Magnetic Resonance Imaging of Atherosclerotic Manifestations in Familial Hypercholesterolemia

Cardiovascular diseases (CVD) are, in developed countries, the leading cause of mortality. The majority of premature deaths and disability caused by CVD are due to atherosclerosis, a degenerating inflammatory disease affecting arterial walls. Early identification of lesions and initiation of treatment is crucial because the first manifestations quite often are major disabling cardiovascular events. Methods of finding individuals at high risk for these events are under development. Because magnetic resonance imaging (MRI) is an excellent non-invasive tool to study the structure and function of vascular system, we sought to discover whether existing MRI methods are able to show any difference in aortic and intracranial atherosclerotic lesions between patients at high risk for atherosclerosis and healthy controls. Our younger group (age 6-48) comprised 39 symptomless familial hypercholesterolemia (FH) patients and 25 healthy controls. Our older group (age 48-64) comprised 19 FH patients and 18 type 2 diabetes mellitus (DM) patients with coronary heart disease (CHD) and 29 healthy controls. Intracranial and aortic MRI was compared with carotid and femoral ultrasound (US). In neither age-group did MRI reveal any difference in the number of ischemic brain lesions or white matter hyperintensities (WMHIs) - possible signs of intracranial atherosclerosis - between patients and controls. Furthermore, MRI showed no difference in the structure or function of the aorta between FH patients and controls in either group. DM patients had lower compliance of the aorta than did controls, while no difference appeared between DM and FH patients. However, ultrasound showed greater plaque burden and increased thickness of carotid arterial walls in FH and DM patients in both age-groups, suggesting a more advanced atherosclerosis. The mortality of FH patients has decreased substantially after the late 1980´s when statin treatment became available. With statins, the progression of atherosclerotic lesions slows. We think that this, in concert with improvements in treatment of other risk factors, is one reason for the lack of differences between FH patients and controls in MRI measurements of the aorta and brain despite the more advanced disease of the carotid arteries assessed with US. Furthermore, whereas atherosclerotic lesions between different vascular territories correlate, differences might still exist in the extent and location of these lesions among different diseases. Small (<5 mm in diameter) WMHIs are more likely a phenomenon related to aging, but the larger ones may be the ones related to CVD and may be intermediate surrogates of stroke. The image quality in aortic imaging, although constantly improving, is not yet optimal and thus is a source of bias.

Proton magnetic resonance spectroscopy of a boron neutron capture therapy 10B-carrier, L-p-boronophenylalanine-fructose complex

Boron neutron capture therapy (BNCT) is a radiotherapy that has mainly been used to treat malignant brain tumours, melanomas, and head and neck cancer. In BNCT, the patient receives an intravenous infusion of a 10B-carrier, which accumulates in the tumour area. The tumour is irradiated with epithermal or thermal neutrons, which result in a boron neutron capture reaction that generates heavy particles to damage tumour cells. In Finland, boronophenylalanine fructose (BPA-F) is used as the 10B-carrier. Currently, the drifting of boron from blood to tumour as well as the spatial and temporal accumulation of boron in the brain, are not precisely known. Proton magnetic resonance spectroscopy (1H MRS) could be used for selective BPA-F detection and quantification as aromatic protons of BPA resonate in the spectrum region, which is clear of brain metabolite signals. This study, which included both phantom and in vivo studies, examined the validity of 1H MRS as a tool for BPA detection. In the phantom study, BPA quantification was studied at 1.5 and 3.0 T with single voxel 1H MRS, and at 1.5 T with magnetic resonance imaging (MRSI). The detection limit of BPA was determined in phantom conditions at 1.5 T and 3.0 T using single voxel 1H MRS, and at 1.5 T using MRSI. In phantom conditions, BPA quantification accuracy of ± 5% and ± 15% were achieved with single voxel MRS using external or internal (internal water signal) concentration references, respectively. For MRSI, a quantification accuracy of <5% was obtained using an internal concentration reference (creatine). The detection limits of BPA in phantom conditions for the PRESS sequence were 0.7 (3.0 T) and 1.4 mM (1.5 T) mM with 20 × 20 × 20 mm3 single voxel MRS, and 1.0 mM with acquisition-weighted MRSI (nominal voxel volume 10(RL) × 10(AP) × 7.5(SI) mm3), respectively. In the in vivo study, an MRSI or single voxel MRS or both was performed for ten patients (patients 1-10) on the day of BNCT. Three patients had glioblastoma multiforme (GBM), and five patients had a recurrent or progressing GBM or anaplastic astrocytoma gradus III, and two patients had head and neck cancer. For nine patients (patients 1-9), MRS/MRSI was performed 70-140 min after the second irradiation field, and for one patient (patient 10), the MRSI study began 11 min before the end of the BPA-F infusion and ended 6 min after the end of the infusion. In comparison, single voxel MRS was performed before BNCT, for two patients (patients 3 and 9), and for one patient (patient 9), MRSI was performed one month after treatment. For one patient (patient 10), MRSI was performed four days before infusion. Signals from the tumour spectrum aromatic region were detected on the day of BNCT in three patients, indicating that in favourable cases, it is possible to detect BPA in vivo in the patient’s brain after BNCT treatment or at the end of BPA-F infusion. However, because the shape and position of the detected signals did not exactly match the BPA spectrum detected in the in vitro conditions, assignment of BPA is difficult. The opportunity to perform MRS immediately after the end of BPA-F infusion for more patients is necessary to evaluate the suitability of 1H MRS for BPA detection or quantification for treatment planning purposes. However, it could be possible to use MRSI as criteria in selecting patients for BNCT.

Hybrid Modelling of Titan's Interaction with the Magnetosphere of Saturn

In this dissertation we study the interaction between Saturn's moon Titan and the magnetospheric plasma and magnetic field. The method of research is a three-dimensional computer simulation model, that is used to simulate this interaction. The simulation model used is a hybrid model. Hybrid models enable individual tracking or tracing of ions and also take into account the particle motion in the propagation of the electromagnetic fields. The hybrid model has been developed at the Finnish Meteorological Institute. This thesis gives a general description of the effects that the solar wind has on Earth and other planets of our solar system. Planetary satellites can also have similar interactions with the solar wind but also with the plasma flows of planetary magnetospheres. Titan is clearly the largest among the satellites of Saturn and also the only known satellite with a dense atmosphere. It is the atmosphere that makes Titan's plasma interaction with the magnetosphere of Saturn so unique. Nevertheless, comparisons with the plasma interactions of other solar system bodies are valuable. Detecting charged plasma particles requires in situ measurements obtainable through scientific spacecraft. The Cassini mission has been one of the most remarkable international efforts in space science. Since 2004 the measurements and images obtained from instruments onboard the Cassini spacecraft have increased the scientific knowledge of Saturn as well as its satellites and magnetosphere in a way no one was probably able to predict. The current level of science on Titan is practically unthinkable without the Cassini mission. Many of the observations by Cassini instrument teams have influenced this research both the direct measurements of Titan as well as observations of its plasma environment. The theoretical principles of the hybrid modelling approach are presented in connection to the broader context of plasma simulations. The developed hybrid model is described in detail: e.g. the way the equations of the hybrid model are solved is shown explicitly. Several simulation techniques, such as the grid structure and various boundary conditions, are discussed in detail as well. The testing and monitoring of simulation runs is presented as an essential routine when running sophisticated and complex models. Several significant improvements of the model, that are in preparation, are also discussed. A main part of this dissertation are four scientific articles based on the results of the Titan model. The Titan model developed during the course of the Ph.D. research has been shown to be an important tool to understand Titan's plasma interaction. One reason for this is that the structures of the magnetic field around Titan are very much three-dimensional. The simulation results give a general picture of the magnetic fields in the vicinity of Titan. The magnetic fine structure of Titan's wake as seen in the simulations seems connected to Alfvén waves an important wave mode in space plasmas. The particle escape from Titan is also a major part of these studies. Our simulations show a bending or turning of Titan's ionotail that we have shown to be a direct result of the basic principles in plasma physics. Furthermore, the ion flux from the magnetosphere of Saturn into Titan's upper atmosphere has been studied. The modelled ion flux has asymmetries that would likely have a large impact in the heating in different parts of Titan's upper atmosphere.

Inhomogeneity of asteroid 2008 TC3 (Almahata Sitta meteorites) revealed through magnetic susceptibility measurements

Magnetic susceptibility measurements were performed on freshly fallen Almahata Sitta meteorites. Most recovered samples are polymict ureilites. Those found in the first four months since impact, before the meteorites were exposed to rain, have a magnetic susceptibility in the narrow range of 4.92 ± 0.08 log 10-9 Am2/kg close to the range of other ureilite falls 4.95 ± 0.14 log 10-9 Am2/kg reported by Rochette et al. (2009). The Almahata Sitta samples collected one year after the fall have similar values (4.90 ± 0.06 log 10-9 Am2/kg), revealing that the effect of one-year of terrestrial weathering was not severe yet. However, our reported values are higher than derived from polymict (brecciated) ureilites 4.38 ± 0.47 log 10-9 Am2/kg (Rochette et al. 2009) containing both falls and finds confirming that these are significantly weathered. Additionally other fresh-looking meteorites of non-ureilitic compositions were collected in the Almahata Sitta strewn field. Magnetic susceptibility measurements proved to be a convenient non-destructive method for identifying non-ureilitic meteorites among those collected in the Almahata Sitta strewn field, even among fully crusted. Three such meteorites, no. 16, 25, and 41, were analyzed and their composition determined as EH6, H5 and EL6 respectively (Zolensky et al., 2010). A high scatter of magnetic susceptibility values among small (< 5 g) samples revealed high inhomogeneity within the 2008 TC3 material at scales below 1-2 cm.

Optimization of sample preparation for next-generation sequencing with Illumina Genome Analyzer II

The growing interest for sequencing with higher throughput in the last decade has led to the development of new sequencing applications. This thesis concentrates on optimizing DNA library preparation for Illumina Genome Analyzer II sequencer. The library preparation steps that were optimized include fragmentation, PCR purification and quantification. DNA fragmentation was performed with focused sonication in different concentrations and durations. Two column based PCR purification method, gel matrix method and magnetic bead based method were compared. Quantitative PCR and gel electrophoresis in a chip were compared for DNA quantification. The magnetic bead purification was found to be the most efficient and flexible purification method. The fragmentation protocol was changed to produce longer fragments to be compatible with longer sequencing reads. Quantitative PCR correlates better with the cluster number and should thus be considered to be the default quantification method for sequencing. As a result of this study more data have been acquired from sequencing with lower costs and troubleshooting has become easier as qualification steps have been added to the protocol. New sequencing instruments and applications will create a demand for further optimizations in future.

Magnetic resonance imaging and ultrasonography in brachial plexus birth injury

Brachial plexus birth injury (BPBI) is caused by stretching, tearing or avulsion of the C5-C8 or Th1 nerve roots during delivery. Foetal-maternal disproportion is the main reason for BPBI. The goal of this study was to find out the incidence of posterior subluxation of the humeral head during first year of life in BPBI and optimal timing of the ultrasonographic screening of the glenohumeral joint. The glenohumeral congruity and posterior subluxation of the humeral head associated to muscle atrophy were assessed and surgical treatment of the shoulder girdle as well as muscle changes in elbow flexion contracture were evaluated. The prospective, population based part of the study included all neonates born in Helsinki area during years 2003-2006. Patients with BPBI sent to the Hospital for Children and Adolescents because of decreased external rotation, internal rotation contracture or deformation of the glenohumeral joint as well as patients with elbow flexion contracture were also included in this prospective study. The incidence of BPBI was calculated to be 3.1/1000 newborns in Helsinki area. About 80% of the patients with BPBI recover totally during the follow-up within the first year of life. Permanent plexus injury at the age of one year was noted in 20% of the patients (0.64/1000 newborns). Muscle imbalance resulted in sonographically detected posterior subluxation in one third of the patients with permanent BPBI. If muscle imbalance and posterior subluxation are left untreated bony deformities will develop. All patients with internal rotation contracture of the glenohumeral joint presented muscle atrophy of the rotator cuff muscles. Especially subscapular and infraspinous muscles were affected. A correlation was found particularly between greatest thickness of subscapular muscle and subluxation of the humeral head, degree of glenoid retroversion, as well as amount of internal rotation contracture. Supinator muscle atrophy was evident among all the studied patients with elbow flexion contracture. Brachial muscle pathology seemed to be an important factor for elbow flexion contracture in BPBI. Residual dysfunction of the upper extremity may require operative treatment such as tendon lengthening, tendon transfers, relocation of the humeral head or osteotomy of the humerus. Relocation of the humeral head improved the glenohumeral congruency among patients under 5 years of age. Functional improvement without remodeling of the glenohumeral joint was achieved by other reconstructive procedures. In conclusion: Shoulder screening by US should be done to all patients with permanent BPBI at the age of 3 and 6 months. Especially atrophy of the subscapular muscle correlates with glenohumeral deformity and posterior subluxation of the humeral head, which has not been reported in previous studies. Permanent muscle changes are the main reason for diminished range of motion of the elbow and forearm. Relocation of the humeral head, when needed, should be performed under the age of 5 years.