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  • 151.
    Domert, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sackmann, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Severinsson, Emelie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Gothenburg, Sweden.
    Bergstrom, Joakim
    Uppsala University, Sweden.
    Ingelsson, Martin
    Uppsala University, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes2016In: PLOS ONE, ISSN 1932-6203, Vol. 11, no 12, article id e0168700Article in journal (Refereed)
    Abstract [en]

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

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  • 152.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Arnesen, Thomas
    Haukeland Hosp, Norway; Univ Bergen, Norway; Univ Bergen, Norway.
    Heie, Anette
    Haukeland Hosp, Norway.
    Walz, Martin
    Klin Chirurg and Zentrum Minimal Invas Chirurg, Germany.
    Alesina, Piero
    Klin Chirurg and Zentrum Minimal Invas Chirurg, Germany.
    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.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 5, p. K37-K41Article in journal (Refereed)
    Abstract [en]

    Objective: To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs). Description: Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (CIC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured. Conclusion: In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.

  • 153.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Genetics of primary hyperaldosteronism2016In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 23, no 10, p. R437-R454Article, review/survey (Refereed)
    Abstract [en]

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

  • 154.
    Edvardsson, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång, Primary Health Care in Finspång.
    Sund-Levander, Märtha
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Grodzinsky, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Rättsmedicinalverket, Linköping, Sweden.
    Clinical use of conventional reference intervals in the frail elderly2015In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 21, no 2, p. 229-235Article in journal (Refereed)
    Abstract [en]

    Rationale, aims and objectives

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

    Methods

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

    Results

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

    Conclusion

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

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  • 155.
    Edvardsson, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång, Health care Center Finspång.
    Sund-Levander, Märtha
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Milberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Advanced Home Care in Norrköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Division of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Sweden.
    Elevated levels of CRP and IL-8 are related to reduce survival time: 1-year follow-up measurements of different analytes in frail elderly nursing home residents2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 5, p. 288-292Article in journal (Refereed)
    Abstract [en]

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

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  • 156.
    Ehlersson, Gustaf
    et al.
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Hellmark, Bengt
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Svartström, Olov
    Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Stenmark, Bianca
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Soderquist, Bo
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Phenotypic characterisation of coagulase-negative staphylococci isolated from blood cultures in newborn infants, with a special focus on Staphylococcus capitis2017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 10, p. 1576-1582Article in journal (Refereed)
    Abstract [en]

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

  • 157.
    Ehsan Saffari, Seyed
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Sabzevar University of Medical Science, Iran.
    Love, Askell
    Lund University, Sweden; Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Smedby, Örjan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    Regression models for analyzing radiological visual grading studies - an empirical comparison2015In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 15, no 49Article in journal (Refereed)
    Abstract [en]

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

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  • 158.
    Ekholm, Maria
    et al.
    Lund University, Sweden; Ryhov County Hospital, Sweden.
    Grabau, Dorthe
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Bendahl, Par-Ola
    Lund University, Sweden.
    Bergh, Jonas
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Elmberger, Goran
    University of Örebro, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Russo, Leila
    University of Milan, Italy.
    Viale, Giuseppe
    University of Milan, Italy.
    Ferno, Marten
    Lund University, Sweden.
    Highly reproducible results of breast cancer biomarkers when analysed in accordance with national guidelines - a Swedish survey with central re-assessment2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 7, p. 1040-1048Article in journal (Refereed)
    Abstract [en]

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

  • 159.
    Ekman, Agneta
    et al.
    Institutionen för medicin Göteborg, Sweden.
    Böttiger, Ylva
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Eriksson, Anna
    Sahlgrenska akademin, Göteborg.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Skåne, Sweden.
    Person, Katarina
    Institutionen for Medicinska Vetenskaper, Örebro, Sweden.
    Pettersson Kymmer, Ulrika
    Umeå universitet , Sweden .
    Wallerstedt, Susanna M.
    Sahlgrenska akademin, Sweden.
    Läkemedelsarbete behöver vara integrerat i klinisk utbildning [Preparing for the licence to prescribe in medical school - a questionnaire study on medical students professional confidence in the art of prescribing]2019In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116Article in journal (Refereed)
    Abstract [en]

    A prerequisite for rational use of medicines is adequate prescribing skills; drug treatment is a complex task requiring diagnostic competence combined with pharmacologic knowledge and patient communication skills. Acquiring professional confidence in the art of prescribing is essential during medical training. The results of this questionnaire study, conducted in four medical schools in Sweden after the course in internal medicine (252 respondents; response rate: 74%; median age: 24 years, 61% female), show that 45% and 62% were confident in performing medication reviews and writing medication summary reports, respectively, i.e. the basics of prescribing. The confidence increased by the number of reviews and reports performed, i.e. the extent of practice (correlation coefficients: 0.41 and 0.38, respectively, both pamp;lt;0.0001), as did the extent of the students reflection on important aspects of drug treatment such as adherence, adverse reactions, renal function, dosing, and drug interactions. In multivariate regression analyses, major predictors for confidence in performing medication reviews were extent of practice and extent of clinical supervision. The results suggest that these factors are keys to acquiring professional confidence in the art of prescribing.

  • 160.
    Ekman, Bertil
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Wahlberg Topp, Jeanette
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Landberg, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Urine oligosaccharide pattern in patients with hyperprolactinaemia2015In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 32, no 8, p. 635-641Article in journal (Refereed)
    Abstract [en]

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

  • 161.
    Elawa, Sherif
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Mirdell, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    The microvascular response in the skin to topical application of methyl nicotinate: Effect of concentration and variation between skin sites2019In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 124, p. 54-60Article in journal (Refereed)
    Abstract [en]

    Background

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

    Methods

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

    Results

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

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

    Conclusion

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

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  • 162.
    Eleftheriou, Andreas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Blystad, Ida
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Tisell, Anders
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Gasslander, Johan
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Norrköping.
    Lundin, Fredrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Indication of Thalamo-Cortical Circuit Dysfunction in Idiopathic Normal Pressure Hydrocephalus: A Tensor Imaging Study2020In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 10, no 1Article in journal (Refereed)
    Abstract [en]

    Idiopathic normal pressure hydrocephalus (iNPH) is a disorder with unclear pathophysiology. The diagnosis of iNPH is challenging due to its radiological similarity with other neurodegenerative diseases and ischemic subcortical white matter changes. By using Diffusion Tensor Imaging (DTI) we explored differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in iNPH patients (before and after a shunt surgery) and healthy individuals (HI) and we correlated the clinical results with DTI parameters. Thirteen consecutive iNPH-patients underwent a pre- and post-operative clinical work-up: 10m walk time (w10mt) steps (w10ms), TUG-time (TUGt) and steps (TUGs); for cognitive function MMSE. Nine HI were included. DTI was performed before and 3 months after surgery, HI underwent DTI once. DTI differences analyzed by manually placing 12 regions-of-interest. In patients motor and balance function improved significantly after surgery (p=0.01, p=0.025). Higher nearly significant FA values found in the patients vs HI pre-operatively in the thalamus (p=0.07) accompanied by an almost significant lower ADC (p=0.08). Significantly FA and ADC-values were found between patients and HI in FWM (p=0.02, p=0.001) and almost significant (p=0.057) pre- vs postoperatively. Postoperatively we found a trend towards the HIs FA values and a strong significant negative correlation between FA changes vs. gait results in the FWM (r=-0.7, p=0.008). Our study gives a clear indication of an ongoing pathological process in the periventricular white matter, especially in the thalamus and in the frontal white matter supporting the hypothesis of a shunt reversible thalamo-cortical circuit dysfunction in iNPH.

  • 163.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-12015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed)
    Abstract [en]

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

  • 164.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Khalid, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. King Khalid Univ, Saudi Arabia.
    Svanberg, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Holgersson, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thoren, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Wittgren, Mirja Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Shankar, Esaki M.
    Univ Malaya, Malaysia; Cent Univ Tamil Nadu, India.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed)
    Abstract [en]

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

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  • 165.
    Elmasry, Moustafa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Mirdell, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Department of Medical and Health Sciences.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Laser speckle contrast imaging in children with scalds: Its influence on timing of intervention, duration of healing and care, and costs2019In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 45, no 4, p. 798-804Article in journal (Refereed)
    Abstract [sv]

    Background

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

    Methods

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

    Results

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

    Conclusion

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

  • 166.
    Engström, Karolina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Vanky, Farkas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rehnberg, Malin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Trinks, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Jonasson, Jon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Green, Anna
    Orebro Univ, Sweden.
    Gunnarsson, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection2020In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, article id e1089Article in journal (Refereed)
    Abstract [en]

    Background Pathogenic variants in the SMAD3 gene affecting the TGF-beta/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome. Methods Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis. Results We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G amp;gt; C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta. Conclusion A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.

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  • 167.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Ronnelid, Johan
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 5, p. 817-825Article in journal (Refereed)
    Abstract [en]

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

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  • 168.
    Enocsson, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Padyukov, Leonid
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Urowitz, Murray B.
    Toronto Western Hosp, Canada; Univ Toronto, Canada.
    Gladmane, Dafna D.
    Toronto Western Hosp, Canada; Univ Toronto, Canada.
    Romero-Diaz, Juanita
    Inst Nacl Ciencias Med and Nutr Salvador Zubiran, Mexico.
    Bae, Sang-Cheol
    Hanyang Univ, South Korea.
    Fortin, Paul R.
    Univ Laval, Canada.
    Sanchez-Guerrero, Jorge
    Toronto Western Hosp, Canada; Univ Toronto, Canada.
    Clarke, Ann E.
    Univ Calgary, Canada.
    Bernatsky, Sasha
    McGill Univ, Canada.
    Gordon, Caroline
    Univ Birmingham, England.
    Hanly, John G.
    Queen Elizabeth 2 Hlth Sci Ctr, Canada; Queen Elizabeth 2 Hlth Sci Ctr, Canada; Dalhousie Univ, Canada.
    Wallace, Daniel J.
    Univ Calif Los Angeles, CA USA.
    Isenberg, David A.
    UCL, England.
    Rahman, Anisur
    UCL, England.
    Merrill, Joan T.
    Oklahoma Med Res Fdn, OK 73104 USA.
    Ginzler, Ellen
    Suny Downstate Med Ctr, NY 11203 USA.
    Alarcon, Graciela S.
    Univ Alabama Birmingham, AL 35294 USA.
    Chatham, W. Winn
    Univ Alabama Birmingham, AL 35294 USA.
    Petri, Michelle
    Johns Hopkins Univ, MD USA.
    Khamashta, Munther
    Kings Coll London, England.
    Aranow, Cynthia
    Feinstein Inst Med Res, NY USA.
    Mackay, Meggan
    Feinstein Inst Med Res, NY USA.
    Dooley, Mary Anne
    Univ N Carolina, NC 27515 USA.
    Manzi, Susan
    Allegheny Hlth Network, PA USA.
    Ramsey-Goldman, Rosalind
    Northwestern Univ, IL 60611 USA; Feinberg Sch Med, IL USA.
    Nived, Ola
    Lund Univ, Sweden.
    Steinsson, Kristjan
    Landspitali Univ Hosp, Iceland.
    Zoma, Asad A.
    Hairmyres Hosp, Scotland.
    Ruiz-Irastorza, Guillermo
    Univ Basque Country, Spain.
    Lim, S. Sam
    Emory Univ, GA USA.
    Kalunian, Kenneth C.
    UCSD Sch Med, CA USA.
    Inanc, Murat
    Istanbul Univ, Turkey.
    van Vollenhoven, Ronald F.
    Univ Amsterdam, Netherlands; Free Univ VU Amsterdam, Netherlands; Amsterdam Rheumatol and Immunol Ctr, Netherlands.
    Ramos-Casals, Manuel
    Hosp Clin Barcelona, Spain.
    Kamen, Diane L.
    Med Univ South Carolina, SC 29425 USA.
    Jacobsen, Soren
    Copenhagen Univ Hosp, Denmark.
    Peschken, Christine A.
    Univ Manitoba, Canada.
    Askanase, Anca
    Columbia Univ, NY USA.
    Stoll, Thomas
    Kantousspital, Switzerland.
    Bruce, Ian N.
    Univ Manchester, England; Manchester Univ Hosp NHS Fdn Trust, England.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus2020In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 106, article id 102340Article in journal (Refereed)
    Abstract [en]

    Objective

    The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE.

    Methods

    Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI).

    Results

    The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03–1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007).

    Conclusion

    Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

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  • 169.
    Eriksson, Anders
    et al.
    Umeå University, Sweden.
    Gustafsson, Torfinn
    Umeå University, Sweden.
    Hoistad, Malin
    Swedish Agency Health Technology Assessment and Assessment, Sweden; Karolinska Institute, Sweden.
    Hultcrantz, Monica
    Swedish Agency Health Technology Assessment and Assessment, Sweden; Karolinska Institute, Sweden.
    Jacobson, Stella
    Swedish Agency Health Technology Assessment and Assessment, Sweden.
    Mejare, Ingegerd
    Swedish Agency Health Technology Assessment and Assessment, Sweden.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Diagnostic accuracy of postmortem imaging vs autopsy-A systematic review2017In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 89, p. 249-269Article, review/survey (Refereed)
    Abstract [en]

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

  • 170.
    Eriksson, D.
    et al.
    Karolinska Institute, Sweden; Metab and Diabet Karolinska University Hospital, Sweden.
    Bianchi, M.
    Uppsala University, Sweden.
    Landegren, N.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Nordin, J.
    Uppsala University, Sweden.
    Dalin, F.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Mathioudaki, A.
    Uppsala University, Sweden.
    Eriksson, G. N.
    Karolinska Institute, Sweden.
    Hultin-Rosenberg, L.
    Uppsala University, Sweden.
    Dahlqvist, J.
    Uppsala University, Sweden.
    Zetterqvist, H.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Karlsson, A.
    Uppsala University, Sweden.
    Hallgren, A.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Farias, F. H. G.
    Uppsala University, Sweden.
    Muren, E.
    Uppsala University, Sweden.
    Ahlgren, K. M.
    Uppsala University, Sweden.
    Lobell, A.
    Uppsala University, Sweden.
    Andersson, G.
    Swedish University of Agriculture Science, Sweden.
    Tandre, K.
    Uppsala University, Sweden.
    Dahlqvist, S. R.
    Umeå University, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rönnblom, L.
    Uppsala University, Sweden.
    Hulting, A. -L.
    Karolinska Institute, Sweden.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ekwall, O.
    University of Gothenburg, Sweden.
    Dahlqvist, P.
    Umeå University, Sweden.
    Meadows, J. R. S.
    Uppsala University, Sweden.
    Bensing, S.
    Metab and Diabet Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Lindblad-Toh, K.
    Uppsala University, Sweden; Broad Institute MIT and Harvard, MA USA.
    Kampe, O.
    Karolinska Institute, Sweden; Metab and Diabet Karolinska University Hospital, Sweden; Uppsala University, Sweden.
    Pielberg, G. R.
    Uppsala University, Sweden.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addisons disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed)
    Abstract [en]

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

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  • 171.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Landegren, Nils
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Dalin, Frida
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Skov, Jakob
    Karolinska Inst, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala Univ, Sweden.
    Mathioudaki, Argyri
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Hallgren, Asa
    Karolinska Inst, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Hulting, Anna-Lena
    Not Found:[Eriksson, Daniel; Landegren, Nils; Dalin, Frida; Hallgren, Asa; Kampe, Olle] Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; [Eriksson, Daniel; Bensing, Sophie; Kampe, Olle] Karolinska Univ Hosp, Dept Endocrinol Metab and Diabet, Stockholm, Sweden; [Bianchi, Matteo; Hultin-Rosenberg, Lina; Mathioudaki, Argyri; Nordin, Jessika; Meadows, Jennifer R. S.; Lindblad-Toh, Kerstin; Pielberg, Gerli Rosengren] Uppsala Univ, Dept Med Biochem and Microbiol, Sci Life Lab, Uppsala, Sweden; [Landegren, Nils; Dalin, Frida; Tandre, Karolina; Ronnblom, Lars] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden; [Skov, Jakob; Bensing, Sophie] Karolinska Inst, Dept Mol Med and Surg, Stockholm, Sweden; [Andersson, Goran] Swedish Univ Agr Sci, Dept Anim Breeding and Genet, Uppsala, Sweden; [Dahlqvist, Solbritt Rantapaa; Dahlqvist, Per] Umea Univ, Dept Publ Hlth and Clin Med, Umea, Sweden; [Soderkvist, Peter; Wahlberg, Jeanette] Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Endocrinol, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol and Inflammat Res, Gothenburg, Sweden; [Lindblad-Toh, Kerstin] Broad Inst MIT and Harvard, Cambridge, MA USA; [Kampe, Olle] KG Jebsen Ctr Autoimmune Dis, Bergen, Norway;.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT and Harvard, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Kampe, Olle
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; KG Jebsen Ctr Autoimmune Dis, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addisons disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

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

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  • 172.
    Eriksson, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bornefall, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Villamil Giraldo, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Impact of high cholesterol in a Parkinsons disease model: Prevention of lysosomal leakage versus stimulation of alpha-synuclein aggregation2017In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 96, no 2, p. 99-109Article in journal (Refereed)
    Abstract [en]

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

  • 173.
    Eriksson, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Analysis of Lysosomal pH by Flow Cytometry Using FITC-Dextran Loaded Cells2017In: Lysosomes: Methods and Protocols / [ed] Karin Öllinger;Hanna Appelqvist, Humana Press, 2017, Vol. 1594, p. 179-189Chapter in book (Refereed)
    Abstract [en]

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

  • 174.
    Eriksson, Irene
    et al.
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Wettermark, Bjorn
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Persson, Marie
    Stockholm County Council, Sweden.
    Edström, Morgan
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Godman, Brian
    University of Liverpool, England; Karolinska University Hospital, Sweden; University of Strathclyde, Scotland.
    Lindhe, Anna
    Regional Vastra Gotaland, Sweden.
    Malmstrom, Rickard E.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Ramstrom, Helena
    Stockholm County Council, Sweden.
    von Eulerz, Mia
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bergkvist Christensen, Anna
    Regional Skåne, Sweden.
    The Early Awareness and Alert System in Sweden: History and Current Status2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 674Article, review/survey (Refereed)
    Abstract [en]

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

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  • 175.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Andersson, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Cassel, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Letter: Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 1, p. 80-83Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 176.
    Ewerman, Lea
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Landberg, Eva
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hellberg, Sandra
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Hovland, Mina
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Sundin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ernerudh, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia2020In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 52, no 4, p. 228-235Article in journal (Refereed)
    Abstract [en]

    Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p&lt;0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (&gt;3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.

  • 177.
    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.

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  • 178.
    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.

  • 179.
    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.

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  • 180.
    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.

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  • 181.
    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.

  • 182.
    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.

  • 183.
    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 Linköping/Motala. Lund Univ, Sweden.
    Andersson, Oskar
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Klang Årstrand, Hanna
    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.
    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 and Forens Toxicol, Linkoping, Sweden.
    Olsson, Hans
    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.
    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.
    The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood2019In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 43, article id UNSP 102111Article in journal (Refereed)
    Abstract [en]

    Introduction: Sudden cardiac death (SCD) in the young is rare and should always lead to suspicion of a genetic cardiac disorder. We describe a family, in which the proband was a girl deceased by sudden cardiac death in the playground at thirteen years of age. The index-patient had short stature, cleft palate but no previous cardiac symptoms. We found an uncommon cause of cardiomyopathy, due to a congenital disorder of glycosylation (CDG), previously described to cause a variable range of usually mild symptoms, and not previously found to cause SCD as the first symptom of the condition. Methods: The index patient underwent postmortem genetic testing/molecular autopsy for genes known to cause SCD, without a detection of causative agent, why two siblings of similar phenotype as the deceased sister underwent clinical-exome genetic sequencing (next generation sequencing). All first-degree relatives underwent clinical examination including cardiac ultrasound, Holzer-ECG, exercise stress test and biochemistry panel. Results: A genetic variant in the gene for phosphoglucomutase 1 (PGM1) was identified in the index patient and her two brothers, all were found to be homozygous for the genetic variant (G230E) NM_002633.2:c.689 G amp;gt; A in PGM1. This variant has been linked to a congenital disorder of glycosylation (PGM1-CDG), explaining the clinical picture of short stature, cleft palate, liver engagement and cardiomyopathy. During follow-up one of the brothers died unexpectedly after physical exertion during daily life at the age of twelve years. The other brother fainted during similar circumstances at the age of thirteen years. Both parents and three other siblings were found to be heterozygous gene carriers without risk for the disease. Conclusion: Our findings suggest that there is a need of multidisciplinary discussion and genetic testing after unexpected cardiac death in the young. We have to be more flexible in our evaluation of diseases and to consider even uncommon diseases including rare recessive inherited disorders. Our findings also suggest that the autosomal recessive PGM1-CDG might be highly associated with life-threatening cardiomyopathy with arrhythmia or sudden cardiac death as the first symptom presenting from childhood and adolescence.

  • 184.
    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.

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  • 185.
    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.

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  • 186.
    Forsberg, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Huoman, Johanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Bhai Mehta, Ratnesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Abrahamsson, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, 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 Linköping/Motala.
    Ernerudh, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Pre- and postnatal Lactobacillus reuteri treatment alters DNA methylation of infant T helper cells2020In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038Article in journal (Refereed)
    Abstract [en]

    Background Perinatal childhood exposures, including probiotic supplementation, may affect epigenetic modifications and impact on immune maturation and allergy development. The aim of this study was to assess the effects of pre- and postnatal Lactobacillus reuteri supplementation on DNA methylation in relation to immune maturation and allergy development. Methods DNA methylation patterns were investigated for allergy-related T helper subsets using a locus-specific method and at a genome-wide scale using the Illumina 450K array. From a randomised, double-blind, placebo-controlled allergy prevention trial with pre- and postnatal probiotic supplementation, CD4+ T helper cells were obtained at birth (from cord blood), and 12 and 24 months of age (total (placebo/probiotics); locus-specific method: CB = 32 (17/15), 12 months = 24 (9/15), 24 months = 35 (15/20); Illumina: CB = 19 (10/9), 12 months = 10 (6/4), 24 months = 19(11/8)). Results Comparing probiotics to placebo, the greatest genome-wide differential DNA methylation was observed at birth, where the majority of sites were hypomethylated, indicating transcriptional accessibility in the probiotic group. Bioinformatic analyses, including network analyses, revealed a module containing 91 genes, enriched for immune-related pathways such as chemotaxis, PI3K-Akt, MAPK and TGF-beta signalling. A majority of the module genes were associated with atopic manifestations (OR = 1.43, P = 2.4 x 10(-6)), and a classifier built on this model could predict allergy development (AUC = 0.78, P = 3.0 x 10(e-3)). Pathways such as IFN-gamma signalling and T-cell activation were more hypermethylated at birth compared with later in life in both intervention groups over time, in line with DNA methylation patterns in the IFNG locus obtained by the locus-specific methodology. Conclusion Maternal L. reuteri supplementation during pregnancy alters DNA methylation patterns in CD4+ T cells towards enhanced immune activation at birth, which may affect immune maturation and allergy development.

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  • 187.
    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.

  • 188.
    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.

  • 189.
    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, 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.

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    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort
  • 190.
    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.

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  • 191.
    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.

  • 192.
    Fotouhi, Omid
    et al.
    Karolinska Inst, Sweden.
    Kjellin, Hanna
    Karolinska Inst, Sweden.
    Juhlin, C. Christofer
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Pan, Yanbo
    Karolinska Inst, Sweden; SciLifeLab, Sweden.
    Vesterlund, Mattias
    Karolinska Inst, Sweden; SciLifeLab, Sweden.
    Ghaderi, Mehran
    Karolinska Inst, Sweden.
    Yousef, Abdelhamid
    Univ Cambridge, England.
    Andersson-Sand, Hillevi
    SciLifeLab, Sweden.
    Kharaziha, Pedram
    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.
    Caramuta, Stefano
    Uppsala Univ, Sweden.
    Kjellman, Magnus
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Zedenius, Jan
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Larsson, Catharina
    Karolinska Inst, Sweden.
    Orre, Lukas M.
    Karolinska Inst, Sweden; SciLifeLab, Sweden.
    Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors2019In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 43, p. 6881-6897Article in journal (Refereed)
    Abstract [en]

    Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.

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  • 193.
    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.

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  • 194.
    Fransson, Sven Göran
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Det stora vita huset i Kolmårdsskogen: 100-årigt vittne om Sveriges kamp mot tuberkulosen2019In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, no 7Article in journal (Other (popular science, discussion, etc.))
  • 195.
    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

  • 196.
    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.

  • 197.
    Frodlund, Martina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Skogh, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Ronnelid, J.
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease2020In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 199, no 3, p. 245-254Article in journal (Refereed)
    Abstract [en]

    Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS (TM) Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjogrens syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.

    The full text will be freely available from 2020-11-28 12:24
  • 198.
    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.

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  • 199.
    Fuchs, Alexander
    et al.
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. KTH, Sweden.
    Berg, Niclas
    KTH, Sweden.
    Wittberg, Lisa Prahl
    KTH, Sweden.
    Stenosis Indicators Applied to Patient-Specific Renal Arteries without and with Stenosis2019In: FLUIDS, ISSN 2311-5521, Vol. 4, no 1, article id 26Article in journal (Refereed)
    Abstract [en]

    Pulsatile flow in the abdominal aorta and the renal arteries of three patients was studied numerically. Two of the patients had renal artery stenosis. The aim of the study was to assess the use of four types of indicators for determining the risk of new stenosis after revascularization of the affected arteries. The four indicators considered include the time averaged wall shear stress (TAWSS), the oscillatory shear index (OSI), the relative reference time (RRT) and a power law model based in platelet activation modeling but applied to the endothelium, named endothelium activation indicator (EAI). The results show that the indicators can detect the existing stenosis but are less successful in the revascularized cases. The TAWSS and, more clearly, the EAI approach seem to be better in predicting the risk for stenosis relapse at the original location and close to the post-stenotic dilatation. The shortcomings of the respective indicators are discussed along with potential improvements to endothelial activation modeling and its use as an indicator for risks of restenosis.

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  • 200.
    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.

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