Mollnes T.E.,Nordland Hospital
Advances in Experimental Medicine and Biology | Year: 2012
Background: Sepsis Sepsis is a major world-wide medical problem with high morbidity and mortality. Gram-negative bacteria are among the most important pathogens of sepsis and their LPS LPS content is regarded to be important for the systemic inflammatory reaction. The CD14 CD14 /myeloid differentiation factor 2 (MD-2 MD-2 )/TLR4 complex plays a major role in the immune response to LPS LPS . The aim of this study was to compare the effects of inhibiting MD-2 MD-2 and CD14 CD14 on ultra-pure LPS LPS - versus whole E. coli E. coli bacteria-induced responses. Methods: Fresh human whole blood was incubated with upLPS or whole E. coli E. coli bacteria in the presence of MD-2 MD-2 or CD14 CD14 neutralizing monoclonal antibodies, or their respective controls, and/or the specific complement-inhibitor compstatin. Cytokines Cytokines were measured by a multiplex (n=27) assay. NFκB activity was examined in cells transfected with CD14 CD14 , MD-2 MD-2 and/or Toll-like receptors. Results: LPS LPS -induced cytokine response was efficiently and equally abolished by MD-2 MD-2 and CD14 CD14 neutralization. In contrast, the response induced by whole E. coli E. coli bacteria was only modestly reduced by MD-2 MD-2 neutralization, whereas CD14 CD14 neutralization was more efficient. Combination with compstatin enhanced the effect of MD-2 MD-2 neutralization slightly. When compstatin was combined with CD14 CD14 neutralization, however, the response was virtually abolished for all cytokines, including IL-17, which was only inhibited by this combination. The MD-2 MD-2 -independent effect observed for CD14 CD14 could not be explained by TLR2 signaling. Conclusion: Inhibition of CD14 CD14 is more efficient than inhibition of MD-2 MD-2 on whole E. coli E. coli -induced cytokine response, suggesting CD14 CD14 to be a better target for intervention in Gram-negative sepsis, in particular when combined with complement inhibition.
Nieder C.,Nordland Hospital |
Nieder C.,University of Tromsø
Strahlentherapie und Onkologie | Year: 2012
Background and purpose. Tight budgets and increasing competition for research funding pose challenges for highly specialized medical disciplines such as radiation oncology. Therefore, a systematic review was performed of successfully completed research that had a high impact on clinical practice. These data might be helpful when preparing new projects.Methods. Different measures of impact, visibility, and quality of published research are available, each with its own pros and cons. For this study, the article citation rate was chosen (minimum 15 citations per year on average). Highly cited German contributions to the fields of radiation oncology, biology, and physics (published between 1990 and 2010) were identified from the Scopus database.Results. Between 1990 and 2010, 106 articles published in 44 scientific journals met the citation requirement. The median average of yearly citations was 21 (maximum 167, minimum 15). All articles with 40 citations per year were published between 2003 and 2009, consistent with the assumption that the citation rate gradually increases for up to 2 years after publication. Most citations per year were recorded for meta-analyses and randomized phase III trials, which typically were performed by collaborative groups.Conclusion. A large variety of clinical radiotherapy, biology, and physics topics achieved high numbers of citations. However, areas such as quality of life and side effects, palliative radiotherapy, and radiotherapy for nonmalignant disorders were underrepresented. Efforts to increase their visibility might be warranted. © Springer-Verlag 2012.
The effects of selective complement and CD14 inhibition on the E. coli-induced tissue factor mRNA upregulation, monocyte tissue factor expression, and tissue factor functional activity in human whole blood.
Brekke O.L.,Nordland Hospital
Advances in experimental medicine and biology | Year: 2013
The complement pathway and CD14 play essential roles in inflammation, but little is known about the relative roles of complement and CD14 in E. coli-induced tissue factor (TF) mRNA upregulation, expression by monocytes, and functional activity in human whole blood. Whole E. coli bacteria were incubated for up to 4 h in human whole blood containing the anticoagulant lepirudin, which does not affect complement activation. TF mRNA levels were analyzed using reverse transcription, quantitative real-time PCR (RT-qPCR), and the expression of TF on the cell surface was analyzed using flow cytometry. Complement was selectively inhibited using the C3 convertase inhibitor compstatin or a C5a receptor antagonist (C5aRa), while CD14 was blocked by an anti-CD14 F(ab')2 monoclonal antibody. The E. coli-induced TF mRNA upregulation was reduced to virtually background levels by compstatin, whereas anti-CD14 had no effect. Monocyte TF expression and TF activity in plasma microparticles were significantly reduced by C5aRa. Anti-CD14 alone only slightly reduced E. coli-induced monocyte TF expression but showed a modest additive effect when combined with the complement inhibitors. Inhibiting complement and CD14 efficiently reduced the expression of the E. coli-induced cytokines IL-1beta, IL-6, IL-8, and platelet-derived growth factor bb. Our results indicate that E. coli-induced TF mRNA upregulation is mainly dependent on complement activation, while CDI4 plays a modest role in monocyte TF expression and the plasma TF activity in human whole blood.
Nieder C.,Nordland Hospital |
Nieder C.,University of Tromsø |
Spanne O.,University of Tromsø |
Mehta M.P.,Ohio State University |
And 2 more authors.
Cancer | Year: 2011
BACKGROUND: It is largely unknown to what extent new oncologic treatment options have improved survival of patients with brain metastasis in recent decades. Therefore, a multi-institutional time-staggered analysis was performed. METHODS: Two cohorts of 103 patients each were analyzed, one treated between 2005 and 2009 and the other between 1983 and 1989, ie, approximately 20 years earlier. Stratified analyses by prognostic groups were also performed (graded prognostic assessment [GPA] and Radiation Therapy Oncology Group recursive partitioning analysis [RTOG-RPA]). RESULTS: Patterns of care have changed significantly. Contemporary patients received focal treatments such as stereotactic radiosurgery and surgical resection far more frequently. Furthermore, systemic treatment was used more often in contemporary patients, both before and after diagnosis of brain metastasis. Improved survival was observed in the contemporary cohort (P = .03). The 1-year survival rate increased from 15% (95% confidence interval [CI], 7%-25%) to 34% (95% CI, 25%-44%). However, this improvement was largely driven by patients with favorable prognostic features. More than 40% of the patients still belong to unfavorable prognostic groups with limited median survival and little improvement. CONCLUSIONS: Contemporary patients were managed on a much more individualized basis, requiring multidisciplinary case discussion and thorough assessment of prognostic features. Progress has been made, but the overall outcome needs to be improved further. Avoiding overtreatment in patients with poor prognosis is as important as aggressive treatment in patients who might survive for several years. © 2010 American Cancer Society.
Von Hanno T.,Nordland Hospital |
Kinge B.,Retinaklinikken Aleris |
Fossen K.,University of Tromsø
Acta Ophthalmologica | Year: 2010
Purpose: Anti-vascular endothelial growth factor (anti-VEGF) therapy effectively inhibits angiogenesis and is now enjoying widespread use in the treatment of age-related macular degeneration (AMD). It may also have a role in the treatment of macular oedema secondary to other conditions. VEGF is a signalling molecule that has a variety of roles, including vasoregulation and effects on the coagulation homeostasis. Anti-VEGF therapy may therefore have adverse effects on ocular blood flow. Methods: Two cases of retinal artery occlusion after intravitreal injection of anti-VEGF are presented. Both patients were given the treatment to reduce macular oedema secondary to central retinal vein occlusion. Possible mechanisms are discussed. Results: Patient 1 developed a central retinal artery occlusion within 1 month of an intravitreal injection of ranibizumab (Lucentis®). The macular oedema was totally resolved at 1 month; final visual acuity (VA) was light perception. Patient 2 developed a branch retinal artery occlusion in the macula 2 days after an intravitreal injection of bevacizumab (Avastin®). The macular oedema was almost resolved within 1 week and did not recur; final VA was 0.6. Conclusions: Anti-VEGF therapy may have a role in the treatment of macular oedema caused by central retinal vein occlusions. However, our report indicates that the therapeutic principle may be associated with an increased risk of retinal arterial occlusions. © 2009 Acta Ophthalmol.
Hansen T.E.,Nordland Hospital |
Evjenth B.,Nordland Hospital |
Holt J.,Nordland Hospital |
Holt J.,University of Tromsø
Acta Paediatrica, International Journal of Paediatrics | Year: 2013
Aim The prevalence of asthma, allergic rhinoconjunctivitis (AR) and eczema among children has increased worldwide in the last four decades, but recent studies disagree as to whether the prevalence is continuing to rise or is levelling off or declining. The aim of this study was to assess time trends in a subarctic population. Methods: A cross-sectional, questionnaire-based survey was carried out in 2008 among children aged 7-14years in randomly selected schools in Nordland County, Norway (n=4150). The Results are compared with results from identical studies in 1985 (n=4870) and 1995 (n=4456). Results: The main findings were an increasing prevalence of asthma ever (7.3% in 1985 to 17.6% in 2008, p for trend<0.001) and AR ever (15.9% in 1985 to 24.5% in 2008, p for trend<0.001), while the prevalence of eczema ever, after an increase between 1985 and 1995, remained unchanged in the last time period. The prevalence of current disease doubled and trebled between 1995 and 2008 for all three diseases. Conclusion: A repeated cross-sectional survey between 1985 and 2008 documented an increasing prevalence of asthma ever and AR ever among schoolchildren (7-14years), together with a considerably increase in current asthma, AR and eczema between 1995 and 2008. © 2012 The Author(s)/Acta Pædiatrica.
Prokic V.,University Hospital Freiburg |
Wiedenmann N.,University Hospital Freiburg |
Fels F.,University Hospital Freiburg |
Schmucker M.,University Hospital Freiburg |
And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013
Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 ± 0.62 Gy and 6.29 ± 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 ± 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 ± 0.7 Gy and 32.7 ± 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 ± 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery- equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used. © 2013 Elsevier Inc.
Haugen A.S.,University of Bergen |
Softeland E.,University of Bergen |
Almeland S.K.,Forde Central Hospital |
Sevdalis N.,Imperial College London |
And 4 more authors.
Annals of Surgery | Year: 2015
Objectives: We hypothesized reduction of 30 days' in-hospital morbidity, mortality, and length of stay postimplementation of the World Health Organization's Surgical Safety Checklist (SSC). Background: Reductions of morbidity and mortality have been reported after SSC implementation in pre-/postdesigned studies without controls. Here, we report a randomized controlled trial of the SSC. Methods: A stepped wedge cluster randomized controlled trial was conducted in 2 hospitals. We examined effects on in-hospital complications registered by International Classification of Diseases, Tenth Revision codes, length of stay, and mortality. The SSC intervention was sequentially rolled out in a random order until all 5 clusters-cardiothoracic, neurosurgery, orthopedic, general, and urologic surgery had received the Checklist. Data were prospectively recorded in control and intervention stages during a 10-month period in 2009-2010. Results: A total of 2212 control procedures were compared with 2263 SCC procedures. The complication rates decreased from 19.9% to 11.5% (P < 0.001), with absolute risk reduction 8.4 (95% confidence interval, 6.3-10.5) from the control to the SSC stages. Adjusted for possible confounding factors, the SSC effect on complications remained significant with odds ratio 1.95 (95% confidence interval, 1.59-2.40). Mean length of stay decreased by 0.8 days with SCC utilization (95% confidence interval, 0.11-1.43). In-hospital mortality decreased significantly from 1.9% to 0.2% in 1 of the 2 hospitals post-SSC implementation, but the overall reduction (1.6%-1.0%) across hospitals was not significant. Conclusions: Implementation of the WHO SSC was associated with robust reduction in morbidity and length of in-hospital stay and some reduction in mortality. © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Troseid M.,University of Oslo |
Nestvold T.K.,Nordland Hospital |
Rudi K.,Norwegian University of Life Sciences |
Thoresen H.,Nordland Hospital |
And 4 more authors.
Diabetes Care | Year: 2013
OBJECTIVE-It is of vital importance to elucidate the triggering factors of obesity and type 2 diabetes to improve patient care. Bariatric surgery has been shown to prevent and even cure diabetes, but the mechanism is unknown. Elevated levels of lipopolysaccharide (LPS) predict incident diabetes, but the sources of LPS are not clarified. The objective of the current study was to evaluate the potential impact of plasma LPS on abdominal obesity and glycemic control in subjects undergoing bariatric surgery. RESEARCH DESIGN AND METHODS-This was a prospective observational study involving a consecutive sample of 49 obese subjects undergoing bariatric surgery and 17 controls. Main assessments were plasma LPS, HbA1c, adipose tissue volumes (computed tomography), and quantified bacterial DNA in adipose tissue compartments. RESULTS-Plasma levels of LPS were elevated in obese individuals compared with controls (P < 0.001) and were reduced after bariatric surgery (P = 0.010). LPS levels were closely correlated with HbA1c (r = 0.56; P = 0.001) and intra-abdominal fat volumes (r = 0.61; P < 0.001), but only moderately correlated with subcutaneous fat volumes (r = 0.33; P = 0.038). Moreover, there was a decreasing gradient (twofold) in bacterial DNA levels going from mesenteric via omental to subcutaneous adipose tissue compartments (P = 0.041). Finally, reduced LPS levels after bariatric surgery were directly correlated with a reduction in HbA1c (r = 0.85; P < 0.001). CONCLUSIONS-Our findings support a hypothesis of translocated gut bacteria as a potential trigger of obesity and diabetes, and suggest that the antidiabetic effects of bariatric surgery might be mechanistically linked to, and even the result of, a reduction in plasma levels of LPS. © 2013 by the American Diabetes Association.
Nieder C.,Nordland Hospital |
Grosu A.L.,University Hospital Freiburg |
Gaspar L.E.,Aurora University
Radiation Oncology | Year: 2014
In many patients with brain metastases, the primary therapeutic aim is symptom palliation and maintenance of neurologic function, but in a subgroup, long-term survival is possible. Local control in the brain, and absent or controlled extracranial sites of disease are prerequisites for favorable survival. Stereotactic radiosurgery (SRS) is a focal, highly precise treatment option with a long track record. Its clinical development and implementation by several pioneering institutions eventually rendered possible cooperative group randomized trials. A systematic review of those studies and other landmark studies was undertaken. Most clinicians are aware of the potential benefits of SRS such as a short treatment time, a high probability of treated-lesion control and, when adhering to typical dose/volume recommendations, a low normal tissue complication probability. However, SRS as sole first-line treatment carries a risk of failure in non-treated brain regions, which has resulted in controversy around when to add whole-brain radiotherapy (WBRT). SRS might also be prescribed as salvage treatment in patients relapsing despite previous SRS and/or WBRT. An optimal balance between intracranial control and side effects requires continued research efforts. © 2014 Nieder et al.; licensee BioMed Central Ltd.