Research Institute of Internal Medicine

Medicine, Norway

Research Institute of Internal Medicine

Medicine, Norway
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Valentino L.A.,Rush University | Holme P.A.,Research Institute of Internal Medicine | Holme P.A.,University of Oslo
Haemophilia | Year: 2015

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings. © 2015 John Wiley & Sons Ltd.


Knudsen A.,Copenhagen University | Hoel H.,University of Oslo | Kjaer A.,Copenhagen University | Kristoffersen U.S.,Copenhagen University | And 15 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2016

Objectives: HIV infection is associated with increased risk of coronary heart disease beyond that explained by traditional risk factors, and altered gut microbiota has been proposed as a potential trigger. Trimethylamine-N-oxide (TMAO) is a proatherogenic substance formed in the liver from trimethylamine, exclusively generated by gut microbiota from dietary phosphatidylcholine. We aimed to investigate whether TMAO is associated with subclinical and clinical coronary heart disease in HIV infection. Methods: Two previously described cohorts were examined as follows: (1) cross-sectional cohort of HIV-infected persons and uninfected controls with known atherosclerotic plaque burden as assessed by myocardial perfusion scintigraphy, coronary artery calcium score, and intima-media thickness and (2) nested case-control study of HIV-infected persons with first-time myocardial infarction (MI) compared with HIV-infected persons without MI, assessed at 4 time points from before initiation of antiretroviral therapy (ART) to last sample before the case's MI (median: 51, range: 0-239 days). Results: There was no difference in plasma TMAO when comparing HIV-infected persons and uninfected controls. TMAO was elevated in HIV-infected persons with myocardial perfusion defects but was not associated with coronary artery calcium score, intima media thickness, or Framingham risk score. In the nested case control study, plasma TMAO was not associated with first-time MI. However, TMAO increased after ART introduction and was associated with the use of protease inhibitors in both cohorts. Conclusions: TMAO was elevated in HIV-infected persons with myocardial perfusion defects, but was not associated with first-time MI. Our data question TMAO as a useful biomarker of cardiovascular risk in HIV infection, at least in ART-treated individuals. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Gregersen S.,University of Oslo | Holm A.M.,University of Oslo | Fevang B.,Research Institute of Internal Medicine | Fevang B.,University of Oslo | And 8 more authors.
Scandinavian Journal of Clinical and Laboratory Investigation | Year: 2013

Introduction. Besides hypogammaglobulinemia and recurrent infections, abnormalities of T-cells might contribute to lung damage in common variable immunodeficiency disorders (CVID). Materials and methods. In 16 adult patients, the majority of whom had pulmonary abnormalities, we studied T-cell subsets and markers of inflammation in bronchoalveolar lavage fluid (BALF) and blood and their relations with pulmonary function and high resolution computed tomography (HRCT). Results. We demonstrated that some of the lymphocyte abnormalities previously demonstrated in peripheral blood from CVID patients, such as low CD4/CD8 T-cell ratio, were also present in BALF. Moreover, low BALF CD4/CD8 ratio (≤ 1), found in seven patients, was significantly associated with higher blood CD8+ cell count and to lower values of the lung function variables; forced expiratory volume (FVC), total lung capacity (TLC), vital capacity (VC) and residual volume (RV) in % of predicted. The expression of the inflammatory markers HLA-DR and CCR5 on T-cells was significantly higher, and the expression of CCR7 significantly lower, in BALF compared to blood, possibly reflecting an inflammatory/cytotoxic T-cell phenotype within pulmonary tissue in CVID. Furthermore, patients with bronchiectasis had higher concentrations of the pro-inflammatory cytokine TNFα in plasma, compared to those without. Conclusion. Our findings suggest that inflammation and T-cell activation may be involved in the immunopathogenesis of pulmonary complications in CVID. © 2013 Informa Healthcare.


Andreassen O.A.,University of Oslo | McEvoy L.K.,Multimodal Imaging Laboratory | McEvoy L.K.,University of California at San Diego | Wang Y.,University of Oslo | And 16 more authors.
Hypertension | Year: 2014

Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional false discovery rate method, we systematically investigated genetic overlap between systolic blood pressure (SBP) and 12 comorbid traits and diseases. We found significant enrichment of single nucleotide polymorphisms associated with SBP as a function of their association with body mass index, low-density lipoprotein, waist/hip ratio, schizophrenia, bone mineral density, type 1 diabetes mellitus, and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high-density lipoproteins, type 2 diabetes mellitus, rheumatoid arthritis, and height). Applying the conditional false discovery rate method to the enriched phenotypes, we identified 62 loci associated with SBP (false discovery rate <0.01), including 42 novel loci. The observed polygenic overlap between SBP and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors but also reflect an etiologic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in SBP. © 2014 American Heart Association, Inc.


Askevold E.T.,University of Oslo | Nymo S.,Research Institute of Internal Medicine | Ueland T.,Section of Clinical Immunology and Infectious Diseases | Gravning J.,Institute for Surgical Research | And 6 more authors.
Circulation: Heart Failure | Year: 2013

Background-Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods and Results-The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged =60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11-1.93]; P=0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01-1.87]; P=0.042), and death from worsening HF (hazard ratio, 1.85 [1.09-3.14]; P=0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84-1.50]; P=0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses. Conclusions-Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause. © 2013 American Heart Association, Inc.


Troseid M.,University of Oslo | Troseid M.,Research Institute of Internal Medicine | Troseid M.,Kg Jebsen Center For Inflammation Research | Hov J.R.,Research Institute of Internal Medicine | And 9 more authors.
Metabolic Syndrome and Related Disorders | Year: 2016

Background: Trimethylamine-N-oxide (TMAO) is formed in the liver from trimethylamine (TMA), a product exclusively generated by the gut microbiota from dietary phosphatidylcholine and carnitine. An alternative pathway of TMAO formation from carnitine is via the microbiota-dependent intermediate γ-butyrobetaine (γBB). Elevated TMAO levels are associated with cardiovascular disease (CVD), but little is known about TMAO in obesity. Given the proposed contribution of microbiota alterations in obesity and type 2 diabetes (T2D), we investigated the potential impact of obesity, lifestyle-induced weight loss, and bariatric surgery on plasma levels of TMAO, its microbiota-dependent intermediate γBB, and its diet-dependent precursors carnitine and choline. Methods: TMAO, γBB, carnitine, and choline were measured by high-performance liquid chromatography in 34 obese individuals (17 with and 17 without T2D) undergoing bariatric surgery and 17 controls. Results: TMAO was not elevated in obese patients or reduced by lifestyle interventions but increased approximately twofold after bariatric surgery. Similar to TMAO, plasma levels of γBB were not influenced by lifestyle interventions but increased moderately after bariatric surgery. In contrast, carnitine and choline, which are abundant in nutrients, such as in red meat and eggs, and not microbiota dependent, were reduced after lifestyle interventions and rebounded after bariatric surgery. Conclusions: The major increase in TMAO after bariatric surgery was unexpected because high TMAO levels have been linked to CVD, whereas bariatric surgery is known to reduce CVD risk. Prospective studies of gut microbiota composition and related metabolites in relation to long-term cardiovascular risk after bariatric surgery are warranted. © Marius Trøseid, et al., 2016; published by Mary Ann Liebert, Inc. 2016.


Tran H.T.T.,Research Institute of Internal Medicine | Tran H.T.T.,University of Oslo | Tjonnfjord G.E.,University of Oslo | Paus A.,University of Oslo | Holme P.A.,University of Oslo
Haemophilia | Year: 2011

The use of recombinant FVIIa (rFVIIa) to control bleed in individuals with FVII deficiency has been proven to be effective. The main problems associated with its use are that it requires frequent bolus injections to counteract its short half-life and high cost. Our study aimed to evaluate whether any advantage could be gained by providing rFVIIa by continuous infusion during surgery with regard to haemostatic efficacy, safety and cost. The prospective study included 10 patients with severe FVII deficiency, who underwent 25 surgical procedures (13 major and 12 minor procedures) and were treated with rFVIIa administered by continuous infusion. Tranexamic acid was given concomitantly every 8h. Prothrombin time, FVII:C assay and thrombin generation assay were used to monitor the treatment. The mean total dose given was 10mg during a major surgery and 4.4mg during a minor surgery for a mean treatment duration of 7.5 and 4.0days respectively. This corresponds to a reduction of 70-90% in drug usage and medication cost compared with bolus injections. Except for one major perioperative bleeding, excellent haemostasis was achieved in all procedures. One patient developed a transient inhibitory activity. None of these events affected the postoperative course or prolonged the hospital stay. Our study demonstrated that continuous infusion of rFVIIa during surgery is safe, effective and highly cost effective. © 2011 Blackwell Publishing Ltd.


Kaikkonen L.,University of Oulu | Magga J.,University of Oulu | Ronkainen V.-P.,University of Oulu | Koivisto E.,University of Oulu | And 14 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2014

cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38. PLB phosphorylation was enhanced in cardiomyocytes by chemical p38 inhibition, by overexpression of dominant negative p38α and by p38α RNAi, but not with dominant negative p38β. Treatment of cardiomyocytes with dominant negative p38α significantly decreased Ca2+-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca2+-ATPase function and increased cardiomyocyte contractility. Analysis of signaling mechanisms involved showed that inhibition of p38 decreased the activity of protein phosphatase 2A, which renders protein phosphatase inhibitor-1 phosphorylated and thereby inhibits PP1. In conclusion, inhibition of p38α enhances PLB phosphorylation and diastolic Ca2+ uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition. © 2013 Elsevier Ltd.


Astrup E.,Akershus University Hospital | Astrup E.,Research Institute of Internal Medicine | Ranheim T.,Research Institute of Internal Medicine | Ranheim T.,University of Oslo | And 11 more authors.
BMC Infectious Diseases | Year: 2014

Background: Based on their essential role in concerting immunological and inflammatory responses we hypothesized that the homeostatic chemokines CCL19 and CCL21 may play a pathogenic role in rickettsiae infection. Methods: Serum levels of CCL19 and CCL21 in patients with R. africae and R. conorii infection were analyzed by enzyme immunoassays. Lungs from R. conorii infected mice were examined for CCL19, CCL21 and CCR7 expression by immunohistochemistry. Results: We found that patients with R. africae infection (n = 15) and in particular those with R. conorii infection (n = 16) had elevated serum levels of CCL19 on admission, with a decline during follow-up. While a similar pattern was seen for CCL21 in R. africae infection, patients with R. conorii infection showed persistently increased CCL21 levels during follow-up. In experimental R. conorii infection, we found strong immunostaining of CCL19 and CCL21 in the lungs, particularly in individuals that had received lethal doses. Immunofluorescence showed co-localization of CCR7 to endothelial cells, macrophages and fibroblasts within the lung tissue of R. conorii infected mice.Conclusions: Our findings suggest that the CCL19/CCL21/CCR7 axis is up-regulated during R. africae and in particular during R. conorii infection, which may potentially contribute to the pathogenesis of these disorders. © 2014 Astrup et al.; licensee BioMed Central Ltd.


PubMed | Research Institute of Internal Medicine and Rush University
Type: Journal Article | Journal: Haemophilia : the official journal of the World Federation of Hemophilia | Year: 2015

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings.

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