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Sahdo, Berolla
Publications (10 of 10) Show all publications
Asfaw Idosa, B., Sahdo, B., Balcha, E., Kelly, A., Söderquist, B. & Särndahl, E. (2014). C10X polymorphism in the CARD8 gene is associated with bacteraemia. Immunity, inflammation and disease, 2(1), 13-20
Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
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2014 (English)In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
West Sussex, UK: John Wiley & Sons, 2014
Keywords
Bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisims, sepsis
National Category
Clinical Laboratory Medicine Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:oru:diva-42421 (URN)10.1002/iid3.14 (DOI)25400921 (PubMedID)
Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2018-11-30Bibliographically approved
Sahdo, B., Evans, A. L., Arnemo, J. M., Fröbert, O., Särndahl, E. & Blanc, S. (2013). Body temperature during hibernation is highly correlated with a decrease in circulating innate immune cells in the brown bear (Ursus arctos): a common feature among hibernators?. International Journal of Medical Sciences, 10(5), 508-514
Open this publication in new window or tab >>Body temperature during hibernation is highly correlated with a decrease in circulating innate immune cells in the brown bear (Ursus arctos): a common feature among hibernators?
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2013 (English)In: International Journal of Medical Sciences, ISSN 1449-1907, E-ISSN 1449-1907, Vol. 10, no 5, p. 508-514Article in journal (Refereed) Published
Abstract [en]

Background: Hibernation involves periods of severely depressed metabolism (torpor) and decreases in body temperature (Tb). Small arctic mammals (<5kg), in which Tb generally drop drastically, display leukopenia during hibernation. This raised the question of whether the decreased leukocyte counts in mammalian hibernators is due to torpor per se or is secondary to low Tb. The present study examined immune cell counts in brown bears (Ursus arctos), where torpor is only associated with shallow decreases in Tb. The results were compared across hibernator species for which immune and Tb data were available.

Methods and Results: The white blood cell counts were determined by flow cytometry in 13 bears captured in the field both during summer and winter over 2 years time. Tb dropped from 39.6+/-0.8 to 33.5+/-1.1 degrees C during hibernation. Blood neutrophils and monocytes were lower during hibernation than during the active period (47%, p=0.001; 43%, p=0.039, respectively), whereas no change in lymphocyte counts was detected (p=0.599). Further, combining our data and those from 10 studies on 9 hibernating species suggested that the decline in Tb explained the decrease in innate immune cells (R-2=0.83, p<0.0001).

Conclusions: Bears have fewer innate immune cells in circulation during hibernation, which may represent a suppressed innate immune system. Across species comparison suggests that, both in small and large hibernators, Tb is the main driver of immune function regulation during winter dormancy. The lack of a difference in lymphocyte counts in this context requires further investigations.

Place, publisher, year, edition, pages
Sydney, Australia: Ivyspring International Publisher, 2013
Keywords
Brown bear, Ursus arctos, hibernation, hnnate immunity, leukocytes, torpor
National Category
Medical and Health Sciences Immunology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-28913 (URN)10.7150/ijms.4476 (DOI)000316997300003 ()23532623 (PubMedID)2-s2.0-84875126243 (Scopus ID)
Available from: 2013-05-06 Created: 2013-05-03 Last updated: 2018-08-27Bibliographically approved
Sahdo, B., Fransén, K., Asfaw Idosa, B., Eriksson, P., Söderquist, B., Kelly, A. & Särndahl, E. (2013). Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome. PLoS ONE, 8(10)
Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed) Published
Abstract [en]

Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.

Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2013
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-35447 (URN)10.1371/journal.pone.0075457 (DOI)000325483600018 ()24098386 (PubMedID)2-s2.0-84884894455 (Scopus ID)
Funder
Swedish Research Council, ES: K2010-57X-21435-01-3
Note

Funding Agencies:

Research committee of the County Council of Örebro

Nyckelfonden at Örebro University Hospital

Sund's Foundation for Rheumatic Research

King Gustaf V Memorial Foundation

Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2019-06-14Bibliographically approved
Sahdo, B. (2013). Inflammasomes: defense guardians in host-microbe defence. (Doctoral dissertation). Örebro: Örebro universitet
Open this publication in new window or tab >>Inflammasomes: defense guardians in host-microbe defence
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The inflammasomes are emerging as key regulators of the innate immune response as they response to cellular infection, tissue damage and/or stress. Activated inflammasomes provide a signalling platform for caspase-1 activation which subsequently processes the maturation of interleukin (IL)-1β and IL-18, and in addition promotes cell death, named pyroptosis. These effector mechanisms of the inflammasome constitute an important part of the innate immune response in host-defence.

The aims of this thesis were to elucidate if the inflammasome is activated by specific pathogens, and if genetic variations lead to susceptibility to severe inflammatory diseases, such as blood stream infections. We found that the commensal pathogens Staphylococcus aureus and Propionibacterium acnes induce caspase-1 activation, the latter being a stronger activator. The data also propose that it is rather the bacterial ligands than the secreted toxins of P. acnes that induce inflammasome activation. Even though the S. aureus PVL-toxin induces a caspase-1 activation, involvement of other virulence factors are of importance. Upon S. aureus and P. acnes stimulation, inter-individual variations were found, implying that the characteristics of the host innate immune system, rather than the properties of the bacteria, are decisive for the inflammatory response. Indeed, healthy individuals with the combined polymorphisms of the NLRP3 inflammasome (C10X/Q705K) have higher levels of spontaneous IL-1β, and most intriguingly C10X polymorphism showed a strong correlation with patients with bacteremia.

In conclusion, these studies suggest that different pathogens activate the inflammasomes to various degrees. The genetics of the host innate immune system, rather than the properties of the bacteria, define the inflammatory response against these bacteria, and specific genetic variations such as C10X polymorphism can increase the susceptibility for disease development.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 76
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 88
Keywords
Innate immunity, inflammasome, leukocytes, cytokines, Staphylococcus aureus, Propionibacterium acnes, inflammation, infection, gene variants, polymorphism.
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-28523 (URN)978-91-7668-923-3 (ISBN)
Public defence
2013-06-05, Wilandersalen, M-huset, Universitetetssjukhuset Örebro, Grev Rosen gatan 18, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-10-17Bibliographically approved
Stenvinkel, P., Fröbert, O., Anderstam, B., Palm, F., Eriksson, M., Bragfors-Helin, A.-C., . . . Johnson, R. J. (2013). Metabolic Changes in Summer Active and Anuric Hibernating Free-Ranging Brown Bears (Ursus arctos). PLoS ONE, 8(9), Article ID e72934.
Open this publication in new window or tab >>Metabolic Changes in Summer Active and Anuric Hibernating Free-Ranging Brown Bears (Ursus arctos)
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, article id e72934Article in journal (Refereed) Published
Abstract [en]

The brown bear (Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-54768 (URN)10.1371/journal.pone.0072934 (DOI)000326405300035 ()24039826 (PubMedID)2-s2.0-84883625178 (Scopus ID)
Note

Funding agency:

Swedish Medical Research Council (VR) 

Swedish Environmental Protection Agency 

Norwegian Directorate for Nature Management 

Swedish Association for Hunting and Wildlife Management 

Research Council of Norway 

Austrian Science Foundation a Nordforsk research network 44042

Lundbeck Foundation R126-2012-12408 

Available from: 2017-01-17 Created: 2017-01-17 Last updated: 2018-05-27Bibliographically approved
Sahdo, B., Särndahl, E., Elgh, F. & Söderquist, B. (2013). Propionibacterium acnes activates caspase-1 in human neutrophils. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 121(7), 652-63
Open this publication in new window or tab >>Propionibacterium acnes activates caspase-1 in human neutrophils
2013 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 7, p. 652-63Article in journal (Refereed) Published
Abstract [en]

Propionibacterium acnes is a Gram-positive, slow-growing, anaerobic bacillus, predominantly found as a commensal on the skin and mucous membranes of adults. It is, however, also considered an opportunistic pathogen; mostly associated with acne vulgaris, but rarely also with severe infections such as infective endocarditis, prosthetic joint infections, and deep sternal wound infections following cardiothoracic surgery. In addition, P. acnes has recently been found in high frequency in prostate tissue from patients with prostatitis and prostate cancer. The NOD-like receptors (NLR) act as intracellular sensors of microbial components, and a number of various bacteria have been found to induce assembling and activation of NLR-inflammasomes; leading to a pro-inflammatory response. The inflammasome-mediated formation of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 involves the auto-proteolytic maturation of caspase-1. This study investigated if P. acnes activates inflammasomes. Propionibacterium acnes isolates (n = 29) with diverse origin were used as stimuli for peripheral leukocytes obtained from blood donors (BDs). The activity of inflammasomes was determined by measuring caspase-1 by flow cytometry and cytokine production by ELISA. A significant amount of caspase-1 was found in neutrophils upon P. acnes stimulation, whereas only a modest activation was seen in monocytes. The activation was mainly produced by components of the bacterial cell and no exo-products, because heat-killed and live bacteria caused high activation of caspase-1 as well as cytokine production, whereas the bacterial supernatant elicited minor effect. The response among different BDs varied significantly, almost fivefold. In addition, P. acnes of various origins showed considerable variation, however, the commensal isolates showed a stronger response compared with the invasive. In conclusion, although regarded as a harmless commensal of the skin, P. acnes strongly activates the inflammasome of human peripheral neutrophils.

Place, publisher, year, edition, pages
Hoboken, USA: Wiley-Blackwell, 2013
Keywords
Propionibacterium acnes, anaerobic bacteria, innate immunity, inflammasome, leukocytes, prostate.
National Category
Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-30113 (URN)10.1111/apm.12035 (DOI)000320614200009 ()23278288 (PubMedID)2-s2.0-84879497934 (Scopus ID)
Note

Funding Agencies:

Research Committee of the County Council of Orebro 

Nyckelfonden at Orebro University Hospital 

King Gustaf V Memorial Foundation 

Available from: 2013-08-02 Created: 2013-08-02 Last updated: 2018-09-11Bibliographically approved
Verma, D., Eriksson, P., Sahdo, B., Persson, A., Ejdeback, M., Särndahl, E. & Söderkvist, P. (2010). Two adult siblings with atypical Cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3. Arthritis and Rheumatism, 62(7), 2138-2143
Open this publication in new window or tab >>Two adult siblings with atypical Cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3
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2010 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 7, p. 2138-2143Article in journal (Refereed) Published
Abstract [en]

Objective. The NALP3 inflammasome is a multiprotein complex that triggers caspase 1-mediated interleukin-1 beta (IL-1 beta) release. Mutations in the gene encoding NALP3 (NLRP3) underlie the cryopyrin-associated periodic syndrome (CAPS). The aim of this study was to report a novel NLRP3 mutation in 2 siblings of Swedish descent in whom symptoms first presented in adulthood.

Methods. Mutation analysis of NLRP3 was performed on DNA from patients with CAPS and 100 control subjects. For assessment of caspase 1 and IL-1 beta, blood was collected from patients and age-and sex-matched healthy control subjects. Genetic constructs containing mutant or wild-type NLRP3 were transduced into THP-1 cells, followed by assessment of IL-1 beta levels in cell supernatant.

Results. Both siblings carried a novel M299V mutation in NLRP3, which was not present in the control population. The samples obtained from the patients displayed increased caspase 1 activity and elevated IL-1 beta levels at basal conditions as compared with healthy control subjects. THP-1 cells expressing mutated M299V revealed almost 10-fold higher IL-1 beta production compared with the wild-type construct.

Conclusion. M299V is an activating mutation in NLRP3 resulting in elevated spontaneous caspase 1 activity and IL-1 beta levels. The classic CAPS phenotype was lacking in these adult siblings. Whereas one sibling displayed a milder phenotype that has so far responded satisfactorily to oral nonsteroidal antiinflammatory drugs in combination with low-dose corticosteroids, the inflammatory symptoms in the sibling with the more severe case responded well to IL-1 beta blockade. Understanding the pathogenic mechanism underlying such disorders can be helpful for the physician. Our study reinforces the importance of genetic testing and laboratory investigations in combination with careful phenotypic evaluation for the diagnosis of such patients.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-12863 (URN)10.1002/art.27489 (DOI)000282758500034 ()
Note

ARTHRITIS AND RHEUMATISM ended 2013

Available from: 2011-01-10 Created: 2011-01-03 Last updated: 2017-12-11Bibliographically approved
Idosa, B. A., Sahdo, B., Balcha, E., Kelly, A., Söderquist, B. & Särndahl, E.C10X polymorphism in the CARD8 gene is associated with bacteraemia.
Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction:: 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.

Methods:: 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.

Results:: 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 eithergroup of patients.

Conclusions:: Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

Keywords
bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisms, sepsis
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32015 (URN)
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2017-10-17Bibliographically approved
Sahdo, B., Fransén, K., Idosa, B. A., Eriksson, P., Söderquist, B., Kelly, A. & Särndahl, E.Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasome.
Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasome
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched noncarrier controls.

Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K/C10X polymorphisms compared to controls, whereas no difference was found for IL- 18 and the other cytokines measured. These data suggest that these combined polymorphisms creates inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

Keywords
Auto-inflammation, Cytokines, Inflammasome, Interleukin-1β, Leukocytes
National Category
Medical and Health Sciences Immunology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32006 (URN)
Available from: 2013-10-15 Created: 2013-10-14 Last updated: 2017-10-17Bibliographically approved
Sahdo, B., DeLeo, F. R., Söderqvist, B. & Särndahl, E.Staphylococcus aureus-mediated caspase-1 activation in human neutrophils: a role for Panton-Valentine Leukocidin?.
Open this publication in new window or tab >>Staphylococcus aureus-mediated caspase-1 activation in human neutrophils: a role for Panton-Valentine Leukocidin?
(English)Manuscript (preprint) (Other academic)
National Category
Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-30115 (URN)
Available from: 2013-08-02 Created: 2013-08-02 Last updated: 2017-10-17Bibliographically approved
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