Medicine and Health Sciences Commons^™

The Role Of Dentate Gyrus Pituitary Adenylate Cyclase Activating Polypeptide (Pacap) In Contextual Fear Discrimination, Samantha Kelly Moriarty

Graduate College Dissertations and Theses

When dysregulated, neural systems important for fear behaviors can contribute to mental health disorders such as anxiety, phobias, and post-traumatic stress disorder (PTSD). In PTSD, a myriad of symptoms is possible, but a hallmark feature of the disorder is generalizing fear. This occurs when fear is experienced inappropriately in relation to the environment or circumstances. To study this behavior in rodent models, contextual fear conditioning is used. Contextual fear conditioning is a learning theory preparation where rodents are conditioned with an aversive stimulus such as foot-shock in one distinct context (A), while concurrently being exposed to a safe context (B). …

The Effect Of Tryptamine Producing Bacteria On Gut Motility In Mice, Emilia Sofia Norberg

Graduate College Dissertations and Theses

It has become increasingly clear that there is bidirectional communication between the microbes that exist in the lumen of the gastrointestinal (GI) tract and the nervous system. Research within the last 20 years has revealed GI bacterial metabolites to have a significant effect on gut motility, and some of these actions involve influencing serotonin signaling in the epithelial layer of the intestines. Serotonin, abbreviated as 5- HT, has many functions within the gut including propulsive and segmentation motility, vasodilation, and epithelial cell secretion. There are several bacterial species that have been discovered to synthesize one of 5-HT’s precursory molecules, including …

Impact Of Preexisting Autoimmune Disease On Outcomes Of Patients With Myelodysplastic Syndromes, Diego Andres Adrianzen Herrera

Graduate College Dissertations and Theses

Myelodysplastic syndromes (MDS) are a group of heterogeneous hematologic malignancies characterized by ineffective hematopoiesis and risk of progression to acute myeloid leukemia. MDS has been linked with immune dysregulation, as overly active immunity promotes inflammation and oncogenesis within the hematopoietic system. In recent years, autoimmunity has been defined as an important pathogenic pathway in patients with MDS and numerous studies have demonstrated high prevalence of autoimmune diseases among these patients. Despite this association, the clinical and prognostic implications of preexisting autoimmune disease for patients with MDS remains to be elucidated. An important gap in knowledge is defining the effect of …

The Evaluation Of The Prokinetic Action Of A Luminally Restricted 5-Ht4 Receptor Agonist In Mice, Emma Schoeling

Graduate College Dissertations and Theses

Serotonin (5-HT) is a neurotransmitter mainly produced in the enteric nervous system (ENS) of the gastrointestinal (GI) system. Serotonin has widespread function throughout the body including regulating mood, cognition, sleep, sex, and appetite. In the context of the gut, the monoamine modulates vasodilation, mucus secretion, pain, and peristaltic reflexes for motility. The 5-HT4 receptor is expressed on enteric epithelial cells and nerve terminals in the intestinal mucosa. The agonists available to act on these receptors are a favorable target to promote epithelial healing, recovery from colitis or constipation, and epithelial cell proliferation. The non-absorbable, luminally restricted, 5-HT4R agonist (5HT4-LA1; Takeda …

Investigating The Effects Of Medroxy-Progesterone And Hormonal Birth Control On Habit Behavior In Female Rats, Sarah Charlotte Von Doepp

Graduate College Dissertations and Theses

Recent research has shown that there is a significant sex difference in the rate of habit acquisition in rats, with intact females acquiring the behavior with fewer action-outcome reinforcer pairings than intact males. This difference is shown to be related to the presence of cyclic estrogen and progesterone during habit behavior acquisition training. Specifically, the presence of progesterone has been shown to be crucial in early habit acquisition. However, the mechanism of action through which progesterone is influencing this behavior is unknown. Additionally, this project explores the impacts of long-term hormonal (levonorgestrel - progestin based) birth control on habit behavior …

Quantifying Glial-Glial Interactions In Drosophila Using Automated Image Analysis, Gabriela Salazar Lopez

Graduate College Dissertations and Theses

Imaging is an immensely powerful tool in biomedical research. Technological advances in the last half century have led to the development of new tools for image analysis, with major strides being made in the last 20 years especially with machine and deep learning. However, researchers still often hit a bottleneck during the image analysis phase of their projects that often leads to delays and sometimes even limits the scope of their studies. In this thesis I demonstrate some of the issues that arise while quantifying images to answer a biological question by using a dataset of fly central nervous system …

Building A Learning Healthcare System: A Path To Optimizing Big Health Data To Inform Clinical Care Decisions, Danne Charlotte Emily Elbers

Graduate College Dissertations and Theses

The explosive growth of data and computing power of the last decades has had large impacts on a myriad of domains, not in the least on one of society’s most complex systems: healthcare. In this work, a version of the resulting Learning Healthcare System (LHS) is explored and elements of it have been implemented and are in use at the Department of Veterans’ Affairs today. After an overview of what a LHS is and what it could be once executed in its full form, the chapters will describe in detail some of the individual elements and how they address cogs …

Designer Biologics Composed Of Hepatocyte Growth Factor, Fibroblast Growth Factor 2 And Immunoglobulin G For Treatment Of Acute Myocardial Infarction, Benjamin Liebman

Graduate College Dissertations and Theses

ABSTRACT Coronary artery disease leading to myocardial infarction (a.k.a. MI, heart attack) is one of the leading causes of death globally. Each year an estimated 605,000 Americans suffer a heart attack, which equates to one MI every 40 seconds. As such, MI represents one of the largest health burdens to society. The current standard of care is revascularization therapy achieved by fibrinolytics and Percutaneous Coronary Intervention (PCI); both of which re-open occluded proximal arteries to restore blood flow to the affected areas. Despite revascularization therapy, 30-50% of patients exhibit a form of reperfusion injury termed “no/low-reflow” in which the blood …

Regulation Of Neuroinflammation After Ischemic Stroke By Astroglial Endothelin Receptor Type-B Signaling, John Mcinnis

Graduate College Dissertations and Theses

A large body of neuroscientific research has focused on reactive gliosis and glial scar formation because these are among the most prominent features of the cellular response to central nervous system (CNS) injury. Despite much progress in our understanding, controversy remains regarding the relative balance between the protective nature of the astroglial scar and its anti-regenerative features. Recent work suggests that astrocytes are heterogeneous in their resting state and in their reactivity. In traumatic injuries such as stroke and spinal cord injury, proliferative reactive astrocytes protect CNS tissue. By contrast, under neuroinflammatory and/or neurodegenerative conditions, neurotoxic astrocyte phenotypes may contribute …

Association Of Sickle Cell Trait With Exertional Rhabdomyolysis And Atrial Fibrillation., Daniel R. Douce

Graduate College Dissertations and Theses

Sickle cell trait (SCT), sickle cell disease’s carrier status, is a common genetic variant found in many people of African, South Asian, Middle Eastern and Mediterranean descent. While overall considered a benign carrier status, it has been associated with an increased risk of several diseases, including exertional rhabdomyolysis (ER), and chronic kidney disease. While epidemiological evidence links SCT with ER, the actual pathophysiological mechanism less understood. Additionally, while there is an increased prevalence of atrial fibrillation (AF) documented in people with sickle cell disease, studies in individuals with SCT are lacking.

The objectives of this thesis are twofold: The first …

Chronic Kidney Disease And The Risk Of Venous Thromboembolism, Katharine Lana Cheung

Graduate College Dissertations and Theses

Chronic kidney disease (CKD) affects more than 30 million adults in the U.S. and is strongly associated with cardiovascular events and mortality. Venous thromboembolism (VTE) is the third leading vascular disease, affects up to 900,000 Americans each year and contributes to as many as 100,000 deaths annually. The relationship of CKD and VTE has been described in patients receiving dialysis, kidney transplants recipients and in nephrotic syndrome, however, data supporting the association of VTE in mild to moderate CKD is conflicted. The overall goal of this research was to study the association of CKD and VTE and to understand the …

21st Century Approaches To Addressing Childhood Diarrhea In Low And Middle-Income Countries: Zinc As A Cornerstone Of New Prevention Strategies, Elizabeth Ross Colgate

Graduate College Dissertations and Theses

During the 20th century, significant strides were made in curtailing the burden of childhood diarrhea, including advances in vaccine research, the advent of antibiotics, improved water and sanitation, and expanded access to health information across the globe. Despite this progress, today diarrhea ranks second only to pneumonia as a leading cause of mortality in children under five years, with a disproportionate burden of 90% of diarrheal deaths in South Asia and Sub-Saharan Africa. Additionally, substantial morbidity due to diarrhea persists in young children, with more than 45 million disability-adjusted life years (DALYs) lost due to diarrhea in 2015. Long-term consequences …

Methods To Identify And Develop Drugs For Cryptosporidiosis, Rajiv Satish Jumani

Graduate College Dissertations and Theses

Cryptosporidiosis is a common diarrheal disease caused by intestinal infection with the apicomplexan parasite Cryptosporidium, in humans usually either with C. hominis or C. parvum. Unfortunately, given a large burden of disease in children and immunocompromised people like AIDS patients, the only currently approved treatment, nitazoxanide, is unreliable for these patient populations. To address the urgent need for new drugs for the most vulnerable populations, large phenotypic screening efforts have been established to identify anti-Cryptosporidium growth inhibitors in vitro (hits). However, in the absence of a gold standard drug, the in vitro and in vivo characteristics that should be used …

Methylation Controlled J Protein Is A Master Regulator Of Mitochondrial Metabolism, Devin Pierre Champagne

Graduate College Dissertations and Theses

Methylation controlled J protein (MCJ) is a negative regulator of mitochondrial metabolism that has a substantial impact on overall cell metabolism and function. MCJ is highly expressed by naïve CD8+ T cells, however its role in their immune effector functions was unknown. In this dissertation, it will be demonstrated that MCJ restricts the mitochondrial metabolism of CD8+ T cells, in part by reducing respiratory supercomplex formation. MCJ deficiency enhances the immune effector functions and memory responses of CD8+ T cells in a mitochondrial ATP dependent manner. As a consequence, protection to influenza virus infection is substantially improved. Reduced expression of …

Traumatic Brain Injury Screening Tools In Primary Care, Lee John Bizon Jr

Graduate College Dissertations and Theses

Traumatic brain injuries are a significant health concern, being responsible for over 52,000 deaths each year. Unfortunately, many traumatic brain injuries often go misdiagnosed or undiagnosed. Primary care providers are the principal and first source of medical contact for individuals, meaning that they are vital in the diagnosis of previous traumatic brain injuries in order to prevent future sequelae. There are currently several well-validated screening tools currently available for use by primary care providers. This study uses a self-reported survey to determine which of these tools are used by primary care nurse practitioners from a northern New England state and …

Provider Attitudes And Practice Patterns Of Obesity Management With Pharmacotherapy, Brittany Granara

Graduate College Dissertations and Theses

Background and Purpose: More than one-third of American adults are obese. The prevalence of extreme obesity is rapidly rising. Nine medications are currently approved for weight loss yet they remain under utilized with the focus primarily on lifestyle modifications. The study's objective was to determine current prescribing patterns and attitudes of weight loss medications in the management of obesity among primary care providers (PCPs).

Methods: PCPs were surveyed to determine practice patterns, attitudes, barriers, and facilitators for prescribing weight loss medications.

Conclusions: A total of 105 surveys were completed. 76% of all PCPs did not prescribe weight loss medications for …

A Mechanistically Guided Approach To Treatment Of Multi-Wavelet Reentry: Experiments In A Computational Model Of Cardiac Propagation, Richard T. Carrick

Graduate College Dissertations and Theses

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States today. However, treatment options remain limited despite the enormous magnitude of both AF prevalence and the associated economic cost. Of those treatment options that are available, ablation-based interventional methods have demonstrated the highest rates of long-term cure. Unfortunately, these methods have substantially lower efficacy in patients with heavier burdens of disease, thus leaving the most affected individuals with the least hope for successful treatment.

The focus of this research is to develop a mechanistically guided approach towards the treatment of multi-wavelet reentry (MWR), one of the primary …

A Role For Transforming Growth Factor-Beta In Urinary Bladder Dysfunction With Cyclophosphamide-Induced Cystitis, Eric James Gonzalez

Graduate College Dissertations and Theses

Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain disorder characterized by at least six weeks of lower urinary tract symptoms and unpleasant sensations (pain, pressure and discomfort) thought to be related to the urinary bladder and not meeting exclusion criteria. While the etiology is not known, BPS/IC may involve a "vicious circle" of uroepithelial dysfunction, inflammation and peripheral and central sensitization. We propose that the urinary bladder inflammatory insult partly mediates voiding dysfunction and visceral neurogenic pain characteristic of BPS/IC. Several studies from our laboratory have already demonstrated the role(s) of cytokines and their downstream targets in the …

Nurse Practitioners' Discussion Of Sexual Identity, Attraction And Behavior, Sarah J. Mclaughlin

Graduate College Dissertations and Theses

ABSTRACT

Background: Sexual orientation is comprised of distinct components, including sexual identity, sexual attraction and sexual behavior. Lesbian, gay and bisexual adolescents are at an increased risk of experiencing poor health outcomes compared to non-sexual minority youth. Health care professional organizations recommend that health care providers discuss each component of sexual orientation at every adolescent health supervision visits in order to best assess the adolescent's health risks and needs for intervention and education.

Objective: This survey assessed the frequency with which nurse practitioners (NPs) in the state of Vermont discussed sexual identity, attraction and behavior with adolescents during annual health …

Role Of Interleukin-6 In Cd4 And Cd8 T Cell Effector Functions, Rui Yang

Graduate College Dissertations and Theses

IL-6 is an inflammatory cytokine that contributes to the pathogenesis of many immunological diseases including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, allergic asthma, as well as the protection against infections caused by various pathogens. These are linked to its role in regulating CD4 T cell differentiation and effector function.

Most of these functions are dependent on the IL-6-mediated signaling through the transcription factor Stat3. In this thesis, we identify a novel molecular mechanism by which IL-6 regulates CD4 T cell effector function. We show that IL-6-dependent signal raises the levels of mitochondrial Ca2+ late during activation of CD4 T …

Epicardial Cell Engraftment And Signaling Promote Cardiac Repair After Myocardial Infarction, Krithika Rao

Graduate College Dissertations and Theses

The epicardium is a single layer of epithelial (mesothelial) cells that covers the entire heart surface, but whose function in adult mammals is poorly understood. Defining the role of epicardial cells during homeostasis, growth and injury has potential to provide new treatment strategies for human diseases that result in heart failure, due to extensive loss of viable cardiac tissue. We hypothesized that epicardial cells contribute to repair as transplantable progenitor cells for cellular regeneration and as a source of secreted growth factors for cell protection after myocardial infarction.

Adult epicardial cells were prospectively isolated as uncommitted epithelial cells using epithelial-specific …

Modeling The Spatiotemporal Dynamics Of Cells In The Lung, Joshua Jeremy Pothen

Graduate College Dissertations and Theses

Multiple research problems related to the lung involve a need to take into account the spatiotemporal dynamics of the underlying component cells. Two such problems involve better understanding the nature of the allergic inflammatory response to explore what might cause chronic inflammatory diseases such as asthma, and determining the rules underlying stem cells used to engraft decellularized lung scaffolds in the hopes of growing new lungs for transplantation. For both problems, we model the systems computationally using agent-based modeling, a tool that enables us to capture these spatiotemporal dynamics by modeling any biological system as a collection of agents (cells) …

Impact Of Acl Injury On Patellar Cartilage Thickness, Ethan Leveillee

Graduate College Dissertations and Theses

ACL injury has been shown to have long-lasting and severe consequences on the different structures of the knee such as the articular cartilage and meniscus. Cartilage thickness changes in particular are indicative of osteoarthritic changes in the tibiofemoral joint. While there has been significant research focused on cartilage changes of the tibia and femur, there has been little work looking at patellar cartilage. The following goals were set forth for this study. First, to establish a robust coordinate system to accurately determine the location and orientation of the patella. Secondly, to determine the effects of ACL injury on patellar cartilage …

Reducing Preventable Hospitalizations: A Study Of Two Models Of Transitional Care, Jessica Morrison

Graduate College Dissertations and Theses

Purpose: Transitional care is an emerging model of health care designed to decrease preventable adverse events and associated utilization of healthcare through temporary follow-up after hospital discharge. This study describes the approach and outcomes of two transitional care programs: one is provided by masters-prepared clinical nurse specialists (CNS) with a chronic disease self-management focus, another by physicians specializing in palliative care (PPC). Existing research has shown that transitional care programs with intensive follow up reduce hospitalizations, emergency room visits, and costs. Few studies, however, have included side-by-side comparisons of the efficacy of transitional care programs varying by health care providers …

Regulation Of Middle Meningeal Artery Diameter By Pacap And Atp-Sensitive Potassium Channels, Arsalan Urrab Syed

Graduate College Dissertations and Theses

Migraine is one of the most prevalent contributors to the global burden of mental and neurological disorders. It is a complex episodic condition that presents as intense recurrent unilateral headaches lasting hours to days that can be accompanied by nausea, photophobia, phonophobia and other neurological symptoms. The causes of migraine appear multifactorial and are not fully understood. However, activation of the trigeminovascular system and sphenopalatine parasympathetic neurons and the resulting vasodilation of meningeal arteries have been associated with the development of migraine pain. Recently, the neurotransmitter and neurotrophic peptide pituitary adenylate cyclase activating polypeptide (PACAP) has been implicated in this …

Telemedicine Enhances Communication In The Intensive Care Unit, Prema Ramachandran Menon

Graduate College Dissertations and Theses

Patients admitted to the Intensive Care Unit (ICU) are critically ill and often at extremely high risk of death. These patients receive aggressive interventions to prolong their lives. Despite these measures, many patients still succumb to their illness. Although ICU physicians are good at predicting which patients have a high risk of mortality, they are still offering interventions that do not prolong life, but potentially cause more suffering at the end of life. This is because there is a lack of high quality and early communication to discuss prognosis and establish patients' goals of care. This gap in communication is …

Maternal Hypertension Influences Mortality And Severe Morbidity In Infants Born Extremely Preterm, Carole Anne Mcbride

Graduate College Dissertations and Theses

Worldwide, more than 1 million infants die as a result of premature birth. In the United States, where 1 in 10 births occurs preterm, premature birth is the leading cause of infant mortality. Premature infants have high rates of mortality and morbidity, with the highest rates seen in those infants born extremely preterm -- prior to 30 weeks gestation. Severe morbidity in these infants often contributes to life-long health problems. Maternal hypertension (HTN) is one contributor to preterm birth and also contributes to fetal growth restriction, resulting in birth weights which are small for gestational age (SGA, and generally within …

Towards A Structural Understanding Of Spore Germination In Clostridium Difficile, Chloe M. Adams

Graduate College Dissertations and Theses

Clostridium difficile is a Gram-positive bacterium that causes a toxin-mediated disease, typically in individuals whose normal intestinal flora has been compromised by antibiotic therapy. C. difficile is naturally resistant to many antibiotics and produces spores that can withstand harsh environmental conditions and many disinfectants, making the infection difficult to clear and easy to spread. The infection begins when spores from the environment are ingested and germinate upon exposure to taurocholate and glycine in the digestive tract. This germination process is required to initiate infection and thus represents a good target for the development of novel therapeutics. Although spore germination is …

Reverse Engineering The Human Brain: An Evolutionary Computation Approach To The Analysis Of Fmri, Nicholas Allgaier

Graduate College Dissertations and Theses

The field of neuroimaging has truly become data rich, and as such, novel analytical methods capable of gleaning meaningful information from large stores of imaging data are in high demand. Those methods that might also be applicable on the level of individual subjects, and thus potentially useful clinically, are of special interest. In this dissertation we introduce just such a method, called nonlinear functional mapping (NFM), and demonstrate its application in the analysis of resting state fMRI (functional Magnetic Resonance Imaging) from a 242-subject subset of the IMAGEN project, a European study of risk-taking behavior in adolescents that includes longitudinal …

Inhibitory Control Efficiency In Successful Weight Loss Participants, Kathryn Curran Olds

Graduate College Dissertations and Theses

Eating unhealthy foods and eating past satiety are inappropriate behaviors that promote obesity. The ability to effectively inhibit an inappropriate behavior is a key component of cognitive restraint and its impairment has been previously linked to obesity. In this study, a Go/No-Go fMRI task was completed by a cohort of adult women that had experienced initial weight loss followed by various levels of weight regain or continued weight loss. Region of interest fMRI analysis revealed that greater total weight loss was significantly related to decreasing activation in the right inferior frontal gyrus and the right superior frontal gyrus. These results …