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  • 51.
    Hanberger, Håkan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Walther, Sten
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Leone, Marc
    Department of Anesthesiology and Intensive Care Medicine, Nord Hospital, Marseille, France.
    Barie, Philip S
    Department of Surgery, Weill Cornell Medical College, New York, USA.
    Rello, Jordi
    Critical Care Department, Vall d’Hebron University Hospital, CIBERES, VHIR, Universitat Autónoma de Barcelona, Spain.
    Lipman, Jeffrey
    Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital and Burns Trauma Critical Care Research Centre, University of Queensland, Queensland, Australia.
    Marshall, John C
    Department of Surgery, University of Toronto, St Michael's Hospital, Toronto, Ontario, Canada.
    Anzueto, Antonio
    Department of Pulmonary/Critical Care, University of Texas Health Science Center, San Antonio, TX, USA.
    Sakr, Yasser
    Department of Anesthesiology and Intensive Care, Friedrich-Schiller University, Jena, Germany.
    Pickkers, Peter
    Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    Felleiter, Peter
    Intensive Care Medicine, Swiss Paraplegic Centre, Nottwil, Switzerland.
    Engoren, Milo
    Department of Anesthesiology, Mercy St Vincent Medical Center, Toledo, OH, USA.
    Vincent, Jean-Louis
    Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.
    Increased mortality associated with meticillin-resistant Staphylococcus aureus (MRSA) infection in the Intensive Care Unit: results from the EPIC II study2011In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 38, no 4, p. 331-335Article in journal (Refereed)
    Abstract [en]

    Controversy continues regarding whether the presence of meticillin resistance increases mortality risk in Staphylococcus aureus infections. In this study, we assessed the role of meticillin resistance in survival of patients with S. aureus infection included in the EPIC II point-prevalence study of infection in critically ill patients performed on 8 May 2007. Demographic, physiological, bacteriological and therapeutic data were collected for 13 796 adult patients in 1265 participating Intensive Care Units (ICUs) from 75 countries on the study day. ICU and hospital outcomes were recorded. Characteristics of patients with meticillin-sensitive S. aureus (MSSA) and meticillin-resistant S. aureus (MRSA) infections were compared. Co-morbidities, age, Simplified Acute Physiology Score (SAPS) II, site of infection, geographical region and MRSA/MSSA were entered into a multivariate model, and adjusted odds ratios (ORs) [95% confidence interval (CI)] for ICU and hospital mortality rates were calculated. On the study day, 7087 (51%) of the 13 796 patients were classified as infected. There were 494 patients with MRSA infections and 505 patients with MSSA infections. There were no significant differences between the two groups in use of mechanical ventilation or haemofiltration/haemodialysis. Cancer and chronic renal failure were more prevalent in MRSA than in MSSA patients. ICU mortality rates were 29.1% and 20.5%, respectively (P andlt; 0.01) and corresponding hospital mortality rates were 36.4% and 27.0% (P andlt; 0.01). Multivariate analysis of hospital mortality for MRSA infection showed an adjusted OR of 1.46 (95% CI 1.03-2.06) (P = 0.03). In ICU patients, MRSA infection is therefore independently associated with an almost 50% higher likelihood of hospital death compared with MSSA infection.

  • 52.
    Hedenstierna, Magnus
    et al.
    Karolinska Institutet.
    Uhnoo, Ingrid
    Academic Hospital, Uppsala.
    Aleman, Soo
    Karolinska Institutet.
    Frydén, Aril
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Norkrans, Gunnar P
    Sahlgrenska University Hospital.
    Eilard, Anders
    Sahlgrenska University Hospital.
    Glaumann, Hans
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Weiland, Ola
    Karolinska Institutet.
    DURABILITY OF SVR AND FIBROSIS IMPROVEMENT AFTER SOC TREATMENT FOR CHRONIC HCV-10 YEARS FOLLOW-UP in HEPATOLOGY, vol 54, issue , pp 839A-840A2011In: HEPATOLOGY vol 54, Wiley-Blackwell , 2011, Vol. 54, p. 839A-840AConference paper (Refereed)
    Abstract [en]

    n/a

  • 53. Hedin, K
    et al.
    Babic, Ankica
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Frydén, Aril
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Liver guide for monitoring of chronic hepatitis C2000In: JAMIA Journal of the American Medical Informatics Association, ISSN 1067-5027, E-ISSN 1527-974X, p. 340-343Article in journal (Refereed)
    Abstract [en]

    The severity of chronic hepatitis C infection in the Individual patient is monitored using blood laboratory findings and liver biopsy. Lf blood test results could be shown to provide sufficient information concerning the disease, the invasive procedure of liver biopsy could perhaps be avoided in some instances. This study assessed the clinical relevance of blood laboratory tests for detecting disease-related changes. in the liver. Histopathological classification was used ta assign class membership of the patients and data mining operations were performed in an elaborate way on 19 different data sets. Disease activity could be detected by a small set of blood tests. Extended sets could identify more severe changes, but failed to distinguish them. The extracted rules are implemented as a part of the knowledge base of a corresponding decision support system aimed at specialists and general practitioners.

  • 54. Hedin, K
    et al.
    Babic, Ankica
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Frydén, Aril
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Take care: Patient oriented information system regarding chronic hepatitis C1999In: JAMIA Journal of the American Medical Informatics Association, ISSN 1067-5027, E-ISSN 1527-974X, p. 1075-1075Conference paper (Other academic)
  • 55.
    Hedin-Skogman, Barbro
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Croner, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . 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, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Lahdenne, Pekka
    Hospital for Children and Adolescents, Helsinki University Central Hospital.
    Sillanpää, Heidi
    Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki.
    Seppälä, Ilkka
    Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki.
    Improved Laboratory Diagnostics of Lyme Neuroborreliosis in Children2008In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 27, no 7, p. 605-612Article in journal (Refereed)
    Abstract [en]

    Background: Laboratory diagnostics in Lyme neuroborreliosis need improvement. We hereby investigate 4 new recombinant or peptide Borrelia antigens in cerebrospinal fluid in children with neuroborreliosis to evaluate their performance as diagnostic antigens.

    Methods: An enzyme-linked immunosorbent assay was used to detect IgG antibodies to recombinant decorin binding protein A (DbpA), BBK32, outer surface protein C (OspC), and the invariable region 6 peptide (IR6). The recombinant antigens originated from 3 pathogenic subspecies; Borrelia afzelii, Borrelia garinii, and Borrelia burgdorferi sensu stricto. Cerebrospinal fluid and serum from children with clinical features indicative for neuroborreliosis (n = 57) were analyzed. Classification of patients was based on clinical symptoms and laboratory findings. Controls were children with other neurologic diseases (n = 20) and adult patients with no proven infection (n = 16).

    Results: Sensitivity for DbpA was 82%, for BBK32 70%, for OspC 58% and for IR6 70%. Specificities were 94%, 100%, 97%, and 97%, respectively. No single antigen was superior. When new antigens were combined in a panel, sensitivity was 80% and specificity 100%. The reference flagella antigen showed a sensitivity of 60% and a specificity of 100%. Over all, the B. garinii related antigens dominated.

    Conclusions: Recombinant DbpA and BBK32 as well as the peptide antigen IR6 perform well in laboratory diagnostics of neuroborreliosis in children. New antigens seem to improve diagnostic performance when compared with the routine flagella antigen. If different antigens are combined in a panel to cover the antigenic diversity, sensitivity improves further and a specificity of 100% can be achieve.

  • 56.
    Hedin-Skogman, Barbro
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Croner, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Nordwall, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Norrköping.
    Eknefelt, Mattias
    Pediatric Clinic, Jönköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Lyme Neuroborreliosis in Children - a Prospective Study of Clinical features, Prognosis, and Outcome2008In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 27, no 12, p. 1089-1094Article in journal (Refereed)
    Abstract [en]

     

    Background: Evaluation of children with clinically suspected neuroborreliosis (NB) is difficult. With a prospective study design we wanted to characterize children with signs and symptoms indicative for NB, investigate clinical outcome and, if possible, identify factors of importance for recovery.

    Material/Methods: Children being evaluated for NB (n = 177) in Southeast Sweden were categorized into 3 groups: "confirmed neuroborreliosis" (41%) with Borrelia antibodies in the cerebrospinal fluid, "possible neuroborreliosis" (26%) with pleocytosis but 110 Borrelia antibodies in the cerebrospinal fluid, and "not determined" (33%) with no pleocytosis and no Borrelia antibodies in the cerebrospinal fluid, Antibiotic treatment was given to 69% of children. Patients were followed during 6 months and compared with a matched control group (n = 174).

    Results: Clinical recovery at the 6-month follow-up (n = 177) was generally good and no patient was found to have recurrent or progressive neurologic symptoms. However, persistent facial nerve palsy caused dysfunctional and cosmetic problems in 11% of patients. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. Influence on daily life was reported to the same extent in patients and controls. Consequently, persistent headache and fatigue at follow-up should not be considered as attributable to NB. No prognostic factors could be identified.

    Conclusions: Clinical recovery was satisfactory in children being evaluated for NB although persistent symptoms from facial nerve palsy occurred. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls.

  • 57.
    Hellmark, B.
    et al.
    Örebro University Hospital, Sweden.
    Berglund, C.
    Aleris MEDILAB, Täby, Sweden .
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Unemo, M
    Örebro University Hospital, Sweden.
    Söderquist, B
    Örebro University Hospital, Sweden.
    Staphylococcal cassett chromosome med (SCCmec) and arginine catabolic mobile element (ACME) in Staphylococcus epidermidis isolated from prosthetic joint infections2013In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 32, no 5, p. 691-697Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to characterise the staphylococcal cassette chromosome mec (SCCmec) in Staphylococcus epidermidis isolated from prosthetic joint infections (PJIs) and, if possible, assign them to any of the presently known SCCmec types. In addition, the isolates were examined for the presence of the arginine catabolic mobile element (ACME). Sixty-one S. epidermidis isolates obtained from PJIs and 24 commensal S. epidermidis isolates were analysed. The mecA gene was detected in 49 of the 61 (80 %) PJI isolates and in four of the 24 (17 %) commensal isolates, and the composition of the SCCmec was further analysed. SCCmec types I and IV were the most common types among the PJI isolates. However, for over half (57 %) of the isolates, it was not possible to assign an SCCmec type. ACME was detected in eight (13 %) of the PJI isolates and in 14 (58 %) of the commensal isolates. The characterisation of the SCCmec elements revealed a large heterogeneity, with a high frequency of isolates carrying more than one type of the ccr gene complex. ACME was more common among the commensal isolates and may represent a survival benefit for S. epidermidis colonising healthy individuals in the community.

  • 58.
    Hellmark, B
    et al.
    Örebro University Hospital.
    Unemo, M
    Örebro University Hospital.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Soderquist, B
    Örebro University Hospital.
    Antibiotic susceptibility among Staphylococcus epidermidis isolated from prosthetic joint infections with special focus on rifampicin and variability of the rpoB gene2009In: CLINICAL MICROBIOLOGY AND INFECTION, ISSN 1198-743X, Vol. 15, no 3, p. 238-244Article in journal (Refereed)
    Abstract [en]

    Staphylococcus epidermidis is the most important pathogen in infections related to implanted foreign materials, especially prosthetic joint infections (PJIs). The aim of this study was to investigate the antimicrobial activities of 16 antibiotics against S. epidermidis isolated from PJIs, with special focus on rifampicin and rpoB variability. Ninety-one per cent of the isolates were multiresistant (i.e. resistant to members of more than three classes of antibiotics). Thirty-nine per cent were resistant to rifampicin, associated with one or two single-nucleotide polymorphisms (SNPs) in rpoB. Using IsoSensitest agar with supplements, 61% were resistant to oxacillin, and using Mueller-Hinton II agar with supplement, 84% were resistant. Using the Etest, 58% were resistant to cefoxitin, and using the disk diffusion test, 91% were resistant. The mecA gene was detected in 85% of the isolates. Regarding recently available antibiotics, all isolates were susceptible to tigecycline and linezolid, and 97% were susceptible to daptomycin. In addition, two novel antibiotics, dalbavancin and ceftobiprole, were tested, although not yet available for routine use. The MIC50 and MIC90 values of these novel antibiotics were 0.032 and 0.047 mg/L and 0.5 and 1.5 mg/L, respectively. Among the other antibiotics, the rates of resistance varied between 0% (vancomycin) and 82% (trimethoprim-sulphamethoxazole). S. epidermidis strains causing PJIs often show multiresistance, including resistance to rifampicin, which is mainly caused by one or two SNPs. Some of the newer antimicrobial agents may provide alternatives for monotherapy or combination therapy with rifampicin. Detection of mecA is necessary before initiating treatment of infections due to S. epidermidis when it displays intermediate susceptibility to cefoxitin.

  • 59.
    Hellmark, B
    et al.
    Örebro University Hospital.
    Unemo, M
    Örebro University Hospital.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Soderquist, B
    Örebro University Hospital.
    In vitro antimicrobial synergy testing of coagulase-negative staphylococci isolated from prosthetic joint infections using Etest and with a focus on rifampicin and linezolid2010In: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY and INFECTIOUS DISEASES, ISSN 0934-9723, Vol. 29, no 5, p. 591-595Article in journal (Refereed)
    Abstract [en]

    In recent years, coagulase-negative staphylococci (CoNS) have been increasingly recognised as causative agents of various infections, especially in immunocompromised patients and related to implanted foreign body materials. CoNS, and especially Staphylococcus epidermidis, transform into a stationary growth phase and produce biofilm when involved in a foreign body infection, making them difficult to eradicate with antimicrobials. Rifampicin has the ability to penetrate biofilm, but resistance may develop rapidly. To reduce the emergence of resistance, rifampicin should be combined with additional antimicrobials, of which several different ones have been proposed, including the relatively new class of antimicrobials, oxazolidinones, represented by linezolid. Thirty-seven CoNS isolates from patients with prosthetic joint infection were investigated by synergy testing using Etest. Nine antimicrobial combinations, based on either rifampicin or linezolid, were tested. For 16 (43%) of the isolates, a synergistic (n = 5), additive (n = 14) and/or antagonistic (n = 11) effect were identified. In conclusion, Etest is an objective and easily performed in vitro method for antimicrobial synergy testing. However, each isolate requires testing for the specific combination considered for treatment.

  • 60.
    Hellmark, Bengt
    et al.
    Örebro University Hospital, Sweden.
    Söderquist, Bo
    Örebro University Hospital and University of Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital, Sweden.
    Nilsdotter-Augustinsson, Åsa
    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.
    Comparison of Staphylococcus epidermidis isolated from prosthetic joint infections and commensal isolates in regard to antibiotic susceptibility, agr type, biofilm production, and epidemiology2013In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 303, no 1, p. 32-39Article in journal (Refereed)
    Abstract [en]

    Staphylococcus epidermidis is the predominant bacterial species in the normal flora of the human skin and superficial mucosal membranes. However, it has also emerged as the most important pathogen in infections related to foreign-body materials, such as prosthetic joints and heart valves. The aims of this study were to characterise S. epidermidis isolated from prosthetic joint infections (PJI; n=61) and commensal isolates from healthy individuals (n=24) in regard to antimicrobial sensitivity, agr type, hld gene presence, biofilm production including presence of ica and aap genes involved in the biofilm formation process and epidemiology using both phenotypic (the PhenePlate-system) and genotypic [multilocus sequence typing (MLST)] methods. Among the PJI isolates, the majority (67%) were multidrug-resistant. Two major clusters of PJI isolates could be identified; 44% belonged to MLST sequence type (ST) 2, all but one were of agr type 1, and 31% were assigned ST215 and were of agr type 3. Of the commensal isolates, only one isolate was multidrug-resistant, and they were more molecular epidemiologically diverse with mainly MLST singletons and a maximum of 3 isolates assigned to the identical ST. Biofilm production was detected in 41% of the PJI isolates and 58% of the commensal isolates, with the aap gene (95%) more frequently detected than the ica genes (62%) in the biofilm-positive isolates. In conclusion, S. epidermidis isolated from PJIs and commensal isolates differed regarding antimicrobial sensitivity and molecular epidemiological typing using MLST, but not substantially in the distribution of agr types, biofilm production, or the presence of ica and aap genes.

  • 61.
    Henningsson, A J
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Malmvall, Bo-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Matussek, Andreas
    Klinisk mikrobiologi, Länssjuhuset Ryhov, Jönköping.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden2010In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 16, no 8, p. 1245-1251Article in journal (Refereed)
    Abstract [en]

    We studied retrospectively the medical records of all patients (n = 150) diagnosed, by cerebrospinal fluid (CSF) analysis, with neuroborreliosis (NB) in Jonkoping County, Sweden during 2000-2005. The number of NB cases increased from 5/100 000 to 10/100 000 inhabitants/year. In 17% of the patients, anti-Borrelia antibodies were found in CSF but not in serum at the time of diagnosis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients. Post-treatment symptoms persisting for more than 6 months occurred in 13%, and the patients concerned were significantly older, had longer-lasting symptoms prior to treatment, had higher levels of Borrelia-specific IgG in CSF, and more often had radiculitis. The total cost of NB-related healthcare was estimated to be euro500 000 for the entire study group (euro3300 per patient), and the cost of social benefits was estimated to be euro134 000 (euro2000 per patient). CSF analysis is necessary for the diagnosis of NB, because some patients develop antibodies in serum later than in CSF. Early diagnosis of borreliosis would result in reduced human suffering and in economic gain.

  • 62.
    Henningsson, Anna J
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Clinical, epidemiological and immunological aspects of Lyme borreliosis with special focus on the role of the complement system2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere. The infection is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and it is transmitted to humans by ticks. LB is associated with several clinical manifestations, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common inEurope. The course of the disease is usually benign, but can vary between individuals. The underlying pathogenic mechanisms are not fully understood, but the prognosis is probably determined by a complex interplay between the bacteria and the host’s immune response. Previous studies have indicated that a strong initial T helper (Th) 1-response followed by a Th2 response is beneficial for the clinical outcome in LB.

    The aims of this thesis were to follow the incidence of NB inJönköping County,Sweden, over time, to search for clinical and laboratory markers associated with the risk of developing long-lasting post-treatment symptoms, and to explore the role of the complement system as well as the relative balance between Th-associated cytokine/chemokine responses in LB.

    The number of NB cases, diagnosed by cerebrospinal fluid (CSF) analysis, increased from 5 to 10/100,000 inhabitants/year in Jönköping County during 2000-2005. Post-treatment symptoms persisting more than 6 months occurred in 13 %, and were associated with higher age, longer-lasting symptoms prior to treatment, higher levels of Borrelia-specific IgG in CSF, and reported symptoms of radiculitis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients.

    Complement activation occurred both locally in the skin in EM and in CSF of NB patients. However, no activation could be detected in blood in NB patients. Elevated levels of C1q, C4 and C3a in CSF, along with correlation between C1q and C3a levels, suggest complement activation via the classical pathway locally in the central nervous system in NB. In vitro experiments with two clinical Borrelia isolates revealed that B. garinii LU59 induced higher complement activation in human plasma compared to B. afzelii K78 that recruited more of complement regulator factor H. To elucidate the role of complement in the phagocytosis process, experiments were performed using whole blood from healthy donors incubated with fluorescence-labelled spirochetes and different complement inhibitors. The results illustrated a central role of complement for phagocytosis of Borrelia spirochetes.

    We also studied the relative contribution of different Th-associated cytokines/chemokine responses in NB. The results support the notion that early NB is dominated by a Th1 response, eventually accompanied by a Th2 response. IL-17A was increased in CSF in half of the patients with confirmed NB, suggesting a hitherto unknown role of Th17 in NB.

    In conclusion, the risk of developing long-lasting post-treatment symptoms tend to increase mainly with age and duration of symptoms prior to treatment in NB. The complement system seems to play an important role in host defence to recognize and kill Borrelia spirochetes. However, complement activation in inappropriate sites or to an excessive degree may cause tissue damage, and therefore, the role of complement in relation to disease course needs to be studied further. Likewise, the role of Th17 in LB pathogenesis and host defence should be further evaluated in prospective studies.

    List of papers
    1. Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden
    Open this publication in new window or tab >>Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden
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    2010 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 16, no 8, p. 1245-1251Article in journal (Refereed) Published
    Abstract [en]

    We studied retrospectively the medical records of all patients (n = 150) diagnosed, by cerebrospinal fluid (CSF) analysis, with neuroborreliosis (NB) in Jonkoping County, Sweden during 2000-2005. The number of NB cases increased from 5/100 000 to 10/100 000 inhabitants/year. In 17% of the patients, anti-Borrelia antibodies were found in CSF but not in serum at the time of diagnosis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients. Post-treatment symptoms persisting for more than 6 months occurred in 13%, and the patients concerned were significantly older, had longer-lasting symptoms prior to treatment, had higher levels of Borrelia-specific IgG in CSF, and more often had radiculitis. The total cost of NB-related healthcare was estimated to be euro500 000 for the entire study group (euro3300 per patient), and the cost of social benefits was estimated to be euro134 000 (euro2000 per patient). CSF analysis is necessary for the diagnosis of NB, because some patients develop antibodies in serum later than in CSF. Early diagnosis of borreliosis would result in reduced human suffering and in economic gain.

    Place, publisher, year, edition, pages
    Blackwell Publishing Ltd, 2010
    Keywords
    Clinical, epidemiology, healthcare economy, Lyme disease, neuroborreliosis
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:liu:diva-58536 (URN)10.1111/j.1469-0691.2009.03059.x (DOI)000280359900034 ()
    Note
    This is the pre-reviewed version of the following article: A J Henningsson, Bo-Eric Malmvall, Jan Ernerudh, A Matussek and Pia Forsberg, Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden, 2010, CLINICAL MICROBIOLOGY AND INFECTION, (16), 8, 1245-1251. which has been published in final form at: http://dx.doi.org/10.1111/j.1469-0691.2009.03059.x Copyright: Blackwell Publishing Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html Available from: 2010-08-13 Created: 2010-08-13 Last updated: 2017-12-12Bibliographically approved
    2. Complement activation in Lyme neuroborreliosis - Increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS
    Open this publication in new window or tab >>Complement activation in Lyme neuroborreliosis - Increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS
    Show others...
    2007 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 183, no 01-Feb, p. 200-207Article in journal (Refereed) Published
    Abstract [en]

    A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.

    Keywords
    complement, neuroborreliosis, inflammation, Lyme borreliosis, cerebrospinal fluid
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:liu:diva-45964 (URN)10.1016/j.jneuroim.2006.10.022 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
    3. Early Immune Responses to Borrelia garinii and Borrelia afzeliiin Lyme Borreliosis: Local Complement Activation in Erythema Migrans and in vitro Studies ofComplement Activation, Phagocytosis and Cytokine Profile
    Open this publication in new window or tab >>Early Immune Responses to Borrelia garinii and Borrelia afzeliiin Lyme Borreliosis: Local Complement Activation in Erythema Migrans and in vitro Studies ofComplement Activation, Phagocytosis and Cytokine Profile
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    An optimal eradication of spirochetes in Lyme borreliosis depends on the early immune response, including the potent actions of the complement system. We here assessed possible differences between two Borrelia burgdorferi genospecies in their ability to activate complement, and the consequences of complement activation in terms of phagocytosis and induction of cytokines.

    Early local complement activation was assessed immunohistochemically in skin biopsies from patients with erythema migrans (EM) caused by B. afzelii or B. garinii. Complement activation, phagocytosis and early cytokine and chemokine release were studied in vitro by incubating clinical isolates of B. afzelii (K78 from a human skin biopsy) and B. garinii (LU59 from human cerebrospinal fluid) in human whole blood.

    B. afzelii and B. garinii were detected in skin biopsies from EM and deposition of C3-fragments and IgG was found adjacent to the spirochetes. In vitro, B. garinii LU59 induced higher complement activation (measured as the generation of C3a and C5b-9), while B. afzelii K78 recruited more factor H. Phagocytosis by granulocytes and monocytes was demonstrated to be largely dependent on complement activation since phagocytosis was substantially reduced by addition of the C3 inhibitor compstatin or a C5a receptor antagonist. The early cytokine and chemokine release in human blood in response to live spirochetes revealed a rapid and pronounced pro-inflammatory response, mainly associated with the Th1- and Th17-types.

    We conclude that complement is activated locally in the skin in EM, and that B. garinii LU59 activates complement more than B. afzelii K78. Complement activation is pivotal for efficient phagocytosis of Borrelia spirochetes, especially in early infection before specific antibodies are produced. Both B. garinii LU59 and B. afzelii K78 induce proinflammatory cytokines rapidly, but no clear differences were seen between the two genospecies in this respect.

    Keywords
    Lyme borreliosis, erythema migrans, inflammation, complement, cytokine, chemokine, phagocytosis
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:liu:diva-71065 (URN)
    Available from: 2011-09-29 Created: 2011-09-29 Last updated: 2012-08-23Bibliographically approved
    4. Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study
    Open this publication in new window or tab >>Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study
    Show others...
    2011 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 8, no 36Article in journal (Refereed) Published
    Abstract [en]

    Background: Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB) is associated with a strong T helper (Th) 1-type cytokine response in the cerebrospinal fluid (CSF) followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown. Methods: To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker), CCL22 (Th2 marker), IL-17 (Th17 marker) and CXCL8 (general inflammation marker), in serum and in CSF from untreated patients with confirmed NB (n = 133), and non-NB patients (n = 96), and related the findings to clinical data. Samples from patients with possible early NB (n = 15) and possible late NB (n = 19) were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17), where CSF was obtained at spinal anaesthesia. Results: The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p andlt; 0.0001 for all comparisons). Patients in the early NB group, showing a short duration of symptoms, had lower CCL22 levels in CSF than did the confirmed NB group (p andlt; 0.0001). Furthermore, patients within the confirmed NB group showing a duration of symptoms andlt; 2 weeks, tended to have lower CCL22 levels in CSF than did those with longer symptom duration (p = 0.023). Cytokine/chemokine levels were not correlated with clinical parameters or to levels of anti-Borrelia-antibodies. Conclusion: Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.

    Place, publisher, year, edition, pages
    BioMed Central, 2011
    Keywords
    Lyme neuroborreliosis, cerebrospinal fluid, T helper cell, cytokine, chemokine
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:liu:diva-69177 (URN)10.1186/1742-2094-8-36 (DOI)000291317900001 ()
    Note

    Original Publication: Anna J Henningsson, Ivar Tjernberg, Bo-Eric Malmvall, Pia Forsberg and Jan Ernerudh, Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study, 2011, JOURNAL OF NEUROINFLAMMATION, (8), 36. http://dx.doi.org/10.1186/1742-2094-8-36 Licensee: BioMed Central http://www.biomedcentral.com/

    Available from: 2011-06-17 Created: 2011-06-17 Last updated: 2017-12-11Bibliographically approved
  • 63.
    Henningsson, Anna J.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Department of Infectious Diseases, Ryhov County Hospital, Jönköping.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Sandholm, Kerstin
    Department of Chemistry and Biomedical Sciences, University of Kalmar, Kalmar.
    Carlsson, Sten-Anders
    Åland Borrelia Group, Åland Central Hospital, Finland.
    Granlund, Hans
    Åland Borrelia Group, Åland Central Hospital, Finland.
    Jansson, Christian
    Åland Borrelia Group, Åland Central Hospital, Finland.
    Nyman, Dag
    Åland Borrelia Group, Åland Central Hospital, Finland.
    Forsberg, Pia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Nilsson Ekdahl, Kristina
    Department of Chemistry and Biomedical Sciences, University of Kalmar, Kalmar.
    Complement activation in Lyme neuroborreliosis - Increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS2007In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 183, no 01-Feb, p. 200-207Article in journal (Refereed)
    Abstract [en]

    A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.

  • 64.
    Henningsson, Anna J
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Ryhov County Hospital, Jönköping.
    Tjernberg, Ivar
    Kalmar County Hospital, Kalmar.
    Malmvall, Bo-Eric
    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.
    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.
    Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study2011In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 8, no 36Article in journal (Refereed)
    Abstract [en]

    Background: Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB) is associated with a strong T helper (Th) 1-type cytokine response in the cerebrospinal fluid (CSF) followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown. Methods: To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker), CCL22 (Th2 marker), IL-17 (Th17 marker) and CXCL8 (general inflammation marker), in serum and in CSF from untreated patients with confirmed NB (n = 133), and non-NB patients (n = 96), and related the findings to clinical data. Samples from patients with possible early NB (n = 15) and possible late NB (n = 19) were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17), where CSF was obtained at spinal anaesthesia. Results: The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p andlt; 0.0001 for all comparisons). Patients in the early NB group, showing a short duration of symptoms, had lower CCL22 levels in CSF than did the confirmed NB group (p andlt; 0.0001). Furthermore, patients within the confirmed NB group showing a duration of symptoms andlt; 2 weeks, tended to have lower CCL22 levels in CSF than did those with longer symptom duration (p = 0.023). Cytokine/chemokine levels were not correlated with clinical parameters or to levels of anti-Borrelia-antibodies. Conclusion: Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.

  • 65.
    Hällgren, Anita
    et al.
    Department ofMolecularandClinicalMedicine Linköping University.
    Claesson, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Saeedi, Baharak
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Monstein, Hans-Jurg
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Molecular detection of aggregation substance, enterococcal surface protein, and cytolysin genes and in vitro adhesion to urinary catheters of Enterococcus faecalis and E. faecium of clinical origin2009In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 299, no 5, p. 323-332Article in journal (Refereed)
    Abstract [en]

    It has been hypothesized that nosocomial enterococci might have virulence factors that enhance their ability to colonise hospitalised patients. The objectives of this study were to investigate the prevalence of genes encoding 3 virulence factors: aggregation substance (asa1), enterococcal surface protein (esp), and 5 genes within the cytolysin operon (cylA, cylB, cylM, cylL(L), cylL(S)) and cytolysin production in 115 enterococcal clinical isolates (21 Enterococcus faecium and 94 E. faecalis). Adhesion to siliconized latex urinary catheters in relation to presence of esp was analysed in a subset of isolates. The isolates were previously characterised by pulsed-field gel electrophoresis (PFGE). esp was the only virulence gene found in E. faecium. It was found in 71% of the 21 E. faecium isolates. asa1, esp, and the cyl operon were found in 79%, 73% and 13% respectively, of the 94 E. faecalis isolates. There was a complete agreement between presence of the cyl operon and phenotypic cytolysin production. Isolates belonging to a cluster of genetically related isolates carried esp and asa1 more often when compared to unique isolates. No difference was found with respect to cyl genes. E. faecalis isolates adhered with higher bacterial densities than E. faecium. E. faecalis isolates within the same PFGE cluster adhered with similar bacterial densities, but there was no association between adhesion and the presence of esp when isolates within the same cluster were compared. In conclusion, E. faecalis isolates with high-level gentamicin resistance (HLGR) belonging to clusters of genetically related isolates widely distributed in Swedish hospitals, were likely to carry both esp and asa1. Adhesion was not affected by esp.   

  • 66.
    Hällgren, Anita
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Lindqvist, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases.
    Enterococcal endocarditis among intravenous drug users: Report of a cluster of cases, possibly caused by contaminated amphetamine2011In: SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES, ISSN 0036-5548, Vol. 43, no 5, p. 395-398Article in journal (Refereed)
    Abstract [en]

    Intravenous drug use imposes a high risk of acquiring bacterial infections. In this report we present 3 cases of enterococcal endocarditis in intravenous drug users, diagnosed over a period of 3 months. Genotyping revealed that 2 of the cases were caused by closely related isolates, suggesting possible spread by contaminated drugs.

  • 67.
    Håkan, Hanberger
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Odenholt, I.
    Universitetssjukhuset MAS, Malmö, Sweden.
    Giske, C.G.
    Karolinska universitetssjukhuset, Sweden.
    Kahlmeter, G.
    Uppsala universitet, Kliniskt mikrobiologiska laboratoriet, Centrallasarettet, Växjö, Sweden.
    Cefalosporinerna bör ersättas med smalare och mer riktad behandling2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 38Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 68.
    Isaksson, Barbro
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Maller, Rolf
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Maud
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Synergic post-antibiotic effect of amikacin in combination with beta-lactam antibiotics on gram-negative bacteria.1991In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 28, no 1, p. 25-34Article in journal (Refereed)
    Abstract [en]

    The post-antibiotic effect (PAE) of amikacin alone and in combination with ceftazidime, ceftriaxone and piperacillin was studied for two strains each of Pseudomonas aeruginosa and Serratia marcescens using a bioluminescent assay of bacterial ATP. Two models were used for combining beta-lactam antibiotics and amikacin: in one model the cultures were incubated with 32 mg/L of ceftazidime, 128 mg/L of ceftriaxone or 32 mg/L of piperacillin for 1 h. Different concentrations of amikacin (0.5-64 mg/L) were then added. Incubation of the combinations continued for one more hour. The antibiotics were eliminated by dilution. In the second model tested, one strain of S. marcescens was simultaneously exposed to amikacin and a beta-lactam antibiotic for 2 h. The PAEs produced by the drugs in combination were longer than the sum of the individual effects of the drugs when they were used alone. Results were equally good with both models. A synergic PAE was also found with amikacin concentrations close to the MIC in combination with low concentrations of ceftazidime, ceftriaxone and piperacillin.

  • 69.
    Jarefors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Bennet, Louise
    Department of Clinical Sciences, University Hospital of Malmö, Lund University, Malmö .
    You, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Berglund, Johan
    Department of Clinical Sciences, University Hospital of Malmö, Lund University, Malmö .
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Lyme borreliosis reinfection: might it be explained by gender difference in immune response?2006In: Immunology, ISSN 0019-2805, Vol. 118, no 2, p. 224-235Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis is a tick-borne disease often manifesting as a circular skin lesion. This cutaneous form of the disease is known as erythema migrans. In a 5-year follow-up study in southern Sweden, 31 of 708 individuals initially diagnosed with erythema migrans and treated with antibiotics were found to be reinfected with Borrelia burgdorferi. Although men and women were tick-bitten to the same extent, 27 of the 31 reinfected individuals were women, all of whom were over 44 years of age. The aim of this study was to determine whether this discrepancy in gender distribution could be a result of differences in immunological response. Twenty single-infected and 21 reinfected women and 18 single-infected and three reinfected men were included in the study. None of the participants showed any sign of an ongoing B. burgdorferi infection, and thus the habitual response was captured. Lymphocytes were separated from blood and stimulated with antigens. The secretion of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumour necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) or Immulite. No difference was detected in cytokine secretion between single-infected and reinfected individuals. We also compared the immunological response in men and women, regardless of the number of B. burgdorferi infections. Women displayed a significantly higher spontaneous secretion of all cytokines measured. The ratios of IL-4:IFN-γ and IL-10:TNF-α were significantly higher in women. Gender differences in immune reactivity might in part explain the higher incidence of reinfection in women. The higher IL-4:IFN-γ and IL-10:TNF-α ratios seen in women indicate that postmenopausal women have T helper type 2 (Th2)-directed reactivity with impaired inflammatory responses which might inhibit the elimination of spirochetes.

  • 70.
    Jarefors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . 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, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 1, p. 18-27Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rβ2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rβ2 and FoxP3 mRNA expression was analysed with real-time reverse transcription–polymerase chain reaction (RT–PCR). The protein expression of IL-12Rβ2 on CD3+, CD4+, CD8+ and CD56+ cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-γ, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rβ2 on CD8+ cells and also a lower number of Borrelia-specific IFN-γ-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.

  • 71.
    Jarefors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Karlsson, Marika
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Eliasson, I.
    Department of Clinical Microbiology, Kalmar County Hospital, Sweden .
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 2, p. 322-328Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis and human granulocytic ehrlichiosis are tick-borne diseases caused by Borrelia burgdorferi and Anaplasma phagocytophilum, respectively. Infection with A. phagocytophilum has been observed to induce immunosuppression and animal studies suggest that the bacteria might also have prolonged inhibitory effects on immune cells. The aim of this study was to investigate the cytokine secretion in patients exposed previously to A. phagocytophilum and currently infected with B. burgdorferi compared with patients infected with B. burgdorferi and seronegative for A. phagocytophilum. Eight patients with erythema migrans and antibodies against A. phagocytophilum, 15 patients with erythema migrans and negative A. phagocytophilum serology and 15 non-exposed healthy individuals were included in the study. Blood mononuclear cells were stimulated with Borrelia-antigen and the number of cytokine [interleukin (IL)-4, IL-5, IL-12, IL-13 and interferon (IFN)-γ]-secreting cells was detected by enzyme-linked immunospot (ELISPOT). This study shows that patients with a previous exposure to A. phagocytophilum and a current infection with B. burgdorferi have a lower number of Borrelia-specific cells secreting IL-12 compared to Ap seronegative patients infected with B. burgdorferi (P < 0·001), indicating impairment in the ability to mount strong Th1-responses. We suggest that this mirrors a reduced Th1 response caused by A. phagocytophilum which could influence the outcome of the Borrelia infection and, speculatively, may also have implications in other conditions.

  • 72.
    Johansson, Eva
    et al.
    Karolinska Institute, Sweden .
    Hammarskjold, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Ryhov County Hospital, Sweden .
    Lundberg, Dag
    Skåne University Hospital, Sweden .
    Heibert Arnlind, Marianne
    Swedish Council Health Technology Assessment SBU, Sweden .
    Letter: A survey of the current use of peripherally inserted central venous catheter (PICC) in Swedish oncology departments2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 6, p. 1241-1242Article in journal (Other academic)
    Abstract [en]

    n/a

  • 73.
    Johansson, M
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    M Phuong, D
    Department of Microbiology, Bach Mai Hospital, Hanoi, Vietnam.
    Walther, Sten
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Need for improved antimicrobial and infection control stewardship in Vietnamese intensive care units2011In: TROPICAL MEDICINE and INTERNATIONAL HEALTH, ISSN 1360-2276, Vol. 16, no 6, p. 737-743Article in journal (Refereed)
    Abstract [en]

    Pandgt;Objective Survey of antibiotic consumption, microbial resistance and hygiene precautions in the intensive care units of three hospitals in northern Vietnam. Methods Observational study. Data were collected from the microbiological laboratories. Antibiotic consumption was determined based on quantities of drugs delivered from the pharmacy. A protocol to observe the application of hygiene precautions was developed and used. Bacteria were typed and tested for drug susceptibility using the disc-diffusion method. Results The mean antibiotic consumption was 811 defined daily doses per 1000 occupied bed days. The most commonly used antibiotics were third-generation cephalosporins, followed by carbapenems, amoxicillin and ampicillin. Eighty per cent of bacterial isolates were Gram-negative. The most common pathogens found in blood cultures were Escherichia coli and Klebsiella spp., Pseudomonas spp., Acinetobacter spp., Staphylococcus aureus and Enterococcus faecalis. Acinetobacter and Pseudomonas spp. were the two most frequently isolated bacteria from the respiratory tract and all other sources together. Seventy per cent of Acinetobacter species showed reduced susceptibility to imipenem, 80% to ciprofloxacin and 89% to ceftazidime. Forty-four per cent of Pseudomonas spp. showed reduced susceptibility to imipenem, 49% to ciprofloxacin and 49% to ceftazidime. Escherichia coli was fully susceptible to imipenem, but 57% of samples were resistant to both ciprofloxacin and cefotaxime. Hygiene precautions were poor, and fewer than 50% of patient contacts incorporated appropriate hand hygiene. Conclusion Low antibiotic consumption, poor hygiene precautions and the high level of antibiotic resistance indicate that there is room for improvement regarding antibiotic use and infection control.

  • 74.
    Johansson, Rose-Marie
    et al.
    Jönköping University, Sweden.
    Malmvall, Bo-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Andersson-Gäre, Boel
    Futurum – The Academy of Healthcare, County Council, Jönköping and Jönköping University, Sweden.
    Larsson, Bruno
    County Hospital Ryhov, Jönköping, Sweden.
    Erlandsson, Ingrid
    County Hospital Ryhov, Jönköping, Sweden.
    Sund-Levander, Märta
    Höglandssjukhuset, Eksjö, Sweden.
    Rensfelt, Gunhild
    County Hospital Ryhov, Jönköping, Sweden.
    Mölstad, Sigvard
    Futurum, Sweden .
    Christensson, Lennart
    Jönköping University, Sweden.
    Guidelines for preventing urinary retention and bladder damage during hospital care2013In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 22, no 3-4, p. 347-355Article in journal (Refereed)
    Abstract [en]

    AIMS AND OBJECTIVES:

    To develop evidence-based guidelines for adult patients in order to prevent urinary retention and to minimise bladder damage and urinary tract infection.

    BACKGROUND:

    Urinary retention causing bladder damage is a well known complication in patients during hospital care. The most common treatment for urinary retention is an indwelling urinary catheter, which causes 80% of hospital-acquired urinary tract infections. Appropriate use of bladder ultrasonography can reduce the rate of bladder damage as well as the need to use an indwelling urinary catheter. It can also lead to a decrease in the rate of urinary tract infections, a lower risk of spread of multiresistant Gram-negative bacteria, and lower hospital costs.

    DESIGN:

    An expert group was established, and a literature review was performed.

    METHODS:

    On the basis of literature findings and consensus in the expert group, guidelines for clinical situations were constructed.

    RESULTS:

    The main points of the guidelines are the following: identification of risk factors for urinary retention, managing patients at risk of urinary retention, strategies for patients with urinary retention and patient documentation and information.

    CONCLUSION:

    Using literature review and consensus technique based on a multiprofessional group of experts, evidence-based guidelines have been developed. Although consensus was reached, there are parts of the guidelines where the knowledge is weak.

    RELEVANCE TO CLINICAL PRACTICE:

    These guidelines are designed to be easy to use in clinical work and could be an important step towards minimising bladder damage and hospital-acquired urinary tract infections and their serious consequences, such as bacteraemia and the spread of multidrug-resistant bacteria in hospitals.

  • 75.
    Karlsson, Daniel
    et al.
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Ekdahl, Christer
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Wigertz, Ove
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Shahsavar, Nosrat
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Gill, Hans
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Forsum, Urban
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Extended telemedical consultation using Arden Syntax based decision support, hypertext and WWW technique1997In: Methods of Information in Medicine, ISSN 0026-1270, Vol. 36, no 2, p. 108-114Article in journal (Refereed)
    Abstract [en]

    There is an obvious need for geographic distribution of expert knowledge among several health care units without increasing the cost of on-site expertise in locations where health care is provided. This paper describes the design of a knowledge-based decision-support system for extended consultation in clinical medicine. The system is based on Arden Syntax for Medical Logic Modules and hypertext using World Wide Web technology. It provides advice and explanations regarding the given advice. The explanations are presented in a hypertext format allowing the user to browse related information and to verify the relevance of the given advice. The system is intended to be used in a closed local network. With special precautions regarding issues of safety and patient security, the system can be used over wider areas such as in rural medicine. A prototype has been developed in the field of clinical microbiology and infectious diseases regarding infective endocarditis.

  • 76.
    Koskela, A
    et al.
    Örebro University Hospital.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Persson, L
    Örebro University Hospital.
    Soderquist, B
    Örebro University Hospital.
    Prevalence of the ica operon and insertion sequence IS256 among Staphylococcus epidermidis prosthetic joint infection isolates2009In: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY and INFECTIOUS DISEASES, ISSN 0934-9723, Vol. 28, no 6, p. 655-660Article in journal (Refereed)
    Abstract [en]

    Joint replacement surgery has improved the quality of life for hundreds of thousands of patients. However, the infection of a joint implant is an important and serious complication, though the prevalence is low. Staphylococcus epidermidis is the most important pathogen involved in foreign-body infections. S. epidermidis is also a commensal that comprises a substantial part of the normal skin flora of humans. The possibility to demonstrate potential specific virulence markers may facilitate the interpretation of the bacteriological findings, as well as the clinical decision. The prevalence of the ica locus and insertion sequence IS256 by using polymerase chain reaction (PCR) among 32 clinical S. epidermidis isolates from prosthetic joint infections (PJIs) and 24 commensal isolates from nares and skin was investigated. Sixteen (50%) of the 32 PJI isolates harbored the ica operon compared with one-third of the commensal isolates obtained from the samples of the skin and nares of healthy individuals. The IS256 was demonstrated in 26 (81%) out of 32 PJI isolates. By contrast, IS256 was found in one of 24 commensal isolates. In conclusion, IS256 may be superior to the ica operon as a marker of the invasive capacity of S. epidermidis, since it was found in most of the PJI isolates, but rarely among commensals.

  • 77.
    Langö-Warensjö, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Cardell, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Lindblom, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Haplotypes comprising subtypes of the DQB1*06 allele direct the antibody response after immunisation with hepatitis B surface antigen1998In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 52, no 4, p. 374-380Article in journal (Refereed)
    Abstract [en]

    Two HLA class II haplotypes, HLA-[DQB1*0602; DQA1*0102; DR15] and HLA-[DQB1*0603; DQA1*0103; DRB1*1301] were found to be less common in 52 nonresponders compared with 68 responders, P<0.025 and P<0.05 respectively, after vaccination with hepatitis B surface antigen (HBsAg). Another haplotype, HLA-[DQB1*0604; DQA1*0102; DRB1*1302], had a significantly higher frequency in the nonresponders (P<0.005). The nonresponders and responders were nonsmoking, healthy individuals with an antibody concentration of <10 IU/l and >100 IU/l respectively. The three haplotypes comprise either of three different DQB1*06 subtypes. Two of the seven amino acids that differ between the two responder alleles DQB1*0602 and *0603 and the nonresponder allele *0604 are located in the peptide-binding groove of the DQB1 molecule. In addition to this finding, amino acid 86 in the DRB1 molecule seems to determine the response against HBsAg. DRB1*1301 and DR15 in the responder haplotypes have a Val at this position while the nonresponder haplotype has a Gly. These results suggest a role for both the DQB1*06 alleles and the DRB1 alleles *1301, *1302 and DR15 to direct either a response or a nonresponse against HBsAg. Sixteen HLA class II genotypes were found to be shared by 25 nonresponders and 32 responders. This finding of HLA-identical nonresponders and responders indicates an influence of other genetic factors in addition to the HLA system in the response to HBsAg.

  • 78.
    Lindblom, A.
    et al.
    Uppsala University, Sweden.
    Wallménius, K.
    Uppsala University, Sweden.
    Nordberg, M.
    Linköping University, Department of Clinical and Experimental Medicine. 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 Centre, Department of Infectious Diseases in Östergötland.
    Eliasson, I.
    Norra Älvsborg County Hospital (NÄL), Trollhättan, Sweden .
    Påhlson, C.
    Uppsala University, Sweden.
    Nilsson, K.
    Uppsala University, Sweden and Center of Clinical Research, Falun, Sweden.
    Seroreactivity for spotted fever rickettsiae and co-infections with other tick-borne agents amond habitants in central and southern Sweden2013In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 32, no 3, p. 317-323Article in journal (Refereed)
    Abstract [en]

    Patients seeking medical care with erythema migrans or flu-like symptoms after suspected or observed tick bite in the southeast of Sweden and previously investigated for Borrelia spp. and/or Anaplasma sp. were retrospectively examined for serological evidence of rickettsial infection (Study 1). Twenty of 206 patients had IgG and/or IgM antibodies to Rickettsia spp. equal to or higher than the cut-off titre of 1:64. Seven of these 20 patients showed seroconversion indicative of recent or current infection and 13 patients had titres compatible with past infection, of which five patients were judged as probable infection. Of 19 patients with medical records, 11 were positive for Borrelia spp. as well, and for Anaplasma sp., one was judged as positive. Five of the 19 patients had antibodies against all three pathogens. Erythema migrans or rash was observed at all combinations of seroreactivity, with symptoms including fever, muscle pain, headache and respiratory problems. The results were compared by screening an additional 159 patients (Study 2) primarily sampled for the analysis of Borrelia spp. or Mycoplasma pneumoniae. Sixteen of these patients were seroreactive for Rickettsia spp., of which five were judged as recent or current infection. Symptoms of arthritis, fever, cough and rash were predominant. In 80 blood donors without clinical symptoms, approximately 1 % were seroreactive for Rickettsia spp., interpreted as past infection. The study shows that both single and co-infections do occur, which illustrate the complexity in the clinical picture and a need for further studies to fully understand how these patients should best be treated.

  • 79.
    Lindqvist, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Health and Developmental Care, Vårdhygien.
    Isaksson, Barbro
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology. Östergötlands Läns Landsting, Centre for Health and Developmental Care, Vårdhygien.
    Grub, C.
    Oslo University Hospital.
    Jonassen, T. Ö.
    Oslo University Hospital.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Detection and characterisation of SCCmec remnants in multiresistant methicillin-susceptible Staphylococcus aureus causing a clonal outbreak in a Swedish county2012In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 31, no 2, p. 141-147Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate if multiresistant methicillin-susceptible Staphylococcus aureus (MR-MSSA) causing a clonal outbreak in A-stergotland County, Sweden, were derived from methicillin-resistant S. aureus (MRSA) by carrying remnants of SCCmec, and, if so, to characterise this element. A total of 54 MSSA isolates with concomitant resistance to erythromycin, clindamycin and tobramycin from 49 patients (91% clonally related, spa type t002) were investigated with the BD GeneOhm MRSA assay and real-time polymerase chain reaction (PCR) targeting the SCCmec integration site/SCCmec right extremity junction. DNA sequencing of one isolate representing the MR-MSSA outbreak clone was performed by massive parallel 454 pyrosequencing. All isolates that were part of the clonal outbreak carried SCCmec remnants. The DNA sequencing revealed the carriage of a pseudo-SCC element 12 kb in size, with a genomic organisation identical to an SCCmec type I (TM) I (TM) element, except for a 41-kb gap. This study demonstrates the presence of a pseudo-SCC element resembling SCCmec type II among MR-MSSA, suggesting possible derivation from MRSA. The presence of SCCmec remnants should always be considered when SCCmec typing is used for MRSA detection, and may not be suitable in locations with a high prevalence of MR-MSSA, since this might give a high number of false-positive results.

  • 80.
    Lindqvist, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Isaksson, Barbro
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Samuelsson, Annika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    A clonal outbreak of methicillin-susceptible Staphylococcus aureus with concomitant resistance to erythromycin, clindamycin and tobramycin in a Swedish county2009In: SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES, ISSN 0036-5548, Vol. 41, no 5, p. 324-333Article in journal (Refereed)
    Abstract [en]

    In contrast to methicillin-resistant Staphylococcus aureus (MRSA), studies on clonal distribution of methicillin-susceptible S. aureus (MSSA) are scarce. Since 2004, an increasing incidence of concomitant resistance to erythromycin, clindamycin and tobramycin (ECT) among MSSA has been detected in Ostergotland County, Sweden. The objectives of this study were to investigate the genetic relatedness among these isolates with 2 genotyping methods, pulsed-field gel electrophoresis (PFGE), and sequence-based typing of the polymorphic region X of the staphylococcal protein A gene (spa typing), and to determine the incidence of the Panton-Valentine leukocidin (PVL) gene. When genotyping 54 ECT-resistant MSSA isolates from 49 patients (1 isolate per patient per y), 91% were shown to be part of a clonal outbreak with both methods used (spa type t002). The clonal outbreak was concentrated in 8 hospital departments and 2 primary care centres, all located in the city of Linkoping. All isolates were negative for the PVL gene. In conclusion, this study demonstrates an ongoing clonal outbreak of PVL-negative ECT-resistant MSSA. This stresses the need to continuously maintain basic hygiene rules, since nosocomial transmission of pathogens is not limited to known resistant bacteria such as MRSA.

  • 81.
    Lönn, J.
    et al.
    Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Starkhammar Johansson, Carin
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Garvin, Peter
    Linköping University, Department of Medical and Health Sciences, Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Särndahl, E.
    Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Ravald, Nils
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Richter, Arina
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Bengtsson, T.
    Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nayeri, Fariba
    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.
    Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition2012In: Results in Immunology, ISSN 2211-2839, Vol. 2, p. 7-12Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.

  • 82.
    Lönn, J.
    et al.
    Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Starkhammar Johansson, Carin
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Sridhar, Sravya
    Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Bengtsson, T.
    PEAS Institute, Linköping, Sweden.
    Nayeri, Fariba
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Ravald, Nils
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    High concentrations of hepatocyte growth factor but low biological activity in patients with periodontitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background: High levels of hepatocyte growth factor (HGF), a healing factor with regenerative and cytoprotective effects, has been associated to inflammatory diseases including periodontitis. To induce cellular responses, biologic active HGF requires binding to its receptor c-Met and the co-receptor heparan sulphate proteoglycan (HSPG) on cell membranes and extracellular matrix. The aim of this study was to investigate the concentration and the biological activity of HGF and the relationship with subgingival microbiota in medically healthy subject with / without periodontitis.

    Methods: Saliva, gingival crevicular fluid (GCF) and blood samples from thirty patients with severe periodontitis and thirty periodontally healthy controls were analysed for the concentration of HGF and the binding affinity to HSPG and c-Met, using ELISA and surface plasmon resonance (SPR). Subgingival plaque were analysed for the presence of 18 bacterial species.

    Results: Compared to controls, patients with periodontitis showed higher concentrations of HGF in all three locations (P<0.001), however the binding affinity to HSPG and c-Met were markedly reduced in GCF and in saliva (P<0.002). The patients had higher prevalence of periodontal related bacterial species.

    Conclusion: The increased concentration of HGF in GCF and saliva in patients with severe periodontitis was also reflected in the circulation indicating a systemic effect by periodontitis. However, the biological activity of HGF at local sites of inflammation was reduced. A loss of function of healing factors such as HGF may be one important mechanism in the dominant degenerative processes in periodontally susceptible subjects.

  • 83.
    Lönn, Johanna
    et al.
    PEAS Institute, Linköping, Sweden.
    Almroth, Gabriel
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Nayeri, Fariba
    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.
    An antithrombin III product containing biologically active hepatocyte growth factor may be beneficial in depp ulcer infections2012In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 60, no 2, p. 478-486Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Widely studied for the past 20 years, hepatocyte growth factor (HGF) has been identified as a regenerative marker and an important factor in the development and healing of injuries. Antithrombin III (AT III) is a protein in the blood stream with anti-thrombotic and anti-inflammatory properties and has been used as an adjuvant treatment along with antibiotics in severe sepsis.

    OBJECTIVE:

    To study the content and properties of HGF in plasma-derived AT III products, and the regenerative effect in severe deep ulcer infections.

    METHODS:

    Commercial AT III products were analyzed for the presence and biological activity of HGF. One AT III product containing biologically active HGF was used to treat 18 cases of critical, deep ulcer infections scheduled for major invasive intervention. The patients were followed up for 6-60 months.

    RESULTS:

    The AT III products contained HGF with different biological activity. No adverse reactions were observed after local administration of AT III during the study or follow-up period. In 16 of 18 cases no surgical intervention was needed within the first 6 month of inclusion.

    CONCLUSION:

    AT III products containing biologically active HGF may contribute to regeneration and healing in severe deep ulcer infections which do not respond adequately to different combinations of antibiotics alone.

  • 84.
    Lönn, Johanna
    et al.
    PEAS Institut AB, Linköping, Sweden.
    Shahzad, Faisal
    PEAS Institut AB, Linköping, Sweden.
    Uhlin, Fredrik
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Bengtsson, Torbjörn
    Örebro University, Sweden.
    Almroth, Gabriel
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Nayeri, Fariba
    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.
    High concentration but low biological activity of hepatocyte growth factor in patients with chronic renal failure2012In: Advances in Bioscience and Biotechnology, ISSN 2156-8456, E-ISSN 2156-8502, Vol. 3, no 4, p. 516-523Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is a renotropic, an- tifibrotic and regenerative factor with cytoprotective effects that is produced by mesenchymal cells and shows high affinity to components of extra cellular matrix, such as heparan sulphate proteoglycan (HS- PG), in healthy. Patients with chronic renal failure (CRF) suffer from a chronic inflammatory disorder. In order to assess the underlying mechanisms for de- velopment of CRF we aimed to assess the amounts and affinity of HGF in this patient group. ELISA, western blot and surface plasmon resonance (SPR) were used to study HGF in blood samples, as well as in isolated neutrophils, in CRF patients compared to healthy controls. Patients with CRF showed higher HGF levels in serum (P < 0.0001), but decreased af- finity to HSPG (P < 0.0001). Addition of protease in-hibitors decreased the difference between patients with CRF compared to healthy individuals. HGF with potent regenerative function during injury lacks af-finity to HSPG in patients with CRF that may depend on production of proteases from activated immune cells. This information might be used to highlight un-derlying mechanisms for chronicity and leading to new strategies for treatment of chronic injuries.

     

     

  • 85.
    Lönn, Johanna
    et al.
    PEAS Institut, Linköping, Sweden.
    Sravya, Nakka
    PEAS Institut, Linköping, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Bengtsson, Torbjörn
    Örebro University, Sweden.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology. Karolinska Institutet, Stockholm, Sweden.
    Nayeri, Fariba
    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. PEAS Institut, Linköping.
    Differences in the expression of hepatocyte growth factor in acute and chronic bowel inflammation - Implications for diagnosis?2013In: Advances in Bioscience and Biotechnology, ISSN 2156-8456, E-ISSN 2156-8502, Vol. 4, no 8A2, p. 33-42Article in journal (Refereed)
    Abstract [en]

    Background: Hepatocyte growth factor (HGF) acts as an acute phase protein with regenerative properties. HGF is produced systemically and locally during inflammation but exhibits decreased binding affinity to heparan sulphate proteoglycan (HSPG)/glycosaminoglycan during chronic inflammation. We previously observed a high faecal concentration and binding affinity of HGF to HSPG during acute gastroenteritis. High faecal concentrations of calprotectin and HGF have been reported in chronic inflammatory bowel disease (IBD).

    Methods: Stool samples from patients with ulcerative colitis in remission (n = 11) or exacerbation (n = 5), microscopic colitis (n = 11), colon cancer (n = 6), or acute gastroenteritis caused by Clostridium difficile (n = 20), as well as healthy controls (n = 7), were analysed for the presence of HGF by ELISA, surface plasmon resonance, SDS-PAGE, and Western blot. Then in two patients with ulcerative colitis exacerbation and C. difficile infection, the expression of HGF and calprotectin was studied in colonic biopsies.

    Results: The faecal concentration of HGF was significantly higher in patients with ulcerative colitis compared to the other groups. The binding affinity to dextran was lower in all groups compared to acute inflammation. HGF receptor binding was similar across groups. In a patient with concomitant C. difficile infection and distal ulcerative colitis, HGF was highly expressed in the part of the bowel unaffected by ulcerative colitis, but no expression was found at the site of chronic inflammation. In the patient with total colitis the biopsies showed low expression of HGF. The areas with chronic inflammation exhibited infiltrating calprotectin-stained neutrophils.

    Conclusion: HGF is produced locally during inflammation of the bowel. The HGF produced during acute inflammation or exacerbations of chronic inflammation by the unaffected area shows binding affinity to glucosaminoglycans. Measuring HGF binding in faeces and biopsies may be a tool for differentiating between acute and chronic bowel inflammation, which should be assessed thoroughly in future studies.

  • 86.
    Makdoumi, Karim
    et al.
    Örebro University Hospital.
    Mortensen, Jes
    Örebro University Hospital.
    Sorkhabi, Omid
    Ryhov County Hospital.
    Malmvall, Bo-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Crafoord, Sven
    Örebro University Hospital.
    UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study2012In: Graefe's Archives for Clinical and Experimental Ophthalmology, ISSN 0721-832X, E-ISSN 1435-702X, Vol. 250, no 1, p. 95-102Article in journal (Refereed)
    Abstract [en]

    The aim of this work as to investigate the photochemical interaction used in corneal crosslinking (CXL) as the primary therapy for bacterial keratitis. less thanbrgreater than less thanbrgreater thanA prospective non-randomized study was conducted including 16 patients with a clinical diagnosis of bacterial keratitis. No patient had any prior antibiotic treatment for the current infection. Photography and microbial culturing of the infected cornea were performed. Riboflavin was topically administered for 20 min and ultraviolet light (UVA) exposure settings for treatment of keratoconus were used. After the procedure, clinical examinations were done at least once daily until signs of improvement had been established. The frequency of examinations was thereafter reduced. Antibiotic therapy was initiated if infectious progression was suspected. The trial was registered at ISCRTN.org (no: 21432643). less thanbrgreater than less thanbrgreater thanAll eyes responded to the photochemical treatment with improvement in symptoms and signs of reduced inflammation. Epithelial healing was achieved in all cases. Antibiotic administration was necessary in two cases. One patient required a human amniotic membrane transplant. less thanbrgreater than less thanbrgreater thanThis trial illustrates that photosensitization of riboflavin using UVA at 365 nm has the potential to induce healing in patients with microbial keratitis. The results from the treatment of these 16 patients with corneal ulcers indicate that UVA-riboflavin photochemical therapy merits a controlled study in order to assess its efficacy and safety compared to antibiotics.

  • 87.
    Maller, Rolf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Isaksson, Barbro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sörén, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Nilsson, Maud
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    A study of amikacin given once versus twice daily in serious infections.1988In: Scandinavian Journal of Infectious Diseases. Supplementum, ISSN 0300-8878, E-ISSN 1651-2502, Vol. 22, no 1, p. 75-79Article in journal (Refereed)
    Abstract [en]

    Forty-five mostly elderly patients with serious infections were treated in a prospective, comparative and randomized pharmacokinetic study with amikacin 11.0 or 15.0 mg/kg administered in a single daily dose as an intravenous, short-term infusion or with amikacin 7.5 mg/kg administered twice daily in the same way. The results indicate that administration of amikacin 15 mg/kg in a single daily dose should be a practical and safe principle of administration. However elderly patients often have reduced creatinine clearance and should preferably be given a lower dose of 11 mg/kg bw. The risk of nephrotoxicity did not increase, but conclusions on ototoxicity and clinical efficacy cannot be drawn from this limited study. This should be considered as an initial part of a future multicentre trial.

  • 88.
    Mölstad, Sigvard
    et al.
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences. Unit of Research and Development in Primary Care, Jönköping.
    Erntell, M
    Halmstad County Hospital.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Melander, E
    Malmö University Hospital.
    Norman, C
    Swedish Institute for Infectious Disease Control.
    Skoog, G
    Swedish Institute for Infectious Disease Control.
    Stålsby Lundborg, C
    Department of Public Health Sciences, Stockholm.
    Söderström, A
    University of Gothenburg.
    Torell, E
    Uppsala University Hospital.
    Cars, O
    Swedish Institute for Infectious Disease Control.
    Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme2008In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 8, no 2, p. 125-132Article in journal (Refereed)
    Abstract [en]

    Increasing use of antibiotics and the spread of resistant pneumococcal clones in the early 1990s alarmed the medical profession and medical authorities in Sweden. Strama (Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance) was therefore started in 1994 to provide surveillance of antibiotic use and resistance, and to implement the rational use of antibiotics and development of new knowledge. Between 1995 and 2004, antibiotic use for outpatients decreased from 15.7 to 12.6 defined daily doses per 1000 inhabitants per day and from 536 to 410 prescriptions per 1000 inhabitants per year. The reduction was most prominent in children aged 5–14 years (52%) and for macrolides (65%). During this period, the number of hospital admissions for acute mastoiditis, rhinosinusitis, and quinsy (peritonsillar abscess) was stable or declining. Although the epidemic spread in southern Sweden of penicillin-resistant Streptococcus pneumoniae was curbed, the national frequency increased from 4% to 6%. Resistance remained low in most other bacterial species during this period. This multidisciplinary, coordinated programme has contributed to the reduction of antibiotic use without measurable negative consequences. However, antibiotic resistance in several bacterial species is slowly increasing, which has led to calls for continued sustained efforts to preserve the effectiveness of available antibiotics.

  • 89.
    Nayeri, Fariba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Holmgren Peterson, Kajsa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Perskvist, Nasrin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    An in vitro model for assessment of the biological activity of hepatocyte growth factor2007In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 25, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is a multifunctional growth factor with potent wound-healing properties that functions in the healing of chronic injuries. However, there may be a loss of HGF activity in certain chronic cases; this might be indicated by the presence of high amounts of HGF in body fluids and by the elevated expression of the HGF receptor in tissue biopsies. In such cases, a reliable means of assessing the activity of endogenous HGF would be valuable in allowing clinicians to decide if treatment with HGF would be useful. In this study, we developed an in vitro wound assay that used a mouse skin epithelial cell line to evaluate the biological activity of HGF. We showed that HGF accelerated the motility of the epithelial cells in a dose-dependent fashion with high sensitivity and specificity. This in vitro assay might be used to determine the activity of both endogenous and recombinant HGF.

  • 90.
    Nayeri, Fariba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Nayeri, Tayeb
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Clinical impact of real-time evaluation of the biological activity and degradation of hepatocyte growth factor2008In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 26, no 3, p. 163-171Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is essential for injury repair. Despite high HGF levels in chronic ulcers, up-regulation of HGF receptor in ulcer tissue and decreased biological activity of HGF in ulcer secretions have been observed. With a surface plasmon resonance-based method, we assessed the binding of HGF to antibodies, receptors, and the basement membrane and identified binding interactions that are indispensable for the biological activity of HGF. Recombinant HGF (rHGF) lots were tested for activity, structural integrity, and degradation, and the results were verified in an in vitro model of cell injury. Biologically active rHGF, as well as plasma from healthy volunteers, bound to heparan sulphate proteoglycan (HSPG) and to anti-HGF antibodies. Decreased binding to HSPG was the first event in rHGF degradation. This study established the feasibility of identifying patients with chronic inflammation who need exogenous HGF and of using ligand-binding assessment to evaluate rHGF lots for biological activity.

  • 91.
    Nayeri, Fariba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Söderström, Claes
    Department of Infectious Diseases, County Hospital in Kalmar, Sweden.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Brudin, Lars
    Department of Clinical Physiology, County Hospital in Kalmar, Sweden.
    Peterson, Curt
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Hepatocyte growth factor in chronic leg ulcers – no biological activity – no improvement2005In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 39, no 1, p. 62-64p. 62-64Article in journal (Other academic)
    Abstract [en]

    No abstract available.

  • 92.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Coagulase-negative staphylococci in prosthetic hip infections2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    More than 11,000 primary total hip replacements were performed in Sweden in the year 2000, corresponding to 125 primary total hip replacements per 100,000 inhabitants, according to The Swedish Total Hip Replacement Register. In general, this procedure provides highly satisfactory results. The most common complications associated with prosthetic hip joints are aseptic biomechanical failures and infections. Delayed low-grade infections occur most often, and they are also the most difficult to distinguish from aseptic mechanical failures because of similar symptoms.

    During the period 1994 to 2001, a prospective study was conducted to compare inflammatory markers in blood, synovial fluid, and histopathological specimens in patients diagnosed with aseptic or septic loosening of hip prostheses. Coagulase-negative staphylococci (CoNS) were found to be the most common pathogens in the patients with prosthetic hip joint infections.

    Further characterisation of the CoNS revealed that patients were co-infected with the following: (i) CoNS and other bacterial species, (ii) various CoNS species, and (iii) different S. epidermidis clones. Expression of the icaADB gene complex, which is important for the biofilm mode-of-growth characteristic of S. epidermidis, was not necessary to allow S. epidermidis to infect orthopaedic prostheses. The majority of the S. epidermidis isolates, both from prostheses and normal bacteria flora, were able to bind to at least one of the extracellular matrix proteins we tested, this adhesion ability is a probable virulence factor. Histologically, the extent of cell infiltration differed between aseptic and septic loosening of prostheses, and neutrophils in tissue at a rate of ≥ 5 cells/high power field greatly favoured infection. Periprosthetic tissue contained the cells that are required not only for an innate, but also a specific, immune response, which supports the theory that the limited systemic inflammatory response in infections of hip prostheses is not due to failure of inflammatory cells to reach the infected area, but is more likely caused by an inadequate response to the infecting organisms.

    Therefore, we studied the interactions between neutrophils and S. epidermidis (the most common CoNS species in hip prosthetic infections). Neutrophils phagocytosed both surfaceadherent and planktonic S. epidermidis, but they ingested adherent S. aureus isolates more readily than they consumed adherent S. epidermidis. The reduced phagocytosis of S. epidermidis by neutrophils is viewed as a virulence factor, together with the lack of an ability to prime or sufficiently activate the neutrophil oxidase, and thereby evade adequate killing by neutrophils. The weak oxidative activation agrees with the low inflammatory response seen in patients with S. epidermidis infections related to implanted devices. Furthermore, both planktonic and adherent S. epidermidis delayed neutrophil apoptosis, and we suggest that this leads to the accumulation of neutrophils at the site of inflammation. We propose that the complex interplay between the S. epidermidis-induced delay in apoptosis in neutrophils and the interaction of S. epidermidis-containing neutrophils with macrophages in periprosthetic tissue has negative impact on the outcome in patients with prosthetic hip joint infections, resulting in low grade inflammation, tissue damage, and finally loosening of the prosthesis.

    List of papers
    1. Inflammatory response in 85 patients with loosened hip prostheses: A prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening
    Open this publication in new window or tab >>Inflammatory response in 85 patients with loosened hip prostheses: A prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening
    Show others...
    2007 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 78, no 5, p. 629-639Article in journal (Refereed) Published
    Abstract [en]

    Over the past decades, prosthetic hip joints have improved the quality oflife for many patients. The most common complications are aseptic biornechanical failures and prosthetic joint infections. For prosthetic hip joints, delayed low-grade infections are seen most often and they are also most difficult to distinguish from aseptic mechanical failures. A prospective study was conducted to campare inilammatory markers in patients diagnosed with aseptic or septic prosthetic loosenffig. The diagnostic criteria were based on the decisions of experienced orthoperlic surgeons and microbiological analys is of periprosthetic tissue samplestaken perioperatively. Coagulase-negative staphylococci were the most common pathogens in the infected patients. Pre- or perioperative results for C-reactive protein and erytlu-ocyte sedimentation rate were valuable tools for diagnosing most, hut not all, low virulence infections. White blood cell count in synavial fluid was an important marker of infection, which was not the case for lactate. Levels of the cytokines turnor necrosis factor-α, interleukin-1 ß. and interleukin-6 in synavial fluid were significantly higher in the infected group. Patterus of inilammatory cell infiltration in periprosthetic tissue differed significantly between the groups, and infiltration of polymorphonuclear cells proved to be the best marker of distinguish between septic and aseptic loosenffig. Treatment and outcome are described for the infected patients.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81959 (URN)10.1080/17453670710014329 (DOI)
    Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2017-12-07Bibliographically approved
    2. Interaction of staphylococcus epidermidis from infected hip prostheses with neutrophil granulocytes
    Open this publication in new window or tab >>Interaction of staphylococcus epidermidis from infected hip prostheses with neutrophil granulocytes
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    2001 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 33, no 6, p. 408-412Article in journal (Refereed) Published
    Abstract [en]

    This study focuses on the interaction of Staphylococcus epidermis isolated from granulation tissue covering infected hip prostheses and neutrophil granulocytes. Bacterial strains isolated from normal flora were used as controls. The bacteria were well characterized with routine methods and further characterized with random amplified polymorphic DNA analyses and slime tests. Phagocytosis and chemiluminescence (CL) assays were used in the neutrophil interaction studies. The prostheses strains were ingested to a lesser extent than strains from normal flora (p ≤ 0.001). There was no significant difference between the prostheses strains and the normal flora strains in terms of total CL response. However, the extracellular CL response from the neutrophils was lower in comparison with the normal flora when interacting with the prostheses strains. The results of this study support the notion that S. epidermidis strains isolated from infected hip prostheses have an enhanced capacity to resist phagocytosis and that most of these strains elicit a reduced inflammatory response, measured as the production of extracellular oxidative metabolites from the neutrophils, compared to normal flora.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25771 (URN)10.1080/00365540152029855 (DOI)10205 (Local ID)10205 (Archive number)10205 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    3. Staphylococcus aureus, but not Staphylococcus epidermidis, modulates the oxidative response and induces apoptosis in human neutrophils
    Open this publication in new window or tab >>Staphylococcus aureus, but not Staphylococcus epidermidis, modulates the oxidative response and induces apoptosis in human neutrophils
    Show others...
    2004 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 112, no 2, p. 109-118Article in journal (Refereed) Published
    Abstract [en]

    S. epidermidis is the most common isolate in foreign body infections. The aim of this study was to understand why S. epidermidis causes silent biomaterial infections. In view of the divergent inflammatory responses S. epidermidis and S. aureus cause in patients, we analyzed how they differ when interacting with human neutrophils. Neutrophils interacting with S. epidermidis strains isolated either from granulation tissue covering infected hip prostheses or from normal skin flora were tested by measuring the oxidative response as chemiluminescence and apoptosis as annexin V binding. Different S. aureus strains were tested in parallel. All S. epidermidis tested were unable to modulate the oxidative reaction in response to formyl-methionyl-leucyl-phenylalanine (fMLP) and did not provoke, but rather inhibited, apoptosis. In contrast, some S. aureus strains enhanced the oxidative reaction, and this priming capacity was linked to p38-mitogen-activated-protein-kinase (p38-MAPK) activation and induction of apoptosis. Our results may explain why S. epidermidis is a weak inducer of inflammation compared to S. aureus, and therefore responsible for the indolent and chronic course of S. epidermidis biomaterial infections.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-23732 (URN)10.1111/j.1600-0463.2004.apm1120205.x (DOI)3239 (Local ID)3239 (Archive number)3239 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Adherence of Staphylococcus epidermidis to extracellular matrix proteins and effects of fibrinogen-bound bacteria on oxidase activity and apoptosis in neutrophils
    Open this publication in new window or tab >>Adherence of Staphylococcus epidermidis to extracellular matrix proteins and effects of fibrinogen-bound bacteria on oxidase activity and apoptosis in neutrophils
    Show others...
    2005 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 113, no 5, p. 361-373Article in journal (Refereed) Published
    Abstract [en]

    Staphylococcus epidermidis often causes foreign-body infections such as those associated with hip prostheses, but the underlying pathogenic mechanisms are not fully understood. We performed spectrophotometry to study the ability of S. epidermidis to bind to immobilised fibrinogen, fibronectin, vitronectin, and collagen. The strains were isolated from infected hip prostheses or from normal flora and the well-known protein-binding strain Staphylococcus aureus Cowan was used as positive control. We also analysed the interaction between neutrophils and a fibrinogen-bound prosthesis-derived strain of S. epidermidisby measuring chemiluminescence to determine the neutrophil oxidative response and binding of annexin V to indicate neutrophil apoptosis. We found that binding of S. epidermidis to extracellular matrix proteins varied under different growth conditions, and that prosthesis isolates adhered better to vitronectin than did strains from normal flora. The oxidative response caused by fibrinogen-bound S. epidermidis was not above the background level, which was in marked contrast to the distinct response induced by fibrinogen-associated S. aureus Cowan. Furthermore, fibrinogen-adhering S. epidermidis retarded neutrophil apoptosis. We conclude that surface-bound S. epidermidis induces only a weak inflammatory response, which in combination with the ability of the adherent bacteria to retard neutrophil apoptosis may contribute to low-grade inflammation and loosening of prostheses.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-28719 (URN)10.1111/j.1600-0463.2005.apm_113508.x (DOI)13888 (Local ID)13888 (Archive number)13888 (OAI)
    Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
    5. Characterization of coagulase-negative staphylococci isolated from patients with infected hip prostheses: use of phenotypic and genotypic analyses, including tests for the presence of the ica operon
    Open this publication in new window or tab >>Characterization of coagulase-negative staphylococci isolated from patients with infected hip prostheses: use of phenotypic and genotypic analyses, including tests for the presence of the ica operon
    2007 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 26, no 4, p. 255-265Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to investigate phenotypic and/or genotypic heterogeneity in coagulase-negative staphylococci (CoNS) obtained from multiple tissue samples taken perioperatively during exchange surgery from each of 19 patients with clinically and/or microbiologically proven hip prosthesis infections. CoNS are important pathogens in prosthetic hip joint infections. Several virulence factors have been suggested for CoNS, such as phenotypic variation, yet the pathogenic processes that are involved remain unclear. The PhenePlate system (PhPlate AB, Stockholm Sweden) was used for phenotyping and pulsed-field gel electrophoresis for genotyping of polymorphisms in isolates of CoNS. Furthermore, polymerase chain reaction was used to determine the presence of the icaADB gene complex in the isolates. Some patients were infected with CoNS and other species, some were infected with multiple CoNS species, although infections with Staphylococcus epidermidis alone were most common, and some were infected with different S. epidermidis clones. Phenotypic variation was found among isolates both from the same tissue sample and from different samples from the same patient, and in some cases such variation represented the presence of different clones. One-third of the patients infected with S. epidermidis carried the icaADB genes. CoNS isolates showing phenotypic and/or genotypic heterogeneity were identified in tissue samples from half of the patients. The presence of the intercellular adhesion (ica) operon does not seem to be a prerequisite for establishing infection with CoNS.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81976 (URN)10.1007/s10096-007-0281-9 (DOI)
    Note

    On the day of the defence day the status of this article was

    Manuscript

    Available from: 2012-09-27 Created: 2012-09-27 Last updated: 2017-12-07Bibliographically approved
  • 93.
    Nilsson, Bengt-Olof
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    The Immune System in the Oldest-Old: Clinical and Immunological Studies in the NONA Immune Cohort2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The oldest-old (people aged 80 or older) constituted 5 % of the population in Sweden in 2000, an increase from 1.5 % fifty years earlier. The immune system undergoes dramatic changes at high age, sometimes referred to as “immunosenescence”. However, the natures of these changes, and in particular, their clinical consequences are incompletely understood. In a previous longitudinal study, a set of immune parameters were identified and termed immune risk phenotype (IRP) because of an association with increased mortality. The IRP consists of changes in the T lymphocyte compartment, in particular an inverted CD4/CD8 ratio. The IRP was found to be associated with cytomegalovirus (CMV) infection, which through expansions of cytolytic anti-viral CD8 cell responses was ascribed a role in the development of IRP. The general aim of this thesis was to increase the knowledge of changes in the immune system and their clinical consequences in the oldest-old. The population-based random sample of the longitudinal NONA-Immune Study (n = 138, mean age 90 years at baseline) was used for all investigations.

    In paper I, the effects on sample size of various exclusion protocols for immune studies of the elderly was examined. The commonly used SENIEUR protocol, selecting individuals representing ‘normal ageing’, excluded 90 % of nonagenarians. Based on different protocol criteria, individuals were grouped into ‘very healthy’, ‘moderately healthy’ or ‘frail’. The prevalence of CMV was similar across the groups. Further, differentiated CD8 populations associated with CMV, i.e. those expressing CD56, CD57 and CD45RA while lacking expression of CD27 and CD28, were equally distributed across the groups of the oldest-old, but were, as expected, significantly increased in the elderly compared to a middle aged control group. The findings showed that lymphocyte subsets associated with IRP might serve as significant biomarkers of ageing independent of the overall health status, also supporting the notion that immunological studies of the oldest-old should be done in population-based non-selected populations.

    The IRP and the presence of low-grade inflammation, for example increase of   IL-6 in plasma, constitute major predictors of 2-year mortality in the oldest-old. In paper II, the CD4/CD8 ratio and IL-6 were found to predict 97 % of observed survival and 57 % of deaths over 2 years. The impact of IRP and IL-6 on 2-year survival was independent of age, sex and several diseases. The longitudinal design allowed temporal evaluations, suggesting a sequence of events starting with IRP and leading to inflammation in the decline state.                                      Four-year mortality in the oldest-old (paper III) was found to be mainly related to markers of inflammation and IRP. Individuals with both inverted CD4/CD8 ratio and high IL-6 level had significantly higher 4 year mortality (82 %) compared to individuals with CD4/CD8 ratio ³ 1 and low IL-6 level (29 %) at baseline. The presence of IRP and increased IL-6 level showed some associations with presence of diseases; in particular, IL6 was associated with the presence of cognitive impairment. However, despite being strong predictors of mortality, IRP and IL-6 could not be linked to any specific cause of death, probably due to the multi-factorial nature of these factors.                                                                                                                             The prevalence of antinuclear antibodies (ANA) in the oldest-old was higher compared to younger controls (paper IV). The difference across age was most pronounced in men, showing low levels at younger age, whereas the prevalence among the oldest-old men reached a similar level as in women. There was no association between the presence of ANA and IRP, CMV status or health status in the oldest-old.

    List of papers
    1. Morbidity does not influence the T-cell immune risk phenotype in the elderly: Findings in the Swedish NONA Immune Study using sample selection protocols
    Open this publication in new window or tab >>Morbidity does not influence the T-cell immune risk phenotype in the elderly: Findings in the Swedish NONA Immune Study using sample selection protocols
    Show others...
    2003 (English)In: Mechanisms of Ageing and Development, ISSN 0047-6374, E-ISSN 1872-6216, Vol. 124, no 4, p. 469-476Article in journal (Refereed) Published
    Abstract [en]

    A critical issue in our understanding of ageing and the immune system refers to the health status of the population from which inferences are drawn. The commonly used SENIEUR protocol, selecting individuals representing 'normal ageing' has recently been under debate because a substantial amount of individuals with various health problems are excluded. The aim of the present study was to investigate the influence of morbidity on immune parameters and to evaluate the associations with the T-cell immune risk phenotype (IRP), related to cytomegalovirus (CMV) seropositivity by applying the SENIEUR protocol and the OCTO-Immune protocol in the unselected population based sample (n = 138) of oldest-olds, participating in the Swedish NONA Immune Study. The SENIEUR protocol excluded over 90% of the sample whereas the OCTO-Immune protocol excluded almost 65% of the sample. Three independent groups, very healthy (SENIEUR), moderately healthy (OCTO-Immune) and frail (non-SENIEUR/non-OCTO-Immune) were created. Flow cytometry studies on lymphocyte sub-populations revealed no significant difference in CD4/CD8 ratio, CD3+CD4-CD8+, CD3+CD4+CD8-, CD8+CD57+CD28-, CD8+CD56+CD57- or CD8+CD56+CD57+ between the very healthy, moderately healthy and the frail subsamples. Our findings indicate that morbidity does not significantly influence the T-cell immune risk profile in the elderly, and we suggest the inclusion of broader samples in future immunogerontological studies.

    Place, publisher, year, edition, pages
    Elesvier, 2003
    Keywords
    Elderly, Selection, Health status, Lymphocyte subsets, CD8, CMV
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26438 (URN)10.1016/S0047-6374(03)00024-1 (DOI)10981 (Local ID)10981 (Archive number)10981 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13
    2. The immune risk phenotype is associated with IL-6 in the terminal decline stage: Findings from the Swedish NONA immune longitudinal study of very late life functioning
    Open this publication in new window or tab >>The immune risk phenotype is associated with IL-6 in the terminal decline stage: Findings from the Swedish NONA immune longitudinal study of very late life functioning
    Show others...
    2006 (English)In: Mechanisms of Ageing and Development, ISSN 0047-6374, E-ISSN 1872-6216, Vol. 127, no 8, p. 695-704Article in journal (Refereed) Published
    Abstract [en]

    In the present NONA immune longitudinal study, we further examine the previously identified T cell immune risk phenotype (IRP), relative inflammatory activity, morbidity and 2-year mortality in very old individuals >90 years. T-cell subsets as well as the inflammatory markers IL-6, IL-10, C-reactive protein, transthyretin and albumin were evaluated. IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells. The further characterisation of these exceptional individuals may allow insight into remedial approaches for those who remain in the IRP category until death. © 2006 Elsevier Ireland Ltd. All rights reserved.

    Place, publisher, year, edition, pages
    Elsevier, 2006
    Keywords
    Immune risk; T-cells; Inflammation; Interleukin 6; Survival
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-37496 (URN)10.1016/j.mad.2006.04.003 (DOI)36405 (Local ID)36405 (Archive number)36405 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    3. The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality: Findings from the Swedish NONA Immune Longitudinal Study
    Open this publication in new window or tab >>The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality: Findings from the Swedish NONA Immune Longitudinal Study
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In this NONA immune longitudinal study, we examine 4-year mortality in relation to a set of laboratory parameters, morbidity and cause of death in a population-based sample of oldest-old individuals (n=138). Four groups were constructed based on levels for the CD4/CD8 ratio (above or below one = IRP, immune risk phenotype group) and levels for IL-6 (below or above the median 3.15 pg/mL). 4-year mortality was higher in the “IRP” group (73 %), the “IL-6” group (64 %), and the “Double risk group” (82 %) compared with the “No risk” group (29 %; p-values between .005 and .000). Cognitive dysfunction and dementia were more common in the two groups with elevated IL-6 levels (p-values between .014 and .001), whereas cardiovascular disease tended (p = .081) to be associated with both “IRP” and “IL-6” groups. The most common cause of death was related to cardio- and cerebrovascular disease (59 %,), followed by infection in 15 % of the cases and cancer in 7 %. Despite their strong associations with 4-year mortality, neither IRP nor IL-6 could be linked to any specific cause of death, possibly because both IRP and IL-6 are multi-factorial risk factors, being associated with several different diseases and mechanisms which cause death.

    Keywords
    survival, mortality, CMV, cytomegalovirus, CD8, T-cells, inflammation, immuner risk phenotype, IRP, cause of death
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-54674 (URN)
    Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2018-01-12
    4. Antinuclear antibodies in the oldest-old women and men
    Open this publication in new window or tab >>Antinuclear antibodies in the oldest-old women and men
    Show others...
    2006 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, no 4, p. 281-288Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to compare the prevalence of antinuclear antibodies (ANA) in very old individuals (≥86 years of age) with healthy younger (18-68 years) blood donors (n = 200) regarding gender, health status, ratio of circulating CD4/CD8 cells and cytomegalovirus (CMV) serology. Frozen plasma was used for ANA detection in two study groups, i.e. 'OCTO' (97 persons aged 86-92 years, 65% women) and 'NONA' (136 persons aged 86-95 years, 70% women). OCTO participants were recruited on the basis that they were healthy or moderately healthy according to a selection protocol. No exclusion criteria regarding health status were applied in the NONA sample. The prevalence of ANA was significantly higher in the oldest-old samples compared to blood donors. There was no association between health status and the presence of ANA in the oldest-old. The difference across age was most pronounced in men, with low levels at younger age, whereas the prevalence among the oldest-old men reached similar levels as in women. There were no associations between the presence of ANA and CD4/CD8 ratio or with CMV status in the oldest-old. Our findings confirm an increased prevalence of ANA in the oldest-old, and emphasize the importance of taking gender and age into consideration when evaluating ANA. © 2006 Elsevier Ltd. All rights reserved.

    Place, publisher, year, edition, pages
    Elsevier, 2006
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-37559 (URN)10.1016/j.jaut.2006.10.002 (DOI)36598 (Local ID)36598 (Archive number)36598 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
  • 94.
    Nilsson, Bengt-Olof
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Strindhall, Jan
    Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Jönköping, Sweden.
    Löfgren, Sture
    Department of Microbiology, Ryhov Hospital, Jönköping, Sweden.
    Forsey, Rosalyn
    Unilever Corporate Research, Colworth House, Sharnbrook.
    Thompson, Julie
    LCG Bioscience, Bourn Hall, Bourn, Cambridge.
    Johansson, Boo
    Department of Psychology, Göteborg University, Göteborg, Sweden.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Wikby, Anders
    Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Jönköping, Sweden.
    The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality: Findings from the Swedish NONA Immune Longitudinal StudyManuscript (preprint) (Other academic)
    Abstract [en]

    In this NONA immune longitudinal study, we examine 4-year mortality in relation to a set of laboratory parameters, morbidity and cause of death in a population-based sample of oldest-old individuals (n=138). Four groups were constructed based on levels for the CD4/CD8 ratio (above or below one = IRP, immune risk phenotype group) and levels for IL-6 (below or above the median 3.15 pg/mL). 4-year mortality was higher in the “IRP” group (73 %), the “IL-6” group (64 %), and the “Double risk group” (82 %) compared with the “No risk” group (29 %; p-values between .005 and .000). Cognitive dysfunction and dementia were more common in the two groups with elevated IL-6 levels (p-values between .014 and .001), whereas cardiovascular disease tended (p = .081) to be associated with both “IRP” and “IL-6” groups. The most common cause of death was related to cardio- and cerebrovascular disease (59 %,), followed by infection in 15 % of the cases and cancer in 7 %. Despite their strong associations with 4-year mortality, neither IRP nor IL-6 could be linked to any specific cause of death, possibly because both IRP and IL-6 are multi-factorial risk factors, being associated with several different diseases and mechanisms which cause death.

  • 95. Nimeri, G
    et al.
    Majeed, Meytham
    Linköping University, Faculty of Arts and Sciences. Linköping University, Department of health and environment.
    Elwing, H
    Öhman, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Wetterö, Jonas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology .
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Oxygen radical production in neutrophils interacting with platelets and surface-immobilized plasma proteins: role of tyrosine phosphorylation2003In: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 67A, no 2, p. 439-447Article in journal (Refereed)
    Abstract [en]

    The interaction between neutrophil granulocytes and platelets is considered to play an important role in the inflammatory process induced by an implanted foreign material. However, the cellular mechanisms involved remain incompletely understood. We used a luminol-dependent chemiluminescence (CL) technique to analyze the generation of reactive oxygen species (ROS) in human neutrophils interacting with different plasma protein-coated surfaces in the presence or absence of unstimulated or stimulated platelets. The role of tyrosine phosphorylation in the regulation of NADPH oxidase activity was evaluated with quantitative fluorescence microscopy and the specific tyrosine kinase inhibitor genistein. We found that the ROS-production is 2 to 3 times higher in neutrophils on immunoglobulin G (IgG)coated surfaces than in cells interacting with albumin- or fibrinogen-coated surfaces. Incubation with superoxide dismutase and catalase revealed that about 45% of the ROS was released extracellularly on IgG surfaces whereas corresponding values were 90% and 85% in neutrophils interacting with albumin and fibrinogen, respectively. The presence of platelets markedly increased the extracellular generation of ROS, mainly in neutrophils. interacting with IgG- or fibrinogen-coated surfaces whereas the intracellular production was only modestly affected. Quantitative fluorescence microscopy of neutrophils stained with FITC-conjugated anti-phosphotyrosine antibodies showed a correlation between tyrosine phosphorylation, cell spreading, and ROS production. Platelets markedly amplified the anti-phosphotyrosine staining on both fibrinogen- and IgG-coated surfaces whereas the low level of tyrosine phosphorylation in neutrophils on albumin-coated surfaces was not further elevated by platelets. Furthermore, the tyrosine kinase inhibitor genistein inhibited both extra- and intracellular ROS production in neutrophils regardless of the presence of platelets. We demonstrate that plasma protein coating and the presence of platelets are crucial for the inflammatory response of adhering neutrophils and that the oxidative response correlates with the extent of tyrosine phosphorylation of proteins in focal contacts. (C) 2003 Wiley Periodicals, Inc.

  • 96.
    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 Centre, Department of Infectious Diseases in Östergötland.
    Berglund, Johan
    Blekinge Institute of Technology, School of Health Science, Karlskrona, Sweden.
    Bjöersdorff, Anneli
    Läckeby Animal Hospital, Läckeby, Sweden.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Garpmo, Ulf
    Department of Clinical Microbiology and 7Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.
    Haglund, Mats
    Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.
    Nilsson, Kenneth
    Unit of Clinical Microbiology/Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Eliasson, Ingvar
    Department of Laboratory Medicine, Norra Älvsborg County Hospital, Trollhättan, Sweden.
    Aetiology of Tick-Borne Infections in an Adult Swedish Population: are Co-Infections with Multiple Agents Common?Manuscript (preprint) (Other academic)
    Abstract [en]

    In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tickborne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (e38.0°C) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM). A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical coinfection with Anaplasma phagocytophilum, based on serology. Both TBE cases had coinfections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.

  • 97.
    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, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Johansson, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases.
    Nyman, Dag
    Aland Central Hospital.
    Jansson, Christian
    Aland Central Hospital.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology.
    Cytotoxic mechanisms may play a role in the local immune response in the central nervous system in neuroborreliosis2011In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 232, no 1-2, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Aiming to investigate the role of cytotoxic mechanisms in neuroborreliosis (NB), the cytokines IL-2, IL-7, IL-10, IL-12p70, IL-15, GM-CSF and the Th17-cytokine IL-17 were analyzed in cerebrospinal fluid (CSF) and plasma from NB-patients. NB-patients showed increased levels in CSF compared to controls of all analyzed cytokines except IL-15 but not in plasma. Blood lymphocytes from three NB-patients showed functional cytotoxicity in response to autologous Borrelia-infected macrophages. The findings support a role for cytotoxic mechanisms in the local immune response in NB and in addition suggest an increase of IL-17.

  • 98.
    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.

  • 99.
    Nyström, Jessica
    et al.
    Karolinska University Hospital.
    Cardell, Kristina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Bjorg Bjornsdottir, Thora
    Karolinska University Hospital.
    Frydén, Aril
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Hultgren, Catharina
    Karolinska University Hospital.
    Sallberg, Matti
    Karolinska University Hospital.
    Improved cell mediated immune responses after successful re-vaccination of non-responders to the hepatitis B virus surface antigen (HBsAg) vaccine using the combined hepatitis A and B vaccine2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 47, p. 5967-5972Article in journal (Refereed)
    Abstract [en]

    We Successfully re-vaccinated hepatitis B Virus (HBV) vaccine non-responders Using a double dose of the combined hepatitis A virus (HAV) and HBV vaccine. The hope was to improve priming of hepatitis B surface antigen (HBsAg)-specific cell mediated immune response (CMI) by an increased antigen dose and a theoretical adjuvant-effect from the local presence of a HAV-specific CMI. A few non-responders had a detectable HBsAg-specific CMI before re-vaccination. An in vitro detectable HBsAg-specific CMI was primed equally effective in non-responders (58%) as in first time vaccine recipients (68%). After the third dose a weak, albeit significant, association was observed between the magnitude of HBsAg-specific proliferation and anti-HBs levels. This regimen improves the priming of HBsAg-specific CMIs and antibodies.

  • 100.
    Paues, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Eriksson, Lars
    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.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Tuberculous meningitis with positive cell-count in lumbar puncture CSF though negative cell-count from ventricular drainage CSF2011In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 62, no 5, p. 404-405Article in journal (Other academic)
123 51 - 100 of 149
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