Publikasjoner

2024 - 2010

• Cryptosporidium species and subtypes in Norway: Predominance of C. parvum and emergence of C. mortiferum

  Forfattere: Jahid Hasan Tipu, Audun Sivertsen, Jan-Egil Afset, Lars Sandven, Hanne Brekke, Hilde Marie Lund, Linnea Sofie Elburg, Peter Gaustad, Tore Lier, Liv Reidun Tverelv, Øystein Haarklau Johansen, Lucy J Robertson, Kurt Hanevik
  Publiseringssted: Taylor & Francis
  Les utdrag

  PCR-based diagnostics has revealed the previously largely unknown Cryptosporidium transmission and infections in high-income countries. This study aimed to determine domestic and imported subtypes of Cryptosporidium species in Norway, evaluate their demographic distribution, and identify potential small outbreaks. Cryptosporidium-positive human faecal samples were obtained from six medical microbiology laboratories between February 2022 and January 2024, together with 22 Cryptosporidium-positive animal samples. Species and subtypes were identified by sequencing PCR products from gp60 and SSU rRNA genes. Most cryptosporidiosis cases occurred during late summer/early autumn, primarily in children and young adults. Of 550 human samples, 359 were successfully characterized molecularly (65%), revealing infection with 10 different Cryptosporidium species. C. parvum occurred in 245 (68%) human isolates with IIa and IId being major allele families, with distinct regional distribution patterns of common subtypes. A kindergarten outbreak with 5 cases was due to C. parvum IIaA14G1R1. C. mortiferum was identified in 33 (9.2%) human cases of which 24 were known to be of domestic origin, making it the second most common species in human autochthonous cases in Norway. All C. mortiferum isolates were of the same genotype; XIVaA20G2T1, including 13 cases from a suspected small outbreak in Trøndelag. C. hominis occurred in 68 typed cases (19%), but mostly in infections acquired abroad, with allele families Ib and If occurring most often. In conclusion, this study of recent Cryptosporidium spp. and subtypes in Norway, highlights the predominance of C. parvum and the emergence of C. mortiferum among autochthonous cases.

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• Real-world impact of transitioning from one lipoprotein(a) assay to another in a clinical setting

  Forfattere: Janeni Jeevanathan, Sigrid M. Blom, Thomas Olsen, Kirsten B. Holven, Erik K. Arnesen, Torleif Trydal, Børge G. Nordestgaard, Michael Sovershaev, Ying Chen , Kjetil Retterstøl, Jacob J. Christensen
  Publiseringssted: American Journal of Preventive Cardiology
  Les utdrag

  Background and aims

  Different lipoprotein(a) [Lp(a)] assays may affect risk stratification of individuals and thus clinical decision-making. We aimed to investigate how transitioning between Lp(a) assays at a large central laboratory affected the proportion of individuals with Lp(a) result above clinical thresholds.

  Methods

  We studied nationwide clinical laboratory data including 185,493 unique individuals (47.7% women) aged 18-50 years with 272,463 Lp(a) measurements using Roche- (2000-2009) and Siemens Lp(a) assay (2009-2019).

  Results

  While the majority of individuals (66-75%) had low levels of Lp(a) (<30 mg/dL) independent of the assay used, the Roche assay detected 20% more individuals with Lp(a) >50 mg/dL, 40% more individuals with Lp(a) >100 mg/dL and 80% more individuals with Lp(a) > 180 mg/dL than the currently used Siemens assay, likely due to calibration differences.

  Conclusion

  Transitioning from one Lp(a) immunoassay to another had significant impact on Lp(a) results, particularly in individuals approaching clinically relevant Lp(a) thresholds.

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• DDR2 expression in breast cancer is associated with blood vessel invasion, basal-like tumors, tumor associated macrophages, regulatory T cells, detection mode and prognosis

  Forfattere: Tor Audun Klingen, Ying Chen, Hans Aas, og Lars A Akslen
  Publiseringssted: Hum Pathol .
  Les utdrag

  Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase for collagen, stimulating epithelial-mesenchymal transition and stiffness in breast cancer. Here, we investigated levels of DDR2 in breast tumor cells in relation to vascular invasion, TIL subsets, macrophages, molecular tumor subtypes, modes of detection and prognosis. This retrospective, population-based series of invasive breast carcinomas from the Norwegian Screening Program in Vestfold County (Norway), period 2004-2009, included 200 screening patients and 82 cases detected in screening intervals. DDR2 was examined on core needle biopsies using a semi-quantitative, immunohistochemical staining index and dichotomized as low or high DDR2 expression. Counts of macrophages and TIL subsets were dichotomized based on immunohistochemistry using TMA. We also recorded blood or lymphatic vessel invasion (BVI or LVI) as present or absent by immunohistochemistry. High expression of DDR2 in tumor cells showed significant relation with high counts of CD163+ macrophages (p < 0.001) and FOXP3 TILs (p = 0.011), presence of BVI (p = 0.028), high tumor cell proliferation by Ki67 (p = 0.033), ER negativity (p = 0.001), triple-negative cases (p = 0.038), basal-like features (p < 0.001) as well as interval detection (p < 0.001). By multivariate analysis, high DDR2 expression was related to reduced recurrence-free survival (HR, 2.3, p = 0.017), when examined together with histologic grading, lymph node assessment, tumor diameter, BVI, and molecular tumor subtype. This study supports a link between high DDR2 expression, high counts of macrophages by CD163 (tumor associated) and regulatory T cells by FOXP3 together with the presence of BVI, possibly indicating increased tumor motility and intravasation in aggressive breast tumors.

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• Expert-level detection of M-proteins in serum protein electrophoresis using machine learning

  Forfattere: Eike Elfert, Wolfgang E. Kaminski, Christian Matek, Gregor Hoermann, Eyvind W. Axelsen, Carsten Marr and Armin P. Piehler
  Publiseringssted: Clin Chem Lab Med
  Les utdrag

  Objectives: Serum protein electrophoresis (SPE) in combination with immunotyping (IMT) is the diagnostic standard for detecting monoclonal proteins (M-proteins). However, interpretation of SPE and IMT is weakly standardized, time consuming and investigator dependent. Here, we present five machine learning (ML) approaches for automated detection of M-proteins on SPE on an unprecedented large and well-curated data set and compare the performance with that of laboratory experts.

  Methods: SPE and IMT were performed in serum samples from 69,722 individuals from Norway. IMT results were used to label the samples as M-protein present (positive, n=4,273) or absent (negative n=65,449). Four feature-based ML algorithms and one convolutional neural network (CNN) were trained on 68,722 randomly selected SPE patterns to detect M-proteins. Algorithm performance was compared to that of an expert group of clinical pathologists and laboratory technicians (n=10) on a test set of 1,000 samples.

  Results: The random forest classifier showed the best performance (F1-Score 93.2 %, accuracy 99.1 %, sensitivity 89.9 %, specificity 99.8 %, positive predictive value 96.9 %, negative predictive value 99.3 %) and outperformed the experts (F1-Score 61.2 ± 16.0 %, accuracy 89.2 ± 10.2 %, sensitivity 94.3 ± 2.8 %, specificity 88.9 ± 10.9 %, positive predictive value 47.3 ± 16.2 %, negative predictive value 99.5 ± 0.2 %) on the test set. Interestingly the performance of the RFC saturated, the CNN performance increased steadily within our training set (n=68,722).

  Conclusions: Feature-based ML systems are capable of automated detection of M-proteins on SPE beyond expert-level and show potential for use in the clinical laboratory.

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• SLE: a cognitive step forward—a synthesis of rethinking theories, causality, and ignored DNA structures

  Forfattere: Ole Petter Rekvig
  Publiseringssted: Frontiers in Immunology
  Les utdrag

  Systemic lupus erythematosus (SLE) is classified by instinctual classification criteria. A valid proclamation is that these formally accepted SLE classification criteria legitimate the syndrome as being difficult to explain and therefore enigmatic. SLE involves scientific problems linked to etiological factors and criteria. Our insufficient understanding of the clinical condition uniformly denoted SLE depends on the still open question of whether SLE is, according to classification criteria, a well-defined one disease entity or represents a variety of overlapping indistinct syndromes. Without rational hypotheses, these problems harm clear definition(s) of the syndrome. Why SLE is not anchored in logic, consequent, downstream interdependent and interactive inflammatory networks may rely on ignored predictive causality principles. Authoritative classification criteria do not reflect consequent causality criteria and do not unify characterization principles such as diagnostic criteria. We need now to reconcile legendary scientific achievements to concretize the delimitation of what SLE really is. Not all classified SLE syndromes are “genuine SLE”; many are theoretically “SLE-like non-SLE” syndromes. In this study, progressive theories imply imperative challenges to reconsider the fundamental impact of “the causality principle”. This may offer us logic classification and diagnostic criteria aimed at identifying concise SLE syndromes as research objects. Can a systems science approach solve this problem?

  Keywords: systemic lupus erythematosus, SLE, SLE classification criteria, unique DNA structures, the causality principle, lupus nephritis, system science

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• The greatest contribution to medical science is the transformation from studying symptoms to studying their causes—the unrelenting legacy of Robert Koch and Louis Pasteur—and a causality perspective to approach a definition of SLE

  Forfattere: Ole Petter Rekvig
  Publiseringssted: Frontiers in Immunology
  Les utdrag

  The basic initiative related to this study is derived from the fact that systemic lupus erythematosus (SLE) is a unique and fertile system science subject. We are, however, still far from understanding its nature. It may be fair to indicate that we are spending more time and resources on studying the complexity of classified SLE than studying the validity of classification criteria. This study represents a theoretical analysis of current instinctual SLE classification criteria based on "the causality principle." The discussion has its basis on the radical scientific traditions introduced by Robert Koch and Louis Pasteur. They announced significant changes in our thinking of disease etiology through the implementation of the modern version of "the causality principle." They influenced all aspects of today's medical concepts and research: the transformation of medical science from studies of symptoms to study their causes, relevant for monosymptomatic diseases as for syndromes. Their studies focused on bacteria as causes of infectious diseases and on how the immune system adapts to control and prevent contagious spreading. This is the most significant paradigm shift in the modern history of medicine and resulted in radical changes in our view of the immune system. They described acquired post-infection immunity and active immunization by antigen-specific vaccines. The paradigm "transformation" has a great theoretical impact also on current studies of autoimmune diseases like SLE: symptoms and their cause(s). In this study, the evolution of SLE classification and diagnostic criteria is discussed from "the causality principle" perspective, and if contemporary SLE classification criteria are as useful as believed today for SLE research. This skepticism is based on the fact that classification criteria are not selected based on cogent causal strategies. The SLE classification criteria do not harmonize with Koch's and Pasteur's causality principle paradigms and not with Witebsky's Koch-derived postulates for autoimmune and infectious diseases. It is not established whether the classification criteria can separate SLE as a "one disease entity" from "SLE-like non-SLE disorders"-the latter in terms of SLE imitations. This is discussed here in terms of weight, rank, and impact of the classification criteria: Do they all originate from "one basic causal etiology"? Probably not.

  Keywords: anti-dsDNA antibodies; circumstantial evidence; classification criteria; forensic science definitions; hard evidence; lupus nephritis; systemic lupus erythematosus; tentative diagnostic criteria.

  Copyright © 2024 Rekvig.

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• Influence of therapeutic plasma exchange treatment on short-term mortality of critically ill adult patients with sepsis-induced organ dysfunction: a systematic review and meta-analysis

  Forfattere: Vladimir Kuklin, Michael Sovershaev, Johan Bjerner, Philip Keith, L Keith Scott, Owen Matthew Truscott Thomas, Wladimir Szpirt, Gail Rock, Bernd Stegmayr
  Publiseringssted: PubMed
  Les utdrag

  Introduction: The impact of therapeutic plasma exchange (TPE) on short-term mortality in adult patients with sepsis-induced organ dysfunction remains uncertain. The objective of the study is to assess the effect of adjunct TPE in this setting through a comprehensive literature review.

  Methods: The National Library of Medicine's Medline, Ovid (Embase), the Cochrane Library database and clinicaltrial.gov from January 01, 1966, until October 01, 2022, were searched for terms: therapeutic plasma exchange, plasmapheresis, sepsis, and septic shock. We reviewed, selected and extracted data from relevant randomized clinical trials (RCTs) and matched cohort studies (MCSs) comparing short-term mortality in critically ill adult septic patients treated with standard therapy versus those receiving adjunct TPE. Risk of bias was assessed in the RCTs using Cochrane Collaboration tool and in MCSs using ROBINS-I tool. Summary statistics, risk ratios (RRs), and confidence intervals (CIs) were calculated using random effects model.

  Results: This systematic review included 937 adult critically ill septic patients from five RCTs (n = 367) and fifteen MCSs (n = 570). Of these total, 543 received treatment with TPE in addition to standard care. The meta-analysis includes all five RCTs and only six MCSs (n = 627). The adjunct TPE treatment (n = 300) showed a significant reduction in short-term mortality (RR 0.59, 95% CI 0.47-0.74, I2 3%) compared to standard therapy alone (n = 327). The systematic review of all 20 trials revealed that adding TPE to the standard therapy of critically ill septic patients resulted in faster clinical and/or laboratory recovery.

  Conclusions: Our comprehensive and up-to-date review demonstrates that adjunct TPE may provide potential survival benefits when compared to standard care for critically ill adult patients with sepsis-induced organ dysfunction. While results of this meta-analysis are encouraging, large well-designed randomized trials are required to identify the optimal patient population and TPE procedure characteristics prior to widespread adoption into practice.

  © 2024. The Author(s).

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• Performance of automated antimicrobial susceptibility testing for the detection of antimicrobial resistance in gram-negative bacteria: a NordicAST study

  Forfattere: Truls M Leegaard, Ulrik S Justesen, Erika Matuschek, Christian G Giske; NordicAST study group on automated AST
  Publiseringssted: PubMed
  Les utdrag

  Automated testing of antimicrobial susceptibility is common in clinical microbiology laboratories but their ability to detect low-level resistance has been questioned. This Nordic multicentre study aimed to evaluate the performance of commercially available automated AST systems. A phenotypically well-characterised collection of gram-negative bacilli (Escherichia coli (n = 7), Klebsiella pneumoniae (n = 6) and Pseudomonas aeruginosa (n = 7)) with and without resistance mechanisms was examined by Danish (n = 1), Finnish (n = 6), Norwegian (n = 16) and Swedish (n = 5) laboratories. Minimum inhibitory concentrations (MICs) were determined for 12 antimicrobials with automated systems and compared with MICs obtained with gold standard broth microdilution. The automated systems used were VITEK 2 (n = 23), Phoenix (n = 4), MicroScan (n = 1), and ARIS (n = 1). Very major errors were identified for six antimicrobials; cefotaxime (6.9%), meropenem (0.4%), ciprofloxacin (0.7%), ertapenem (4.3%), amikacin (3.4%) and colistin (6.4%). Categorical agreement of MIC for the automated systems compared to broth microdilution ranged from 83% for imipenem to 100% for ampicillin and trimethoprim-sulfamethoxazole. The analysis revealed several important antimicrobials where resistance was underestimated, potentially with significant consequences in patient treatment. The results cast doubt on the use of automated AST in the management of patients with serious infections and suggests that more work is needed to define their limitations.

  Keywords: Automated antimicrobial susceptibility testing; EUCAST; NordicAST; carbapenems; cephalosporins; colistin.

  © 2023 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.

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• Nationwide, population-based observational study of the molecular epidemiology and temporal trend of carbapenemase-producing Enterobacterales in Norway, 2015 to 2021

  Forfattere: Oskar Ljungquist, Bjørg Haldorsen, Anna Kaarina Pöntinen, Jessin Janice, Ellen Haldis Josefsen, Petter Elstrøm, Oliver Kacelnik; Norwegian Study Group on CPE; Arnfinn Sundsfjord, Ørjan Samuelsen; Members of The Norwegian Study Group on CPE
  Publiseringssted: PubMed
  Les utdrag

  IntroductionNational and regional carbapenemase-producing Enterobacterales (CPE) surveillance is essential to understand the burden of antimicrobial resistance, elucidate outbreaks, and develop infection-control or antimicrobial-treatment recommendations.AimThis study aimed to describe CPE and their epidemiology in Norway from 2015 to 2021.MethodsA nationwide, population-based observational study of all verified clinical and carriage CPE isolates submitted to the national reference laboratory was conducted. Isolates were characterised by antimicrobial susceptibility testing, whole genome sequencing (WGS) and basic metadata. Annual CPE incidences were also estimated.ResultsA total of 389 CPE isolates were identified from 332 patients of 63 years median age (range: 0-98). These corresponded to 341 cases, 184 (54%) being male. Between 2015 and 2021, the annual incidence of CPE cases increased from 0.6 to 1.1 per 100,000 person-years. For CPE-isolates with available data on colonisation/infection, 58% (226/389) were associated with colonisation and 38% (149/389) with clinical infections. WGS revealed a predominance of OXA-48-like (51%; 198/389) and NDM (34%; 134/389) carbapenemases in a diversified population of Escherichia coli and Klebsiella pneumoniae, including high-risk clones also detected globally. Most CPE isolates were travel-related (63%; 245/389). Although local outbreaks and healthcare-associated transmission occurred, no interregional spread was detected. Nevertheless, 18% (70/389) of isolates not directly related to import points towards potentially unidentified transmission routes. A decline in travel-associated cases was observed during the COVID-19 pandemic.ConclusionsThe close-to-doubling of CPE case incidence between 2015 and 2021 was associated with foreign travel and genomic diversity. To limit further transmission and outbreaks, continued screening and monitoring is essential.

  Keywords: Enterobacterales; NDM; OXA-48; carbapenemase; high-risk clones; molecular epidemiology; whole genome sequencing.

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• Baseline Serum Prostate-specific Antigen Value Predicts the Risk of Subsequent Prostate Cancer Death-Results from the Norwegian Prostate Cancer Consortium

  Forfattere: Johan Bjerner , Ola Bratt , Kirsti Aas , Peter C Albertsen , Sophie D Fosså , Rune Kvåle , Hans Lilja , Christoph Müller , Stig Müller , Andreas Stensvold , Owen Thomas , Oluf D Røe , Andrew Vickers , Jochen Walz , Sigrid V Carlsson , Jan Oldenburg
  Publiseringssted: Eur Urol .
  Les utdrag

  Background and objective: Prostate-specific antigen (PSA) levels in midlife are strongly associated with the long-term risk of lethal prostate cancer in cohorts not subject to screening. This is the first study evaluating the association between PSA levels drawn as part of routine medical care in the Norwegian population and prostate cancer incidence and mortality. The objective of the study was to determine the association between midlife PSA levels <4.0 ng/ml, drawn aspart of routine medical care, and long-term risk of prostate cancer death.

  Methods: The Norwegian Prostate Cancer Consortium collected >8 million PSA results from >1 million Norwegian males (more than or equal to) 40 yr of age. We studied 176 099 men (predefined age strata: 40-54 and 55-69 yr) without a prior prostate cancer diagnosis who had a nonelevated baseline PSA level (<4.0 ng/ml) between January 1,1995 and December 31, 2005. We assessed the 16-yr risk of prostate cancer mortality. We calculated the discrimination (C-index) between predefined PSA strata (<0.5, 0.5-0.9, 1.0-1.9, 2.0-2.9, and 3.0-3.9 ng/ml) and subsequent prostate cancer death. Survival curves were plotted using the Kaplan-Meier method.

  Key findings and limitations: The median follow-up time of men who did not get prostate cancer was 17.9 yr. Overall, 84% of men had a baseline PSA level of <2.0 ng/ml and 1346 men died from prostate cancer, with 712 deaths (53%) occurring in the 16% of men with the highest baseline PSA of 2.0-3.9 ng/ml. Baseline PSA levels were associated with prostate cancer mortality (C-index 0.72 for both age groups, 40-54 and 55-69 yr). The fact that the reason for any given PSA measurement remains unknown represents a limitation.

  Conclusions and clinical implications: We replicated prior studies that baseline PSA at age 40-69 yr can be used to stratify a man's risk of dying from prostate cancer within the next 15-20 yr.

  Patient summary: A prostate-specific antigen level obtained as part of routine medical care is strongly associated with a man's risk of dying from prostate cancer in the next two decades.

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• Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults

  Forfattere: Joel Selvakumar, MD; Lise Beier Havdal, MD; Martin Drevvatne, MD; Elias Myrstad Brodwall, MD; Lise Lund Berven, PhD; Tonje Stiansen-Sonerud, MSc; Gunnar Einvik, MD, PhD; Truls Michael Leegaard, MD, PhD; Trygve Tjade, MD; Annika E. Michelsen, PhD; TomEirik Mollnes, MD, PhD; Fridtjof Lund-Johansen, MD, PhD; Trygve Holmøy, MD, PhD; Henrik Zetterberg, MD, PhD; Kaj Blennow, MD, PhD; Carolina X. Sandler, PhD; Erin Cvejic, PhD; Andrew R. Lloyd,MD, PhD; Vegard Bruun BratholmWyller,MD, PhD
  Publiseringssted: Jama Network Open
  Les utdrag

  IMPORTANCE The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19.

  OBJECTIVES To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors.

  DESIGN, SETTING, AND PARTICIPANTS This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to theWorld Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed.

  EXPOSURES SARS-CoV-2 infection.

  MAIN OUTCOMES AND MEASURES The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95%CIs.

  RESULTS A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5%in the SARS-CoV-2– positive group and 47.1%in the control group (risk difference, 1.5%; 95%CI, −10.2%to 13.1%). SARSCoV- 2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95%CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95%CI, 1.27-1.56). Low physical activity (RR, 0.96; 95%CI, 0.92-1.00) and loneliness (RR, 1.01; 95%CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits.

  CONCLUSIONS AND RELEVANCE The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of theWorld Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

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• CD47 and CD68 expression in breast cancer is associated with tumor-infiltrating lymphocytes, blood vessel invasion, detection mode, and prognosis

  Forfattere: Ying Chen, Tor Audun Klingen, Hans Aas, Elisabeth Wik og Lars A Akslen
  Publiseringssted: Pathological Society
  Les utdrag

  CD47 expressed on tumor cells binds to signal regulatory protein alpha on macrophages, initiating inhibition of phagocytosis. We investigated the relationships between tumor expression of CD47 and CD68 macrophage content, subsets of tumor-infiltrating lymphocytes (TILs), and vascular invasion in breast cancer. A population-based series of 282 cases (200 screen detected and 82 interval patients) from the Norwegian Breast Cancer Screening Program was examined. Immunohistochemical staining for CD47 and CD68 was evaluated on tissue microarray (TMA) slides. For CD47 evaluation, a staining index was used. CD68 tumor-associated macrophages were counted and dichotomized. TIL subsets (CD45, CD3, CD4, CD8, and FOXP3) were counted and dichotomized using immunohistochemistry on TMA slides. Vascular invasion (both lymphatic and blood vessel) was determined on whole tissue slides. High CD47 tumor cell expression or high counts of CD68 macrophages were significantly associated with elevated levels of all TIL subsets (p < 0.02), CD163 macrophages (p < 0.001), blood vessel invasion (CD31 positive) (p < 0.01), and high tumor cell Ki67 (p < 0.004). High CD47 expression was associated with ER negativity (p < 0.001), HER2 positive status (p = 0.03), and interval-detected tumors (p = 0.03). Combined high expression of CD47–CD68 was associated with a shorter recurrence-free survival (RFS) by multivariate analysis (hazard ratio [HR]: 2.37, p = 0.018), adjusting for tumor diameter, histologic grade, lymph node status, and molecular subtype. Patients with luminal A tumors showed a shorter RFS for CD47–CD68 high cases by multivariate assessment (HR: 5.73, p = 0.004). This study demonstrates an association of concurrent high CD47 tumor cell expression and high CD68 macrophage counts with various TIL subsets, blood vessel invasion (CD31 positive), other aggressive tumor features, and interval-presenting breast cancer. Our findings suggest a link between CD47, tumor immune response, and blood vessel invasion (CD31 positive). Combined high expression of CD47–CD68 was an independent prognostic factor associated with poor prognosis in all cases, as well as in the luminal A category.

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• Falsely low phosphatidylethanol may be associated with biomarkers of haemolytic disease

  Forfattere: Alexander Årving, Thor Hilberg, Michael Sovershaev, Stig Tore Bogstrand, Gudrun Høiseth
  Publiseringssted: Wiley Online Library
  Les utdrag

  Aims

  Falsely lower or even negative phosphatidylethanol (PEth) levels may theoretically be seen in patients with haemolytic diseases, and the present study aimed to elucidate this hypothesis.

  Methods

  PEth and carbohydrate-deficient transferrin (CDT) from 9893 serum and whole blood samples were included along with markers of haemolysis (i.e. haptoglobin, HbA1c, reticulocytes, LD and Hb). Cases showing discrepancy between PEth and CDT, that is, a low PEth value and a high CDT value, were considered to be possibly caused by falsely lowered PEth despite high alcohol consumption. These cases (N = 233) were compared to the control group without PEth and CDT mismatch.

  Results

  The levels of haptoglobin were significantly lower in the cases showing low PEth and high CDT (estimate = −0.62, p = 0.002). The levels of HbA1c (estimate = −3.26, p = 0.001) and Hb (estimate = −0.507, p < 0.001) were also significantly lower in this group. These findings indicate haemolytic diseases in the low PEth/high CDT group. There were no significant differences for reticulocytes and LD concentrations between the low PEth/high CDT group and the control group.

  Conclusions

  These results indicate that falsely low PEth values could be associated with markers of haemolytic diseases, although more research is needed to highlight this further.

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• SLE classification criteria: Science-based icons or algorithmic distractions – an intellectually demanding dilemma

  Forfattere: Ole Petter Rekvig
  Publiseringssted: Frontiers
  Les utdrag

  It is, so to say, not a prerogative authority assigned to SLE classification criteria that allow them to declare something definitively important about SLE. This is particularly true as criteria-based classification processes overrule the highly needed evolution of concise diagnostic criteria. It is classification criteria that allocate SLE patients into cohorts intended to describe the nature of their disease. Therefore, all major SLE classification criteria since the 1971 preliminary criteria usurp the role of diagnostic criteria. Today´s practice silently accept that the SLE classification process “diagnose” SLE patients despite the fact that classification criteria are not accepted as diagnostic criteria! This is a central paradox in contemporary SLE research strategies. Contemporary SLE cohorts are designed to investigate SLE´s etiological features. However, each cohort that is categorized by classification criteria has one central inherent problem. From theoretical and practical arguments, they embody multiple distinct clinical phenotypes. This raises the critical and principal question if phenotypically heterogenic SLE cohorts are useful to identify basic SLE-specific etiology(ies) and disease process(es). In times to come, we must prioritize development of firm diagnostic criteria for SLE, as the classification criteria have not contributed to reduce the enigmatic character of the syndrome. No radical improvements are visible in the horizon that may lead to concise investigations of SLE in well-defined homogenous SLE cohorts. We must develop new strategies where studies of phenotypically standardized cohorts of SLE must be central elements. Problems related to contemporary SLE classification criteria are contemplated, analyzed, and critically discussed in this study.

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• Dental and Periodontal Health in Acute Intermittent Porphyria

  Forfattere: Elin Storjord, Stella Airila-Månsson, Katarzyna Karlsen, Martin Madsen, Jim André Dahl, Anne Landsem, Hilde Fure, Judith Krey Ludviksen, Johannes Østrem Fjøse, Amy K. Dickey, Bård Ove Karlsen, Erik Waage Nielsen, Tom Eirik Mollnes og Ole-Lars Brekke
  Publiseringssted: Life
  Les utdrag

  In the inherited metabolic disorder acute intermittent porphyria (AIP), high sugar intake prevents porphyric attacks due to the glucose effect and the following high insulin levels that may lower AIP disease activity. Insulin resistance is a known risk factor for periodontitis and sugar changes diabetogenic hormones and affects dental health. We hypothesized differences in homeostasis model assessment (HOMA) scores for insulin resistance in AIP cases vs. controls and in those with periodontitis. Our aim was to systematically study dental health in AIP as poor dental health was previously only described in case reports. Further, we aimed to examine if poor dental health and kidney failure might worsen AIP as chronic inflammation and kidney failure might increase disease activity. In 47 AIP cases and 47 matched controls, X-rays and physical examination of clinical attachment loss (CAL), probing pocket depth (PPD), and decayed missing filled teeth (DMFT) were performed. Dietary intake was evaluated through a diet logbook. Plasma cytokines and diabetogenic hormones were measured using multiplex technology and urine porphobilinogen and kidney and liver function by routine methods. An excel spreadsheet from the University of Oxford was used to estimate HOMA scores; beta cell function, HOMA%B (%B), insulin sensitivity, HOMA%S (%S), and insulin resistance HOMA-IR (IR), based on glucose and plasma (P) C-peptide. The Wilcoxon matched-pairs signed rank test, the Mann–Whitney U-test, and Spearman’s non-parametric correlation were used. Insulin (p = 0.007) and C-peptide (p = 0.006) were higher in the AIP cases with periodontitis versus those without. In AIP patients, the liver fibrosis index 4 correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.006); the estimated glomerular filtration rate correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.02). CAL ≥4 mm was correlated with chemokine ligand 11 and interleukin (IL)-13 (p = 0.04 for both), and PPD >5 mm was correlated with plasminogen activator inhibitor-1 (p = 0.003) and complement component 3 (p = 0.02). In conclusion, dental health in AIP cases was correlated with insulin resistance, inflammatory markers, and biomarkers of kidney and liver function, demonstrating that organ damage in the kidney and liver are associated with poorer dental health.

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• Characterization and Fitness Cost of Tn7100, a Novel Integrative and Conjugative Element Conferring Multidrug Resistance in Haemophilus influenzae

  Forfattere: Helene Johannessen, Inger Lill Anthonisen, Nermin Zecic, Kristin Hegstad, Trond Egil Ranheim og Dagfinn Skaare
  Publiseringssted: Frontiers
  Les utdrag

  A multidrug-resistant (MDR) strain of Haemophilus influenzae, Hi-228, with phenotypic resistance toward ampicillin, cefotaxime, chloramphenicol, gentamicin, and azithromycin, was isolated in Oslo, Norway. The strain was part of a clonal outbreak (2016–2017) comprising five ST143 strains with identical resistotypes. Hi-228 carries a novel integrative and conjugative element (ICE), Tn7100, contributing to this remarkable and previously unreported MDR profile. Tn7100 contains the following resistance genes: blaTEM−1B, catA2, aac(6′)-Im, aph(2″)-Ib, mef (E), and mel. The latter four are previously unreported or rarely reported in H. influenzae. In this study, we investigated the genetic environment, mechanisms of transfer, impact on phenotypic susceptibility, and fitness cost of this ICE. We found that Tn7100 has an overall structure similar to the previously described ICE Tn6686, with blaTEM−1B and catA2 carried by Tn3 and Tn10, respectively. The major difference between Tn7100 and Tn6686 is that Tn7100 lacks tet(B) but carries the resistance gene pairs aac(6′)-Im and aph(2″)-Ib and mef (E) and mel. The gene pairs are located on the novel transposable elements Tn7470 and Tn7471, which have high sequence identities to a plasmid in Enterobacterales and an ICE in streptococcal species, respectively. Tn7100 does circularize and is transferable, however, at a low frequency. Head-to-head competition experiments showed that uptake of Tn7100 reduces bacterial fitness. Our study shows that MDR strains are capable of clonal spread and that the H. influenzae supragenome comprises an increasingly wide range of transferable resistance genes, with evidence of transfer from unrelated genera. The findings offer a glimpse into the genome dynamics of H. influenzae, highlighting the importance of rational antibiotic usage to contain antimicrobial resistance and the emergence of MDR strains in this important pathogen.

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• Identification of 121 variants of honey bee Vitellogenin protein sequences with structural differences at functional sites

  Forfattere: Vilde Leipart, Jane Ludvigsen, Matthew Kent, Simen Sandve, Thu-Hien To, Mariann Árnyasi, Claus D. Kreibich, Bjørn Dahle, Gro V. Amdam
  Publiseringssted: Wiley Online Library
  Les utdrag

  Proteins are under selection to maintain central functions and to accommodate needs that arise in ever-changing environments. The positive selection and neutral drift that preserve functions result in a diversity of protein variants. The amount of diversity differs between proteins: multifunctional or disease-related proteins tend to have fewer variants than proteins involved in some aspects of immunity. Our work focuses on the extensively studied protein Vitellogenin (Vg), which in honey bees (Apis mellifera) is multifunctional and highly expressed and plays roles in immunity. Yet, almost nothing is known about the natural variation in the coding sequences of this protein or how amino acid-altering variants might impact structure–function relationships. Here, we map out allelic variation in honey bee Vg using biological samples from 15 countries. The successful barcoded amplicon Nanopore sequencing of 543 bees revealed 121 protein variants, indicating a high level of diversity in Vg. We find that the distribution of non-synonymous single nucleotide polymorphisms (nsSNPs) differs between protein regions with different functions; domains involved in DNA and protein–protein interactions contain fewer nsSNPs than the protein's lipid binding cavities. We outline how the central functions of the protein can be maintained in different variants and how the variation pattern may inform about selection from pathogens and nutrition.

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• Point-of-care testing in primary healthcare: a scoring system to determine the frequency of performing internal quality control

  Forfattere: Gro Gidske, Sverre Sandberg, Anne L. Fossum, Stein Binder, Eva C. Langsjøen, Anne E. Solsvik and Anne Stavelin
  Publiseringssted: De Gruyter
  Les utdrag

  Objectives

  Internal quality control (IQC) plays an important role in quality assurance in laboratory medicine. However, there is no universal consensus or guideline on when and how IQC should be analyzed on point-of-care testing (POCT) devices. The aim of this study was to develop a scoring system to determine how often IQC should be analyzed in primary healthcare on the various POCT devices.

  Methods

  Based on a systematic literature review and a thorough process involving the whole Noklus, a nationwide POC organization, a scoring system for when to analyze IQC was developed. Four factors were considered to significantly impact IQC frequency: The importance of the analyte in diagnosing and monitoring patients, type of POCT device, user-friendliness, and number of patient samples. For each POCT device, the first three factors were given a score, and the sum of the scores determined the general recommended IQC frequency. The number of patient samples determined whether and how to adjust these frequencies in each individual general practice.

  Results

  The scoring system was applied to 17 analytes and 134 different POCT devices (153 analyte-device combinations). Most of the devices analyzing high-risk analytes (71 out of 74) obtained daily or weekly IQC frequency. For example, all blood-cell counters and all glucose meters should undergo IQC daily and weekly, respectively.

  Conclusions

  This study presents a consensus-based scoring system for differentiated and device-specific recommendations for IQC frequency on POCT devices in primary healthcare. The scoring system can easily be adopted to other local environments and is easy to use.

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• Inflammatory Markers, Pulmonary Function, and Clinical Symptoms in Acute COVID-19 Among Non-Hospitalized Adolescents and Young Adults

  Forfattere: Lise Lund Berven, Joel Selvakumar, Lise Havdal, Tonje Stiansen-Sonerud, Gunnar Einvik, Truls Michael Leegaard, Trygve Tjade, Annika E. Michelsen, Tom Eirik Mollnes and Vegard Bruun Bratholm Wyller
  Publiseringssted: Frontiers in Immunology
  Les utdrag

  •  

  Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers.

  Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 – 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group.

  Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively.

  Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1β, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers.

  Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

  
  

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• NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype

  Forfattere: Tom Rune Karlsen, Xiang Yi Kong, Sverre Holm, Ana Quiles-Jiménez, Tuva B Dahl, Kuan Yang, Ellen L Sagen, Tonje Skarpengland, Jonas D S Øgaard, Kristian Holm, Beate Vestad, Maria B Olsen, Pål Aukrust, Magnar Bjørås, Johannes R Hov, Bente Halvorsen, Ida Gregersen
  Publiseringssted: PubMed
  Les utdrag

  Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe-/- mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe-/-Neil3-/- mice and Apoe-/- mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe-/-Neil3-/- mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.

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• The alcohol marker phosphatidylethanol is closely related to AST, GGT, ferritin and HDL-C

  Forfattere: Gudrun Høiseth, Thor Hilberg, Torleif Trydal, Asgeir Husa, Vigdis Vindenes, Stig Tore Bogstrand
  Publiseringssted: BCPT
  Les utdrag

  Background: The aim of this study was to evaluate the quantitative relation between common clinical chemical analyses and ethanol use, measured by a combination of the two alcohol markers phosphatidylethanol (PEth) and carbohydrate-deficient transferrin (CDT).

  Methods: Results of PEth and CDT in whole blood and serum, respectively, were included, together with information on ten different commonly measured clinical chemical analytes, as well as age and sex. PEth was analysed by UPC2 -MS/MS and CDT was measured by capillary electrophoresis.

  Results: Samples from 4 873 patients were included. The strongest relation to alcohol consumption as measured by PEth, when correcting for age and sex, was found for HDL-C (standardized β=0.472, p<0.001), AST (standardized β=0.372, p<0.001), ferritin (standardized β=0.332, p<0.001) and GGT (standardized β=0.325, p<0.001). The relation to PEth was weak for total cholesterol, TG and ALP. No relation was found for Hb and LDL-C.

  Conclusions: When using PEth as a marker for alcohol consumption, this study demonstrated the quantitative relation to commonly used test as AST or GGT, but also an important relation to ferritin or HDL-C. In clinical practice, elevated levels of these clinical chemical analytes should initiate further work-up on possibly harmful alcohol use.

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• Synergistic Antifungal Activity of Chito-Oligosaccharides and Commercial Antifungals on Biofilms of Clinical Candida Isolates

  Forfattere: Monica Ganan, Silje B Lorentzen, Peter Gaustad, Morten Sørlie
  Publiseringssted: J. Fungi
  Les utdrag

  The development of yeast biofilms is a major problem due to their increased antifungal resistance, which leads to persistent infections with severe clinical implications. The high antifungal activity of well-characterized chitosan polymers makes them potential alternatives for treating yeast biofilms. The activity of a chito-oligosaccharide with a depolymerization degree (DPn) of 32 (C32) and a fraction of acetylation (FA) of 0.15 on Candida sp. biofilms was studied. The results showed a concentration-dependent reduction in the number of viable cells present in C. albicans, C. glabrata, and C. guillermondii preformed biofilms in the presence of C32, especially on intermediate and mature biofilms. A significant decrease in the metabolic activity of yeast biofilms treated with C32 was also observed. The antifungals fluconazole (Flu) and miconazole (Mcz) decreased the number of viable cells in preformed early biofilms, but not in the intermediate or mature biofilms. Contrary to Flu or Mcz, C32 also reduced the formation of new biofilms. Interestingly, a synergistic effect on yeast biofilm was observed when C32 and Flu/Mcz were used in combination. C32 has the potential to become an alternative therapeutic agent against Candida biofilms alone or in combination with antifungal drugs and this will reduce the use of antifungals and decrease antifungal resistance.

  Keywords: Candida; antifungal; biofilm; chito-oligosaccharides; chitosan; yeast.

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• Rapid diagnosis and reduced workload for urinary tract infection using flowcytometry combined with direct antibiotic susceptibility testing

  Forfattere: Hanne Margrethe Gilboe, Olaug Marie Reiakvam, Linda Aasen, Trygve Tjade, Johan Bjerner, Trond Egil Ranheim, Peter Gaustad
  Publiseringssted: PLOS ONE
  Les utdrag

  Background

  We evaluated if flowcytometry, using Sysmex UF-5000, could improve diagnosis of urinary tract infections by rapid identification of culture negative and contaminated samples prior to culture plating, thus reducing culture plating workload and response time. We also evaluated if it is possible to reduce the response time for antibiotic susceptibility profiles using the bacteria information flag on Sysmex UF-5000 to differentiate between Gram positive and negative bacteria, followed by direct Antibiotic Susceptibility Testing (dAST) on the positive urine samples.

  Methods

  One thousand urine samples were analyzed for bacteria, white blood cells and squamous cells by flowcytometry before culture plating. Results from flowcytometric analysis at different cut-off values were compared to results of culture plating. We evaluated dAST on 100 urine samples that were analyzed as positive by flowcytometry, containing either Gram positive or Gram negative bacteria.

  Results

  Using a cut-off value with bacterial count ≥100.000/mL and WBCs ≥10/μL, flowcytometry predicted 42,1% of samples with non-significant growth. We found that most contaminated samples contain few squamous cells. For 52/56 positive samples containing Gram negative bacteria dAST was identical to routine testing. Overall, there was concordance in 555/560 tested antibiotic combinations.

  Conclusion

  Flowcytometry offers advantages for diagnosis of urinary tract infections. Screening for negative urine samples on the day of arrival reduces culture plating and workload, and results in shorter response time for the negative samples. The bacteria information flag predicts positive samples containing Gram negative bacteria for dAST with high accuracy, thus Antibiotic Susceptibility Profile can be reported the day after arrival. For the positive samples containing Gram negative bacteria the concordance was very good between dAST and Antibiotic Susceptibility Testing in routine. For positive samples containing Gram positive bacteria the results were not convincing. We did not find any correlation between epithelial cells and contamination.

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• Tumor-associated lymphocytes and macrophages are related to stromal elastosis and vascular invasion in breast cancer

  Forfattere: Ying Chen, Tor Audun Klingen, Hans Aas, Elisabeth Wik, Lars A Akslen
  Publiseringssted: Pathological Society
  Les utdrag

  The tumor microenvironment plays a critical role in breast cancer progression. Here, we investigated tumor-infiltrating lymphocytes (TILs) and associations with macrophage numbers, tumor stromal elastosis, vascular invasion, and tumor detection mode. We performed a population-based retrospective study using data from The Norwegian Breast Cancer Screening Program in Vestfold County (2004–2009), including 200 screen-detected and 82 interval cancers. The number of TILs (CD45+, CD3+, CD4+, CD8+, and FOXP3+) and tumor-associated macrophages (CD163+) was counted using immunohistochemistry on tissue microarray slides. Lymphatic and blood vessel invasion (LVI and BVI) were recorded using D2-40 and CD31 staining, and the amount of elastosis (high/low) was determined on regular HE-stained slides. High numbers of all TIL subsets were associated with LVI (p ≤ 0.04 for all), and high counts of several TIL subgroups (CD8+, CD45+, and FOXP3+) were associated with BVI (p ≤ 0.04 for all). Increased levels of all TIL subsets, except CD4+, were associated with estrogen receptor-negative tumors (p < 0.001) and high tumor cell proliferation by Ki67 (p < 0.001). Furthermore, high levels of all TIL subsets were associated with high macrophage counts (p < 0.001) and low-grade stromal elastosis (p ≤ 0.02). High counts of CD3+, CD8+, and FOXP3+ TILs were associated with interval detected tumors (p ≤ 0.04 for all). Finally, in the luminal A subgroup, high levels of CD3+ and FOXP3+ TILs were associated with shorter recurrence-free survival, and high counts of FOXP3+ were linked to reduced breast cancer-specific survival. In conclusion, higher levels of different TIL subsets were associated with stromal features such as high macrophage counts (CD163+), presence of vascular invasion, absence of stromal elastosis, as well as increased tumor cell proliferation and interval detection mode. Our findings support a link between immune cells and vascular invasion in more aggressive breast cancer. Notably, presence of TIL subsets showed prognostic value within the luminal A category.

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• Fibulin-2 expression associates with vascular invasion and patient survival in breast cancer

  Forfattere: Tor A. Klingen, Ying Chen ,Hans Aas ,Elisabeth Wik ,Lars A. Akslen
  Publiseringssted: PLOS ONE
  Les utdrag

  Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004–2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1–3) and dichotomized as high expression (grade 2–3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0–2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.

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• Prevalence and Determinants of Fatigue after COVID-19 in Non-Hospitalized Subjects: A Population-Based Study

  Forfattere: Knut Stavem, Waleed Ghanima, Magnus K. Olsen, Hanne M. Gilboe og Gunnar Einvik
  Publiseringssted: International Journal of Environmental Research and Public Health
  Les utdrag

  This study assessed the prevalence and determinants of fatigue in a population-based cohort of non-hospitalized subjects 1.5–6 months after COVID-19. It was a mixed postal/web survey of all non-hospitalized patients ≥18 years with a positive PCR for SARS-CoV-2 until 1 June 2020 in a geographically defined area. In total, 938 subjects received a questionnaire including the Chalder fatigue scale (CFQ-11) and the energy/fatigue scale of the RAND-36 questionnaire. We estimated z scores for comparison with general population norms. Determinants were analyzed using multivariable logistic and linear regression analysis. In total, 458 subjects (49%) responded to the survey at median 117.5 days after COVID-19 onset, and 46% reported fatigue. The mean z scores of the CFQ-11 total was 0.70 (95% CI 0.58 to 0.82), CFQ-11 physical 0.66 (0.55 to 0.78), CFQ-11 mental 0.47 (0.35 to 0.59) and RAND-36 energy/fatigue −0.20 (−0.31 to −0.1); all CFQ-11 scores differed from those of the norm population (p < 0.001). Female sex, single/divorced/widowed, short time since symptom debut, high symptom load, and confusion during acute COVID-19 were associated with higher multivariable odds of fatigue. In conclusion, the burden of post-viral fatigue following COVID-19 was high, and higher than in a general norm population. Symptoms of fatigue were most prevalent among women, those having a high symptom load, or confusion during the acute phase.

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• Persistent symptoms 1.5–6 months after COVID-19 in non-hospitalised subjects: a population-based cohort study

  Forfattere: Knut Stavem, Waleed Ghanima, Magnus Kringstad Olsen, Hanne Margrethe Gilboe, Gunnar Einvik
  Publiseringssted: BMJ Journals
  Les utdrag

  This study assessed symptoms and their determinants 1.5–6 months after symptom onset in non-hospitalised subjects with confirmed COVID-19 until 1 June 2020, in a geographically defined area. We invited 938 subjects; 451 (48%) responded. They reported less symptoms after 1.5–6 months than during COVID-19; median (IQR) 0 (0–2) versus 8 (6–11), respectively (p<0.001); 53% of women and 67% of men were symptom free, while 16% reported dyspnoea, 12% loss/disturbance of smell, and 10% loss/disturbance of taste. In multivariable analysis, having persistent symptoms was associated with the number of comorbidities and number of symptoms during the acute COVID-19 phase.

  http://creativecommons.org/licenses/by-nc/4.0/

  This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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• Medisinsk mikrobiologi og infeksjonssykdommer

  Forfattere: Trygve Tjade
  Publiseringssted: Fagbokforlaget 5. utgave
  Les utdrag

  Vi har gode metoder for å forebygge, påvise og behandle infeksjonssykdommer. Likevel er disse sykdommene et stort helseproblem; de er svært vanlige, og de er smittsomme. I 4. utgave av Medisinsk mikrobiologi og infeksjonssykdommer blir kunnskap om infeksjonssykdommer knyttet til mikroorganismene som forårsaker dem.

  Medisinsk mikrobiologi og infeksjonssykdommer er egnet for studenter og yrkesaktive innenfor alle helseprofesjonene.

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• Comparison of the Diagnostic Value of Phosphatidylethanol and Carbohydrate-Deficient Transferrin as Biomarkers of Alcohol Consumption

  Forfattere: Alexander Arving, Gudrun Høiseth, Thor Hilberg, Torleif Trydal, Asgeir Husa, Aleksandar Djordjevic, Saranda Kabashi, Vigdis Vindenes and Stig Tore Bogstrand
  Les utdrag

  Background

  The aim of this study was to compare the results of Phosphatidylethanol (PEth) and carbohydrate‐deficient transferrin (CDT) in blood as biomarkers of alcohol consumption in a large clinical cohort and to evaluate concentrations in relation to age and sex.

  Methods

  Results of PEth 16:0/18:1 in blood and CDT in serum were included, together with information of age and sex, which were extracted from a clinical chemistry database containing samples mostly from patients of primary care physicians and social care institutions. PEth concentrations were determined using Ultra Performance Convergence chromatography mass spectrometer. CDT was quantified by electrophoretic Capillary System. CDT values ≥ 1.7 %‐units and PEth values ≥ 0.31 µmol/L were considered to indicate heavy alcohol consumption.

  Results

  Samples from 6705 patients were included. The median age was 54.5 years, and 34 % were females. Only 47 % of the patients with PEth ≥ 0.31 µmol/L had increased CDT ≥ 1.7 %‐units examined in the same specimen (Cohen’s kappa was 0.43, p < 0.001). Patients above 50 years had significantly higher concentrations for both CDT (1.0 %‐units vs. 0.9 %‐units, p < 0.001) and PEth (0.340 µmol/L vs. 0.200 µmol/L, p < 0.001) compared with younger patients. Concentrations of CDT were significantly higher in males compared with females (p = 0.002), while no significant sex differences were seen for PEth (p = 0.465).

  Conclusions

  A high fraction of the patients had PEth values above the suggested cutoff for heavy drinking and normal CDT values, verifying the superior sensitivity of PEth compared with CDT. The effect of age seems to be minor for both markers. Higher concentrations of CDT, but not PEth, were seen in males, indicating that PEth, as opposed to CDT, might be formed equally in men and women. Therefore, the bias due to sex is possibly present only for CDT, not for PEth.

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• Invasive pulmonary aspergillosis treatment duration in haematology patients in Europe: An EFISG, IDWP-EBMT, EORTC-IDG and SEIFEM survey

  Forfattere: Lanternier F, Seidel D, Pagano L, Styczynski J, Mikulska M, Pulcini C, Maertens J, Munoz P, Garcia-Vidal C, Rijnders B, Arendrup MC, Sabino R, Verissimo C, Gaustad P, Klimko N, Arikan-Akdagli S, Arsic V, Barac A, Skiada A, Klingspor L, Herbrecht R, Donnelly P, Cornely OA, Lass-Flörl C, Lortholary O.Lanternier F, et al.
  Publiseringssted: Mycoses
  Les utdrag

  Invasive pulmonary aspergillosis (IPA) optimal duration of antifungal treatment is not known. In a joint effort, four international scientific societies/groups performed a survey to capture current practices in European haematology centres regarding management of IPA. We conducted a cross-sectional internet-based questionnaire survey in 2017 to assess practices in sixteen European countries concerning IPA management in haematology patients including tools to evaluate treatment response, duration and discontinuation. The following four groups/societies were involved in the project: European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG), Infectious Diseases Working Party-European Society for Blood and Bone Marrow Transplantation (IDWP-EBMT), European Organisation for Research and Treatment-Infectious Disease group (EORTC-IDG) and Sorveglianza Epidemiologica Infezioni nelle Emopatie (SEIFEM). A total of 112 physicians from 14/16 countries answered the survey. Galactomannan antigen was available in serum and bronchoalveolar lavage in most centres (106/112 [95%] and 97/112 [87%], respectively), quantitative Aspergillus PCR in 27/112 (24%) centres, β-D-glucan in 24/112 (21%) and positron emission tomography in 50/112 (45%). Treatment duration differed between haematological malignancies, with a median duration of 6 weeks [IQR 3-12] for patients with AML, 11 [4-12] for patients with allogenic stem cell transplantation and GvHD and 6 [3-12] for patients with lymphoproliferative disease. Treatment duration significantly differed according to country. Essential IPA biomarkers are not available in all European countries, and treatment duration is highly variable according to country. It will be important to provide guidelines to help with IPA treatment cessation with algorithms according to biomarker availability.

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• The Eurasian lactase persistence variant LCT-13910 C/T is associated with vitamin D levels in individuals living at high latitude, more so than exposure to sunlight

  Forfattere: Amir Moghaddam
  Publiseringssted: J Nutr Sci
  Les utdrag

  Rapid selection of a genetic variant that confers continuous life-long lactase production in Europeans (LCT-13910 C/T) has been attributed to the advantages of acquiring nutrients from consuming milk without the disadvantages of lactose malabsorption. Individuals with this genetic lactase persistence (LP) variant generally consume more milk and have been shown to have higher levels of serum vitamin D. Vitamin D is the principal regulator of Ca absorption and its synthesis in skin is dependent on UVB exposure. The primary aim of the present study was to compare serum vitamin D concentrations with LP variant and to control for UVB exposure. Data from over 100 000 individuals living in Norway, a country with low UVB exposure, was retrospectively retrieved for comparison of genetic LP variant, serum 25-hydroxyvitamin D (25(OH)D) concentration and the time of year when serum samples were taken. For comparison, a similar analysis was performed with a natural dairy micronutrient, namely vitamin B12. It was found that individuals with the genetic LP variant had considerably higher levels of serum 25(OH)D (P < 2 × 10-16, Cohen's d = 0·73) but lower levels of vitamin B12 (P < 2 × 10-16, Cohen's d = 0·11), compared with genetic lactase non-persistent individuals, even when controlled for seasonality, age and sex. The difference in serum 25(OH)D levels did not diminish in summer months, showing the role of vitamin D in LP variant selection in areas of low UVB irradiation. LP variant selection advantage through acquiring another dairy micronutrient, vitamin B12, was not observed.

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• Harmful alcohol use among acutely ill hospitalized medical patients in Oslo and Moscow: A cross-sectional study

  Forfattere: S Kabashi, V Vindenes, E A Bryun, E A Koshkina, A V Nadezhdin, E J Tetenova, A J Kolgashkin, A E Petukhov, S N Perekhodov, E N Davydova, D Gamboa, T Hilberg, A Lerdal, G Nordby, C Zhang, S T Bogstrand
  Publiseringssted: Drug and Alcohol Dependence
  Les utdrag

  Background: The aim was to estimate the prevalence of harmful alcohol use in relation to socio-demographic characteristics among acutely ill medical patients, and examine identification measures of alcohol use, including the alcohol biomarker phosphatidylethanol 16:0/18:1 (PEth).

  Methods: A cross-sectional study, lasting one year at one hospital in Oslo, Norway and one in Moscow, Russia recruiting acute medically ill patients (≥ 18 years), able to give informed consent. Self-reported data on socio-demographics, mental distress (Symptom Check List-5), alcohol use (Alcohol Use Disorder Identification Test-4 (AUDIT-4) and alcohol consumption past 24 h were collected. PEth and alcohol concentration were measured in whole blood.

  Results: Of 5883 participating patients, 19.2% in Moscow and 21.1% in Oslo were harmful alcohol users, measured by AUDIT-4, while the prevalence of PEth-positive patients was lower: 11.4% in Oslo, 14.3% in Moscow. Men in Moscow were more likely to be harmful users by AUDIT-4 and PEth compared to men in Oslo, except of those being ≥ 71 years. Women in Oslo were more likely to be harmful users compared to those in Moscow by AUDIT-4, but not by PEth for those aged < 61 years.

  Conclusions: The prevalence of harmful alcohol use was high at both study sites. The prevalence of harmful alcohol use was lower when assessed by PEth compared to AUDIT-4. Thus, self-reporting was the most sensitive measure in revealing harmful alcohol use among all groups except for women in Moscow. Hence, screening and identification with objective biomarkers and self-reporting might be a method for early intervention.

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• The relationship between IFNL4 genotype and the rate of fibrosis in hepatitis C patients

  Forfattere: Rachna Shridhar Gulati, Thakshani Wimalanathan, Solveig Norheim Andersen, Kjetil Isaksen, Martin Lagging, Håvard Midgard, Amir Moghaddam og Olav Dalgard
  Publiseringssted: Multicenter Study Scand J Gastroenterol
  Les utdrag

  Introduction: IFNL4 rs12979860 genotype CC is associated with increased ALT activity and liver stiffness in hepatitis C virus (HCV) genotype (G) 3 infection but not in G1. The primary aim of this study is to assess an interaction between IFNL4 genotype, viral genotype and the stage of liver fibrosis. Secondary aims are to study the potential interactions between IFNL4 genotype, viral genotype and viral load as well as ALT levels. Methods: We performed a cross sectional study of patients with untreated chronic hepatitis C. Inflammation and liver fibrosis were scored using METAVIR. DNA was extracted from serum samples and the rs12979860 was genotyped using a custom made Taqman assay. Results: About 304 consecutive patients with chronic Hepatitis C were included. 52% had G1 infection and 48% had G3. Among patients with G3, advanced fibrosis or cirrhosis (F3F4) was present in 35% of the patients with IFNL4 CC and 28% with CT/TT (p = 0.24). Among patients with G1, F3F4 was present in 20% of the patients with IFNL4 CC and 19% with CT/TT (p = 0.52). IFNL4 CC was associated with higher mean value of normalized (n)ALT both in HCV G1 and G3 infection. Conclusions: IFNL4 genotype was not a predictor of advanced liver fibrosis in G3 or G1 infected patients. IFNL4 CC predicted a higher mean value of ALT among both G1 and G3 infected patients.

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• Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study

  Forfattere: Kristiansen MS, Stabursvik J, O'Leary EC, Pedersen M, Asprusten TT, Leegaard T, Osnes LT, Tjade T, Skovlund E, Godang K, Wyller VBB
  Publiseringssted: Brain, Behavior and Immunity
  Les utdrag

  INTRODUCTION:

  Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

  MATERIALS AND METHODS:

  A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

  RESULTS:

  The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p=0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 x 106cells/L, p=0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p=0.01) and plasma epinephrine (363 vs 237 nmol/L, p=0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p=0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p=0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B= 4.5 x 10-4, p<0.001), urine norepinephrine (B=9.6 x 10-2, p=0.044) and high-frequency power of heart rate variability (B= -3.7 x 10-2, p=0.024).

  CONCLUSIONS:

  In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

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• Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study

  Forfattere: Maria Pedersen, Tarjei Tørre Asprusten, Kristin Godang, Truls Michael Leegaard, Liv Toril Osnes, Eva Skovlund, Trygve Tjade, Merete Glenne Øie, Vegard Bruun Bratholm Wyller
  Publiseringssted: Journal of Psychosomatic Research
  Les utdrag

  Objective

  Acute Epstein-Barr virus (https://www.sciencedirect.com/topics/neuroscience/epstein-barr-virus) (EBV) infection is a known trigger of both acute and chronic fatigue. The aim of this study was to investigate associations to fatigue in adolescents with EBV infection during the initial stage and six months after, as well as in healthy controls.

  Methods

  200 adolescents (12–20 years old) with EBV infection were assessed as soon as possible after the onset of symptoms (EBVbaseline) and six months later (EBVsix months, 5 drop-outs). Also, 70 healthy controls (HC) were included. Associations between current fatigue and 148 different variables (including symptoms, functional abilities and biomarkers) were investigated separately for EBVbaseline, EBVsix monthsand HC using linear regression (https://www.sciencedirect.com/topics/medicine-and-dentistry/linear-regression-analysis) modelling.

  Results

  Fatigue was associated with symptoms of sleeping difficulties, negative emotions, and quality of life under all circumstances. Fatigue was independently associated with markers of immune response at EBVsix months and in HC, not at EBVbaseline. An association between fatigue and markers of autonomic cardiovascular control was only present at EBVsix months. Cognitive functioning (https://www.sciencedirect.com/topics/psychology/cognitive-functioning) shifted from a positive association to fatigue at EBVbaseline to a negative trend at EBVsix months. Markers of infection were not associated with fatigue at EBVbaseline, EBVsix months nor in HC.

  Conclusion

  Irrespective of the cause, fatigue is important for quality of life and is highly associated with negative emotions. Markers of infection and immune response had respectively none and barely any association to fatigue. Autonomic alterations and cognitive dysfunction (https://www.sciencedirect.com/topics/medicine-and-dentistry/cognitive-defect) were exclusively associated with fatigue long after infection, corroborating findings from studies of the Chronic Fatigue Syndrome (https://www.sciencedirect.com/topics/medicine-and-dentistry/chronic-fatigue-syndrome).

  Keywords

  AdolescentsEpstein-Barr virus infectionFatigueChronic fatigue

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• Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: a prospective cohort study

  Forfattere: MariaPedersen, Tarjei Tørre Asprusten, Kristin Godang, Truls Michael Leegaard, Liv Toril Osnes, Eva Skovlund, Trygve Tjade, Merete Glenne Øie, Vegard Bruun Bratholm Wyller
  Publiseringssted: Brain, Behavior, and Immunity
  Les utdrag

  •  

  Introduction

  Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection.

  Materials and methods

  A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. We performed linear regression to assess possible associations between baseline predictors and fatigue (Chalder Fatigue Questionnaire total score) six months after the acute EBV infection. A total of 70 healthy controls were included for cross-sectional reference. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

  Results

  In the final multiple linear regression model, fatigue six months after acute EBV infection was significantly and independently predicted by the following baseline variables (regression coefficient B[95% CI]): Sensory sensitivity (0.8[0.09 to 1.6]), pain severity (0.2[0.02 to 0.3]), functional impairment (1000 steps/day) (-0.3[-0.5 to -0.08]), negative emotions (anxiety) (0.4[0.2 to 0.6]), verbal memory (correct word recognition) (1.7[0.1 to 3.3]), plasma C-reactive protein (2.8[1.1 to 4.4] for CRP values >0.86) and plasma Vitamin B12 (-0.005[-0.01 to -0.001]).

  Conclusions

  Development of fatigue after acute EBV infection is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes.

  
  

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• The Role of Polymorphonuclear Leukocyte Counts from Urethra, Cervix, and Vaginal Wet Mount in Diagnosis of Nongonococcal Lower Genital Tract Infection

  Forfattere: Ivana Randjelovic, Amir Moghaddam, Birgitte Freiesleben de Blasio og Harald Moi
  Publiseringssted: Infect Dis Obstet Gynecol
  Les utdrag

  Objective: The aim of this study was to evaluate whether the polymorphonuclear leukocyte (PMNL) inflammatory response in women with nongonococcal lower genital tract infection (LGTI) can be used to optimize criteria for syndromic treatment.

  Methods: A cross-sectional study of 375 women attending the STI clinic in Oslo. Urethral, cervical, and vaginal specimens underwent microscopy for PMNLs. Chlamydia trachomatis (Ct) and other STIs were detected in the cervical/vaginal swabs and urine, using nucleic acid amplification test (NAAT). After excluding vulvovaginal candidiasis, genital herpes, and trichomoniasis, we correlated clinical and microscopic signs of inflammation with positive NAAT for Ct, mycoplasma genitalium (Mg), and Ureaplasma urealyticum (Uu) in a subgroup of 293 women.

  Results: To predict a positive Ct, the combination of high cut-off urethritis (≥10 PMNLs/HPF) and microscopic cervicitis had a high specificity of 0.93, a PPV of 0.37, and a sensitivity of 0.35. LGTI criteria had low predicting values for Mg and Uu.

  Conclusion: Including microscopic criteria for the diagnosis of LGTI gives better indication for presumptive antibiotic treatment than anamnestic and clinical diagnosis alone.

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• Lactase persistence may explain the paradoxical findings of high vitamin D concentrations in Europeans living in areas of low UV-B irradiation

  Forfattere: Joakim Sorthe, Amir Moghaddam
  Publiseringssted: Eur J Clin Nutr
  Les utdrag

  •  

  Background/objectives: Vitamin D has a critical role in skeletal health and maintaining serum calcium levels. Calcium is needed for a variety of cellular and metabolic processes in the body. Large amounts of vitamin D can be produced in the skin when exposed to UV-B radiation. It is therefore a paradox that in Europe, Caucasians living in higher latitude countries, such as Scandinavia and Iceland, have higher serum vitamin D compared with those living in lower latitude. In a recent study of adult-type lactase persistence (LP), it was shown that Caucasian of European descent, who carried the C-13910T LP allele, had higher levels of total serum 25-hydroxyvitamin D compared with those who were lactase non-persistent. This was attributed to higher consumption of dairy. We postulated that the distribution of the LP C-13910T allele in Caucasian populations may explain the vitamin D concentration pattern seen in Europe.

  Subjects/methods: Baseline mean total serum 25 hydroxyvitamin D concentration from a clinical trial of post-menopausal women with osteoporosis was correlated to published LP frequencies in European populations.

  Results: In multiple regression analysis, mean total serum 25 hydroxyvitamin D concentrations in both winter and summer were in turn correlated to LP phenotype frequency (winter: r2 = 0.51, p < 0.05; summer: r2 = 0.4, p < 0.05).

  Conclusions: High frequency of LP in northern Europe may explain high mean total serum 25 hydroxyvitamin D concentrations despite low UV-B radiation exposure.

  
  

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• Lowered reference limits for hCG improve follow-up of patients with hCG-producing tumors.

  Forfattere: Nome RV, Bjøro T, Paus E, Bjerner J, Fosså SD, Steen R, Nustad K, Bolstad N.
  Publiseringssted: Clinical Biochemistry
  Les utdrag

  BACKGROUND:

  Human Chorionic Gonadotropin (hCG) is produced by germ cell tumors, but can also be elevated in benign conditions such as primary hypogonadism, where hCG is produced by the pituitary gland. In our experience, the reference limits for hCG (Elecsys hCG+β-assay, Roche Diagnostics), were unnecessarily high and did not reflect levels encountered in clinical practice. We wanted to establish new reference limits to increase the clinical utility of the hCG-assay.

  METHODS:

  We analysed hCG in serum samples from a healthy adult population and in a cohort of testicular cancer survivors. The gonadotropins LH and FSH were measured in the cohort and in a selection of the reference population to assess gonadal function.

  RESULTS:

  We found low hCG levels for all men and women <45years (97.5 percentiles 0.1 and 0.2IU/L, respectively) from the healthy population (n=795) having normal FSH and LH. Due to assay limitations, we suggest a common reference limit of <0.3IU/L. For the age group ≥45, the 97.5 percentiles in the healthy population were 0.5IU/L for men and 6.0IU/L for women. In all subjects from both the reference population and the cohort (n=732), hCG levels exceeding the reference limit could be fully explained by reduced gonadal function indicated by elevated LH and FSH levels.

  CONCLUSION:

  The Elecsys hCG+β-assay should have lower reference limits than recommended by the manufacturer, with important implications for tumor follow-up. Elevated hCG is rare with intact gonadal function, both in a normal population and among survivors of testicular cancer, and should lead to further investigations when encountered in clinical practice.

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• erm gene distribution among Norwegian Bacteroides isolates and evaluation of phenotypic tests to detect inducible clindamycin resistance in Bacteroides species.

  Forfattere: Johnsen BO, Handal N, Meisal R, Bjørnholt JV, Gaustad P, Leegaard TM.
  Publiseringssted: Anaerobe
  Les utdrag

  • The aims of this study were to describe the distribution of the most common erm genes in a collection of Norwegian Bacteroides isolates and to investigate whether the phenotypic tests for determining inducible clindamycin resistance among Bacteroides species recommended by EUCAST, NordicAST and the manufacturer of E-test®, are effective. We investigated 175 unique Bacteroides isolates for the presence of erm(B), erm(F) and erm(G) genes, determined their minimum inhibitory concentrations (MICs) to clindamycin and categorised their susceptibility according to EUCAST breakpoints. 27 isolates were resistant to clindamycin. Furthermore, we investigated whether these recommended methods could detect inducible resistance in the Bacteroides isolates: 1) EUCAST recommendation: Dissociated resistance to erythromycin (clindamycin susceptible with erythromycin MIC > 32 mg/L), 2) NordicAST recommendation: Double disk diffusion test (DDD) or 3) Manufacturer of E-test®'s recommendation: prolonged incubation of clindamycin E-test® for 48 h. erm genes were detected in 30 (17%, 95% CI 12%-23%) of 175 Bacteroides isolates with erm(F) as the dominating gene. There were six (4%, 95% CI 1%-7%) of 148 clindamycin susceptible isolates harbouring erm genes, they were considered inducibly resistant to clindamycin. None of the methods for phenotypic detection of inducible clindamycin resistance performed satisfactory with sensitivities of 33%, 17% and 0% and specificities of 90%, 99% and 97% for dissociated resistance, DDD and prolonged incubation of clindamycin E-test®, respectively. In our view, the scientific basis for investigating every Bacteroides isolate for inducible resistance to clindamycin is weak. Molecular detection of erm genes may prove a better option than the phenotypic methods we evaluated.

  
  

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• Incidental findings of monoclonal proteins from carbohydrate-deficient transferrin analysis using capillary electrophoresis.

  Forfattere: Oppen K, Bjerner J, Buchmann M, Piehler AP
  Publiseringssted: Clin Chem Lab Med.
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• Routine Supercritical Fluid Chromatography Tandem Mass Spectrometry Method for Determination of Vitamin K1 Extracted from Serum with a 96-Well Solid-Phase Extraction Method

  Forfattere: Trude Athammer Sandvik, Asgeir Husa, Marie Buchmann, Elsa Lundanes
  Publiseringssted: The Journal of Applied Laboratory Medicine
  Les utdrag

  Background:

  The concentration of vitamin K1 in serum or plasma is the most common index for assessing vitamin K status. The aim of this study was to develop and validate a rapid and reliable routine method for quantifying vitamin K1 above 0.1 ng/mL. Semi-automation of a simple sample preparation with fast analysis by supercritical fluid chromatography–tandem mass spectrometry (SFC-MS/MS) was exploited.

  Methods:

  Vitamin K1 was extracted from 250-μL serum samples by the use of protein precipitation and reversed-phase solid-phase extraction (SPE) in 96-well plates and quantified by SFC on a 2.1 × 100 mm Torus 1-Aminoanthracene (1-AA) column in 3.8 min with electrospray ionization—tandem mass spectrometry (MS/MS) detection.

  Results:

  This method shows good linearity in the concentration range of 0.1–50 ng/mL with a correlation coefficient of R2 >0.999. Imprecision was satisfactory, with repeatability and reproducibility <10% CV. The lower limit of the measuring interval was 0.1 ng/mL, and no systematic bias was observed for the method, which used vitamin K1-d7 as internal standard. Recovery of vitamin K1 in external quality controls was satisfactory compared to other laboratories participating in the external quality assurance scheme. The method is currently in routine use for analysis of serum samples.

  Conclusions:

  The method allows high-throughput reliable determination of vitamin K1 in serum in the range 0.1–50 ng/mL.

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• Draft Genome Sequences of Candida glabrata Isolates 1A, 1B, 2A, 2B, 3A, and 3B.

  Forfattere: Håvelsrud OE, Gaustad P.
  Publiseringssted: Genome Announc.
  Les utdrag

  Here, we report the draft genome sequences of six Candida glabrata isolates. The isolates were taken from blood samples from patients after recurrent C. glabrata infection. Two isolates were taken from each of three patients a minimum 3 months apart.

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• Microscopy of Stained Urethral Smear in Male Urethritis; Which Cutoff Should be Used?

  Forfattere: Harald Moi, MD, PhD, Usha Hartgill, MD, Kristin Helene Skullerud, MD, Elina J. Reponen, MD, Line Syvertsen, MD, and Amir Moghaddam, PhD
  Publiseringssted: Sexually Transmitted Diseases
  Les utdrag

  Background: The microscopical diagnosis of male urethritis was recentlyquestioned by Rietmeijer and Mettenbrink, lowering the diagnosticcriteria of the diagnosis to ≥2 polymorphonuclear leucocytes (PMNL)per high power field (HPF), and adopted by Centers for Disease Controland Prevention in their 2015 STD Treatment Guidelines. The EuropeanNon-Gonococcal Urethritis Guideline advocates a limit of ≥5 PMNL/HPF.

  Objective: To determine if syndromic treatment of urethritis should beconsidered with a cutoff value of ≥2 PMNL/HPF in urethral smear.

  Methods: The design was a cross-sectional study investigating the presenceand degree of urethritis relative to specific infections in men attendingan STI clinic as drop-in patients.

  Results: The material included 2 cohorts: a retrospective study of 13,295men and a prospective controlled study including 356 men.We observed amean chlamydia prevalence of 2.3% in the 0–9 stratum, and a 12-foldhigher prevalence (27.3%) in the strata above 9. Of the chlamydia cases,89.8% were diagnosed in strata above 9. For Mycoplasma genitalium, theprevalence was 1.4% in the 0–9 stratum and 11.2% in the stratum ≥10,and 83.6% were diagnosed in strata above 9. For gonorrhea, a significantincrease in the prevalence occurred between the 0–30 strata and >30 stratafrom 0.2% to 20.7%. The results of the prospective study were similar.

  Conclusions: Our data do not support lowering the cutoff to ≥2 PMNL/HPF. However, a standardization of urethral smear microscopy seems to beimpossible. The cutoff value should discriminate between low and highprevalence of chlamydia, mycoplasma, and gonorrhea to include as manyas possible with a specific infection in syndromic treatment, withoutovertreating thosewith few PMNL/HPFand high possibility of having nonspecificor no urethritis.

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• Diversity and antifungal susceptibility of Norwegian Candida glabrata clinical isolates

  Forfattere: Andersen KM, Kristoffersen AK, Ingebretsen A, Vikholt KJ, Örtengren UT, Olsen I, Enersen M, Gaustad P.
  Publiseringssted: J Oral Microbiol.
  Les utdrag

  BACKGROUND:

  Increasing numbers of immunocompromised patients have resulted in greater incidence of invasive fungal infections with high mortality. Candida albicans infections dominate, but during the last decade, Candida glabrata has become the second highest cause of candidemia in the United States and Northern Europe. Reliable and early diagnosis, together with appropriate choice of antifungal treatment, is needed to combat these challenging infections.

  OBJECTIVES:

  To confirm the identity of 183 Candida glabrata isolates from different human body sites using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and VITEK(®)2, and to analyze isolate protein profiles and antifungal susceptibility. The minimum inhibitory concentration (MIC) of seven antifungal drugs was determined for the isolates to elucidate susceptibility.

  DESIGN:

  A total of 183 C. glabrata isolates obtained between 2002 and 2012 from Norwegian health-care units were analyzed. For species verification and differentiation, biochemical characterization (VITEK(®)2) and mass spectrometry (MALDI-TOF) were used. MIC determination for seven antifungal drugs was undertaken using E-tests(®).

  RESULTS:

  Using VITEK(®)2, 92.9% of isolates were identified as C. glabrata, while all isolates (100%) were identified as C. glabrata using MALDI-TOF. Variation in protein spectra occurred for all identified C. glabrata isolates. The majority of isolates had low MICs to amphotericin B (≤1 mg/L for 99.5%) and anidulafungin (≤0.06 mg/L for 98.9%). For fluconazole, 18% of isolates had MICs >32 mg/L and 82% had MICs in the range ≥0.016 mg/L to ≤32 mg/L.

  CONCLUSIONS:

  Protein profiles and antifungal susceptibility characteristics of the C. glabrata isolates were diverse. Clustering of protein profiles indicated that many azole resistant isolates were closely related. In most cases, isolates had highest susceptibility to amphotericin B and anidulafungin. The results confirmed previous observations of high MICs to fluconazole and flucytosine. MALDI-TOF was more definitive than VITEK(®)2 for C. glabrata identification.

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• Five-year mortality in patients treated for severe community-acquired pneumonia - a retrospective study.

  Forfattere: Lenz H, Norby GO, Dahl V, Ranheim TE, Haagensen RE.
  Publiseringssted: Acta Anaesthesiol Scand.
  Les utdrag

  BACKGROUND:

  The mortality rate in patients with severe community-acquired pneumonia (SCAP) is high. We investigated the 5-year mortality rate and causes of death in a patient population treated for SCAP in our intensive care unit (ICU), and compared the mortality rate in patients with or without chronic obstructive pulmonary disease (COPD) as comorbidity.

  METHODS:

  This retrospective study, which covers a period of 10 years, included patients aged > 18 years admitted to our ICU with SCAP as primary diagnosis and in need of mechanical ventilation for more than 24 h. Data were collected from the ICU internal database and the patients' medical records. The times of death were collected from the Norwegian National Registry, and the causes of death from the Norwegian Cause of Death Registry.

  RESULTS:

  Hundred and seventy three patients were included in the study. The 5-year mortality rate for the total study population was 57.2%. There were no significant differences in the mortality rate between the group with COPD and the group without COPD (61.2% vs. 54.7%, P = 0.43). There was a wide range of comorbidities. The most common were COPD, myocardial infarction and diabetes mellitus. The two main causes of death after discharge were COPD (17 deaths) and cardiovascular diseases (seven deaths).

  CONCLUSIONS:

  The 5-year mortality rate of the study population was high (57.2%). COPD did not seem to be a risk factor for mortality compared to non-COPD patients. The most common causes of death after discharge were COPD and cardiovascular diseases.

  
  

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• Visceral adiposity and metabolic syndrome after very high-fat and low-fat isocaloric diets: a randomized controlled trial

  Forfattere: Veum VL, Laupsa-Borge J, Eng Ø, Rostrup E, Larsen TH, Nordrehaug JE, Nygård OK, Sagen JV, Gudbrandsen OA, Dankel SN, Mellgren G.
  Publiseringssted: Am J Clin Nutr.
  Les utdrag

  BACKGROUND:

  Different aspects of dietary pattern, including macronutrient and food profiles, may affect visceral fat mass and metabolic syndrome.

  OBJECTIVE:

  We hypothesized that consuming energy primarily from carbohydrate or fat in diets with similar food profiles would differentially affect the ability to reverse visceral adiposity and metabolic syndrome.

  DESIGN:

  Forty-six men (aged 30-50 y) with body mass index (in kg/m2) >29 and waist circumference >98 cm were randomly assigned to a very high-fat, low-carbohydrate (VHFLC; 73% of energy fat and 10% of energy carbohydrate) or low-fat, high-carbohydrate (LFHC; 30% of energy fat and 53% of energy carbohydrate) diet for 12 wk. The diets were equal in energy (8750 kJ/d), protein (17% of energy), and food profile, emphasizing low-processed, lower-glycemic foods. Fat mass was quantified with computed tomography imaging.

  RESULTS:

  Recorded intake of carbohydrate and total and saturated fat in the LFHC and VHFLC groups were 51% and 11% of energy, 29% and 71% of energy, and 12% and 34% of energy, respectively, with no difference in protein and polyunsaturated fatty acids. Mean energy intake decreased by 22% and 14% in the LFHC and VHFLC groups. The diets similarly reduced waist circumference (11-13 cm), abdominal subcutaneous fat mass (1650-1850 cm3), visceral fat mass (1350-1650 cm3), and total body weight (11-12 kg). Both groups improved dyslipidemia, with reduced circulating triglycerides, but showed differential responses in total and low-density lipoprotein cholesterol (decreased in LFHC group only), and high-density lipoprotein cholesterol (increased in VHFLC group only). The groups showed similar reductions in insulin, insulin C-peptide, glycated hemoglobin, and homeostasis model assessment of insulin resistance. Notably, improvements in circulating metabolic markers in the VHFLC group mainly were observed first after 8 wk, in contrast to more acute and gradual effects in the LFHC group.

  CONCLUSIONS:

  Consuming energy primarily as carbohydrate or fat for 3 mo did not differentially influence visceral fat and metabolic syndrome in a low-processed, lower-glycemic dietary context. Our data do not support the idea that dietary fat per se promotes ectopic adiposity and cardiometabolic syndrome in humans. This study was registered at clinicaltrials.gov as NCT01750021 (http://clinicaltrials.gov/show/NCT01750021).

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• Incidental findings of monoclonal proteins from carbohydrate-deficient transferrin analysis using capillary electrophoresis.

  Forfattere: Oppen K, Bjerner J, Buchmann M, Piehler AP.
  Publiseringssted: Clin Chem Lab Med.
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• Nye markører for påvisning av alkoholbruk

  Forfattere: Rachel Aakerøy, Ragnhild Bergene Skråstad, Arne Helland, Thor Hilberg, Trond Aamo, Roar Dyrkorn, Olav Spigset
  Publiseringssted: Tidsskriftet
  Les utdrag

  Alcohol abuse has significant medical, social and socioeconomic consequences. Alcohol biomarkers may serve as a useful tool in identifying individuals with excessive alcohol consumption in medical as well as medico-legal contexts.

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• Urethral inflammatory response to ureaplasma is significantly lower than to Mycoplasma genitalium and Chlamydia trachomatis

  Forfattere: Moi H, Reinton N, Randjelovic I, Reponen EJ, Syvertsen L, Moghaddam A
  Publiseringssted: Int J STD AIDS
  Les utdrag

  A non-syndromic approach to treatment of people with non-gonococcal urethritis (NGU) requires identification of pathogens and understanding of the role of those pathogens in causing disease. The most commonly detected and isolated micro-organisms in the male urethral tract are bacteria belonging to the family of Mycoplasmataceae, in particular Ureaplasma urealyticum and Ureaplasma parvum To better understand the role of these Ureaplasma species in NGU, we have performed a prospective analysis of male patients voluntarily attending a drop in STI clinic in Oslo. Of 362 male patients who were tested for NGU using microscopy of urethral smears, we found the following sexually transmissible micro-organisms: 16% Chlamydia trachomatis, 5% Mycoplasma genitalium, 14% U. urealyticum, 14% U. parvum and 5% Mycoplasma hominis We found a high concordance in detecting in turn U. urealyticum and U. parvum using 16s rRNA gene and ureD gene as targets for nucleic acid amplification testing (NAAT). Whilst there was a strong association between microscopic signs of NGU and C. trachomatis infection, association of M. genitalium and U. urealyticum infections in turn were found only in patients with severe NGU (>30 polymorphonuclear leucocytes, PMNL/high powered fields, HPF). U. parvum was found to colonise a high percentage of patients with no or mild signs of NGU (0-9 PMNL/HPF). We conclude that urethral inflammatory response to ureaplasmas is less severe than to C. trachomatis and M. genitalium in most patients and that testing and treatment of ureaplasma-positive patients should only be considered when other STIs have been ruled out.

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• Incidence and impact on prognosis of peri-procedural myocardial infarction in 2760 elective patients with stable angina pectoris in a historical prospective follow-up study.

  Forfattere: Christensen MK, Huang H, Torp-Pedersen C, Trydal T, Ravkilde J.
  Publiseringssted: BMC Cardiovasc Disord.
  Les utdrag

  BACKGROUND:

  The clinical significance of myocardial infarction related to treatment with percutaneous coronary intervention (PCI) has been subject of great discussion. This subject has been studied for many years using different definitions of peri-procedural myocardial infarction and different biomarkers, the results have varied greatly depending on methods and time of the study. This study was to determine the incidence and prognostic significance of elevated cardiac biomarkers after elective PCI in patients with stable angina pectoris using the current cut-off set by the Third Universal Definition of Myocardial Infarction and current biomarkers.

  METHODS:

  We performed a historical prospective follow-up study of all patients with stable angina pectoris who underwent elective PCI at Aalborg University Hospital, Denmark from January 1(st) 2000 to December 31(st) 2012. We stratified patients according to peak post-PCI troponin T (cTnT) and Creatine Kinase MB mass (CK-MBmass).

  RESULTS:

  Follow-up for time to all-cause mortality was mean 5.8 years and total 15,891 years and mean 3.7 years and total 10,160 years for the combined endpoint of all-cause mortality and new onset heart failure. During the follow up period 399 of 2760 patients died (14.5 %) and 1095 (39.7 %) suffered the combined endpoint. Post-PCI concentration of cTnT and CK-MBmass was elevated above the defined cut-off in 419 patients (15.2 %) and 113 patients (4.1 %) respectively. There was no statistically significant difference between the groups in stratified analysis of the hazard rates by time regarding all-cause mortality for cTnT nor CK-MBmass. Regarding the combined endpoint the results were ambiguous. The results were unchanged in multivariable analyses that included age and gender.

  CONCLUSION:

  The incidence of elevated biomarkers after elective PCI in patients with stable angina pectoris using the defined cut-off (>5 x URL) was 15.2 % using cTnT and 4.1 % using CK-MBmass. The independent prognostic value for both cardiac biomarkers of any cut-off showed no statistical significance for all-cause mortality, whereas the combined endpoint (all-cause mortality or new-onset heart failure) were ambiguous in both short- and long-term follow-up.

  
  

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• Bilirubin isomer distribution in jaundiced neonates during phototherapy with LED light centered at 497 nm (turquoise) vs. 459 nm (blue).

  Forfattere: Ebbesen F, Madsen PH, Vandborg PK, Jakobsen LH, Trydal T, Vreman HJ.
  Publiseringssted: Pediatr Res.
  Les utdrag

  BACKGROUND:

  Phototherapy using blue light is the treatment of choice worldwide for neonatal hyperbilirubinemia. However, treatment with turquoise light may be a desirable alternative. Therefore, the aim of this randomized, controlled study was to compare the bilirubin isomer distribution in serum of jaundiced neonates after 24 h of therapy with narrow-band (LED) light centered at 497 nm (turquoise) vs. 459 nm (blue), of essentially equal irradiance.

  MATERIALS:

  Eighty-three neonates (≥33 wk gestational age) with uncomplicated hyperbilirubinemia were included in the study. Forty neonates were exposed to light centered at 497 nm and 43 infants with light centered at 459 nm. Irradiances were 5.2 × 10(15) and 5.1 × 10(15) photons/cm(2)/s, respectively.

  RESULTS:

  After 24 h of treatment no significant differences in serum concentrations of total bilirubin isomers and Z,Z-bilirubin were observed between the 2 groups. Interestingly, concentrations of Z,E-bilirubin, and thus also total bilirubin isomers formed during therapy, were highest for infants receiving light centered at 459 nm, while the concentration of E,Z-bilirubin was highest for those receiving light centered at 497 nm. No significant difference was found between concentrations of E,Z-lumirubin.

  CONCLUSION:

  Therapy with LED light centered at 497 nm vs. 459 nm, applied with equal irradiance on the infants, resulted in a different distribution of bilirubin isomers in serum.

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• Lean Seafood Intake Reduces Postprandial C-peptide and Lactate Concentrations in Healthy Adults in a Randomized Controlled Trial with a Crossover Design

  Forfattere: Aadland EK, Graff IE, Lavigne C, Eng Ø, Paquette M, Holthe A, Mellgren G, Madsen L, Jacques H, Liaset B.
  Publiseringssted: The Journal of Nutrition
  Les utdrag

  BACKGROUND:

  Recently we showed that lean seafood consumption reduced circulating triacylglycerol (TG) and VLDL concentrations and prevented an elevated total-to-HDL-cholesterol ratio relative to intake of a nonseafood diet.

  OBJECTIVE:

  We aimed to elucidate whether diet-induced altered carbohydrate metabolism could be a contributing factor to the previously observed different lipoprotein patterns.

  METHODS:

  This was a secondary outcome and explorative randomized controlled trial with a crossover design in 20 healthy adults (7 men and 13 women) that were 50.6 ± 3.4 (mean ± SEM) y old, weighed 75.7 ± 2.5 kg, and had a body mass index (BMI, in kg/m(2)) of 25.6 ± 0.7. After a 3-wk run-in period and separated by a 5-wk wash-out period, the participants consumed 2 balanced diets [in percentage of energy (energy%); 29% fat, 52% carbohydrates, 19% protein] for 4 wk. The diets varied in the main protein sources; 60 energy% of total protein was from either lean seafood or nonseafood sources. On the first and last day of each diet period, fasting and postprandial blood samples were collected before and after consumption of test meals (in energy%; 28% fat, 52% carbohydrates, 20% protein) with cod or lean beef.

  RESULTS:

  The diets did not alter serum insulin and glucose concentrations. However, relative to the nonseafood diet period, the lean seafood diet period reduced postprandial C-peptide (P = 0.04) and lactate (P = 0.012) concentrations and fasting and postprandial TG/HDL-cholesterol ratios (P = 0.002). Hence, different postprandial lactate levels occurred at equal glucose concentrations.

  CONCLUSIONS:

  Even though the diets did not alter serum insulin and glucose concentrations, intake of the lean seafood compared with the nonseafood diet reduced postprandial concentrations of C-peptide and lactate and the TG/HDL-cholesterol ratio in healthy adults in a manner that may affect the long-term development of insulin resistance, type 2 diabetes, and cardiovascular disease. This trial was registered at www.clinicaltrials.gov as NCT01708681 (http://clinicaltrials.gov/show/NCT01708681).

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• Serum concentration measurements of addictive drugs

  Forfattere: Arne Helland, Jon Andsnes Berg, Ingebjørg Gustavsen, Kristin Nordal, Thor Hilberg, Lena Aronsen, Marianne Arnestad, Sigrid Narum
  Publiseringssted: Tidsskriftet
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• Lean-seafood intake decreases urinary markers of mitochondrial lipid and energy metabolism in healthy subjects: Metabolomics results from a randomized crossover intervention study

  Forfattere: Schmedes M, Aadland EK, Sundekilde UK, Jacques H, Lavigne C, Graff IE, Eng Ø, Holthe A, Mellgren G, Young JF, Bertram HC, Liaset B, Clausen MR.
  Publiseringssted: Mol Nutr Food Res.
  Les utdrag

  SCOPE:

  Proteins constitute an important part of the human diet, but understanding of the effects of different dietary protein sources on human metabolism is sparse. We aimed to elucidate diet-induced metabolic changes through untargeted urinary metabolomics after four weeks of intervention with lean-seafood or nonseafood diets. It is shown that lean-seafood intake reduces urinary excretion of metabolites involved in mitochondrial lipid and energy metabolism possibly facilitating a higher lipid catabolism in healthy subjects.

  METHODS:

  In a randomized controlled trial with crossover design, 20 healthy subjects consumed two balanced diets that varied in main protein sources for 4 weeks. Morning spot urine samples were collected before and after each intervention period. Untargeted metabolomics based on (1) H NMR spectroscopy and LC-MS analyses were applied to characterize the urinary metabolic response to the interventions.

  RESULTS:

  The lean-seafood diet period reduced the urinary level of l-carnitine, 2,6-dimethylheptanoylcarnitine, and N-methyl-2-pyridone-5-carboxamide, relative to the nonseafood period. The dietary analysis revealed that the higher urinary level of trimethylamine-N-oxide after the lean-seafood diet period and guanidinoacetate and 3-methylhistidine after the nonseafood diet period was related to the endogenous content of these compounds in the diets.

  CONCLUSIONS:

  Our data reveal that 4 weeks of lean-seafood intake reduces urinary excretion of metabolites involved in mitochondrial lipid and energy metabolism possibly facilitating a higher lipid catabolism in healthy subjects after the lean-seafood intake.

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• In vitro element release and biological aspects of base–metal alloys for metal-ceramic applications

  Forfattere: Charlotta Holm, Else Morisbak, Torill Kalfoss og Jon E. Dahl
  Publiseringssted: Acta Biomaterialia Odontologica Scandinavica
  Les utdrag

  Objective: The aims of this study were to investigate the release of element from, and the biological response in vitro to, cobalt–chromium alloys and other base–metal alloys used for the fabrication of metal-ceramic restorations.Material and methods: Eighteen different alloys were investigated. Nine cobalt–chromium alloys, three nickel–chromium alloys, two cobalt–chromium–iron alloys, one palladium–silver alloy, one high-noble gold alloy, titanium grade II and one type III copper–aluminium alloy. Pure copper served as positive control. The specimens were prepared according to the ISO standards for biological and corrosion testing. Passive leaching of elements was measured by using Inductively Coupled Plasma – Mass Spectrometry (ICP-MS) after incubation in cell culture media, MEM, for 3 days. Corrosion testing was carried out in 0.9% sodium chloride (NaCl) and 1% lactic acid for 7 days, and the element release was measured by Inductively Coupled Plasma – Optical Emission Spectroscopy (ICP-OES). The biological response from the extract solutions was measured though MTT cytotoxicity testing and the Hen's egg test-chorio-allantoic membrane (HET-CAM) technique for irritationt.Results: The corrosion test showed similar element release from base-metal alloys compared to noble alloys such as gold. Apart from the high-copper alloy, all alloys expressed low element release in the immersion test, no cytotoxic effect in the MTT test, and were rated non-irritant in the HET-CAM test.Conclusions: Minimal biological response was observed for all the alloys tested, with the exception of the high-copper alloy.
  In vitro element release and biological aspects of base–metal alloys for metal-ceramic applications. Available from: https://www.researchgate.net/publication/282483253_In_vitro_element_release_and_biological_aspects_of_base-metal_alloys_for_metal-ceramic_applications [accessed Feb 22, 2016].

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• Hemophagocytic lymphohistiocytosis in leprosy.

  Forfattere: Høyvoll LR, Fløisand Y, Orrem HL, Gunnarsson R, Landrø L, Brevig T, Gaustad P, Nordøy I.
  Publiseringssted: Lepr Rev.
  Les utdrag

  A patient from Southeast Asia was diagnosed with systemic lupus erythematosus. One year later, she experienced exacerbation of skin lesions and was diagnosed with erythema nodosum leprosum. Upon treatment, the patient developed hemophagocytic lymphohistiocytosis with multi-organ failure and died from invasive fungal infection. Hemophagocytic lymphohistiocytosis has to our knowledge, not previously been reported in leprosy.

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• Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services

  Forfattere: Tormod Karlsen Bjånes, Espen Mjåset Hjertø, Lars Lønne, Lena Aronsen, Jon Andsnes Berg, Stein Bergan, Grim Otto Berg-Hansen, Jean-Paul Bernard, Margrete Larsen Burns, Jan Toralf Fosen, Joachim Frost, Thor Hilberg, Hege-Merete Krabseth, Elena Kvan, Sigrid Narum, Andreas Austgulen Westin
  Publiseringssted: Clinical Therapeutics
  Les utdrag

  Purpose: More than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis.

  Methods: The Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification.

  Findings: All laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway.

  Implications: The database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries.

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• Characteristics of methadone-related fatalities in Norway

  Forfattere: Jean-Paul Bernard, Hassan Z Khiabani, Thor Hilberg, Ritva Karinen, Lars Slørdal, Helge Waal, Jørg Mørland
  Publiseringssted: Journal of Forensic and Legal Medicine
  Les utdrag

  There are currently over 7000 patients enrolled in opioid maintenance treatment (OMT) programs in Norway. A rise in methadone-related deaths proportional to increasing methadone sales over the period 2000-2006 has been observed, but the causative factors for these fatalities have been elusive. In the present study, individual characteristics, methadone concentrations and additional toxicological findings were analyzed. Methadone intoxication deaths (n = 264) were divided into 3 groups according to toxicological findings in whole blood: group 1 - methadone detected alone, or together with one additional drug at low or therapeutic levels, or a low concentration of ethanol (<1 g/L) (n = 21); group 2 - multiple additional drugs/substances detected below lethal levels (n = 175); group 3 - one or more additional drugs/substances detected at lethal levels, or ethanol >3 g/L (n = 55). Methadone blood concentrations in decedents who had been enrolled in OMT were higher than for decedents not in treatment, in all groups. Blood methadone concentrations around 1 mg/L were present in fatal multi-drug intoxications in OMT patients. Results suggest that some patients may be at risk of dying when combining therapeutic concentrations of methadone with other psychoactive substances. Somatic disease was a common finding among deceased OMT patients. Concentrations in methadone users not enrolled in OMT were predominantly between 0.3 and 0.4 mg/L and were not related to the presence of other drugs. However, methadone concentrations below 0.1 mg/L may be associated with intoxication following methadone use, both alone and in combination with other drugs. Younger male users (mean age 34 years) seemed to have a higher susceptibility to methadone intoxication.

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• Effect of phototherapy with turquoise vs. blue LED light of equal irradiance in jaundiced neonates

  Forfattere: Ebbesen F, Vandborg PK, Madsen PH, Trydal T, Jakobsen LH, Vreman HJ.
  Publiseringssted: Pediatr Res.
  Les utdrag

  BACKGROUND:

  Blue light with peak emission around 460 nm is the preferred treatment of neonatal hyperbilirubinemia. However, studies using fluorescent light tubes have suggested that turquoise light with peak emission at 490 nm may be more efficient. At present, the predominant light source for phototherapy is light emitting diodes (LEDs). Hence, the aim of this study was to compare the bilirubin-reducing effect in jaundiced neonates treated either with turquoise or with blue LED light with peak emission at 497 or 459 nm, respectively, with equal irradiance on the infants.

  METHODS:

  Infants with gestational age ≥33 wk and uncomplicated hyperbilirubinemia were randomized to either turquoise or blue LED light and were treated for 24 h. The mean irradiance footprint at skin level was 5.2 × 10(15) and 5.1 × 10(15) photons/cm(2)/s, respectively.

  RESULTS:

  Forty-six infants received turquoise light and 45 received blue light. The median (95% confidence interval) decrease of total serum bilirubin was 35.3% (32.5; 37.3) and 33.1% (27.1; 36.8) for infants treated with turquoise and blue lights, respectively. The difference was nonsignificant (P = 0.53). The decrease was positively correlated to postnatal age and negatively to birth weight.

  CONCLUSION:

  Using LED light of equal irradiance, turquoise and blue lights had equal bilirubin-reducing effect on hyperbilirubinemia of neonates.

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• Functional analysis of an unusual type IV pilus in the Gram-positive Streptococcus sanguinis

  Forfattere: Gurung I, Spielman I, Davies MR, Lala R, Gaustad P, Biais N, Pelicic V.
  Publiseringssted: Mol Microbiol.
  Les utdrag

  Type IV pili (Tfp), which have been studied extensively in a few Gram-negative species, are the paradigm of a group of widespread and functionally versatile nano-machines. Here, we performed the most detailed molecular characterisation of Tfp in a Gram-positive bacterium. We demonstrate that the naturally competent Streptococcus sanguinis produces retractable Tfp, which like their Gram-negative counterparts can generate hundreds of piconewton of tensile force and promote intense surface-associated motility. Tfp power 'train-like' directional motion parallel to the long axis of chains of cells, leading to spreading zones around bacteria grown on plates. However, S. sanguinis Tfp are not involved in DNA uptake, which is mediated by a related but distinct nano-machine, and are unusual because they are composed of two pilins in comparable amounts, rather than one as normally seen. Whole genome sequencing identified a locus encoding all the genes involved in Tfp biology in S. sanguinis. A systematic mutational analysis revealed that Tfp biogenesis in S. sanguinis relies on a more basic machinery (only 10 components) than in Gram-negative species and that a small subset of four proteins dispensable for pilus biogenesis are essential for motility. Intriguingly, one of the piliated mutants that does not exhibit spreading retains microscopic motility but moves sideways, which suggests that the corresponding protein controls motion directionality. Besides establishing S. sanguinis as a useful new model for studying Tfp biology, these findings have important implications for our understanding of these widespread filamentous nano-machines.

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• Chronic fatigue in 812 testicular cancer survivors during long-term follow-up: increasing prevalence and risk factors

  Forfattere: Sprauten M, Haugnes HS, Brydøy M, Kiserud C, Tandstad T, Bjøro T, Bjerner J, Cvancarova M, Fosså SD, Oldenburg J.
  Publiseringssted: Annals of Oncology
  Les utdrag

  BACKGROUND:

  Chronic fatigue (CF) has been reported to be slightly more prevalent in testicular cancer survivors (TCSs) than in the general population. In this study, we wished to explore possible determinants of CF in TCSs median 12 (survey I) and 19 years (survey II) after treatment, in particular the relation to late effects after treatment.

  PATIENTS AND METHODS:

  Overall, 812 TCSs treated between 1980 and 1994 provided blood samples (testosterone and luteinizing hormone) and completed questionnaires at survey I (1998-2002) and survey II (2007-2008). Hormone levels were categorized according to quartile thresholds for decadal age groups of controls. Associations between CF and possible risk factors, including the Hospital Anxiety and Depression Scale (HADS), treatment, physical activity, hormone levels, neurotoxicity, and comorbidity, were analyzed by logistic regression.

  RESULTS:

  Prevalence of CF increased from 15% at survey I to 27% at survey II (P < 0.001). At survey II, risk for CF was increased three- to four-fold for high levels of neuropathy compared with no neuropathy, and two- to three-fold for high levels of Raynaud-like phenomena, and having testosterone levels in the lowest quartile, while being moderately and highly physically active, had a protective effect. Risk for CF in TCSs with higher levels of HADS-Anxiety and HADS-Depression was increased two- to five-fold, respectively.

  CONCLUSIONS:

  The increasing prevalence of CF in TCSs is a novel finding. Lifestyle interventions, early detection and treatment of depression and anxiety, and possibly testosterone substitution might reduce the risk of CF. Extended long-term follow-up seems to be important.

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• Identification of macrolide-resistant Mycoplasma genitalium using real-time PCR

  Forfattere: Wold C, Sorthe J, Hartgill U, Olsen AO, Moghaddam A, Reinton N.
  Publiseringssted: J Eur Acad Dermatol Venereol.
  Les utdrag

  OBJECTIVES:

  Mycoplasma genitalium is a common cause of non-gonococcal urethritis (NGU) in Western Europe, but is not routinely tested for in all clinics. A high prevalence of macrolide-resistant M. genitalium has been reported. An easy to use test that can predict likely macrolide treatment failure is potentially very valuable. We report the development of a rapid and reliable real-time PCR-assay which detects all relevant resistance loci in the M. genitalium 23S rRNA gene.

  METHODS:

  Mycoplasma genitalium-positive clinical samples were collected between December 2012 and May 2013, from samples sent routinely to the laboratory for diagnostic testing for M. genitalium. The real-time PCR assay was designed using forward amplification primers complementary to all relevant commonly identified 23s rRNA gene mutations, a common reverse amplification primer and a common TaqMan Probe.

  RESULT:

  We report a Taqman assay for detection of common 23S rRNA genotypes at position 2058 and 2059 (Escherichia coli numbering) associated with macrolide resistance, directly from clinical samples. We validated the assay by comparison with DNA sequence determination.

  CONCLUSION:

  Our TaqMan assay detects common genotypes associated with macrolide-resistant M. genitalium, namely, A2058G, A2059G and A2058C. We show association between the presence of resistant M. genitalium and treatment failure, thereby confirming the validity of testing for these mutants to prevent further spread of antimicrobial resistance and to allow informed choice of antibiotics for treatment.

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• Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus.

  Forfattere: van der Linden JW, Arendrup MC, Warris A, Lagrou K, Pelloux H, Hauser PM, Chryssanthou E, Mellado E, Kidd SE, Tortorano AM, Dannaoui E, Gaustad P, Baddley JW, Uekötter A, Lass-Flörl C, Klimko N, Moore CB, Denning DW, Pasqualotto AC, Kibbler C, Arikan-Akda
  Publiseringssted: Emerg Infect Dis.
  Les utdrag

  To investigate azole resistance in clinical Aspergillus isolates, we conducted prospective multicenter international surveillance. A total of 3,788 Aspergillus isolates were screened in 22 centers from 19 countries. Azole-resistant A. fumigatus was more frequently found (3.2% prevalence) than previously acknowledged, causing resistant invasive and noninvasive aspergillosis and severely compromising clinical use of azoles.

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• Twenty-two years of candidaemia surveillance: results from a Norwegian national study.

  Forfattere: Hesstvedt L, Gaustad P, Andersen CT, Haarr E, Hannula R, Haukland HH, Hermansen NO, Larssen KW, Mylvaganam H, Ranheim TE, Sandven P, Nordøy I; Norwegian Yeast Study Group., Kanestrøm A, Grub C, Onken A, Thielsen C, Skaare D, Tofteland S, Sønsteby LJ, Hjet
  Publiseringssted: Clinical Microbiology and Infection
  Les utdrag

  Several studies have reported an increased incidence of candidaemia and a redistribution of species, with a decrease in the number of Candida albicans isolates. In Norway, a prospective, national surveillance study of candidaemia has been ongoing since 1991. Data from the period 1991-2003 have been published previously. The aim of this study was to follow up the incidence, species distribution and antifungal susceptibility of Candida species isolates from blood cultures in the period 2004-2012, and compare them with the corresponding findings from the period 1991-2003. Blood culture isolates of Candida species from all medical microbiological laboratories in Norway were identified and susceptibility tested at the Norwegian Mycological Reference Laboratory. A total of 1724 isolates were recovered from 1653 patients in the period 2004-2012. Comparison of the two periods showed that the average incidence of candidaemia episodes per 100 000 inhabitants increased from 2.4 (1991-2003) to 3.9 (2004-2012). The increase in incidence in the latter period was significantly higher in patients aged >40 years (p 0.001), and a marked increase was observed in patients aged >60 years (p < 0.001). In conclusion, the average incidence in Norway over a period of 22 years modestly increased from 2.4 to 3.9 per 100,000 inhabitants, this being mainly accounted for by candidaemia in the elderly. The species distribution was stable, and the rate of acquired resistance was low.

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• Skin Barrier Function and Staphylococcus aureus Colonization in Vestibulum Nasi and Fauces in Healthy Infants and Infants with Eczema: A Population-Based Cohort Study.

  Forfattere: Berents TL, Carlsen KC, Mowinckel P, Skjerven HO, Kvenshagen B, Rolfsjord LB, Bradley M, Lieden A, Carlsen KH, Gaustad P, Gjersvik P.
  Publiseringssted: Plos One
  Les utdrag

  Atopic eczema (AE) is associated with Staphylococcus aureus (S. aureus) colonization and skin barrier dysfunction, often measured by increased transepidermal water loss (TEWL). In the present study, the primary aim was to see whether S. aureus colonization in the vestibulum nasi and/or fauces was associated with increased TEWL in infants with healthy skin and infants with eczema. Secondarily, we aimed to investigate whether TEWL measurements on non-lesional skin on the lateral upper arm is equivalent to volar forearm in infants. In 167 of 240 infants, recruited from the general population, TEWL measurements on the lateral upper arm and volar forearm, using a DermaLab USB, fulfilled our environmental requirements. The mean of three TEWL measurements from each site was used for analysis. The infants were diagnosed with no eczema (n = 110), possible AE (n = 28) or AE (n = 29). DNA samples were analysed for mutations in the filaggrin gene (FLG). Bacterial cultures were reported positive with the identification of at least one culture with S. aureus from vestibulum nasi and/or fauces. S. aureus colonization, found in 89 infants (53%), was not associated with increased TEWL (i.e. TEWL in the upper quartile), neither on the lateral upper arm or volar forearm (p = 0.08 and p = 0.98, respectively), nor with AE (p = 0.10) or FLG mutation (p = 0.17). TEWL was significantly higher on both measuring sites in infants with AE compared to infants with possible AE and no eczema. FLG mutation was significantly associated with increased TEWL, with a 47% difference in TEWL. We conclude that S. aureus in vestibulum nasi and/or fauces was not associated with TEWL, whereas TEWL measurements on the lateral upper arm and volar forearm appear equally appropriate in infants.

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• Topical treatment with fresh human milk versus emollient on atopic eczema spots in young children: a small, randomized, split body, controlled, blinded pilot study.

  Forfattere: Berents TL, Rønnevig J, Søyland E, Gaustad P, Nylander G, Løland BF.
  Publiseringssted: BMC Dermatology
  Les utdrag

  BACKGROUND:

  Public health nurses report on effects of fresh human milk as treatment for conjunctivitis, rhinitis and atopic eczema (AE), the latter being highly prevalent in early childhood. Emollients and topical corticosteroids are first line treatment of AE. As many caregivers have steroid phobia, alternative treatment options for mild AE are of interest. The aim of this small pilot study was to assess the potential effects and risks of applying fresh human milk locally on eczema spots in children with AE.

  METHODS:

  This was a split body, controlled, randomized and physician blinded pilot study, of children with AE with two similar contralateral eczema spots having a mother breastfeeding the child or a sibling. Fresh expressed milk and emollient was applied on the intervention spot and emollient alone on the control area, three times a day for four weeks. The severity and area of the eczema spots was evaluated weekly, and samples from milk and the spots were analysed weekly with respect to bacterial colonisation.

  RESULTS:

  Of nine patients included, six completed the study. Mean age at inclusion was 18.5 months. The spots examined were localized on the arms, legs or cheeks. The spots were similar in severity, but differed in area. In one patient the eczema ceased after inclusion. In four patients both control and intervention areas increased during the intervention. The relative change in eczema area compared to baseline showed less increase in the intervention spots in two patients, whereas the opposite was observed in three. In four children Staphylococcus aureus was found in their eczema once or more. In three of the 28 human milk samples, Staphylococcus aureus, alfa haemolytic streptococci or coagulase negative staphylococci were detected. Staphylococcus aureus was found once both in human milk and in the eczema spots, no clinical signs of infection were however observed. No secondary infection due to milk application was detected.

  CONCLUSION:

  In this small pilot study, no effect was found on eczema spots treated with topical application of fresh human milk. (ClinicalTrials.gov Identifier, NCT02381028 (http://clinicaltrials.gov/show/NCT02381028) ).

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• Six-day stability of erythrocyte and reticulocyte parameters in-vitro: a comparison of blood samples from healthy, iron-deficient, and thalassemic individuals

  Forfattere: Sudmann-Day ÅA, Piehler A, Klingenberg O, Urdal P.
  Publiseringssted: Scand J Clin Lab Invest.
  Les utdrag

  INTRODUCTION:

  Stability for up to 6 days' storage of erythrocyte and reticulocyte parameters in samples from iron-deficient and thalassemic individuals has not yet been reported. This lack of knowledge challenges evaluation of the full blood count in referral samples for hemoglobinopathy evaluation. We therefore hereby present such sample stability data.

  METHODS:

  We included fresh (less than 4 hours old) blood samples from eight healthy, eight iron-deficient, and 11 thalassemic individuals. A full blood count, including reticulocyte parameters, was performed on a Sysmex XE-2100 once daily during a 6-day storage period at room temperature. For healthy individuals, we also studied stability of refrigerated samples and investigated analytical and biological variation.

  RESULTS:

  Hemoglobin concentration, erythrocyte count, and mean corpuscular hemoglobin were stable for 6 days in all diagnostic groups. Mean corpuscular volume increased less in samples from iron-deficient individuals while the number of reticulocytes increased more in samples from thalassemic, as compared to healthy individuals. Ret-He stability depended on its baseline value. Within-person biological variation in samples from healthy individuals was low both for erythrocyte parameters and for reticulocyte hemoglobin, while higher for reticulocyte counts.

  CONCLUSION:

  Results for hemoglobin concentration, erythrocyte count, and mean corpuscular hemoglobin are reliable in hemoglobinopathy investigation of referred samples for up to 6 days. Storage time-dependent changes of other erythrocyte and reticulocyte parameters in blood samples from iron-deficient and thalassemic individuals differ from those of healthy individuals.

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• Corynebacterium pseudotuberculosis Pneumonia in a Veterinary Student Infected During Laboratory Work.

  Forfattere: Heggelund L, Gaustad P, Håvelsrud OE, Blom J, Borgen L, Sundset A, Sørum H, Frøland SS.
  Publiseringssted: Open Forum Infect Dis.
  Les utdrag

  We present a case of Corynebacterium pseudotuberculosis pneumonia in a veterinary student, with molecular genetic evidence of acquisition during laboratory work, an observation relevant for laboratory personnel working with C pseudotuberculosis isolates. The patient was clinically cured with 14 months trimethoprim/sulfamethoxazole and rifampicin combination treatment.

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• Interference of common haemoglobin variants with the Tosoh G7 standard mode HbA1c method

  Forfattere: Piehler AP, Grimholt RM, Bjerner J, Buchmann MS.
  Publiseringssted: Scand J Clin Lab Invest.
  Les utdrag

  BACKGROUND:

  HbA1c methods may be prone to interference by the presence of haemoglobin variants. In contrast to the variant mode of the HbA1c method on the Tosoh G7 instrument, the literature lacks investigations of haemoglobin variant interference with the standard mode. The current study sought to investigate whether different haemoglobin variants interfere with the Tosoh G7 standard mode HbA1c method, and whether present haemoglobin variants are identifiable on respective chromatograms.

  METHODS:

  Samples routinely analyzed for HbA1c and suspected of having haemoglobin variants (N = 103) were included. HbA1c was measured on a Tosoh G7 in standard mode (Tosoh Corporation, Japan), and on the DCA Vantage (Siemens, Germany). Haemoglobin variants were identified using the VARIANT(™)β-Thalassemia Short Program (Bio-Rad Laboratories, Hercules, CA, USA) and by DNA sequencing.

  RESULTS:

  The Tosoh G7 in standard mode measured significantly lower HbA1c results (between 1.0 and 2.5 percentage points absolute bias corresponding to between 11 and 27 mmol/mol, p < 0.001) in samples in which common haemoglobin variants (HbS, HbC, HbD or HbE) were present (n = 61). No significant difference in HbA1c (0.04 percentage points, p = 0.74) was found between Tosoh G7 standard mode and DCA Vantage in samples in which haemoglobin variants were absent (n = 36). In contrast to HbS and HbD, HbE and HbC trait could be identified on respective chromatograms.

  CONCLUSION:

  The presence of common haemoglobin variants results in falsely low HbA1c measurements on the Tosoh G7 in standard mode. HbS and HbD trait are not identifiable on respective haemoglobin chromatograms.

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• Copy number variation in the ATP-binding cassette transporter ABCC6 gene and ABCC6 pseudogenes in patients with pseudoxanthoma elasticum

  Forfattere: Kringen MK, Stormo C, Berg JP, Terry SF, Vocke CM, Rizvi S, Hendig D, Piehler AP.
  Publiseringssted: Mol Genet Genomic Med.
  Les utdrag

  Single mutations in the ATP-binding cassette transporter (ABCC6) gene (OMIM 603234) are known to cause the rare autosomal recessive disease pseudoxanthoma elasticum (PXE). Recently, we have found that copy number variations (CNVs) in pseudogenes of the ABCC6 gene are quite common. The aim of this study was to investigate the frequency and possible contribution of CNV in ABCC6 and its pseudogenes in PXE. Genomic DNA from 212 PXE individuals were examined for copy number by pyrosequencing and quantitative polymerase chain reaction (PCR) and compared with healthy individuals. The frequency of PXE individuals with any CNV was higher than in healthy individuals. The majority of variation comprised known and possibly new deletions in the ABCC6 gene and duplications of the ABCC6P1 and ABCC6P2 genes. ABCC6 deletions and ABCC6P2 duplications were not observed in 142 healthy individuals. In conclusion, by pyrosequencing and quantitative PCR, we were able to detect known and possibly new deletions in the ABCC6 gene that may have caused the PXE phenotype. Pyrosequencing may be used in PXE patients who have obtained incomplete genotype from conventional techniques. The frequency of ABCC6P2 pseudogene duplication was more common in PXE patients than healthy individuals and may affect the PXE phenotype.

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• Development of DinQ from Escherichia coli as an anti-cell-envelope antibiotic

  Forfattere: Booth JA, Suganthan R, Gaustad P, Bjørås M.
  Publiseringssted: Int J Antimicrob Agents.
  Les utdrag

  The increasing prevalence of antibiotic-resistant bacterial infections together with a lack of new classes of antibiotics requires a search for new antimicrobial agents from unique sources. The need is particularly acute for Gram-negative infections, as highlighted by several recent reports. We have previously published a characterisation of the LexA-sensitive dinQ gene and agrB sRNA from Escherichia coli. One of the defining phenotypes of DinQ was that modest overexpression led to a greatly increased sensitivity to DNA damage, and ectopic expression was highly lethal [1].

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• RNA-sequencing analysis of HepG2 cells treated with atorvastatin

  Forfattere: Stormo C, Kringen MK, Lyle R, Olstad OK, Sachse D, Berg JP, Piehler AP.
  Publiseringssted: PLoS One
  Les utdrag

  The cholesterol-lowering drug atorvastatin is among the most prescribed drug in the world. Alternative splicing in a number of genes has been reported to be associated with variable statin response. RNA-seq has proven to be a powerful technique for genome-wide splice variant analysis. In the present study, we sought to investigate atorvastatin responsive splice variants in HepG2 cells using RNA-seq analysis to identify novel candidate genes implicated in cholesterol homeostasis and in the statin response. HepG2 cells were treated with 10 µM atorvastatin for 24 hours. RNA-seq and exon array analyses were performed. The validation of selected genes was performed using Taqman gene expression assays. RNA-seq analysis identified 121 genes and 98 specific splice variants, of which four were minor splice variants to be differentially expressed, 11 were genes with potential changes in their splicing patterns (SYCP3, ZNF195, ZNF674, MYD88, WHSC1, KIF16B, ZNF92, AGER, FCHO1, SLC6A12 and AKAP9), and one was a gene (RAP1GAP) with differential promoter usage. The IL21R transcript was detected to be differentially expressed via RNA-seq and RT-qPCR, but not in the exon array. In conclusion, several novel candidate genes that are affected by atorvastatin treatment were identified in this study. Further studies are needed to determine the biological significance of the atorvastatin responsive splice variants that have been uniquely identified using RNA-seq.

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• Serum bilirubin concentration in healthy adult North-Europeans is strictly controlled by the UGT1A1 TA-repeat variants

  Forfattere: Kringen MK, Piehler AP, Grimholt RM, Opdal MS, Haug KB, Urdal P.
  Publiseringssted: PLoS One
  Les utdrag

  The major enzyme responsible for the glucuronidation of bilirubin is the uridine 5'-diphosphoglucose glucuronosyltransferase A1 (UGT1A1) enzyme, and genetic variation in the UGT1A1 gene is reported to influence the bilirubin concentration in the blood. In this study, we have investigated which gene-/haplotype variants may be useful for genetic testing of Gilbert's syndrome. Two groups of samples based on serum bilirubin concentrations were obtained from the Nordic Reference Interval Project Bio-bank and Database (NOBIDA): the 150 individuals with the highest bilirubin (>17.5 µmol/L) and the 150 individuals with normal bilirubin concentrations (<17.5 µmol/L). The individuals were examined for the TA6>TA7 variant in the UGT1A1 promoter and 7 tag-SNPs in an extended promoter region of UGT1A1 (haplotype analysis) and in selected SNPs in candidate genes (SLCO1B3, ABCC2 and NUP153). We found significant odds ratios for high bilirubin level for all the selected UGT1A1 variants. However, in stepwise multivariate logistic regression analysis of all genetic variants together with age, sex, country of origin and fasting time, the repeat variants of UGT1A1 TA6>TA7 and SLCO1B3 rs2117032 T>C were the only variants significantly associated with higher bilirubin concentrations. Most individuals with high bilirubin levels were homozygous for the TA7-repeat (74%) while only 3% were homozygous for the TA7-repeat in individuals with normal bilirubin levels. Among individuals heterozygous for the TA7-repeat, a low frequent UGT1A1-diplotype harboring the rs7564935 G-variant was associated with higher bilirubin levels. In conclusion, our results demonstrate that in testing for Gilbert's syndrome, analyzing for the homozygous TA7/TA7-genotype would be appropriate.

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• Longitudinal serum testosterone, LH and FSH levels in a population-based sample of long-term testicular cancer survivors.

  Forfattere: Mette Sprauten, Marianne Brydøy, Hege Sagstuen Haugnes, Milada Cvancarova, Trine Bjøro, Johan Bjerner, Sophie Dorothea Fosså, and Jan Oldenburg
  Publiseringssted: Journal of Clinical Oncology
  Les utdrag

  Purpose: To assess longitudinal long-term alterations of testosterone (T), LH, and FSH intesticular cancer survivors (TCSs).

  Methods: In all, 307 TCSs treated from 1980-1994 provided blood samples after orchiectomybut before further treatment, at Survey I (SI) (1998-2002), and Survey II (SII) (2007-2008).Levels of sex hormones were categorized according to quartiles and reference range (2.5- and 97.5 percentiles) of 599 controls for each decadal age group. TCSs were categorizedaccording to treatment; surgery (S), radiotherapy (RT) or chemotherapy (CT). The risk ofhigher (LH) or lower (T) levels was assessed with Chi-square test (FSH) or ordinal logisticregression analysis, and expressed as odds ratios (ORs) with 95% Confidence Interval (CI).

  Results: Risk of lower T and higher LH and FSH levels was significantly increased for TCSsat all time points after RT or CT. At SII, ORs for lower T categories were 3.3 (95%CI; 2.3–4.7) and 5.2 (95%CI; 3.5– 7.9) for RT and CT respectively. ORs for increased LH and FSHwere: 4.4 (95%CI; 3.1-6.5) and 18.9 (95%CI; 11.0-32.6), respectively (RT), and 3.6 (95%CI;2.4-5.3) and 14.2 (95%CI; 8.3-24.4), respectively (CT). The cumulative platinum dose wassignificantly associated with risk of higher LH levels at both surveys and FSH at SI. In total,half of TCSs had at least one out of three sex hormone levels outside the reference range atSII.

  Conclusion: Long-term TCSs are at risk of premature hormonal ageing. Our findings maypertain to cancer survivors in general, underlining the importance of extended follow-up.

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• Rapid and reliable detection of α-globin copy number variations by quantitative real-time PCR

  Forfattere: Grimholt RM, Urdal P, Klingenberg O, Piehler AP.
  Publiseringssted: BMC Hematol.
  Les utdrag

  BACKGROUND:

  Alpha-thalassemia is the most common human genetic disease worldwide. Copy number variations in the form of deletions of α-globin genes lead to α-thalassemia while duplications of α-globin genes can cause a severe phenotype in β-thalassemia carriers due to accentuation of globin chain imbalance. It is important to have simple and reliable methods to identify unknown or rare deletions and duplications in cases in which thalassemia is suspected but cannot be confirmed by multiplex gap-PCR. Here we describe a copy number variation assay to detect deletions and duplications in the α-globin gene cluster (HBA-CNV).

  RESULTS:

  Quantitative real-time PCR was performed using four TaqMan® assays which specifically amplify target sequences representing both the α-globin genes, the -α3.7 deletion and the HS-40 region. The copy number for each target was determined by the 2-ΔΔCq method. To validate our method, we compared the HBA-CNV method with traditional gap-PCR in 108 samples from patients referred to our laboratory for hemoglobinopathy evaluation. To determine the robustness of the four assays, we analyzed samples with and without deletions diluted to obtain different DNA concentrations. The HBA-CNV method identified the correct copy numbers in all 108 samples. All four assays showed the correct copy number within a wide range of DNA concentrations (3.2-100 ng/μL), showing that it is a robust and reliable method. By using the method in routine diagnostics of hemoglobinopathies we have also identified several deletions and duplications that are not detected with conventional gap-PCR.

  CONCLUSIONS:

  HBA-CNV is able to detect all known large deletions and duplications affecting the α-globin genes, providing a flexible and simple workflow with rapid and reliable results.

  
  

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• Vitamin D deficiency in alcohol-use disorders and its relationship to comorbid major depression: A cross-sectional study of inpatients in Nepal.

  Forfattere: Neupane SP, Lien L, Hilberg T, Bramness JG.
  Publiseringssted: Drug Alcohol Depend.
  Les utdrag

  BACKGROUND: Mounting evidence suggests that deficiency of vitamin D may be associated with major health problems, including alcohol-use disorders (AUD) and major depression (MD). This study aimed to identify the vitamin D status of Nepalese inpatients with an AUD. We explored socio-demographic and alcohol-use related correlates and the relationship between vitamin D deficiency and comorbid MD.

  METHODS: A cross-sectional study was conducted on AUD inpatients (N=174) at eight alcohol/drug treatment centres around Kathmandu. Structured questionnaires were administered to assess the socio-demographic and alcohol-use parameters and to establish DSM-IV diagnoses of AUD and MD. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25(OH)D) concentration of <50nmol/L.

  RESULTS: The prevalence of vitamin D deficiency was 64%. Higher age, having a stable job or business, shorter time since last alcohol intake and winter serum samples were related to having lower 25(OH)D levels. Several features of AUD severity were associated with low vitamin D levels: guilt about drinking, using alcohol as eye-opener, and history of relapse after alcohol treatment (p≤0.03). Patients with a comorbid major depression, in particular secondarily depressed cases, were less likely to have vitamin D deficiency (X(2)=6.8; p=0.01).

  CONCLUSIONS: This study confirms high rates of vitamin D deficiency in alcohol treatment sample and shows a positive association between vitamin D deficiency and severity of alcohol-use disorders. Competing risk and other confounders may help explain the vitamin D status among patients with alcohol-use disorders and comorbid major depression.

  
  

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• Hb Ullevaal [β78(EF2)Leu→Val; HBB: c.235C>G], a new hemoglobin variant interfering with Hb A1c measurement using a cation exchange high performance liquid chromatography method.

  Forfattere: Grimholt RM, Sudmann ÅA, Piehler AP, Urdal P, Klingenberg O.
  Publiseringssted: Hemoglobin
  Les utdrag

  A new hemoglobin (Hb) variant was detected during Hb A1c measurement. DNA sequencing showed heterozygosity for the single nucleotide substitution (C > G) on the β-globin gene causing an amino acid change [β78(EF2)Leu→Val; HBB: c.235C > G]. The new Hb variant was designated Hb Ullevaal after the hospital at which it was discovered. Heterozygosity for Hb Ullevaal appears to have no clinical significance. However, it interferes with Hb A1c measurement by cation exchange high performance liquid chromatography (HPLC), causing falsely low Hb A1c concentration when using the Tosoh G7 apparatus in variant mode.

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• Varsling av sterkt avvikende analyseresultater til rekvirenter utenfor sykehus

  Forfattere: Aakre KM, Hov GG, Skadberg O, Piehler A, Distante S, Hager HB.
  Publiseringssted: Tidsskriftet Den Norske Legeforening
  Les utdrag

  BAKGRUNN: Når laboratoriet påviser analyseresultater som kan medføre alvorlig helsefare for pasienten, skal behandlingsansvarlig lege varsles. Det er per i dag ingen enighet om når et prøvesvar er så avvikende at varsling bør gjøres.

  MATERIALE OG METODE: En arbeidsgruppe i regi av Norsk selskap for medisinsk biokjemi innhentet oversikt over hvilke varslingsgrenser som blir brukt ved norske laboratorier samt i internasjonal litteratur, og foretok en spørreundersøkelse blant allmennpraktikere som rekvirerte analyser fra seks norske laboratorier. Det ble utført litteratursøk for å innhente kunnskapsbasert informasjon om når et analyseresultat medfører akutt livsfare. Konsekvenser for ressursbruk ved bruk av ulike grenser ble estimert på bakgrunn av analyseresultater fra en 6 måneders periode fra et større norsk sykehuslaboratorium.

  RESULTATER: Hvilke grenser som brukes nasjonalt og internasjonalt varierer, men medianverdiene for disse er relativt sammenfallende. Allmennpraktikerne ønsket at en del analyser skulle varsles, hovedsakelig elektrolytter og hematologiske parametre. De varslingsgrensene allmennpraktikerne foreslo var gjennomgående mindre avvikende sammenlignet med de som ble brukt av laboratoriene (medianverdier). Hvilke grenser som brukes har stor betydning for hvor mye ressurser laboratoriene vil bruke på varsling av laboratorieresultater.

  FORTOLKING: Laboratorier og allmennleger har ulike oppfatninger av hva som bør være varslingsgrenser for medisinsk biokjemiske analyseresultater hos voksne. Anbefalingen fra arbeidsgruppen må oppfattes som veiledende.

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• UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone.

  Forfattere: Stormo C, Bogsrud MP, Hermann M, Åsberg A, Piehler AP, Retterstøl K, Kringen MK
  Publiseringssted: Mol Diagn Ther.
  Les utdrag

  BACKGROUND: Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels.

  METHODS: DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing.

  RESULTS: Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA) 6.

  CONCLUSION: The low-expression UGT1A1*28(TA) 7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite atorvastatin lactone.

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• Anatomic distribution of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium infections in men who have sex with men.

  Forfattere: Reinton N, Moi H, Olsen AO, Zarabyan N, Bjerner J, Tønseth TM, Moghaddam A.
  Publiseringssted: Sexual Health
  Les utdrag

  BACKGROUND: New cases of gonorrhoea (Neisseria gonorrhoeae) and chlamydia (Chlamydia trachomatis) infections have been steadily increasing in Scandinavian countries over the last decade. There is a particular urgency in reducing new infections as isolation of multiple drug resistant strains of gonorrhoea is becoming more frequent. The aim of this study was to determine the prevalence and sites of infection of common sexually transmissible infections (STIs) in men who have sex with men (MSM).

  METHODS: We have performed a retrospective analysis of the three major STIs, gonorrhoea, chlamydia and Mycoplasma genitalium in urogenital, anorectal and oropharyngeal samples from MSM that attended two STI clinics in Oslo.

  RESULTS: One hundred and thirty-six men (6.0%) out of 2289 MSM tested were found to be positive for gonorrhoea using a porA gene targeted nucleic acid amplification test (NAAT). Of these, 106 (77.9%) would not have been identified through testing first-void urine alone. Two hundred and twenty eight (10.0%) patients from 2289 tested were found to be positive for chlamydia, 164 (71.9%) of which were identified through anorectal specimens. Ninety-one (5.1%) patients from 1778 tested were found to be positive for M. genitalium, with 65 (71.4%) identified through testing of anorectal specimens.

  CONCLUSIONS: Our results supports the European findings that the MSM population carries a high burden of STIs and that testing the anorectum and oropharynx will identify a significantly higher percentage of infected patients and reservoirs of STIs.

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• Discrepancy between HbA1c and fasting glucose results

  Forfattere: Piehler AP, Grimholt RM, Bjerner J, Urdal P, Buchmann M
  Publiseringssted: Scand J Clin Lab Invest.
  Les utdrag

  Case report

  SIR : A 51-year-old man from Northern Pakistan(parents from the Kashmir and Peshawar areas,respectively) with type 2 diabetes attended to hisgeneral practitioner for a routine visit. Previous laboratorytests had shown satisfactory HbA1c levels(5.0 – 5.9%, recommended  7%) analyzed with cation-exchange HPLC on a Tosoh G7 in standard mode.In contrast, simultaneously measured fasting glucoseconcentrations exhibited increased levels between 7.9and 11.4 mmol/L (142 and 205 mg/dL) [referenceinterval, 4.0 – 6.0 mmol/L (72 – 108 mg/dL)].

  [...]

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• Respiratory tract infections during the 2011 Mycoplasma pneumoniae epidemic.

  Forfattere: Reinton N, Manley L, Tjade T, Moghaddam A.
  Publiseringssted: Eur J Clin Microbiol Infect Dis.
  Les utdrag

  In 2011, Norway experienced a surge in community acquired Mycoplasma pneumoniae infections. Norway also has one of the highest rates of reported Bordetella pertussis infections, despite high vaccine coverage. We aimed to determine the prevalence of upper respiratory tract pathogens in patients attending primary care physicians for respiratory illness during the 2011 M. pneumoniae epidemic period. A retrospective analysis of data from 26,039 patients that have had nasopharyngeal swabs analysed by nucleic acid amplification testing (NAAT) for M. pneumoniae, C. pneumoniae and B. pertussis was performed. Subsets of samples were tested for additional pathogenic bacteria, including B. parapertussis and B. holmesii, as well as influenza virus. M. pneumoniae, C. pneumoniae and B. pertussis were detected in 2,484 (9.5 %), 261 (1.0 %) and 821 (3.2 %) patients, respectively. Co-infection of M. pneumoniae and B. pertussis was found in 50 (0.19 %) patients, C. pneumoniae and B. pertussis in 4 (0.02 %). Influenza virus was found in 899 (24.5 %) of 3,661 nasopharyngeal swabs. Co-infection of influenza virus and bacterial pathogens was common, although influenza virus co-infection with B. pertussis occurred significantly more often than with C. pneumoniae and M. pneumoniae (20.4 % versus 2.9 % and 9.1 %, respectively; p<0.005). Testing for Bordetella species genes IS1001, IS1002 and recA showed that B. holmesii was most likely misdiagnosed as B. pertussis in 5.8 % of cases. The most prevalent respiratory tract pathogen in the general population in 2011 was M. pneumoniae. B. pertussis was also found frequently as was B. pertussis and influenza virus co-infections.

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• Metabolic changes in urine during and after pregnancy in a large, multiethnic population-based cohort study of gestational diabetes.

  Forfattere: Sachse D, Sletner L, Mørkrid K, Jenum AK, Birkeland KI, Rise F, Piehler AP, Berg JP
  Publiseringssted: PLoS One
  Les utdrag

  • This study aims to identify novel markers for gestational diabetes (GDM) in the biochemical profile of maternal urine using NMR metabolomics. It also catalogs the general effects of pregnancy and delivery on the urine profile. Urine samples were collected at three time points (visit V1: gestational week 8–20; V2: week 28±2; V3:10–16 weeks post partum) from participants in the STORK Groruddalen program, a prospective, multiethnic cohort study of 823 healthy, pregnant women in Oslo, Norway, and analyzed using 1H-NMR spectroscopy. Metabolites were identified and quantified where possible. PCA, PLS-DA and univariate statistics were applied and found substantial differences between the time points, dominated by a steady increase of urinary lactose concentrations, and an increase during pregnancy and subsequent dramatic reduction of several unidentified NMR signals between 0.5 and 1.1 ppm. Multivariate methods could not reliably identify GDM cases based on the WHO or graded criteria based on IADPSG definitions, indicating that the pattern of urinary metabolites above micromolar concentrations is not influenced strongly and consistently enough by the disease. However, univariate analysis suggests elevated mean citrate concentrations with increasing hyperglycemia. Multivariate classification with respect to ethnic background produced weak but statistically significant models. These results suggest that although NMR-based metabolomics can monitor changes in the urinary excretion profile of pregnant women, it may not be a prudent choice for the study of GDM.

  
  

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• Recovery of Bordetella pertussis from PCR-positive Nasopharyngeal Samples is Dependent on Bacterial Load.

  Forfattere: Vestrheim DF, Steinbakk M, Bjørnstad ML, Moghaddam A, Reinton N, Dahl ML, Grude N, Sandven P.
  Publiseringssted: J Clin Microbiol.
  Les utdrag

  Viable Bordetella pertussis isolates are essential for surveillance purposes. We performed culture of 223 PCR-positive nasopharyngeal samples. B. pertussis was recovered from 45 (20.2%) of the samples. Growth was associated with a high bacterial load, as determined by PCR. Culture from PCR-positive samples is a feasible approach to recover B. pertussis isolates, and culture can be limited to samples with a high bacterial load.

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• Calcium, Magnesium, Albumin, and Total-Protein Measurement in Serum as Assessed with 20 Fresh-Frozen Single-Donation Sera.

  Forfattere: Van Houcke SK, Rustad P, Stepman HC, Kristensen GB, Stöckl D, Røraas TH, Sandberg S, Thienpont LM.
  Publiseringssted: Clin Chem.
  Les utdrag

  To the Editor:
  The scope of external quality assessment (EQA) in laboratory medicine has evolved considerably (1). With the increasing worldwide interest in the use of common reference intervals and/or medical-decision limits, modern EQA schemes need to be better at assessing the standardization status of commercial in vitro diagnostic tests. This need has led to new challenges in the design of EQA surveys.
  We report the outcomes of a Norwegian pilot study that investigated the use of commutable, fresh-frozen single donations to assess the current standardization status as part of an initiative toward producing common reference intervals (2).

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• Recommended Nordic paediatric reference intervals for 21 common biochemical properties.

  Forfattere: Hilsted L, Rustad P, Aksglæde L, Sørensen K, Juul A.
  Publiseringssted: Scand J Clin Lab Invest.
  Les utdrag

  Paediatric reference intervals based on samples from healthy children are difficult to establish and consequently data are often from hospitalized children. Furthermore, biases may present in published data due to differences in the analytical methods employed. Blood samples from 1429 healthy Danish children were collected for establishing reference intervals for 21 common biochemical properties (Alanine transaminase, Albumin, Alkaline phosphatase, Aspartate transaminase, Bilirubin, Calcium, Cholesterol, Creatinine, Creatine kinase, HDL-Cholesterol, Iron, Lactate dehydrogenase, LDL- Cholesterol, Magnesium, Phosphate, Potassium, Protein, Sodium, Transferrin, Triglycerides and Urate). Samples were analyzed on a Roche-Modular-P/ISE-system. The NORIP reference material (NFKK Reference Serum X) was included in all the analytical runs. Reference values were recalculated according to the target values of X for the properties and statistical calculations carried out as performed in the NORIP study. Thus commutable (regarding analytical method) reference intervals for 20 properties were established and for LDL-Cholesterol reference intervals were reported for the specific analytical method employed. The data were compared to previous studies and to those obtained from the youngest age group in the NORIP study. Marked age differences were observed for most of the properties. Several properties also showed gender-related differences, mainly at the onset of puberty. Data are presented as suggested intervals for combined age groups, but can be accessed via the NORIP home page if more detailed division according to age or gender is desired.

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• A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) splice variant with an alternative exon 1 potentially encoding an extended N-terminus

  Forfattere: Stormo C, Kringen MK, Grimholt RM, Berg JP, Piehler AP
  Publiseringssted: BMC Mol Biol.
  Les utdrag

  BACKGROUND: The major rate-limiting enzyme for de novo cholesterol synthesis is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). HMGCR is sterically inhibited by statins, the most commonly prescribed drugs for the prevention of cardiovascular events. Alternative splicing of HMGCR has been implicated in the control of cholesterol homeostasis. The aim of this study was to identify novel alternatively spliced variants of HMGCR with potential physiological importance.

  RESULTS: Bioinformatic analyses predicted three novel HMGCR transcripts containing an alternative exon 1 (HMGCR-1b, -1c, -1d) compared with the canonical transcript (HMGCR-1a). The open reading frame of the HMGCR-1b transcript potentially encodes 20 additional amino acids at the N-terminus, compared with HMGCR-1a. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to examine the mRNA levels of HMGCR in different tissues; HMGCR-1a was the most highly expressed variant in most tissues, with the exception of the skin, esophagus, and uterine cervix, in which HMGCR-1b was the most highly expressed transcript. Atorvastatin treatment of HepG2 cells resulted in increased HMGCR-1b mRNA levels, but unaltered proximal promoter activity compared to untreated cells. In contrast, HMGCR-1c showed a more restricted transcription pattern, but was also induced by atorvastatin treatment.

  CONCLUSIONS: The gene encoding HMGCR uses alternative, mutually exclusive exon 1 sequences. This contributes to an increased complexity of HMGCR transcripts. Further studies are needed to investigate whether HMGCR splice variants identified in this study are physiologically functional.

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• Copy number variations of the ATP-binding cassette transporter ABCC6 gene and its pseudogenes

  Forfattere: Kringen MK, Stormo C, Grimholt RM, Berg JP, Piehler AP.
  Publiseringssted: BMC Research Notes
  Les utdrag

  Background:

  The ATP-binding cassette transporter ABCC6 gene is located on chromosome 16 between its two pseudogenes (ABCC6P1 and ABCC6P2). Previously, we have shown that ABCC6P1 is transcribed and affects ABCC6 at the transcriptional level. In this study we aimed to determine copy number variations of ABCC6, ABCC6P1 and ABCC6P2 in different populations. Moreover, we sought to study the transcription pattern of ABCC6 and ABCC6 pseudogenes in 39 different human tissues.

  Findings:

  Genomic DNA from healthy individuals from five populations, Chinese (n = 24), Middle East (n = 20), Mexicans (n = 24), Caucasians (n = 50) and Africans (n = 24), were examined for copy number variations of ABCC6 and its pseudogenes by pyrosequencing and quantitative PCR. Copy number variation of ABCC6 was very rare (2/142; 1.4%). However, one or three copies of ABCC6P1 were relatively common (3% and 8%, respectively). Only one person had a single copy of ABCC6P2 while none had three copies. In Chinese, deletions or duplications of ABCC6P1 were more frequent than in any other population (9/24; 37.5%). The transcription pattern of ABCC6P2 was highly similar to ABCC6 and ABCC6P1, with highest transcription in liver and kidney. Interestingly, the total transcription level of pseudogenes, ABCC6P1 + ABCC6P2, was higher than ABCC6 in most tissues, including liver and kidney.

  Conclusions:

  Copy number variations of the ABCC6 pseudogenes are quite common, especially in populations of Chinese ancestry. The expression pattern of ABCC6P2 in 39 human tissues was highly similar to that of ABCC6 and ABCC6P1 suggesting similar regulatory mechanisms for ABCC6 and its pseudogenes.

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• Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.

  Forfattere: Eskesen AN, Melum E, Moghaddam A, Bjøro K, Verbaan H, Ring-Larsen H, Dalgard O.
  Publiseringssted: Eur J Gastroenterol Hepatol.
  Les utdrag

  OBJECTIVES: Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response.

  METHODS: Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4.RESULTS: Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22).

  CONCLUSION: We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.

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• Reticulocyte hemoglobin equivalent to detect thalassemia and thalassemic hemoglobin variants

  Forfattere: Sudmann AA, Piehler AP, Urdal P.
  Publiseringssted: Int J Lab Hematol.
  Les utdrag

  INTRODUCTION:

  Thalassemia and iron deficiency may both result in hypochromic microcytic anemia. Hematological algorithms that differentiate the two are mainly established in adult selected diagnostic groups. We aimed at creating an algorithm applicable in the presence of children, hemoglobin variants, and iron deficiency.

  METHODS:

  Our study material constituted blood samples referred during 1 year for routine diagnostics of hemoglobinopathy. We included 443 samples, of which 37% were from children 3 months or older. We found β-thalassemia trait, α-thalassemia, combined α-/β-thalassemia hemoglobin variants, and no-hemoglobinopathy, of whom 107 had a ferritin at or below 20 μg/L. We included reticulocyte hemoglobin equivalent, ferritin, and erythrocyte count in our algorithm.

  RESULTS:

  Our algorithm differentiated β-thalassemia from no-hemoglobinopathy with a sensitivity of 99% at 83% specificity. It performed better than other published algorithms when applied to all patient samples, while equally or moderately better in the 63% adult samples. Our algorithm also detected the clinically significant α-thalassemias, and most of the combined α-/β-thalassemias and thalassemic hemoglobin variants.

  CONCLUSION:

  Our algorithm efficiently differentiated thalassemia and thalassemic hemoglobin variants from iron deficiency in children and adults.

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• Belief is only half the truth – or why screening for heterophilic antibody interference in certain assays makes double sense

  Forfattere: Bjerner J, Bolstad N, Piehler AP.
  Publiseringssted: Ann Clin Biochem.
  Les utdrag

  Introduction:

  Interference in immunoassays may cause both false negative and false positive results.It may be detected using a number of affirmative tests such as re-analysis of certain samples usingdifferent asssay’s platform with known bias; after the addition of blockers antibodies or assessmentof linearity and parallelism following serial doubling dilutions.One should look for interference where it is likely and has high medical impact. Probabilistic Bayesianreasoning is a statistical tool to identify samples where interference is most likely. But when lookingfor interference where it is likely, do we find it where it has the largest population healthconsequences?

  Methods:

  We use information theory to quantify the effect of assay interference by calculating theShannon information content (using logarithms with base 2). We then obtain lower bounds of thepopulation health consequences of a particular test and combine these expressions to get lowerbounds of the population health consequences of interference

  Results and conclusion:

  We suggest that assays having a low frequency of true positives should bethe primary target of retesting, because: (i) assays with a low frequency of true positives exhibit ahigh likelihood of interference and (ii) the population health consequences of false positive resultsare generally higher for assays with a low frequency of true positives. Finally, we give a workedexample having a realistic frequency of interference and test costs. In some immunoassays (e.g.)tumour marker), adding a blocker to all tests can be a more cost-efficient mean than retestingpositive samples.

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• Commentary on "Pleural effusion in a patient with multiple myeloma."

  Forfattere: Piehler ap
  Publiseringssted: Clin Chem.
  Les utdrag

  Whereas pleural effusions in multiple myeloma (MM) due to benign causes, including heart failure, renal impairment, and hypoalbuminemia, occur in about 6% of all patients, myelomatous pleural effusion (MPE) is a rarity. MPE indicates an aggressive course of MM, with an associated median survival time of approximately 4 months. Thus, prompt and appropriate workup of pleural effusions in MM is imperative. In addition to detection of atypical plasma cells in the pleural fluid and histologic confirmation of MPE, identification of a monoclonal protein in the pleural effusion is essential. Protein electrophoresis is often used. As in the case described by Oudart et al., however, light chain MM may represent a diagnostic obstacle, because only about 50% of cases exhibit a monoclonal band after serum protein electrophoresis, and even immunofixation of serum may not demonstrate a monoclonal band in all patients with light chain MM. In the reported case, immunofixation analysis and quantification of free light chains in the pleural effusion demonstrated the presence of monoclonal free light chains. Quantification of free light chains in a pleural effusion is a novel approach, and a higher concentration of free light chains in the pleural effusion than in the serum indicated local production in this case. With a median survival time of about 4 months in MPE patients, neither patients nor physicians have much time to obtain a proper diagnosis and to start adequate therapy. In such cases, the most sensitive diagnostic methods have to be used. Today, the most sensitive routine tests for detecting monoclonal components in serum are a combination of protein electrophoresis, immunofixation, and free light chain quantification. This is most likely also true for the detection of monoclonal proteins in pleural effusions, and these methods should therefore also be used to uncover the origin of pleural effusions associated with MM.

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• Chlamydia trachomatis, Mycoplasma genitalium and Ureaplasma urealyticum among students in northern Norway.

  Forfattere: Jensen AJ, Kleveland CR, Moghaddam A, Haaheim H, Hjelmevoll SO, Skogen V.
  Publiseringssted: J Eur Acad Dermatol Venereol.
  Les utdrag

  BACKGROUND: The prevalence of Mycoplasma genitalium and Ureaplasma genitalium in populations outside sexually transmitted infection clinics in Norway is unknown.

  OBJECTIVE: To assess the prevalence of potential sexually transmitted organisms in a non-clinical setting, among college students in Northern Norway.

  METHODS: In total 655 students, 449 men and 206 women, were tested for Chlamydia trachomatis, M. genitalium, and U. urealyticum by nucleic acid amplification testing of urine samples. All subjects completed questionnaires.

  RESULTS: Among the included men, the prevalences of C. trachomatis, M. genitalium, and U. urealyticum were 4.2%, 1.1% and 8.9%, respectively. Prevalence among included women was 1.9%, 1% and 8.2%, respectively. In men, the number of sexual partners in the preceding 6 months was associated with prevalence of U. urealyticum and C. trachomatis.

  CONCLUSIONS: U. urealyticum appeared more prevalent than C. trachomatis and increased number of sexual partners was associated with increased risk of a positive test. M. genitalium had a low prevalence.

  
  

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• A-Subclass ATP-Binding Cassette Proteins in Brain Lipid Homeostasis and Neurodegeneration.

  Forfattere: Piehler AP, Ozcürümez M, Kaminski WE.
  Publiseringssted: Front Psychiatry
  Les utdrag

  The A-subclass of ATP-binding cassette (ABC) transporters comprises 12 structurally related members of the evolutionarily highly conserved superfamily of ABC transporters. ABCA transporters represent a subgroup of “full-size” multispan transporters of which several members have been shown to mediate the transport of a variety of physiologic lipid compounds across membrane barriers. The importance of ABCA transporters in human disease is documented by the observations that so far four members of this protein family (ABCA1, ABCA3, ABCA4, ABCA12) have been causatively linked to monogenetic disorders including familial high-density lipoprotein deficiency, neonatal surfactant deficiency, degenerative retinopathies, and congenital keratinization disorders. Recent research also point to a significant contribution of several A-subfamily ABC transporters to neurodegenerative diseases, in particular Alzheimer’s disease (AD). This review will give a summary of our current knowledge of the A-subclass of ABC transporters with a special focus on brain lipid homeostasis and their involvement in AD.

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• Human epididymis protein 4 reference limits and natural variation in a Nordic reference population.

  Forfattere: Bolstad N, Oijordsbakken M, Nustad K, Bjerner J.
  Publiseringssted: Tumour Biol.
  Les utdrag

  • The objectives of this study are to establish reference limits for human epididymis protein 4, HE4, and investigate factors influencing HE4 levels in healthy subjects. HE4 was measured in 1,591 samples from the Nordic Reference Interval Project Bio-bank and Database biobank, using the manual HE4 EIA (Fujirebio) for 802 samples and the Architect HE4 (Abbott) for 792 samples. Reference limits were calculated using the statistical software R. The influence of donor characteristics such as age, sex, body mass index, smoking habits, and creatinine on HE4 levels was investigated using a multivariate model. The study showed that age is the main determinant of HE4 in healthy subjects, corresponding to 2% higher HE4 levels at 30 years (compared to 20 years), 9% at 40 years, 20% at 50 years, 37% at 60 years, 63% at 70 years, and 101% at 80 years. HE4 levels are 29% higher in smokers than in nonsmokers. In conclusion, HE4 levels in healthy subjects are associated with age and smoking status. Age-dependent reference limits are suggested.

  
  

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• Infeksjon; medisinsk mikrobiologi, infeksjonssykdommer, smittevern. Repetisjon og oppgaver.

  Forfattere: Trygve Tjade
  Publiseringssted: Gyldendal Akademisk
  Les utdrag

  Dette heftet tar for seg sentrale temaer i medisinsk mikrobiologi, infeksjonssykdommer og smittevern for bachelorstudenter i helsefag.

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• Evolutionary history and functional characterization of three large genes involved in sporulation in Bacillus cereus group bacteria.

  Forfattere: Reiter L, Tourasse NJ, Fouet A, Loll R, Davison S, Økstad OA, Piehler AP, Kolstø AB.
  Publiseringssted: J Bacteriol.
  Les utdrag

  The Bacillus cereus group of bacteria is a group of closely related species that are of medical and economic relevance, including B. anthracis, B. cereus, and B. thuringiensis. Bacteria from the Bacillus cereus group encode three large, highly conserved genes of unknown function (named crdA, crdB, and crdC) that are composed of 16 to 35 copies of a repeated domain of 132 amino acids at the protein level. Bioinformatic analysis revealed that there is a phylogenetic bias in the genomic distribution of these genes and that strains harboring all three large genes mainly belong to cluster III of the B. cereus group phylogenetic tree. The evolutionary history of the three large genes implicates gain, loss, duplication, internal deletion, and lateral transfer. Furthermore, we show that the transcription of previously identified antisense open reading frames in crdB is simultaneously regulated with its host gene throughout the life cycle in vitro, with the highest expression being at the onset of sporulation. In B. anthracis, different combinations of double- and triple-knockout mutants of the three large genes displayed slower and less efficient sporulation processes than the parental strain. Altogether, the functional studies suggest an involvement of these three large genes in the sporulation process.

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• Effect of ambient temperature on analytical performance of self-monitoring blood glucose systems.

  Forfattere: Nerhus K, Rustad P, Sandberg S.
  Publiseringssted: Diabetes Technol Ther.
  Les utdrag

  BACKGROUND: The analytical quality of self-monitoring of blood glucose (SMBG) can be affected by environmental conditions such as temperature. The objective of this study was to determine the influence of (1) a shift in the ambient temperature immediately before measurement and (2) taking measurements in the lower and upper part of the operating temperature range.

  METHODS: Nine different SMBG systems on the Norwegian market were tested with heparinized venous blood (4.8 and 19.0 mmol/L). To test the shift in ambient temperature effect, the glucometer and strips were equilibrated for 1 h at 5°C or 1 h at 30°C before the meter and strips were moved to room temperature, and measurements were performed after 0, 5, 10, 15, and 30 min. To test the lower and upper temperature range, measurements were performed at 10°C and at 39°C after 1 h for temperature equilibration of the glucometer and strips. All these measurements were compared with measurements performed simultaneously on a meter and strips kept at room temperature the whole time.

  RESULTS: Six of nine SMBG systems overestimated and/or underestimated the results by more than 5% after moving meters and strips from 5°C or 30°C to room temperature immediately before the measurements. Two systems underestimated the results at 10°C. One system overestimated and another underestimated the results by more than 5% at 39°C.

  CONCLUSIONS: The effect on analytical performance was most pronounced after a rapid shift in the ambient temperature. Therefore patients need to wait at least 15 min for temperature equilibration of affected meters and strips before measuring blood glucose.

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• Heterophilic antibody interference in commercial immunoassays; a screening study using paired native and pre-blocked sera.

  Forfattere: Bolstad N, Warren DJ, Bjerner J, Kravdal G, Schwettmann L, Olsen KH, Rustad P, Nustad K.
  Publiseringssted: Clin Chem Lab Med.
  Les utdrag

  • Abstract Background: Heterophilic antibodies are still an important source of interference in immunoassays. We have conducted a screening study for interference in a panel of commercially available assays using two sera known to contain high titer Fc-reactive heterophilic antibodies. Methods: The sera were distributed to laboratories participating in the Nordic External Quality Assessment cooperation (EQANord). Duplicate samples pre-blocked with aggregated murine monoclonal MAK33 were also supplied. Discrepancies (>50%) between the results for native and blocked samples were used to classify the tested assays as susceptible to interference. A total of 170 different assay kits covering 91 analytes were tested. Results: We found that 21 assays, covering 19 different analytes, were susceptible to interference from the heterophilic antibodies in the two sera. Many of these are clinically and commercially important assays. Some of the false results were grossly elevated and could have been detrimental to patient care in a clinical setting. Conclusions: Heterophilic antibodies with Fc-reactivity remain a threat. A more widespread use of antibody fragments and aggregated immunoglobulin could potentially improve the heterophilic antibody resistance of assays intended for clinical use.

  
  

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• Reference genes for quantitative, reverse-transcription PCR in Bacillus cereus group strains throughout the bacterial life cycle.

  Forfattere: Reiter L, Kolstø AB, Piehler AP.
  Publiseringssted: J Microbiol Methods
  Les utdrag

  Quantitative reverse-transcription PCR (RT-qPCR) has become a major tool to better understand the biology and pathogenesis of bacteria. One prerequisite of valid RT-qPCR data is their proper normalization to stably expressed reference genes. To identify and evaluate reference genes suitable for normalization of gene expression data in Bacillus cereus group strains, mRNA levels of eleven candidate reference genes (rpsU, nifU, udp (UDP-N-acetylglucosamine 2-epimerase), BT9727_5154/BC_5475, BT9727_4034/BC_4293, BT9727_4549/BC_4813, pspA, gatB_Yqey (gatB_Yqey domain containing protein), helicase (SWF/SNF family protein), adk and pta) and a target gene (BT9727_3305/BC3547+BC3546) were quantified by RT-qPCR at different time points throughout the entire life cycle of the wild-type B. cereus ATCC 14579 and Bacillus thuringiensis subsp. konkukian 97-27, a phylogenetically closely related strain to Bacillus anthracis. The programs geNorm and Normfinder were used to calculate expression stabilities and identified the genes gatB_Yqey, rpsU and udp as the most stably expressed reference genes. Compared to this combination or the sets of reference genes as recommended by geNorm or Normfinder, normalization using a traditional housekeeping gene (adk) alone resulted in significantly different gene expression results and in a significant overestimation of the target gene transcription. Normalization of the data to the reference gene gatB_Yqey alone showed no or only small differences to the reference gene combinations indicating that gatB_Yqey may be used as a single reference gene when investigating rather large changes in mRNA transcription. Otherwise, a combination of the stably expressed reference genes is recommended. In conclusion, the present study underlines the importance of normalization to stably expressed reference genes and presents valid endogenous controls suitable for normalization of transcriptional data throughout the life cycle of B. cereus group strains.

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• Standardisert hemoglobin A1c til diagnostisk bruk?

  Forfattere: Berg JP, Hanssen KF, Bjerve KS, Claudi T, Dahl-Jørgensen K, Rustad P, Sandberg S, Skrivarhaug T.
  Publiseringssted: Tidsskriftet Den Norske Legeforening
  Les utdrag

  Analyse av hemoglobin A1c (HbA1c) er det viktigste hjelpemidlet til å vurdere hvor godt regulert blodsukkernivået til en pasient med diabetes er over tid. I januar i år anbefalte WHOs ekspertgruppe at måling av HbA1c også kan benyttes diagnostisk. Dette vil gjøre det enklere å diagnostisere diabetes, men forutsetter en standardisert analyse av høy kvalitet.

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• IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection

  Forfattere: Moghaddam A., Melum E., Reinton N., Ring-Larsen H., Verbaan H., Bjøro K. og Dalgard O.
  Publiseringssted: Hepatology.
  Les utdrag

  • Polymorphisms near the IL28B gene, which code for interferon (IFN)-λ3, predict response to pegylated interferon-α (PEG-IFN) and ribavirin treatment in hepatitis C virus (HCV) genotype 1 infected patients. Follow-up studies of the effect of IL28B gene in HCV non-genotype 1 infected patients have almost always used predominantly HCV genotype 2-infected or mixed genotype 2/3-infected cohorts with results partly conflicting with HCV genotype 1. We performed a retrospective analysis of 281 patients infected with HCV genotype 3 for association of response to therapy with IL28B polymorphisms. We found that the HCV genotype 1 responder genotypes at rs12979860 and rs8099917 did not associate with sustained virological response to PEG-IFN/ribavirin therapy. However, the responder genotypes of both SNPs showed association with rapid viral response measured at 4 weeks (rs12979860, P = 3 × 10(-5) ; rs8099917, P = 3 × 10(-4) ). In multivariate analysis, age (<40 years), baseline viral load (<4 × 10(5) IU/mL) and the responder genotypes of SNPs rs12979860 or rs8099917 remained significant independent predictors of rapid viral response to therapy. Furthermore, we show that IL28B polymorphisms are associated with relapse in patients who achieve rapid viral response to PEG-IFN/ribavirin therapy. The responder genotypes also showed association with markers of stage and activity of liver disease, namely high aspartate aminotransferase platelet ratio index (APRI, rs12979860, P = 0.018; rs8099917, not significant) and high alanine aminotransferase (ALT, rs12979860, P = 0.002; rs8099917, P = 0.001), in addition to a high baseline viral load (rs12979860, P = 1.4 × 10(-5) ; rs8099917, P = 7.3 × 10(-6) ). CONCLUSION: Polymorphisms near the IL28B gene show association with rapid viral response but not sustained viral response to PEG-IFN/ribavirin therapy in HCV genotype 3-infected patients.

  
  

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• En inte så kort introduktion till probabilistiska (Bayesianska) metoder

  Forfattere: Bjerner J.
  Publiseringssted: Klinisk Biokemi i Norden
  Les utdrag

  Precis som datavärlden har sina Windows och Macintoshanhängare, så är statistik ofta delat mellan anhängare av ”klassiska metoder” och ”probabilistiska metoder”. En grov gissning är väl att statistikvärlden fördelar sig 50/50 mellan dessa, och diskussionen mellan anhängarna är ofta både intensiv och emotionell. I medicinsk biokemi har alltid ”klassiska metoder” dominerat fullständigt, men en ändring verkar vara på väg. Den mycket omdiskuterade ekvationen för att beräkna ”estimated average glucose” från HbA1c blev härledd med probabilistiska metoder

• Asthma prediction in school children; the value of combined IgE-antibodies and obstructive airways disease severity score.

  Forfattere: Lødrup Carlsen KC, Söderström L, Mowinckel P, Håland G, Pettersen M, Munthe Kaas MC, Devulapalli CS, Buchmann M, Ahlstedt S, Carlsen KH.
  Publiseringssted: Allergy
  Les utdrag

  BACKGROUND: Allergic sensitisation increases the risk for asthma development. In this prospective birth cohort (Environment and Childhood Asthma) study, we hypothesized that combining quantitative measures of IgE antibodies (Sigma-IgE) and Severity score of obstructive airways disease (OAD) at 2 years of age (Severity score) is superior to predict current asthma (CA) at 10 years than either measure alone. Secondarily, we assessed if gender modified the prediction of CA.

  METHODS: A follow-up study at 10 years of age was performed in 371 2-year-old children with recurrent (n = 219) or no (n = 152) bronchial obstruction with available serum analysed for Sigma-IgE to common food and inhalant allergens through a panel test, Phadiatop Infant) (Phadia, Uppsala, Sweden). Clinical variables included allergic sensitisation and exercise testing to characterise children with CA vs not CA at 10 years and the Severity score (0-12, 0 indicating no OAD) was used to assess risk modification.

  RESULTS: Severity score alone explained 24% (Nagelkerke R(2) = 0.24) of the variation in CA, whereas Sigma-IgE explained only 6% (R(2) = 0.06). Combining the two increased the explanatory capacity to R(2) = 0.30. Gender interacted significantly with Sigma-IgE; whereas Severity score predicted CA in both genders, the predictive capacity of Sigma-IgE for CA at 10 years was significant in boys only.

  CONCLUSION: Combining Sigma-IgE to inhalant allergens and Severity score at 2 years was superior to predict asthma at 10 years than either alone. Severity score predicted CA in both genders, whereas Sigma-IgE significantly predicted CA in boys only.

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• Bestemmelse av utlekking av metaller fra odontologiske legeringer i cellekulturmedium ved induktivt koplet plasma massespektrometri (ICP-MS)

  Forfattere: Kalfoss T.
  Publiseringssted: Masteroppgave ved Universitetet for miljø- og biovitenskap
  Les utdrag

  Det finnes over tusen odontologiske legeringer på markedet i dag, og bruken av uedle legeringer har i stor grad erstattet bruken av gullbaserte legeringer. Felles for disse legeringene er at de er i kontakt med oralt vev, og at metaller lekker fra legeringene ut i munnhulen. Det stilles derfor mange spørsmål om den biologiske sikkerheten omkring bruken av disse legeringene. Korrosjonstester, hvor de ulike legeringene blir utsatt for det samme sure miljøet som finnes i munnhulen, har vist at uedle legeringer lekker ut større konsentrasjoner av metaller sammenlignet med edle legeringer.

  Nordisk Institutt for Odontologiske Materialer (NIOM) har undersøkt ekstrakter av ulike legeringer i cellekulturer og sett på hvilken påvirkning de har på cellene. I den sammenheng ønsket de å kvantifisere utlekking av metaller fra de ulike legeringene i cellekulturmediet for å bestemme konsentrasjonen av de ulike grunnstoffene som cellene hadde blitt utsatt for. Fürst Medisinsk Laboratorium fikk i oppdrag å utvikle en metode for kvantitativ bestemmelse av grunnstoffer i Minimal Essential Medium with Earle’s salts (MEM).

  Atten ulike odontologiske legeringer, hovedsakelig uedle, ble sandlåst, slipt og renset før inkubering i MEM cellekulturmedium under bevegelse i tre døgn ved 37 C. Legeringene ble deretter fjernet fra mediet og løsningene ble analysert ved induktivt koplet plasma massespektrometri (ICP-MS). Alle prøvene ble analysert for grunnstoffene litium (Li), beryllium (Be), aluminium (Al), vanadium (V), mangan (Mn), kobolt (Co), nikkel (Ni), kobber (Cu), sink (Zn), gallium (Ga), arsen (As), selen (Se), rubidium (Rb), strontium (Sr), yttrium (Y), zirkonium (Zr), niob (Nb), molybden (Mo), ruthenium (Ru), palladium (Pd), sølv (Ag), kadmium (Cd), indium (In), tinn (Sn), antimon (Sb), cesium (Cs), barium (Ba), lantan (La), cerium (Ce), praseodym (Pr), neodym (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), hafnium (Hf), tantal (Ta), wolfram (W), rhenium (Re), osmium (Os), iridium (Ir), platina (Pt), gull (Au), bly (Pb), vismut (Bi) og thorium (Th). Resultater fra analysering av de odontologiske legeringene viste bare utlekking av de metallene som var oppgitt fra produsenten av legeringene, og det er kun disse grunnstoffene som er presentert i resultatkapittelet. Som korrosjonstestene gav også her de uedle legeringene et høyere utslipp av metaller enn de edle legeringene.

  Målemetoden som ble utviklet på ICP-MS gav tifredsstillende deteksjons- og kvantifiseringsgrenser, gjenfinning, presisjon og nøyaktighet for grunnstoffene Cr, Mn, Co, Ni, Cu, Zn, Ga, Nb, Mo, In, Sn, W, Pt og Au. Metoden gav bare ca 80 % gjenfinning av Ag og den kunne ikke brukes for bestemmelse av Pd < 50 µg/L. Metoden hadde ikke tilstrekkelig sensitivitet for bestemmelse av Fe på det nivået som lakk fra de 18 legeringene som ble analysert i denne oppgaven. Den største usikkerheten i metoden lå i prepareringen av løsningene. For mye manipulering av noen av legeringene ødela det beskyttende oksidlaget som ble dannet på overflaten og økte dermed utlekking av metaller.

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• Den svenske Chlamydiavarianten nvC. trachomatis i Norge

  Forfattere: Reinton N., Moi H., Bjerner J., Moghaddam A.
  Publiseringssted: Tidsskriftet Den Norske Legeforening
  Les utdrag

  Bakgrunn. En variant av Chlamydia trachomatis (nvC trachomatis) har skapt problemer for chlamydiadiagnostikken i Sverige. Andelen nvC trachomatis i Sverige i 2006–07 var fylkesvis 25–80 % av dem som var smittet av C trachomatis. Vårt formål har vært å overvåke nvC trachomatis blant våre pasienter fra januar 2007 frem til juli 2008.

  Materiale og metode. 1.1. 2007–30.6. 2008 ble alle chlamydiaprøver ved Fürst Medisinsk Laboratorium dobbeltanalysert. Deteksjon av C trachomatis ble utført på isolert DNA med Cobas TaqMan 48 (Roche Diagnostics). Deteksjon og verifikasjon av nvC trachomatis ble utført med egenutviklede sanntid polymerasekjedereaksjonsmetoder.

  Resultater. 61 av 23 726 pasienter ble identifisert som bærere av nvC trachomatis. Andelen C trachomatis-bærere som var nvC trachomatis-positive økte fra 1,0 % i første kvartal 2007 til 3,2 % i andre kvartal 2008.

  Fortolkning. Våre resultater viser en langsom, men jevn økning i andelen nvC trachomatis-positive prøver. Sammenliknet med tidligere prevalenstall rapportert i Sverige (25–80 %), er forekomsten av nvC trachomatis lav i våre data. Epidemiologien til nvC trachomatis bidrar til kunnskapen om spredning av seksuelt overførbare infeksjoner og understreker at man finner bare det man leter etter.

  
  

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• Lineær regresjon med flere variabler.

  Forfattere: Bjerner J.
  Publiseringssted: Klinisk Biokemi i Norden
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  ”Når jeg går til min lege vil jeg at han skal gi meg den beste medisinen, ikke den beste medisinen som han forstår virkningen av.” Engelsk statistiker om leger og statistiske modeller .

  I medisinsk biokjemi har vi ofte flere enn to variabler. Vi vet at gamma-GT er økt både for personer med høyt alkoholinntak og for personer med høy BMI. Hva med en person som har høy BMI, vil alkoholinntak føre til enda høyere gamma-GT eller ikke? Med lineær regresjon kan vi se sammenhenger mellom flere variabler

• Characterization of Treatment Response to Recombinant Interferon-a2b in Osteosarcoma Xenografts

  Forfattere: Müller CR, Namløs HM, Bjerner J, Østensen IHG, Saeter G, Smeland S, Bruland ØS, Myklebost O.
  Publiseringssted: J Cancer Sci Ther.
  Les utdrag

  Interferons (IFNs) may target cancer cells both through their regulation of the immune response, effect on angiogenesis and through direct effect on cancer cells. Treatment response has been demonstrated in osteosarcoma patients, but tumour resistance to IFN-a is common. Hence, understanding the molecular mechanisms involved in response and resistance is essential for improving therapeutic efficacy. Of five xenografts screened for specific growth delay in response to treatment with unconjugated and PEGylated IFN-a2b, one displayed growth inhibition and tumour shrinkage. Growth inhibition increased on a dosing schedule of PEGylated IFN every third day. Xenografts resistant to PEGylated IFN were similarly resistant to unconjugated IFN. Combination treatment with IFN-a2b and doxorubicin resulted in improved growth control rates. Transcriptional profiling analysis of the one sensitive and two resistant xenografts identified a common set of 79 genes significantly affected by IFN- a2b treatment independent of tumour growth inhibition. All but four of the 79 genes were up-regulated. The majority of these genes were well characterized IFN-stimulated genes and core members of the IFN-a signalling pathway. The expression of a set of 128 unique genes changed only in the sensitive xenograft; 52/128 genes were up-regulated. The specific geneexpression pattern seen in the responsive xenograft identified possible pathways important for the antitumor effect of IFN-a in osteosarcoma, including subsets of genes involved in cell adhesion and osteogenic tissue development. The observed improved control rates of combined treatment with IFN and doxorubicin are encouraging and should be further explored.

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• NORIP og NOBIDA fyller ti år!

  Forfattere: Bjerner J.
  Publiseringssted: Klinisk Biokemi i Norden
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  Nordisk referanseintervallprosjekt (NORIP) ble iverksatt i 1999-2000. initiativtakere var opprinnelig heidi Steensland og Petter Urdal som ved hjelp av NFKK fikk etablert en samnordisk gruppe som koordinerte studiet: Peter Felding, Leifur Franzson, Veli Kairisto, Per Hyltoft Pedersen, Pål Rustad og Per Simonsson.

  Friske individer mellom 18 og 80 år ble rekruttert på i alt 80 laboratorier i de nordiske landene og det ble samlet inn serum, plasma og fullblod . Prøvetakingen var nøye standardisert . Prøvene ble analysert for de vanligste komponentene i medisinsk biokjemi lokalt på de deltakende laboratoriene sammen med kontroller fra prosjektet, spesielt det som etter hvert ble kalt NFKK Reference Serum X. I tillegg ble materiale frosset ved – 80° C

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