Forskning og utvikling

Fürst Medisinsk Laboratorium driver aktiv forskning innenfor laboratoriemedisin, både for å holde seg oppdatert på fagområdet og for å bidra aktivt til videreutvikling av faget.

• 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.
  Publisert i: BMC Research Notes 2012, 5:425

  • 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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• Reticulocyte hemoglobin equivalent to detect thalassemia and thalassemic hemoglobin variants

  Forfattere: Sudmann AA, Piehler AP, Urdal P.
  Publisert i: Int J Lab Hematol. 2012 Jul 6.

  • 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.
  Publisert i: Ann Clin Biochem. 2012 Jul;49(Pt 4):381-6.

  • 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
  Publisert i: Clin Chem. 2012 Apr;58(4):675-6.

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

  Forfattere: Piehler AP, Ozcürümez M, Kaminski WE.
  Publisert i: Front Psychiatry. 2012;3:17.

  • 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.
  Publisert i: Tumour Biol. 2012 Feb;33(1):141-8.

  • 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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• 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.
  Publisert i: J Bacteriol. 2011 Oct;193(19):5420-30.

  • 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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• 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.
  Publisert i: Clin Chem Lab Med. 2011 Sep 8.

  • 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.
  Publisert i: J Microbiol Methods. 2011 Aug;86(2):210-7.

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

  Forfattere: Bjerner J.
  Publisert i: Klinisk Biokemi i Norden. 2011;3:38-42.

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

  Forfattere: Kalfoss T.
  Publisert i: Masteroppgave ved Universitetet for miljø- og biovitenskap, Jun 2010

  • 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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• 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.
  Publisert i: Hepatology. 2011 Mar;53(3):746-54.

  • 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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• Lineær regresjon med flere variabler.

  Forfattere: Bjerner J.
  Publisert i: Klinisk Biokemi i Norden. 2010;4:36-41.

  • Les utdrag

    ”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

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• Den svenske Chlamydiavarianten nvC. trachomatis i Norge

  Forfattere: Reinton N., Moi H., Bjerner J., Moghaddam A.
  Publisert i: Tidsskr Nor Legeforen nr. 4, 2010; 130: 380–1.

  • 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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• 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.
  Publisert i: J Cancer Sci Ther. 2010;2:33-42.

  • 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.
  Publisert i: Klinisk Biokemi i Norden. 2010;1:36.

  • Les utdrag

    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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• Reference intervals for serum testosterone, SHBG, LH and FSH in males from the NORIP project.

  Forfattere: Bjerner J, Biernat D, Fosså SD, Bjøro T.
  Publisert i: Scand J Clin Lab Invest. 2009;69(8):873-9.e1-11.

  • Les utdrag
    Reference intervals were calculated for male testosterone, SHBG, FSH and LH in serum from 599 individuals in the NORIP study. At 30 years of age, reference limits were calculated to 10.4-32.6 nmol/L testosterone, 13.5-57.4 nmol/L SHBG, 1.93-9.7 IU/L LH and 1.5-10.3 IU/L FSH, at 50 years, 9.3-31.3 nmol/L (testosterone), 18.4-75.6 nmol/L (SHBG), 2.01-10.4 IU/L (LH) and 2.04-12.4 IU/L (FSH), and at 70 years 8.6 to 30.7 nmol/L (testosterone), 27.8-101 nmol/L (SHBG), 2.22-11.2 IU/L (LH) and 2.71-14.2 IU/L (FSH). All age-+related changes were statistically significant. Reference intervals were also calculated for indices derived from testosterone, SHBG and albumin. Free androgen index, simply the ratio between testosterone and SHBG, returned results differing from the other elaborate indices, and the study thus favors use of a more elaborate index such as calculated free testosterone (CFT).
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• Usikkerhetsberegninger.

  Forfattere: Bjerner J.
  Publisert i: Klinisk Biokemi i Norden. 2009;3:36-42.

  • Les utdrag
    Ofte rapporter vi en størrelse som er beregnet fra en eller flere måleresultater. Vi kan ha direkte mål (internkontroller) og indirekte mål (eksterne kontroller) for usikkerheten i en beregnet størrelse, men det er ofte nyttig å kalkulere hvordan usikkerhet i måleresultatene forplanter seg til den beregnede størrelsen. Denne artikkelen vil omhandle grunnleggende begreper bak usikkerhetsberegninger og gi noen regneeksempler.
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• Bootstrap – slik fungerer det

  Forfattere: Bjerner J.
  Publisert i: Klinisk Biokemi i Norden. 2009;2:24-27.

  • Les utdrag
    Bootstrap er en statistisk metode som baserer seg på tilfeldig (på svensk ”slumpvis”) trekning av dataobservasjoner (såkalt resampling). Ved å bruke bootstrap kan en lage konfidensintervaller for komplekse beregninger, som det ellers hadde vært umulig å lage konfidensintervaller for. Artikkelen er tenkt å gi en oversikt over bootstrap uten formler.
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• Mycoplasma genitalium in women with lower genital tract inflammation.

  Forfattere: Moi H., Reinton N., Moghaddam A.
  Publisert i: Sex Transm Infect. 2009 Feb;85(1):10-4.

  • Les utdrag

    OBJECTIVES: To examine the prevalence of Mycoplasma genitalium in a large number of female patients attending a sexually transmitted infections (STI) clinic and to determine if there is an association with signs or symptoms of lower genital tract inflammation (LGTI).

    METHODS: Altogether, 7646 female patients who had symptoms or microscopic signs of LGTI or were perceived to be at high risk of exposure to an STI were tested for both M genitalium and Chlamydia trachomatis. Urethral and cervical smears were examined quantitatively for polymorphic mononuclear leucocytes (PMNLs).

    RESULTS: The prevalence of C trachomatis and M genitalium was 10.1% and 4.5%, respectively. We found a clear association between detecting M genitalium in first void urine (FVU) of patients and signs of urethral inflammation. The strongest association was between detecting M genitalium in FVU and number of PMNLs in urethral smears (n = 6790; OR 2.1; 95 % CI 1.5 to 2.9). The association was less significant between detecting M genitalium in cervical swabs and the number of PMNLs in urethral smears (n = 6785; OR 1.4; 95% CI 1.1 to 1.9), although cervical swabs gave higher sensitivity than FVU in detecting M genitalium (86% vs 62%). C trachomatis detection in FVU and cervical swabs was highly concordant and both significantly associated with urethritis (n = 6790; OR 3.6; 95% CI 3.0 to 4.4).

    CONCLUSIONS: This data support the hypothesis that M genitalium causes urethritis in women and that M genitalium infection of the genitourinary tract leads to different clinical manifestations depending on whether the site of infection is the urethral or the cervical epithelium.

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• Non-parametric estimation of reference intervals in small non-Gaussian sample sets

  Forfattere: Bjerner J, Theodorsson E, Hovig E, Kallner A.
  Publisert i: Accred Qual Assur. 2009 Feb 14:185–192.

  • Les utdrag
    This study aimed at validating common bootstrap algorithms for reference interval calculation.We simulated 1500 random sets of 50–120 results originating from eight different statistical distributions. In total, 97.5 percentile reference limits were estimated from bootstrapping 5000 replicates, with confidence limits obtained by: (a) normal, (b) from standard error, (c) bootstrap percentile (as in RefVal) (d) BCa, (e) basic, or (f) student methods. Reference interval estimates obtained with ordinary bootstrappingand confidence intervals by percentile methodwere accurate for distributions close to normality anddevoid of outliers, but not for log-normal distributions with outliers. Outlier removal and transformation to normality improved reference interval estimation, and the basic method was superior in such cases. In conclusions, if the neighborhood of the relevant percentile contains non-normally distributed results, bootstrapping fails. The distribution of bootstrap estimates should be plotted, and a non-normal distribution should warrant transformation oroutlier removal.
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• Mycoplasma genitalium is associated with symptomatic and asymptomatic non-gonococcal urethritis in men.

  Forfattere: Moi H, Reinton N, Moghaddam A.
  Publisert i: Sexually Transmitted Infections 2009;85:15-18

  • Les utdrag

    Objectives: To examine the prevalence of Mycoplasma genitalium in a large number of male patients attending a sexually transmitted infections (STI) clinic and to determine if there is an association with objective non-gonococcal urethritis (NGU) in patients with and without clinical symptoms.

    Methods: Patients were tested for both M genitalium and Chlamydia trachomatis if they had symptoms or microscopic signs of NGU or if they were perceived to be at high-risk of exposure to a STI (n = 8468). Urethral smears were examined for polymorphic mononuclear leucocytes.

    Results: We found that M genitalium infection was associated with symptoms of non-chlamydial NGU (discharge and dysuria; OR 4.3; 95% CI 3.4 to 5.5). We also found that M genitalium infection was associated with signs of non-chlamydial NGU independently with or without symptoms of NGU (with symptoms: OR 4.7; 95% CI 3.2 to 6.7; without symptoms: OR 3.1; 95% CI 2.0 to 4.6). Prevalence of M genitalium was also associated with severity of urethritis as quantified by microscopic examination of urethral smears.

    Conclusions: These data add further evidence to the association of M genitalium infection with NGU and should allow better risk analysis of recent recommendations of not performing urethral smears in asymptomatic men attending STI clinics.

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• Comment on the article entitled "How to deal with dichotomous tests? Application of a Rankit ordinal scale model with examples from the Nordic ordinal scale project on screening tests" by Petersen et al.

  Forfattere: Bjerner J.
  Publisert i: Scand J Clin Lab Invest. 2009;69(1):28-30.

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    In an article in the previous issue of this journal, entitled “How to deal with dichotomous tests? Application of a rankit ordinal scale model with examples from the Nordic ordinal scale project on screening tests”, the authors address the issue of how to evaluate test strips returning the results “presence” or “absence” of the pregnancy marker beta‐hCG. How should the detection limits of such a test be stated, and how should beta‐hCG test strips from different manufacturers be compared?
    ...
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• Hvordan kommunisere statistikk med grafer?

  Forfattere: Bjerner J.
  Publisert i: Klinisk Biokemi i Norden. 2009;1:18-25.

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    Dette er den indirekte fortsettelsen av en tidligere artikkel jeg har skrevet i KBN om filformater og figurer, som avhandler teknisk kvalitet på figurer .like viktig er at figurer uttrykker det de skal . Mange av tankene i denne artikkelen er hentet direkte eller indirekte fra referanselitteraturen: ”The Visual Display of Quantitative Information”,  “Envisioning information”  og “Visual explanations” av Edward R .Tufte, ”The Elements of Graphing Data” av William S .Cleveland og ”The Grammar of Graphics” av leland Wilkinson . Gode eksempler på hvordan en skal bruke grafikk i praksis finnes i ofte i artiklene fra den desiderte favorittstatistikeren min, Andrew Gelman, og den interesserte anbefales å lese hans artikkel ”Let’s Practice What We Preach: Turning Tables into Graphs” i The American Statistician 2002:56:2 (http://www.stat.columbia.edu/~gelman/). Denne artikkelen er skrevet samtidlig som jeg har gjort opp et materiale fra Rikshospitalet-Radiumhospitalet på fertilitetshormoner for menn, hvor prøvene er hentet fra NOBIDAbiobanken. Jeg har brukt statistikkprogrammet ”R” for alle beregninger og illustrasjoner, noen ganger med standardgrafikk, noen ganger med hjelp av pakken ”ggplot2” av Hadley Wickham. Etterredigering er gjort i ”InkScape”. Med andre ord, alle figurer er kun produsert med gratisprogrammer.
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