VictorJuiz/thesis huggingface dataset:
Coronary Artery Outcome in Kawasaki Disease: The Role of Matrix Metalloproteinase-9 and Therapeutic Modulation of Its Activity

Kawasaki disease (KD) is a multisystem vasculitis that results in localized coronary artery elastin breakdown and aneurysm formation. It is the leading cause of acquired heart disease of children in North America. Despite conventional treatment, a significant proportion of patients continue to develop coronary sequelae. The mechanisms of arterial aneurysm formation in KD are not known. Using a murine model of KD, Lactobacillus casei cell wall extract-induced coronary arteritis, the processes leading to coronary aneurysm formation were examined. Vessel damage occurred as a result of the increased enzymatic activity of the elastase, matrix metalloproteinase (MMP)-9. MMP-9 protein and activity levels were elevated in the heart post-disease induction. Expression and activity were specific for and localized to inflamed coronary arteries. The pro-inflammatory cytokine, tumour necrosis factor (TNF)-α, was required for increasing local MMP-9 expression. Importantly, MMP-9-deficient animals had a significantly reduced incidence of elastin breakdown. Furthermore, in a cohort of KD patients, serum MMP-9 did not correlate with coronary outcome, highlighting the importance of local expression of this elastase. Intravenous immunoglobulin (IVIG) and aspirin/salicylate are therapeutic agents in current use for the treatment of KD, though their exact mechanisms of action in KD are not known. The biologic effects of IVIG and salicylate on critical stages of disease development were examined. IVIG and salicylate had differential effects on TNF-α expression, with therapeutic concentrations of IVIG inhibiting, and salicylate inducing, TNF-α expression leading to an indirect modulation of MMP-9 expression. Interestingly, TNF-α expression and MMP-9 activity were both directly inhibited by the metal-chelating drug doxycycline. Treatment of affected mice with doxycycline significantly improved coronary outcome. Inhibiting both the inflammatory response as well as the downstream effects of inflammation were of therapeutic value in this model of KD. These results taken together demonstrate the importance of MMP-9 in the pathogenesis of coronary artery aneurysms in KD. Targeting MMP activity holds the promise of transforming KD from the leading cause of acquired heart disease to a self-limited febrile illness.

Keywords: vasculitis
matrix metalloproteinase
Kawasaki disease
tumour necrosis factor
Advisor: Yeung, Rae S. M.
Ito, Shinya
Application of Quantitative Structure-activity Relationships to Investigate Xenobiotic Cytotoxicity Mechanisms in Hepatocyte Systems

Hepatotoxicity is a serious adverse health effect caused by drugs and other chemical toxins generally detected in the later stages of drug development or in whole animal studies. Thus, development of screening approaches available for earlier identification of hepatotoxic molecules is necessary. A novel in vitro- in silico test system for the evaluation of the molecular mechanisms of xenobiotic toxicity in primary hepatocyte systems is presented here. It is well established that hepatocytes in vitro are most representative of hepatotoxicity in vivo, and are most useful for the determination of xenobiotic hepatotoxicity mechanisms at the molecular and cellular level. There is an on-going interest in Quantitative Structure-Activity Relationships (QSAR) in toxicology, as it can identify correlations between chemical structure and biological activity. QSAR can be used to evaluate the effects of metabolism and toxicity as many physicochemical descriptors reflect simple molecular properties that can provide insight into the physicochemical nature of the activity under consideration. QSARs were determined for hepatotoxicity of halobenzenes, p-benzoquinones, α,β-unsaturated carbonyl compounds and nitroaromatics towards isolated hepatocytes. A molecular link was established for their proposed toxicity pathways. For example oxidative activation was linked to EHOMO (energy of the highest occupied molecular orbital) values and hydrophobicity (log P) of the chemicals, while reductive activation was linked with ELUMO (energy of the lowest molecular orbital) values and log P. Such relationships may thus be useful for predicting toxicity of other chemicals of the same mechanism of toxicity. Due to the complexity involved in the phenomena of hepatotoxicity, unravelling of structure-hepatotoxicity relationships is a complicated task. A conceptual framework for QSAR modeling is proposed that involves recognition of molecular initiating events as potential endpoints to improve the prediction potential of QSAR models. Acute toxicity of reactive chemicals could be based on an initial reaction with biomolecules, thus the theory of covalent binding reactivity was used to test this concept. Reactivity assays with thiol and amine surrogate nucleophiles were used to determine susceptibility to toxicity. The derived QSAR expressions suggested that covalent binding reactivity is a good correlate to hepatotoxicity, however only if electrophilicity was the main mechanism of toxicity.

Keywords: xenobiotic metabolism
hepatotoxicity
QSAR
Advisor: O'Brien, Peter J.
The Metaphysics of Agency: Avicenna and his Legacy

This dissertation begins with the Islamic philosopher Avicenna, who transforms Aristotle’s conception of the efficient cause in the Metaphysics of his Shifā’. Its first goal is to examine the arguments which constitute Avicenna’s metaphysical account of agency. Its second goal is to examine Scholastic disputes about the causal powers of natural agents that arise in connection with his view. In its final chapter, it relates Medieval debates about efficient causality to Descartes’ account of the causal powers of bodies. One of the original features of Avicenna’s account of agency is his argument for the claim that the existence of contingent things requires an efficient cause. This aspect of his view was influential in the Latin West. Avicenna also holds that the cause of the existence of contingent things is an incorporeal principle, which he describes as an agent who “bestows forms”. I argue that Avicenna fails to resolve the tension between this claim and his commitment to an Aristotelian account of generation. This failure sets the stage for Avicenna’s role in Scholastic disputes about the causal powers of natural agents in cases of generation. Both Aquinas and Suarez attribute to Avicenna the view that generation requires the creation of form. They argue that generation occurs through natural processes. Suarez’s view includes the claim that the substantial form of a substance is an immediate efficient cause of its actions. Suarez defends this claim against other Aristotelians, who hold that a substantial form gives being to a composite substance as a formal cause and that the actions of substances depend directly on their accidents alone. Descartes claims in his letter to Regius of January 1642 that it is absurd to hold that substantial forms are immediate principles of action. He thinks that bodies act in virtue of their modes. Here Descartes sides with those Aristotelians who hold that the actions of substances depend directly on their accidents alone. I argue that this aspect of Descartes’ view tells against Daniel Garber’s claim that his denial of substantial forms deprives bodies of causal efficacy.

Keywords: causality
Avicenna
Advisor: Black, Deborah
Rozemond, Marleen
Intuition as Evidence in Philosophical Analysis: Taking Connectionism Seriously

1. Intuitions are often treated in philosophy as a basic evidential source to confirm/discredit a proposed definition or theory; e.g. intuitions about Gettier cases are taken to deny a justified-true-belief analysis of ‘knowledge’. Recently, Weinberg, Nichols & Stitch (WN&S) provided evidence that epistemic intuitions vary across persons and cultures. In-so-far as philosophy of this type (Standard Philosophical Methodology – SPM) is committed to provide conceptual analyses, the use of intuition is suspect – it does not exhibit the requisite normativity. I provide an analysis of intuition, with an emphasis on its neural – or connectionist – cognitive backbone; the analysis provides insight into its epistemic status and proper role within SPM. Intuition is initially characterized as the recognition of a pattern. 2. The metaphysics of ‘pattern’ is analyzed for the purpose of denying that traditional symbolic computation is capable of differentiating the patterns of interest. 3. The epistemology of ‘recognition’ is analyzed, again, to deny that traditional computation is capable of capturing human acts of recognition. 4. Fodor’s informational semantics, his Language of Thought and his Representational Theory of Mind are analyzed and his arguments denied. Again, the purpose is to deny traditional computational theories of mind. 5. Both intuition and a theory of concepts – pragmatic conceptualism - are developed within the connectionist computational paradigm. Intuition is a particular sort of occurrent signal, and a concept is a counterfactually defined set of signals. Standard connectionist theory is significantly extended to develop my position, and consciousness plays a key functional role. This extension – taking connectionism seriously – is argued to be justified on the basis of the failure of the traditional computing paradigm to account for human cognition. 6. Repercussions for the use of intuition in SPM are developed. Variance in intuition is characterized – and expected - as a kind of bias in the network, either inherent or externally-provoked. The WN&S data is explained in the context of this bias. If SPM remains committed to the use of intuition, then intuition must be taken as a part of a larger body of evidence, and it is from experts – not the folk – that intuitions should be solicited.

Keywords: Connectionism
Intuition
Neural Networks
Connectionist Networks
Concepts
Pragmatism
Advisor: Sedivy, Sonia
Nuclear Factor (Erythroid 2-like) Factor 2 (Nrf2) as Cellular Protector in Bile Acid and Retinoid Toxicities

Exposure to toxic bile acids (BA) and retinoic acids (RA) is implicated in toxicities related to excessive oxidative stress. This thesis examined roles and mechanisms of the oxidative stress-responsive nuclear factor (erythroid 2-like) factor 2 (Nrf2) in adaptive cell defense against BA and RA toxicities. Using liver cells and mouse models, many antioxidant proteins known to be Nrf2 target genes, particularly the rate-limiting enzyme for glutathione (GSH) biosynthesis, i.e., glutamate-cysteine ligase subunits (GCLM/GCLC), were induced by BA [lithocholic acid (LCA)] or RA (all-trans, 9-cis and 13-cis) treatment. Evidence for increased Nrf2 transactivation by LCA and all-trans-RA was exemplified in HepG2 by: (1) reduced constitutive and inducible expression of GCLM/GCLC upon Nrf2 silencing via small-interfering RNA; (2) increased inducible expression of GCLM/GCLC genes by Nrf2 overexpression, but overexpression of dominant-negative Nrf2 decreased it; (3) increased nuclear accumulation of Nrf2 as signature event of receptor activation; (4) enhanced Nrf2-dependent antioxidant-response-element (ARE) reporter activity as indicative of increased Nrf2 transactivation; and (5) increased Nrf2 occupancy to AREs of GCLM and GCLC. Additionally, in BA-treated HepG2 cells, we observed concomitant increases of many ATP-binding cassette (ABC) transporters (MRPs 1-5, MDR1 and BCRP) in parallel with increased cellular efflux. Nrf2 silencing in HepG2 cells decreased constitutive and inducible expression of MRP2, MRP3 and ABCG2. However, Nrf2-silenced mouse hepatoma cells, Hepa1c1c7, and Nrf2-/- mice had decreased constitutive and/or inducible expression of Mrps 1-4, suggesting species differences in Nrf2-dependent regulation of hepatic ABC transporters. Protection by Nrf2 against BA and RA toxicities was confirmed by observations that Nrf2 silencing increased cell susceptibility to BA- and RA-induced cell death. Moreover, Nrf2-/- mice suffered more severe liver injury than the wildtype. Increased GSH and efflux activity following increased GCLM/GCLC and ABC transporters, respectively, can mitigate LCA toxicity. Activation of MEK1-ERK1/2 MAPK was shown to primarily mediate Nrf2 transactivation and LCA-induced expression of antioxidant proteins and Nrf2-dependent and -independent ABC transporters. In conclusion, Nrf2 activation by BA and RA led to coordinated induction of antioxidant and ABC proteins, thereby counteracting resultant oxidative cytotoxicity. The potential of targeting Nrf2 in management of BA and RA toxicities merits further investigation.

Keywords: oxidative stress
glutathione
bile acid
Nrf2
retinoic acid
cholestasis
ATP-binding cassette transporters
mitogen activated protein kinase
multidrug resistance associated proteins
adaptive response
antioxidants
thioredoxin reductase
4-hydroxynonenal
lipid peroxidation
glutathione S-transferase
liver toxicity
antioxidant response element
cell defense
Advisor: Ito, Shinya
A Randomized Controlled Trial of the Effects of Guided Imagery on Blood Pressure in Hypertensive Pregnant Women

Hypertension occurs in nearly 10% of pregnancies, and is associated with infant and maternal morbidity and mortality. Prior studies of non-pregnant adults have demonstrated the effectiveness of a variety of relaxation therapies in reducing blood pressure. A pilot randomized controlled trial was conducted, the purposes of which were 1) to provide preliminary evidence regarding the usefulness of guided imagery (GI) in reducing blood pressure in hypertensive pregnant women, and 2) to answer feasibility questions for a larger trial. Pregnant women with hypertension prior to 37 weeks gestation (n = 69) were randomized to either 15-minute periods of guided imagery (n = 34), or of quiet rest (QR) (n = 35), twice daily for four weeks or until delivery, whichever came first. Daytime ambulatory mean arterial pressure (MAP), systolic and diastolic blood pressures, anxiety, rest and GI use were measured weekly, to a maximum of four weeks. Sixty women completed at least one week in the study; 46.4% completed four weeks. Compliance was excellent. Intention to treat analysis was used. In the unadjusted analysis, women allocated to GI had significantly lower average daytime ambulatory mean MAP elevations from baseline to their last week of study participation than women allocated to quiet rest (GI: M = 1.58 mmHg, SD = 7.63; QR: M = 5.93 mmHg, SD = 6.55; t = 2.36, p = .02). However, the effect was no longer statistically significant (p = 0.14) when adjusted for baseline mean arterial pressure and gestation. There was no statistically significant difference in the numbers of women who were prescribed antihypertensive medication after randomization (GI: n = 16, QR: n = 13, X2 = 0.74, p = .46). There was also no evidence of an effect of guided imagery on anxiety. Nearly 90% (n = 26) of the guided imagery group indicated they would use it again, either in a subsequent pregnancy or during stressful life events. Given the ease of use, low cost, acceptability to women, and lack of risk of guided imagery, an adequately-powered randomized controlled trial is warranted.

Keywords: Hypertension
Pregnancy
Guided imagery
Relaxation
Anxiety
Randomized controlled trial
Blood pressure
Advisor: Hodnett, Ellen
Feeding the Brethren: Grain Provisioning of Norwich Cathedral Priory, c. 1280-1370

The present dissertation attempts to follow and analyze each and every individual stage of food provisioning of a late medieval monastic community. Chapter One is an introductory survey, describing the topic, its status quaestionis, problems and methodology. Chapter Two establishes the geography of crops in the rural hinterland of Norwich, with each manor specializing in different crop. A close analysis of the crop geography partially supports the Von Thünen thesis. Chapter Three looks at the agricultural trends of the demesnes. Roughly speaking, the period between c. 1290 and 1370 was a history of wheat’s expansion at the expense of rye, on the one hand, and legume shrinkage at the expense of grazing land. Chapter Four discusses annual grain acquisition, its components and disposal. It shows that about eighty per cent of the total supply derived from harvest, while the remainder came in form of tithes, grants and purchases. Chapter Five deals with the human and equine interaction. The bovine population was certainly dominant, but the draught horses easily outnumbered the oxen. Each year,the Priory authorities saved a great deal of money, because of (virtually) free customary carting service. Chapter Six explores the space for storing and processing of the annual grain supply. The five adjacent buildings, namely the Great Granary, brewery, bakery, mill and staples, allowed most effective cooperation between dozens of Priory labourers working in victual departments, on the one hand, and decreased transportation costs. Chapter Seven attempts to establish the relation between the Priory population, its annual grain supply and demand. Conversion of the grain into approximate calorific and financial equivalent reveals that the supply must have exceeded the demand. Chapter Eight is deals with the actual consumption of the grain supply. As far as Norwich monks are concerned, their annual bread and ale supply has certainly exceeded their normal requirements and there is no hint about selling the surplus. Joining the bread and ale accounts with those of the cellar, we arrive at astonishing calorific figures. Chapter Nine discusses the charity activities of Norwich Priory, particularly connected to the distribution of bread and ale among the needy. There were three distinctive groups: hermits, prisoners and paupers. According to almoner’s accounts, the Priory allocated generous sums of loaves and ale to the paupers.

Keywords: Late-Medieval England
Economic History
Agrarian History
History of Food
Environmental History
Fourteenth-Century Europe
Monasticism
Norwich Cathedral Priory
Advisor: Goering, Joseph
Bone Marrow Stem Cell-mediated Airway Epithelial Regeneration

It has been suggested that some adult bone marrow cells (BMC) can localize to the injured tissues and develop tissue-specific characteristics including those of the pulmonary epithelium. In Chapter 2 we show that the combination of mild airway injury as a conditioning regimen to direct the site of BMC localization and transtracheal delivery of short-term cultured BMC enhances airway localization and adoption of an epithelial-like phenotype expressing Clara cell secretory protein (CCSP) and pro-surfactant protein-C. Bone marrow cells from transgenic mice expressing green fluorescent protein driven by the epithelial-specific cytokeratin-18 promoter were injected transtracheally into airway-injured wild-type recipients. BMC retention in the lung was observed to be at least 120 days following cell delivery with increasing transgene expression over time. The results indicate that targeted delivery of BMC can promote airway regeneration. Although bone marrow stem/progenitor cells can develop into lung epithelial cells, the specific subpopulation remains unknown. In Chapter 3 we identify a newly discovered population of murine and human BMC that express CCSP. These CCSP+ cells increase in the bone marrow and blood after airway injury and can be expanded in culture. CCSP+ cells are unique in that they express both hematopoietic and mesenchymal stromal cell markers and can give rise to various lung epithelial lineages in vitro. Importantly, bone marrow transplant of CCSP+ cells to CCSP knockout recipients confirms that bone marrow CCSP+ cells contribute to airway epithelium after airway injury. In Chapter 4 we enrich for a stem/progenitor cell population within the CCSP+ using the stem cell antigen (Sca)-1 as a marker. Here we identified a putative epithelial stem/progenitor cell that can be induced to differentiate into various lung epithelial cell lineages expressing markers exclusive to airway or alveolar epithelial cells when cultured under an air liquid interface. These cells also have self-renewal potential in vitro that can proliferate in vivo and repopulate the injured airway epithelium. This newly discovered epithelial-like cells may play a central role in the bone marrow contribution to lung repair and are exciting candidates for cell-based targeted therapy for treatment of lung diseases.

Keywords: Lung biology
Stem cell biology
Bone marrow
Tissue regeneration
Advisor: Waddell, Thomas K.
Supporting Communication Between Nurses and Physicians

Nurses and physicians in General Internal Medicine (GIM) work in a complex environment where patients present with complex (co)morbidities; management of such patients requires input from a full range of medical disciplines. In addition, there is regular resident physician changeover every 8-9 weeks in this teaching environment, and patient “flow” problems caused by overcrowding and placement issues. This complexity causes difficulties in the information exchange between nurses and physicians necessary to manage patient care. Multidisciplinary team meetings have been suggested as helpful to interprofessional communication, and in General Internal Medicine these take place in the form of daily “Bullet Rounds”. More recently the use of process engineering approaches has been suggested as a way to increase efficiency in healthcare; this dissertation evaluates its impact on communication between nurses and physicians. The initial observational field study showed that information exchange was the main focus of dialogue in Bullet Rounds, and identified information gaps between nurses and physicians. Script Theory (Schank and Abelson 1977) was used to propose that information gaps in Bullet Rounds are caused by different knowledge and goals, which result in inconsistent scripts. A process engineering intervention took place in General Internal Medicine. Process engineering methods have been proposed as being helpful in process design and improvement in healthcare but have not been systematically evaluated. The researcher conducted a pre and post intervention study of Bullet Rounds in order to identify and analyse the impacts of a process engineering intervention on information exchange between nurses and physicians. The results showed that information loss decreased after the intervention but that resident physicians were not satisfied with the nurses-physician information exchange. The staff and resident physicians appeared to have distinct and different information needs and perspectives, while the nurses felt that the Bullet Rounds process had improved, but that it needed revisiting, and were not aligned with staff physicians on respective roles and responsibilities. The overall results suggest that even after the process engineering intervention, there was still misalignment of goals and scripts between the two groups of physicians and between the physicians and nurses, and strategies for addressing these gaps are proposed.

Keywords: Process Engineering
Interprofessional Care
Multidisciplinary Health Care
Advisor: Chignell, Mark