| 1. |
- Lendaro, Eva, 1989
(författare)
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On the use of Phantom Motor Execution for the treatment of Phantom Limb Pain
- 2020
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Phantom limb pain (PLP) is a common complaint among amputees and despite having been studied for centuries, it remains a mysterious object of debate among researcher. To date, a vast number of ways to treat PLP has been proposed in the literature, however none of them has proven to be universally effective, thus creating uncertainty on how to operate clinically. The uncertainty is largely attributable to the scarcity of well conducted randomized controlled trials (RCTs) to prove the efficacy of PLP treatments. Phantom Motor Execution (PME) -exertion of voluntary phantom limb movements – aims at restoring the control over the phantom limb and the exercise of such control has been hypothesized to reverse neural changes implicated in PLP. Preliminary evidence supporting this hypothesis has been provided by clinical investigations on upper limb amputees. The main purpose of this Licentiate thesis was to enable a RCT on the use of PME for the treatment of PLP in order to provide robust and unbiased evidence for clinical practice. However, the implementation and kick-off of this clinical investigation required to complete few preparatory steps. For example, most amputees and PLP patients have lower limb amputation, thus PME needed to be adapted and validated for this population. Further, the RCT protocol needed to be carefully planned and made openly accessible, as per guidelines for conducting and publishing clinical RCT. Finally, a secondary aim of this thesis emerged with the need of providing long term relief from PLP to patient. Preliminary evidence seemed to indicate that in order to maintain pain relief, periodic rehearsal of the phantom motor skills acquired through PME is necessary. This raised the question of whether it is beneficial and possible to translate the technology from clinic to home use, question that was explored employing both quantitative and qualitative methods from engineering, medical anthropology, and user interface design. The work conducted within this thesis resulted in the extension of PME to lower limb patients by proposal and validation of a new and more user-friendly recording configuration to record EMG signals. The use of PME was then shown to be efficacious in relieving PLP with a case study on a patient. The protocol for the RCT was then designed and published. These two first steps permitted the establishment of the RCT, which is currently ongoing and expected to close in March 2021. With regard to the secondary aim of this thesis, the work conducted enabled PME to be used by the patients in the comfort of their home, while it also allowed investigate the benefits and challenges generally faced (not only by PME) in the transition from the clinic to home and its effects on treatment adherence. The work conducted is presented in the three appended publications. Future work includes the presentation of the results of the RCT. Further, having a way to modulate PLP is an incredibly useful tool to study the neural basis of PLP. By capitalizing on this tool, we are currently conducting brain imaging studies using fMRI and electroencephalography that are the main focus of the work that lies ahead.
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| 2. |
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| 3. |
- Johansson, Annica, 1969
(författare)
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Susceptibility Genes in Alzheimer’s Disease: Associations and Mechanisms
- 2004
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the most common form of dementia, followed by frontotemporal dementia (FTD), in the elderly. It is a genetically heterogeneous disease characterized by progressive cognitive decline and memory impairment. In the rare early-onset familial form of the disease (FAD), causative mutations have been found in three different genes, the amyloid precursor protein (APP) gene and the presenilins 1 and 2 (PSEN-1 and -2). The predominant late-onset form of AD (LOAD) is a genetically complex disorder probably involving a combination of genetic factors together with environmental influences. To date, the only genetic risk factor identified for this complex form of AD is the APOE-ε4 allele. This only account for a fraction of all AD cases, thus several susceptibility genes remain to be found. The overall aim of this thesis is to study potential candidate genes for AD and FTD, and to see how variants of these genes influence quantitative traits related to AD pathology, both in cerebrospinal fluid (CSF), and in brain tissue. In the initial investigation, a polymorphism designated Ex6+7I/D in the cell division cycle (CDC2) gene was identified. Cdc2 is a protein kinase involved in cell cycle regulation and in neuronal differentiation. In AD brain, cdc2 is expressed in neurons and is involved in the abnormal phosphorylation of tau. The polymorphism was tested for association with LOAD. A significant association between the Ex6+7II genotype and AD was found, and also an increased frequency of the Ex6+7I allele in both AD and FTD. In the second paper, variants of CYP46A1, encoding cholesterol 24-hydroxylase (CYP46), were investigated for their association with AD. The polymorphisms were tested for association with quantitative traits related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42 amino-acid cleavage product of β-amyloid (β-amyloid1-42), and the tau protein. In stratified analyses, one of the polymorphisms (rs754203) significantly influenced both CSF β-amyloid1-42 and phospho-tau in elderly APOE-ε4 carriers. In the final paper, AD and FTD patients were genotyped for a polymorphism in the Saitohin (STH) gene, a previously described gene located in the intron of the human Tau gene. Numerous polymorphisms span the human tau gene and are in complete linkage disequilibrium with each other yielding two separate haplotypes, termed H1 and H2. The H1 haplotype has been associated with both AD and FTD, and our patients were also investigated for this haplotype. In all patients (AD and FTD) and controls, the STH polymorphism and the Tau haplotype were in complete disequilibrium. The Tau haplotype and STH were not associated with AD and FTD, neither did they influence CSF-levels of total-tau, phospho-tau and β-amyloid1-42, nor neuropathological scores of plaque and tangles in brain tissue.
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| 4. |
- Vumma, Ravi
(författare)
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Functional Characterization of Tyrosine Transporters in fibroblast from Healthy Controls and Schizophrenic Patients
- 2008
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cultured human fibroblasts offer an advantageous system to investigate the amino acid transport properties without confounding the affects of disease state and its treatment in many systemic psychiatric disorders. In previous studies, fibroblast cells have been used to investigate the tyrosine transport across plasma membranes in patients with schizophrenia and autism with out characterizing the particular amino acid transporters.The importance of the major tyrosine transporters (system-L and system-A) was investigated in this study. Systemic functional characterization of tyrosine transport in fibroblasts from healthy controls and patients with schizophrenia, with respect to the system-L isoforms (LAT1, LAT2, LAT3, and LAT4) was performed.Ten (n=10) fibroblast cell lines from healthy controls and ten (n=10) from patients with schizophrenia were included in this study. Transport and uptake of [14-C] L-tyrosine in fibroblasts was measured using the cluster tray method in the absence and presence of different specific inhibitors. The maximal transport capacity, Vmax and the affinity constant of the tyrosine-binding site, Km, of LAT1 isoform were determined.The results of this study showed that tyrosine transport in fibroblasts is facilitated mainly by the system-L and LAT1 isoform is involved in 90% of total tyrosine uptake. LAT2 isoform seems to be functionally weak in uptake of tyrosine, as not more than 3% could be contributed by it. LAT3 and LAT4 contributed around 7%. System-A (ATA2 isoform) contributed around 10%. Alanine consequently inhibited the tyrosine transport by up to 60%. Tyrosine uptake and kinetics did not differ between patients and controls at the LAT1 isoform. Moreover, the affinity of LAT1 isoform for tyrosine was higher when compared to system-L. LAT1 is also involved in around 51% of uptake of alanine.In conclusion, the present thesis, confirms the presence of system-L with its isoform LAT1 as a main transporter of tyrosine in human fibroblast cells. The competition between tyrosine and alanine to get transported is shown to probably exist mainly at LAT1 isoform. Aberrant tyrosine transport observed in previous studies in patients with schizophrenia is probably not linked to the LAT1 isoform. This study gave further importance and established fibroblast cells as a suitable experimental model for studying amino acid transport properties in humans.Key words: Fibroblasts, Tyrosine and alanine transport, System-L, LAT1, LAT2, LAT3, LAT4, Schizophrenia, Precursor of Dopamine.
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| 5. |
- Deyhle Jr, Richard
(författare)
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Cross-modal Imaging in Lung Research: From µCT dosimetry to synchrotron phase contrast microtomography biomechanical insights in preclinical lung injury models
- 2024
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung diseases continue to present a large burden to public health, especially in industrialized countries. For abetter understanding of the underlying patho-mechanisms in lung related diseases as well as for testing theefficacy of novel therapies, preclinical studies in animal models are indispensable. The significance of preclinical X-ray based micro-computed tomography (µCT) research lies in its ability to provide high-resolution, non-invasive lung imaging of small animals as the air inside the lung acts as a natural contrast and to image the lung parenchyma longitudinally to assess functional and morphological alterations and test efficacy of therapeutic interventions. This often requires requires imaging protocols that balance between sufficient image quality and clinically relevant radiation absorbed doses. A reproducible method for evaluation of absorbed radiation absorbed doses is desirable. Absorbed radiation absorbed doses were measured in a polymethyl methacrylate (PMMA) phantom using standard TLD and a novel type of OSLD made form household salt. Four imaging protocols from MILabs “xUHR-µCT” scanner were tested. A large discrepancy was observed from results compared to vendor-provided values. The results indicate a need for thorough empirical dose measurements prior to performing longitudinal studies. Four-dimensional imaging, allows for investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. It is of significant interest to have direct visualization and quantification of interstitial lung diseases at spatial resolutions beyond the capabilities of clinical and conventional absorption-based only CT. Thus far, the high intensity of synchrotron X-ray light sources offer a tool to investigate dynamic morphological and mechanistic features, enabling dynamic in-vivo microscopy. This investigation elucidates the direct effects of interventions targeting the pathophysiology of Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury (VILI) on the terminal airways and alveolar microstructure within intact lungs. In such conditions, the relationship between microscopic strain within the mechanics of the alveolar structure and the broader mechanical characteristics and viscoelastic properties of the lungs remains poorly understood. A time-resolved synchrotron phase-contrast micro-computed tomography imaging acquisition protocol based on the synchronization between the mechanical ventilation and the cardiac activity was used to resolve the lung parenchyma motion with an effective isotropic voxel size of 6 µm. Quantitative maps of microscopic local lung tissue strain within aerated lung alveolar tissue under protective mechanical ventilation in anesthetized rats were obtained. This approach was used to assess the effect of alterations in lung tissue biomechanics induced by lung injury at 7 days after single-dose, intratracheal bleomycin instillation in combination with short-term high-tidal volume (VT) mechanical ventilation. Overall, this work address the aspects of radiation exposure to in experimental imaging of small animals and lays a foundation for a more nuanced understanding of lung injury and mechanical ventilation. In the future, it may result in a more effective and less injurious respiratory support for patients with acute lung injury or chronic lung diseases.
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| 6. |
- Karamanis, Georgios
(författare)
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Gender dysphoria : Insights on etiology and outcomes
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gender Dysphoria (GD) is defined as significant distress or impairment caused by the discrepancy between an individual's experienced gender and the sex assigned at birth. This work explores the etiology and outcomes of GD through two studies. The first assesses its prevalence in different twin categories, and the second examines the incidence of idiopathic intracranial hypertension (IIH) in individuals undergoing gonadotropin-releasing hormone analogue (GnRHa) treatment for GD.The first study utilizes a population-based approach to analyze the prevalence of GD in twins, using data from a Swedish population-based cohort collected over a 16-year period. The objective is to assess the influence of genetic and environmental factors on the development of GD by comparing its prevalence in different-sex twins, same-sex twins, and non-twin siblings. The results indicate a higher prevalence of GD in different-sex twins and suggest a potential influence of intrauterine factors in the development of GD, necessitating further examination of current genetic and environmental theories.The second study focuses on evaluating the occurrence of IIH in individuals undergoing treatment with GnRHa for GD in Sweden between 2006 and 2016. The study did not observe any cases of IIH within the studied cohort. While better-powered studies are needed to clarify any potential association between GnRHa and IIH, the study results do not present substantial evidence to support this association.
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| 7. |
- Rigato, Cristina, 1989
(författare)
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Direct Drive Bone Conduction Stimulation: Experimental Studies on Functionality and Transmission with Focus on the Bone Conduction Implant
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sound is conducted to the inner ear in two ways: by air and by bone. Air conduction (AC) hearing consists of sound waves entering the ear canal and reaching the cochlea, the main hearing organ, via the middle ear. In bone conduction (BC) hearing, instead, the transmission is through soft tissues and bone. These two pathways coexist and complement each other, although innormal hearing subjects the AC part is prevalent over the BC part in most of the ordinary hearing situations.BC hearing can represent an effective way to rehabilitate hearing impaired patients who would not benet from conventional AC hearing aids. This is the case when the hearing impairment is located in the outer or middle ear, or if the patients have chronic infections or malformations preventing them from wearing earmolds. The key idea in bone conduction devices (BCDs) isto generate vibrations with a transducer and transmit them via the skull bone to the inner ear.At present, the most common BCD is probably the bone anchored hearing aid (BAHA), consisting of a single-unit device attached to a skin penetrating screw in the parietal bone. To overcome the issues related to the skin penetration, the development of BCDs is recently focusing on so-called active transcutaneous devices, whose main feature is to have the bone transducer implanted under intact skin.In this thesis, the novel active transcutaneous bone conduction implant (BCI), currently in advanced clinical trial phase, was compared to BAHAs in terms of audiological tests and perceived rehabilitation effect. The outcomes showed that the BCI can be a valid alternative to BAHAs for indicated patients. Preliminary investigations were also performed on how the transmission of vibrations is affected by different ways of attaching the transducer to the skull bone. It was found that the relation varies substantially with frequency, with a general trend of improved transmission when the contact area between transducer and bone is limited.Finally, a new verication method of the implant functionality was evaluated intra- and post- operatively. The method, consisting in the measurement of the sound pressure in the nostril, seems promising and the implant to bone transmission was found stable over time.
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| 8. |
- Wang, Chunliang, 1980-
(författare)
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Computer Assisted Coronary CT Angiography Analysis : Disease-centered Software Development
- 2009
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The substantial advances of coronary CTA have resulted in a boost of use of this new technique in the last several years, which brings a big challenge to radiologists by the increasing number of exams and the large amount of data for each patient. The main goal of this study was to develop a computer tool to facilitate coronary CTA analysis by combining knowledge of medicine and image processing.Firstly, a competing fuzzy connectedness tree algorithm was developed to segment the coronary arteries and extract centerlines for each branch. The new algorithm, which is an extension of the “virtual contrast injection” method, preserves the low density soft tissue around the coronary, which reduces the possibility of introducing false positive stenoses during segmentation.Secondly, this algorithm was implemented in open source software in which multiple visualization techniques were integrated into an intuitive user interface to facilitate user interaction and provide good over¬views of the processing results. Considerable efforts were put on optimizing the computa¬tional speed of the algorithm to meet the clinical requirements.Thirdly, an automatic seeding method, that can automatically remove rib cage and recognize the aortic root, was introduced into the interactive segmentation workflow to further minimize the requirement of user interactivity during post-processing. The automatic procedure is carried out right after the images are received, which saves users time after they open the data. Vessel enhance¬ment and quantitative 2D vessel contour analysis are also included in this new version of the software. In our preliminary experience, visually accurate segmentation results of major branches have been achieved in 74 cases (42 cases reported in paper II and 32 cases in paper III) using our software with limited user interaction. On 128 branches of 32 patients, the average overlap between the centerline created in our software and the manually created reference standard was 96.0%. The average distance between them was 0.38 mm, lower than the mean voxel size. The automatic procedure ran for 3-5 min as a single-thread application in the background. Interactive processing took 3 min in average with the latest version of software. In conclusion, the presented software provides fast and automatic coron¬ary artery segmentation and visualization. The accuracy of the centerline tracking was found to be acceptable when compared to manually created centerlines.
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| 9. |
- de Lazzari, Mattia, 1996
(författare)
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Practical Implementation of Quality Assurance Guidelines for Hyperthermia Therapy
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyperthermia therapy (HT) has been proven to be a potent enhancer of chemotherapy and radiotherapy in numerous clinical trials. The effectiveness of HT is strictly dependent on the administered thermal dose, which, in turn, is dependent on the quality of the therapeutic heat applied to the patient. Quality Assurance (QA) protocols in HT exist to ensure that heating devices can consistently deliver controlled, reproducible, and high-quality treatments. The physical characterization of HT devices requires specific procedures and instrumentation as well as adequate tissue-mimicking phantoms to perform QA experimental procedures. However, the implementation of QA guidelines is hampered due to the unavailability of suitable phantom materials and limited equipment for the QA experimental evaluation. This work addresses these gaps by (i) proposing the design of tissue-mimicking materials for routine use in HT QA procedures and (ii) demonstrating the practical implementation of the latest QA guidelines for both superficial and deep HT. A novel fat-mimicking material was developed to mimic superficial fatty tissue. This fat phantom is based on an ethylcellulose stabilized glycerol in oil emulsion and is intended to be used in superficial HT QA procedures. Measured dielectric and thermal properties were consistent with fatty tissue properties, with an acceptable variability in most of the frequency range used in HT. This fat-mimicking material was then used in the experimental implementation of HT guidelines. The physical characterization of a superficial HT device (Lucite Cone Applicator, LCA) was conducted by assessing the quality metrics defined in the HT guidelines, demonstrating acceptable performance. These findings were further validated through computational studies. For deep HT, a comparative study engaged six HT centers across Europe to assess the performance of commonly used deep regional heating devices. Preliminary results in experimental phantoms showed a good performance in terms of device heating capability and steerability. This study provided practical insights into implementing QA guidelines involving phantom properties, experimental setup, temperature acquisition, and time constraints. We are positive this research will benefit the routine implementation of deep HT guidelines in a clinical setting.
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| 10. |
- Ali, Muhaddisa Barat, 1986
(författare)
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Deep Learning Methods for Classification of Glioma and its Molecular Subtypes
- 2021
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diagnosis and timely treatment play an important role in preventing brain tumor growth. Clinicians are unable to reliably predict LGG molecular subtypes from magnetic resonance imaging (MRI) without taking biopsy. Accurate diagnosis prior to surgery would be important. Recently, non-invasive classification methods such as deep learning have shown promising outcome in prediction of glioma-subtypes based upon pre-operative brain scans. However, it needs large amount of annotated medical data on tumors. This thesis investigates methods on the problem of data scarcity, specifically for molecular LGG-subtypes. The focus of this thesis is on two challenges for improving the classification performance of gliomas and its molecular subtypes using MRIs; data augmentation and domain mapping to overcome the lack of data and using data with unavailable GT annotation to tackle the issue of tedious task of manually marking tumor boundaries. Data augmentation includes generating synthetic MR images to enlarge the training data using Generative Adversarial Networks (GANs). Another type of GAN, CycleGAN, is used to enlarge the data size by mapping data from different domains to a target domain. A multi-stream Convolutional Autoencoder (CAE) classifier is proposed with a 2-stage training strategy. To enable MRI data to be used without tumor annotation, ellipse bounding box is proposed that gives comparable classification performance. The thesis comprises of papers addressing the challenging problems of data scarcity and lacking of tumor annotation. These proposed methods can benefit the future research in bringing machine learning tools into clinical practice for non-invasive diagnostics that would assist surgeons and patients in the shared decision making process.
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