Publications by authors named "Søren E Pischke"

14 Publications

  • Page 1 of 1

Inflammation in the early phase after kidney transplantation is associated with increased long-term all-cause mortality.

Am J Transplant 2022 08 29;22(8):2016-2027. Epub 2022 Apr 29.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

In the general population, low-grade inflammation has been established as a risk factor for all-cause mortality. We hypothesized that an inflammatory milieu beyond the time of recovery from the surgical trauma could be associated with increased long-term mortality in kidney transplant recipients (KTRs). This cohort study included 1044 KTRs. Median follow-up time post-engraftment was 10.3 years. Inflammation was assessed 10 weeks after transplantation by different composite inflammation scores based on 21 biomarkers. We constructed an overall inflammation score and five pathway-specific inflammation scores (fibrogenesis, vascular inflammation, metabolic inflammation, growth/angiogenesis, leukocyte activation). Mortality was assessed with Cox regression models adjusted for traditional risk factors. A total of 312 (29.9%) patients died during the follow-up period. The hazard ratio (HR) for death was 4.71 (95% CI: 2.85-7.81, p < .001) for patients in the highest quartile of the overall inflammation score and HRs 2.35-2.54 (95% CI: 1.40-3.96, 1.52-4.22, p = .001) for patients in the intermediate groups. The results were persistent when the score was analyzed as a continuous variable (HR 1.046, 95% CI: 1.033-1.056, p < .001). All pathway-specific analyses showed the same pattern with HRs ranging from 1.19 to 2.70. In conclusion, we found a strong and consistent association between low-grade systemic inflammation 10 weeks after kidney transplantation and long-term mortality.
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http://dx.doi.org/10.1111/ajt.17047DOI Listing
August 2022

Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

Mol Immunol 2022 01 11;141:273-279. Epub 2021 Dec 11.

Department of Immunology, Oslo University Hospital and University of Oslo, Norway; Division of Emergencies and Critical Care, Oslo University Hospital, Norway. Electronic address:

Background: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone.

Materials And Methods: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean.

Results: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio.

Conclusion: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.
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http://dx.doi.org/10.1016/j.molimm.2021.11.016DOI Listing
January 2022

Elevated Terminal C5b-9 Complement Complex 10 Weeks Post Kidney Transplantation Was Associated With Reduced Long-Term Patient and Kidney Graft Survival.

Front Immunol 2021 25;12:738927. Epub 2021 Oct 25.

Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway.

Background: The major reason for graft loss is chronic tissue damage, as interstitial fibrosis and tubular atrophy (IF/TA), where complement activation may serve as a mediator. The association of complement activation in a stable phase early after kidney transplantation with long-term outcomes is unexplored.

Methods: We examined plasma terminal C5b-9 complement complex (TCC) 10 weeks posttransplant in 900 patients receiving a kidney between 2007 and 2012. Clinical outcomes were assessed after a median observation time of 9.3 years [interquartile range (IQR) 7.5-10.6].

Results: Elevated TCC plasma values (≥0.7 CAU/ml) were present in 138 patients (15.3%) and associated with a lower 10-year patient survival rate (65.7% . 75.5%,  < 0.003). Similarly, 10-year graft survival was lower with elevated TCC; 56.9% . 67.3% ( < 0.002). Graft survival was also lower when censored for death; 81.5% . 87.3% ( = 0.04). In multivariable Cox analyses, impaired patient survival was significantly associated with elevated TCC [hazard ratio (HR) 1.40 (1.02-1.91), = 0.04] along with male sex, recipient and donor age, smoking, diabetes, and overall survival more than 1 year in renal replacement therapy prior to engraftment. Likewise, elevated TCC was independently associated with graft loss [HR 1.40 (1.06-1.85), = 0.02] along with the same covariates. Finally, elevated TCC was in addition independently associated with death-censored graft loss [HR 1.69 (1.06-2.71), = 0.03] as were also HLA-DR mismatches and higher immunological risk.

Conclusions: Early complement activation, assessed by plasma TCC, was associated with impaired long-term patient and graft survival.
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http://dx.doi.org/10.3389/fimmu.2021.738927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573334PMC
December 2021

Elevated plasma sTIM-3 levels in patients with severe COVID-19.

J Allergy Clin Immunol 2021 01 21;147(1):92-98. Epub 2020 Sep 21.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Microbiology, Oslo University Hospital, Oslo, Norway.

Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation.

Objective: We examined the parameters of activation of different leukocyte subsets in COVID-19-infected patients in relation to disease severity.

Methods: We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19-infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment.

Results: Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B-type natriuretic peptide.

Conclusion: Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell-targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.
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http://dx.doi.org/10.1016/j.jaci.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503135PMC
January 2021

Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair.

J Clin Med 2020 Jan 17;9(1). Epub 2020 Jan 17.

Department of Surgery, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.
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http://dx.doi.org/10.3390/jcm9010253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019324PMC
January 2020

IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction.

Front Immunol 2018 12;9:2035. Epub 2018 Sep 12.

Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. NSTEMI patients were randomized to one dose of tocilizumab ( = 28) or placebo ( = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, = 21) and ST-elevation myocardial infarction (STEMI, = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly ( < 0.001) and substantially (>50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients ( < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group ( < 0.05) and C3aR in the NSTE-ACS group ( < 0.05). Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.
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http://dx.doi.org/10.3389/fimmu.2018.02035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143659PMC
September 2019

Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock.

ESC Heart Fail 2018 06 9;5(3):292-301. Epub 2018 Feb 9.

Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Aims: Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction.

Methods And Results: The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention-treated ST-elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow-up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non-shock group (n = 52). Controls (n = 44) were age-matched and sex-matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b-9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non-shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b-9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b-9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM-1 and sVCAM-1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b-9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively).

Conclusions: Complement activation discriminated cardiogenic shock from non-shock in acute ST-elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.
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http://dx.doi.org/10.1002/ehf2.12266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933968PMC
June 2018

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis.

J Intensive Care 2017 27;5:21. Epub 2017 Feb 27.

Department of Immunology, Oslo University Hospital Rikshospitalet, and K.G. Jebsen IRC, University of Oslo, N-0027 Oslo, Norway.

Background: Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis.

Methods: Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated administered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group ( = 12) receiving saline and to an interventional group ( = 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin.

Results: A substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group ( = 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-γ by 75% ( = 0.0001), tumor necrosis factor by 50% ( = 0.01), Interleukin (IL)-8 by 50% ( = 0.03), IL-10 by 40% ( = 0.04), IL-12p40 by 50% ( = 0.03), and granulocyte CD11b (CR3) expression by 20% ( = 0.01).

Conclusion: Inhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.
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http://dx.doi.org/10.1186/s40560-017-0217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327570PMC
February 2017

Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More Efficiently Than Antagonizing the Toll-like Receptor 4-MD2 Complex.

J Infect Dis 2016 07 14;214(1):140-50. Epub 2016 Mar 14.

Department of Immunology K. G. Jebsen IRC, University of Oslo Research Laboratory, Nordland Hospital Bodø Faculty of Health Sciences K. G. Jebsen TREC, University of Tromsø Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.

Background: Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood.

Methods: Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry.

Results: Lipopolysaccharide (LPS)-induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS-binding to HEK-293E cells transfected with CD14 and Escherichia coli-induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti-CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli-induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria-induced inflammatory responses (mean P < .0001).

Conclusions: Whole bacteria-induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis.
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http://dx.doi.org/10.1093/infdis/jiw100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907417PMC
July 2016

Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial.

Medicine (Baltimore) 2015 Oct;94(42):e1786

From the Intervention Centre (AAF, NP, AMK, SEP, BE); Department of HPB surgery (AAF, BAB, BE); Department of Immunology, Oslo University Hospital, Oslo (AS, PHN, INR, TEM); Institute of Clinical Medicine (AAF, AMK, BE), University of Oslo, Oslo; Department of Surgery, Finnmark Hospital, Kirkenes (AMK); Division of Emergencies and Critical Care (SEP); Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo (MWF); Research Laboratory, Nordland Hospital, Bodo, and Faculty of Health Sciences, University of Tromso (TEM); and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (TEM).

Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial.This was a predefined exploratory substudy within the Oslo CoMet-study. Forty-five patients with CLM were randomized to laparoscopic (n = 23) or open (n = 22) resection. Ethylenediaminetetraacetic acid-plasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at -80 C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cell-free DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation.Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1β, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, C-reactive protein, and macrophage inflammatory protein -1β, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.Laparoscopic resection of CLM reduced the inflammatory response compared with open resection. The lower level of HMGB-1 is interesting because of the known association with oncogenesis.
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http://dx.doi.org/10.1097/MD.0000000000001786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620756PMC
October 2015

Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14.

Immunobiology 2015 Aug 27;220(8):999-1005. Epub 2015 Apr 27.

Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway; Research Laboratory, Nordland Hospital and Faculty of Health Sciences, K. G. Jebsen TREC, University of Tromsø, Tromsø, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address:

Sepsis is an infection-induced systemic inflammatory syndrome, potentially causing organ failure. We previously showed attenuating effects on inflammation, thrombogenicity and haemodynamics by inhibiting the Toll-like receptor co-factor CD14 and complement factor C5 in a porcine Escherichia coli-induced sepsis model. The present study explored the effect on organ inflammation in these pigs. Tissue samples were examined from the combined treatment group (n = 8), the positive (n = 8) and negative (n = 6) control groups after 4h of sepsis. Inflammatory biomarkers were measured using ELISA, multiplex and qPCR analysis. Combined inhibition of C5 and CD14 markedly attenuated IL-1β by 31-66% (P < 0.05) and IL-6 by 54-96% (P < 0.01) in liver, kidney, lung and spleen; IL-8 by 65-100% in kidney, lung, spleen, and heart (P < 0.05) and MCP-1 by 46-69% in liver, kidney, spleen and heart (P < 0.05). Combined inhibition significantly attenuated tissue factor mRNA upregulation in spleen (P < 0.05) and IP-10 mRNA upregulation in four out of five organs. Finally, C5aR mRNA downregulation was prevented in heart and kidney (P < 0.05). Combined inhibition of C5 and CD14 thus markedly attenuated inflammatory responses in all organs examined. The anti-inflammatory effects observed in lung and heart may explain the delayed haemodynamic disturbances observed in septic pigs receiving combined inhibition of C5 and CD14.
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http://dx.doi.org/10.1016/j.imbio.2015.04.002DOI Listing
August 2015

Continuous monitoring of regional function by a miniaturized ultrasound transducer allows early quantification of low-grade myocardial ischemia.

J Am Soc Echocardiogr 2015 Apr 27;28(4):486-94. Epub 2015 Jan 27.

The Intervention Centre, Rikshospitalet, Oslo University Hospital, Oslo, Norway; Department of Cardiology, Rikshospitalet, Oslo University Hospital, Oslo, Norway. Electronic address:

Background: Sensitive methods for the early detection of myocardial dysfunction are still needed, as ischemia is a leading cause of decreased ventricular function during and after heart surgery. The aim of this study was to test the hypothesis that low-grade ischemia could be detected quantitatively by a miniaturized epicardial ultrasound transducer (Ø = 3 mm), allowing continuous monitoring.

Methods: In 10 pigs, transducers were positioned in the left anterior descending and circumflex coronary artery areas. Left ventricular pressure was obtained by a micromanometer. The left internal mammary artery was grafted to the left anterior descending coronary artery, which was occluded proximal to the anastomosis. Left internal mammary artery flow was stepwise reduced by 25%, 50%, and 75% for 18 min each. From the transducers, M-mode traces were obtained, allowing continuous tissue velocity traces and displacement measurements. Regional work was assessed as left ventricular pressure-displacement loop area. Tissue lactate measured from intramyocardial microdialysis was used as reference method to detect ischemia.

Results: All steps of coronary flow reduction demonstrated reduced peak systolic velocity (P < .05) and regional work (P < .01).The decreases in peak systolic velocity and regional work were closely related to the degree of ischemia, demonstrated by their correlations with lactate (R = -0.74, P < .01, and R = -0.64, P < .01, respectively). The circumflex coronary artery area was not affected by any of the interventions.

Conclusions: The epicardially attached miniaturized ultrasound transducer allowed the precise detection of different levels of coronary flow reduction. The results also showed a quantitative and linear relationship among coronary flow, ischemia, and myocardial function. Thus, the ultrasound transducer has the potential to improve the monitoring of myocardial ischemia and to detect graft failure during and after heart surgery.
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http://dx.doi.org/10.1016/j.echo.2014.12.014DOI Listing
April 2015

Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice.

J Immunol 2014 Jun 30;192(11):5324-31. Epub 2014 Apr 30.

Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo N-0027, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Research Laboratory, Nordland Hospital Bodø, University of Tromsø, Tromsø 9019, Norway; and Faculty of Health Sciences, University of Tromsø, Tromsø 9019, Norway

Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.
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http://dx.doi.org/10.4049/jimmunol.1400341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025614PMC
June 2014
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