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  • 1.
    Abdelrahman, Islam
    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. The Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    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.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    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. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Elmasry, Moustafa
    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 Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Use of the burn intervention score to calculate the charges of the care of burns2019In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 45, no 2, p. 303-309Article in journal (Refereed)
    Abstract [en]

    Background To our knowledge this is the first published estimate of the charges of the care of burns in Sweden. The Linköping Burn Interventional Score has been used to calculate the charges for each burned patient since 1993. The treatment of burns is versatile, and depends on the depth and extension of the burn. This requires a flexible system to detect the actual differences in the care provided. We aimed to describe the model of burn care that we used to calculate the charges incurred during the acute phase until discharge, so it could be reproduced and applied in other burn centres, which would facilitate a future objective comparison of the expenses in burn care. Methods All patients admitted with burns during the period 2010–15 were included. We analysed clinical and economic data from the daily burn scores during the acute phase of the burn until discharge from the burn centre. Results Total median charge/patient was US$ 28 199 (10th–90th centiles 4668-197 781) for 696 patients admitted. Burns caused by hot objects and electricity resulted in the highest charges/TBSA%, while charges/day were similar for the different causes of injury. Flame burns resulted in the highest mean charges/admission, probably because they had the longest duration of stay. Mean charges/patient increased in a linear fashion among the different age groups. Conclusion Our intervention-based estimate of charges has proved to be a valid tool that is sensitive to the procedures that drive the costs of the care of burns such as large TBSA%, intensive care, and operations. The burn score system could be reproduced easily in other burn centres worldwide and facilitate the comparison regardless of the differences in the currency and the economic circumstances.

  • 2.
    Abtahi, Jahan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology. Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Bisphosphonate coating might improve fixation of dental implants in the maxilla: A pilot study2010In: International Journal of Oral and Maxillofacial Surgery, ISSN 0901-5027, E-ISSN 1399-0020, Vol. 39, no 7, p. 673-677Article in journal (Refereed)
    Abstract [en]

    This pilot study evaluates the clinical stability of bisphosphonate-coated dental implants placed using a two-stage surgical procedure in five patients. Each patient received seven regular Branemark implants, one of which was coated with bisphosphonate in a fibrinogen matrix. The coated implant was inserted where the bone was expected to have the least favourable quality. The level of the marginal bone around each implant was measured by intraoral periapical radiographs and implant stability was recorded using resonance frequency measurements. Frequency values (ISQ) were obtained peroperatively before flap closure and after 6 months at abutment connection. At abutment connection the bisphosphonate-coated implants were removed en bloc in two patients for histological examination. An animal experiment had previously confirmed that gamma-sterilization did not reduce bioactivity of the bisphosphonate coating. In each patient, the bisphosphonate-coated implant showed the largest improvement in ISQ level of all implants. Their values at the start tended to be lower, and the absolute value at 6 months did not differ. No complications occurred with the coated implants. Histology showed no abnormalities. Improvement in ISQ values was an expected effect of the bisphosphonate coating, but could be due to the choice of insertion site. This finding warrants a randomized blinded study.

  • 3.
    Alehagen, Urban
    et al.
    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.
    Johansson, Peter
    Linköping University, Department of Social and Welfare Studies, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Aaseth, Jan
    Innlandet Hospital Trust, Norway; Hedmark University of Appl Science, Norway.
    Alexander, Jan
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science NMBU, Norway.
    Brismar, Kerstin
    Karolinska University Hospital, Sweden.
    Increase in insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 after supplementation with selenium and coenzyme Q10. A prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0178614Article in journal (Refereed)
    Abstract [en]

    Background Insulin-like growth factor-1(IGF-1) has a multitude of effects besides cell growth and metabolism. Reports also indicate anti-inflammatory and antioxidative effects. The concentrations of IGF-1 decrease with age and during inflammation. As selenium and coenzyme Q10 are involved in both the antioxidative defense and the inflammatory response, the present study aimed to examine the effects of supplementation with selenium and coenzyme Q10 on concentrations of IGF-1 and its binding protein IGFBP-1 in a population showing reduced cardiovascular mortality following such supplementation. Methods 215 elderly individuals were included and given the intervention for four years. A clinical examination was performed and blood samples were taken at the start and after 48 months. Evaluations of IGF-1, the age adjusted IGF-1 SD score and IGFBP-1 were performed using group mean values, and repeated measures of variance. Findings After supplementation with selenium and coenzyme Q10, applying group mean evaluations, significantly higher IGF-1 and IGF-1 SD scores could be seen in the active treatment group, whereas a decrease in concentration could be seen of the same biomarkers in the placebo group. Applying the repeated measures of variance evaluations, the same significant increase in concentrations of IGF-1 (F = 68; P amp;gt; 0.0001), IGF-1 SD score (F = 29; P amp;lt; 0.0001) and of IGFBP-1 (F = 6.88; P = 0.009) could be seen, indicating the effect of selenium and coenzyme Q10 also on the expression of IGF-1 as one of the mechanistic effects of the intervention. Conclusion Supplementation with selenium and coenzyme Q10 over four years resulted in increased levels of IGF-1 and the postprandial IGFBP-1, and an increase in the age-corrected IGF-1 SD score, compared with placebo. The effects could be part of the mechanistic explanation behind the surprisingly positive clinical effects on cardiovascular morbidity and mortality reported earlier. However, as the effects of IGF-1 are complex, more research on the result of intervention with selenium and coenzyme Q10 is needed.

  • 4.
    Arlinger, Stig
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Lunner, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Technical Audiology. Linköping University, Faculty of Health Sciences.
    Lyxell, Björn
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Pichora-Fuller, M Kathleen
    University of Toronto.
    The emergence of cognitive hearing science.2009In: Scandinavian journal of psychology, ISSN 1467-9450, Vol. 50, no 5, p. 371-384Article, review/survey (Refereed)
    Abstract [en]

    Cognitive Hearing Science or Auditory Cognitive Science is an emerging field of interdisciplinary research concerning the interactions between hearing and cognition. It follows a trend over the last half century for interdisciplinary fields to develop, beginning with Neuroscience, then Cognitive Science, then Cognitive Neuroscience, and then Cognitive Vision Science. A common theme is that an interdisciplinary approach is necessary to understand complex human behaviors, to develop technologies incorporating knowledge of these behaviors, and to find solutions for individuals with impairments that undermine typical behaviors. Accordingly, researchers in traditional academic disciplines, such as Psychology, Physiology, Linguistics, Philosophy, Anthropology, and Sociology benefit from collaborations with each other, and with researchers in Computer Science and Engineering working on the design of technologies, and with health professionals working with individuals who have impairments. The factors that triggered the emergence of Cognitive Hearing Science include the maturation of the component disciplines of Hearing Science and Cognitive Science, new opportunities to use complex digital signal-processing to design technologies suited to performance in challenging everyday environments, and increasing social imperatives to help people whose communication problems span hearing and cognition. Cognitive Hearing Science is illustrated in research on three general topics: (1) language processing in challenging listening conditions; (2) use of auditory communication technologies or the visual modality to boost performance; (3) changes in performance with development, aging, and rehabilitative training. Future directions for modeling and the translation of research into practice are suggested.

  • 5.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Placeboeffekten är övervärderad: »Återgång till medelvärdet« kan förklara förbättring efter skenbehandling – men misstolkas ofta2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Refereed)
  • 6.
    Barathan, Muttiah
    et al.
    Univ Malaya, Malaysia.
    Mohamed, Rosmawati
    Univ Malaya, Malaysia.
    Yong, Yean K.
    Xiamen Univ Malaysia, Malaysia.
    Kannan, Meganathan
    CUTN, India.
    Vadivelu, Jamuna
    Univ Malaya, Malaysia.
    Saeidi, Alireza
    Univ Malaya, Malaysia.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki Muthu
    CUTN, India.
    Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion2018In: CELLS, ISSN 2073-4409, Vol. 7, no 10, article id 165Article, review/survey (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) represents a challenging global health threat to similar to 200 million infected individuals. Clinical data suggest that only similar to 10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.

  • 7.
    Berglund, Caroline
    et al.
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Ekströmer, Karin
    Department of Radiology, Mälarsjukhuset Eskilstuna Hospital, Sweden.
    Abtahi, Jahan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Primary Chronic Osteomyelitis of the Jaws in Children: An Update on Pathophysiology, Radiological Findings, Treatment Strategies, and Prospective Analysis of Two Cases2015In: Case Reports in Dentistry, ISSN 2090-6447, E-ISSN 2090-6455, Vol. 2015, no 152717Article in journal (Refereed)
    Abstract [en]

    Objective. Primary chronic osteomyelitis (PCO) of the jaws in children is associated with pain, trismus, and swelling. In children, temporomandibular joint involvement is rare and few studies have been published due to the relatively low incidence. This paper presents two cases of mandibular PCO in children with the involvement of the collum mandibulae. In addition, a review of the literature regarding demographic data, histological, radiological, and laboratory findings, and treatment strategies of PCO was also performed. Material and Methods. Prospective analyses of two PCO cases. A PubMed search was used and the articles were sorted according to their corresponding key area of focus. Results. Review of the literature revealed twenty-four cases of PCO with two cases of mandibular condyle involvement. The mean age was 18 years; the male to female ratio was 1 : 3. Most of the patients were treated with anti-inflammatory drugs in combination with decortication. Clinical recurrence was seen in 7 cases. Conclusion. A combination of anti-inflammatory drugs and surgical intervention appears to be the first choice of treatment. However, surgical removal of necrotic tissue adjacent to collum mandibulae has its limitations in children. Further investigations are of utmost importance in order to increase our knowledge and understanding of this disease.

  • 8.
    Bergström, Ida
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Lundberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jönsson, Simon
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sarndahl, Eva
    Örebro University, Sweden.
    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.
    Jonasson, Lena
    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.
    Annexin A1 in blood mononuclear cells from patients with coronary artery disease: Its association with inflammatory status and glucocorticoid sensitivity2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174177Article in journal (Refereed)
    Abstract [en]

    Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.

  • 9.
    Borendal Wodlin, Ninnie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Snabbspår har fördelar vid elektiv gynekologisk kirurgi.2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 25-26, p. 2-7Article in journal (Refereed)
    Abstract [en]

    Fast-track is a multimodal strategy aimed at achieving an improved and accelerated postoperative recovery. The strategy combines unimodal evidence-based interventions concerning preoperative preparation, peroperative principles and postoperative care. There is substantial evidence for the benefits of following fast-track concepts in general elective surgery to enhance postoperative recovery. The main findings of this review are that there are benefits likewise within elective gynecological surgery, but studies of quality of life, patient satisfaction and health economics are needed. Studies of fast-track within non-elective surgery and gynaecological oncology surgery are lacking. Widespread information and education is needed to improve the rate of implementation of fast-track. Comprehensive involvement of the entire staff dealing with the patient in the perioperative period is crucial to ensure implementation and development of surgical care aiming for enhanced postoperative recovery.

  • 10.
    Borg, Mathias
    Linköping University, Department of Physics, Chemistry and Biology.
    Study of the insulin-like peptide 3 in human platelets2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The insulin-like 3 peptide is autocrine/paracrine insulin-related hormone with a size of approximately 6kDa [1]. It mediates through a leucine richG-coupled receptor named LGR8. INSL3 is mainly expressed in human Leydig cells and is directly responsible for migration of the testis during the pre-natal period in maledevelopment. [2]

    INSL3 mRNA has recently been verified in human platelets whereas no mRNA has been detected for LGR8 (by Sanofi-Aventis GmbH in Frankfurt,Germany), indicating that INSL3 might be released through paracrine functions at sites of platelet adhesion and aggregation upon a vascular injury.Furthermore, has activated platelets been shown to translate essential proteins upon activation, in a term called “signal-dependent protein synthesis”.The B-Cell lymphoma-3 protein (BCL-3) is an example of such a protein [3], and there is a possibility that INSL3 might be also.

    In this thesis we wanted to detect the relaxin- like peptide 3 hormone (INSL3). (Its function, location and the timeframe of its release, when/if it issecreated in stimulated platelets).The source of platelet-derived INSL3 can be found with Western blotting and Enzyme immunoassay.

    Detection of the insulin-like 3 peptide in human platelets turned out to be a difficult challenge due to the small amount of INSL3 secretion uponplatelet activation; hence the total amount of INSL3 produced might be below detection limit.

  • 11.
    Bäckström, Denise
    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 Anaesthesiology and Intensive Care in Norrköping.
    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.
    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. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Change in child mortality patterns after injuries in Sweden: a nationwide 14-year study.2017In: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 43, no 3, p. 343-349Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Sweden has one of the world's lowest child injury mortality rates, but injuries are still the leading cause of death among children. Child injury mortality in the country has been declining, but this decline seems to decrease recently. Our objective was therefore to further examine changes in the mortality of children's death from injury over time and to assess the contribution of various effects on mortality. The underlying hypothesis for this investigation is that the incidence of lethal injuries in children, still is decreasing and that this may be sex specific.

    PATIENTS AND METHODS: We studied all deaths from injury in Sweden under-18-year-olds during the 14 years 1999-2012. We identified those aged under 18 whose underlying cause of death was recorded as International Classification of Diseases, 10th Revision (ICD-10) diagnosis from V01 to X39 in the Swedish cause of death, where all dead citizens are registered.

    RESULTS: From the 1 January 1999 to 31 December 2012, 1213 children under the age of 18 died of injuries in Sweden. The incidence declined during this period (r = -0.606, p = 0.02) to 3.3 deaths/100,000 children-years (95 % CI 2.6-4.2). Death from unintentional injury was more common than that after intentional injury (p < 0.0001). There was a reduction in the incidence of unintentional injuries during the study period (r = -0.757, p = 0.03). The most common causes of death were injury to the brain (n = 337, 41 %), followed by drowning (n = 109, 13 %). The number of deaths after intentional injury increased (r = 0.585, p = 0.03) and at the end of the period was 1.5 deaths/100,000 children-years. The most common causes of death after intentional injuries were asphyxia (n = 177, 45 %), followed by injury to the brain (n = 76, 19 %).

    DISCUSSION: Mortality patterns in injured children in Sweden have changed from being dominated by unintentional injuries to a more equal distribution between unintentional and intentional injuries as well as between sexes and the overall rate has declined further. These findings are important as they might contribute to the preventive work that is being done to further reduce mortality in injured children.

  • 12.
    Cirillo, Marco Domenico
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Mirdell, Robin
    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.
    Pham, Tuan
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Time-Independent Prediction of Burn Depth using Deep Convolutional Neural Networks2019In: Journal of Burn Care & Research, ISSN 1559-047X, E-ISSN 1559-0488Article in journal (Refereed)
    Abstract [en]

    We present in this paper the application of deep convolutional neural networks, which are a state-of-the-art artificial intelligence (AI) approach in machine learning, for automated time-independent prediction of burn depth. Colour images of four types of burn depth injured in first few days, including normal skin and background, acquired by a TiVi camera were trained and tested with four pre-trained deep convolutional neural networks: VGG-16, GoogleNet, ResNet-50, and ResNet-101. In the end, the best 10-fold cross-validation results obtained from ResNet- 101 with an average, minimum, and maximum accuracy are 81.66%, 72.06% and 88.06%, respectively; and the average accuracy, sensitivity and specificity for the four different types of burn depth are 90.54%, 74.35% and 94.25%, respectively. The accuracy was compared to the clinical diagnosis obtained after the wound had healed. Hence, application of AI is very promising for prediction of burn depth and therefore can be a useful tool to help in guiding clinical decision and initial treatment of burn wounds.

  • 13.
    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.

  • 14.
    Elmasry, Moustafa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Mirdell, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Laser speckle contrast imaging in children with scalds: Its influence on timing of intervention, duration of healing and care, and costs2019In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 45, no 4, p. 798-804Article in journal (Refereed)
    Abstract [sv]

    Background

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

    Methods

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

    Results

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

    Conclusion

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

  • 15.
    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

  • 16.
    Fjälldal, S.
    et al.
    Skåne Univ Hosp, Sweden.
    Follin, C.
    Skane Univ Hosp, Sweden.
    Gabery, S.
    Lund Univ, Sweden.
    Sundgren, P. C.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Bjorkman-Burtscher, I. M.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden; Lund Univ, Sweden.
    Latt, J.
    Skane Univ Hosp, Sweden.
    Mannfolk, P.
    Skane Univ Hosp, Sweden.
    Nordstrom, C. H.
    Skane Univ Hosp, Sweden.
    Rylander, L.
    Lund Univ, Sweden.
    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.
    Cheong, R.
    Lund Univ, Sweden.
    Palsson, A.
    Skane Univ Hosp, Sweden.
    Petersen, A.
    Lund Univ, Sweden.
    Erfurth, E. M.
    Skane Univ Hosp, Sweden.
    Detailed assessment of hypothalamic damage in craniopharyngioma patients with obesity2019In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 43, no 3, p. 533-544Article in journal (Refereed)
    Abstract [en]

    Background/objectives Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. Subjects/methods A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17-56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. Results Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35-1168) mm(3) vs. 879 (775-1086) mm(3); P amp;lt; 0.001. HT volume correlated negatively with fat mass and leptin among CP patients (r(s) = -0.67; P amp;lt; .001; r(s) = -0.53; P = 0.001), and explained 39% of the variation in fat mass. For every 100 mm(3) increase in HT volume fat mass decreased by 2.7 kg (95% CI: 1.5-3.9; P amp;lt; 0.001). Qualitative assessments revealed HT damage in three out of six patients with normal volumetry, but HT damage according to operation records. Conclusions A decrease in HT volume was associated with an increase in fat mass and leptin. We present a method with a high inter-rater reliability (0.94) that can be applied by nonradiologists for the assessment of HT damage. The method may be valuable in the risk assessment of diseases involving the HT.

  • 17.
    Gao, Feng
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Yuan, Y.
    Nanjing University, 210093 China.
    Wang, K. F.
    Nanjing University, 210093 China.
    Chen, X. Y.
    Nanjing University, 210093 China.
    Chen, F.
    Nanjing University, 210093 China.
    Liu, J. -M.
    Nanjing University, 210093 China.
    Preparation and photoabsorption characterization of BiFeO3 nanowires2006In: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 89, no 10, p. 102506-Article in journal (Refereed)
    Abstract [en]

    Perovskite-type polycrystalline BiFeO3 (BFO) nanowires (similar to 50 nm in diameter and similar to 5 mu m in length) were synthesized using the anodized alumina template technique. An energy band gap of similar to 2.5 eV was determined from the UV-visible diffuse reflectance spectrum, and its photocatalytic ability to produce O-2 was revealed under UV irradiation. Weak ferromagnetism at room temperature and superparamagnetism at low temperature were observed for the BFO nanowires, different from the antiferromagnetic order in bulk BFO, reflecting the significant size effects on the magnetic ordering of BFO. (c) 2006 American Institute of Physics.

  • 18.
    Grahn Kronhed, Ann-charlotte
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Rehabilitation in Motala. Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Would the first fragility fracture be tha last one: a physiotherapeutic perspective2017In: Physical Medicine and Rehabilitation Research, ISSN 2398-3353, Vol. 2, no 3, p. 1-2Article in journal (Other academic)
  • 19.
    Grams, M
    et al.
    John Hopkins University, USA.
    Sang, Yingying
    John Hopkins University, USA.
    Ballew, Shoshana
    John Hopkins University, USA.
    Szabó, Zoltán
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Matsushita, Kunihiro
    John Hopkins University, USA.
    Kalantar-Zadeh, Kamyar
    UC Irvine, USA.
    Coresh, Josef
    John Hopkins University, USA.
    Kovesdy, Csaba
    Memphis VA, USA.
    Incidence of and risk factors for acute kidney injury after major surgery2014Conference paper (Refereed)
  • 20.
    Grundström, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Norrköping.
    Alehagen, Siw
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Berterö, Carina
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Impact of Pelvic Pain and Endometriosis on Patient-Reported Outcomes and Experiences of Benign Hysterectomy: A Study from the Swedish National Register for Gynecological Surgery2018In: Journal of Women's Health, ISSN 1540-9996, E-ISSN 1931-843X, Vol. 27, no 5, p. 691-698Article in journal (Refereed)
    Abstract [en]

    Background: The study objective was to analyze and compare patient-reported experience measures (PREMs) and patient-reported outcome measures (PROMs) after hysterectomy in women with and without a preoperative complaint of pelvic pain associated with and without a confirmed diagnosis of endometriosis. Methods: Retrospective nationwide register study. Data on 28,776 hysterectomies performed on benign indication between 2004 and 2016 were retrieved from the Swedish National Register for Gynecological Surgery. Multivariable logistic regression models were used to compare the PREMs and PROMs items. The results are presented as adjusted odds ratios (aORs) and 95% confidence intervals (CI). Results: Regardless of the occurrence of pelvic pain preoperatively and a diagnosis of endometriosis, 1 year after surgery, the women were satisfied or very satisfied (amp;gt;90%) with the hysterectomy, and their medical condition was improved or much improved (amp;gt;95%). The women with a preoperative complaint of pelvic pain and endometriosis more often reported excessively short hospital stays (aOR 1.45, 95% CI 1.17-1.79), more severe complications after discharge (aOR 2.02, 95% CI 1.59-2.66) at the 8-week follow-up and at the 1-year follow-up (aOR 2.31, 95% CI 1.57-3.39), and more dissatisfaction with the operation (aOR 1.83, 95% CI 1.35-2.48) than preoperative pelvic pain-free women without endometriosis at the 1-year follow-up. Conclusions: The majority of the women were satisfied after their hysterectomy. The women with pelvic pain and endometriosis were at a higher risk of being dissatisfied. Pelvic pain per se seemed to be the main factor affecting the rating in the PREMs and PROMs, and the endometriosis was a significant contributing factor.

  • 21.
    Hahn, Robert G.
    et al.
    Sodertalje Hosp, Sweden; Karolinska Inst, Sweden.
    Zdolsek, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Hasselgren, Emma
    Karolinska Univ Hosp, Sweden.
    Zdolsek, Joachim
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Bjoerne, Hakan
    Karolinska Univ Hosp, Sweden.
    Fluid volume kinetics of 20% albumin2019In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, no 6, p. 1303-1311Article in journal (Refereed)
    Abstract [en]

    Aims A population kinetic model was developed for the body fluid shifts occurring when 20% albumin is given by intravenous infusion. The aim was to study whether its efficacy to expand the plasma volume is impaired after major surgery. Methods An intravenous infusion of 3 mL/kg 20% albumin over 30 minutes was given to 15 volunteers and to 15 patients on the 1(st) day after major open abdominal surgery. Blood samples and urine were collected during 5 hours. Mixed-effect modelling software was used to develop a fluid volume kinetic model, using blood haemoglobin and urine excretion the estimate body fluid shifts, to which individual-specific covariates were added in sequence. Results The rise in plasma albumin expanded the plasma volume in excess of the infused volume by relocating noncirculating fluid (rate constant k(21)), but it also increased losses of fluid from the kinetic system (k(b)). The balance between k(21) and k(b) maintained the rise in plasma albumin and plasma volume at a virtual steady-state for almost 2 hours. The rate constant for urinary excretion (k(10)) was slightly reduced by the preceding surgery, by a marked rise in plasma albumin, and by a high preinfusion urinary concentration of creatinine. The arterial pressure, body weight, and plasma concentrations of C-reactive protein and shedding products of the endothelial glycocalyx layer (syndecan-1, heparan sulfate, and hyaluronic acid) did not serve as statistically significant covariates. Conclusions There were no clinically relevant differences in the kinetics of 20% albumin between postoperative patients and volunteers.

  • 22.
    Henriksson, Pontus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, B
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Forsum, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Löf, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Gestational weight gain according to Institute of Medicine recommendations in relation to infant size and body composition.2015In: Pediatric Obesity, ISSN 2047-6302, E-ISSN 2047-6310, Vol. 10, no 5, p. 388-394Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Intrauterine life may be a critical period for programming childhood obesity; however, there is insufficient knowledge concerning how gestational weight gain (GWG) affects infant fat mass (FM) and fat-free mass (FFM).

    OBJECTIVES: The aim of this study was to investigate relationships between GWG according to Institute of Medicine (IOM) recommendations and infant size, FM and FFM. We also investigated if the associations were different for normal-weight and overweight/obese women.

    METHODS: This study included 312 healthy Swedish mother-infant pairs. Infant body composition at 1 week of age was assessed using air-displacement plethysmography. Maternal GWG was defined as below, within or above the 2009 IOM recommendations. Multiple regression analyses were used.

    RESULTS: Compared with women whose weight gain was within IOM recommendations, women with weight gain below the recommendations had infants that were shorter (-0.7 cm, P = 0.008) when adjusting for confounders. Normal-weight women exceeding IOM recommendations had infants with higher FM (+58 g, P = 0.008) compared with normal-weight women who gained within the recommendations. No corresponding association was observed for overweight/obese women.

    CONCLUSIONS: Inadequate GWG was associated with shorter infants, while excessive GWG was associated with greater infant FM for women who were of normal weight before pregnancy.

  • 23.
    Hilborn, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    The role of the androgen receptor and hydroxysteroid 17β dehydrogenase in breast cancer: Impact on tamoxifen treatment2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The healthy breast is a tissue composed of centrally located milk producing glands connected to the nipple by ducts, surrounded by fat tissue and connective tissue. The growth of the breast is primarily mediated by the estrogens, while the androgens mediate tissue homeostasis and protect against growth signals. In breast cancer, the cells of the glands or ducts undergo malignant transformation, and start proliferating in an uncontrollable fashion. Breast cancer is the most common malignancy in women, and it is estimated that 10% of all women will be diagnosed with breast cancer during their life-time. The primary classification of breast cancer is based mainly on the expression of the estrogen receptor, and 70-80% of breast cancers are estrogen receptor positive, and are classified as luminal. The remaining breast cancers are classified into HER2 positive or triple negative breast cancer. Out of all breast cancers, ~80% are androgen receptor positive. This varies in different subtypes, however, with the highest expression in luminal and lowest expression in triple negative breast cancers. The role of androgen receptor varies depending on subtype. It is considered tissue-protective in luminal breast cancer, while it’s role in HER2 positive and triple negative breast cancers is less defined, but is generally considered to be associated with worse outcome. The primary treatment for breast cancer is surgery, followed by chemotherapy and/or radiotherapy to reduce the risk of recurrence. Treatment is also subtype specific, and luminal breast cancers in premenopausalwomen are treated using the estrogen receptor blocker (antagonist) tamoxifen, which blocks estrogen signaling. In postmenopausal women, luminal breast  cancers are treated using tamoxifen or aromatase inhibitors, which prevent the formation of estrogen. The knowledge of which patient will respond and who will develop treatment resistance is of great importance, and the development of markers which can be analyzed prior to treatment in order to reduce the risk of unwanted side effects or complications is the focus of a large body of research. One of the primary goals of this thesis was to establish biomarkers for prognosis and tamoxifen treatment in breast cancer, and paper I, paper II and paper III address this aim.

    Steroid hormones, including estrogens and androgens, are normally synthesized from cholesterol in the adrenal gland, as well as in gender specific tissues such as ovaries in women or the testis or prostate in men. This synthesis takes place as a number of enzymatic conversions, mediated by several different enzymes, and the expression of these enzymes determines the final product of this conversion. In the adrenal gland, testis and prostate, androgens are the end-product, while the ovaries synthesize estrogens. These hormones are transported through the circulation, and upon reaching their target tissues, they mediate their effect. The impact of the steroids on their destination tissue is dependent on their relative concentration and exposure time, which in turn is dependent on the amount in the circulation, but also on the presence of local steroid converting enzymes, which are present in most tissues. The enzymes of the hydroxysteroid 17β dehydrogenase family are present in most tissues, primarily the oxidative member hydroxysteroid 17β dehydrogenase type 2, which facilitate the conversion of estrogens and androgens to the less active forms, thus protecting the tissues from their effect. In breast cancer, the reductive form, hydroxysteroid 17β dehydrogenase type 1 is often up-regulated, and mediates increased activation of estrogens, resulting in increased estrogen signaling, which results in increased proliferation and growth. The second goal of this thesis was to further study the role of hydroxysteroid 17β dehydrogenase enzymes in breast cancer, and paper I and paper IV address different  aspects of their role in breast cancer.

    Following reduction of the expression of hydroxysteroid 17β dehydrogenase type 14, an oxidative member of the family, in breast cancer, the expression of C-X-C ligand 10 was found to be altered. In paper I, in order to determine the role of C-X-C ligand 10 and C-X-C receptor 3 in breast cancer, their expression was quantified using immunohistochemistry in breast cancer patients randomized to tamoxifen or no endocrine treatment irrespectively of estrogen receptor status. The expression of C-XC ligand 10 and C-X-C receptor 3 was found to be associated with increased tamoxifen treatment benefit in the estrogen receptor positive group of patients, indicating that they could be useful markers for determining which patient would respond well to this treatment. Further, C-X-C receptor 3 expression was associated with worse outcome in patients who did not receive tamoxifen, and could be a potential target for inhibitors in order to improve patient outcome. The role of the androgen receptor in breast cancer was evaluated. In paper II the expression was quantified using immunohistochemistry in the same cohort as in paper I. We show that in patients with estrogen receptor negative tumors, the androgen receptor is associated with worse outcome. In patients with high tumoral androgen receptor expression, tamoxifen signaling results in significant improvement in outcome, despite lack of the estrogen receptor. The opposite was observed in patients without tumoral androgen receptor expression, and tamoxifen treatment was associated with adverse outcome. Similar findings were made in the triple negative cases. In the luminal cases, the androgen receptor does not provide further information pertaining to outcome. In paper III we evaluated the role of mutations in the androgen receptor in the cohort of estrogen receptor-negative and androgen receptorpositive cases from paper II. The role of mutations in the androgen receptor appear to have a modest role in regard to patient outcome, but rs17302090 appear associated with tamoxifen treatment benefit. The modulation of the members of the hydroxysteroid 17β dehydrogenase in breast cancer is associated with changes in the local steroid balance, and has been associated with worse outcome and changes in the response to tamoxifen. Further, the inhibition of hydroxysteroid 17β dehydrogenase type 1 has been proposed as an alternate treatment for breast cancer, but no inhibitors are currently used in the clinic. In paper IV, we evaluated several different mechanisms by which the expression of hydroxysteroid 17β dehydrogenase type 1 and type 2 are modulated in breast cancer. We show that the most potent estrogen estradiol, in an estrogen receptor dependent fashion, can result in decreased hydroxysteroid 17β dehydrogenase type 1 expression, and a short term reduction in type 2 expression or long term increased type 2 expression. We also show that the most potent androgen, dihydrotestosterone, can increase hydroxysteroid 17β dehydrogenase type 2 expression, but has limited impact on hydroxysteroid 17β dehydrogenase type 1. Further, we show that a number of genes involved in breast cancer, and microRNA are involved in modulating the expression of the hydroxysteroid 17β dehydrogenase type 1 and type 2 in breast cancer. These findings could potentially be used as an alternative to inhibitors, and help modulate the steroidal balance in target tissue.

    List of papers
    1. C-X-C ligand 10 and C-X-C receptor 3 status can predict tamoxifen treatment response in breast cancer patients
    Open this publication in new window or tab >>C-X-C ligand 10 and C-X-C receptor 3 status can predict tamoxifen treatment response in breast cancer patients
    Show others...
    2014 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 145, no 1, p. 73-82Article in journal (Refereed) Published
    Abstract [en]

    To investigate the expression levels of CXCL10 and CXCR3 in tumors from breast cancer patients randomized to adjuvant tamoxifen treatment or no endocrine treatment, in order to further study the connection to prognosis and prediction of tamoxifen treatment outcome. Immunohistochemistry on tissue microarrays from 912 breast cancer patients randomized to tamoxifen or no endocrine treatment. CXCR3 status was found to be a prognostic tool in predicting distant recurrence, as well as reduced breast cancer-specific survival. In patients with estrogen receptor (ER)-positive tumors, tumors with strong CXCL10 levels had improved effect of tamoxifen treatment in terms of local recurrence-free survival [risk ratio (RR) 0.46 (95 % CI 0.25-0.85, P = 0.01)] compared with patients with tumors expressing weak CXCL10 expression. Further, patients with ER-positive tumors with strong CXCR3 expression had an improved effect of tamoxifen in terms of breast cancer-specific survival [RR 0.34 (95 % CI 0.19-0.62, P less than 0.001)] compared with the group with weak CXCR3 levels [RR 1.33 (95 % CI 0.38-4.79, P = 0.65)]. We show here for the first time that CXCL10 and CXCR3 expression are both predictors of favorable outcome in patients treated with tamoxifen.

    Place, publisher, year, edition, pages
    Springer Verlag (Germany), 2014
    Keywords
    CXCL10; CXCR3; Endocrine treatment; Prognosis; Tamoxifen
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-106833 (URN)10.1007/s10549-014-2933-7 (DOI)000334519400007 ()
    Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2017-12-05Bibliographically approved
    2. Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-alpha-negative breast cancer
    Open this publication in new window or tab >>Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-alpha-negative breast cancer
    Show others...
    2016 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, no 3, p. 248-255Article in journal (Refereed) Published
    Abstract [en]

    Background: Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation. Purpose: To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer. Methods Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point. Results: In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR) = 0.34; 95% confidence interval (CI) = 0.14-0.81; P = 0.015), whereas the opposite was seen in the AR- group (HR = 2.92; 95% CI = 1.16-7.31; P = 0.022). Interaction test was significant P &lt; 0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR = 0.12; 95% CI = 0.014-0.95 P = 0.044), whereas patients with AR- tumours had worse outcome when treated with tamoxifen (HR = 3.98; 95% CI = 1.32-12.03; P = 0.014). Interaction test was significant P = 0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression. Conclusions: AR can predict tamoxifen treatment benefit in patients with ER- tumours and triple-negative breast cancer.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2016
    Keywords
    Androgen receptor; breast cancer; tamoxifen; oestrogen receptor; triple-negative breast cancer
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-125675 (URN)10.1038/bjc.2015.464 (DOI)000369223600003 ()26742006 (PubMedID)
    Note

    Funding Agencies|Swedish research council [A0346701]; Swedish cancer foundation [13 0435]

    Available from: 2016-03-02 Created: 2016-02-29 Last updated: 2017-05-03
  • 24.
    Hildebrand, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Sved, Catarina
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Gottvall, Tomas
    Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Blomberg, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Janerot Sjöberg, Birgitta
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Biomedical Engineering. Linköping University, The Institute of Technology.
    Impact of a standardized training program on midwive’s ability to assess fetal heart anatomy by ultrasound2014In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 14, no 20Article in journal (Refereed)
    Abstract [en]

    Background: Studies of prenatal detection of congenital heart disease (CDH) in the UK, Italy, and Norway indicate that it should be possible to improve the prenatal detection rate of CDH in Sweden. These studies have shown that training programs, visualization of the outflow tracts and color-Doppler all can help to speed up and improve the detection rate and accuracy. We aimed to introduce a more accurate standardized fetal cardiac ultrasound screening protocol in Sweden.

    Methods: A novel pedagogical model for training midwives in standardized cardiac imaging was developed, a model using a think-aloud analysis during a pre- and post-course test and a subsequent group reflection. The self-estimated difficulties and knowledge gaps of four midwives were identified. A two-day course with mixed lectures, demonstrations and handson sessions was followed by a feedback session one month later consisting of an interview and check-up. The long-term effects were tested two years later.

    Results: At the post-course test the self-assessed uncertainty was lower than at the pre-course test. The qualitative evaluation showed that the color Doppler images were difficult to interpret, but the training seems to have enhanced the familiarity with the new technique. The ability to perform the method remained at the new level at follow-up both three months and two years later.

    Conclusions: Our results indicate that by implementing new imaging modalities and providing hands-on training, uncertainty can be reduced and time decreased, but they also show that continuous on-site training with clinical and technical back-up is important.

  • 25.
    Hildebrand, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Källén, Bengt
    Tornblad Institute, University of Lund, Sweden.
    Josefsson, Ann
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Gottvall, Tomas
    Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Blomberg, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Maternal obesity and risk of Down syndrome in the offspring2014In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 34, no 4, p. 310-315Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The objective of this article is to determine if maternal obesity is associated with an increased risk of Down syndrome in the offspring and whether the risk estimates for trisomy 21 based on combined screening is affected by maternal body mass index (BMI).

    METHODS: Study group I consisted of a nationwide cohort of 168 604 women giving birth; outcome was infants born with Down syndrome. Adjustment was made for maternal age. Study group II consisted of 10 224 women undergoing 1st trimester combined screening. Outcome was risk assessment for Down syndrome. All women were divided into six BMI groups, and outcomes were evaluated over the BMI strata with BMI 18.5 to 24.9 as reference and correcting for maternal age.

    RESULTS: Obese women had an increased risk for giving birth to an infant with Down syndrome compared with normal-weight women, BMI 30 to 34.9 odds ratio (OR) 1.31 [95% confidence interval (CI) 1.10-1.55], BMI 35 to 39.9 OR 1.12 (95% CI 0.82-1.53), BMI ≥ 40 OR 1.56 (95% CI 1.00-2.43). The observed and the expected numbers of women with a risk of Down syndrome >1/300 based on 1st trimester combined screen and maternal age were similar in each BMI group.

    CONCLUSION: Maternal obesity seems to increase the risk for Down syndrome births. The risk estimate for Down syndrome with 1st trimester combined screening is unaffected by BMI. © 2013 John Wiley & Sons, Ltd.

  • 26.
    Karlsson, Matilda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Lindgren, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    Jarnhed-Andersson, Ingmarie
    Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Tarpila, Erkki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Dressing the split-thickness skin graft donor site: a randomized clinical trial2014In: Advances in Skin & Wound Care, ISSN 1527-7941, E-ISSN 1538-8654, Vol. 27, no 1, p. 20-25Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The primary objective of this study was to compareAquacel (ConvaTec, Skillman, New Jersey), Allevyn (Smith &Nephew, St Petersburg, Florida), and Mediskin I (Mo¨ lnlycke, HealthCare AB, Gothenburg, Sweden) in the treatment of split-thicknessskin graft donor sites.

    DESIGN: This study was performed as a prospective randomized,3-arm, clinical study.

    SETTING: A clinical study performed at a hand and plastic surgerydepartment with burn unit.

    PARTICIPANTS: The study included 67 adults with a total of73 donor sites, which were on the thigh, not reharvested, andranged between 30- and 400-cm2 area.

    INTERVENTIONS: Subjects were randomly assigned to treatmentwith Aquacel, Allevyn, or Mediskin I.

    MAIN OUTCOME MEASURES: The donor site was assessed onpostoperative days 3, 14, and 21 for healing, infection, pain,impact on everyday life, ease of use, and cost.

    MAIN RESULTS: The obtained results demonstrate significantlyfaster re-epithelialization for patients treated with Aquacel orMediskin I compared with Allevyn. Regarding infections, therewere no significant differences between the groups. Patientswearing Aquacel experienced significantly less pain changing thedressing and less impact on everyday life than the patientswearing Allevyn. Aquacel was shown to be significantly easier forthe caregiver to use than Allevyn and Mediskin I. There is asignificant difference in cost of treatment between the dressings,whereas Mediskin I is the most expensive.

    CONCLUSION: The authors’ results support the use of Aquacel in thetreatment of split-thickness skin graft donor sites. Aquacel has alow cost per unit, is user friendly, gives short healing time, andminimizes patient discomfort.

     

  • 27.
    Kim, Woojin Scott
    et al.
    Neuroscience Research Australia, Barker Street, Randwick 2031, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Halliday, Glenda M
    Neuroscience Research Australia, Barker Street, Randwick 2031, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia.
    Alpha-synuclein biology in Lewy body diseases.2014In: Alzheimer's research & therapy, ISSN 1758-9193, Vol. 6, no 5, article id 73Article in journal (Refereed)
    Abstract [en]

    α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein intracellularly. Primary α-synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, with α-synuclein also found secondarily in a number of other diseases, including Alzheimer's disease. Understanding how α-synuclein aggregates form in these different disorders is important for the understanding of its pathogenesis in Lewy body diseases. PD is the most prevalent of the α-synucleinopathies and much of the initial research on α-synuclein Lewy body pathology was based on PD but is also relevant to Lewy bodies in other diseases (dementia with Lewy bodies and Alzheimer's disease). Polymorphism and mutation studies of SNCA, the gene that encodes α-synuclein, provide much evidence for a causal link between α-synuclein and PD. Among the primary α-synucleinopathies, multiple system atrophy is unique in that α-synuclein deposition occurs in oligodendrocytes rather than neurons. It is unclear whether α-synuclein originates from oligodendrocytes or whether it is transmitted somehow from neurons. α-Synuclein exists as a natively unfolded monomer in the cytosol, but in the presence of lipid membranes it is thought to undergo a conformational change to a folded α-helical secondary structure that is prone to forming dimers and oligomers. Posttranslational modification of α-synuclein, such as phosphorylation, ubiquitination and nitration, has been widely implicated in α-synuclein aggregation process and neurotoxicity. Recent studies using animal and cell models, as well as autopsy studies of patients with neuron transplants, provided compelling evidence for prion-like propagation of α-synuclein. This observation has implications for therapeutic strategies, and much recent effort is focused on developing antibodies that target extracellular α-synuclein.

  • 28.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Biologiska variabler i blod och urin - könsskillnader av stor betydelse för sjukdomsdiagnostik2010In: Genus och kön inom medicin- och vårdutbildningar / [ed] Barbro Wijma, Goldina Smirthwaite, Katarina Swanberg, Lund: Studentlitteratur AB , 2010, 1, p. 497-516Chapter in book (Other academic)
    Abstract [sv]

    Kvinnor och män är delvis lika, delvis olika. Det innebär att kvinnor och män både har behov av likadan behandling och av behandling som är anpassad till det egna könets förutsättningar. Denna antologi belyser kvinnors och mäns förutsättningar och behov inom en rad olika medicinska områden och tar upp både biologiska och sociala faktorer som påverkar hälsa och behandling. Den behandlar även den roll som kön spelar inom vårdens arbetsliv samt hur köns- och genusperspektiv kan integreras inom olika typer av medicin- och vårdutbildningar. Ett av bokens teman är våld, kränkningar och diskriminering, och inom ramen för detta behandlas några av de olika maktordningar som kommer till uttryck vid behandlingar inom hälso- och sjukvården. Antologin har en stor spännvidd när det gäller ämnen och författare. Förhoppningsvis ska den bredd som antologin uppvisar, leda fram till frågeställningar där läsaren utmanar sina förgivettaganden inom både genusvetenskap och mer traditionell medicin samt väcka nya frågor: Om könet snarare ses som en konstruktion än en fysisk realitet - kan då kvinnor lika gärna äta mediciner som är utprovade på män och opereras med metoder och verktyg anpassade till mäns fysiologi? Å andra sidan - hur objektiv är den naturvetenskapligt inriktade medicinska forskningen egentligen om man börjar granska den utifrån frågeställningar om perspektivval och genus? Antologin vänder sig till lärare på utbildningar inom medicin, hälsa och vård. Andra målgrupper är studenter på sådana utbildningar, vårdpersonal och en intresserad allmänhet.

  • 29.
    Latanova, Anastasia
    et al.
    Russian Academic Science, Russia; Gamaleja Research Centre Epidemiol and Microbiol, Russia; Karolinska Institute, Sweden.
    Petkov, Stefan
    Karolinska Institute, Sweden.
    Kuzmenko, Yulia
    Russian Academic Science, Russia.
    Kilpelainen, Athina
    Karolinska Institute, Sweden.
    Ivanov, Alexander
    Russian Academic Science, Russia.
    Smirnova, Olga
    Russian Academic Science, Russia.
    Krotova, Olga
    Russian Academic Science, Russia; Gamaleja Research Centre Epidemiol and Microbiol, Russia.
    Korolev, Sergey
    Lomonosov Moscow State University, Russia.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Karpov, Vadim
    Russian Academic Science, Russia.
    Isaguliants, Maria
    Gamaleja Research Centre Epidemiol and Microbiol, Russia; Riga Stradins University, Latvia; Russian Academic Science, Russia.
    Starodubova, Elizaveta
    Russian Academic Science, Russia; Karolinska Institute, Sweden; Russian Academic Science, Russia.
    Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice2017In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 7407136Article in journal (Refereed)
    Abstract [en]

    Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug-resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1.14oil. Promotion of secretion prohibited proteasomal degradation increasing the half-life and content of RT1.14oil in cells and cell culture medium, drastically reduced the residual polymerase activity, and downmodulated oxidative stress. BALB/c mice were DNA-immunized with RT1.14opt-in or parental RT1.14oil by intradermal injections with electroporation. Fluorospot and ELISA tests revealed that RT1.14opt-in and RT1.14oil induced IFN-gamma/IL-2, RT1.14opt-in induced granzyme B, and RT1.14oil induced perforin production. Perforin secretion correlated with coproduction of IFN-gamma and IL-2 (R = 0,97). Both DNA immunogens induced strong anti-RT antibody response. Ld peptide was not immunogenic. Thus, Ld-driven secretion inferred little change to RT performance in DNA immunization. Positive outcome was the abrogation of polymerase activity increasing safety of RT-based DNA vaccines. Identification of the molecular determinants of low cellular immunogenicity of RT requires further studies.

  • 30.
    Lundgren, Charlotte
    et al.
    Linköping University, Department of Culture and Communication, Language and Culture. Linköping University, Faculty of Arts and Sciences.
    Molander, Carl
    Institutionen för neurovetenskap, Uppsala universitet.
    Teamarbete i medicinsk rehabiltering2008 (ed. 1)Book (Other academic)
    Abstract [sv]

    Inom medicinsk rehabilitering har behovet av nära samarbete mellan olika personalkategorier ökat starkt. Denna bok ger grundläggande kunskaper för ett fungerande multiprofessionellt teamarbete inom medicinsk rehabilitering. Den vänder sig till såväl vårdpersonal som till administrativ personal och beslutsfattare inom sjukvården.Läs merBoken tecknar inledningsvis teamarbetets och rehabiliteringsmedicinens utveckling fram till dagens situation. Den belyser vidare olika sätt att organisera teamet och fördela arbetsuppgifterna och ansvaret. Skapandet och vården av ett team samt faktorer som påverkar teamarbetet är andra ämnen. I texten finns invävt exempel på varianter av teamarbete med de förutsättningar som gäller inom primärvård, företagshälsovård och kommunal rehabilitering. Den teoretiska framställningen kompletteras med fallbeskrivningar från bland annat smärtrehabilitering.

  • 31.
    Lundin, Anna-Carin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tendinosis in Trigger Finger2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.

    We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.

    Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.

    Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.

    We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.

    In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.

    List of papers
    1. Trigger finger and tendinosis
    Open this publication in new window or tab >>Trigger finger and tendinosis
    2012 (English)In: Journal of Hand Surgery, European Volume, ISSN 1753-1934, E-ISSN 2043-6289, Vol. 37, no 3, p. 233-236Article in journal (Refereed) Published
    Abstract [en]

    The pathogenesis of trigger finger has generally been ascribed to primary changes in the pulley. Histological examination of the affected tendons has rarely been done. We studied biopsies from tendons of trigger fingers from 29 patients and compared these to biopsies from six intact tendons. We used a modified Movin score, which describes the tendinosis of the Achilles tendon. Trigger finger tendons had a high score (14.2; SD, 2.2) consistent with tendinosis, while the controls were almost normal (2.5; SD, 1.9). This suggests that the tendon is also affected, and that trigger finger is a form of tendinosis.

    Place, publisher, year, edition, pages
    Sage Publications, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-76086 (URN)10.1177/1753193411421853 (DOI)000300994100007 ()21987275 (PubMedID)
    Available from: 2012-03-26 Created: 2012-03-26 Last updated: 2017-12-07Bibliographically approved
    2. Trigger finger, tendinosis, and intratendinous gene expression
    Open this publication in new window or tab >>Trigger finger, tendinosis, and intratendinous gene expression
    2014 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 24, no 2, p. 363-368Article in journal (Refereed) Published
    Abstract [en]

    The pathogenesis of trigger finger has generally been ascribed to primary changes in the first annular ligament. In contrast, we recently found histological changes in the tendons, similar to the findings in Achilles tendinosis or tendinopathy. We therefore hypothesized that trigger finger tendons would show differences in gene expression in comparison to normal tendons in a pattern similar to what is published for Achilles tendinosis. We performed quantitative real-time polymerase chain reaction on biopsies from finger flexor tendons, 13 trigger fingers and 13 apparently healthy control tendons, to assess the expression of 10 genes which have been described to be differently expressed in tendinosis (collagen type 1a1, collagen 3a1, MMP-2, MMP-3, ADAMTS-5, TIMP-3, aggrecan, biglycan, decorin, and versican). In trigger finger tendons, collagen types 1a1 and 3a1, aggrecan and biglycan were all up-regulated, and MMP-3and TIMP-3 were down-regulated. These changes were statistically significant and have been previously described for Achilles tendinosis. The remaining four genes were not significantly altered. The changes in gene expression support the hypothesis that trigger finger is a form of tendinosis. Because trigger finger is a common condition, often treated surgically, it could provide opportunities for clinical research on tendinosis.

    Place, publisher, year, edition, pages
    Wiley, 2014
    Keywords
    tendinopathy; tendinosis; stenosing tendovaginitis; tendovaginitis stenosans; quantitative real-time PCR; qPCR
    National Category
    Orthopaedics Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-106131 (URN)10.1111/j.1600-0838.2012.01514.x (DOI)000332982700018 ()
    Available from: 2014-04-25 Created: 2014-04-24 Last updated: 2018-01-11
  • 32.
    Mattson, Lina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Badam, Tejaswi
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Ledin, Torbjörn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Serra I Musach, Jordi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Björkander, Janne
    County Council Jonköping, Sweden.
    Xiang, Zou
    Hong Kong Polytech University, Peoples R China.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Potential Involvement of Type I Interferon Signaling in Immunotherapy in Seasonal Allergic Rhinitis2016In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 5153184Article in journal (Refereed)
    Abstract [en]

    Specific immunotherapy (SIT) reverses the symptoms of seasonal allergic rhinitis (SAR) in most patients. Recent studies report type I interferons shifting the balance between type I T helper cell (Th1) and type II T helper cells (Th2) towards Th2 dominance by inhibiting the differentiation of naive Tcells into Th1 cells. As SIT is thought to cause a shift towardsTh1 dominance, we hypothesized that SIT would alter interferon type I signaling. To test this, allergen and diluent challenged CD4(+) T cells from healthy controls and patients from different time points were analyzed. The initial experiments focused on signature genes of the pathway and found complex changes following immunotherapy, which were consistent with our hypothesis. As interferon signaling involves multiple genes, expression profiling studies were performed, showing altered expression of the pathway. These findings require validation in a larger group of patients in further studies.

  • 33.
    Myrelid, Pär
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Druvefors, Pelle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Andersson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Recurrent volvulus of an ileal pouch requiring repeat pouchopexy: a lesson learnt.2014In: Case Reports in Surgery, ISSN 2090-6919, E-ISSN 2090-6900, Vol. 2014, p. 807640-Article in journal (Refereed)
    Abstract [en]

    Introduction. Restorative surgery for ulcerative colitis with ileal pouch anal anastomosis (IPAA) is frequently accompanied by complications. Volvulus of the ileal pouch is one of the most rarely reported late complications and to our knowledge no report exists on reoperative surgery for this condition. Case Report. A 58-year-old woman who previously had undergone restorative proctocolectomy due to ulcerative colitis with an IPAA presented with volvulus of the pouch. She was operated with a single row pouchopexy to the presacral fascia. Two months later she returned with a recurrent volvulus. At reoperation, the pouch was found to have become completely detached from the fascia. A new pexy was made by firmly anchoring the pouch with two rows of sutures to the presacral fascia as well as with sutures to the lateral pelvic walls. At follow-up after five months she was free of symptoms. Conclusion. This first report ever on reoperative surgery for volvulus of a pelvic pouch indicates that a single row pouchopexy might be insufficient for preventing retwisting. Several rows seem to be needed.

  • 34.
    Nelzén, Oskar
    et al.
    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.
    Skoog, Johan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Länne, Toste
    Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Zachrisson, Helene
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Prediction of Post-interventional Outcome in Great Saphenous Vein Incompetence: The Role of Venous Plethysmography with Selective Superficial Vein Occlusion2016In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 52, no 3, p. 377-384Article in journal (Refereed)
    Abstract [en]

    Objective/Background

    To evaluate whether the outcome of radiofrequency ablation (RFA) treatment of great saphenous vein (GSV) incompetence may be predicted using strain-gauge plethysmography (SGP) with selective occlusion of the superficial venous system.

    Methods

    Seventeen patients (20 limbs) underwent endovenous RFA treatment for GSV incompetence (Clinical Etiology Anatomy Pathophysiology classification C2–C5; “C-group”). Duplex ultrasound (DUS) and SGP were performed with selective occlusion of superficial veins before and after RFA. Selective superficial occlusion was validated, in a control group (C-group) of 12 patients (14 legs), by ascending phlebography. In the RFA group, the time taken to reach 50% and 90% (T50, T90) of maximum venous volume was measured, as well as relative maximal reflux rates (%EV/min). The methodological error and coefficient of variation (CV) were assessed.

    Results

    Nineteen of 20 legs had complete post-operative GSV obliteration using DUS, and refilling times were improved after RFA (T50 11 ± 3 vs. 19 ± 3 s; p < .001; T90 27 ± 5 vs. 47 ± 6 s; p < .001). With SGP, the methodological error and CV for T50 were 4 s and 16%, respectively. Equivalence between pre-operative superficial occlusion and post-operative baseline measurements was achieved in 15 of 17 legs for T50, and 12 of 17 for T90 (three of the 20 legs were excluded due to treatment failure [n = 1], and untreated perforating veins [n = 2]). Mean differences (95% confidence interval) were within the equivalence ranges (T50 1 [–1 to 3] seconds; T90 –3 [–11 to 4] seconds). In the C-group superficial vein occlusion was possible in 12 of 14 legs. The remaining patient (two legs) showed incomplete superficial vein occlusion at ankle level (lipodermatosclerosis) and complete superficial vein occlusion at calf level.

    Conclusion

    SGP with standardized superficial venous occlusion seems to be a reliable method for identifying venous reflux and may be useful in predicting the results of successful RFA treatment.

  • 35.
    Nestor, Colm E
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Ottaviano, Raffaele
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Reinhardt, Diana
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Cruickshanks, Hazel A
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Mjoseng, Heidi K
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    McPherson, Rhoanne C
    MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Thomson, John P
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK .
    Dunican, Donncha S
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK .
    Pennings, Sari
    Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
    Anderton, Stephen M
    MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Meehan, Richard R
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK .
    Rapid reprogramming of epigenetic and transcriptional profiles in mammalian culture systems.2015In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, p. 11-Article in journal (Refereed)
    Abstract [en]

    BackgroundThe DNA methylation profile of mammalian cell lines differs from the primary tissue from which they were derived, exhibiting increasing divergence from the in vivo methylation profile with extended time in culture. Few studies have directly examined the initial epigenetic and transcriptional consequences of adaptation of primary mammalian cells to culture, and the potential mechanisms through which this epigenetic dysregulation occurs is unknown.ResultsWe demonstrate that adaptation of mouse embryonic fibroblast, MEFS, to cell culture results in a rapid reprogramming of epigenetic and transcriptional states. We observed global 5-hydroxymethylcytosine (5hmC) erasure within three days of culture initiation. Loss of genic 5hmC was independent of global 5-methylcytosine (5mC) levels and could be partially rescued by addition of Vitamin C. Significantly, 5hmC loss was not linked to concomitant changes in transcription. Discrete promoter-specific gains of 5mC were also observed within seven days of culture initiation. Against this background of global 5hmC loss we identified a handful of developmentally important genes that maintained their 5hmC profile in culture, including the imprinted loci Gnas and H19. Similar outcomes were identified in the adaption of CD4+ T-cells to culture.ConclusionsWe report a dramatic and novel consequence of adaptation of mammalian cells to culture in which global loss of 5hmC occurs; suggesting rapid concomitant loss of methylcytosine dioxygenase activity. The observed epigenetic and transcriptional re-programming occurs much earlier than previously assumed, and has significant implications for the use of cell lines as faithful mimics of in vivo epigenetic and physiological processes.

  • 36.
    Nezirevic Dernroth, Dzeneta
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Pheomelanin markers in melanoma with reference to their excretion into urine2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Skin pigmentation is an important issue in most cultures. Until recently we have not understood the most important elements of pigmentation regarding detailed chemical structure. The synthesis of melanin is very complex, and although core enzymes, other important proteins, and parts of the melanin structure have been identified much information in this context awaits disclosure.

    The function of the melanocyte and the deposition of melanin pigments into the keratinocytes are very important in the protection against UV light. Melanin pigments consist of high-molecular structures often described as brown to black eumelanin and yellow to red pheomelanin. Eumelanin is photoprotective, whereas pheomelanin is believed to be carcinogenic after UV radiation. There is strong evidence that people of fair complexion with freckles who tan poorly are at higher risk of developing melanoma. These people have a higher pheomelanin to eumelanin ratio in their skin.

    Melanoma, one of the most widely spread cancers, is derived from melanocytes. There is accumulating evidence that pigment constitution is highly involved in the development of melanoma. We found that patients with advanced melanoma secrete substantial amounts of pigment structures into the urine, in particular those with diffuse melanosis. In subsequently performed experiments we purified these pigments and subjected the product to chemical degradation by either hydrogen peroxide oxidation or hydriodic hydrolysis. Several new chromatographic methods were developed for the structural analysis of these products. Structural analysis of new chromatographic peaks was performed. In conclusion, complex pheomelanin structures as well as low molecular weight pigments and free benzothiazoles have been identified in the urine of patients with melanoma and diffuse melanosis.

    The present thesis provides new insight into melanogenesis and melanoma progression. This opens the doorway to further approaches to the investigation of melanins and can help to understand fundamental problems about the structure and biosynthesis of natural melanins.

    List of papers
    1. HPLC analysis of pheomelanin degradation products in human urine
    Open this publication in new window or tab >>HPLC analysis of pheomelanin degradation products in human urine
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    2003 (English)In: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 16, no 5, p. 480-486Article in journal (Refereed) Published
    Abstract [en]

    A sensitive and specific high performance liquid chromatography (HPLC) method was developed to quantify 4-amino-3-hydroxyphenylalanine (4-AHP) and 3-amino-4-hydroxyphenylalanine (3-AHP) in urine. In degradation studies of melanin pigment, 4-AHP and 3-AHP are derived from benzothiazine units of pheomelanin and pheomelanin-related metabolites such as trichochromes. 5-S-Cysteinyldopa-derived benzothiazine products give 4-AHP while 2-S-cysteinyldopa-derived benzothiazine products give 3-AHP. 3-AHP is also derived from nitrotyrosine formed by nitration of tyrosine with reactive nitrogen species. For this reason, the influence of this biological process on the amount of 3-AHP found in biological material have been investigated. The method is based on hydriodic acid hydrolysis of the melanin polymer and reversed-phase HPLC with electrochemical detection of the degradation products 4-AHP and 3-AHP. The mobile phase consists of 25 mM ammonium acetate and sodium octanesulfonate as an ion-pairing reagent. The 4-AHP and 3-AHP peaks were well separated and the detector response was linear within the range 0-2 ng injected for both compounds. With the developed chromatographic system, 4-AHP and 3-AHP showed good separation in the biological samples. There was a strong correlation between 4-AHP and 3-AHP in the urine of 50 malignant melanoma patients and two healthy subjects (R0.977). The two compounds were also strongly correlated with 5-S-cysteinyldopa in urine, the correlation coefficients being 0.862 and 0.907, respectively. The method described is sensitive enough for analysis of pheomelanin in urine and in several other biological samples. The results indicate that 3-AHP in urine is not influenced by excreted 3-nitrotyrosine and the data indicate that pheomelanins are excreted in the urine of melanoma patients.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-21494 (URN)10.1034/j.1600-0749.2003.00086.x (DOI)12950724 (PubMedID)
    Available from: 2009-10-02 Created: 2009-10-02 Last updated: 2017-12-13Bibliographically approved
    2. Hydrophilic interaction liquid chromatographic analysis of aminohydroxyphenylalanines from melanin pigments
    Open this publication in new window or tab >>Hydrophilic interaction liquid chromatographic analysis of aminohydroxyphenylalanines from melanin pigments
    2007 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1163, no 1-2, p. 70-79Article in journal (Refereed) Published
    Abstract [en]

    Malignant melanomas are more often seen in subjects with light colored skin who tan poorly than in persons who tan more rapidly. This has been attributed to the structure of their pigment, pheomelanin, which differs markedly from the eumelanin of persons with darker skin. To study the hydrolysis products of pheomelanin pigments a new method was developed for analysis of 4-amino-3-hydroxyphenylalanine (4-AHP) and 3-amino-4-hydroxyphenylalanine (3-AHP). Pheomelanin samples were hydrolyzed and extracted with solid-phase extraction columns using strong cation-exchange (SCX) cartridges. Separation of 4-AHP and 3-AHP was achieved on a ZIC-HILIC column (150 mm × 2.1 mm I.D.) with a mobile phase consisting of acetonitrile:0.1 M ammonium acetate buffer, pH 4.5 (82:18, v/v). Detection was performed with an electrochemical detector at +400 mV. Run time was 30 min. The limits of detection were 73 pg and 51 pg for 4-AHP and 3-AHP respectively, using 2 μl injections. Good linearity was found within the range 0.05-5.0 μg/ml. Absolute recovery was 70% and relative recovery was 100%. The AHPs were stable for 1 year in the hydrolyzed samples, for 4 days in the eluates from solid-phase sorbents stored in the refrigerator, and for 2 days diluted with mobile phase and stored in the autosampler at 10 °C. The within-day imprecision was <5% and the between-day imprecision was <7% for the two analytes. The method, applied to the analysis of pheomelanin in urine from human melanoma patients, allows the analysis of 30 samples in one set and is suitable for routine work with human hair and melanoma cells. By using the ZIC-HILIC stationary phase, ion-pairing reagents could be avoided, which makes the method suitable to further analysis of degradation products from pheomelanins using mass spectrometric detection. © 2007 Elsevier B.V. All rights reserved.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-39471 (URN)10.1016/j.chroma.2007.06.007 (DOI)48765 (Local ID)48765 (Archive number)48765 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    3. Gas chromatography-mass spectrometry analysis of pheomelanin degradation products
    Open this publication in new window or tab >>Gas chromatography-mass spectrometry analysis of pheomelanin degradation products
    2009 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1216, no 30, p. 5730-5739Article in journal (Refereed) Published
    Abstract [en]

    Melanoma is most rapidly increasing in the white population and people with pheomelanin skin type are at high risk to develop melanoma. However, little is known about the pheomelanin structure and function, and further elucidation of this melanin is therefore an important task. A GC/MS method was developed based on hydriodic acid hydrolysis of pheomelanin in the urine. Derivatization was performed with ethyl chloroformate and ethanol:pyridine (4:1, v/v). N,O-Ethoxycarbonyl-ethyl esters were extracted with chloroform and analyzed by GC/MS. 4-Amino-3-hydroxyphenylaianine and 3-amino4-hydroxyphenylaianine together with one benzothiazinone and two benzothiazole compounds were detected and identified in hydrolyzed samples of synthetic pheomelanin and melanin from the urine of a patient with melanoma. These findings strongly suggest that heterocyclic pheomelanin-type units are incorporated in the pigment structures.

    Keywords
    Alkyl chloroformate; Aminohydroxyphenylalanine; Derivatization; Gas chromatography-mass spectrometry; Melanin; Melanoma; Pheomelanin; 7-(2-Amino-2-carboxyethyl)-5-hydroxy-3, 4-dihydro-2H-1, 4-benzothiazine-3-one 6-(2-Amino-2-carboxyethyl)-4-hydroxybenzothiazole 6-(2-Amino-2-carboxyethyl)-4-hydroxy-2-methyl-benzothiazole; Benzothiazine; Benzothiazole; Benzothiazinone
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20135 (URN)10.1016/j.chroma.2009.05.063 (DOI)
    Available from: 2009-08-31 Created: 2009-08-31 Last updated: 2017-12-13Bibliographically approved
    4. Pheomelanin-related benzothiazole isomers in the urine of patients with diffuse melanosis of melanoma
    Open this publication in new window or tab >>Pheomelanin-related benzothiazole isomers in the urine of patients with diffuse melanosis of melanoma
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    2010 (English)In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 411, no 17-18, p. 1195-1203Article in journal (Refereed) Published
    Abstract [en]

    Currently used as structural markers for pheomelanin identification and quantitation, benzothiazole compounds derived from isomeric cysteinyldopas have been indicated by recent in vitro studies as new potential pheomelanogenesis intermediates. Prompted by previous reports on the occurrence of large amounts of 5-S-cysteinyldopa (5-S-CD) and trichochromes in urine of patient with diffuse melanosis of melanoma we investigated the presence of benzothiazole compounds in the urine of these patients.

    Hydrophilic interaction liquid chromatography on zwitterionic stationary phase (ZIC-HILIC) and photo-diode array (PDA) detection was used for analysis of 6-(2-amino-2-carboxyethyl)-4-hydroxybenzothiazole-2-carboxylic acid (BTCA-5), and 7-(2-amino-2-carboxyethyl)-4-hydroxybenzothiazole-2-carboxylic acid (BTCA-2), derived from 5-S-CD and 2-S-cysteinyldopa (2-S-CD) isomers, respectively. Isocratic mobile phase with minimal sample preparation allowed efficient separation of the compounds, which were safely identified by their typical absorption features.

    Among 21 melanoma patients examined three showed diffuse melanosis. The levels of urinary BTCAs were found to be highly associated with melanosis but more loosely to excreted 5-S-CD. Analysis of the pigmented fraction of urine following alkaline hydrogen peroxide degradation and quantitation of BTCAs provided evidence for the presence of pheomelanins at higher levels in patients with melanosis.

    Place, publisher, year, edition, pages
    lsevier Science B.V., Amsterdam, 2010
    Keywords
    Benzothiazole, benzothiazole-2-carboxylic acids, diffuse melanosis, melanoma, HILIC, pheomelanin, BTCA
    National Category
    Other Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-21817 (URN)10.1016/j.cca.2010.04.019 (DOI)000280033400005 ()
    Available from: 2009-10-05 Created: 2009-10-05 Last updated: 2017-12-13Bibliographically approved
  • 37.
    Nezirevic Dernroth, Dzeneta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Årstrand, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Greco, Giorgia
    Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Via Cyntia 4 I-80126, Naples Italy.
    Panzella, Lucia
    Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Via Cyntia 4 I-80126, Naples Italy.
    Napolitano, Alessandra
    Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Via Cyntia 4 I-80126, Naples Italy.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Pheomelanin-related benzothiazole isomers in the urine of patients with diffuse melanosis of melanoma2010In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 411, no 17-18, p. 1195-1203Article in journal (Refereed)
    Abstract [en]

    Currently used as structural markers for pheomelanin identification and quantitation, benzothiazole compounds derived from isomeric cysteinyldopas have been indicated by recent in vitro studies as new potential pheomelanogenesis intermediates. Prompted by previous reports on the occurrence of large amounts of 5-S-cysteinyldopa (5-S-CD) and trichochromes in urine of patient with diffuse melanosis of melanoma we investigated the presence of benzothiazole compounds in the urine of these patients.

    Hydrophilic interaction liquid chromatography on zwitterionic stationary phase (ZIC-HILIC) and photo-diode array (PDA) detection was used for analysis of 6-(2-amino-2-carboxyethyl)-4-hydroxybenzothiazole-2-carboxylic acid (BTCA-5), and 7-(2-amino-2-carboxyethyl)-4-hydroxybenzothiazole-2-carboxylic acid (BTCA-2), derived from 5-S-CD and 2-S-cysteinyldopa (2-S-CD) isomers, respectively. Isocratic mobile phase with minimal sample preparation allowed efficient separation of the compounds, which were safely identified by their typical absorption features.

    Among 21 melanoma patients examined three showed diffuse melanosis. The levels of urinary BTCAs were found to be highly associated with melanosis but more loosely to excreted 5-S-CD. Analysis of the pigmented fraction of urine following alkaline hydrogen peroxide degradation and quantitation of BTCAs provided evidence for the presence of pheomelanins at higher levels in patients with melanosis.

  • 38.
    Nord, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Levodopa pharmacokinetics -from stomach to brain: A study on patients with Parkinson’s disease2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients.

    In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment.

    To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.

    List of papers
    1. Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
    Open this publication in new window or tab >>Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
    2017 (English)In: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 06, no 01Article in journal (Refereed) Published
    Abstract [en]

    Levodopa uptake from the gastrointestinal tract in patients with Parkinson’s disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark® was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01). In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.

    Place, publisher, year, edition, pages
    Scientific Research Publishing, 2017
    National Category
    Neurology Gastroenterology and Hepatology Anesthesiology and Intensive Care Surgery Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:liu:diva-136685 (URN)10.4236/apd.2017.61001 (DOI)
    Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2018-01-12
    2. The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
    Open this publication in new window or tab >>The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
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    2010 (English)In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, no 3, p. 363-367Article in journal (Refereed) Published
    Abstract [en]

    Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa. shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day I; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg bid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C-max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C-max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2010
    Keywords
    Parkinsons Disease, levodopa, continuous infusion, COMT
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54855 (URN)10.1002/mds.22613 (DOI)000276136900016 ()
    Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2018-01-12
    3. Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
    Open this publication in new window or tab >>Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
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    2014 (English)In: Neurology and Clinical Neuroscience, ISSN 2049-4173, Vol. 2, no 5, p. 149-155Article in journal (Refereed) Published
    Abstract [en]

    Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there might be alterations of neurotransmitter levels in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus. Aim In this study, we examined whether deep brain stimulation of the nucleus subthalamicus and levodopa infusion interact and affect the levels of neurotransmitters. Methods Five patients with advanced Parkinson’s disease took part in the study. During subthalamic nucleus surgery, microdialysis catheters were inserted bilaterally in the globus pallidum interna and unilaterally in the right putamen. A study protocol was set up and was followed for 3 days. Levodopa infusion with and without concomitant bilateral deep brain stimulation of the nucleus subthalamicus was also carried out. Results The putaminal dopamine levels increased during deep brain stimulation of the nucleus subthalamicus. In addition, an increase of gamma amino buturic acid concentrations in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus and during levodopa infusion was found. Conclusions These findings provide evidence that the subthalamic nucleus has a direct action on the substantia nigra pars compacta, and that deep brain stimulation of the nucleus subthalamicus might indirectly release putaminal dopamine. There is also evidence that deep brain stimulation of the nucleus subthalamicus interferes with levodopa therapy resulting in higher levels of levodopa in the brain, explaining why it is possible to decrease levodopa medication after deep brain stimulation surgery.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2014
    Keywords
    deep brain stimulation, levodopa, microdialysis, neurotransmitters, Parkinson
    National Category
    Medical Bioscience Medical Biotechnology Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-113590 (URN)10.1111/ncn3.109 (DOI)
    Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2019-02-11Bibliographically approved
    4. Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
    Open this publication in new window or tab >>Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
    2017 (English)In: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 6, no 2, p. 52-66Article in journal (Refereed) Published
    Abstract [en]

    Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.

    Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.

    Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.

    Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

    Place, publisher, year, edition, pages
    Scientific Research Publishing Inc, 2017
    Keywords
    Parkinson’s Disease, Levodopa, Dopamine, Brain, Microdialysis, Deep Brain Stimulation
    National Category
    Neurology Cardiac and Cardiovascular Systems Gastroenterology and Hepatology Anesthesiology and Intensive Care Other Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-139251 (URN)10.4236/apd.2017.62006 (DOI)
    Available from: 2017-07-07 Created: 2017-07-07 Last updated: 2018-01-12Bibliographically approved
  • 39.
    Nord, Maria
    et al.
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Zsigmond, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Kullman, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease2017In: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 6, no 2, p. 52-66Article in journal (Refereed)
    Abstract [en]

    Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.

    Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.

    Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.

    Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

  • 40.
    Nordberg, Marika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Nyman, Dag
    The Åland Borrelia Group, Åland, 22100 Mariehamn, Åland, Finland.
    Skogman, Barbro H.
    Center for Clinical Research (CKF) Dalarna, 791 36 Falun, Sweden.
    Nyberg, Clara
    The Åland Borrelia Group, Åland, 22100 Mariehamn, Åland, Finland.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Eliasson, Ingvar
    Department of Laboratory Medicine, NÄL, 461 85 Trollhättan, Sweden.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Can ELISPOT Be Applied to A Clinical Setting as A Diagnostic Utility for Neuroborreliosis?2012In: Cells, ISSN 2073-4409, Vol. 13, no 48, p. 153-167Article in journal (Refereed)
    Abstract [en]

    The aim of this prospective study was to investigate the diagnostic performance of Borrelia (Bb)-induced interferon (IFN)-γ secretion detected by ELISPOT modified to be feasible for clinical laboratories as a supplementary test to the laboratory diagnosis of Lyme neuroborreliosis (LNB) in an endemic setting. Between 2002 and 2004, patients with symptoms of suspected clinical LNB were included in a study conducted on the Åland islands in the Finnish archipelago, which is a hyper-endemic area for Lyme borreliosis (LB). Fourteen patients with confirmed LNB and 103 patients with non-LNB were included, and the numbers of spontaneous and Bb-induced IFN-γ-secreting cells were assayed by the ELISPOT test. The ELISPOT assay showed a weak diagnostic performance with a sensitivity of 36% and a specificity of 82%. The findings in this study show that this ELISPOT-assay modified to be feasible in clinical routine laboratories is not useful as a supplementary diagnostic tool in the laboratory diagnosis of patients with clinically suspected LNB.

  • 41.
    Olsson, Anders
    et al.
    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.
    Angelin, B.
    Karolinska Institute, Sweden; Karolinska University Hospital Huddinge, Sweden.
    Assmann, G.
    University of Munster, Germany.
    Binder, C. J.
    Medical University of Vienna, Austria; Austrian Academic Science, Austria.
    Bjoerkhem, I.
    Karolinska University Hospital Huddinge, Sweden; Karolinska Institute, Sweden.
    Cedazo-Minguez, A.
    Karolinska Institute Huddinge, Sweden.
    Cohen, J.
    UTSouthwesternMedical Centre, TX USA.
    von Eckardstein, A.
    University of Zurich, Switzerland.
    Farinaro, E.
    University of Naples Federico II, Italy.
    Mueller-Wieland, D.
    University of Cologne, Germany.
    Parhofer, K. G.
    Ludwig Maximilians University of Munchen, Germany.
    Parini, P.
    Karolinska University Hospital Huddinge, Sweden; Karolinska Institute, Sweden.
    Rosenson, R. S.
    Mt Sinai Hospital, NY 10029 USA.
    Starup-Linde, J.
    University of Aarhus, Denmark.
    Tikkanen, M. J.
    University of Helsinki, Finland.
    Yvan-Charvet, L.
    University of Nice Sophia Antipolis, France.
    Can LDL cholesterol be too low? Possible risks of extremely low levels2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 6, p. 534-553Article, review/survey (Refereed)
    Abstract [en]

    Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important. This is an article from the symposium: Risks and benefits of Extremely Low LDL Cholesterol.

  • 42.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Studies on warfarin treatment with emphasis on inter-individual variations and drug monitoring2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Warfarin was introduced more than 60 years ago and is used worldwide for the prophylaxis of arterial and venous thromboembolism in primary and secondary prevention. The drug is orally administered as a racemic mixture of (R)- and (S)-enantiomers. The (S)-form is mainly responsible for the anticoagulant effect and is metabolised by CYP2C9 enzyme in the liver microsomes. Warfarin exerts its pharmacological action by inhibiting the key enzyme (VKORC1) that regenerates vitamin K from an oxidised state to a reduced form. The latter is a cofactor for the post-translational modification of a number of proteins including coagulation factors II, VII, IX and X. The vitamin K-dependent modification provides these factors with the calcium-binding ability they require for the interaction with cell membranes of their target cells such as platelets.

    Warfarin is monitored by measuring prothrombin time (PT) expressed as INR. Two main methods exist for PT analysis. The Owren method is used mainly in the Nordic and Baltic countries, in Japan, whereas the Quick method is employed in most other countries. Warfarin management is associated with some complications. Unlike many other drugs the dose for a given patient cannot be estimated beforehand, dose-response relationship is not predictable, and the prevention of thrombosis must be balanced against the risk of bleeding. Furthermore, the different PT methods used to monitor the drug are sometimes not in agreement and show significant discrepancies in results.

    In an attempt to clarify the mechanisms influencing the inter-individual variations in warfarin therapy and to detect the factors that contribute to differences between PT methods, studies were conducted in collaboration with hospitals and anticoagulation clinics in the south-eastern region of Sweden. First, a stereo-specific HPLC method for measurement of warfarin enantiomers was developed and validated. With this method, the levels of plasma warfarin following its oral administration can be studied and evaluated. Abnormal clearance in some patients can be detected, and patient compliance can be verified. Furthermore, differing ratios of (S)- and (R)-isomers can be identified.

    The impact of common VKORC1 polymorphisms on warfarin therapy was investigated. This study has shown that the VKORC1*2 haplotype is an important genetic determinant for warfarin dosage and is associated with difficulties in attaining and retaining therapeutic PT-INR. Further, significant differences in warfarin S/R-ratio was detected between patients with VKORC1*2 and VKORC1*3 or VKORC1*4 variants. This difference was not coupled with CYP2C9 genotype.

    The effects of predilution of patient plasma samples, sources of thromboplastin and deficient plasma on between PT methods agreement were studied. This study has revealed that sample predilution according to the Owren method is to be preferred for the harmonisation of PT results. Undiluted samples, in contrast, according to the Quick method have shown reduced correlation between two different thromboplastin reagents. Sources of thromboplastin and deficient plasma were only of minor importance.

    List of papers
    1. A new high-performance liquid chromatographic method for determination of warfarin enantiomers.
    Open this publication in new window or tab >>A new high-performance liquid chromatographic method for determination of warfarin enantiomers.
    2005 (English)In: Journal of Chromatography B, ISSN 1570-0232, Vol. 826, no 1-2, p. 75-80Article in journal (Refereed) Published
    Abstract [en]

    Warfarin is the most common agent used for control and prevention of venous as well as arterial thromboembolism. Although warfarin is administered as a racemic mixture of two stereoisomers (S and R), the S-form is mainly responsible for the anticoagulant effect. The anticoagulant effect of the drug is monitored by analysis of prothrombin complex (International Normalised Ratio,INR). In some cases, however, the measurements of plasma warfarin concentration are needed. Here, we present a new, rapid, sensitive and cost-effective HPLC-method for the determination of warfarin enantiomers in plasma. The chromatographic system consisted of Waters 616 gradient pump, Waters 996 photo diode array detector, Gilson 230 autoinjector and Pirkle (R,R) Whelk-O1 column (25 cm × 4.6 mm I.D., 5 μm). An isocratic mobile phase of methanol/acetonitrile/water (50/10/40, v/v) with 0.1% glacial acetic acid was used. The follow rate was 1 mL/min. Data analysis was carried out with Waters Millennium32. The absorbance at 305 nm was measured with a total run-time of 15 min. Method linearity was studied by establishing regression data containing eight points over the range 0.08–10 μg/mL. In this range, warfarin showed to be linear (r2 = 0.9997 for S-warfarin and r2 = 0.9998 for R-warfarin). The limit of detection in plasma was 16 ng/mL for S-warfarin and 18 ng/mL for R-warfarin. Limit of quatitation was defined as 10 × LOD. The extraction recovery was approximately 80%. Also the relation between INR and warfarin concentration was investigated. As expected, there was a low correlation between these two variables (r = 0.23, y = 0.3044x + 0.9712). This method offers a rapid and cost-effective determination of warfarin enantiomers in human plasma.

    Keywords
    S- and R-warfarin; Oxybenzone; INR
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14487 (URN)10.1016/j.jchromb.2005.08.011 (DOI)
    Available from: 2007-05-21 Created: 2007-05-21 Last updated: 2013-09-03
    2. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records
    Open this publication in new window or tab >>Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records
    Show others...
    2006 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, Vol. 4, no 8, p. 1723-1729Article in journal (Refereed) Published
    Abstract [en]

    Background: Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Several reports have shown that mutations in the gene encoding VKORC1 affect the sensitivity of the enzyme for warfarin. Recently, three main haplotypes of VKORC1; *2, *3 and *4 have been observed, that explain most of the genetic variability in warfarin dose among Caucasians.

    Objectives: We have investigated the main haplotypes of the VKORC1 gene in a Swedish population. Additional objective was to screen the studied population for mutations in the coding region of VKORC1 gene.

    Patients/methods: Warfarin doses and plasma S- and R-warfarin of 98 patients [with a target International Normalized Ratio (INR) of 2.0–3.0] have been correlated to VKORC1 haplotypes. Controls of 180 healthy individuals have also been haplotyped. Furthermore, a retrospective analysis of case records was performed to find any evidence indicating influence of VKORC1 haplotypes on warfarin response in the first 4 weeks (initiation phase) and the latest 12 months of warfarin treatment.

    Results and conclusions: Our result shows that VKORC1*2 is the most important haplotype for warfarin dosage. Patients with VKORC1*2 haplotype had more frequent visits than patients with VKORC1*3 or *4 haplotypes, higher coefficient of variation (CV) of prothrombin time-INR and higher percentage of INR values outside the therapeutic interval (i.e. 2.0–3.0) than patients with VKORC1*3 or *4 haplotypes. Also, there was a statistically significant difference in warfarin dose (P < 0.001) and R-warfarin plasma levels (P < 0.01) between VKORC1*2 and VKORC1*3 or 4 haplotypes. Patients with VKORC1*2 haplotype seem to require much lower warfarin doses than other patients.

    Keywords
    INR, VKORC1, warfarin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14488 (URN)10.1111/j.1538-7836.2006.02039.x (DOI)
    Available from: 2007-05-21 Created: 2007-05-21 Last updated: 2013-09-03
    3. Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype
    Open this publication in new window or tab >>Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype
    2007 (English)In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 18, no 3, p. 293-296Article in journal (Refereed) Published
    Abstract [en]

    We recently reported that the low-dose VKORC1*2 haplotype is an important genetic determinant for warfarin dose requirement and is associated with difficulties to attain stable therapeutic prothrombin time-International Normalized Ratio in patients undergoing anticoagulation therapy. The aim of this study was to investigate whether patients with VKORC1*2 compared with patients carrying high-dose haplotypes VKORC1*3 or VKORC1*4 had different warfarin S/R ratios in their plasma, and whether that was related to CYP2C9 variants CYP2C9*2 and CYP2C9*3 or other factors. Samples from patients previously haplotyped for VKORC1 and measured for plasma warfarin concentration were genotyped for the CYP2C9 variants CYP2C9*2 and CYP2C9*3. Nonparametric statistical analysis was performed to elucidate whether there was any significant difference in the warfarin S/R ratio between the two patient groups. Our result shows that there is a significant difference (P < 0.01) in warfarin S/R ratios between VKORC1*2 and VKORC1*3 or VKORC1*4 patients. This difference did not originate from CYP2C9 variants CYP2C9*2 and CYP2C9*3. We speculate that VKORC1 haplotypes possibly are linked to some unidentified factors involved in the metabolic clearance of warfarin enantiomers. Dose-dependent variations in (S)-warfarin and (R)-warfarin clearance in these patients can also be a probable explanation for the difference in warfarin S/R ratios.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14489 (URN)10.1097/MBC.0b013e3280444bfd (DOI)
    Available from: 2007-05-21 Created: 2007-05-21 Last updated: 2017-12-13Bibliographically approved
    4. Plasma sample dilution improves the correlation: between reagents for PT methods
    Open this publication in new window or tab >>Plasma sample dilution improves the correlation: between reagents for PT methods
    2007 (English)In: XXIst ISTH Congress, 2007Conference paper, Published paper (Refereed)
    Abstract [en]

    Introduction: The Quick (plain thromboplastins) and Owren (combined thromboplastins) PT methods are used worldwide for the monitoring of anticoagulation therapy with vitamin K antagonists. Although both methods measure the activity of vitamin K dependent coagulation factors, the Quick PT-result in addition is dependent on the activity of factor V and of fibrinogen. The Quick PT-methods are also associated with larger inter-laboratory variations than Owren PT-methods. We have investigated whether the dilution of the sample, the source of depleted plasma or the source of thromboplastin have an impact on the correlation between the different PT-reagents.

    Methods: Patient and quality control samples were analysed undiluted and prediluted 2x, 7x, 10x, and 12x in Owren's buffer. One part of sample was then mixed with two parts of reagent and calcium. Bovine vs. human depleted plasmas and rabbit brain vs. human placenta thromboplastins were compared in combinations. The assays were run on an ACL Top from Instrumentation Laboratory (Italy).

    Results: Our results show that the dilution of the sample is important for the correlation between different PT-reagents. We found the best correlation (r = 0.95) when the sample was 7-fold prediluted (1 part + 6 parts). The lowest correlation was found when the sample was undiluted (r = 0.67). The source of thromboplastin had a small, if any, impact on the PT-results provided the sample was prediluted.The source of depleted plasma had no significance for the relationship between the PT-reagents. The depleted plasma is necessary to in order enable clotting of prediluted plasma.

    Conclusions: We conclude that the Owren style sample dilution is to prefer for the harmonization of PT-results and to overcome the large inter-laboratory variations that are associated with Quick PT-methods.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14490 (URN)
    Note
    This paper is published in volume 5, supplement 1 of Journal of Thrombosis and Haemostasis (2007).Available from: 2007-05-21 Created: 2007-05-21 Last updated: 2009-12-18
  • 43.
    Papakyritsis, Ioannis
    et al.
    Western Illinois University, Macomb, USA.
    Müller, Nicole
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Perceptual and acoustic analysis of lexical stress in Greek speakers with dysarthria2014In: Clinical Linguistics & Phonetics, ISSN 0269-9206, E-ISSN 1464-5076, Vol. 28, no 7-8, p. 555-572Article in journal (Refereed)
    Abstract [en]

    The study reported in this paper investigated the abilities of Greek speakers with dysarthria to signal lexical stress at the single word level. Three speakers with dysarthria and two unimpaired control participants were recorded completing a repetition task of a list of words consisting of minimal pairs of Greek disyllabic words contrasted by lexical stress location only. Fourteen listeners were asked to determine the attempted stress location for each word pair. Acoustic analyses of duration and intensity ratios, both within and across words, were undertaken to identify possible acoustic correlates of the listeners judgments concerning stress location. Acoustic and perceptual data indicate that while each participant with dysarthria in this study had some difficulty in signaling stress unambiguously, the pattern of difficulty was different for each speaker. Further, it was found that the relationship between the listeners judgments of stress location and the acoustic data was not conclusive.

  • 44.
    Pettersson, Sandra
    Linköping University, Department of Physics, Chemistry and Biology.
    Bestämning av syntetiska cannabinoider med gaskromatografi-masspektrometri2011Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    This thesis has been performed at Clinical Chemistry at Sahlgrenska University Hospital in Gothenburg. The purpose of the project was to investigate new and alternative ways to determinate synthetic cannabinoids by gas chromatography-mass spectrometry. Currently, the possibilities to quantify synthetic cannabinoids are very limited. This can lead to an increased use of synthetic cannabinoids as the risk of detection is low, which may be known by drug users. The synthetic cannabinoids are sold mixed with different herbs and have varying names like Spice Gold, Spice Silver, K2, Smoke and Pot-pourri.

    The synthetic cannabinoids analyzed were JWH-018 and JWH-073, which are commonly found in seized Spice material. At intake of these drugs, usually through smoking, cannabis-like effects arise. This is because they bind to cannabinoid receptors in a similar way as THC does, which is the primary active cannabinoid of cannabis.

    For urine samples an analytical method would probably be the most sensitive if the major metabolite could be analyzed, as it is expected to be present in high concentrations in this sample type. Since information regarding the metabolism of synthetic cannabinoids is very limited there may be reasons to analyze the mother substance in urine. Further, in plasma and serum samples the mother substance is expected in high concentrations. Thus different ways to detect JWH-018 and JWH-073 directly were investigated in this project.

    Derivatization of JWH-018 and JWH-073 was the first step to get more selective and sensitive GC-MS analysis. Different derivatization-reagents were investigated, for example BSTFA and TFAA. The results show that the derivatization of JWH-018 with BSTFA after reduction and extraction was successful. To achieve this, samples had to be heated at 115°C for 1-3 hours, but still the samples were not completely derivatized.

    The results indicate that JWH-substances are difficult to derivatized, but they are possible to derivatize with BSTFA. This could mean that a GC-MS-method maybe could be established for these substances, preferably trough TFAA-derivatization.

  • 45.
    Rakkolainen, Ilmari
    et al.
    Department of Plastic Surgery, Helsinki Burn Centre, Helsinki University Hospital, Finland; University of Helsinki, Helsinki, Finland.
    Elmasry, Moustafa
    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. Surgery Department, Plastic Surgery Unit, Suez Canal University, Egypt .
    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.
    Vuola, Jyrki
    Department of Plastic Surgery, Helsinki Burn Centre, Helsinki University Hospital, Finland; University of Helsinki, Helsinki, Finland.
    N-Terminal Brain Natriuretic Peptide First Week After Burn Injury2018In: Journal of Burn Care & Research, ISSN 1559-047X, E-ISSN 1559-0488, Vol. 39, no 5, p. 805-810Article in journal (Refereed)
    Abstract [en]

    B-type natriuretic peptide has shown promising results as a biomarker for acute kidney injury in general intensive care patients. It may also indirectly reflect fluid balance of the circulation. Among burn patients, it has been observed to indicate excessive fluid resuscitation and organ dysfunction, although its clinical use to indicate acute kidney injury or guide fluid resuscitation has not been validated. The aim of this study was to evaluate whether the N-terminal pro-brain natriuretic peptide values are related to the amount of fluids given after severe burn injury and whether it can act as a novel biomarker for acute kidney injury in these patients. Nineteen consecutive burn patients were included. Plasma N-terminal pro-brain natriuretic peptide was measured daily during 1 week from admission. Other variables such as laboratory values and intravenous infusions were also recorded. The association between acute kidney injury and N-terminal pro-brain natriuretic peptide values was analyzed with a multivariable panel regression model, adjusted for burned total body surface area, age, body mass index, and laboratory values. N-terminal pro-brain natriuretic peptide values varied between single patients, and even more between the patients who developed acute kidney injury. Older age, lower body mass index, and cumulative infusions were independently associated with higher N-terminal pro-brain natriuretic peptide values, whereas acute kidney injury was not. N-terminal pro-brain natriuretic peptide values correlated with cumulative infusions given during the first week. The authors could not validate the role of N-terminal pro-brain natriuretic peptide as a biomarker for acute kidney injury in burns.

  • 46.
    Ramö Isgren, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Blomberg, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Obstetric Outcomes in Adolescents Related to Body Mass Index and Compared with Low-Risk Adult Women2017In: Journal of Women's Health, ISSN 1540-9996, E-ISSN 1931-843X, Vol. 26, no 5, p. 426-434Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate in adolescents the association between body mass index (BMI) and obstetric outcomes and to determine whether the outcomes in the BMI groups of adolescents differ from those of a low-risk population of adult women. Materials and Methods: This is a nationwide population-based register study. Obstetric outcomes of 31,386 singleton primiparous adolescents were evaluated in relation to BMI classes. Furthermore, the outcomes of the adolescents and 178,844 normal weight, nonsmoking, singleton primiparous women, 25-29 years old with no known comorbidity, defined as standard women, were compared. Multiple logistic regression models were used. Results are presented as crude odds ratios (ORs) or adjusted ORs and with a 95% confidence interval. Results: Compared with normal weight adolescents, obese adolescents had a lower chance of a normal vaginal delivery (VD)76% versus 85% [adjusted OR 0.61 (0.55-0.68)], a higher risk for acute cesarean section (CS)8.9% versus 4.5% [adjusted OR 2.45 (2.08-2.88)], and stillbirth0.7% versus 0.2% [adjusted OR 3.17 (1.74-5.77)]. Compared with standard women, overweight adolescents had a higher chance of a normal VD82% versus 75% [crude OR 1.53 (1.44-1.64)] and a lower risk for acute CS6.3% versus 7.1% [crude OR 0.85 (0.76-0.95)]. Obese adolescents had a lower risk for instrumental VD8% versus 13% [crude OR 0.61 (0.53-0.71)] and obstetric anal sphincter injury1% versus 3% [crude OR 0.38 (0.26-0.57)]. Conclusion: Several adverse obstetric outcomes were obesity related among adolescents. Overweight adolescents seemed to have better obstetric outcomes than standard women, something to consider when optimizing resources for women during pregnancy and delivery.

  • 47.
    Rasmusson, Lars
    et al.
    Department Oral and Maxillofacial Surgery, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,.
    Abtahi, Jahan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Bisphosphonate associated osteonecrosis of the jaw: an update on pathophysiology, risk factors, and treatment.2014In: International Journal of Dentistry, ISSN 1687-8728, E-ISSN 1687-8736, article id 71035Article, review/survey (Refereed)
    Abstract [en]

    Osteonecrosis of the jaw in patients treated with bisphosphonates is a relatively rare but well known complication at maxillofacial units around the world. It has been speculated that the medication, especially long-term i.v. bisphosphonate treatment, could cause sterile necrosis of the jaws. The aim of this narrative review of the literature was to elaborate on the pathological mechanisms behind the condition and also to gather an update on incidence, risk factors, and treatment of bisphosphonate associated osteonecrosis of the jaw. In total, ninety-one articles were reviewed. All were published in internationally recognized journals with referee systems. We can conclude that necrotic lesions in the jaw seem to be following upon exposure of bone, for example, after tooth extractions, while other interventions like implant placement do not increase the risk of osteonecrosis. Since exposure to the bacterial environment in the oral cavity seems essential for the development of necrotic lesions, we believe that the condition is in fact chronic osteomyelitis and should be treated accordingly.

  • 48.
    Ristenvik, Emma
    et al.
    Linköping University, Department of Clinical and Experimental Medicine.
    Vikström, Lina
    Linköping University, Department of Clinical and Experimental Medicine.
    Fonologisk intervention baserad på en icke-linjär fonologisk analys: En multipel fallstudie2017Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Children with phonological problems often come in contact with a speech and language pathologist for intervention. The intervention can be based on different theoretical frameworks, whereof non-linear phonology is one.

    The present study was carried out as a multiple single-case study with three participants aged 4;3-4;4 years. They had all been diagnosed with speech sound disorder but not yet been given any treatment. Before the intervention was started, three baseline measurements were made with the Swedish phonology test LINUS. The intervention took place once a week for five weeks and ended with two follow-up measurements. The first follow-up measurement occurred in connection to the last intervention and the other one after three weeks. The children’s caretakers filled in a questionnaire about their perception of the intervention at the last follow up measurement. Correctly produced segments and clusters in the words in LINUS were calculated and compared to the children’s productions at the base-line measurements. Percentage Phonemes Correct and Reliable Change Index were calculated to check whether any change was reliable.

    The targeted segments and clusters improved to a greater extent than other segments. Clusters demonstrated greater result regarding to the segments. The RCI-index was >1,96 for all participants indicating that the results were reliable in terms of improved phonological ability. In the parental questionnaire, it was indicated that the caretakers thought that the treatment was valuable, that they perceived improvements in their children’s speech and that the children thought that the treatment was funny. The study shows that an intervention based on a nonlinear phonological analysis is effective and can be used clinically.

  • 49.
    Rohini Rajan, Meenu
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Unraveling Mechanisms of Insulin Resistance in Type 2 Diabetes in Human Adipocytes: Role of extracellular signal regulated kinase 1/2 (ERK1/2) and forkhead box protein 01 (FOX01)2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 2 Diabetes is characterized by hyperglycemia primarily caused due to insulin resistance in insulin responsive tissues and insufficient production of insulin by the β-cells. Insulin resistance appears to develop first in the expanding adipose tissue during caloric surplus and affects other tissues like liver and muscle by ectopic fat accumulation. In spite of significant research in field of insulin signaling, very little has been known about the mechanisms that lead to insulin resistance and T2D.

    We aim for network-wide knowledge of insulin signaling in human adipocytes and to identify mechanisms that can induce insulin resistance in diabetic individuals. We have herein focused on the transcriptional control of insulin via ERK and FOXO1, and have used mathematical modelling to gain a systems-level understanding of insulin signaling network.

    Through the work in this thesis, we present for the first time a dynamic comprehensive model for insulin signaling for the adipocytes, for both metabolic and transcriptional control, and that can simulate data from both normal and diabetic individuals. We described insulin regulation of ERK phosphorylation and showed that both its insulin sensitivity and maxima  response to insulin was curtailed in adipocytes from diabetic individuals (Paper I). Our findings indicate that insulin regulated ERK pathway exerts control on transcription not only through phosphorylation of Elk-1 but also through phosphorylation of FOXO1 and exerts translational control via phosphorylation of ribosomal protein S6 (Paper I, II). Furthermore, we showed that insulin-induced FOXO1 phosphorylation or its insulin sensitivity was not impaired in diabetic individuals, although FOXO1 protein level was reduced by 45% in adipocytes from patients with type 2 diabetes. Comprehensive analysis of the detailed insulin signaling model showed that attenuation of the feedback from mTORC1 to IRS1-Ser307 explained dominant part of the insulin resistance seen in adipocytes from diabetic individuals (Paper II). More interestingly, inhibition of FOXO1 with a dominant negative construct of FOXO1, mimicked the diabetic state in the adipocytes, with the similarity extending to both insulin signaling as well as the reduced protein levels, as seen in the diabetic adipocytes. We also show that mTORC1 and FOXO1 maintain each other’s expression/activity in the human adipocytes (Paper II, III). Our findings thus demonstrate that the interplay between mTORC1 and FOXO1 maintains normal insulin signaling in the human adipocytes.

    List of papers
    1. A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes
    Open this publication in new window or tab >>A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes
    Show others...
    2014 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 48, p. 33215-33230Article in journal (Refereed) Published
    Abstract [en]

    The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the MAPKs ERK1/2. We found that in human adipocytes, insulin stimulates phosphorylation of the ribosomal protein S6 and hence protein synthesis about equally via ERK1/2 and mTORC1. Using mathematical modeling, we examined the signaling network as a whole and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, and mTOR and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non-diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance.

    Place, publisher, year, edition, pages
    American Society for Biochemistry and Molecular Biology, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-113198 (URN)10.1074/jbc.M114.608927 (DOI)000345636600015 ()25320095 (PubMedID)
    Note

    Funding Agencies|Swedish Diabetes Fund; University of Linkoping; Swedish Research Council

    Available from: 2015-01-13 Created: 2015-01-12 Last updated: 2017-12-05
    2. Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes
    Open this publication in new window or tab >>Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes
    Show others...
    2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 30, p. 15806-15819Article in journal (Refereed) Published
    Abstract [en]

    Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance. We report a detailed mechanistic analysis of insulin control of FOXO1 in human adipocytes obtained from non-diabetic subjects and from patients with T2D. We show that FOXO1 is mainly phosphorylated through mTORC2-mediated phosphorylation of protein kinase B at Ser(473) and that this mechanism is unperturbed in T2D. We also demonstrate a cross-talk from the MAPK branch of insulin signaling to stimulate phosphorylation of FOXO1. The cellular abundance and consequently activity of FOXO1 are halved in T2D. Interestingly, inhibition of mTORC1 with rapamycin reduces the abundance of FOXO1 to the levels in T2D. This suggests that the reduction of the concentration of FOXO1 is a consequence of attenuation of mTORC1, which defines much of the diabetic state in human adipocytes. We integrate insulin control of FOXO1 in a network-wide mathematical model of insulin signaling dynamics based on compatible data from human adipocytes. The diabetic state is network-wide explained by attenuation of an mTORC1-to-insulin receptor substrate-1 (IRS1) feedback and reduced abundances of insulin receptor, GLUT4, AS160, ribosomal protein S6, and FOXO1. The model demonstrates that attenuation of the mTORC1-to-IRS1 feedback is a major mechanism of insulin resistance in the diabetic state.

    Place, publisher, year, edition, pages
    Rockville, Maryland: American Society for Biochemistry and Molecular Biology, 2016
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:liu:diva-130998 (URN)10.1074/jbc.M116.715763 (DOI)000380584200033 ()27226562 (PubMedID)
    Note

    Funding agencies|Swedish Diabetes Fund, University of Linköping; Swedish Research Council; AstraZeneca

    Available from: 2016-09-02 Created: 2016-09-02 Last updated: 2017-04-24Bibliographically approved
  • 50.
    Röcklinsberg, Christoph
    Linköping University, Department of Management and Engineering, Division of Languages for Specific Purposes. Linköping University, Faculty of Arts and Sciences.
    Der 'kulturelle Raum' als Ressource in detuschen und schwedischen Tischgesprächen2014In: Verstehen und Verständigung.: Programm und Informationen, 2014, p. 166-167Conference paper (Refereed)
12 1 - 50 of 63
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