The mobile phase consisted of 0.8% acetonitrile and 99.2% ammonium acetate (20mM, pH 7.2). A post-column infusion with 0.05% formic acid in acetonitrile was used to enhance sensitivity. Quantitation as well as enantiomeric ratio measurements were covered by quality controls. Validation parameters for all eight enantiomers included selectivity (high), matrix effects (no ion suppression/enhancement), calibration model (linear, weight 1/X(2), in the range of 0.25-250ng/g), limit of quantitation (0.125-0.50ng/g), repeatability (2-6%) and intermediate precision (2-7%), accuracy (83-114%), dilution integrity (98-115%), carry over (not exceeding 0.07%) and stability (stable in blood and extract). The method was applied to blood samples from a healthy volunteer administrated a single 100mg dose and to a case sample concerning an impaired driver, which confirmed its applicability in human pharmacokinetic studies as well as in toxicological and forensic investigations.

  • 199.
    Haarhaus, Mathias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Karolinska Institute, Sweden.
    Brandenburg, Vincent
    RWTH University Hospital Aachen, Germany.
    Kalantar-Zadeh, Kamyar
    University of Calif Irvine, CA 92868 USA; University of Calif Los Angeles, CA 90502 USA.
    Stenvinkel, Peter
    Karolinska Institute, Sweden.
    Magnusson, Per
    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.
    Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD2017In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 13, no 7, p. 429-442Article, review/survey (Refereed)
    Abstract [en]

    Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing. Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification. This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role. Four genes encode ALP isozymes in humans. Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney. TNALP has a pivotal role in bone calcification. Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM. Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli. Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases. We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.

  • 200.
    Haarhaus, Mathias
    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, Heart and Medicine Center, Department of Nephrology. Karolinska University Hospital, Sweden.
    Monier-Faugere, Marie-Claude
    University of Kentucky, KY 40536 USA.
    Magnusson, Per
    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.
    Malluche, Hartmut H.
    University of Kentucky, KY 40536 USA.
    Bone Alkaline Phosphatase Isoforms in Hemodialysis Patients With Low Versus Non-Low Bone Turnover: A Diagnostic Test Study2015In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 66, no 1, p. 99-105Article in journal (Refereed)
    Abstract [en]

    Background: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (bALP) isoform B1x is exclusively found in serum of some patients with CKD. Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum bALP isoform activity and histomorphometric parameters of bone in patients with CKD receiving maintenance hemodialysis. Settings and Participants: Anterior iliac crest bone biopsy samples from 40 patients with CKD were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover. Index Test: In serum, bALP, bALP isoforms (B/I, B1x, B1, and B2), and parathyroid hormone (PTH) were measured. Reference Test: Low bone turnover was defined by mineral apposition rate, 0.36 mu m/d. Non-low bone turnover was defined by mineral apposition rate greater than= 0.36 mu m/d. Other Measurements: PTH. Results: B1x was found in 21 patients (53%) who had lower median levels of bALP, 18.6 versus 46.9 U/L; B/I, 0.10 versus 0.22 mu kat/L; B1, 0.40 versus 0.88 mu kat/L; B2, 1.21 versus 2.66 mu kat/L; and PTH, 49 versus 287 pg/mL, compared with patients without B1x (P less than 0.001). 13 patients (65%) with low bone turnover and 8 patients (40%) with non-low bone turnover (P less than 0.2) had detectable B1x. B1x correlated inversely with histomorphometric parameters of bone turnover. Receiver operating characteristic curves showed that B1x can be used for the diagnosis of low bone turnover (area under the curve [AUC], 0.83), whereas bALP (AUC, 0.89) and PTH (AUC, 0.85) are useful for the diagnosis of non-low bone turnover. Limitations: Small number of study participants. Requirement of high-performance liquid chromatography methods for measurement of B1x. Conclusions: B1x, PTH, and bALP have similar diagnostic accuracy in distinguishing low from non-low bone turnover. The presence of B1x is diagnostic of low bone turnover, whereas elevated bALP and PTH levels are useful for the diagnosis of non-low bone turnover.

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