305 research outputs found
Harald Klingelholler : Sculptures
No full textRefering to notions of language and nature, and to Heidegger's conception of "dwelling", Moos analyses Klingelholler's sculptures made of materials contiguous with those of modern building. The author examines these forms' pervasive spatiality and considers the artist's peculiar use of paper. Biographical notes. 11 bibl. ref
Immunoliposomes for Targeting Cancer Cells and Tumor Vasculature in a Mouse Model of Glioblastoma Multiforme
No full textThe most common malignant tumor of astrocytic origin is the highly aggressive glioblastoma multiforme. The median survival time measured from the time of the diagnosis is only approximately one year due to the late stage of diagnosis and the lack of efficacy of currently available therapies. However, significant progress in uncovering cancer biology during the past decades has prompted extensive research within novel classes of anticancer drugs, exploiting molecular differences between the tumor and the normal tissue for inducing specific cancer cell toxicity. Drug carriers can be directed to molecules aberrantly expressed by the cancer cells or the tumor vasculature for inducing direct cancer cell toxicity or regression of the tumoral blood supply, respectively. Liposomal systems comprise one main type of targeted drug carriers and have potential for transporting a wide variety of drugs at a high load per carrier. A recent development within liposomal cancer therapy is to combine several types of liposomes directed to different targets or to use multitargeted liposomes, in order to achieve a synergistic targeting effect. In glioblastoma multiforme, this strategy could be used for simultaneous targeting of cancer cells and tumor endothelial cells, in order to benefit from the separate advantages of the two targeting strategies. The subject of this thesis has been to investigate liposomes as a possible drug carrier system for targeting cancer cells and tumor endothelial cells of glioblastoma multiforme. One of the primary aims was to develop and characterize an intracranial animal model of human glioblastoma multiforme. Cells of a human glioblastoma multiforme cell line, U-87 MG, were inoculated into the striatum of immunodeficient nude mice which lead to tumor development in two thirds of animals. Histological investigations of brain sections revealed extensive growth and local invasion of the tumor xenografts. As a measure of vascular permeability, the intratumoral accumulation of intraperitoneally injected peroxidase and endogenous mouse albumin was investigated. Both substances demonstrated a diffuse pattern of accumulation in the tumor area, compatible with increased leakiness of the tumor vessels. In summary, the intracranial U-87 MG tumor xenograft model was observed to recapitulate important features of human glioblastoma multiforme such as aggressive growth, local invasion, and probably also some degree of vascular leakiness. Furthermore, a protocol for preparation of immunoliposomes was developed, based on the post insertion technique. Using this protocol cancer cell and vascular targeted liposomes was prepared. For targeting of U-87 MG cells liposomes was conjugated with the EGFR-antibody Erbitux® and for targeting of murine brain endothelial cells liposomes was conjugated with VCAM-1 antibody. Erbitux®-liposomes demonstrated significant cellular uptake by the U-87 MG cells in contrast to unconjugated liposomes. However, no uptake of anti-VCAM-1 liposomes by activated murine brain endothelial cells could be detected. One major reason for this was probably the fact that a much lower amount of antibody was conjugated to the anti-VCAM-1 liposomes compared to the Erbitux®-liposomes. Methods for assessing the tissue distribution of fluorescent liposomes in vivo were investigated, since the next is investigation of the liposome behavior in vivo. Fluorescence microscopy of tissue sections was hampered by a high background signal and fluorescent liposomes could only be detected in the liver and the spleen. Fluorescence spectroscopy of tissue homogenates yielded promising results, however due to time constraints data have only been obtained for some tissues. After further optimization and validation of these methods, it would be interesting to explore the in vivo characteristics of the Erbitux®-liposomes in the established U-87 MG tumor xenograft model, perhaps along with liposomes targeting the tumor endothelial cells via an alternative to VCAM-1. <br/
The Significance of Mesenchymal Stem Cells for the Tumor Formation and Progression in Glioblastoma Multiforme
No full textTargeted Delivery to the Central Nervous System utilizing Magnetically Guided Immunomagnetoliposomes
No full textBackground: The delivery of therapeutics across the blood-brain barrier (BBB) constitutes a significant hurdle for the treatment of patients suffering from CNS disorders. This is especially evident for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, since the BBB limits the treatment options to small lipophilic drugs, which has a limited therapeutic potential. Therefore several nanoparticulate drug delivery systems are being investigated to enable macromolecular drug delivery to the CNS and thereby improving the treatment options.Methods: The purpose of this study was to construct a magnetic responsive drug delivery system to enable drug delivery across the BBB. The starting platform was starch coated magnetic nanoparticles (S-MNPs), which were encapsulated in phospholipids to yield magnetoliposomes (MLs). Finally OX26 antibodies, targeting the transferrin receptor, was purified from an in-house hybridoma cell culture and utilized to produce OX26 conjugated magnetoliposomes (OX26-MLs). Initially cellular uptake of all particle types were screened in vitro in rat brain endothelial cells (RBE4 cells). The biodistribution of MLs and OX26-MLs was investigated after intravenous injection in 16 day old rats (P16). The morphological biodistribution was studied on tissue sections from brain, liver, spleen, lungs, and kidneys by fluorescence microscopy. Finally the ability of MLs and OX26-MLs to traverse the BBB both with and without the application of a magnetic field was tested on P16 rats using the in situ brain perfusion method (n = 10). Traversal of the BBB was evaluated by immunohistochemical staining of laminin in the basement membrane of the capillary bed, and sections were then analyzed by fluorescence microscopy to detect particles beyond the BBB. P16 rats were used due to their high expression and recycling rate of transferrin receptors in the brain capillary endothelial cells (BCECs). Results: In vitro screening of the cellular uptake in RBE4 cells revealed a 4.3 fold and 7.3 fold increase in median cell fluorescence intensity for MLs and OX26-MLs compared to S-MNPs, respectively. Furthermore OX26-MLs demonstrated a 1.6 fold increase compared to MLs. Mann-Whitney-U tests revealed that all groups were significantly different from each other (p < 0.05). The biodistribution revealed a preferential uptake of both MLs and OX26-MLs in the liver and spleen, whereas a small amount of particles were present in the lungs and virtually absent in the kidney. Surprisingly no significant accumulation of both MLs and OX26-MLs were seen in the brain capillaries. In situ brain perfusion experiments revealed, that OX26-MLs demonstrated a good potential as a drug delivery system to the BCECs with enhanced uptake compared to MLs. Furthermore the uptake did not dependent on an external magnetic field and hence OX26-MLs are probably transported into the BCECs by receptor mediated endocytosis. When investigating the permeation of OX26-MLs under the influence of a magnetic field a small amount of OX26-MLs was found beyond the BBB, which suggests transcytosis occurred. However, no convincing and consistent evidence was found for this phenomenon to support widespread transcytosis and cellular accumulation of OX26-MLs beyond the BBB. Conclusion: OX26-MLs were synthesized and constitute a novel drug delivery system, which has the ability to target the BCECs. This suggests that OX26-MLs are suitable for blood to endothelium transport. However, the potential of OX26-MLs to enhance the permeation of the BBB remains obscure. Furthermore the stability in blood must be improved to make intravenous administration feasible.<br/
Effect of Iron Deficiency in Offspring Rats: An Investigation of Fear and Anxiety-like Behavior Related to the Developing Hippocampus
No full textIntroduktion: Jernmangel er en udbredt mikro ernæringsforstyrrelse og påvirker omkring 2 milliarder mennesker på verdens- plan. Behovet for jern forøges kraftigt under graviditet, fra 0.8 mg/dag i første trimester til > 6 mg/dag i tredje trimester, hvilket gør det svært at opretholde et tilstrækkeligt jern niveau uden brug af jerntilskud. Hippocampus spiller en vigtig rolle i bearbejdelsen af information og adfærd gennem en kompleks interaktion med amygdala og hypothalamus. Igennem oxidativ fosforylering bliver det høje energiforbrug fra hippocampus mødt. Cytochrome c oxidase er et jernholdig terminal enzyme som er involveret i sidste stadie af oxidativ fosforylering. Dette gør enzymet til en kvalificeret markør for neuronal metabolisk aktivitet. Formål: Formålet med studiet var at etablere et experimental model med gnaver for at undersøge jernmangel effekten på adfærd og den neurale udvikling i afkom fra rotter og hvorvidt tilskud med jern isomaltoside (Monofer) på to forskellige stadier (gestationsdag 1 og femte postnatale dag) af udviklingen kan forebygge hjerne abnormaliteter. Metode: 14 Wistar rotter blev inddelt i fire grupper; Kontrolgruppen (CN), gestationsdag 19 (G19), første postnatale dag (ID) og femte postnatale dag (P5). G19, ID, og P5 modtog alle jernmangel diæt og injektioner med Monofer på de tilsvarende dage. Afkommet blevet testet for frygt og angst-lignende adfærd med open field, elevated zero maze og light/dark boks, hvor udforskning var observeret i 10 minutter. Områder i hippocampus blev farvet for cytochrome c oxidase aktivitet og blev brugt til at understøtte observationerne i adfærdstestene. Resultater: I open field, viste stort set alle testene at CN var signifikant bedre sammenlignet med de tre andre grupperinger. Ved dag >28, viste G19 en forøgelse i distance sammenlignet med ID. Elevated zero maze viste en signifikant forøgelse i antallet af stræk mellem G19 og ID. I light/dark boksen viste ID og P5 sig at være mere signifikant end de resterende 2 grupper. Dot blot analyse viste ingen signifikant forskel mellem grupperne. Der blev dog observeret en tendens for CN, G19, og P5 til at have en forøget cytochrome c oxidase aktivitet sammenlignet med ID. Konklusion: Vægt og hæmoglobin niveau viste at jerntilskud havde en effekt sammenlignet med ID. Ad- færdsstudiet viste svagt at G19 klarede sig bedre sammenlignet med ID. P5 havde en tendens til at være bedre sammenlignet med ID. CN præsterede bedre i open field sammenlignet med ID og G19. Der var ingen signifikante oberservering i de biokemiske analyse.Introduction: Iron deficiency is a widespread micro nutritional disorder and affects approximately 2 billion people worldwide. Iron demand increases notably during pregnancy, from 0.8 mg/day in the first trimester to >6 mg/day in the third trimester, thus, making it difficult to maintain an acquired iron level without any iron supplementation. Hippocampus plays an important role in processing information and behavior through a complex interaction with amygdala and hypothalamus. Through oxidative phosphorylation, the high energy requirement from hippocampus is met. Cytochrome c oxidase is an iron-containing terminal enzyme involved in the last step of the oxidative phosphorylation reaction. Thus, making it a quantifiable marker for neuronal metabolic activity. Aim: The aim of this study was to establish a rodent experimental model to investigate how iron deficiency will affect behaviour and neurodevelopment in offspring rats and whether supplementation with iron isomaltoside (Monofor) at two various stages (gestation day 19 and postnatal day five) of development can prevent brain abnormalities. Method: 14 Wistar rats were divided into four groups; Control group (CN), gestation day 19 (G19), postnatal day one (ID) and postnatal day five (P5). G19, ID and P5 received all iron deficient diet and injection of Monofer at the corresponding days. Offsprings were tested for any fear and anxiety-like behavior with open field, elevated zero maze, and light/dark box, where exploration were assessed for 10 min. Areas in hippocampus were stained for cytochrome c oxidase activity and used to support the findings in the behavior tests. Results: In open field, nearly all tests showed CN was significant different compared to all three groups. At day >28 in distanced travelled, G19 showed a significant increase compared to ID. Elevated zero maze revealed a significant increase in number of stretches between G19 and ID. Light/dark box showed that ID and P5 performed better compared to CN and G19. Dot blot assays did not reveal any significant difference between groups, however, there was seen a tendency for CN, G19, and P5 to have an increased cytochrome c oxidase activity compared to ID. Conclusion: Growth and hemoglobin showed that iron supplementation had an effect compared to ID. The behavioral study did not revealed any significant difference between the two supplementation groups compared to ID. However, CN had a better performance in open field compared to ID. There were no significant findings in the biochemical assay
THE CONSEQUENCES AND REVERSIBILITY OF CONGENITAL IRON DEFICIENCY ON THE AMOUNT OF NEURONS IN THE HIPPOCAMPAL AREA AND THE FATTY ACID COMPOSITION OF THE CEREBELLUM
No full textAbstractBackground: Iron deficiency is the most prevalent nutritional disorder worldwide, especially amongpregnant women and children. Congenital iron deficiency causes several deleterious effects on thecognitive and motoric development of the infant.Objective: The objective of this study is to assess the consequences of severe congenital irondeficiency on the neuron count in the hippocampus and the fatty acid composition of the cerebellum inmale Wistar rats, and to discover whether or not iron supplementation injected during the window ofopportunity, which is equivalent to the 3rd trimester in human development, can restore thedeleterious effects of iron deficiency.Design: Adult female rats were randomly divided into two groups. The rats assigned for irondeficiency were exsangiunated and fed an iron depleted diet (<10mg Fe/kg), while the control ratswere fed a commercial diet. The offspring of the iron deficient (ID) dams were designated into twogroups, a treatment group where pups received iron injections (45mg/kg iron isomaltoside 1000) anda group receiving saline injections, thus remaining ID. The severity of iron deficiency was confirmed bymeasuring hematocrit values on postnatal day (P) 8-13, P15-18 and P86-94. A footprint analysis testwas performed on male rats on P85-90 and the rats were euthanized on P86-94, and their brains wereexcised for brain iron analysis of the mesencephalon, stereological analysis of the hippocampus andfatty acid analysis.Results: The results of the footprint analysis showed significantly increased gait width in ID animalscompared to both control and ID animals receiving iron supplement (ID + im1000). The fatty acidanalysis showed a significant decrease in both docosahexaenoic acid (DHA) and total amount of polyunsaturatedfatty acids (PUFAs) in the ID + im1000 group compared to the control group.Furthermore, the control group had a higher amount of n-3 fatty acids compared to both the ID and ID+ im1000 group, and the ID group had a higher amount of n-6 fatty acids compared to the ID + im1000and control group. The results of stereological counting of the hippocampus showed a larger amountof neurons in the dentate gyrus (DG) of the ID + im1000 groups compared to the ID group.Conclusion: The deleterious effects of congenital ID can be reversed to some degree by administeringiron isomaltoside 1000 during the window of opportunity. While motor defects and low hematologicalvalues resulting from congenital ID are reversed completely, the results suggest that the lipidcomposition of the cerebellum cannot be fully recovered to that of normal individuals. In addition, theresults suggest that the amount of neurons in the DG can be improved by administering iron in earlylife
Effects of iron status and development on ferroportin and hepcidin gene expression in rat brain
No full textWhile iron is essential in living organisms, deficiencies or excesses can lead to pathological conditions such as iron deficiency anemia or hemochromatosis. Consequently, iron metabolism is tightly regulated by several factors. Ferroportin, the sole characterized mammalian iron exporter, and hepcidin, a liver produced peptide capable of degrading ferroportin, has recently been identified in the brain.In the present study, the effect of development and iron status on ferroportin and hepcidin gene expression in the rat brain was investigated. In the experiment investigating the effects of development, Wistar rats were killed after 2 weeks, 8 weeks and 8 months. The brain was microdissected into cerebellum, ventral tegmental area (VTA) and habenula. In the experiment studying the effects of iron status, adult Wistar rats were subjected to iron deficiency ensuring a reduced iron access for the the fetus during the gestational period. The offspring of iron deficient dams were designated into two groups, a treatment group where pups received iron injections and a group receiving saline injections. At the age of 8 weeks, female rats were killed and key organs were harvested. The brain was dissected into samples of cerebral cortex, cerebellum, striatum and brain stem. The results revealed that aging significantly increased brain iron concentrations with the highest amount in the cerebellum. Ferroportin gene expression in all brain areas declined significantly with aging despite an increase in iron. The presence of hepcidin mRNA in the rat brain was confirmed, however to a minimal extent. Furthermore, age had no significant effect on hepcidin gene expression.Iron status was shown to have an effect on cerebral cortex iron content, although not significant. Ferroportin gene expression was significantly up regulated in the duodenum of iron deficient rats compared to rats receiving iron supplements. In the liver, ferroportin gene expression was vice versa to that of the duodenum. No significant alteration in ferroportin gene expression was observed in different brain areas of iron deficient, iron reverted and control rats. The level of hepcidin mRNA expression in the liver and duodenum, of rats receiving iron supplements compared to iron deficient rats, was significantly higher. Moreover, hepcidin expression was extremely low in all brain areas investigated despite differences in brain iron level.In total, iron status and development have some effects on ferroportin and hepcidin gene expression and it seems that other factors, than brain iron content, might influence the expression of key iron transport molecules in the brain. <br/
MOOS as Virtual Communities
No full textMany researchers have observed that the Internet has changed the concept of virtual communities (Barnes, 2001, 2003; Jones, 1995, 1998; Rheingold, 1993). A unique example of virtual communities is a MOO—a specialized interactive online community that is usually based on a work of fiction such as book series, theater or television (Bartle, 1990). MOOs share many of the features of multi-user dimensions (MUDs) in that both allow participants to create their own virtual worlds, but some researchers consider MOOs to be “more sophisticated” (Barnes, 2001, p. 94). In a MOO community, the participants or “players” create their own virtual communities—fantasy communities complete with world structures, interpersonal norms and social constructs. Individual participants create characters complete with environment, history and personality constructs. The characters interact and influence each other and their environments, just as do the members of real-world communities. The MOO discussed in this case study is based on acclaimed fantasy author Anne McCaffery’s book series set on the fictional world of “Pern.” The players on DragonWings1 MOO create and develop characters over long periods, often many years, leading to the establishment and creation of a strong MOO. In this article we provide a case study of the DragonWings MOO as a unique virtual community. Because the concept of virtual communities is evolving with the Internet, and no definitive understanding of virtual community or virtual culture yet exists, we have chosen to structure our analysis of DragonWings MOO around the classical anthropological definition of culture and community. A seminal definition of culture, first articulated by Tylor (1871), provides the springboard for a number of anthropological definitions widely used today. Building on Tylor, White (1959), a prominent cultural scholar, defined culture as “within human organisms, i.e., concepts, beliefs, emotions, attitudes; within processes of social interaction among human beings; and within natural objects” (p. 237). He also identified symbols as a primary defining characteristic of culture. White’s simple yet comprehensive definition yields clear criteria that lend themselves to our analysis of MOOs. At the broadest level, an application of the criteria provides support for the acceptance of the Internet as a distinct and unique culture. At a more particular level, they provide a convenient tool for the analysis of a MOO as a virtual community. In the remainder of this article, we will utilize the definition outlined above to demonstrate the features that make DragonWings MOO a unique example of a virtual community. </jats:p
Iron-metabolism in neurons of the motor system of the central nervous system:lessons from iron deficiency and overloading pathologies
No full text- …
