Severe anemia is the most prevalent life-threatening complication of malaria infection. In addition to destruction of red blood cells (RBC), decreased RBC production or erythropoietic suppression has been shown to contribute to malarial anemia. The mechanism of this suppression is unknown, but it is considered to be multifactorial since erythropoietic suppression can be observed in the presence of both inflammatory mediators and parasite-derived factors. Experiments presented in this thesis aimed at determining the role of host cytokines released in response to blood-stage malaria infection and parasite-derived factors in erythropoietic suppression underlying the development of malarial anemia. Pro-inflammatory cytokines released during malaria infection have been proposed to play a central role in erythroid suppression. To dissect the discrete roles of these cytokines in the processes leading to anemia, mice were treated with CpG-oligodeoxynucleotides (CpG-ODN) which, like malaria infection in humans and experimental mouse models, induces an acute type 1 pro-inflammatory response. CpG-ODN treatment induced anemia, which was associated with suppressed erythropoiesis and reduced RBC survival. Importantly, CpG-ODN-induced IFN-gamma was found to be the major factor mediating erythropoietic suppression but not decreased RBC survival. We also studied the roles of Th1, Th2 and anti-inflammatory cytokines produced in response to Plasmodium chabaudi AS infection in the development of erythropoietic suppression during blood-stage malaria. Signal transducer and activator of transcription (STAT)6, required for signaling of the Th2 cytokines IL-4 and IL-13, was shown to play a critical role in malarial anemia by inhibiting the proliferation and differentiation of erythroid cells. We also observed that suppressed erythropoiesis is a general feature in mice infected with various rodent Plasmodium species that differ in their clinical manifestations and immune responses. Since parasite-derived factors have been shown to contribute to malarial pathogenesis including anemia, the contribution of P. falciparum - and P. yoelii-derived products to erythropoietic suppression was investigated. Both Plasmodium-derived and synthetic hemozoin (Hz) suppressed the proliferation but not the maturation of erythroid progenitor cells in vitro. However, P. yoelii-derived Hz but not synthetic Hz induced transient anemia in mice. These findings provide novel insights into the complex interactions between the parasite and host immune system and the regulation of erythropoiesis during severe malarial anemia.

The study of high power fusion plasmas at the JET tokamak has been further enhanced through the development of instrumentation for neutron emission spectroscopy (NES) measurements. This has involved the upgrade of the magnetic proton recoil (MPR) spectrometer used for deuterium-tritium plasmas earlier so that the MPRu can now be also employed for deuterium (D) plasmas. A neutron time-of-flight (TOF) spectrometer designed for optimized rate (TOFOR) has been constructed and put into operation. The MPRu and TOFOR spectrometers were carried out as part of the JET enhanced performance program and represent the most advanced instrumentation for NES diagnosis of both D and DT tokamak plasmas setting a central platform for R&D direct to the next step in fusion research to be carried out with ITER. The MPRu work presented in this thesis concerns the development of a new focal plane detector based on the phoswich scintillator technique. The main objective of this sub-project was to increase the signal-to-background ratio to permit measurement of the 2.5-MeV neutron emission from d+d-->3He+n reactions and, hence, allow NES diagnosis of D plasmas. The objective was achieved as demonstrated in preliminary measurements at JET. The development of TOFOR from concept to construction is presented in the thesis including, in particular, the commissioning of the instrument at JET. The objective of the TOFOR project was to achieve the same high performance in the NES diagnosis of D plasmas as had earlier been demonstrated by the MPR for DT plasmas. TOFOR has been used in the first plasma physics experiments reported in this thesis. These demonstrate that the performance objectives have been achieved as tested, in particular, in the observation of auxiliary heating effects on velocity distribution of the deuterium population.

The pharmaceutical industry now recognises the importance of the newly defined discipline of pharmacometrics. Pharmacometrics uses mathematical models to describe and then predict the performance of new drugs in clinical development. To ensure these models are useful, the clinical studies need to be designed such that the data generated allows the model predictions to be sufficiently accurate and precise. The capability of the available software to reliably estimate the model parameters must also be well understood.  This thesis investigated two important areas in pharmacometrics: optimal design and software estimation performance. The three optimal design papers progressed significant areas of optimal design research, especially relevant to phase II dose response designs. The use of exposure, rather than dose, was investigated within an optimal design framework. In addition to using both optimal design and clinical trial simulation, this work employed a wide range of metrics for assessing design performance, and was illustrative of how optimal designs for exposure response models may yield dose selections quite different to those based on standard dose response models. The investigation of the optimal designs for Poisson dose response models demonstrated a novel mathematical approach to the necessary matrix calculations for non-linear mixed effects models. Finally, the enormous potential of using optimal adaptive designs over fixed optimal designs was demonstrated. The results showed how the adaptive designs were robust to initial parameter misspecification, with the capability to "learn" the true dose response using the accruing subject data. The two estimation performance papers investigated the relative performance of a number of different algorithms and software programs for two complex pharmacometric models. In conclusion these papers, in combination, cover a wide spectrum of study designs for non-linear dose/exposure response models, covering: normal/non-normal data, fixed/mixed effect models, single/multiple design criteria metrics, optimal design/clinical trial simulation, and adaptive/fixed designs.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. institutet, 2006. / Härtill 5 uppsatser.