Publications by authors named "Thor Ueland"

392 Publications

Effect of Continuous Positive Airway Pressure on Arrhythmia in Atrial Fibrillation and Sleep Apnea: A Randomized Controlled Trial.

Am J Respir Crit Care Med 2021 May 3. Epub 2021 May 3.

Oslo University Hospital, 155272, Oslo, Norway.

Rationale: Sleep apnea (SA) is highly prevalent in patients with atrial fibrillation (AF), and both conditions are associated with adverse cardiovascular outcomes.

Objectives: To determine the effect of continuous positive airway pressure (CPAP) on AF burden.

Methods: This open-label, parallel-group, randomized, controlled trial included patients with paroxysmal AF and moderate-to-severe SA (apnea-hypopnea index ≥15). Eligible patients were randomized (1:1) to 5 months' treatment with CPAP plus usual care (CPAP, n=55) or usual care alone (control, n=54) by a computerised system. Outcome assessment was blinded. The planned primary outcome was the difference between CPAP treatment and control in change of AF burden (% of time in AF), as measured by implantable loop recorder.

Measurements And Main Results: A total of 579 patients with paroxysmal AF had respiratory polygraphy, of whom 244 (42.1%) had moderate-to-severe SA. Of these, 158 (64.8%) participated in the CPAP run-in period, of whom 40 (25.3%) patients did not tolerate the treatment. One-hundred-eight patients were available for the primary analysis. The mean time in AF decreased from 5.6% at baseline to 4.1% during the last three months of CPAP intervention and from 5.0% to 4.3% in the control group. The adjusted between-group difference at follow-up was -0.63 (95% confidence interval: -2.55 to 1.30) percentage points; P=0.52. Seven serious adverse events (13%) occurred in the CPAP group, and two (4%) occurred in the control group.

Conclusions: In patients with paroxysmal AF and SA, treatment with CPAP did not result in a statistically significant reduction in the burden of AF. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02727192.
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http://dx.doi.org/10.1164/rccm.202011-4133OCDOI Listing
May 2021

Secreted Wnt antagonists in scrub typhus.

PLoS Negl Trop Dis 2021 Apr 29;15(4):e0009185. Epub 2021 Apr 29.

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

Background: The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus.

Methodology/principal Findings: Plasma levels of secreted Wnt antagonists (i.e. DKK-1, sFRP-3, WIF-1 and SOST) were analyzed in patients with scrub typhus (n = 129), patients with similar febrile illness without O. tsutsugamushi infection (n = 31), febrile infectious disease controls, and in healthy controls (n = 31) from the same area of South India, and were correlated to markers of inflammation, immune and endothelial cell activation as well as for their association with organ specific dysfunction and mortality in these patients. We found i) Levels of SOST and in particular sFRP-3 and WIF-1 were markedly increased and DKK-1 decreased in scrub typhus patients at admission to the hospital compared to healthy controls. ii) In recovering scrub typhus patients, SOST, sFRP-3 and WIF-1 decreased and DKK-1 increased. iii) SOST was positively correlated with markers of monocyte/macrophage and endothelial/vascular activation as well as with renal dysfunction and poor outcome iv) Finally, regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients with scrub typhus, as evaluated by gene expression studies available in public repositories, revealed markedly attenuated canonical Wnt signaling.

Conclusions/significance: Our findings suggest that scrub typhus is characterized by attenuated Wnt signaling possibly involving dysregulated levels of several secreted pathway antagonists. The secreted Wnt antagonist SOST was strongly associated with renal dysfunction and poor prognosis in these patients.
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http://dx.doi.org/10.1371/journal.pntd.0009185DOI Listing
April 2021

Hepcidin and Ferritin Predict Microbial Etiology in Community-Acquired Pneumonia.

Open Forum Infect Dis 2021 Apr 18;8(4):ofab082. Epub 2021 Feb 18.

Department of Internal Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.

Background: Iron is crucial for survival and growth of microbes. Consequently, limiting iron availability is a human antimicrobial defense mechanism. We explored iron and iron-related proteins as potential biomarkers in community-acquired pneumonia and hypothesized that infection-induced changes in these potential biomarkers differ between groups of pathogens and could predict microbial etiology.

Methods: Blood samples from a prospective cohort of 267 patients with community-acquired pneumonia were analyzed for hepcidin, ferritin, iron, transferrin, and soluble transferrin receptor at admission, clinical stabilization, and a 6-week follow-up. A total of 111 patients with an established microbiological diagnosis confined to 1 microbial group (atypical bacterial, typical bacterial, or viral) were included in predictive analyses.

Results: High admission levels of ferritin predicted atypical bacterial versus typical bacterial etiology (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.18-4.32; = .014). Furthermore, hepcidin and ferritin predicted atypical bacterial versus viral etiology (hepcidin: OR = 3.12, 95% CI = 1.34-7.28, = .008; ferritin: OR = 2.38, 95% CI = 1.28-4.45, = .006). The findings were independent of C-reactive protein and procalcitonin.

Conclusions: Hepcidin and ferritin are potential biomarkers of microbial etiology in community-acquired pneumonia.
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http://dx.doi.org/10.1093/ofid/ofab082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043258PMC
April 2021

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2021 Apr;77(15):1845-1855

Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response.

Objectives: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI.

Methods: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days.

Results: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups.

Conclusions: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).
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http://dx.doi.org/10.1016/j.jacc.2021.02.049DOI Listing
April 2021

Circulating regulators of the wingless pathway in precapillary pulmonary hypertension.

Respirology 2021 Apr 8. Epub 2021 Apr 8.

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

Background And Objective: Dysregulated Wnt signalling has been implicated in pulmonary hypertension (PH). We hypothesized that plasma levels of secreted Wnt proteins would be increased in patients with precapillary PH, correlate with indices of vascular resistance and cardiac function and give information on long-term prognosis.

Methods: We measured the Wnt ligand Wnt5a and secreted Wnt antagonists Dickkopf (DKK) DKK1, DKK3, secreted frizzled-related protein 3 (sFRP3), Wnt inhibitory factor-1 (WIF1) and sclerostin (SOST) in 106 patients with precapillary PH and 40 healthy controls. A second sample was obtained after a median of 4 months (n = 52). During a median of 90 months follow-up, 67 patients died.

Results: Our main findings were (i) Precapillary PH is characterized by enhanced systemic Wnt activity as reflected by elevated plasma levels of Wnt5a and secreted antagonists irrespective of diagnostic subgroups. (ii) WIF1 and in particular Wnt5a correlated with pulmonary vascular resistance and cardiac dysfunction. (iii) High levels of Wnt5a, sFRP3, DKK3 and WIF1 were associated with poor prognosis in age- and sex-adjusted analysis (hazard ratios per log/SD change ~1.4) and for DKK3 after further adjustment with right arterial pressure, pulmonary oxygen saturation, cardiac index, N-terminal pro B-type natriuretic peptide and peak oxygen uptake (VO ). Finally, an elevation of Wnt5a and DKK3 during follow-up was independently associated with poor prognosis.

Conclusion: Our data indicate that Wnt signalling pathways could be implicated in the pathogenesis of precapillary PH, and that some of the Wnt-related molecules (i.e., Wnt5a and DKK3) should be further investigated in these patients.
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http://dx.doi.org/10.1111/resp.14048DOI Listing
April 2021

Re-appraisal of the obesity paradox in heart failure: a meta-analysis of individual data.

Clin Res Cardiol 2021 Mar 11. Epub 2021 Mar 11.

Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, 6202AZ, Maastricht, The Netherlands.

Background: Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population.

Methods: In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m, 18.5-25.0 kg/m; 25.0-30.0 kg/m; 30.0 kg/m). Primary endpoints included all-cause mortality and HF hospitalization-free survival.

Results: Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity.

Conclusions: The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged < 75 years without co-morbidities (top). The prognostic effect largely disappears in multivariable analyses even for the former group. These findings question the protective effect of obesity in chronic heart failure (HF).
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http://dx.doi.org/10.1007/s00392-021-01822-1DOI Listing
March 2021

The relationship between Fibroblast Growth Factor 23 (FGF23) and cardiac MRI findings following primary PCI in patients with acute first time STEMI.

Int J Cardiol Heart Vasc 2021 Apr 19;33:100727. Epub 2021 Feb 19.

Department of Cardiology, Stavanger University Hospital, Stavanger, Norway.

Background: Fibroblast growth factor 23 (FGF23) is a regulator of mineral metabolism, that has been linked to myocardial remodeling including development of left ventricular (LV) hypertrophy and myocardial fibrosis. The aim of this study was to investigate the relationship between intact FGF23 (iFGF23), myocardial infarct size and LV remodeling following a first acute ST-elevation myocardial infarction (STEMI).

Methods And Results: Forty-two consecutive patients with first-time STEMI, single vessel disease, successfully treated with primary percutaneous coronary intervention were included. Cardiac magnetic resonance (CMR) imaging was performed at day 2, 1 week, 2 months and 1 year post MI, and blood samples were drawn at admittance and at the same time points as the CMRs. The cohort was divided according to the presence or not of heart failure post MI. In the total cohort, iFGF23 (mean ± SD) was significantly lower at day 0 (33.7 ± 20.6 pg/ml) and day 2 (31.5 ± 23.4 pg/ml) compared with a reference interval based on 8 healthy adults (43.9 pg/ml ± 19.0 pg/ml). iFGF23 increased to normal levels (55.8 ± 23.4 pg/ml) seven days post MI. In the subset of patients with signs of acute heart failure, FGF23 was higher at all measured timepoints, reaching significantly higher FGF23 levels at 2 months and 1 year following revascularization.

Conclusion: There was a reduction in iFGF23 levels during the acute phase of MI, with a normalization at seven days following revascularization. During one-year follow-up, there was a gradual increase in iFGF23 levels in patients with heart failure.
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http://dx.doi.org/10.1016/j.ijcha.2021.100727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905449PMC
April 2021

Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.

Sci Rep 2021 Mar 4;11(1):5127. Epub 2021 Mar 4.

Department of Haematology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450000, China.

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.
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http://dx.doi.org/10.1038/s41598-021-84695-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933411PMC
March 2021

Plasma levels of von Willebrand factor and future risk of incident venous thromboembolism.

Blood Adv 2021 01;5(1):224-232

K. G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, The University of Tromsø-The Arctic University of Norway, Tromsø, Norway.

Several case-control studies have reported elevated plasma von Willebrand factor (VWF) levels in patients with venous thromboembolism (VTE) compared with controls. However, because few studies have investigated the association in a prospective design, it is unclear whether elevated plasma VWF is a risk factor or a consequence of the VTE event. Therefore, we aimed to investigate the prospective association between plasma VWF levels and risk of VTE, as well as to perform subgroup analyses of deep vein thrombosis (DVT) and pulmonary embolism. We established a population-based nested case-control study of 414 VTE cases and 843 age- and sex-matched controls based on the Tromsø study cohort (1994-2007). Blood samples were collected at cohort baseline (1994-1995). Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across quartiles of VWF levels. We found that the risk of VTE increased linearly across quartiles of VWF levels (P for trend = .023). Participants with VWF in the highest quartile had an OR of 1.45 (95% CI, 1.03-2.03) for VTE compared with those in the lowest quartile. The association was strongest for unprovoked VTE (OR, 2.74; 95% CI, 1.66-4.54) and unprovoked DVT in particular (OR, 6.73; 95% CI, 3.07-14.76). Further adjustment for body mass index, C-reactive protein, hypertension, estrogen use, and smoking had a modest effect on the risk estimates. To conclude, we found a dose-dependent relationship between plasma VWF levels and future risk of incident VTE, and unprovoked events in particular. Our findings suggest that VWF may represent a promising biomarker for future risk of incident VTE.
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http://dx.doi.org/10.1182/bloodadvances.2020003135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805310PMC
January 2021

Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction.

JACC Basic Transl Sci 2020 Dec 9;5(12):1210-1224. Epub 2020 Dec 9.

Faculty of Medicine, University of Oslo, Oslo, Norway.

An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1β and -18) in MI patients.
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http://dx.doi.org/10.1016/j.jacbts.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775960PMC
December 2020

Subjects with familial hypercholesterolemia have lower aortic valve area and higher levels of inflammatory biomarkers.

J Clin Lipidol 2021 Jan-Feb;15(1):134-141. Epub 2020 Dec 16.

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway; Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway.

Background: Reduction of the aortic valve area (AVA) may lead to aortic valve stenosis with considerable impact on morbidity and mortality if not identified and treated. Lipoprotein (a) [Lp(a)] and also inflammatory biomarkers, including platelet derived biomarkers, have been considered risk factor for aortic stenosis; however, the association between Lp(a), inflammatory biomarkers and AVA among patients with familial hypercholesterolemia (FH) is not clear.

Objective: We aimed to investigate the relation between concentration of Lp(a), measurements of the aortic valve including velocities and valve area and circulating inflammatory biomarkers in adult FH subjects and controls.

Methods: In this cross-sectional study aortic valve measures were examined by cardiac ultrasound and inflammatory markers were analyzed in non-fasting blood samples. The study participants were 64 FH subjects with high (n = 29) or low (n = 35) Lp(a), and 14 healthy controls.

Results: Aortic valve peak velocity was higher (p = 0.02), and AVA was lower (p = 0.04) in the FH patients compared to controls; however, when performing multivariable linear regression, there were no significant differences. Furthermore, there were no significant differences between the high and low FH Lp(a) groups regarding the aortic valve. FH subjects had higher levels of platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to controls (0.003 ≤ P ≤ 0.03). This result persisted after multiple linear regression.

Conclusions: Middle-aged, intensively treated FH subjects have higher aortic valve velocity, lower AVA, and higher levels of the platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to healthy control subjects. The aortic valve findings were not significant after multiple linear regression, whereas the higher levels of platelet-derived markers were maintained.
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http://dx.doi.org/10.1016/j.jacl.2020.12.006DOI Listing
December 2020

Exploring the potential effect of paricalcitol on markers of inflammation in de novo renal transplant recipients.

PLoS One 2020 16;15(12):e0243759. Epub 2020 Dec 16.

Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest. [NCT01694160 (2012/107D)]; [www.clinicaltrials.gov].
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243759PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743930PMC
January 2021

Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19.

Sci Rep 2020 12 10;10(1):21697. Epub 2020 Dec 10.

Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.

In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment. In this study we analyzed plasma cytokines in COVID-19 patients and investigated their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Hospitalized patients (n = 34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2-5 and 7-10 days. RF was defined as PaO2/FiO2 ratio (P/F) < 40 kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79-0.80, p < 0.05). During hospitalization the decline was most significant for IP-10 (p < 0.001). Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.
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http://dx.doi.org/10.1038/s41598-020-78710-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729930PMC
December 2020

Distinct patterns of soluble leukocyte activation markers are associated with etiology and outcomes in precapillary pulmonary hypertension.

Sci Rep 2020 10 29;10(1):18540. Epub 2020 Oct 29.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0027, Oslo, Norway.

Activation of inflammatory processes has been identified as a major driver of pulmonary vascular remodeling that contributes to the development of precapillary pulmonary hypertension (PH). We hypothesized that circulating markers of leukocyte activation, reflecting monocytes/macrophages (sCD163, sCD14), T-cells (sCD25) and neutrophils (myeloperoxidase [MPO], neutrophil gelatinase-associated lipocalin [NGAL]) activity, could give prognostic information in precapillary PH. Circulating markers of leucocyte activation, sCD163, sCD14, sCD25, MPO and NGAL were measured by enzyme immunoassays in plasma from patients with idiopathic PAH (IPAH; n = 30); patients with PAH related to associated conditions (APAH; n = 44) and patients with chronic thromboembolic PH (CTEPH) (n = 32), and compared with 23 healthy controls. Markers of leucocyte activation were elevated in precapillary PH with particularly high levels in APAH. The elevated levels of monocyte/macrophage marker sCD163 was independently associated with poor long-term prognosis in the group as a whole, and elevated levels of sCD25 was associated with poor prognosis in APAH, while elevated levels of sCD163 and NGAL was associated with poor prognosis in IPAH and CTEPH. Our data show leucocyte activation in precapillary PH with different profiles and impact on prognosis according to etiology. The association of sCD163 with poor outcome in fully adjusted model may be of particular interest.
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http://dx.doi.org/10.1038/s41598-020-75654-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596076PMC
October 2020

Gut Microbiota-Dependent Trimethylamine N-Oxide Associates With Inflammation in Common Variable Immunodeficiency.

Front Immunol 2020 16;11:574500. Epub 2020 Sep 16.

Division of Surgery, Inflammatory Diseases and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

A substantial proportion of patients with common variable immunodeficiency (CVID) have inflammatory and autoimmune complications of unknown etiology. We have previously shown that systemic inflammation in CVID correlates with their gut microbial dysbiosis. The gut microbiota dependent metabolite trimethylamine N-oxide (TMAO) has been linked to several metabolic and inflammatory disorders, but has hitherto not been investigated in relation to CVID. We hypothesized that TMAO is involved in systemic inflammation in CVID. To explore this, we measured plasma concentrations of TMAO, inflammatory markers, and lipopolysaccharide (LPS) in 104 CVID patients and 30 controls. Gut microbiota profiles and the bacterial genes and , which encode enzymes that can convert dietary metabolites to trimethylamine in the colon, were examined in fecal samples from 40 CVID patients and 86 controls. Furthermore, a food frequency questionnaire and the effect of oral antibiotic rifaximin on plasma TMAO concentrations were explored in these 40 patients. We found CVID patients to have higher plasma concentrations of TMAO than controls (TMAO 5.0 [2.9-8.6] vs. 3.2 [2.2-6.3], = 0.022, median with IQR). The TMAO concentration correlated positively with tumor necrosis factor ( = 0.008, rho = 0.26), interleukin-12 ( = 0.012, rho = 0.25) and LPS ( = 0.034, rho = 0.21). Dietary intake of meat ( = 0.678), fish ( = 0.715), egg ( = 0.138), dairy products ( = 0.284), and fiber ( = 0.767) did not significantly impact on the TMAO concentrations in plasma, nor did a 2-week course of the oral antibiotic rifaximin ( = 0.975). However, plasma TMAO concentrations correlated positively with gut microbial abundance of ( = 0.021, rho = 0.36). Bacterial gene was present in significantly more CVID samples (75%) than controls (53%), = 0.020, potentially related to the increased abundance of in these samples. The current study demonstrates that elevated TMAO concentrations are associated with systemic inflammation and increased gut microbial abundance of in CVID patients, suggesting that TMAO could be a link between gut microbial dysbiosis and systemic inflammation. Gut microbiota composition could thus be a potential therapeutic target to reduce systemic inflammation in CVID.
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http://dx.doi.org/10.3389/fimmu.2020.574500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525000PMC
September 2020

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

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

Circ Heart Fail 2020 10 23;13(10):e006643. Epub 2020 Sep 23.

Research Institute of Internal Medicine (F.A., A.A., A.E.M., T.L., S.H., B.H., A.V.F., L.-E.V., S.N., T.R., P.A., T.U.), Institute of Basic Medical Sciences, University of Oslo, Norway.

Background: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS.

Methods: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed.

Results: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, <0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], <0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice).

Conclusions: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006643DOI Listing
October 2020

Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.

Proc Natl Acad Sci U S A 2020 10 17;117(40):25018-25025. Epub 2020 Sep 17.

Department of Internal Medicine, Vestre Viken Hospital Trust, 3004 Drammen, Norway.

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO/FiO ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure ( = 0.008 and = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin ( = 0.64, < 0.001; = 0.69, < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.
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http://dx.doi.org/10.1073/pnas.2010540117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547220PMC
October 2020

Reduced levels of circulating adhesion molecules in adolescents with early-onset psychosis.

NPJ Schizophr 2020 Aug 18;6(1):20. Epub 2020 Aug 18.

NORMENT Center of Excellence, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

It is suggested that neurodevelopmental abnormalities are involved in the disease mechanisms of psychotic disorders. Although cellular adhesion molecules (CAMs) participate in neurodevelopment, modulate blood-brain barrier permeability, and facilitate leukocyte migration, findings concerning their systemic levels in adults with psychosis are inconsistent. We examined plasma levels and mRNA expression in peripheral blood mononuclear cells (PBMCs) of selected CAMs in adolescents with early-onset psychosis (EOP) aged 12-18 years (n = 37) and age-matched healthy controls (HC) (n = 68). EOP patients exhibited significantly lower circulating levels of soluble platelet selectin (~-22%) and soluble vascular cell adhesion molecule-1 (~-14%) than HC. We found no significant associations with symptom severity. PSEL mRNA expression was increased in PBMCs of patients and significantly negatively correlated to duration of illness. These findings suggest a role for CAMs in the pathophysiology of psychotic disorders.
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http://dx.doi.org/10.1038/s41537-020-00112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434772PMC
August 2020

Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial.

J Am Heart Assoc 2020 09 15;9(17):e016360. Epub 2020 Aug 15.

Research Institute for Internal Medicine Oslo University Hospital Rikshospitalet Oslo Norway.

Background The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. Methods and Results Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow-up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04-1.21), =0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02-1.19; =0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44-0.88; =0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37-0.88; =0.0114). Conclusions Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00391872.
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http://dx.doi.org/10.1161/JAHA.120.016360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660754PMC
September 2020

Atherogenic Lipid Ratios Related to Myeloperoxidase and C-Reactive Protein Levels in Psychotic Disorders.

Front Psychiatry 2020 10;11:672. Epub 2020 Jul 10.

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

Background: Cardiovascular disease (CVD) is a major cause of premature death in patients with psychotic disorders, where dyslipidemia occurs frequently. In the pathogenesis of these serious mental disorders, a low-grade inflammation seems to be a possible contributor. Concurrently, systemic inflammation and its interplay with dyslipidemia is a central driver in the pathogenesis of CVD. We hypothesize that evaluation of atherogenic lipid ratios together with inflammatory markers reflecting different inflammatory pathways with relevance for atherogenesis, could give novel information on immune-related mechanisms involved in early CVD risk in patients with psychotic disorders.

Methods: As a measure for CVD risk we calculated atherogenic lipid ratios using established sex-specific cut-offs: Total cholesterol/high-density lipoprotein; HDL-c (TC/HDL) and triglyceride/HDL-c (TG/HDL) were evaluated in 571 schizophrenia (SCZ) and 247 bipolar disorder (BD) patients, and in 99 healthy controls (HC). In addition, as a measure of low-grade inflammation, we measured fasting plasma levels of nine stable atherogenic inflammatory markers in patients (SCZ, BD) and in HC. The elevated inflammatory markers and CVD risk in patients, as reflected by TC/HDL and TG/HDL, were further assessed in multivariable analyses adjusting for comorbid cardio-metabolic risk factors.

Results: A markedly higher proportion (26%-31%) of patients had increased TC/HDL and TG/HDL ratios compared with HC. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO) were higher (p<0.05, p<0.001) in patients with psychotic disorders than in HC, and hs-CRP and MPO were independently associated with atherogenic lipid ratios in the multivariable analyses.

Conclusions: Our findings suggest that low-grade inflammation and abnormal neutrophil activation may cause increased CVD risk in patients with psychotic disorders. These mechanisms should be further examined to determine the potential for development of novel risk evaluation strategies.
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http://dx.doi.org/10.3389/fpsyt.2020.00672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365890PMC
July 2020

Use Is Associated With Increased Levels of Soluble gp130 in Schizophrenia but Not in Bipolar Disorder.

Front Psychiatry 2020 2;11:642. Epub 2020 Jul 2.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

The complex effects of plant cannabinoids on human physiology is not yet fully understood, but include a wide spectrum of effects on immune modulation. The immune system and its inflammatory effector pathways are recently emerging as possible causative factors in psychotic disorders. The present study aimed to investigate whether self-administered use was associated with changes in circulating immune and neuroendocrine markers in schizophrenia (SCZ) and bipolar disorder (BD) patients. A screening of 13 plasma markers reflecting different inflammatory pathways was performed in SCZ (n = 401) and BD patients (n = 242) after subdividing each group into user and non-user subgroups. We found that i) soluble gp130 (sgp130) concentrations were significantly elevated among users in the SCZ group (p = 0.002) after multiple testing correction, but not in BD. ii) Nominally significant differences were observed in the levels of IL-1RA (p = 0.0059), YKL40 (p = 0.0069), CatS (p = 0.013), sTNFR1 (p = 0.031), and BDNF (p = 0.020), where these factors exhibited higher plasma levels in user SCZ patients than in non-users. iii) These differences in systemic levels were not reflected by altered mRNA expression of genes encoding sgp130, IL-1RA, YKL40, CatS, sTNFR1, and BDNF in whole blood. Our results show that self-administration is associated with markedly higher sgp130 levels in SCZ, but not in BD, and that this phenomenon is independent of the modulation of peripheral immune cells. These findings warrant further investigation into the potential IL-6 trans-signaling modulatory, anti-inflammatory, neuroimmune, and biobehavioral-cognitive effects of use in SCZ.
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http://dx.doi.org/10.3389/fpsyt.2020.00642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343889PMC
July 2020

Interleukin 18 (IL-18) and its binding protein (IL-18BP) are increased in patients with epilepsy suggesting low-grade systemic inflammation.

Seizure 2020 Aug 29;80:221-225. Epub 2020 May 29.

ERGO - Epilepsy Research Group of Oslo, Department of Neurology, Oslo University Hospital, Norway.

Purpose: Proinflammatory cytokines seems to play a role in epileptogenesis independent of the underlying cause. The purpose of this study was to assess if IL-18 and its binding protein IL-18BP are related to epilepsy and could act as a predictive biomarker for epileptogenesis.

Methods: In this cross-sectional study, circulating levels of IL-18 and IL-18BP were analysed in 119 epilepsy patients, and 80 healthy controls. Participants completed a questionnaire regarding epilepsy, use of drug(-s) and comorbidity.

Results: Epilepsy patients had significantly higher serum levels of IL-18 (p = 0.003) and IL-18BP (p = 0.009) than healthy controls. The groups differed in sex, age and weight, however none of those variables were significantly correlated with IL-18 and IL-18BP in patients or controls. Weight was considered an important confounder in our study. Subgroup investigations revealed that in participants with BMI under 30 kg/m², serum IL-18 (p = 0.032) and IL-18BP (p = 0.029) remained significantly higher in patients than controls. Further analyses showed significantly higher concentration of IL-18 among participants using carbamazepine (CBZ) (p = 0.016) or lamotrigine (LTG) (p = 0.024), but not in those using levetiracetam (LEV) (p = 0.102) compared to controls. No associations were found between serum levels of IL-18 and IL-18BP and epilepsy duration, seizures type, or presence of seizures in the last six months.

Conclusion: The study shows an elevation of IL-18 and IL-18BP serum levels in epilepsy patients. This result indicates the presence of a low-grade systemic inflammation involving IL-18 in epilepsy. Further investigations should explore the character and clinical impact of IL-18 as well its possible role as a biomarker for epilepsy.
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http://dx.doi.org/10.1016/j.seizure.2020.05.018DOI Listing
August 2020

Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism.

Blood 2020 10;136(16):1863-1870

K.G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.

Growth differentiation factor 15 (GDF-15), a marker of inflammation and oxidative stress, has emerged as a biomarker for arterial cardiovascular disease. However, the association between GDF-15 and venous thromboembolism (VTE) remains uncertain. We therefore investigated the association between plasma GDF-15 levels and future risk of incident VTE and explored the potential of a causal association using Mendelian randomization (MR). We conducted a population-based nested case-control study comprising 416 VTE patients and 848 age- and sex-matched controls derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) for VTE across GDF-15 quartiles. For the MR, we used data from the International Network on Venous Thrombosis (INVENT) consortium to examine whether single nucleotide polymorphisms (SNPs) associated with GDF-15 levels with genome-wide significance were related to VTE. We found that the ORs for VTE increased across GDF-15 quartiles (Ptrend = .002). Participants with GDF-15 values in the highest quartile (≥358 pg/mL) had an OR for VTE of 2.05 (95% confidence interval, 1.37-3.08) compared with those with GDF-15 in the lowest quartile (<200 pg/mL) in the age- and sex-adjusted model. ORs remained essentially the same after further adjustment for body mass index, smoking, hormone therapy, physical activity, and C-reactive protein. Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. GDF-15 levels, as predicted by the SNPs, were not associated with VTE in MR. Our results indicate that high GDF-15 levels are associated with increased risk of VTE, but MR suggests that this association is not causal.
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http://dx.doi.org/10.1182/blood.2019004572DOI Listing
October 2020

Novel Insights Into the Effects of Interleukin 6 Antagonism in Non-ST-Segment-Elevation Myocardial Infarction Employing the SOMAscan Proteomics Platform.

J Am Heart Assoc 2020 06 9;9(12):e015628. Epub 2020 Jun 9.

K.G. Jebsen Thrombosis Research and Expertise Center University of Tromsø Tromsø Norway.

Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non-ST-segment-elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C-reactive protein and troponin T were reduced in the active treatment arm. In this follow-up study, an aptamer-based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention-treated patients, 24 in the active intervention and 24 in the placebo-control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off-rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1-3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute-phase proteins lipopolysaccharide-binding protein, hepcidin, and insulin-like growth factor-binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C-C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMAscan aptamer-based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non-ST-segment-elevation myocardial infarction.
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http://dx.doi.org/10.1161/JAHA.119.015628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429051PMC
June 2020

Rosuvastatin alters the genetic composition of the human gut microbiome.

Sci Rep 2020 03 25;10(1):5397. Epub 2020 Mar 25.

Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.
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http://dx.doi.org/10.1038/s41598-020-62261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096534PMC
March 2020

Decreased IL-1β-induced CCL20 response in human iPSC-astrocytes in schizophrenia: Potential attenuating effects on recruitment of regulatory T cells.

Brain Behav Immun 2020 07 25;87:634-644. Epub 2020 Feb 25.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address:

Schizophrenia (SCZ) is a severe mental disorder with a high heritability. Although its pathophysiology is mainly unknown, dysregulated immune activation and inflammation have recently emerged as possible candidates in the underlying mechanisms of SCZ. Previous studies suggest that aberrant inflammasome activation, glia dysregulation, and brain inflammation may be involved in the pathophysiology of the disorder. Here, we studied the effects of inflammatory modulation on human induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Inflammasome activation was mimicked by short-term IL-1β exposure, and gene expression were measured with high-coverage RNA-Seq to ensure a global characterization of the transcriptional effects of the treatment. IL-1β exposure modulated several pathways involved in innate immune responses, cell cycle regulation, and metabolism in both SCZ and CTRL astrocytes. Significant differences were found in the expression of HILPDA and CCL20 genes, both of which had reduced up-regulation upon IL-1β treatment in SCZ astrocytes compared to CTRL astrocytes. CCL20 data were further validated and confirmed using qPCR, ELISA, and regulatory T lymphocyte (T) migration assays. Additionally, we found significantly decreased mRNA expression of the T-specific marker FOXP3 in the blood of a large cohort of SCZ patients (n = 484) compared to CTRL (n = 472). Since CCL20 is a specific chemoattractant for CD4CD25CCR6 T, which are crucially involved in anti-inflammatory responses during brain (auto)inflammation, our results imply a plausible role for an altered astroglia-CCL20-CCR6-T axis in SCZ pathophysiology.
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http://dx.doi.org/10.1016/j.bbi.2020.02.008DOI Listing
July 2020

Plasma parasitemia as assessed by quantitative PCR in relation to clinical disease severity in African adults with falciparum malaria with and without HIV co-infection.

Infection 2020 Jun 19;48(3):367-373. Epub 2020 Feb 19.

Norwegian National Advisory Unit On Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway.

Purpose: When considering malaria disease severity, estimation of parasitemia in erythrocytes is important, but sometimes misleading, since the infected erythrocytes may be sequestered in peripheral capillaries. In African children and Asian adults with falciparum malaria, parasitemia as assessed by quantitative PCR (qPCR) in plasma seems to be a valuable indicator of disease severity, but data on African adults as well as the impact of co-infection with HIV is lacking.

Methods: In 131 patients with falciparum malaria in a public tertiary teaching hospital in Mozambique, plasma malaria parasitemia as assessed by qPCR, compared to qualitative malaria PCR in blood cell fraction, was related to malaria disease severity and HIV co-infection.

Results: Of the 131 patients with falciparum malaria, based on positive qualitative PCR in the blood cell fraction, 93 patients (72%) had positive malaria qPCR in plasma. Patients with severe malaria as defined by the WHO criteria had higher malaria quantitative plasma parasitemia (median 143 genomes/µL) compared to those with uncomplicated malaria (median 55 genomes/µL, p = 0.037) in univariate analysis, but this difference was attenuated after adjusting for age, sex and HIV co-infection (p = 0.055). A quarter of the patients with severe malaria had negative qPCR in plasma.

Conclusions: This study of adult African in-patients with falciparum malaria with and without HIV co-infection, neither confirms nor rejects previous studies of malaria qPCR in plasma as an indicator of disease severity in patients with falciparum malaria. There is a need for further and larger studies to clarify if parasitemia as assessed malaria qPCR in plasma could be a surrogate marker of disease severity in falciparum malaria.
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http://dx.doi.org/10.1007/s15010-020-01399-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256066PMC
June 2020