Coming theses from other universities
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Beating of hammers
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-526438
I've been investigating the connection between migraine and depression—two debilitating disorders with high comorbidity. My overarching goal is to unravel their pathophysiology and pinpoint associated risk factors to pave the way for more effective therapeutic interventions. The fruits of my labor is discussed in the introductory part of the thesis and comprises four first-author publications in international peer-reviewed journals.
In the first two projects, I worked mostly on the comorbid aspects of migraine and depression. I conducted a meta-analysis on the efficacy of onabotulinumtoxinA injections as a treatment for those grappling with both migraine and depression. The findings were promising, showing not only the treatment's safety and effectiveness but also hinting at a shared pathophysiology between the two conditions. The second project delved into the structural brain anatomy, utilizing voxel-based magnetic resonance imaging measures to explore subcortical volumes in migraine and depression patients. The distinct patterns observed suggest a nuanced relationship at the subcortical level.
Expanding beyond comorbidity, my research ventured into the occupational determinants of migraine, scrutinizing the impact of job-related factors on migraine prevalence. Leveraging data from the UK Biobank, the third project identified strong associations between migraine and specific job categories, setting the stage for future interventions and policies to enhance workers' well-being. Additionally, my exploration into the role of the cerebellum and brainstem in migraine pathophysiology, using the UK Biobank data, unveiled larger gray matter volumes in multiple cerebellar regions in individuals with migraines. This sheds light on potential mechanisms underlying migraine attacks, contributing significantly to our understanding and potential treatments for these challenging disorders.
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Cerebral hemodynamics in stroke, cerebral small vessel disease and pharmacological interventions : a 4D flow MRI study
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-223865
Background and aim: Current cerebrovascular imaging techniques provide important information on arterial anatomy and structural pathologies, such as stenoses and occlusions, but physicians are left to infer how the blood flow is affected. In addition, the relationship between blood pressure and cerebral blood flow is complex and poorly understood. Increased transmission of cardiac pulsatility to the cerebral microvasculature has been suggested as a causative factor of cerebral small vessel disease (CSVD) but previous research have yielded conflicting results regarding this relationship. 4D flow magnetic resonance imaging (MRI) is a novel and promising technique enabling time-resolved blood flow quantification with whole-brain coverage and relatively short scan times. However, despite its obvious potential, there is not yet an evidence-based application for the use of 4D flow MRI within stroke or CSVD. This dissertation aimed to apply 4D flow MRI to describe blood flow patterns in posterior circulation stroke and cerebral blood flow responses to common pharmacological agents used to alter arterial blood pressure as well as to examine the relationship between cerebral arterial pulsatility and CSVD.
Methods and Results: This doctoral dissertation consisted of four papers, referred to by roman numerals. 4D flow MRI and computed tomography angiography (CTA) were applied in 25 patients with acute ischemic stroke in the posterior circulation and a reference population of 15 healthy elderly (paper I). Individual flow profiles were created for each stroke patient and hemodynamic disturbances as well as collateral compensation were described. We show that hemodynamic findings were related to structural findings from CTA.
The cross-sectional relationship between cerebral arterial pulsatility (quantified using 4D flow MRI as pulsatility index [PI] and flow volume pulsatility [FVP]) and features of CSVD were examined using regression analysis in 89 patients with acute ischemic stroke (paper II) and a population-based sample of 862 elderly (paper III). Internal carotid artery FVP was associated with increasing white matter hyperintensity (WMH) volume in patients with stroke and TIA (paper II). In addition, increasing middle cerebral artery FVP and PI were associated with worse cognitive function. In the population sample, high FVP and PI were associated with increasing WMH volume, lower brain volume and the presence of lacunes, but not the composite MRI-CSVD (paper III). Among subjects with MRI-CSVD, displaying symptoms consistent with cerebral small vessel disease was associated with higher WMH volume, lower brain volume and active smoking, but not any measure of pulsatility.
Eighteen healthy volunteers were administered noradrenaline to increase mean arterial pressure by 20% above baseline, and labetalol to decrease mean arterial pressure to 15% below baseline (paper IV). Cerebral blood flow was measured using phase-contrast MRI at each blood pressure level and compared to baseline. Despite a marked increase in blood pressure, noradrenaline administration caused a reduction in cerebral blood flow and cardiac output. Meanwhile, labetalol administration caused no change in cerebral blood flow but an increased cardiac output.
Conclusions: 4D flow MRI can detect hemodynamic disturbances and discriminate between hemodynamic disturbances and normal flow in patients with structural vascular pathologies. This additional information compared to structural imaging alone could potentially be used for prognosis and selection for procedures in clinical care. Cerebral arterial pulsatility is modestly associated with several MRI and clinical features of CSVD but not all. Cerebral arterial pulsatility as the main risk factor of CSVD seems unlikely but its involvement in the pathophysiology cannot be ruled out. Raising the blood pressure with noradrenaline decreases cerebral blood flow and cardiac output without any redistribution from peripheral to cerebral flow. This highlights the pitfalls of using blood pressure as a surrogate for cerebral blood flow and questions the validity of our understanding of cerebral autoregulation. Lowering the blood pressure with labetalol does not affect cerebral blood flow, reassuring its use in clinical routine. 4D flow MRI can be integrated into an in-patient work-up in selected cases of acute ischemic stroke and into the workflow of large epidemiological studies.
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Design and synthesis of enzyme inhibitors against Gram-negative bacteria : Targeting protein secretion and lipid A biosynthesis
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524499
The discovery and implementation of antibiotics for clinical use was unquestionably the greatest medical breakthrough of the 20th century. However, the widespread misuse and overuse of these antibiotics, has led to the rapid emergence and spread of antibiotic resistance. The 'ESKAPE' pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) represent a critical threat in multidrug-resistant infections. The Gram-negative species (such as E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii) are especially difficult to combat due to their dual-membrane and efficient efflux pumps, which limit the efficacy of many antibiotics. Despite significant efforts, no new antibiotic class with a new mechanism of action has been approved for Gram-negative pathogens in over five decades. New chemical classes of antibacterial compounds targeting distinct mechanisms within Gram-negative bacteria are therefore urgently called for. The studies outlined in this thesis addresses these challenges by designing and synthesising new antibacterial compounds of three distinct chemical classes, which interact with two unrealized targets, LepB and LpxH, in Gram-negative bacteria, including E. coli and K. pneumoniae. This thesis investigates the effect of macrocyclization of type I signal peptidase (LepB) inhibitors by optimizing previously studied linear lipopeptide boronic acids and esters to address their cytotoxic and hemolytic liabilities while retaining activity. This resulted in the synthesis of first-in-class P2-P1' boronic ester-linked macrocycles with modest improvement of cytotoxicity but at the cost of reduced antibacterial activity (paper I). In another optimization attempt, isosteric modification of LepB inhibitors was explored by introducing the sulfonimidamide motif into oligopeptide boronic esters, displaying potent LepB inhibitors. Prior to the synthesis of these pseudopeptides novel methods were developed to introduce sulfonimidamides into peptides on solid-phase (paper II and paper III). These studies demonstrated the potential of sulfonimidamides to alter the drug properties and which was herein compared to a corresponding sulfonamide. Additionally, the thesis describes how a new series of LpxH inhibitors, meta-sulfonamidobenzamide-based sulfonyl piperazine derivatives, were identified and prepared. This resulted in inhibitors with wild-type activity without causing hemolysis, cell toxicity or inhibition of hERG ion channel (paper IV). In summary, strategies suitable for the synthesis and optimization of new antibacterial compounds targeting two distinct Gram-negative bacterial targets, LepB and LpxH, are described in this thesis. While there was no success in separating toxicity from antibacterial activity of the LepB inhibitors, these results highlight the challenge in this task and contribute to a better understanding of the structure-activity and toxicity relationships of such inhibitors and provide strategies that could be of use in antibacterial drug discovery. The identification of the meta-sulfonamidobenzamide derivatives offer promising LpxH-targeting hits with the potential for further development in future hit-to-lead antibacterial programs.