Refine
Year of publication
- 2004 (4) (remove)
Document Type
- Doctoral Thesis (3)
- Article (1)
Language
- English (4) (remove)
Has Fulltext
- yes (4)
Is part of the Bibliography
- no (4)
Keywords
- - (1)
- ARDS (1)
- Animal models (1)
- Bacillus subtilis (1)
- Blutspiegel (1)
- Diabetes mellitus (1)
- General Stress (1)
- Glycemic control (1)
- Heubacillus (1)
- Metabolic syndrome (1)
Institute
Publisher
- IOP Publishing (1)
Severe trauma results in alterations in immune functions, correlated with a dysbalanced cytokine synthesis. This imbalance endangers severely injured patients for post-traumatic complications such as MODS, liver failure, renal dysfunction and ARDS. IL-10, a powerful immunosuppressive cytokine, plays a central role in the immune response after severe trauma. The relevance of IL-10 for single and multiple organ failure was studied in a prospective study at a level I trauma center. Blood was systematically obtained from a total of 118 severely injured [median (IQR) ISS=34 (27-34)] patients. IL-10 plasma levels were measured by ELISA. Patients showed elevated IL-10 levels throughout the whole observation period of 5 days. IL-10 plasma levels rose rapidly after trauma and gradually declined towards day 5. Patients who developed complications demonstrated significantly elevated IL-10 levels compared with patients who did not. The odds of developing MODS were 9.6 times greater in patients with IL-10 plasma levels higher than 124 pg/mL 6 hours after arrival at the ICU. Multivariate analysis showed that IL-10 plasma levels >124 pg/mL at time-point 6h, severe head injury and an arterial pH <7.34 were simultaneously significant predictors of the development of MODS in severely injured patients. The dynamic with rapid increase and gradual decline in IL-10 plasma levels indicated that IL-10 is a marker of the initial damage to the organism caused by trauma, rather than a marker of somatic dysregulations.
The present work consists of four parts, containing experimental data obtained from analysis of 'Bacillus subtilis' specific and general defense strategies against reactive oxygen species. In the first part, the peroxide and superoxide stress stimulons ob 'B. subtilis' were analyzed by means of transcriptomics and proteomics. Oxidative stress responsive genes were classified into two groups: the gene expression pattern was either similar after both stresses or the genes primarily responded to one stimulus. The high induction observed for members of the PerR-regulon after both stimuli supported the assumption that activation of the peroxide specific PerR-regulon represented the primary stress response after superoxide and peroxide stress. The second part focuses on protein carbonylation in 'B. subtilis' wild-type and 'sigB' mutant cells. The introduction of carbonyl groups into amino acid side chains of proteins represents one possible form of protein modification after attack by reactive oxygen species. Carbonyl groups are readily detectable and the observed amounts can thus serve as an indicator for the severity of protein damage. The resultsdemonstrate clearly that 'B. subtilis' proteins are susceptible to hydrogen peroxide (H2O2) mediated carbonylation damage. The application of low concentrations of H2O2 prior to the exposure to otherwise lethal levels of peroxide reduced markedly the degree of protein carbonylation, which also held true for glucose starved cells. Artificial preloading with general stress proteins resulted in a lower level of protein carbonylation when cells were subjected to oxidative stress, but no differences were detected between wild-type and 'sigB' mutant cells. In the third part, strains with mutations in genes encoding general stress proteins were screenedfor decreased resistance after H2O2 challenge. It was demonstrated that resistance to H2O2 challenge. It was demonstrated that resistance to H2O2 after transient heat treatment, likewise to conditions of glucose starvation, was at least partly mediated by the sB-dependent general stress response. The screening of mutants in sB-controlled genes revealed an important role for the deoxyribonucleic acid (DNA)-binding protein Dps in the context of sB-mediated resistance to oxidative stress underlining previous reports. Therefore, the experimental strategy opens a global view on the importance of DNA integrity in 'B. subtilis' under conditions of oxidative stress. The fourth part includes analysis of a 'B. subtilis' thioredoxin conditional mutant. The thiol-disulfide oxidoreductase TrxA is an essential protein in 'B. subtilis' that is suggested to be involved in maintaining the cytoplasmic thiol-disulfide state even under conditions of oxidative stress. To investigate the physiological role of TrxA, growth experiments and two-dimensional gel electrophoresis were carried out with exponentially growing cells that were depleted of TrxA. The observations indicate that TrxA essentially involved in the re-reduction of phosphoadenosyl phosphosulfate reductase CysH within the sulfate assimilation pathway of 'B. subtilis'.
The insulin dependent type 1 diabetes mellitus (IDDM) and the metabolic syndrome are complex human diseases. Both diseases are heterogeneous, genetically inherited and do not follow a simple Mendelian single-locus pattern. The analysis of complex human diseases is complicated both by genetic heterogeneity and by environmental factors. One way to overcome the problem of genetic heterogeneity in humans may be to cluster patients by kinship. It was shown by analysis of maternal lines of type 1 diabetics using mitochondrial DNA that 89% of maternal lines are related to each other. Moreover, an alternative to the genetic differential analysis of complex mammalian diseases is the use of animal models. The availability of inbred animal models closely resembling the human disease is an essential component of genetic investigations in this field, as shown in the results of this work. These findings do not only underscore the utility of the congenic and subcongenic approach in differentially analyzing complex traits, but also show that candidate genes can be identified and that chromosomal exchange can variously influence the phenotype, leading to sub-phenotypes which may be representative for human beings. Furthermore, it will also be possible to locate the syntenic region in the human genome and congenic and subcongenic strains can also be used to study interactions between chromosomal regions and various selected environmental conditions. In this way, it may be possible to learn which region can be influenced by environmental factors and to which extent, an undertaking which will require prospective projects.
Colossal magneto-resistance manganites are characterized by a complex interplay of charge, spin, orbital and lattice degrees of freedom. Formulating microscopic models for these compounds aims at meeting two conflicting objectives: sufficient simplification without excessive restrictions on the phase space. We give a detailed introduction to the electronic structure of manganites and derive a microscopic model for their low-energy physics. Focusing on short-range electron–lattice and spin–orbital correlations we supplement the modelling with numerical simulations.