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  • 1.
    Abdsaleh, Shahin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Azavedo, E
    Lindgren, P G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Comparison of core needle biopsy and surgical specimens in malignant breast lesions regarding histological features and hormone receptor expression2008Inngår i: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 52, nr 6, 773-775 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 2. Aho, Leena
    et al.
    Jolkkonen, Jukka
    Alafuzoff, Irina
    Kuopio University, Finland.
    Beta-amyloid aggregation in human brains with cerebrovascular lesions.2006Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 37, nr 12, 2940-5 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE: The present study assessed beta-amyloid (Abeta) protein aggregates in postmortem human brains in subjects who had experienced stroke to examine the proposed association between ischemic stress and the accumulation of Abeta reported in rodents.

    METHODS: A sample of 484 postmortem brains from nondemented subjects, lacking isocortical neurodegenerative pathology with verified cerebrovascular lesions, and 57 age-matched controls were assessed with respect to Abeta, Abeta40, and Abeta42 aggregates in the cortex and thalamus by immunohistochemical techniques.

    RESULTS: The load of Abeta aggregates did not display a significant association with cerebrovascular lesions. The load of Abeta, Abeta40, and Abeta42 aggregates increased with age, and there was a tendency toward higher odds ratios for Abeta aggregates, though not statistically significant, in subjects with acute cerebrovascular lesions. In the oldest subjects with cerebrovascular lesions and with both thalamic and cortical Abeta aggregates, the load of thalamic Abeta42 was significantly higher than the load of Abeta40.

    CONCLUSIONS: Our findings indicate that cerebrovascular disease does not influence the load of Abeta, whereas a shift of aggregation from the Abeta40 to the Abeta42 residue is noted in the thalamus but only in aged subjects. It is impossible, however, to state whether this result is attributable to increased Abeta production, its insufficient elimination, or other susceptibility factors.

  • 3. Aho, Leena
    et al.
    Parkkinen, Laura
    Pirttila, Tuula
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Systematic appraisal using immunohistochemistry of brain pathology in aged and demented subjects.2008Inngår i: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 25, nr 5, 423-32 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND/AIMS: Abnormal processing of hyperphosphorylated tau (HPtau), amyloid-beta (Abeta) and alpha-synuclein (alphaS) proteins is considered as causative with regard to the clinical symptoms in age-related neurodegenerative diseases.

    METHODS: In this retrospective, postmortem study applying immunohistochemical methodology, we assessed Alzheimer's-disease (AD)-related HPtau and Abeta pathology in 178 subjects with alphaS pathology.

    RESULTS: These pathologies were frequently seen concomitantly, i.e. HPtau in 83% and Abeta in 62% of the alphaS-positive cases. Furthermore, the striatum was frequently involved, particularly in subjects with cognitive impairment (65%). The predictive value of widespread HPtau pathology, i.e. stages V-VI, with respect to cognitive impairment was high, since all 18 subjects presenting with this stage were demented. In contrast, the predictive value of widespread alphaS pathology, i.e. stages 5-6 according to Braak's Parkinson disease staging, was debatable. Fifty-three percent of the subjects with widespread alphaS pathology and no or mild AD-related HPtau pathology were cognitively unimpaired. It is noteworthy that striatal Abeta pathology was more often seen in demented subjects independently of HPtau and/or alphaS status.

    CONCLUSION: The causative pathology in subjects with clinically diagnosed dementia with Lewy bodies needs to be clarified in future studies.

  • 4. Aho, Leena
    et al.
    Pikkarainen, Maria
    Hiltunen, Mikko
    Leinonen, Ville
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Immunohistochemical Visualization of Amyloid-β Protein Precursor and Amyloid-β in Extra- and Intracellular Compartments in the Human Brain2010Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, Vol. 20, nr 4, 1015-1028 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid-beta (Abeta) peptide, a cleavage product of the amyloid-beta protein precursor (AbetaPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Abeta are based on the use of immunohistochemistry. In this study, the presence of AbetaPP and Abeta was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages independent of the disease state or existence of extracellular Abeta aggregates with all antibodies directed to AbetaPP, with three Abeta antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Abeta from AbetaPP. These results suggest that it is AbetaPP rather than Abeta that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Abeta was detected with antibodies directed to the C-terminus of Abeta (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Abeta.

  • 5.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Alzheimerin tauti: (Alzheimer’s sjukdom)2012Inngår i: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, 1029-1031 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 6.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Alzheimer's disease-related lesions2013Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, Vol. 33, nr Suppl 1, S173-S179 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The invitation to contribute to "Alzheimer's Disease: Advances for a New Century" gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.

  • 7.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Cerebral amyloid angiopathy, hemorrhages and superficial siderosis.2008Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 39, nr 10, 2699-700 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 8.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Frontotemporaaliset lobaariset degeneraatiot: (Frontoremporal degeneration)2012Inngår i: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, 1032-1033 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 9.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Neuropatologinen tutkimus: Neuropatologisk undersökning2010Inngår i: Muistisairaudet: (Minnestörningar) / [ed] Erkinjuntti T, Rinne J, Soininen H, Helsingfors: Duodecim , 2010, 1, 438-446 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 10.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Neuropatologinen tutkimus: Neuropatologisk undersökning2015Inngår i: Muistisairaudet: (Minnestörningar) / [ed] Erkinjuntti T, Rinne J, Soininen H, Helsingfors: Duodecim , 2015, 2, 426-434 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 11.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Parkinsonin tauti ja lewynkappaledementia: (Parkinsons sjukdom)2012Inngår i: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, 1031-1032 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 12.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Rapeuttavat aivosairaudet: (Degenerativa hjärnsjukdomar)2012Inngår i: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, 1023-1028 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 13.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Arzberger, Thomas
    Al-Sarraj, Safa
    Bodi, Istvan
    Bogdanovic, Nenad
    Braak, Heiko
    Bugiani, Orso
    Del-Tredici, Kelly
    Ferrer, Isidro
    Gelpi, Ellen
    Giaccone, Giorgio
    Graeber, Manuel B
    Ince, Paul
    Kamphorst, Wouter
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Larionov, Sergey
    Meyronet, David
    Monoranu, Camelia
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Tagliavini, Fabrizio
    Stadelmann, Christine
    Streichenberger, Nathalie
    Thal, Dietmar R
    Wharton, Stephen B
    Kretzschmar, Hans
    Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium.2008Inngår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 18, nr 4, 484-96 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and beta-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-microm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V-VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I-II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.

  • 14.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Parkkinen, Laura
    Staged pathology in Parkinson's disease2014Inngår i: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 20, nr Suppl. 1, S57-S61 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There has been a tremendous development since a regional progression of pathology in subjects with Lewy bodies (LB) was initially proposed 30 years ago. The entity of dementia with Lewy bodies has been acknowledged, the main protein constituent of LBs--aggregated α-synuclein (αS)--has been identified and a stepwise progression of the pathology has been reported. Implementation of the staging strategies published provides a common ground for handling a case with a suspected α-synucleinopathy. It is always important to state the staging strategy implemented while assessing a case, as the strategy applied might influence both the reported stage of LB pathology and, ultimately, the final diagnosis of the patient.

  • 15.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Parkkinen, Laura
    Al-Sarraj, Safa
    Arzberger, Thomas
    Bell, Jeanne
    Bodi, Istvan
    Bogdanovic, Nenad
    Budka, Herbert
    Ferrer, Isidro
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Kamphorst, Wouter
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Larionov, Sergey
    Meyronet, David
    Monoranu, Camelia
    Morris, Jodie
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Streichenberger, Nathalie
    Thal, Dietmar R
    Kretzschmar, Hans
    Assessment of alpha-synuclein pathology: a study of the BrainNet Europe Consortium.2008Inngår i: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 67, nr 2, 125-43 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To determine the reliability of assessment of alpha-synuclein-immunoreactive (alphaS-IR) structures by neuropathologists, 28 evaluators from 17 centers of BrainNet Europe examined current methods and reproducibility of alphaS-IR evaluation using a tissue microarray (TMA) technique. Tissue microarray blocks were constructed of samples from the participating centers that contained alphaS-IR structures. Slides from these blocks were stained in each center and assessed for neuronal perikaryal inclusions, neurites, and glial cytoplasmic inclusions. The study was performed in 2 phases. First, the TMA slides were stained with the antibody of the center's choice. In this phase, 59% of the sections were of good or acceptable quality, and 4 of 9 antibodies used performed consistently. Differences in interpretation and categorization of alphaS-IR structures, however, led to differing results between the laboratories. Prior to the second phase, the neuropathologists participated in a training session on the evaluation of alphaS-IR structures. Based on the results of the first phase, selected antibodies using designated antigen retrieval methods were then applied to TMA slides in the second phase. When the designated methods of both staining and evaluation were applied, all 26 subsequently stained TMA sections evaluated were of good/acceptable quality, and a high level of concordance in the assessment of the presence or absence of specific alphaS-IR structures was achieved. A semiquantitative assessment of alphaS-IR neuronal perikaryal inclusions yielded agreements ranging from 49% to 82%, with best concordance in cortical core samples. These results suggest that rigorous methodology and dichotomized assessment (i.e. determining the presence or absence of alphaS-IR) should be applied, and that semiquantitative assessment can be recommended only for the cortical samples. Moreover, the study demonstrates that there are limitations in the scoring of alphaS-IR structures.

  • 16.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Pikkarainen, M
    Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
    Parkkinen, L
    Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
    Synucleinopathies2015Inngår i: Neuropathology of neurodegenerative diseases: A practical guide / [ed] Gabor G Kovacs, Cambridge University Press, 2015, 149-175 s.Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Definition, structure and biochemical background Similar to other “proteinopathies,” the process that links α-synuclein (αS) protein to disease pathogenesis originated from the discovery that a single point mutation in the αS gene (i.e. SNCA) can cause autosomal-dominant Parkinson’s disease (PD) [1]. This was followed by the breakthrough finding that the actual transcribed protein was a major fibrillar component of pathological hallmarks known as Lewy bodies (LBs), Lewy neurites (LNs) and glial cytoplasmic inclusions characterizing a heterogeneous group of diseases, now collectively referred to as “synucleinopathies,” i.e. PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [2, 3]. Currently, there are five missense mutations (pA53T, p.A30P, p.E46K, p.H50Q and p.G51D) [1, 4–8] and multiplication mutations (SNCA duplication and triplication) [9–11] that are genetically linked to clinical parkinsonism (Table 9.1). This genetic and pathological linkage establishes αS as an important player in the development of these disorders.

  • 17.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Pikkarainen, Maria
    Arzberger, Thomas
    Thal, Dietmar R
    Al-Sarraj, Safa
    Bell, Jeanne
    Bodi, Istvan
    Budka, Herbert
    Capetillo-Zarate, Estibaliz
    Ferrer, Isidro
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Meyronet, David
    Monoranu, Camelia
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Stadelmann, Christine
    Streichenberger, Nathalie
    Tagliavini, Fabricio
    Kretzschmar, Hans
    Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein: a study of the BrainNet Europe consortium.2008Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, nr 5, 533-46 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid-beta-protein (Abeta) is generally assessed by neuropathologists in diagnostics. This BrainNet Europe ( http://www.brainnet-europe.org/ ) (15 centres and 26 participants) study was carried out to investigate the reliability of such an assessment. In the first part of this trial, tissue microarray sections were stained with the antibody of each centre's choice. Reflecting the reality, seven antibodies and a plethora of pretreatment strategies were used. Ninety-two percent of the stainings were of good/acceptable quality and the estimation of presence of Abeta aggregates yielded good results. However, a poor agreement was reached particularly regarding quantitative (density) and qualitative (diffuse/cored plaques) results. During a joint meeting, the clone 4G8 was determined to label best the fleecy/diffuse plaques, and thus, this clone and the formic acid pretreatment technique were selected for the second part of this study. Subsequently, all stained sections were of good/acceptable quality and again a high level of concordance of the dichotomized (presence/absence) assessment of plaques and CAA was achieved. However, even when only one antibody was used, the type of Abeta-aggregates (diffuse/cored), type of vessel and Vonsattel grade, were not reliably assigned. Furthermore, the quantification of lesions was far from reliable. In line with the first trial, the agreement while assessing density (some, moderate and many) was unimpressive. In conclusion, we can confirm the utility of immunohistochemical detection of Abeta-protein in diagnostics and research. It is noteworthy that to reach reproducible results a dichotomized assessment of Abeta-immunoreactivity rather than quantification and assignment of various types of lesions should be applied, particularly when comparing results obtained by different neuropathologists.

  • 18.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Popova, Svetlana N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wanders, Alkwin
    Department of Clinical Pathology and Cytology, Umea University Hospital, Umea, Sweden.
    Veress, Bela
    Department of Clinical Pathology and Cytology, Skane University Hospital, Malmo, Sweden.
    Neuronal Protein Alteration in Enteric Dysmotility Syndrome2016Inngår i: Journal of Alzheimer’s Disease & Parkinsonism, ISSN 2161-0460, Vol. 6, nr 1, 1000212Artikkel i tidsskrift (Annet vitenskapelig)
  • 19. Alamdari, Nima
    et al.
    Toraldo, Gianluca
    Aversa, Zaira
    Smith, Ira J
    Castillero, Estibaliz
    Renaud, Guillaume
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Qaisar, Rizwan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Jasuja, Ravi
    Hasselgren, Per-Olof
    Loss of muscle strength during sepsis is in part regulated by glucocorticoids and is associated with reduced muscle fiber stiffness2012Inngår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 303, nr 10, R1090-R1099 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sepsis is associated with impaired muscle function but the role of glucocorticoids in sepsis-induced muscle weakness is not known. We tested the role of glucocorticoids in sepsis-induced muscle weakness by treating septic rats with the glucocorticoid receptor antagonist RU38486. In addition, normal rats were treated with dexamethasone to further examine the role of glucocorticoids in the regulation of muscle strength. Sepsis was induced in rats by cecal ligation and puncture and muscle force generation (peak twitch and tetanic tension) was determined in lower extremity muscles. In other experiments, absolute and specific force as well as stiffness (reflecting the function of actomyosin cross-bridges) were determined in isolated skinned muscle fibers from control and septic rats. Sepsis and treatment with dexamethasone resulted in reduced maximal twitch and tetanic force in intact isolated extensor digitorum longus muscles. The absolute and specific maximal force in isolated muscle fibers was reduced during sepsis together with decreased fiber stiffness. These effects of sepsis were blunted (but not abolished) by RU38486. The results suggest that muscle weakness during sepsis is at least in part regulated by glucocorticoids and reflects loss of contractility at the cellular (individual muscle fiber) level. In addition, the results suggest that reduced function of the cross-bridges between actin and myosin (documented as reduced muscle fiber stiffness) may be involved in sepsis-induced muscle weakness. An increased understanding of mechanisms involved in loss of muscle strength will be important for the development of new treatment strategies in patients with this debilitating consequence of sepsis.

  • 20.
    Alehagen, Urban
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Johansson, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Aaseth, Jan
    Innlandet Hospital Trust, Norway; Hedmark University of Coll, Norway.
    Alexander, Jan
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science NMBU, Norway.
    Wågsäter, Dick
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Significant changes in circulating microRNA by dietary supplementation of selenium and coenzyme Q10 in healthy elderly males. A subgroup analysis of a prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 4, e0174880Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Selenium and coenzyme Q10 is essential for important cellular functions. A low selenium intake is reported from many European countries, and the endogenous coenzyme Q10 production is decreasing in the body with increasing age. Supplementation with selenium and coenzyme Q10 in elderly have shown reduced cardiovascular mortality and reduced levels of markers of inflammation. However, microRNA analyses could give important information on the mechanisms behind the clinical effects of supplementation. Methods Out of the 443 healthy elderly participants that were given supplementation with 200 mu g Se/ day as organic selenium yeast tablets, and 200 mg/day of coenzyme Q10 capsules, or placebo for 4 years, 25 participants from each group were randomized and evaluated regarding levels of microRNA. Isolation of RNA from plasma samples and quantitative PCR analysis were performed. Volcano- and principal component analyses (PCA)-plots were used to illustrate the differences in microRNA expression between the intervention, and the placebo groups. Serum selenium concentrations were measured before intervention. Findings On average 145 different microRNAs out of 172 were detected per sample. In the PCA plots two clusters could be identified indicating significant difference in microRNA expression between the two groups. The pre-treatment expression of the microRNAs did not differ between active treatment and the placebo groups. When comparing the post- treatment microRNAs in the active and the placebo groups, 70 microRNAs exhibited significant differences in expression, also after adjustment for multiple measurements. For the 20 microRNAs with the greatest difference in expression the difference was up to more than 4 fold and with a P-value that were less than 4.4e(-8). Conclusions Significant differences were found in expression of more than 100 different microRNAs with up to 4 fold differences as a result of the intervention of selenium and coenzyme Q10 combined. The changes in microRNA could be a part of mechanisms underlying the clinical effects earlier reported that reduced cardiovascular mortality, gave better cardiac function, and showed less signs of inflammation and oxdative stress following the intervention. However, more research is needed to understand biological mechanisms of the protective effects of selenium and Q10 supplementation.

  • 21. Alfstad, K Å
    et al.
    Lossius, M I
    Røste, G K
    Mowinckel, P
    Scheie, D
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Dept. of Laboratory medicine/Pathology, Umeå University, Umeå Sweden.
    Larsson, P G
    Nakken, K O
    Acute postoperative seizures after epilepsy surgery: a long-term outcome predictor?2011Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, nr 1, 48-53 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors.

    MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up.

    RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using ≥ six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence.

    CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis.

  • 22.
    Aljabery, Firas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.

    Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.

    Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.

    Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.

  • 23. Allander, Susanne Vilhelmsdotter
    et al.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Marké, Lars-Åke
    Svensson, Maria K
    Björn, Wihlén
    Elinder, Carl-Gustaf
    Kreatinin fortfarande den vanligaste njurfunktionsanalysen: Undersökning av praxis i Sverige2012Inngår i: Läkartidningen, ISSN 0023-7205, Vol. 109, nr 19, 960-962 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Markers of renal function (glomerular filtration rate; GFR) are frequently used. In most cases GFR is estimated based on plasma creatinine, but cystatin C, creatinine clearance (with urine collection), iohexol clearance and 51Cr-EDTA clearance are also used. A questionnaire was sent to representatives for clinical chemistry laboratories in Sweden to collect information regarding the use of these markers during the years 2006 2009. The aim was to compare the use in different parts of Sweden and how it has changed over time. The overall use of markers of renal function, including creatinine, continues to increase on a national level, with the exception for endogenous creatinine clearance and 51Cr-EDTA clearance. Creatinine, the most frequently used marker, continues to grow in numbers. 5,6 million creatinine analyses and about two hundred thousand cystatin C analyses were performed during year 2009. There were considerable variations between counties in the use of the studied markers.

  • 24. Amirian, E Susan
    et al.
    Armstrong, Georgina N
    Zhou, Renke
    Lau, Ching C
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill S
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L
    Merrell, Ryan T
    Wrensch, Margaret R
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I
    Scheurer, Michael E
    Aldape, Kenneth
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Brännström, Thomas
    Broholm, Helle
    Collins, Peter
    Giannini, Caterina
    Rosenblum, Marc
    Tihan, Tarik
    Melin, Beatrice S
    Bondy, Melissa L
    The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium2016Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 183, nr 2, 85-91 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

  • 25.
    Andelin, M.
    et al.
    Department of Medicine, NU Hospital Group, Uddevalla, Sweden..
    Kropff, J.
    Department of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands..
    Matuleviciene, V.
    Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    Joseph, J.I.
    Department of Anaesthesiology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA..
    Attvall, S.
    Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hirsch, I.B.
    University of Washington, Seattle, WA, USA.
    Imberg, H.
    Statistiska Konsultgruppen, Gothenburg, Sweden..
    Dahlqvist, S.
    Department of Medicine, NU Hospital Group, Uddevalla, Sweden.
    Klonoff, D.
    Diabetes Research Institute, Mills-Peninsula Health Services, San Mateo, CA, USA..
    Haraldsson, B.
    Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    DeVries, J.H.
    Department of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands..
    Lind, M.
    Department of Medicine, NU Hospital Group, Uddevalla, Sweden Institute of Medicine, University of Gothenburg, Gothenburg, Sweden lind.marcus@telia.com..
    Assessing the Accuracy of Continuous Glucose Monitoring (CGM) Calibrated With Capillary Values Using Capillary or Venous Glucose Levels as a Reference.2016Inngår i: Journal of Diabetes Science and Technology, ISSN 1932-2968, E-ISSN 1932-2968, Vol. 10, nr 4, 876-884 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Using the standard venous reference for the evaluation of continuous glucose monitoring (CGM) systems could possibly negatively affect measured CGM accuracy since CGM are generally calibrated with capillary glucose and venous and capillary glucose concentrations differ. We therefore aimed to quantify the effect of using capillary versus venous glucose reference samples on estimated accuracy in capillary calibrated CGM.less thanbr /greater thanMethods: We evaluated 41 individuals with type 1 diabetes mellitus (T1DM) using the Dexcom G4 CGM system over 6 days. Patients calibrated their CGM devices with capillary glucose by means of the HemoCue system. During 2 visits, capillary and venous samples were simultaneously measured by HemoCue and compared to concomitantly obtained CGM readings. The mean absolute relative difference (MARD) was calculated using capillary and venous reference samples.less thanbr /greater thanResults: Venous glucose values were 0.83 mmol/L (15.0 mg/dl) lower than capillary values over all glycemic ranges, P less than .0001. Below 4 mmol/l (72 mg/dl), the difference was 1.25 mmol/l (22.5 mg/dl), P = .0001, at 4-10 mmol/l (72-180 mg/dl), 0.67 mmol/l (12.0 mg/dl), P less than .0001 and above 10 mmol/l (180 mg/dl), 0.95 mmol/l (17.1 mg/dl), P less than .0001. MARD was 11.7% using capillary values as reference compared to 13.7% using venous samples, P = .037. Below 4 mmol/l (72 mg/dl) MARD was 16.6% and 31.8%, P = .048, at 4-10 mmol/l (72-180 mg/dl) 12.1% and 12.6%, P = .32, above 10 mmol/l (180 mg/dl) 8.7% and 9.2%, P = .82.less thanbr /greater thanConclusion: Using capillary glucose concentrations as reference to evaluate the accuracy of CGM calibrated with capillary samples is associated with a lower MARD than using venous glucose as the reference. Capillary glucose concentrations were significantly higher than venous in all glycemic ranges.less thanbr /greater than (© 2016 Diabetes Technology Society.)

  • 26.
    Andersson, Charlotta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Wilms’ tumor gene 1 (WT1) is a zinc finger transcriptional regulator with crucial functions in embryonic development. Originally WT1 was described as a tumor suppressor gene, but later studies have shown oncogenic properties of WT1 in a variety of tumors. Because of its dual functions in tumorigenesis, WT1 has been described as a chameleon gene. In this thesis, the significance of WT1 as a biomarker was investigated in acute myeloid leukemia (AML), clear cell renal cell carcinoma (ccRCC), ovarian carcinoma (OC) and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

    Previous studies have suggested that expression of WT1 is a potential marker for detection of minimal residual disease (MRD) in AML. We aimed to define expression of WT1 as an MRD marker in AML. In adult AML patients, we found that a reduction of WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis was associated with an improved overall survival (OS) and freedom from relapse (FFR). In peripheral blood, a reduction of WT1 expression (≥ 2-log) detected between 1 and 6 months after treatment initiation was associated with an improved OS and FFR.

    WT1 harbor pathogenic genetic variants in a considerable proportion of AML and T-lymphoblastic leukemia (T-ALL), but mutations have not been reported in BCP-ALL. We aimed to evaluate the clinical impact of WT1 mutations and single nucleotide polymorphisms (SNPs) in BCP-ALL. Pathogenic mutations in the WT1 gene were rarely seen in childhood BCP-ALL. However, five WT1 SNPs were identified. In survival analyses, WT1 SNP rs1799925 was found to be associated with worse OS, indicating that WT1 SNP rs1799925 may be a useful marker for clinical outcome in childhood BCP-ALL. We also explored whether WT1 mutations and SNPs in ccRCC could be used as biomarkers for risk and treatment stratification. We therefore examined whether SNPs or mutations in WT1 were associated with WT1 expression and clinical outcome. Sequencing analysis revealed that none of the previously reported WT1 mutations were found in ccRCC; however, we identified six different WT1 SNPs. Our data suggest that pathogenic WT1 mutations are not involved in ccRCC, and the prognostic significance of WT1 SNPs in ccRCC is considerably weak. However, a favorable OS and disease-specific survival were found in the few cases harboring the homozygous minor allele.

    OC has a poor prognosis, and early effective screening markers are lacking. Serous OCs are known to express the WT1 protein. Overexpressed oncogenic proteins can be considered potential candidate antigens for cancer vaccines and T-cell therapy. It was therefore of great interest to investigate whether anti-WT1 IgG antibody (Ab) measurements in plasma could serve as biomarkers of anti-OC response. We found limited prognostic impact, but the results indicated that anti-WT1 IgG Ab measurements in plasma and WT1 staining in tissue specimens could be potential biomarkers for patient outcome in the high-risk subtypes of OCs.

    In conclusion, the results of this thesis indicate that WT1 gene expression can provide information about MRD of patients with AML, and WT1 SNP rs1799925 may be used as a biomarker for predicting clinical outcome in childhood BCP-ALL. In ccRCC, the prognostic significance of WT1 SNPs is weak and limited to the subgroup of patients that are homozygous for the minor allele. In OCs anti-WT1 IgG Ab measurement in plasma and WT1 staining in tissue specimens could possibly be used as biomarkers for predicting patient outcome in the high-risk subtypes of OCs.

  • 27.
    Andersson, Patiyan
    et al.
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Kolaric, Aleksandra
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Karlsson, Mats G
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    PIK3CA, HRAS and KRAS gene mutations in human penile cancer2008Inngår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, nr 5, 2030-2034 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

    Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

    Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

    Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

  • 28. Asa, S L
    et al.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Chanson, P
    Delgrange, E
    Earls, P
    Ezzat, S
    Grossman, A
    Ikeda, H
    Inoshita, N
    Karavitaki, N
    Korbonits, M
    Laws, E R
    Lopes, M B
    Maartens, N
    McCutcheon, I E
    Mete, O
    Nishioka, H
    Raverot, G
    Roncaroli, F
    Saeger, W
    Syro, L V
    Vasiljevic, A
    Villa, C
    Wierinckx, A
    Trouillas, J
    From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal2017Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, nr 4, C5-C8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

  • 29.
    Asfaw Idosa, Berhane
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Clinical Medicine.
    Sahdo, Berolla
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Clinical Medicine.
    Balcha, Ermias
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Clinical Medicine.
    Kelly, Anne
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Clinical Medicine.
    Söderquist, Bo
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Department of Laboratory Medicine, Clinical Microbiology.
    Särndahl, Eva
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Clinical Medicine.
    C10X polymorphism in the CARD8 gene is associated with bacteraemia2014Inngår i: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, nr 1, 13-20 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

  • 30.
    Axelson, Hans W
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Melberg, Atle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Askmark, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Microdialysis and electromyography of experimental muscle fatigue in healthy volunteers and patients with mitochondrial myopathy2002Inngår i: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 26, nr 4, 520-526 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Consecutive 60-min microdialysis samples were taken from the tibial anterior muscle in 11 healthy subjects and 4 patients with mitochondrial myopathy before (2-3 samples) and after (3-4 samples, 2 controls and 1 patient excluded) sustained isometric foot dorsiflexions. Before exercise, mean concentrations of lactate, pyruvate, hypoxanthine, urate, aspartate, and glutamate did not significantly differ between controls and patients. After exercise, the controls showed significantly increased concentrations of lactate, pyruvate, and urate, decreased hypoxanthine, and no change in aspartate and glutamate. Similar findings were observed in the patients. Plasma lactate was unchanged. Exercise-induced increase in integrated electromyogram amplitude and rated subjective fatigue were correlated to increased post-exercise lactate concentrations, with no obvious difference between the groups. Microdialysis of skeletal muscle allows the detection and monitoring of biochemical changes in the interstitial space. With the exercise protocol used, however, it was not possible to demonstrate any biochemical difference between healthy controls and patients with mitochondrial myopathy.

  • 31.
    Axelson, Hans W
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Öberg, Gunnar
    Askmark, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP2009Inngår i: BMJ case reports, ISSN 1757-790XArtikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterised by the occurrence of symmetrical weakness and sensory impairment in arms and legs. The course is relapsing or chronic and progressing. CIDP is considered to be an autoimmune disease, which is supported by the beneficial response to immunomodulating therapies in most patients. We report on a patient with CIDP who has been in remission for more than 3 years after treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP on two occasions.

  • 32.
    Barranco, Isabel
    et al.
    University of Murcia, Spain.
    Tvarijonaviciute, Asta
    University of Murcia, Spain.
    Perez-Patino, Cristina
    University of Murcia, Spain.
    Vicente Carrillo, Alejandro
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Parrilla, Inmaculada
    University of Murcia, Spain.
    Ceron, Jose J.
    University of Murcia, Spain.
    Martinez, Emilio A.
    University of Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Roca, Jordi
    University of Murcia, Spain.
    Glutathione Peroxidase 5 Is Expressed by the Entire Pig Male Genital Tract and Once in the Seminal Plasma Contributes to Sperm Survival and In Vivo Fertility2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 9, e0162958Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glutathione peroxidase-5 (GPX5) is an H2O2-scavenging enzyme identified in boar seminal plasma (SP). This study attempted to clarify its origin and role on sperm survival and fertility after artificial insemination (AI). GPX5 was expressed (Western blot and immunocytochemistry using a rabbit primary polyclonal antibody) in testes, epididymis and accessory sex glands (6 boars). SP-GPX5 concentration differed among boars (11 boars, P amp;lt; 0.001), among ejaculates within boar (44 ejaculates, P amp;lt; 0.001) and among portions within ejaculate (15 ejaculates). The first 10 mL of the spermrich fraction (SRF, sperm-peak portion) had a significantly lower concentration (8.87 +/- 0.78 ng/mL) than the rest of the SRF and the post-SRF (11.66 +/- 0.79 and 12.37 +/- 0.79 ng/mL, respectively, P amp;lt; 0.005). Spermmotility of liquid-stored semen AI-doses (n = 44, at 15-17 degrees C during 72h) declined faster in AI-doses with low concentrations of SP-GPX5 compared to those with high-levels. Boars (n = 11) with high SP-GPX5 showed higher farrowing rates and litter sizes than those with low SP-GPX5 (a total of 5,275 inseminated sows). In sum, GPX5 is widely expressed in the boar genital tract and its variable presence in SP shows a positive relationship with sperm quality and fertility outcomes of liquid-stored semen AI-doses.

  • 33. Bell, Jeanne E
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Al-Sarraj, Safa
    Arzberger, Thomas
    Bogdanovic, Nenad
    Budka, Herbert
    Dexter, David T
    Falkai, Peter
    Ferrer, Isidro
    Gelpi, Elena
    Gentleman, Steven M
    Giaccone, Giorgio
    Huitinga, Inge
    Ironside, James W
    Klioueva, Natasja
    Kovacs, Gabor G
    Meyronet, David
    Palkovits, Miklos
    Parchi, Piero
    Patsouris, Efstatios
    Reynolds, Richard
    Riederer, Peter
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Schmitt, Andrea
    Schmitz, Peer
    Streichenberger, Nathalie
    Schwalber, Ameli
    Kretzschmar, Hans
    Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium.2008Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, nr 5, 497-507 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.

  • 34. Bender, Nicole
    et al.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Andersen, Berit
    Hocking, Jane S
    van Bergen, Jan
    Morgan, Jane
    van den Broek, Ingrid Vf
    Zwahlen, Marcel
    Low, Nicola
    Chlamydia infection, pelvic inflammatory disease, ectopic pregnancy and infertility: cross-national study2011Inngår i: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 87, nr 7, 601-608 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives To describe, using routine data in selected countries, chlamydia control activities and rates of chlamydia infection, pelvic inflammatory disease (PID), ectopic pregnancy and infertility and to compare trends in chlamydia positivity with rates of PID and ectopic pregnancy. Methods Cross-national comparison including national data from Australia, Denmark, the Netherlands, New Zealand, Sweden and Switzerland. Routine data sources about chlamydia diagnosis and testing and International Classification of Disease-10 coded diagnoses of PID, ectopic pregnancy and infertility in women aged 15-39 years from 1999 to 2008 were described. Trends over time and relevant associations were examined using Poisson regression. Results Opportunistic chlamydia testing was recommended in all countries except Switzerland, but target groups differed. Rates of chlamydia testing were highest in New Zealand. Chlamydia positivity was similar in all countries with available data (Denmark, New Zealand and Sweden) and increased over time. Increasing chlamydia positivity rates were associated with decreasing PID rates in Denmark and Sweden and with decreasing ectopic pregnancy rates in Denmark, New Zealand and Sweden. Ectopic pregnancy rates appeared to increase over time in 15-19-year-olds in several countries. Trends in infertility diagnoses were very variable. Conclusions The intensity of recommendations about chlamydia control varied between countries but was not consistently related to levels of chlamydia diagnosis or testing. Relationships between levels of chlamydia infection and complication rates between or within countries over time were not straightforward. Development and validation of indicators of chlamydia-related morbidity that can be compared across countries and over time should be pursued.

  • 35. Benyamin, Beben
    et al.
    Maihofer, Adam X
    Schork, Andrew J
    Hamilton, Bruce A
    Rao, Fangwen
    Schmid-Schönbein, Geert W
    Zhang, Kuixing
    Mahata, Manjula
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi. Univ Calif San Diego, La Jolla, CA 92093 USA..
    Schork, Nicholas J
    Biswas, Nilima
    Hook, Vivian Y
    Wei, Zhiyun
    Montgomery, Grant W
    Martin, Nicholas G
    Nievergelt, Caroline M
    Whitfield, John B
    O'Connor, Daniel T
    Identification of novel loci affecting circulating chromogranins and related peptides2017Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, nr 1, 233-242 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10(-30) for rs4253311 and 1.85 × 10(-19) for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.

  • 36.
    Berggren Söderlund, Maria
    et al.
    Klinisk kemi, labmedicin Skåne.
    Nilsson-Ehle, Herman
    Sahlgrenska universitetssjukhuset Göteborg.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Jonsson, Magnus
    Klinisk kemi, labmedicin Skåne.
    Vitaminer och spårämnen2012Inngår i: Laurells klinisk kemi i praktisk medicin / [ed] Nilsson Ehle P, Berggren Söderlund M, Theodorsson E, Lund: Studentlitteratur, 2012, 9, 655-673 s.Kapittel i bok, del av antologi (Fagfellevurdert)
  • 37.
    Björk, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Venge, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Peterson, C G B
    Pharmacia & Upjohn Diagnostics, Uppsala, Sweden .
    Measurements of ECP in serum and the impact of plasma coagulation2000Inngår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 55, nr 5, 442-448 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serum measurement of ECP (eosinophil cationic protein) is used as an indication of eosinophil activation in diseases such as asthma. The levels are dependent on sample handling, since a certain amount of ECP is released during storage. The mechanisms that induce this in vitro release are not known, but are supposed to be related to the coagulation process. The aim of this study was to investigate this further. ECP was measured in EDTA plasma and serum at 22 and 37°C from healthy individuals and patients with asthma and allergy. The serum levels of ECP increased with temperature. Recalcification of citrated plasma in the presence of granulocytes with increasing concentrations of Ca2+ showed a dissociation between the levels of ECP and the occurrence of coagulation. Further experiments indicated that plasma coagulation is not of any importance for the degranulation of eosinophils, nor did the addition of platelets or mononuclear cells affect the ECP levels. Incubations of granulocytes with fresh or frozen plasma and Ca2+suggested the existence of a freezing labile factor in plasma, necessary for the degranulation of healthy eosinophils, but not for allergic/asthmatic eosinophils. Further experiments with pure eosinophils indicated the existence of factors in serum and plasma which facilitate ECP secretion of an active, temperature-dependent nature. We conclude that the raised ECP levels in serum, as compared to EDTA plasma, are unrelated to the coagulation process, but are due to the continuous secretion ex vivo of ECP from active eosinophils. This process is time and temperature dependent and may be facilitated by eosinophil-activating components in the extracellular environment.

  • 38.
    Björkesten, Johan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Shen, Qiujin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wik, Lotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hougaard, David
    Statens Serum Inst, Danish Ctr Neonatal Screening, Copenhagen, Denmark.
    Cohen, Arieh
    Statens Serum Inst, Danish Ctr Neonatal Screening, Copenhagen, Denmark.
    Sörensen, Lene
    Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stability of Proteins in Dried Blood Spot Biobanks.2017Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, nr 7, 1286-1296 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An important motivation for the construction of biobanks is to discover biomarkers that identify diseases at early, potentially curable stages. This will require biobanks from large numbers of individuals, preferably sampled repeatedly, where the samples are collected and stored under conditions that preserve potential biomarkers. Dried blood samples are attractive for biobanking because of the ease and low cost of collection and storage. Here we have investigated their suitability for protein measurements. 92 proteins with relevance for oncology were analyzed using multiplex proximity extension assays (PEA) in dried blood spots collected on paper and stored for up to 30 years at either +4&deg;C or -24&deg;C.</p> <p>Our main findings were that 1) the act of drying only slightly influenced detection of blood proteins (average correlation of 0.970), and in a reproducible manner (correlation of 0.999), 2) detection of some proteins was not significantly affected by storage over the full range of three decades (34% and 76% of the analyzed proteins at +4&deg;C and -24&deg;C, respectively), while levels of others decreased slowly during storage with half-lives in the range of 10 to 50 years, and 3) detectability of proteins was less affected in dried samples stored at -24&deg;C compared to at +4&deg;C, as the median protein abundance had decreased to 80% and 93% of starting levels after 10 years of storage at +4&deg;C or -24&deg;C, respectively. The results of our study are encouraging as they suggest an inexpensive means to collect large numbers of blood samples, even by the donors themselves, and to transport, and store biobanked samples as spots of whole blood dried on paper. Combined with emerging means to measure hundreds or thousands of protein, such biobanks could prove of great medical value by greatly enhancing discovery as well as routine analysis of blood biomarkers.

  • 39.
    Bohjort, Emelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Method verification for homocysteine and a sustainability study on glucose, homocysteine and lactate in different sampling tubes2016Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
    Abstract [en]

    The pre-analytical phase is known for being the most important step in the laboratory process to reach reliable test results. If handling, transport or preparation of the sample is performed incorrectly the results can deviate from the true value. Today, sampling tubes contains various additives to stabilize concentration levels. The aim of this study was to test a new sampling tube containing fluoride/citrate for glucose, lactate and homocysteine. It was also of interest to evaluate the stability of those three analytes in lithium-heparin, sodium-fluoride/potassium oxalate and fluoride/citrate tubes. To perform the sustainability study, a method verification was done for homocysteine in plasma. The study was performed in a hospital laboratory on the routine instrument Roche Cobas 6000 analyzer. Blood was drawn from 20 patients and was analyzed at the hospital laboratory in Gävle. The blood samples were transported frozen to the laboratory in Hudiksvall and were used in the method verification. For the sustainability study, blood was drawn from 10 healthy volunteers in lithium-heparin, sodium-fluoride/potassium oxalate and fluoride/citrate tubes. The method verification was approved. The results showed that glucose was stable for up to 72 hours in Vacuette Glycaemia tube with fluoride/citrate and this tube also gave more accurate results. Lactate and homocysteine were also stable in fluoride/citrate, but needs further studies. All three analytes were more stable if the sample tubes were centrifuged as soon as possible after blood collection. Fluoride/citrate tubes were stable without centrifugation directly.

  • 40.
    Boman, Jens
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Gaydos, Charlotte
    Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
    Juto, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Quinn, Thomas C
    Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
    Failure to detect Chlamydia trachomatis in cell culture by using a monoclonal antibody directed against the major outer membrane protein1997Inngår i: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 35, nr 10, 2679-2680 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two commercially available monoclonal antibodies for cell culture confirmation of Chlamydia trachomatis were compared in two prospective studies and one large retrospective study. In total, more than 33,000 genital specimens were cultured in parallel and stained with both antibodies, one of which was directed against the major outer membrane protein (MOMP) and one uf which was directed against the lipopolysaccharide (LPS). We found the anti-LPS-based assay to be more sensitive and as specific as the anti-MOMP-based assay for C. trachomatis cell culture confirmation of genital specimens.

  • 41.
    Botling, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lohr, Miriam
    Hellwig, Birte
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Lambe, Mats
    Berglund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    König, André
    Fernandes, Oswaldo
    Karlsson, Mats
    Helenius, Gisela
    Karlsson, Christina
    Rahnenführer, Jörg
    Hengstler, Jan G
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation2013Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 1, 194-204 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multi-gene signatures in clinical practice is unclear and the biological importance of individual genes is difficult to assess as the published signatures virtually do not overlap

    Methods:

    Here we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data was used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level p<0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n=860).

    RESULTS:

    The meta-analysis revealed 14 genes that were significantly associated with survival (p<0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from two independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    CONCLUSIONS:

    Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

  • 42.
    Breimer, Lars H.
    et al.
    Region Örebro län. Laboratoriemedicinska länskliniken.
    Eriksson, C. G.
    Laboratoriemedicinska länskliniken, Örebro universitetssjukhus, Örebro, Sweden.
    Nilsson, T. K.
    Laboratoriemedicinska länskliniken, Örebro universitetssjukhus, Örebro, Sweden; Hälsoakademin, Örebro universitet, Örebro, Sweden.
    Morgondagens laboratorium - redan i går2012Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, nr 37, 1624-1624 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 43. Bruzelius, Maria
    et al.
    Iglesias, Maria Jesus
    Hong, Mun-Gwan
    Sanchez-Rivera, Laura
    Gyorgy, Beata
    Carlos Souto, Juan
    Frånberg, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Numerisk analys och datalogi (NADA). Karolinska Institutet, Sweden.
    Fredolini, Claudia
    Strawbridge, Rona J.
    Holmström, Margareta
    Hamsten, Anders
    Uhlén, Mathias
    Silveira, Angela
    Manuel Soria, Jose
    Smadja, David M.
    Butler, Lynn M.
    Schwenk, Jochen M.
    Morange, Pierre-Emmanuel
    Tregouet, David-Alexandre
    Odeberg, Jacob
    PDGFB, a new candidate plasma biomarker for venous thromboembolism: results from the VEREMA affinity proteomics study2016Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, nr 23, E59-E66 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish Venous Thromboembolism Biomarker Study, using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor beta (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (rho similar to 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P = .002). PDGF. was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.

  • 44.
    Brännström, André
    et al.
    Umea Univ, Sports Med Unit, Dept Community Med & Rehabil, SE-90187 Umea, Sweden..
    Yu, Ji-Guo
    Umea Univ, Sports Med Unit, Dept Community Med & Rehabil, SE-90187 Umea, Sweden..
    Jonsson, Per
    Umea Univ, Div Orthopaed, Dept Surg & Perioperat Sci, Umea, Sweden..
    Åkerfeldt, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Svensson, Michael
    Umea Univ, Sports Med Unit, Dept Community Med & Rehabil, SE-90187 Umea, Sweden..
    Vitamin D in relation to bone health and muscle function in young female soccer players2017Inngår i: European Journal of Sport Science, ISSN 1746-1391, E-ISSN 1536-7290, Vol. 17, nr 2, 249-256 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present work investigated serum vitamin D (25(OH)D) status in relation to bone and muscle qualities and functions in 19 female soccer players (13-16 years) resident at northern latitude with very low sun exposure (∼32-36 h/month) during winter season (late January to early March). Serum 25(OH)D, parathyroid hormone and bone turnover markers osteocalcin (OC) and beta carboxy-terminal collagen cross-links (β-Ctx), as well as body composition and muscle performance were examined. Hormones were tested using routine laboratory methods. Fat mass, lean mass, and bone mineral density in whole body, as well as femur and lumbar spine were evaluated with dual-energy X-ray absorptiometry. Muscle performance was assessed through isokinetic knee extension and flexion, countermovement jump, and sprint running. 25(OH)D was low (50.5 ±   12.8 nmol l(-1)), whereas the values of bone turnover markers were markedly high (OC: 59.4 ±   18.6 µg l(-1); β-Ctx: 1075 ±   408 ng l(-1)). All bone and muscle measurements were normal or above normal. 25(OH)D was not significantly correlated with most of the parameters of bone and muscle quality or function, except the knee extension time to peak torque (r   =   -0.50, p =   .03). In conclusion, the level of vitamin D is markedly low in adolescent female soccer players during the winter in Sweden. However, vitamin D levels did not significantly correlate with measures of bone and muscle except a moderate correlation in time to peak torque in the knee extensors. The practical implication of low vitamin D levels in young growing female athletes remains unclear.

  • 45. Buerger, Katharina
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Ewers, Michael
    Pirttilä, Tuula
    Zinkowski, Raymond
    Hampel, Harald
    No correlation between CSF tau protein phosphorylated at threonine 181 with neocortical neurofibrillary pathology in Alzheimer's disease.2007Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, nr Pt 10, e82- s.Artikkel i tidsskrift (Fagfellevurdert)
  • 46. Buerger, Katharina
    et al.
    Ewers, Michael
    Pirttilä, Tuula
    Zinkowski, Raymond
    Alafuzoff, Irina
    Kuopio University, Finland.
    Teipel, Stefan J
    DeBernardis, John
    Kerkman, Daniel
    McCulloch, Cheryl
    Soininen, Hilkka
    Hampel, Harald
    CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.2006Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 129, nr Pt 11, 3035-41 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.

  • 47.
    Byström, Sanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Fredolini, Claudia
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Edqvist, P. -H
    Nyaiesh, Etienne-Nicholas
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Drobin, Kimi
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Matthias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bergqvist, M.
    Pontén, F.
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence2017Inngår i: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, nr 3, 385-395 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Blood-based proteomic profiling may aid and expand our understanding of diseases and their different phenotypes. The aim of the presented study was to profile serum samples from patients with malignant melanoma using affinity proteomic assays to describe proteins in the blood stream that are associated to stage or recurrence of melanoma. MATERIAL AND METHODS: Multiplexed protein analysis was conducted using antibody suspension bead arrays. A total of 232 antibodies against 132 proteins were selected from (i) a screening with 4595 antibodies and 32 serum samples from melanoma patients and controls, (ii) antibodies used for immunohistochemistry, (iii) protein targets previously related with melanoma. The analysis was performed with 149 serum samples from patients with malignant melanoma. Antibody selectivity was then assessed by Western blot, immunocapture mass spectrometry, and epitope mapping. Lastly, indicative antibodies were applied for IHC analysis of melanoma tissues. RESULTS: Serum levels of regucalcin (RGN) and syntaxin 7 (STX7) were found to be lower in patients with both recurring tumors and a high Breslow's thickness (T-stage 3/4) compared to low thickness (T-stage 1/2) without disease recurrence. Serum levels of methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) were instead elevated in sera of T3/4 patients with recurrence. The analysis of tissue sections with S100A6 and MTHFD1L showed positive staining in a majority of patients with melanoma, and S100A6 was significantly associated to T-stage. CONCLUSIONS: Our findings provide a starting point to further study RGN, STX7, MTHFD1L and S100A6 in serum to elucidate their involvement in melanoma progression and to assess a possible contribution to support clinical indications.

  • 48.
    Bäckryd, Emmanuel
    et al.
    Linköping University, Linköping, Sweden.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Gerdle, Björn
    Linköping University, Linköping, Sweden.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    High Levels of Cerebrospinal Fluid Chemokines Point to the Presence of Neuroinflammation in Peripheral Neuropathic Pain: A Cross-Sectional Study of Two Cohorts of Patients Compared to Healthy ControlsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called “gliotransmitters”, a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile for neuropathic pain patients. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation.  

    CSF samples were collected from two cohorts of patients with neuropathic pain (n=11 and n=16, respectively) and healthy controls (n=11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek® Multiplex Inflammation I, Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares – discriminant analysis, were used for statistical analyses.

    CSF levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared to healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in fibromyalgia patients. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Since it has been suggested that prevalent co-morbidities to chronic pain (e.g., depression, anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation is a common mediator.

  • 49.
    Cahill, Nicola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bergh, A-C
    Kanduri, M
    Göransson-Kultima, H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ryan, F
    Smedby, K E
    Juliusson, G
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Rosén, A
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments.2013Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, nr 1, 150-158 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-β and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.

  • 50.
    Cajander, Sara
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden.
    Bäckman, Anders
    Örebro universitet, Institutionen för medicinska vetenskaper. Clinical Research Centre, .
    Tina, Elisabet
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Clinical Research Centre.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital, Sweden; Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Sweden.
    Söderquist, Bo
    Örebro universitet, Institutionen för läkarutbildning. Region Örebro län. Department of Laboratory Medicine, Clinical Microbiology.
    Källman, Jan
    Region Örebro län. Örebro universitet, Institutionen för medicinska vetenskaper. Department of Infectious Diseases.
    Preliminary results in quantitation of HLA-DRA by real-time PCR: a promising approach to identify immunosuppression in sepsis2013Inngår i: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 17, nr 5, R223Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Reduced monocyte human leukocyte antigen (mHLA)-DR surface expression in the late phase of sepsis is postulated as a general biomarker of sepsis-induced immunosuppression and an independent predictor of nosocomial infections. However, traditional monitoring of mHLA-DR by flow cytometry has disadvantages due to specific laboratory requirements. An mRNA-based HLA-DR monitoring by polymerase chain reaction (PCR) would improve the clinical usage and facilitate conduction of large multicenter studies. In this study, we evaluated an mRNA-based HLA-DR monitoring by quantitative real-time PCR (qRT-PCR) as an alternative method to traditional flow cytometry.

    Methods: Fifty-nine patients with sepsis and blood culture growing pathogenic bacteria were studied. Blood samples were collected at day 1 or 2 after admission, for measurement of mHLA-DR by flow cytometry and mRNA expression of HLA-DRA and class II transactivator (CIITA) by qRT-PCR. Blood samples from blood donors were used as controls (n = 30).

    Results: A significant reduced expression of mHLA-DR, HLA-DRA, and CIITA was seen in septic patients compared with controls. HLA-DRA mRNA level in whole blood was highly correlated with surface expression of mHLA-DR.

    Conclusions: Patients with sepsis display a diminished expression of HLA-DR at the monocyte surface as well as in the gene expression at the mRNA level. The mRNA expression level of HLA-DRA monitored by qRT-PCR correlates highly with surface expression of HLA-DR and appears to be a possible future biomarker for evaluation of immunosuppression in sepsis.

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