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- Geli Rolfhamre, Patricia, 1979-
(författare)
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From Penicillin Binding Proteins to Community Interventions : Mathematical and Statistical Models Related to Antibiotic Resistance
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotic resistance has become a major public health concern and mathematical models are important analytical tools for the understanding, evaluation and prediction of the resistance problem and related control strategies.The risk of emerging antibiotic resistance and selection has rarely been a concern in the design of antibiotic drug dosing regimens. In the first paper, a selection of antibiotic resistant subpopulations for different antibiotic dosing regimens was studied in vitro. The demonstrated complex relationship was influenced by both the rise of new mutants and a postantibiotic effect (PAE) (continued inhibition of bacterial growth after removal of the antibiotic drug). By constructing a mathematical model that incorporated biologically relevant parameters, we were able to assess the risks of resistance development under different dosing strategies.In the second paper, the model for PAEs is further developed to determine the implications for different dosing regimens. The result challenges the conventional notion that long PAEs promote extended drug dosing intervals and it allows new hypotheses to be tested experimentally based on the findings from the theoretical framework.Since PAE experiments often are time-consuming and laborious, very few studies have been reporting variation for this phenomenon. In the third paper, an extension to capture the stochastic behavior of bacterial population growth under drug exposure is made. The stochastic nature of the model is also an important complement to the existing deterministic models on drug dose drug effect relationships.The last paper describes a controlled clinical intervention study aiming at determining whether the frequency of trimethoprim resistance in E. coli can be decreased by a sudden and drastic reduction in trimethoprim use. In addition to evaluating the intervention effect, the model, given estimated parameters, is also used for predicting other interesting outcomes.
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| 2. |
- Garbom, Sara, 1975-
(författare)
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A strategy to identify novel antimicrobial compounds : a bioinformatics and HTS approach
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacterial infections are again becoming difficult to treat because the microbes are growing increasingly resistant to the antibiotics in use today. The need for novel antimicrobial compounds is urgent and to achieve this new targets are crucial. In this thesis we present a strategy for identification of such targets via a bioinformatics approach. In our first study we compared proteins with unknown and hypothetical function of the spirochete Treponema pallidum to five other pathogens also causing chronic or persistent infections in humans (Yersinia pestis, Neisseria gonorrhoeae, Helicobacter pylori, Borrelia burgdorferi and Streptococcus pneumoniae). T. pallidum was used as a starting point for the comparisons since this organism has a condensed genome (1.1 Mb). As we aimed at identifying conserved proteins important for in vivo survival or virulence of the pathogens we reasoned that T. pallidum would have deleted genes not important in the human host. This comparison yielded 17 ORFs conserved in all six pathogens, these were deleted in our model organism, Yersinia pseudotuberculosis, and the virulence of these mutant strains was evaluated in a mouse model of infection. Five genes were found to be essential for virulence and thus constitute possible antimicrobial drug targets.We have studied one of these virulence associated genes (vags), vagH, in more detail. Functional and phenotypic analysis revealed that VagH is an S-adenosyl-methionine dependent methyltransferase targeting Release factor 1 and 2 (RF1 and RF2). The analysis also showed that very few genes and proteins were differentially expressed in the vagH mutant compared to wild-type Yersinia. One major finding was that expression of the Type III secretion system effectors, the Yops, were down regulated in a vagH mutant. We dissected this phenotype further and found that the down regulation was due to lowered amounts of the positive regulator LcrF. This can be suppressed either by a deletion of yopD or by over expression of the Ribosomal Recycling Factor (RRF). These results indicate that YopD in addition to its role in translational regulation of the Yops also plays a part in the regulation of LcrF translation. We suggest also that the translation of LcrF is particularly sensitive to the amount of translation competent ribosomes and that one effect of a vagH mutation in Y. pseudotuberculosis is that the number of free ribosomes is reduced; this in turn reduces the amount of LcrF produced thereby causing a down regulation of the T3SS. This down regulation is likely the cause of the attenuated virulence of the vagH mutant.Finally, we set up a high throughput screening assay to screen a library of small molecules for compounds with inhibiting the VagH methyltransferase activity. Five such compounds were identified and two were found to inhibit VagH also in bacterial culture. Furthermore, analogues to one of the compounds showed improved inhibitory properties and inhibited the T3SS-dependent cytotoxic response induced by Y. pseudotuberculosis on HeLa cells.We have successfully identified five novel targets for antimicrobial compounds and in addition we have discovered a new class of molecules with antimicrobial properties.
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| 3. |
- Brabie, Dan, 1975-
(författare)
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On Derailment-Worthiness in Rail Vehicle Design : Analysis of vehicle features influencing derailment processes and consequences
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aims at systematically studying the possibilities of minimizing devastating consequences of high-speed rail vehicle derailments by appropriate measures and features in the train design including the running gear. Firstly, an empirical database is established containing as much relevant information as possible of past incidents and accidents that have occurred at substantial running speeds due to mechanical failure close to the interface between the running gear and the track. Other causes that ultimately brought the train in a derailed condition are also covered. Although various accidental circumstances make each derailment a unique event, certain patterns appear to emerge which lead to several critical vehicle parameters capable of influencing the outcome of a derailment or preventing a derailment to occur. Secondly, the possibility of preventing wheel climbing derailments after an axle journal failure is studied by implementing mechanical restrictions between wheelsets and bogie frame. In this respect, a multi body system (MBS) computer model is developed to account for such an axle failure condition, which is successfully validated on the basis of two authentic passenger car events. In order to study the overall post-derailment vehicle behaviour, in particular the wheelsets’ vertical motion and lateral deviation on sleepers, a comprehensive MBS post-derailment module is developed and implemented in the commercially available software GENSYS. The model detects wheel-sleeper impact conditions and applies valid force resultants calculated through linear interpolation based on a pre-defined look-up table. The table was constructed through exhaustive finite element (FE) wheel to concrete sleeper impact simulations utilising the commercially available software LS-DYNA. The MBS post-derailment module has been validated successfully in several stages, including a correct prediction of the derailing wheelset’s trajectory over ten consecutive sleepers in comparison with an authentic passenger vehicle derailment event. An extensive simulation analysis on the feasibility of utilizing alternative substitute guidance mechanisms attached to the running gear on rail vehicles is presented, as means of minimizing the lateral deviation. Three low-reaching guidance mechanisms attached onto the running gear (bogie frame, brake disc and axle journal box) are analysed in terms of geometrical parameters for a successful engagement with the rail in order to prevent large lateral deviations after twelve different derailment scenarios. Three conventional coupled passenger trailing cars are investigated in terms of lateral deviation and vehicle overturning tendency after derailments on tangent and curved track. This is performed as a function of various vehicle design features and parameters such as: maximum centre coupler yaw angle, carbody height of centre of gravity, coupler height and additional running gear features. In a similar manner, the articulated train concept is investigated in terms of the post-derailment vehicle behaviour as a function of different inter-carbody damper characteristics and running gear features.
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| 4. |
- Nordigården, Daniel, 1978-
(författare)
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Outsourcing in the Wood Product Manufacturing Sector A Combined Customer and Supplier Perspective
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Outsourcing can be defined as transferring an activity from internal to external control. This thesis studies outsourcing in the wood product manufacturing (WPM) sector from both a customer and supplier perspective. The research design is a multiple case study approach, and it is based on six Scandinavian companies in the door, floor and window industries and one larger supplier of raw material. This study provides an understanding of driving forces for outsourcing in a different context than previously studied and has identified cost reduction in combination with reallocating resources from non-core activities as main driving forces. Compared to several other industrial sectors, outsourcing strategies for the WPM firms have little to do with accessing external sources’ capabilities.In the literature, there is often a main focus on the strategic level of outsourcing, however, such heavy resource-based focus in terms of a core competence approach in the formulation of outsourcing strategies at the customer side risks forgetting that components can still be vulnerable to supplier failure. Here, more focus needs to be put on the operational level when considering outsourcing. This thesis illustrates customers considering outsourcing where there are not any given outsourcing supplier partners developed. At the same time, for the supplier side, forward integration and specialising by taking over outsourcing is complicated by an initial divergent production flow of sawn timber. When not all contexts have developed supplier markets for directly managing outsourcing, it should not be assumed that general outsourcing models are directly applicable. In general, the question of whether or not to outsource seems too complex to simply be considered as either “in or out”. A company needs safeguards when conducting outsourcing and in a situation where there is a non-developed supplier market, parallel in-house production becomes an alternative.
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| 5. |
- Olofsson, Sara K., 1977-
(författare)
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Relation Between Drug Exposure and Selection of Antibiotic Resistant Bacteria
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The worldwide increase in antibiotic resistance is a concern for public health. When the appropriate antibiotic dosage is determined, the priorities are efficacy and toxicity. The aim of this thesis was to gain knowledge about the most efficient dosing regimens in order to minimize the emergence and selection of antibiotic-resistant mutants. We also wanted to assess the impact of antibiotic selective pressure and host to host transmission for the dissemination of resistance. Escherichia coli bacteria with different levels of cefotaxime susceptibility were competed in an in vitro kinetic model, demonstrating a complex selection of low-level resistance influenced e.g. by the time duration of selective concentrations and the rise of new mutants. We also constructed a mathematical model incorporating biologically relevant parameters and showed its usefulness when assessing the risks of resistance development. When E. coli populations with pre-existing fluoroquinolone-resistant mutants were exposed to simulated serum concentrations, several currently used doses of fluoroquinolones clearly enhanced the development and selection of resistance. The mutant prevention concentration (MPC) was measured for several E. coli isolates with different fluoroquinolone susceptibilities, and because of fluctuating antibiotic concentrations in the human body, the pharmacokinetics was considered when evaluating MPC. Results indicate that the area under the serum concentration time curve in relation to the MPC may be a useful predictor for emergence of resistance. In the commensal flora of healthy human couples we noted a high frequency of trimethoprim-resistant E. coli. There was also an extensive sharing and transmission of E. coli clones. Treating the female with trimethoprim reduced the number of intestinal E. coli which might have facilitated the transmission from the male partner. These findings suggest that the rate of transmission is high and effectively contributes to the spread of both susceptible and antibiotic-resistant E. coli in intrafamilial settings.
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