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Platelets play an essential role in wound healing by forming thrombi that plug holes in the walls of damaged blood vessels. To achieve this, platelets express a diverse array of cell surface receptors and signaling proteins that induce rapid platelet activation. In this study we show that two platelet glycoprotein receptors that signal via an immunoreceptor tyrosine-based activation motif (ITAM) or an ITAM-like domain, namely the collagen receptor complex glycoprotein VI (GPVI)-FcR γ-chain and the C-type lectin-like receptor 2 (CLEC-2), respectively, support constitutive (i.e. agonist-independent) signaling in a cell line model using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay that can detect low level activation of phospholipase Cγ (PLCγ). Constitutive and agonist signaling by both receptors is dependent on Src and Syk family kinases, and is inhibited by G6b-B, a platelet immunoglobulin receptor that has two immunoreceptor tyrosine-based inhibitory motifs in its cytosolic tail. Mutation of the conserved tyrosines in the two immunoreceptor tyrosine-based inhibitory motifs prevents the inhibitory action of G6b-B. Interestingly, the inhibitory activity of G6b-B is independent of the Src homology 2 (SH2)-domain containing tyrosine phosphatases, SHP1 and SHP2, and the inositol 5′-phosphatase, SHIP. Constitutive signaling via Src and Syk tyrosine kinases is observed in platelets and is associated with tyrosine phosphorylation of GPVI-FcR γ-chain and CLEC-2. We speculate that inhibition of constitutive signaling through Src and Syk tyrosine kinases by G6b-B may help to prevent unwanted platelet activation.
Interleukin (IL)-18, formerly known as interferon (IFN)-γ-inducing factor, is a crucial mediator of host defence and inflammation. Control of IL-18 bioactivity by its endogenous antagonist IL-18 binding protein (IL-18BP) is a major objective of immunoregulation. IL-18BP is strongly up-regulated by IFN-γ, thereby establishing a negative feedback mechanism detectable in cell culture and in vivo. Here we sought to investigate in D.L. Dexter (DLD) colon carcinoma cells molecular mechanisms of IL-18BP induction under the influence of IFN-γ. Mutational analysis revealed that a proximal γ-activated sequence (GAS) at the IL-18BP promoter is of pivotal importance for expression by IFN-γ-activated cells. Use of siRNA underscored the essential role of the signal transducer and activator of transcription (STAT)-1 in this process. Indeed, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis proved STAT1 binding to this particular GAS site. Maximal expression of IL-18BP was dependent on de novo protein synthesis but unaffected by silencing of interferon regulatory factor-1. Altogether, data presented herein indicate that direct action of STAT1 on the IL-18BP promoter at the proximal GAS element is key to IL-18BP expression by IFN-γ-stimulated DLD-1 colon carcinoma cells.
Histone deacetylase (HDAC) inhibitors represent a promising class of antineoplastic agents which affect tumour growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro and in vivo on pre-clinical renal cell carcinoma (RCC) models. Caki-1, KTC-26 or A498 cells were treated with various concentrations of VPA during in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and to evaluate cell cycle manipulation. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. The anti-tumoural potential of VPA combined with low-dosed interferon-α (IFN-α) was also investigated. VPA significantly and dose-dependently up-regulated histones H3 and H4 acetylation and caused growth arrest in RCC cells. VPA altered cell cycle regulating proteins, in particular CDK2, cyclin B, cyclin D3, p21 and Rb. In vivo, VPA significantly inhibited the growth of Caki-1 in subcutaneous xenografts, accompanied by a strong accumulation of p21 and bax in tissue specimens of VPA-treated animals. VPA–IFN-α combination markedly enhanced the effects of VPA monotherapy on RCC proliferation in vitro, but did not further enhance the anti-tumoural potential of VPA in vivo. VPA was found to have profound effects on RCC cell growth, lending support to the initiation of clinical testing of VPA for treating advanced RCC.
The deposition of the amyloid β-protein (Aβ) is one of the pathological hallmarks of Alzheimer's disease (AD). Aβ-deposits show the morphology of senile plaques and cerebral amyloid angiopathy (CAA). Senile plaques and vascular Aβ-deposits occur first in neocorti-cal areas. Then, they expand hierarchically into further brain regions. The distribution of Aβ plaques throughout the entire brain, thereby correlates with the clinical status of the patients. Imaging techniques for Aβ make use of the hierarchical distribution of Aβ to distinguish AD patients from non-AD patients. However, pathology seen in AD patients represents a late stage of a pathological process starting 10–30 years earlier in cognitively normal individuals. In addition to the fibrillar amyloid of senile plaques, oligomeric and monomeric Aβ is found in the brain. Recent studies revealed that oligomeric Aβ is presumably the most toxic Aβ-aggregate, which interacts with glutamatergic synapses. In doing so, dendrites are presumed to be the primary target for Aβ-toxicity. In addition, vascular Aβ-deposits can lead to capillary occlusion and blood flow disturbances presumably contributing to the alteration of neurons in addition to the direct neurotoxic effects of Aβ. All these findings point to an important role of Aβ and its aggregates in the neurodegenerative process of AD. Since there is already significant neuron loss in AD patients, treatment strategies aimed at reducing the amyloid load will presumably not cure the symptoms of dementia but they may stop disease progression. Therefore, it seems to be necessary to protect the brain from Aβ-toxicity already in stages of the disease with minor neuron loss before the onset of cognitive symptoms.
FTY720 is a novel immunosuppressive drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. In its phosphorylated form FTY720 is a potent S1P receptor agonist. Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2). Since prostaglandins are important mediators of nociception, we studied the effects of FTY720 in different models of nociception. We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay. Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced. Surprisingly, intrathecally administered FTY720 reduced the nociceptive behaviour in the formalin assay without altering spinal prostaglandin synthesis, indicating that additional antinociceptive mechanisms beside the inhibition of prostaglandin synthesis are involved. Accordingly, FTY720 reduced also the nociceptive behaviour in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis. In this model the antinociceptive effect of FTY720 was similar to gabapentin, a commonly used drug to treat neuropathic pain. Taken together we show for the first time that FTY720 possesses antinociceptive properties and that FTY720 reduces nociceptive behaviour during neuropathic pain.
ADAM15 belongs to a family of transmembrane multi-domain proteins implicated in proteolysis, cell–cell and cell–matrix interactions in various disease conditions. In osteoarthritis (OA), ADAM15 is up-regulated in the chondrocytes already at early stages of cartilage degeneration where it seems to exert homeostatic effects likely associated with its ability to enhance integrin-mediated chondrocyte adhesion to the surrounding collagen matrix. The aim of our present study was, therefore, to characterize functional domains of ADAM15 involved in collagen II (CII) interaction and to analyse associated outside-in signalling events. Accordingly, ADAM15 and respective deletion mutants were stably transfected into the chondrocyte cell line T/C28a4. Transfected cells were adhered to CII and phosphoproteins analysed by Western blotting. Co-immunoprecipitation served to identify protein binding to ADAM15. Our results elucidate the prodomain as critical for the capacity of ADAM15 to enhance CII adhesion, thereby identifying for the first time a cell-adhesive role of a metalloproteinase prodomain. Moreover, the cytoplasmic tail of ADAM15 confers a modulatory effect on the autophosphorylation site Y397 of the focal adhesion kinase (FAK) during chondrocyte–collagen interaction. In conclusion, the newly uncovered impact of ADAM15 on signalling events that arise from chondrocyte interactions with its collagen matrix might contribute to the elucidation of the mechanism underlying its proposed chondroprotective role in degenerative cartilage disease.
New histone deacetylase inhibitors as potential therapeutic tools for advanced prostate carcinoma
(2008)
The anti-epileptic drug valproic acid is also under trial as an anti-cancer agent due to its histone deacetylase (HDAC) inhibitory properties. However, the effects of valproic acid (VPA) are limited and concentrations required for exerting anti-neoplastic effects in vitro may not be reached in tumour patients. In this study, we tested in vitro and in vivo effects of two VPA-derivatives (ACS2, ACS33) on pre-clinical prostate cancer models. PC3 and DU-145 prostate tumour cell lines were treated with various concentrations of ACS2 or ACS33 to perform in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and to evaluate tumour cell adhesion to endothelial cell monolayers. Analysis of acetylated histones H3 and H4 protein expression was performed by western blotting. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. Tumour sections were assessed by immunohistochemistry for histone H3 acetylation and proliferation. ACS2 and ACS33 significantly up-regulated histone H3 and H4 acetylation in prostate cancer cell lines. In micromolar concentrations both compounds exerted growth arrest in PC3 and DU-145 cells and prevented tumour cell attachment to endothelium. In vivo, ACS33 inhibited the growth of PC3 in subcutaneous xenografts. Immunohistochemistry and western blotting confirmed increased histone H3 acetylation and reduced proliferation. ACS2 and ACS33 represent novel VPA derivatives with superior anti-tumoural activities, compared to the mother compound. This investigation lends support to the clinical testing of ACS2 or ACS33 for the treatment of prostate cancer.
This paper investigates the value of observed river discharge data for global-scale hydrological modeling of a number of flow characteristics that are e.g. required for assessing water resources, flood risk and habitat alteration of aquatic ecosystems. An improved version of the WaterGAP Global Hydrology Model (WGHM) was tuned against measured discharge using either the 724-station dataset (V1) against which former model versions were tuned or an extended dataset (V2) of 1235 stations. WGHM is tuned by adjusting one model parameter (γ) that affects runoff generation from land areas in order to fit simulated and observed long-term average discharge at tuning stations. In basins where γ does not suffice to tune the model, two correction factors are applied successively: the areal correction factor corrects local runoff in a basin and the station correction factor adjusts discharge directly the gauge. Using station correction is unfavorable, as it makes discharge discontinuous at the gauge and inconsistent with runoff in the upstream basin. The study results are as follows. (1) Comparing V2 to V1, the global land area covered by tuning basins increases by 5% and the area where the model can be tuned by only adjusting γ increases by 8%. However, the area where a station correction factor (and not only an areal correction factor) has to be applied more than doubles. (2) The value of additional discharge information for representing the spatial distribution of long-term average discharge (and thus renewable water resources) with WGHM is high, particularly for river basins outside of the V1 tuning area and in regions where the refined dataset provides a significant subdivision of formerly extended tuning basins (average V2 basin size less than half the V1 basin size). If the additional discharge information were not used for tuning, simulated long-term average discharge would differ from the observed one by a factor of, on average, 1.8 in the formerly untuned basins and 1.3 in the subdivided basins. The benefits tend to be higher in semi-arid and snow-dominated regions where the model is less reliable than in humid areas and refined tuning compensates for uncertainties with regard to climate input data and for specific processes of the water cycle that cannot be represented yet by WGHM. Regarding other flow characteristics like low flow, inter-annual variability and seasonality, the deviation between simulated and observed values also decreases significantly, which, however, is mainly due to the better representation of average discharge but not of variability. (3) The choice of the optimal sub-basin size for tuning depends on the modeling purpose. While basins over 60 000 km2 are performing best, improvements in V2 model performance are strongest in small basins between 9000 and 20 000 km2, which is primarily related to a low level of V1 performance. Increasing the density of tuning stations provides a better spatial representation of discharge, but it also decreases model consistency, as almost half of the basins below 20 000 km2 require station correction.
Long-term average groundwater recharge, which is equivalent to renewable groundwater resources, is the major limiting factor for the sustainable use of groundwater. Compared to surface water resources, groundwater resources are more protected from pollution, and their use is less restricted by seasonal and inter-annual flow variations. To support water management in a globalized world, it is necessary to estimate groundwater recharge at the global scale. Here, we present a best estimate of global-scale long-term average diffuse groundwater recharge (i.e. renewable groundwater resources) that has been calculated by the most recent version of the WaterGAP Global Hydrology Model WGHM (spatial resolution of 0.5° by 0.5°, daily time steps). The estimate was obtained using two state-of-the-art global data sets of gridded observed precipitation that we corrected for measurement errors, which also allowed to quantify the uncertainty due to these equally uncertain data sets. The standard WGHM groundwater recharge algorithm was modified for semi-arid and arid regions, based on independent estimates of diffuse groundwater recharge, which lead to an unbiased estimation of groundwater recharge in these regions. WGHM was tuned against observed long-term average river discharge at 1235 gauging stations by adjusting, individually for each basin, the partitioning of precipitation into evapotranspiration and total runoff. We estimate that global groundwater recharge was 12 666 km3/yr for the climate normal 1961–1990, i.e. 32% of total renewable water resources. In semi-arid and arid regions, mountainous regions, permafrost regions and in the Asian Monsoon region, groundwater recharge accounts for a lower fraction of total runoff, which makes these regions particularly vulnerable to seasonal and inter-annual precipitation variability and water pollution. Average per-capita renewable groundwater resources of countries vary between 8 m3/(capita yr) for Egypt to more than 1 million m3/(capita yr) for the Falkland Islands, the global average in the year 2000 being 2091 m3/(capita yr). Regarding the uncertainty of estimated groundwater resources due to the two precipitation data sets, deviation from the mean is 1.1% for the global value, and less than 1% for 50 out of the 165 countries considered, between 1 and 5% for 62, between 5 and 20% for 43 and between 20 and 80% for 10 countries. Deviations at the grid scale can be much larger, ranging between 0 and 186 mm/yr.
We report progress in our exploration of the finite-temperature phase structure of two-flavour lattice
QCD with twisted-mass Wilson fermions and a tree-level Symanzik-improved gauge action
for a temporal lattice size Nt = 8. Extending our investigations to a wider region of parameter
space we gain a global view of the rich phase structure. We identify the finite temperature transition/
crossover for a non-vanishing twisted-mass parameter in the neighbourhood of the zerotemperature
critical line at sufficiently high b . Our findings are consistent with Creutz’s conjecture
of a conical shape of the finite temperature transition surface. Comparing with NLO lattice
cPT we achieve an improved understanding of this shape.
We perform a detailed study of the adjoint static potential in the pseudoparticle approach, which is a model for SU(2) Yang-Mills theory. We find agreement with the Casimir scaling hypothesis and there is clear evidence for string breaking. At the same time the potential in the fundamental representation is linear for large separations. Our results are in qualitative agreement with results from lattice computations.
We present the status of runs performed in the twisted mass formalism with Nf =2+1+1 flavours of dynamical fermions: a degenerate light doublet and a mass split heavy doublet. The procedure for tuning to maximal twist will be described as well as the current status of the runs using both thin and stout links. Preliminary results for a few observables obtained on ensembles at maximal twist will be given. Finally, a reweighting procedure to tune to maximal twist will be described.
We investigate the implications of the r-modes instability on the composition of a compact star rotating at a sub-millisecond period. In particular, the only viable astrophysical scenario for such an object, wich might present inside the Low Mass X-ray Binary associated with the x-ray transient XTE J1739-285, is that it has a strangeness content. Since previous analysis indicate that hyperonic stars or stars containing a kaon condensate are unlikely because of the mass-shedding constraint, the only remaining possibility is that such an object is either a strange quark star or a hybrid quark-hadron star.
The possible role of a first order QCD phase transition at nonvanishing quark chemical potential and temperature for cold neutron stars and for supernovae is delineated. For cold neutron stars, we use the NJL model with nonvanishing color superconducting pairing gaps, which describes the phase transition to the 2SC and the CFL quark matter phases at high baryon densities. We demonstrate that these two phase transitions can both be present in the core of neutron stars and that they lead to the appearance of a third family of solution for compact stars. In particular, a core of CFL quark matter can be present in stable compact star configurations when slightly adjusting the vacuum pressure to the onset of the chiral phase transition from the hadronic model to the NJL model. We show that a strong first order phase transition can have strong impact on the dynamics of core collapse supernovae. If the QCD phase transition sets in shortly after the first bounce, a second outgoing shock wave can be generated which leads to an explosion. The presence of the QCD phase transition can be read off from the neutrino and antineutrino signal of the supernova.
Introduction: Despite the fact that people older than 65 years of age have the highest incidence of developing breast cancer, these patients are excluded from clinical trials in most cases. Furthermore, most physicians tend towards therapy regimens without the use of dose-dense, highly active taxane-based treatments because of a lack of data regarding toxicities of these compounds in older patients.
Methods: Pooled side-effect data were analyzed from four prospective, randomized clinical trials in which patients of different age groups (< 60 years, between 60 and 64 years, and > 64 years) with primary breast cancer received taxane-based chemotherapy.
Results: Dose delays, dose reductions, hospitalization, and therapy discontinuation increased with age. Hematologic toxicities and some nonhematologic toxicities were generally more common in older patients. Leucopenia increased from 55.3% in patients aged < 60 years to 65.5% in patients aged > 64 years (P < 0.001), and neutropenia increased from 46.9% to 57.4% (P < 0.001). There was no difference, however, in clinically more relevant febrile neutropenia between the different age groups. Thrombopenia shows a similar age-dependent increase, whereas there is no difference between the age groups concerning anemia. Hot flushes and elevated liver enzymes decreased with increasing age.
Conclusions: The present pooled analysis of a substantial cohort of older primary breast cancer patients demonstrates that taxane-containing (neo)adjuvant chemotherapy is feasible in older patients and that toxicity can be reduced by sequential therapy regimens.
* The Professionalization of General Practice
* 42nd Congress of the DEGAM German Society of General Practice and Family Medicine
* Online Registration for students now possible
* Opera tickets for participants in the PRoMPT study
* MultiCare: Multimorbidity patterns in General Practice
* Berlin Health Prize 2008: Words are not enough
Background: There are several ways to conduct a job task analysis in medical work environments including pencil-paper observations, interviews and questionnaires. However these methods implicate bias problems such as high inter-individual deviations and risks of misjudgement. Computer-based observation helps to reduce these problems. The aim of this paper is to give an overview of the development process of a computer-based job task analysis instrument for real-time observations to quantify the job tasks performed by physicians working in different medical settings. In addition reliability and validity data of this instrument will be demonstrated.
Methods: This instrument was developed in consequential steps. First, lists comprising tasks performed by physicians in different care settings were classified. Afterwards content validity of task lists was proved. After establishing the final task categories, computer software was programmed and implemented in a mobile personal computer. At least inter-observer reliability was evaluated. Two trained observers recorded simultaneously tasks of the same physician.
Results: Content validity of the task lists was confirmed by observations and experienced specialists of each medical area. Development process of the job task analysis instrument was completed successfully. Simultaneous records showed adequate interrater reliability.
Conclusion: Initial results of this analysis supported the validity and reliability of this developed method for assessing physicians' working routines as well as organizational context factors. Based on results using this method, possible improvements for health professionals' work organisation can be identified.
Since 2002, a workshop entitled “Asthma in animal models” has been held once a year in Hannover, Germany. It is organized by the Fraunhofer Institute of Toxicology and Experimental Medicine in collaboration with the collaborative research centre “Sonderforschungsbereich” 587, “Immune reactions of the lung in infection and allergy” (Hannover Medical School). The aim of these meetings is an intense scientific exchange between researchers and clinicians coming from academic or industrial background. Over the years the topics within the extensive field of asthma and COPD have ranged from methodological aspects to the influence of infections and environmental factors up to perspectives in the development of new therapeutic strategies.
Background: Platelet activating factor and tachykinins (substance P, neurokinin A, neurokinin B) are important mediators contributing to increased airway secretion in the context of different types of respiratory diseases including acute and chronic asthma. Leukotriene receptor antagonists are recommended as add-on therapy for this disease. The cys-leukotriene-1 receptor antagonist montelukast has been used in clinical asthma therapy during the last years. Besides its inhibitory action on bronchoconstriction, only little is known about its effects on airway secretions. Therefore, the aim of this study was to evaluate the effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity.
Methods: The effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity in the rat were assessed by quantification of secreted 35SO4 labelled mucus macromolecules using the modified Ussing chamber technique.
Results: Platelet activating factor potently stimulated airway secretion, which was completely inhibited by the platelet activating factor receptor antagonist WEB 2086 and montelukast. In contrast, montelukast had no effect on tachykinin induced tracheal secretory activity.
Conclusion: Cys-leukotriene-1 receptor antagonism by montelukast reverses the secretagogue properties of platelet activating factor to the same degree as the specific platelet activating factor antagonist WEB 2086 but has no influence on treacheal secretion elicited by tachykinins. These results suggest a role of montelukast in the signal transduction pathway of platelet activating factor induced secretory activity of the airways and may further explain the beneficial properties of cys-leukotriene-1 receptor antagonists.
Metaphorization and selected translation techniques : the case study of "National Geographic"
(2008)
Judging by appearances : a study of human-oriented metonymic developments in the domain of dress
(2008)
Investigations of the micro- and nanostructures and chemical composition of the sponge skeletons as examples for natural structural biocomposites are of fundamental scientific relevance. Recently, we show that some demosponges (Verongula gigantea, Aplysina sp.) and glass sponges (Farrea occa, Euplectella aspergillum) possess chitin as a component of their skeletons. The main practical approach we used for chitin isolation was based on alkali treatment of corresponding external layers of spicules sponge material with the aim of obtaining alkali-resistant compounds for detailed analysis. Here, we present a detailed study of the structural and physicochemical properties of spicules of the glass sponge Rossella fibulata. The structural similarity of chitin derived from this sponge to invertebrate alpha chitin has been confirmed by us unambiguously using physicochemical and biochemical methods. This is the first report of a silica-chitin composite biomaterial found in Rossella species. Finally, the present work includes a discussion related to strategies for the practical application of silica-chitin-based composites as biomaterials.
P-type ATPases are membrane proteins acting as ion pumps that drive an active transport of cations across the membrane against a concentration gradient. The required energy for the ion transport is provided by binding and hydrolysis of ATP. A reaction mechanism of ion transport and energy transduction is assumed to be common for all P-type ATPases and generally described by the Post-Albers cycle. Transient currents and charge translocation of P-type ATPases were extensively investigated by electrical measurements that apply voltage jumps to initiate the reaction cycle. In this study, we simulate an applied voltage across the membrane by an electric field and perform electrostatic calculations in order to verify the experimentally-driven hypothesis that the energy transduction mechanism is regulated by specific structural elements. Side chain conformational and ionization changes induced by the electric field are evaluated for each transmembrane helix and the selectivity in response is qualitatively analyzed for the Ca2+-ATPase as well as for structural models of the Na+/K+-ATPase. Helix M5 responds with more conformer changes as compared to the other transmembrane helices what is even more emphasized when the stalk region is included. Thus our simulations support experimental results and indicate a crucial role for the highly conserved transmembrane helix M5 in the energy transduction mechanism of P-type ATPases.
Betulinic acid is a natural product with a range of biological effects, for example potent antitumor activity. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers.
Keywords: apoptosis, cancer, betulinic acid, mitochondria
Keywords: AIF, apoptosis inducing factor; Apaf-1, Apoptotic protease activating factor-1; BA, betulinic acid; DIABLO, direct IAP Binding protein with Low PI; HtrA2, high temperature requirement protein A; IAPs, Inhibitor of Apoptosis Proteins; MOMP, mitochondrial outer membrane permeabilization; ROS, reactive oxygen species; PARP, Poly (ADP-ribose) Polymerase; Smac, second mitochondria-derived activator of caspase; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; zVAD.fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone
Science in Wonderland
(2008)
Lewis Carroll's Alice, who first explores Wonderland (1865) and later on the country behind the Looking-Glass (1872), belongs to the most well-known characters in world literature. [...] The scientific reception of Carroll's stories – concerning physics as well as the humanities – has taken place on different levels. On the one hand, […] various Carrollian ideas and episodes obviously correspond to topics, subjects and models that are treated in the contexts of scientific discourses. Therefore, they can be quoted or alluded to in order to represent theories and questions […] – as […] physical models of the world […]or theoretical models of language and communication. […] On a more abstract level of observation, Carroll's stories have been used in order to explain and to discuss the pre-conditions, the procedures, and the limits . of scientific modeling as such. Above all, they make it possible to narrate on the problem of defining and observing an 'object' of research. […] According to Deleuze, the paradox structures of the world that Alice experiences give an idea of all meaning being groundless and all logic being subverted by the illogical. Finally, besides all affinities of Alice's adventures to scientific attempts to explain the world, the absolutely incomprehensible is present in Carroll's books as well. Especially the self proves to be something profoundly incomprehensible […].
Water-filtered infrared-A (wIRA) can act as a penetration enhancer for topically applied substances
(2008)
Background: Water-filtered infrared-A (wIRA) irradiation has been shown to enhance penetration of clinically used topically applied substances in humans through investigation of functional effects of penetrated substances like vasoconstriction by cortisone.
Aim of the study: Investigation of the influence of wIRA irradiation on the dermatopharmacokinetics of topically applied substances by use of optical methods, especially to localize penetrating substances, in a prospective randomised controlled study in humans.
Methods: The penetration profiles of the hydrophilic dye fluorescein and the lipophilic dye curcumin in separate standard water-in-oil emulsions were determined on the inner forearm of test persons by tape stripping in combination with spectroscopic measurements. Additionally, the penetration was investigated in vivo by laser scanning microscopy. Transepidermal water loss, hydration of the epidermis, and surface temperature were determined. Three different procedures (modes A, B, C) were used in a randomised order on three separate days of investigation in each of 12 test persons. In mode A, the two dyes were applied on different skin areas without water-filtered infrared-A (wIRA) irradiation. In mode B, the skin surface was irradiated with wIRA over 30 min before application of the two dyes (Hydrosun® radiator type 501, 10 mm water cuvette, orange filter OG590, water-filtered spectrum: 590–1400 nm with dominant amount of wIRA). In mode C, the two dyes were applied and immediately afterwards the skin was irradiated with wIRA over 30 min. In all modes, tape stripping started 30 min after application of the formulations. Main variable of interest was the ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum.
Results: The penetration profiles of the hydrophilic fluorescein showed in case of pretreatment or treatment with wIRA (modes B and C) an increased penetration depth compared to the non-irradiated skin (mode A): The ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum showed medians and interquartile ranges for mode A of 0.017 (0.007/0.050), for mode B of 0.084 (0.021/0.106), for mode C of 0.104 (0.069/0.192) (difference between modes: p=0.0112, significant; comparison mode A with mode C: p<0.01, significant). In contrast to fluorescein, the lipophilic curcumin showed no differences in the penetration kinetics, in reference to whether the skin was irradiated with wIRA or not. These effects were confirmed by laser scanning microscopy. Water-filtered infrared-A irradiation increased the hydration of the stratum corneum: transepidermal water loss rose from approximately 8.8 g m-2 h-1 before wIRA irradiation to 14.2 g m-2 h-1 after wIRA irradiation and skin hydration rose from 67 to 87 relative units. Skin surface temperature increased from 32.8°C before wIRA to 36.4°C after wIRA irradiation.
Discussion: The better penetration of the hydrophilic dye fluorescein after or during skin irradiation (modes B and C) can be explained by increased hydration of the stratum corneum by irradiation with wIRA.
Conclusions: As most topically applied substances for the treatment of patients are mainly hydrophilic, wIRA can be used to improve the penetration of substances before or after application of substances – in the first case even of thermolabile substances – with a broad clinical relevance as a contact free alternative to an occlusive dressing.
Background: Water-filtered infrared-A (wIRA) is a special form of heat radiation with a high tissue-penetration and with a low thermal burden to the surface of the skin. wIRA is able to improve essential and energetically meaningful factors of wound healing by thermal and non-thermal effects.
Aim of the study: prospective study (primarily planned randomised, controlled, blinded, de facto with one exception only one cohort possible) using wIRA in the treatment of patients with recalcitrant chronic venous stasis ulcers of the lower legs with thermographic follow-up.
Methods: 10 patients (5 males, 5 females, median age 62 years) with 11 recalcitrant chronic venous stasis ulcers of the lower legs were treated with water-filtered infrared-A and visible light irradiation (wIRA(+VIS), Hydrosun® radiator type 501, 10 mm water cuvette, water-filtered spectrum 550–1400 nm) or visible light irradiation (VIS; only possible in one patient). The uncovered wounds of the patients were irradiated two to five times per week for 30 minutes at a standard distance of 25 cm (approximately 140 mW/cm2 wIRA and approximately 45 mW/cm2 VIS). Treatment continued for a period of up to 2 months (typically until closure or nearly closure of the ulcer). The main variable of interest was “percent change of ulcer size over time” including complete wound closure. Additional variables of interest were thermographic image analysis, patient’s feeling of pain in the wound, amount of pain medication, assessment of the effect of the irradiation (by patient and by clinical investigator), assessment of feeling of the wound area (by patient), assessment of wound healing (by clinical investigator) and assessment of the cosmetic state (by patient and by clinical investigator). For these assessments visual analogue scales (VAS) were used.
Results: The study showed a complete or nearly complete healing of lower leg ulcers in 7 patients and a clear reduction of ulcer size in another 2 of 10 patients, a clear reduction of pain and pain medication consumption (e.g. from 15 to 0 pain tablets per day), and a normalization of the thermographic image (before the beginning of the therapy typically hyperthermic rim of the ulcer with relative hypothermic ulcer base, up to 4.5°C temperature difference). In one patient the therapy of an ulcer of one leg was performed with the fully active radiator (wIRA(+VIS)), while the therapy of an ulcer of the other leg was made with a control group radiator (only VIS without wIRA), showing a clear difference in favour of the wIRA treatment. All mentioned VAS ratings improved remarkably during the period of irradiation treatment, representing an increased quality of life. Failures of complete or nearly complete wound healing were seen only in patients with arterial insufficiency, in smokers or in patients who did not have venous compression garment therapy.
Discussion and conclusions: wIRA can alleviate pain considerably (with an impressive decrease of the consumption of analgesics) and accelerate wound healing or improve a stagnating wound healing process and diminish an elevated wound exudation and inflammation both in acute and in chronic wounds (in this study shown in chronic venous stasis ulcers of the lower legs) and in problem wounds including infected wounds. In chronic recalcitrant wounds complete healing is achieved, which was not reached before. Other studies have shown that even without a disturbance of wound healing an acute wound healing process can be improved (e.g. reduced pain) by wIRA.
wIRA is a contact-free, easily used and pleasantly felt procedure without consumption of material with a good penetration effect, which is similar to solar heat radiation on the surface of the earth in moderate climatic zones. Wound healing and infection defence (e.g. granulocyte function including antibacterial oxygen radical formation of the granulocytes) are critically dependent on a sufficient energy supply (and on sufficient oxygen). The good clinical effect of wIRA on wounds and also on problem wounds and wound infections can be explained by the improvement of both the energy supply and the oxygen supply (e.g. for the granulocyte function). wIRA causes as a thermal effect in the tissue an improvement in three decisive factors: tissue oxygen partial pressure, tissue temperature and tissue blood flow. Besides this non-thermal effects of infrared-A by direct stimulation of cells and cellular structures with reactions of the cells have also been described. It is concluded that wIRA can be used to improve wound healing, to reduce pain, exudation, and inflammation and to increase quality of life.
A wall-sized canvas by Twombly hanging in a purpose-built pavilion by Renzo Piano, commissioned by the Menil Collection in Houston, bears the scrawled inscription »Anatomy of Melancholy.« Untitled (Say Goodbye Catullus, to the Shores of Asia Minor) is the culminating statement of the artist’s maturity: begun in 1972, it was first exhibited in 1994. In this monumental cenotaph, Twombly’s painting displays phrases from Archilochos, Catullus, Keats and Rilke, as well as the title of Burton’s famous tome, worked into the fabric of the composition, integral to the iconic content. It is the aching heart of the select permanent exhibition of his oeuvre at the pavilion, known as the Twombly Gallery (www.menil.org/twombly.html). The austerity of Piano’s architectural setting, as well as the cunningly filtered Texas sunlight, makes this a site of cult, like the chapel containing the dark, final canvases of Mark Rothko, situated around the corner in the same urban grove of old oak. The setting is a modern Dodona, remote seat of the oaken oracle of Zeus, and it makes an evocative home for Twombly’s enigmatic constructions. These disarm conventional vocabularies of aesthetic response, drawing attention to words and snatches of verse as points of association and recognition. Looking at them involves siting a phrase such as »Anatomy of Melancholy« in other dimensions – in lines, patches, figures, colors.
Lichens are the object of investigation within the framework of the BIOTA Southern Africa project, subproject S04 (http://www.biota-africa.org). This interdisciplinary research project, installed in 2000, focuses on the analysis of biodiversity and its changes along climatic and vegetation gradients (transects) in Namibia and in the Republic of South Africa. In the context of this project, studies on the diversity of lichens are carriedout. Special reference is given to the monitoring of lichens growing on soil, which form the so called biological soil crusts.Lichen diversity is assessed and analysed with respect to its spatial and temporal changes. These are related to various abioticand biotic factors such as climate, soil features and land use. The indicator value of certain terricolouslichen taxaand/or lichen groups (communities) is investigated for the study area, and it is intended to use itin a future long-term monitoring programme in the region. In this brochure, we whish to explain what lichens are, how do they live and where do they grow, and why they are so important as bioindicatorsin arid and semi-arid areas of the world. The activities of the S04 subproject along the BIOTA transect are described, as well as the methods used for monitoring environmental changes in Southern Africa using soil-inhabiting lichens.
Die vorliegende Arbeit diskutiert Auffassungen über Authentizität und Nationale Identität in Julian Barnes’ England, England und Brian Moore’s The Great Victorian Collection. Julian Barnes und Brian Moore bearbeiten postmoderne Themen in ihrer Auseinandersetzung mit Realität und Authentizität. Brian Moore diskutiert die Möglichkeit der Ununterscheidbarkeit zwischen Original und Replika, Julian Barnes verdeutlicht die Konsequenzen eines Nationalgefühls, das sich auf die Vorstellung einer verklärten Vergangenheit stützt anstatt sich den Problemen der Gegenwart zu stellen.
Die postmoderne Diskussion hinterfragt Theorien der Moderne. In der Moderne entwickelten sich Nationalstaaten zur grundlegenden politischen Struktur, die eine für den aufkommenden Kapitalismus unabdingbare Einheit und Gleichheit ermöglichte. Die postmoderne Kritik unterstreicht, dass diese Ordnung nicht natürlich ist, sondern auf ein tatsächliches Chaos von Fragmenten aufgezwungen wurde. Theorien der Postmoderne betonen die Uneinigkeit und Künstlichkeit von Nationalstaaten. Es wird aufgezeigt, dass ein Nationalstaat aus vielen verschiedenen und sogar untereinander gegensätzlichen Gruppierungen besteht. Die einheitliche Identifikation der Bürger mit einem Nationalstaat basiert auf der Vorstellung einer andauernden, geteilten Geschichte, und einer Betonung von Gemeinsamkeiten und vermeintlichen Unterschieden gegenüber Anderen. Diese Vorstellung von Einigkeit und Gemeinsamkeit wird in der Postmoderne als Konstrukt enthüllt.
In ähnlicher Weise betonen postmoderne Theorien die Konstruiertheit der Vorstellung eines einheitlichen, wahren Selbst. Das Selbst wird empfunden als eine Ansammlung von zahlreichen, untereinander teilweise widerstreitenden, Teilen.
Die Entwicklung der Industrialisierung im Kapitalismus der Moderne führte zur Auflösung bestehender lokaler Strukturen, und somit zu einer Entwurzelung der Individuen. Am Ende des zwanzigsten Jahrhunderts verlangt der Konsumkapitalismus von den Menschen Mobilität und Wandelbarkeit. In dieser Phase der Globalisierung verlieren Nationalstaaten an Bedeutung. Persönliche Qualitäten wie Charakterstärke und Authentizität geraten in den Hintergrund, während die Fähigkeit zur Verstellung und ein hohes Maß an Flexibilität geachtet werden und Erfolg versprechen.
Diese Entwicklung bringt ein Gefühl des Verlustes mit sich, ein Gefühl von Heimatlosigkeit, Wurzellosigkeit, und Uneinigkeit mit sich selbst.
Die postmoderne nostalgische Sehnsucht nach einer idealisierten Vergangenheit basiert auf diesem Gefühl des Verlustes einer ehemaligen Einigkeit.
Die Besucher von Themenparks und heritage sites sehnen sich nach dem Erlebnis einer glorifizierten Vergangenheit, wobei die Authentizität der dargestellten Geschichte zweitrangig ist.
Julian Barnes und Brian Moore beschreiben die Errichtung und den Erfolg von Themenparks. Ungeachtet der Künstlichkeit der dargebotenen Shows und so mancher Ausstellungsstücke genießen postmoderne Besucher von Themenparks deren Hyperrealität, die ein Gefühl von Ganzheit und Einheit vermittelt.
Das erste Kapitel der Arbeit stellt zunächst die Gedankenwelt der Postmoderne dar. Die postmoderne Welt am Ende des zwanzigsten Jahrhunderts verlangt Mobilität, Anpassung, und Verstellung. Hierin gründet das Gefühl der Nostalgie nach Ganzheit und Zugehörigkeit, welches im zweiten Kapitel untersucht wird. Das dritte Kapitel ist der Struktur des Nationalstaates gewidmet, die in einem komplexen Zusammenspiel von Politik, Geschichte, und den Bedürfnissen der Gegenwart eine Möglichkeit der Identifikation darstellt, welche Ganzheit und Zugehörigkeit verspricht. Das vierte Kapitel zeigt, dass die Identifikation mit einem Nationalstaat auf der Vorstellung einer gemeinsamen Geschichte basiert, wie sie in Museen und heritage sites bewahrt und bestimmt wird, und wie sie durch die Ausübung – oder Einführung – von Traditionen gelebt wird.
Das fünfte Kapitel diskutiert den Zusammenhang zwischen Authentizität und Erschaffung, und zeigt, dass die Grenzen fließend sind, da seit jeher Traditionen und Gepflogenheiten zugunsten der Bedürfnisse der Gegenwart abgewandelt wurden. Julian Barnes und Brian Moore demonstrieren, dass in der Tourismusindustrie Authentizität an Wert verloren hat, da postmoderne Reisende, die an Simulationen gewöhnt sind, sich mit leichter erreichbaren Nachbildungen begnügen. Abschließend lässt sich feststellen, dass die Vorstellung einer ehemaligen Vollkommenheit und Heimat in der Vergangenheit der Auseinandersetzung mit den Bedürfnissen der Gegenwart im Wege steht. Dies äußert sich letztlich politisch, wie das gegenwärtig vorherrschende Misstrauen gegenüber supranationalen Strukturen wie der Europäischen Union zeigt.
The influence of visual tasks on short and long-term memory for visual features was investigated using a change-detection paradigm. Subjects completed 2 tasks: (a) describing objects in natural images, reporting a specific property of each object when a crosshair appeared above it, and (b) viewing a modified version of each scene, and detecting which of the previously described objects had changed. When tested over short delays (seconds), no task effects were found. Over longer delays (minutes) we found the describing task influenced what types of changes were detected in a variety of explicit and incidental memory experiments. Furthermore, we found surprisingly high performance in the incidental memory experiment, suggesting that simple tasks are sufficient to instill long-lasting visual memories. Keywords: visual working memory, natural scenes, natural tasks, change detection