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Search Results: 1 - 10 of 2971 matches for " Frederik Dagnaes-Hansen "
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Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice
Bettina H Clausen, Kate L Lambertsen, Alicia A Babcock, Thomas H Holm, Frederik Dagnaes-Hansen, Bente Finsen
Journal of Neuroinflammation , 2008, DOI: 10.1186/1742-2094-5-46
Abstract: We used flow cytometry and immunohistochemistry to examine cellular co-expression of IL-1β and TNF-α at 6, 12 and 24 hours after permanent middle cerebral artery occlusion in mice, validating the results by the use of bone marrow chimeric mice.We found that IL-1β and TNF-α were expressed in largely segregated populations of CD11b+CD45dim microglia and CD11b+CD45high macrophages, with cells expressing both cytokines only rarely. The number of Gr1+ granulocytes producing IL-1β or TNF-α was very low, and we observed no IL-1β- or TNF-α-expressing T cells or astrocytes.Taken together, the results show that IL-1β and TNF-α are produced by largely segregated populations of microglia and macrophages after ischemic stroke in mice. Our findings provide evidence of a functional diversity among different subsets of microglia and macrophages that is potentially relevant to future design of anti-inflammatory therapies in stroke.The proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) play key roles in the pathogenesis of ischemic stroke [1-3]. IL-1β exerts neurotoxic effects in ischemic stroke and blocking its action has been shown to reduce ischemic brain damage [4,5]. In comparison, there is evidence that TNF-α has both neurotoxic [6,7] and neuroprotective [8-10] roles after ischemic stroke in rats and in mice. Increasing evidence implicates both cytokines in the early inflammatory response that precedes and accompanies ischemia-induced neuronal damage [6,11]. However, detailed knowledge about the contribution of different cell types to the production of IL-1β and TNF-α is still not available.The relative physiological outcome of increased IL-1β and TNF-α signaling in ischemic stroke may depend on the kinetics and location of cytokine producing cells. There is compelling evidence that IL-1β and TNF-α are primarily synthesized by activated microglia and infiltrating macrophages [12-14], although granulocytes and astrocytes have also been suggested
Protein Replacement Therapy Partially Corrects the Cholesterol-Storage Phenotype in a Mouse Model of Niemann-Pick Type C2 Disease
Gitte Krogh Nielsen, Frederik Dagnaes-Hansen, Ida Elisabeth Holm, Steve Meaney, Derek Symula, Niels Trolle Andersen, Christian Würtz Heegaard
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027287
Abstract: Niemann-Pick type C2 (NPC2) disease is a fatal autosomal recessive neurovisceral degenerative disorder characterized by late endosomal-lysosomal sequestration of low-density lipoprotein derived cholesterol. The breach in intracellular cholesterol homeostasis is caused by deficiency of functional NPC2, a soluble sterol binding protein targeted to the lysosomes by binding the mannose-6-phosphate receptor. As currently there is no effective treatment for the disorder, we have investigated the efficacy of NPC2 replacement therapy in a murine gene-trap model of NPC2-disease generated on the 129P2/OlaHsd genetic background. NPC2 was purified from bovine milk and its functional competence assured in NPC2-deficient fibroblasts using the specific cholesterol fluorescent probe filipin. For evaluation of phenotype correction in vivo, three-week-old NPC2?/? mice received two weekly intravenous injections of 5 mg/kg NPC2 until trial termination 66 days later. Whereas the saline treated NPC2?/? mice exhibited massive visceral cholesterol storage as compared to their wild-type littermates, administration of NPC2 caused a marked reduction in cholesterol build up. The histological findings, indicating an amelioration of the disease pathology in liver, spleen, and lungs, corroborated the biochemical results. Little or no difference in the overall cholesterol levels was observed in the kidneys, blood, cerebral cortex and hippocampus when comparing NPC2?/? and wild type mice. However, cerebellum cholesterol was increased about two fold in NPC2?/? mice compared with wild-type littermates. Weight gain performance was slightly improved as a result of the NPC2 treatment but significant motor coordination deficits were still observed. Accordingly, ultrastructural cerebellar abnormalities were detected in both saline treated and NPC2 treated NPC2?/? animals 87 days post partum. Our data indicate that protein replacement may be a beneficial therapeutic approach in the treatment of the visceral manifestations in NPC2 disease and further suggest that neurodegeneration is not secondary to visceral dysfunction.
The response to oestrogen deprivation of the cartilage collagen degradation marker, CTX-II, is unique compared with other markers of collagen turnover
Anne-Christine Bay-Jensen, Nadine CB Tabassi, Lene V Sondergaard, Thomas L Andersen, Frederik Dagnaes-Hansen, Patrick Garnero, Moustapha Kassem, Jean-Marie Delaissé
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2596
Abstract: The type II collagen degradation markers CTX-II and Helix-II were measured in the body fluids of premenopausal and postmenopausal women and in those of ovariectomised rats receiving oestrogen or not. Levels of PIIANP, a marker of type II collagen synthesis, were also measured in rats. Rat knee cartilage was analysed for immunoreactivity of CTX-II and PIIANP and for type II collagen expression.As expected, urinary levels of CTX-II are significantly increased in postmenopausal women and also in oestrogen-deprived rats, although only transiently. However, in neither case were these elevations paralleled by a significant increase of Helix-II levels and PIIANP levels did not change at any time. CTX-II immunoreactivity and collagen expression were detected in different cartilage areas. The upper zone is the area where CTX-II immunoreactivity and collagen expression best reflected the differences in urinary levels of CTX-II measured in response to oestrogen. However, correlations between urinary levels of CTX-II and tissue immunostainings in individual rats were not statistically significant.We found only a small effect of oestrogen deprivation on cartilage. It was detected by CTX-II, but not by other type II collagen turnover markers typically affected in osteoarthritis.The molecular mechanism of osteoarthritis (OA) development is poorly understood. Cartilage alterations in the joint start very locally, extend progressively and lead to inflammation [1]. Several studies have suggested that changes in the cartilage occur well before damage to the cartilage matrix can be detected, and that they are related to modifications in the metabolism of type II collagen and proteoglycans [2-5]. The trigger switching the chondrocyte to a pathological state has, however, not been identified.OA has multiple aetiologies, but is most often believed to result from mechanical injuries. There are also suggestions that oestrogen deprivation favours OA development [6]. This hypothesis was first
Functional Screening Identifies miRNAs Influencing Apoptosis and Proliferation in Colorectal Cancer
Lise Lotte Christensen, Anja Holm, Juha Rantala, Olli Kallioniemi, Mads H. Rasmussen, Marie S. Ostenfeld, Frederik Dagnaes-Hansen, Bodil ?ster, Troels Schepeler, Heidi Tobiasen, Kasper Thorsen, Oliver M. Sieber, Peter Gibbs, Philippe Lamy, Torben F. Hansen, Anders Jakobsen, Eva M. Riising, Kristian Helin, Jan Lubinski, Rikke Hagemann-Madsen, S?ren Laurberg, Torben F. ?rntoft, Claus L. Andersen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096767
Abstract: MicroRNAs (miRNAs) play a critical role in many biological processes and are aberrantly expressed in human cancers. Particular miRNAs function either as tumor suppressors or oncogenes and appear to have diagnostic and prognostic significance. Although numerous miRNAs are dys-regulated in colorectal cancer (CRC) only a small fraction has been characterized functionally. Using high-throughput functional screening and miRNA profiling of clinical samples the present study aims at identifying miRNAs important for the control of cellular growth and/or apoptosis in CRC. The high-throughput functional screening was carried out in six CRC cell lines transfected with a pre-miR library including 319 synthetic human pre-miRs. Phenotypic alterations were evaluated by immunostaining of cleaved cPARP (apoptosis) or MKI67 (proliferation). Additionally, TaqMan Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosa and 46 microsatellite stable stage II CRC patients. Among the miRNAs that induced growth arrest and apoptosis in the CRC cell lines, and at same time were dys-regulated in the clinical samples, miR-375 was selected for further analysis. Independent in vitro analysis of transient and stable transfected CRC cell lines confirmed that miR-375 reduces cell viability through the induction of apoptotic death. We identified YAP1 as a direct miR-375 target in CRC and show that HELLS and NOLC1 are down-stream targets. Knock-down of YAP1 mimicked the phenotype induced by miR-375 over-expression indicating that miR-375 most likely exerts its pro-apoptotic role through YAP1 and its anti-apoptotic down-stream targets BIRC5 and BCL2L1. Finally, in vivo analysis of mouse xenograft tumors showed that miR-375 expression significantly reduced tumor growth. We conclude that the high-throughput screening successfully identified miRNAs that induce apoptosis and/or inhibit proliferation in CRC cells. Finally, combining the functional screening with profiling of CRC tissue samples we identified clinically relevant miRNAs and miRNA targets in CRC.
The effect of surgery followed by endotoxin on the unspecific cell mediated immunity
P Toft, F Dagnaes-Hansen, MS Petersen, E Tonnesen, HS Jorgensen
Critical Care , 2002, DOI: 10.1186/cc1556
Abstract: Three groups of 40 mice. Each group was divided into four groups of 10 in each. All the animals were anaesthetized and subjected to either (1) laparotomy, (2) treatment with E. coli endotoxin i.p., (3) subjected to laparotomy followed 20 min later by i.p. endotoxin or (4) left untreated as a control group. In the first 40 mice the NK cell activity in spleens and number of NK cells in livers were measured, in the second the oxidative burst of granulocyte and in the third the antigen presentation capacity of monocytes.Endotoxin stimulated the NK cell activity and up-regulated the antigen presentation on monocytes. In contrast, surgical stress reduced the NK cell activity, the number of NK cells in tissues and down-regulated the antigen presentation on monocytes. After surgery, followed by administration of endotoxin, the oxidative burst of granulocytes was stimulated while antigen presentation on monocytes was down-regulated. Endotoxin prevented or reverted the postoperative suppression of NK cell activity.Our two-hit model shows that some cell types of the unspecific immune system exhibit an anti-inflammatory response (monocytes) while others at the same time show an excessive inflammatory response (NK cells, granulocytes). This diversity makes a potential therapeutic immunomodulation very complex, as some cell types would need to be down-regulated while others need to be stimulated.
Retrivability in The Danish National Hospital Registry of HIV and hepatitis B and C coinfection diagnoses of patients managed in HIV centers 1995–2004
Niels Obel, Hanne Reinholdt, Lars H Omland, Frederik Engsig, Henrik T S?rensen, Ann-Brit E Hansen
BMC Medical Research Methodology , 2008, DOI: 10.1186/1471-2288-8-25
Abstract: The Danish HIV Cohort Study (DHCS) encompasses all HIV-infected patients treated in Danish HIV clinics since 1 January 1995. All 2,033 Danish patients in DHCS diagnosed with HIV-1 during the 10-year period from 1 January 1995 to 31 December 2004 were included in the current analysis. We used the DHCS as a reference to examine the completeness of HIV and of HBV and HCV coinfections recorded in DNHR. Cox regression analysis was used to estimate hazard ratios of time to diagnosis of HIV in DNHR compared to DHCS.Of the 2,033 HIV patients in DHCS, a total of 2,006 (99%) were registered with HIV in DNHR. Of these, 1,888 (93%) were registered in DNHR within one year of their first positive HIV test. A CD4 < 200 cells/μl, a viral load >= 100,000 copies/ml and being diagnosed after 1 January 2000, were associated with earlier registration in DNHR, both in crude and adjusted analyses. Thirty (23%) HIV patients registered with chronic HBV (n = 129) in DHCS and 126 (48%) of HIV patients with HCV (n = 264) in DHCS were registered with these diagnoses in the DNHR. Further 17 and 8 patients were registered with HBV and HCV respectively in DNHR, but not in DHCS. The positive predictive values of being registered with HBV and HCV in DHCS were thereby estimated to 0.88 and 0.97 and in DNHR to 0.32 and 0.54.The study demonstrates that secondary data from national hospital databases may be reliable for identification of patients diagnosed with HIV infection. However, the predictive value of co-morbidity data may be low.Since the first AIDS cases were reported, AIDS and HIV infection have been the subject of a wide spectrum of epidemiologic studies [1-3]. The characteristics of HIV infection make it both ideal and highly relevant for epidemiological research: valid diagnostic tools, well-described risk factors, unambiguous disease outcomes, a high impact on morbidity and mortality, worldwide dissemination, and huge economic consequences commanding the attention of national and internati
Hypertrophy Dependent Doubling of L-Cells in Roux-en-Y Gastric Bypass Operated Rats
Carl Frederik Hansen, Marco Bueter, Nadine Theis, Thomas Lutz, Sarah Paulsen, Louise S. Dalb?ge, Niels Vrang, Jacob Jelsing
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065696
Abstract: Background and Aims Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal. Methods The full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells. Results RYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell. Conclusions Collectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB.
Full-field hard x-ray microscopy with interdigitated silicon lenses
Hugh Simons,Frederik St?hr,Jonas Michael-Lindhard,Flemming Jensen,Ole Hansen,Carsten Detlefs,Henning Friis Poulsen
Physics , 2015, DOI: 10.1016/j.optcom.2015.09.103
Abstract: Full-field x-ray microscopy using x-ray objectives has become a mainstay of the biological and materials sciences. However, the inefficiency of existing objectives at x-ray energies above 15 keV has limited the technique to weakly absorbing or two-dimensional (2D) samples. Here, we show that significant gains in numerical aperture and spatial resolution may be possible at hard x-ray energies by using silicon-based optics comprising 'interdigitated' refractive silicon lenslets that alternate their focus between the horizontal and vertical directions. By capitalizing on the nano-manufacturing processes available to silicon, we show that it is possible to overcome the inherent inefficiencies of silicon-based optics and interdigitated geometries. As a proof-of-concept of Si-based interdigitated objectives, we demonstrate a prototype interdigitated lens with a resolution of ~255 nm at 17 keV.
Technological Progress in Radiation Therapy for Brain Tumors  [PDF]
Frederik Jozef Vernimmen, Kathy Rock
Journal of Cancer Therapy (JCT) , 2014, DOI: 10.4236/jct.2014.51005

To achieve a good therapeutic ratio the radiation dose to the tumor should be as high as possible with the lowest possible dose to the surrounding normal tissue. This is especially the case for brain tumors. Technological advancements in diagnostic imaging, dose calculations, and radiation delivery systems, combined with a better understanding of the pathophysiology of brain tumors have led to improvements in the therapeutic results. The widely used technology of delivering 3-D conformal therapy with photon beams (gamma rays) produced by Linear Accelerators has progressed into the use of Intensity modulated radiation therapy (IMRT). Particle beams have been used for several decades for radiotherapy because of their favorable depth dose characteristics. The introduction of clinically dedicated proton beam therapy facilities has improved the access for cancer patients to this treatment. Proton therapy is of particular interest for pediatric malignancies. These technical improvements are further enhanced by the evolution in tumor physiology imaging which allows for improved delineation of the tumor. This in turn opens the potential to adjust the radiation dose to maximize the radiobiological effects. The advances in both imaging and radiation therapy delivery will be discussed.

Gold Nanoparticles in Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations  [PDF]
Frederik Vernimmen, Mikhail L. Shmatov
Journal of Biomaterials and Nanobiotechnology (JBNB) , 2015, DOI: 10.4236/jbnb.2015.63019
Abstract: Objective of the study: To explore the potential for therapeutic gain with gold nanoparticles in arteriovenous malformation radiosurgery based on their interaction with photons and protons. Study methods: Radiation dose enhancement resulting from the interaction of gold nanoparticles with irradiation ranging from kilovoltage to megavoltage photons and protons was researched in the literature. The role of angiogenesis and its regulation via vascular endothelial growth factors and cell membrane receptors, especially for endothelial cells in arteriovenous malformations, was investigated as a way for selective arteriovenous malformation deposition. Results: Radiation dose enhancement with gold nanoparticles is described in the literature but has so far only been investigated for its potential in treating malignancies. Because of the high atomic number of gold (Z = 79), dose enhancement occurs with photons mainly based on secondary photon and Auger electron production and the dose enhancement factor is the highest for irradiation with kilo voltage photons. Dose enhancement happens with megavoltage photons also but to a lesser extend and is mainly due to the ionization of gold by secondary photons and electrons generated by the megavoltage photons passing through tissue. The range of the secondary photo electrons emitted by gold is sufficient to cover the entire endothelial cell content. Protons interact with the production of Auger electrons which have a very short range, insufficient to cover the entire contents of endothelial cells, but sufficient to cause a high cell membrane dose for membrane located gold nanoparticles (AuNPs). Arteriovenous malformations are dynamic entities with angiogenesis taking place. This is reflected by a different expression of angiogenic receptors on the membrane of arteriovenous malformation endothelial cells compared to normal brain blood vessels, thereby opening the opportunity for selective deposition of such particles. For the use in proton therapy a new definition for the dose enhancement factor describing the local effect of nanoparticles is proposed. Conclusion: The concept of nanoparticle enhanced radiosurgery for arteriovenous malfor-mations by selective deposition of gold nanoparticles is a novel approach. The local dose enhancement opens the way for therapeutic gain which in turn could lead to improved obliteration rates and/or a shorter latent period.
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