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About 30 % of epileptic patients are non-responsive to multidrug antiepileptic therapy. One of non-responsiveness in epilepsy hypothesis claims that non-responsiveness occurs because of reduced access of antiepileptic drugs to their targets, as a result of increased efflux of antiepileptic drugs away from these targets. Transporters believed to be involved in non-responsiveness in epilepsy are mainly but not exclusively the members of the ABC superfamily including P-gp (MDR1, ABCB1), MRP1 (ABCC1), MRP2 (ABCC2) and others. These proteins are normally found in the blood-brain barrier and the blood-cerebrospinal fluid barrier where they function as protectors. There is emerging evidence that P-gp, MRP1 and MRP2 are up-regulated in epileptogenic brain tissue. The risk of non-responsiveness could be related also to the MDR1 or MRP2 gene polymorphisms. We hypothesised that changes in expression and function of multidrug transporters involved in non-responsiveness of epilepsy might be detectable not only in the brain but also in other tissues such as lymphocytes. Therefore we evaluated the expression of MDR1, MRP1 and MRP2 and function of P-gp in lymphocytes in patients with epilepsy and healthy subjects. Three groups of epileptic patients and 15 healthy subjects as a control group were included in the study. The patients’ group was defined as follows: Monotherapy – patients treated with carbamazepine monotherapy, without seizures - corresponded to group responders. Combined therapy – patients after monotherapy (two different medicines have been tried) and combined therapy (two trials of combined therapy), not free of seizures. Monotherapy and combined therapy groups each embraced 15 patients. Neurosurgery – patients who had undergone neurosurgery, afterwards were or were not additionally treated with carbamazepine, with or without seizures. This group comprised 24 patients. Combined therapy and neurosurgery groups composed the group of non-responders. The mRNA expression of MRP1, MRP2 and MDR1 by means of quantitative real-time PCR as well as MRP2 and P-gp protein content by Western blot in lymphocytes was measured. For P-gp functional analysis rhodamine efflux from lymphocytes and natural killer (NK) cells was performed. The influence of the polymorphisms C3435T, G2677T/A in the MDR1 gene and C24T, G1249A, C3972T in the MRP2 gene for the transporters expression, function and their association with non-responsive epilepsy phenotype was investigated. Our results showed that MRP1 expression in lymphocytes was significantly lower in epileptics than in healthy subjects. Non-responders had lower MRP1 mRNA content in lymphocytes than responders. We did not find any difference in MRP2 expression between epileptics and healthy volunteers. MRP2 mRNA levels in lymphocytes were higher in non-responders than in responders. However, at protein level epileptic patients had significantly lower MRP2 content in lymphocytes than controls. MRP2 protein content did not differ in responders and non-responders. There was no reliable correlation between MRP2 mRNA expression and MRP2 protein content in lymphocytes. Epileptics had significantly lower MDR1 expression in lymphocytes than healthy individuals. MDR1 expression was decreasing according to the consumption of antiepileptic drugs and seizures frequency: patients after neurosurgery had significantly lower MDR1 expression than patients after combined therapy and monotherapy. MDR1 expression was significantly lower in non-responders than in responders. At protein level epileptics had lower P-gp content than controls. Detected P-gp amount in lymphocytes did not differ between responders and non-responders. Rhodamine efflux from lymphocytes and NK cells did not differ significantly between epileptics and healthy subjects, but it was higher in patients after neurosurgery than in patients after monotherapy. Rhodamine efflux from NK cells, which are known to express the highest levels of P-gp, was significantly higher in non-responders than in responders. In this study, we showed that MRP1 mRNA expression in lymphocytes was significantly correlated to its expression in the brain. We detected also a significant co-correlation between MRP1 expression in the hippocampus and MDR1 expression in lymphocytes. We found no evidence regarding the impact of the MDR1 polymorphisms on mRNA expression, P-gp content and rhodamine efflux from lymphocytes. Our data showed lack of evidence regarding the impact of the MRP2 polymorphisms on mRNA expression and protein content. We did not detect any association between MDR1 or MRP2 polymorphisms and non-responsiveness in epilepsy or epilepsy in the main. In conclusion, our results suggest that lymphocytes are an appropriate surrogate for studies on changes of multidrug transporters expression in epilepsy. Lymphocytes as an easily accessible tissue might serve as a marker for responsiveness to antiepileptic drug therapy in epilepsy studies.
The biodiversity of marine microorganisms opens a promising potential for the discovery of new technical enzymes. During this study a characterization of marine microorganisms, isolated from Arctic or Antarctic ice, sea water or sediment from the ocean was performed based on a comprehensive strain collection at the Alfred-Wegener-Institut für Polar- und Meeresforschung. These marine psychrophilic bacteria indicated a wide spectrum of extracellular cold-active enzymes. 16S rRNA sequencing revealed that many of these psychrophilic bacteria represent new species. Characterization of selected isolates by means of transmission electron or raster electron microscopy showed remarkably pleomorphic cellular structures throughout their growth. The major part of this thesis focuses on a marine Antarctic, psychrophilic bacterium (strain ANT/505) isolated from sea ice covered surface water from the Southern Ocean, which was identified to express a very uncommon enzymatic activity for the marine environment, namely a pectinolytic activity. The sequencing of the 16S rRNA of isolate ANT/505 and biochemical tests indicated a taxonomical affiliation to the specie Pseudoalteromonas haloplanktis. The supernatant of this bacterial isolate showed after growth on citrus pectin three different pectinolytic activities. By activity screening of a genomic DNA library of isolate ANT/505 in Escherichia coli, two different pectinolytic clones could be isolated. Subcloning and sequencing revealed two open reading frames of 1671 and 1968 nt corresponding to proteins of 68 and 75 kDa. The deduced amino acid sequence of the two orfs showed homology to pectate lyases from Erwinia chrysanthemi and Aspergillus nidulans. The pectate lyases contain signal peptides of 17 and 26 amino acids length that were correctly processed after overexpression in E. coli BL21. Both enzymes were purified by anionic exchange chromatography. Maximal enzymatic activities for both pectate lyases were observed at a temperature of 30°C and a pH range of 9-10. The Km values of both lyases for pectate and citrus pectin were 1 g⋅l-1 and 5 g⋅l-1, respectively. Calcium was required for activity on pectic substrates, while the addition of 1 mM ethylenediaminetetraacetic acid (EDTA) resulted in complete inhibition of the enzymes. These two cold-adapted enzymes represent the first pectate lyases isolated and characterized from a marine bacterium. Further cloning and sequence analyses revealed that PelA from P. haloplanktis is an exceptionally big bifunctional enzyme featuring pectate lyase and pectin methylesterase activity. The deduced amino acid sequence of the pectin methylesterase domain showed homology to group I pectin methylesterases from Erwinia chrysanthemi and Erwinia carotovora. The pectin methylesterase domain of PelA was found to show highest homology to a potential pectin methylesterase from Saccharophagus degradans strain MD2-40. Maximum pectin methylesterase activity of PelA was detected at a pH of 7.5 and a maximum temperature of 30°C. This cold-adapted enzyme revealed high remaining pectin methylesterase activity at low temperatures around 5°C and was quickly unstabilized at temperatures above 45°C. The analysis of the localization of the two pectinolytic genes on the genome of P. haloplanktis ANT/505 revelaed that these pectinase genes are expressed from independent cistrons, which are not clustered but located at distant positions on chromosome I of the P. haloplanktis genome. It was found that the transcription of both pectinase genes is induced by the presence of pectin. By means of primer extension the promoter regions of both cistrons were detected.
Recent geochemical and mineralogical alteration processes in tropical coastal sediments of Vietnam
(2006)
The dissertation contains two main parts: (i) Syn-sedimentary hydrodynamic processes & relationship with elemental distribution, clay matter, (ii) Short-term mineral alteration during early diagenes. Samples were taken from the uppermost one metre (<50 year old in RRD, < 300 y old in south central VN). In part one, three principal hydrodynamic factors can be revealed based on End-Member Modelling Algorithm (EMMA), for the polymodal grain-size distribution patterns in coastline of VN (i) Accumulation factor: accumulation of terrigenous sediments linked with a grain size separation (distance dependence), (ii) Erosion factor: synsedimentary erosion by wave activities, (iii) Aeolian factor: deposition from neighbour sand bar by wind (typically only for low sedimentation rate, like in South Central Coast but not to detect in RRD). Distributions of clay matter and chemical elements in the coastal sediments in Vietnam are strongly influenced by hydrodynamic forces (distance from the coastline). In part two, particle-wise analysis by TEM allowed to determined four main mixed layer series: di-Vermiculite/Smectite-ml, Kaolinite/ Expandable-ml, Illite/Smectite-ml, Chlorite/Saponite-ml. Three principal mineral alteration processes can be detected in coastal sediments during early diagenesis: Dissolution, Smectitization, Kaolinitization, based on XRD (CSD, peak area) & TEM-EDX (particle morphology, chemical formula, polytype, particle frequency). Dissolution process of clay matter is typically in the coastal alkaline condition. It is a function of diagenetic time. Dissolution begins with a higher degree of dislocation and is followed by step-wise delamination & dissolution of the first stacks Smectitization (mirrored in diVS-ml series) alters mica-like structures (illite, dioctahedral vermiculite) to smectitic structures (Beidellite, Montmorillonite). Smectitization process occurs in group-wise layer by layer transforming mechanism (mica-like layer to smectitic layer). Each step is indicated by a gauss-like distribution of the octahedral layer charge with K as trigger. Kaolinitization of KE series alters smectitic structure (beidellite, smectitic KE-ml) to kaolinitic structure (kaolinitic KE-ml, kaolinite) "interlayer by interlayer" transformation of KE-ml series is comparable to kaolinitization mechanism discussed by Dudek et al. (2006).OH- groups in ambient could be the trigger. Mangroves biota influences the sediments in two main pathways: Nutrients supply & trapping function (clay matter, heavy metals)Interaction of active root-layer: intensification of dissolution, smectitization & kaolinitization: uptake of K, Na by mangrove root is possible trigger Human activities like shrimp cultivation have stopped the influences of the former active roots.Besides, erosion process related to water discharge gives rise to dispersion of clay species & heavy metals => more toxic for ecosystem.
The non-natural substances in commonly used UV protection creams such as TiO2, are known to have a photocatalytic side effect, which is very harmful to human skin. This study presents some properties of clays and clays minerals concerning UV protection potential, which can be very helpful for the development of new UV protection cream generation. Clays and clay minerals are demonstrated that they have potential to absorb UV-radiation. The structures of clay particles in cream were shown to be dependent on the layer charge of clay minerals. The total amount of Fe2C>3 in chemical composition of clay plays a key role in determining the UV-absorption ability of the clay matter. Moreover, the UV-absorption ability also depends on the expandable or non- expandable property of the clay. The studies were also performed on the mixtures of wool-wax-alcohol cream and nanosuspension obtained by the extraction of fungi mass Ganoderma pfeifferi by using plantacare together with clay. The combination of clays and nanosuspension increased its UV-absorption ability. The skin model test was performed in vivo in mouse ears with skin flora Escherichia coli and infectious bacteria Staphylococcus aureus in order to determine the effects of cream samples on skin under UV irradiation and skin infection. From the results of characterization of clays and clay minerals properties in UV protection cream, this study also brings some ideas about products designing.
Although the benefit of expedient antibiotic therapy remains unquestioned, little is known about the effects that are unrelated to their antimicrobial property but which the antibiotics may exert upon the septic microcirculation. Impairment of intestinal microcirculation has been recognized as an important factor in the pathogenesis of the septic syndrome (intestine = ¡°motor¡± of multiple organ failure). To examine the effects of various antibiotics on microcirculation is justified by the fact that one of major features of sepsis is disturbance of microcirculation. However, monitoring of pharmacological effects on intestinal blood flow is nearly impossible during acute therapy in humans and requires sophisticated equipment when applied to experimental animals. Therefore, the aim of this study was to evaluate the effects of common antibiotics on intestinal microcirculation using intravital microscopy (IVM) and on the release of the cytokines in septic and endotoxemic rats. In a first series of experiments we induced sepsis by using colon ascendens stent peritonitis (CASP) model in the rat (16 hours prior microscopy). We evaluated the effects of common antibiotics on intestinal microcirculation using intravital microscopy (functional capillary density (FCD) and leukocyte-endothelial interactions) and on the release of the cytokines TNF-¥á, IL-1©¬, IL-6 and IL-10. Metronidazole (MET) (10 mg/kg); imipenem (IMI) (20 mg/kg); tobramycin (TOB) (25 mg/kg); vancomycin (VAN) (70 mg/kg); and erythromycin (ERY) (5 mg/kg) were given intravenously 16 hours following sepsis induction. To differentiate antimicrobial from anti-inflammatory effects we performed a second series of experiments using endotoxin (LPS, i. v.) and intravital microscopic examination was performed 2 hours later. Cytokine release was estimated at the end of the experiments. In the CASP model, acute administration of metronidazole was associated with an improvement of markers of the intestinal microcirculation in septic rats (CASP). Our study showed that vancomycin stimulated leukocyte rolling, while erythromycin prevented the activation of leukocyte-endothelial interaction in postcapillary intestinal venules (V1) that occurred within 16 hours after CASP. TNF-¥á release in untreated CASP rats was twice as high in comparison to all antibiotic-treated CASP rats, except in CASP rats treated with tobramycin. Key findings of the present study are that MET and ERY were more potent than other antibiotics in improving the intestinal microcirculation in the CASP model. Protective effects of metronidazole, erythromycin and vancomycin upon the microcirculation were found in LPS model. The administration of MET or VAN or ERY led to significantly higher FCD values within the longitudinal muscular layers. Metronidazole and erythromycin significantly reduced the n umber of sticking leukocytes within the V1-venules of LPS-challenged animals. Leukocyte rolling flux was significant increased within the V1- and V3-venules of the endotoxemic rats treated with VAN. Some antibiotics showed immuno-modulatory effects: MET or IMI or VAN treated LPS rats showed increased IL-10 levels; while ERY treated LPS rats showed decreased IL-1©¬ and increased IL-6 concentrations. In conclusion, metronidazole and erythromycin exerted a positive influence upon the intestinal perfusion not only within septic microcirculation (anti-bacterial effect) but also in a pathogenically independent manner (anti-inflammatory effect); vancomycin had only anti-inflammatory actions in the endotoxin model without bacterial infection. Imipenem and tobramycin had no effect on intestinal microcirculation in septic and endotoxemic rats. The clinical usefulness of studies such as this is that they could provide important information about possible side effects or indicate some potential beneficial effects of the antibiotics. They can influence not only microcirculation but also inflammatory processes by some mechanisms that are probably unrelated to their antibiotic effect. However, these effects may be particularly relevant to the intestinal microcirculation which plays an essential role in the development of multi-organ failure in the instance of sepsis.
The toluene-degrading and solvent-tolerant strain Pseudomonas putida DOT-T1E was investigated with respect to its suitability and economic efficiency as biocatalyst in aqueous-organic two-phase systems with aliphatic solvents as organic phase (Rojas et al. 2004, chapter 4 and 5) and to its adaptive responses to the solvent decanol. The adaptive changes on the level of cell morphology (chapter 2), membrane fatty acids and permeability (chapter 3), as well as energetics and surface properties (chapter 5) of P. putida DOT-T1E have been investigated in order to ascertain information about the strain's suitability for two-phase biotransformation systems (chapter 4). The morphological adaptation to the presence of solvents was observable in changes of the cell size of P. putida DOT-T1E. Those changes were dependent on the cellular activity and occurred only after addition of non-lethal solvent concentrations. The cells reacted to the presence of organic solvents by decreasing the ratio between surface and volume of the cells and therefore reducing their relative surfaces (chapter 2). The cell surface and especially the cytoplasmic membrane are the major targets for toxic effects of membrane-active compounds like solvents. The mechanism of the cis-trans isomerisation of unsaturated fatty acids counteracts the fluidizing effect of solvents by increase the ordering of the membrane and therefore its rigidity. By comparing the responses of the cells to a series of stress factors (like solvents), a direct correlation between the activation of this mechanism and the well investigated K+-uptake pumps was observed (chapter 3). Huertas et al. (1998) reported that this strain tolerated concentrations of heptane, propylbenzene, octanol, and toluene of at least 10 % (vol/vol). 1-decanol is, in comparison to toluene, less hazardous and volatile, and it possesses good extraction properties for the desired fine chemical products. In further investigations of possible biotechnological processes, it was discovered that decanol is also a more suitable solvent as organic phase (chapter 4). Although the cells of P. putida DOT-T1E needed additional energy for their adaptation to the presence of the solvent decanol, they were able to maintain or activate their electron transport phosphorylation allowing homeostasis of ATP level and energy charge in the presence of the solvent, at the price of a reduced growth yield. On the other hand, significantly enhanced cell hydrophobicities converging with more negative cell surface charges were observed in cells grown in the presence of 1-decanol (chapter 5). It is however important to note that all the cell’s properties observed are closely linked to each other since they are all part of the adaptive response of the cells. It can be concluded that the easy adaptability and good growth properties of Pseudomonas putida DOT-T1E in the presence of the organic solvent 1-decanol make this system an excellent candidate for two-phase fermentation processes. Moreover, the absence of differences in the energetics of the bacteria during exposure to 1-decanol as compared to bacteria that grew in the absence of 1-decanol, support that this organism can be used for the industrial production of fine chemicals in an economically sound manner.
For many years, rangeland ecologists have debated about whether the state of semi-arid and arid rangelands is the expression of an ecological equilibrium or non-equilibrium dynamics reached in response to grazing livestock. Since the problem has been considered at different spatial scales, it is recognised that the competing concepts of equilibrium and non-equilibrium dynamics need to be integrated. Furthermore, the role of environmental variables as vegetation driving factors has long been ignored in the discussion on grazing effects on ecosystems. Present thesis, examines the dependence of plant communities on environmental in particular site-ecological conditions in three ecosystems of Western Mongolia established along a precipitation gradient to detect the vegetation-driving ecological factors involved. Furthermore, grazing impact is exemplary assessed in a desert steppe at additional spatial scales of plant communities and population. At the landscape level, a classification of plant communities in dependence on environmental conditions is carried out. Additionally, the investigations focused on the impact of grazing on soil and on the occurrence of grazing-mediated plant communities. Data were sampled along an altitudinal gradient between 1150 m to 3050 m a.s.l. from arid lowland with desert steppe via semi-arid mountain steppe to humid alpine belt. Within each altitudinal belt, data sampling was carried out along grazing gradients, established from grazing hot spots to areas distant from them. By means of an environmentally based vegetation classification, factors with highest explanation values for largest variation in vegetation were identified and considered as most responsible for vegetation patterns. To validate and affirm the classification, three different statistical methods are applied: environmentally adjusted table work of vegetation relevés supported by cluster analysis of species distribution, detrended correspondence analysis of vegetation data separately from environmental data, and the principle component analysis of only environmental data. Vegetation-driving factors change along the altitudinal gradient from abiotic forces in the desert steppe, as e.g. altitude and soil texture, to abiotic and biotic forces in the alpine belt represented by soil texture, soil nutrients and grazing. Vegetation and soil of all ecosystems respond to grazing but with different patterns and to a different extent. While desert steppe does not indicate grazing communities, mountain steppe demonstrates grazing communities at fertilised sites and alpine belt at nutrients depleted sites. Thus, the grazing sensitiveness of the ecosystems is assumed to be linked with plant productivity and the role of vegetation as site-determining factor (Chapter 2). To examine grazing impact at lower spatial scales on desert steppe as the ecosystem with lowest grazing sensitiveness at the landscape scale, at community scale the total number of species, the total vegetation cover, the percentage of annual species, the cover of annual species, and properties of soil nutrient along gradients of grazing intensity within three different communities were assessed. Vegetation parameters respond to grazing in different ways, and the responses of the same parameters vary between plant communities. Correlations with grazing intensity indicate only partly statistical significance. Significant correlations of grazing intensity with concentrations of soil nutrient point to eutrophication in two communities. A comparison of vegetation and soil properties refers to a greater indirect influence of grazing via increased soil nutrients than the direct effect on vegetation (Chapter 4). At the population level, data about stand density, aboveground biomass, individual plant weight, and the proportion of flowering plants of the dominant dwarf semi-shrub Artemisia xerophytica were collected along a grazing gradient. Soil data were used to distinguish between grazing and edaphic influences. All parameters of Artemisia xerophytica reflect the assumed gradient of grazing intensity up to 800 m distance from the grazing hot spot. As grazing pressure decreases, plant density and total biomass per plot increase. The average shrub weight, an indicator of plant vitality, is related to both: distance from the grazing hot spot and stand density, which may be explained by additional intraspecific competition at higher densities. At a longer distance, these effects are masked by variations in soil parameters determining water availability, leading to quite similar degradation forms. These results are in contrast to other studies carried out at the scale of plant communities which did not detect significant changes along a grazing gradient. One explanation is the different map scale: the study took place only within a single plant community comparing populations of one species (Chapter 3). The comparative study demonstrates that even arid desert steppes of western Mongolia display equilibrial and non-equilibrial properties, depending on the observational scale: while no grazing mediated plant communities could be identified at the landscape scale as predicted by the non-equlilibrium model, at the community level vegetation parameters imply an intermediate position between equilibrium and non-equilibrium system. At the population level, the results clearly reflect the grazing gradient as predicted by the equilibrium model (Chapter 4). As a consequence, the assessment of vegetation dynamics and grazing impact in rangelands requires a multiple-scale approach that duly considers different vegetation properties responding differently to grazing, climatic and edaphic variability at different spatial scales. It is further suggested, that future research should draw comparisons between landscapes that co-evolved with herbivory, and those that did without (Chapter 4).
The thesis contains 6 chapter and mentions about the influences of sea level change, climate, tectonic into the sedimentary process. The results show that late Pleistocene facies mostly are weathered facies which content gibbsite-kaolinite, limonite. In transgression, facies assemblage includes lagoon, tidal and estuary. The composition are in-situ reworked minerals like illite, gypsum. In regression, facies are shallow marine, prodelta, delta front, distributary lobe, swamp, tidal and beach, channel infill, flood plain, lake. Abundant minerals are named like smectite, illite, chlorite, quartz, feldspar, rock fragments, gypsum.Gypsum is the evaporited mineral easily to be formed in coastal environment of Red River Delta. It is a good indicative mineral for distinguishing the deposits formed in dry season of monsoon regions. Smectite is good indicative mineral for sea environment which mostly related with the transference and low accumulation and new formed in climate with wet and dry periods. Kaolinite-gibbsite is an indicator of strong chemical weathering with high precipitation. The stratigraphy can be divide into trangressive systems tract (10-8.5 cal. kyr BP) and highstand systems tract with aggradational-progradational parasequence set (8.5-6.5 cal. kyr BP) and progradational parasequence set (6.5 cal. kyr BP-today, with subsets 6.5-4.0; 4.0-1.5; and 1.5-0.0 cal. kyr BP). The subsidence process which reflex in accumulation rate regarded to not only sea level change, tectonics but also human impact - dyke build plays the main role to increased sedimentary thickness. The influence of source variation and climate change are recorded on mineral composition. In late Pleistocene, materials are chemical weathering authigenic components during warm/wet climate. In transgression, dominated materials are reworked terrigenous and chemical weathering components during warm/dry and cool/wet climate. In regression, materials are low maturity, suffered by physical weathering transported from surrounding mountains during 3 warm/dry or wet - cool/dry or wet big climate cycles.
Proteomic signatures select the physiology state of the cell. By using 2-D technique, proteome signature of Bacillus subtilis under different stresses and starvations are analyzed. Consequently, a proteomic map of Bacillus subtilis in non-growing phase was created. The ammonium and tryptophan as well as phenol and catechol stress are analyzed using both of proteomics and transcriptomics. And the proteomic map represents a good application in the prediction of the mode of action of phenol and catechol stress.
In the present thesis, a systematic study of beam driven Alfvén eigenmodes in high-density and low-temperature plasmas of the W7-AS stellarator is performed. The device went out of operation in 2002 and the study is based on stored experimental data. Alfvén instabilities can roughly be divided into ideal MHD Alfvén eigenmodes and those existing due to kinetic effects. The spectrum of ideal MHD Alfvén waves in toroidal fusion devices consists of a continuum of stable waves that are strongly localized. Weakly damped, discrete eigenmodes can exist in gaps of the continuous spectrum which are formed by plasma inhomogeneities and the coupling of Alfvén continua. This allows an identification of ideal MHD Alfvén eigenmodes in terms of their frequency and mode numbers. Kinetic effects can modify this spectrum and cause additional types of eigenmodes, the kinetic Alfvén eigenmodes (KAE) and energetic particle modes (EPM). The goal of this thesis is twofold: (I) identification and description of fast particle driven Alfvén instabilities in W7-AS, and (II) study of energetic particle losses induced by Alfvén instabilities. The reconstruction of the ideal MHD plasma equilibrium for each discharge with sufficient accuracy is the very foundation of all subsequent steps. This is achieved, based on measured plasma parameter profiles that are further refined by validating them to the measurements of other, independent plasma diagnostics. The applied scheme is inspired by an approach of Integrated Data Analysis (IDA) to combine different diagnostic data and provide combined uncertainties. After mode number analysis and eigenmode identification, the theoretically expected, linear growth rate of the instability is calculated where possible, and the various contributions of the fast particle drive to the instability of the mode are identified. Alfvénic activity recorded by the Mirnov diagnostic is analyzed, which consists of a set of spatially distributed coils that measure magnetic fluctuations. On W7-AS, the probes are arranged in three poloidal arrays at different toroidal positions. The spacing between the probes is non-equidistant. In addition, the signals of one probe array are digitized with a different sample rate. These characteristics prohibit the straight-forward use of standard tools available for harmonic analysis. Instead, a new tool has been developed and thoroughly tested. It is a multi-dimensional extension of the Lomb periodogram, able to provide reliable time-resolved frequency and mode number spectra in the case of uneven datapoint spacing. Numerical studies of this periodogram show a good performance with respect to mode number resolution given the low number of available probes, and robustness against perturbations of the signal. Only two of the probe arrays can be used for the analysis of eigenmodes with frequencies >70 kHz, such that for high-frequency phenomena insufficient information about the mode numbers is available. A total of 133 different Alfvén eigenmodes is studied in discharges from different experimental campaigns. A restriction to discharges from various high-beta campaigns with neutral beam heating is required to allow for a realistic reconstruction of plasma equilibrium and velocity distribution functions of energetic particles. The discharges are characterized by high density, ne = 5 x 1019 m-3 to 2.5 x 1020 m-3 at relatively low temperatures of Te = Ti = 150 ... 600 eV. Alfvén eigenmodes often appear transiently in the startup phase of these discharges, where density and heating power are being ramped up. Occasionally, Alfvén eigenmodes are seen in the stationary, high-beta phase in the presence of considerable neutral beam heating. Most of the Alfvén eigenmodes are successfully classified as ideal MHD eigenmodes. 19 global, 47 toroidicity-induced and 8 ellipticity-induced Alfvén eigenmodes (GAEs, TAEs, and EAEs, respectively) are unambiguously identified by their mode numbers and frequencies. Excellent agreement between experimentally observed mode number spectra and theoretically calculated eigenmode structure is shown for a TAE example. Additional 13 events are found to have frequencies inside the EAE gap and could possibly be EAEs. Evidence for high-frequency Alfvén eigenmodes (mirror- and helicity-induced Alfvén eigenmodes) is seen, but can not be proven rigorously due to uncertain mode numbers and the complexity of the Alfvén continuum. The remaining 41 Alfvén eigenmodes can not be classified to be one of the above cases. Reasons are either high frequencies, mode numbers obscured by far-field effects, or mode numbers that could not be related to ideal MHD Alfvén eigenmodes. A selection of these shows indications of strong non-linear wave-particle interactions and are assumed to be EPMs. Kinetic Alfvén eigenmodes are not expected to exist in the experimental conditions that were studied. The radially resolved velocity distribution function is used to describe the parameter regimes in which the modes are observed in terms of the dimensionless parameters vb/vA (beam velocity normalized to the Alfvén velocity) and ßfast/ßth, where beta is the ratio of plasma pressure to magnetic pressure. The first parameter describes through which of the possible resonance velocities particles can interact with the eigenmode. A peculiarity of the fast particle dynamics in fusion devices is that they can resonantly interact with Alfvén eigenmodes through sideband resonances even if v < vA. The second parameter describes the energy content of the destabilizing fast particle population compared to the potentially stabilizing thermal plasma component. These parameters contain relevant information about the instability of an eigenmode and such diagrams are given for all observed modes. In addition to that, the expected linear growth rate of gap modes is calculated based on a theoretical model that extends the ideal MHD by a perturbative, drift-kinetic description of the energy exchange between waves and circulating particles, neglecting the effects of trapped particles. For the discharges under consideration the thermal electron speed is comparable to vA and the electrons provide a significant Landau damping contribution. Due to strong density gradients near the plasma boundary in most of the discharges, the thermal ions can provide a small drive via the spatial inhomogeneity which does not overcome the electron damping, however. The drive by spatial inhomogeneity of thermal ions requires a certain propagation direction of the mode and is equally stabilizing for opposite mode numbers. The fast particles also contribute to the growth rate via spatial inhomogeneity, velocity gradients and velocity anisotropy terms are negligible in W7-AS. Most of the observed GAE or EAE modes have negative mode numbers, which correspond to a propagation direction for which the spatial inhomogeneity of thermal and beam ions is predicted to be stabilizing. A fast particle drive of these modes is not confirmed, whereas the TAEs are found to be strongly destabilized by neutral beam injection. The distribution of plasma parameters for discharges showing TAEs in terms of the dimensionless stability parameters suggests an instability threshold that is qualitatively confirmed by an exploration of the parameter space with the theoretical model. Wave-induced, resonant losses of energetic ions scale linearly with the wave amplitude. To identify them, correlations between ion loss probe signals and wave amplitudes are searched, where correlation times in the order of the slowing-down time of energetic particles are expected. Significant correlations can be established only exceptionally for 3 of the identified ideal MHD Alfvén eigenmodes. Those Alfvén eigenmodes, however, which are assumed to be EPMs frequently show severe losses of energetic ions that are visible in the time traces of the plasma energy as well.
The Gram-positive bacterium Bacillus licheniformis is an important industrial host for the production of enzymes. Genomic DNA arrays and proteomics are being used to investigate the physiology of this bacterium. A genome-wide transcriptional profiling analysis of the adaptation of B. licheniformis to phosphate starvation shows more than 100 induced genes. Most of strongly induced genes belong to the putative Pho regulon. The data of the transcriptome analysis have been verified by the analysis of the extracellular and cytoplasmic proteome. The main response of B. licheniformis to glucose starvation was a switch to the usage of alternative carbon sources. In addition, B. licheniformis seems to be using other organic substances like amino acids and lipids as carbon sources when subjected to glucose starvation. This was indicated by the induction of a high number of genes the proteins of which are involved in amino acid and lipid degradation. During nitrogen starvation genes necessary for the recruitment of nitrogen from alternative sources were induced, e.g. genes for nitrate and nitrite assimilation, several proteases and peptidases. Both starvation conditions led to a down-regulation of the transcription of most vegetative genes and subsequently to a reduced synthesis of the corresponding proteins. Only a few genes were induced by both starvation conditions like yvyD, citA and the methylcitrate shunt genes mmgD, mmgE and yqiQ. Data of this study use to better understand the physiology of this bacterium during fermentation processes and thus to identify and circumvent bottlenecks of B. licheniformis based bioprocesses. In addition, the phytase promoter was tested for the construction of an alternative phosphate regulated expression system for B. licheniformis.
The thesis contains 6 studies and mentions the validation and comparison of several methods for measuring body composition and assessing nutritional status in different groups of pediatric patients. It also deals with the effects of infant formulas supplemented with nucleotides on the growth and body composition of healthy term and preterm babies. The first study shows that BMI-standard deviation score and %BF have a moderate agreement in classifying the nutritional status. The second study done in preterm neonates points out that bioelectrical impedance provides only insignificant information on fat-free mass (FFM) compared to anthropometry. The third study validates published prediction equations and develops a new equation in a group of children with Crohn's disease. The equation of Schaefer et al. is the best to predict FFM. The accuracy of a prediction equation is influenced by weight, height and age other than impedance index alone. The fourth study indicates that impedance index is better than weight, height squared as the predictor for estimating FFM. Addition of weight improves the predictive accuracy of prediction equations. The fifth study shows that birth weight centiles gives a rough estimation of nutritional status. Weight-for-length ratio shows the best correlation with fat mass. The last study shows that weight gain and gain in lean mass are higher in the standard formula group than in the groups nourished with nucleotides or breast milk.
Synthesis and evaluation of pseudosaccharin amine derivatives as potential elastase inhibitions
(2006)
Elastase is a serine protease which by definition is able to solubilize elastin by hydrolytic cleavage.Human Leukocyte Elastase, HLE (EC 3.4.21.37), is involved in deseases such as adult respiatory distress syndrome, pulmonary emphysema, smoking related chronic bronchitits, ischemic-reperfusion injury and rheumatoid arthritis. Hence, the elastase inhibitors have clinical utility in these diseases. Heterocyclic compounds are one of the most important classes of the elastase inhibitiors. In the present work different pseudosaccharin amine derivatives were synthesized and tested against the elastase. The synthesis of pseudosaccharin amine dervatives was carried out from the amines and(1,1-dioxobenzo[d]isothiazol-3-ylsulfanyl)acetonitrile in different solvents. Futhermore, the pseudosaccharin amines were obtained by refluxing the thiosaccarinates in absolute acetic acid. The reaction of 3-ethoxybenzo[d]isothiazole 1,1-dioxide with different amines in dioxane under reflux resulted into the desired pseudosaccharin amine derivatives in higher yields. Pseudosaccharin chloride was also used in the synthesis of these derivatives.A detail study of the synthesis of pseudosaccharin amine dervatives from the above differnt routes is described. Peptides were also synthesized by using the mixed anhydride method. The ester, acid, amide and peptide derivatives were tested against the Porcine Pancreatic Elastase (PPE) and Human Leukocyte Elastase (HLE). The esters were found to be the reversible inhibitors of HLE. The process of the PPE inhibion by cyanomethyl(2S)-2-(1,1-dioxobenzo[d]isothiazol-3-ylamino)-3-methylbutanoate was studied. Michaelis-Menten curve and Lineweaver-Burk double reciprocal plot were constructed in order to study the kinetic of this reaction. The compounds showing high inhibition of HLE were further stuied for determination of their inhibitory constant(Ki). The esters were found to be the higly active compounds against HLE. The cyanomethyl(2S)-2-(1,1-dioxobenzo[d]isothiazol-3-ylamino)-3-methylbutanoate and cyanomethyl(2S,3S)-2-(1,1-dioxobenzo[d]isothiazol-3-ylamino)-3-methylpentanoate showed the competitive reversible inhibition of HLE.The cyanomethyl(2S,3S)-2-(1,1-dioxobenzo[d]isothiazol-3-ylamino)-3-methylpentanoate is highly potent inhibitor of HLE. The possible mechanism of inhibition of elastase by these compounds is discussed. Molecular modelling of some of the ester derivatives is also discussed.
A fluorescent lamp driven with an 'instant start electronic control gear' starts in a glow mode. In the glow mode, which lasts typically for tens of milliseconds, the cathode fall exceeds hundreds of volts. This causes high energy ion bombardment of the electrode which heats the electrode, and induces a transition from glow to arc mode. In the arc mode the electrode emits thermionically and the cathode fall drops to the 12 – 15 V range. Unfortunately, the high energy ion bombardment during the glow mode leads also to intense sputtering of electrode material, including tungsten as well as emitter. Thus, instant started fluorescent lamps often suffer from early failures due to coil fracture. Therefore, the investigation of tungsten erosion during instant start is necessary and was the main goal of this work.
The density of neutral atomic tungsten is determined by laser-induced fluorescence (LIF) and optical emission spectroscopy measurements (OES). Investigations are performed on a low-pressure argon dc discharge and on commercial fluorescent lamps. To include the entire temperature profile along the electrode the diffuse and spot operation modes of the dc lamp are studied experimentally and theoretically. The measured dependencies of the cathode temperature along the coil on the discharge and heating parameters are compared with the calculated results. For the first time the tungsten erosion during instant start of commercial fluorescent lamps was experimentally investigated in this work. The erosion process could be related to sputtering. A reconstruction of the temporal evolution of the absolute tungsten population density of the ground state during the glow mode was presented. The sputtered tungsten density increases immediately with the ignition, reaches a maximum where the discharge contracts at the end of the glow mode, and decreases some milliseconds before the glow-to-arc transition takes place. The maximum tungsten density was observed within a region of a few hundred micrometers only located at the discharge attachment point. The main result achieved in this work is that during the whole glow mode tungsten is sputtered. Therefore, the lifetime of instant started fluorescent lamps can be enhanced by reducing the duration of the glow mode. Additionally, the need for the application of different types of diagnostics for the observation of lamp ignition was shown due to different results of LIF, AAS and OES: The observation of excited tungsten atoms by OES shows the maximum emission signal at the glow-to-arc transition whereas by LIF and AAS measurements of tungsten atoms in the ground state the maximum density is found during the whole glow mode. This can be explained by the fact that the intensity of the spontaneous emitted light is related not only to the density but also to the degree of excitation.
The interaction of partially ionized plasmas with an electromagnetic field is investigated using quantum statistical methods. A general statistical expression for the current density of a plasma in an electromagnetic field is presented and considered in the high field regime. Expressions for the collisional absorption are derived and discussed. Further, partially ionized plasmas are considered. Plasma Bloch equations for the description of bound-free transitions are given and the absorption coefficient as well as rate coefficients for multiphoton ionization are derived and numerical results are presented.
Based on distributions of local Green's functions we present a stochastic approach to disordered systems. specifically we address Anderson localisation and cluster effects in binary alloys. Taking Anderson localisation of Holstein polarons as an example we discuss how this stochastic approach can be used for the investigation of interacting disordered systems.
1,1-Bis(trimethylsilyloxy)ketene acetals represent useful synthetic building blocks which can be regarded as masked carboxylic acid dianions. In recent years, a number of cyclization reactions of 1,1-bis(trimethylsilyloxy)ketene acetals have been reported. Functionalized maleic anhydrides represent important synthetic building blocks, which have been employed, for example, in the synthesis of γ-alkylidenebutenolides, maleimides, 5-alkylidene-5H-pyrrol-2-ones. Substituted maleic anhydrides are available by Michael reaction of nucleophiles with parent maleic anhydride and subsequent halogenation and elimination. Oxalyl chloride is an important synthetic tool for the synthesis of O-heterocycles. 3-hydroxymaleic (1-3) anhydrides were synthesised by one-pot cyclization of 1,1-bis(trimethylsilyloxy)ketene acetals with oxalyl chloride using TMSOTf as a catalyst. The Me3SiOTf mediated reaction of 1,1-bis(trimethylsilyloxy)ketene acetals with 3-silyloxyalk-2-en-1-ones, such as (4), afforded 5-ketoacids, such as (5). Treatment of the latter with TFA in CH2Cl2 afforded pyran-2-ones, such as (6-8). It has been found that 1,1-bis(trimethylsilyloxy)ketene acetals can behave as dinucleophile. Functionalized benzo-azoxabicyclo[3.3.1]nonanones (9-12), were prepared by regio- and diastereoselective condensation of 1,1-bis(silyloxy)ketene acetals with isoquinolinium and quinolinium salts and subsequent regioselective and stereospecific iodolactonization. Our next target was the reaction of silyl ketene acetals with pyrazine and quinoxaline. These reactions provide a facile access to a variety of 2,3-benzo-1,4-diaza-7-oxabicyclo[4.3.0]non-2-en-6-ones and 1,4-diaza-7-oxabicyclo[4.3.0]non-2-en-6-ones (13-14). The second part of my research work was concentrated on bis(silyl enol ethers). The TiCl4-mediated [3+3] cyclization of 2,4-bis(trimethylsilyloxy)penta-1,3-diene with 3-silyloxyalk-2-en-1-ones afforded 2-acetylphenols (15), which were transformed into functionalized chromones (16). The Me3SiOTf-mediated condensation of the latter with 1,3-bis(silyl enol ethers) and subsequent domino ′retro-Michael–aldol–lactonization′ reaction afforded 7-hydroxy-6H-benzo[c]chromen-6-ones (17-18). With regard to our on going investigation with bis(silyl enol ethers), we significantly extended the preparative scope of the methodology. We have successfully developed regioselective cyclizations of unsymmetrical 1,1-diacylcyclopentanes, such as 1-acetyl-1-formylcyclopentane, and also studied cyclizations of 2,2-diacetylindane, 1,1-diacetylcyclopent-3-ene and 3,3-dimethylpentane-2,4-dione. In addition, the mechanism of the domino process was studied. We have synthesised spiro[5.4]decenones (19) and that were transfored into bicyclo[4.4.0]deca-1,4-dien-3-ones (20-21), by domino ′Elimination–Double-Wagner-Meerwein-Rearrangement′ reactions. The Lewis acid mediated domino ′[3+3]-cyclization-homo-Michael′ reaction of 1,3-bis-silyl enol ethers with unsymmetrical 1,1-diacylcyclopentanes, such as 1-acetyl-1-formylcyclopentane, allows an efficient one-pot synthesis of functionalized salicylates containing a halogenated side-chain (22-23). A great variety of substitution patterns have been realized by variation of the starting materials and of the Lewis acid. The mechanism of the domino process was studied.
Expression of the T cell regulatory molecule ICOS (CD278) and LICOS (CD275) on human blood cells
(2006)
Expression of the T cell regulatory molecule ICOS (CD278) and LICOS (CD275) on human blood cells Summary General bacterial infections, which can lead to the clinical picture of sepsis, are a major concern in intensive care units (ICU) and mortality remains high. Recent data have shown that, besides an overreaction of the immune system, also immunosuppression also plays a role in the pathogenesis of sepsis. Immunosuppression has been documented in patients with polytrauma, stroke and burn wounds, which all confer a high risk of severe bacterial infection. Moreover, it has been shown that T cells have an important role in sepsis. A shift of a Th1 dominated T cell response towards a Th2 response has been described as a potential mechanism of immune suppression in patients with sepsis. One of the molecules on the surface of T cells that is involved in the Th2-mediated immune response is the Inducible Costimulator of T cells (ICOS). Its ligand, LICOS, is expressed on the surface of B cells and monocytes. ICOS ligation induces the production of anti-inflammatory cytokines, especially of IL-10. However, nothing is known about the expression of ICOS on T cells and that of LICOS on APCs in patients with severe trauma and stroke. Therefore, in the present study, in a first step, a recombinant human LICOS-Ig fusion protein was generated, which was then used as an antigen for the generation of anti-LICOS monoclonal antibodies. In three fusion experiments, 5,000 primay clones were screened and a single hybridoma was obtained, which produced monoclonal antibodies that specifically reacted with recombinant LICOS, both in form of the LICOS-Ig fusion protein and on the surface of a cell line transfected with a full-length LICOS transgene. Since, it turned out that the antibodies did not bind with high affinity to wild type LICOS, as it is expressed on primary human blood cells, phenotypic analyses were carried out with another anti-LICOS monoclonal antibody, which had become commercially available. Next, the expression of HLA-DR, CD86, LICOS, and ICOS, on the surface of monocytes (CD14+), B cells (CD19+) and T cells (CD3+, CD4+) in whole blood was measured by flow cytometry. Six patients with severe trauma and nine stroke patients were compared with 32 healthy donors. On CD14+ monocytes from healthy donors, the expression levels of HLA-DR and CD86 were over 90%, while the expression of LICOS was much lower (7,5%). In critically ill patients, HLA-DR, CD86 and LICOS expression were strongly reduced. CD86 and HLA-DR were co-regulated, while HLA-DR and LICOS were not. In healthy donors, virtually all B cells expressed HLA-DR and the majority of them co-expressed LICOS (72%), while only a small fraction were CD86+ (14%). After trauma and stroke, HLA-DR, as well as LICOS expression on these cells remained normal; CD86 had a tendency towards being downregulated in most of the trauma patients, while most of the stroke patients exhibited normal CD86+ levels. The levels of HLA-DR and LICOS on T cells in trauma and stroke patients were low and very similar to those of healthy donors. The fraction of CD3+ T lymphocytes or their CD4+ subpopulation, which expressed measurable levels of ICOS (64% and 48%, respectively), did not change after stoke or trauma. However, within the ICOS+ T cell population two subpopulations could be distinguished: ICOSbright and ICOSdim T cells. Interestingly, the ICOSbright subpopulation, but not the ICOSdim and ICOSnegative subpopulations, was markedly increased in all trauma patients and in most of the stroke patients. Given that CD86 was co-regulated with HLA-DR on monocytes it appears that, similar to HLA-DR, CD86 expression could discriminate between patients with a low and high risk of sepsis. In contrast, because of its low basal expression on monocytes and its low signal-noise ratio, LICOS expression levels are not informative. Since ICOS expression on T cells is tightly connected to IL-10 secretion, the high proportion of ICOS bright cells in critically ill patients might contribute to the high IL-10 serum concentrations, which have been reported to be linked to immunosuppression in these patients.
SUMMARY To date, Staphylococcus aureus is the most common cause of nosocomial infections and the species is becoming increasingly resistant to antibiotics. Beyond this, S. aureus colonises the nasal mucosa of circa 35% of the healthy population, so-called carriers. Importantly, S. aureus nasal carriage is a major risk factor for the development of S. aureus infections, which are commonly caused by the colonising strain. This underlines the importance of host factors for the outcome of S. aureus-host interactions. Despite the clinical importance of nasal carriage, little is known about humoral immune responses triggered by colonisation. Therefore, this thesis was focussed on the anti-staphylococcal antibody responses of S. aureus carriers and noncarriers. Staphylococcal superantigens (SAgs) served as indicator antigens for our studies. SAgs are virulence factors with extraordinary variability in the species S aureus and act as extremely potent T cell mitogens. To date, 19 different SAg gene loci are known in the species S. aureus, but molecular-epidemiological studies on the distribution of these genes are limited. Therefore, we established five multiplex PCRs for the detection of all known SAgs. With this robust and high-throughput technique we analysed the SAg gene patterns of more than 300 isolates, including 107 nasal isolates of S. aureus carriers and 88 blood culture isolates of hospital patients from Western Pomerania. The SAg gene patterns were highly heterogeneous, which can be explained by their localisation on mobile genetic elements (MGE), such as genomic islands, pathogenicity islands, phages and plasmids. Most isolates (~80%) harboured SAg genes, on average five to six, and SAgs of the enterotoxin gene cluster (egc) were by far the most prevalent. Additionally, we observed a strict correlation between the presence of SAg genes and the T cell mitogenic potency of clinical isolates. SAg-encoding MGEs can be distributed by two distinct mechanisms: horizontal transfer by bacteriophages and vertical transmission to daughter cells. To investigate the distribution of SAg genes within the S. aureus population, we determined the clonal relationship of our isolates by spa genotyping. Interestingly, SAg-gene encoding MGEs were not randomly distributed, but rather closely linked to clonal lineages. Each clonal lineage was characterised by defined combinations of SAg genes. These data suggest that the simultaneous assessment of virulence gene profiles and the genetic background strongly enhances the discriminatory power of genetic investigations into the mechanisms of S. aureus virulence. Indeed, the comparison of virulence genes within each clonal complex indicated a role in invasiveness for some MGEs, e.g. the exfoliative toxin D-encoding pathogenicity island, while rendering it unlikely for SAgs. It is known that neutralising serum antibodies against the SAgs SEA, SEB, SEC, SED and TSST-1 are frequently present in healthy individuals. However, the neutralising antibody profiles against more recently described SAgs or complex SAg cocktails as secreted by clinical isolates had not been determined so far. Therefore, we screened more than 100 sera for their SAg neutralising capacity with a neutralisation assay. We observed a marked heterogeneity and surprisingly large “gaps” in the neutralising capacity. Interestingly, the egc SAgs were inhibited only rarely (5-10%), whereas between 32 and 86% of the tested sera neutralised “classical” SAgs. This “egc gap” in the SAg-neutralising antibody profiles of healthy individuals was unexpected, since egc SAgs are by far the most prevalent SAgs. We could demonstrate that the “egc gap” is probably not due to different T cell activating properties of egc SAgs compared to classical SAgs, but rather to a differential regulation of SAg gene expression. S. aureus carriers have an increased risk of developing an S. aureus bacteraemia, which is in most cases caused by the colonising strain. Intriguingly, a large prospective clinical trial revealed a considerably higher mortality in noncarriers with invasive S. aureus strains compared to carriers with invasive disease. To explain these paradoxical findings, we hypothesised that in carriers partial immunity against the colonising strain may contribute to their improved outcome. We used SAgs as strain-specific indicator antigens. Importantly, sera from persistent carriers neutralised SAgs of their colonising strain with significantly higher efficiency than sera from noncarriers. This antibody response was strain-specific, since the antibody response of carriers against other SAgs did not differ from that of noncarriers. Thus, colonisation with S. aureus confers a strong and strain-specific antibody response against staphylococcal SAgs. We suggest that in carriers neutralising antibodies directed against SAgs and other staphylococcal virulence factors confer partial protection during systemic infections. This could explain the better prognosis of carriers with S. aureus bacteraemia compared to noncarriers. Moreover, our data imply that the key to understanding the pathogenesis of S. aureus disease may lie in the identification of host factors rather than bacterial factors. Such host factors could be the immune status and gene polymorphisms that contribute to colonisation, susceptibility to infection and outcome of infection. Finally, while the treatment of S. aureus bacteraemia with pooled immunoglobulins was performed in the past without significant success, our findings on strain-specific antibody profiles suggest that therapies with customised cocktails of monoclonal antibodies could have a higher efficacy.