Medicine and Health Sciences Commons^™

Progressive Symmetric Erythrokeratoderma, Sevasti Margetas Do, Stephen Purcell Do

Department of Medicine

No abstract provided.

Efficacious And Safe Tissue-Selective Controlled Gene Therapy Approaches For The Cornea, Rajiv R. Mohan, Sunilima Sinha, Ashish Tandon, Rangan Gupta, Jonathan C. K. Tovey, Ajay Sharma

Pharmacy Faculty Articles and Research

Untargeted and uncontrolled gene delivery is a major cause of gene therapy failure. This study aimed to define efficient and safe tissue-selective targeted gene therapy approaches for delivering genes into keratocytes of the cornea in vivo using a normal or diseased rabbit model. New Zealand White rabbits, adeno-associated virus serotype 5 (AAV5), and a minimally invasive hair-dryer based vector-delivery technique were used. Fifty microliters of AAV5 titer (6.561012 vg/ml) expressing green fluorescent protein gene (GFP) was topically applied onto normal or diseased (fibrotic or neovascularized) rabbit corneas for 2-minutes with a custom vector-delivery technique. Corneal fibrosis and neovascularization in rabbit …

Efficient Replication Of Over 180 Genetic Associations With Self-Reported Medical Data, Joyce Y. Tung, Chuong B. Do, David A. Hinds, Amy K. Kiefer, J. Michael Macpherson, Arnab B. Chowdry, Uta Francke, Brian Naughton, Joanna Mountain, Anne Wojcicki, Nicholas Eriksson

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for obtaining large amounts of medical information from a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web-based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we …

Traumatic Brain Injury: Cyclophilin D As A Therapeutic Target And The Neuropathology Caused By Blast, Ryan Douglas Readnower

University of Kentucky Doctoral Dissertations

With an estimated incidence of 1.5 million each year, traumatic brain injury (TBI) is a major cause of mortality and morbidity in the United States. Opening of the mitochondrial permeability transition pore (mPTP) is a key event contributing to TBI pathology. Cyclophilin D (CypD), a matrix peptidyl-prolyl cis-trans isomerase, is believed to be the regulating component of the mPTP. Cyclosporin A, an immunosuppressant drug, inhibits CypD and blocks mPTP formation and has been shown to be neuroprotective following TBI. However, it is unclear if CsA’s neuroprotective mechanism is due to inhibition of CypD and/or immuno-suppression. Therefore to directly assess the …

Post-Transcriptional Control Of Type I Interferon Genes By Ksrp In The Innate Immune Response Against Viral Infection, Wei-Jye Lin

All ETDs from UAB

Several strategies are used in eukaryotic cells in order to determine the gene expression level, including the transcriptional and post-transcriptional mechanisms. One of the post-transcriptional mechanisms is the regulation of mRNA stability, which varies considerably from one mRNA species to another. Previous studies have shown that inherently unstable mRNAs encoding cytokines and proto-oncogenes contain the AU-rich elements (AREs) in the 3' untranslated regions (UTRs). Their decay requires decay-promoting RNA-binding proteins that recognize the AREs and recruit mRNA decay machineries to facilitate the rapid decay of targeting mRNA. KH-type splicing regulatory protein (KSRP) was previously identified as an ARE decay promoting …

Mechanisms And Consequences Of Thy-1 Shedding, John Edwin Bradley

All ETDs from UAB

Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic fibrosis in the lung interstitium of unknown etiology, and causes death within 2 to 4 years after diagnosis. There are no clinical interventions save for lung transplantation that give any survival benefit. Aberrant collagen deposition and aggregates of proliferating fibroblasts and myofibroblasts called fibroblastic foci (FF) are the classic features of IPF. Therefore, the cell type most often implicated as pathogenic in IPF is the fibroblast, especially its differentiated phenotype, the myofibroblast. Fibroblasts are a remarkably heterogeneous cell type. Expression of the cell surface glycoprotein Thy-1 (Thymocyte differentiation antigen 1) delineates a …

Sox2/Parylated Parp1 Complexes Regulate Pluripotency, Yi-Shin Lai

All ETDs from UAB

Embryonic stem cells (ESCs) were first derived from the inner cell mass (ICM) of blastocyst-stage embryos. ESCs are distinguished from other cell types by their pluripotency and unlimited self-replication. ESCs are able to differentiate into multiple cell types that represent all three primary germ layers (ectoderm, mesoderm and endoderm) and can form an entire adult organism. Under defined conditions, ESCs are self-renewable and have an extended life-span without compromising pluripotency. The plasticity of ESCs provides opportunities for regenerative medicine. The recent production of induced pluripotent stem cells (iPSC) offers an ideal "personalized" substitute for ESCs. Overexpression of four transcription factors, …

Understanding Molecular Mechanisms Of Breast Cancer Metastasis Using Genetically-Engineered Mice, Leah M. Cook

All ETDs from UAB

Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells metastasize to distant organ sites. Effective treatment of metastatic disease has been limited; therefore, an increased molecular understanding to identify biomarkers and therapeutic targets is needed. Breast cancer metastasis suppressor 1 (BRMS1) suppresses development of metastases when expressed in a variety of cancer types, including metastatic mammary carcinoma. Little is known of Brms1 function throughout the initiation and progression of mammary carcinoma. Thus Brms1 transgenic mice (derived on C57BL/6 background) were generated by utilizing MMTV promoter expression (for mammary-selective overexpression) or the beta-actin promoter (for ubiquitous …

Limited Transplantation Of Antigen-Expressing Hematopoietic Stem Cells Induces Long-Lasting Cytotoxic T Cell Responses And Effect Of Altered Suppressive Myeloid Population On Hiv-Disease Progression, Warren L. Denning

All ETDs from UAB

While each type of cancer and chronic viral infection has its own specific pathology, they share two common mechanisms of immune evasion. The first mechanism is the exhaustion or deletion of antigen-specific T cells. The second mechanism is the formation of an immunosuppressive environment responsible for the block of T cell function. Elicitation of antigen-specific T cells be accomplished by immunotherapy in place of conventional treatments such as HAART and chemotherapy. In addition, immunotherapy can alleviate the side-effects associated with long-term use of conventional therapies while reducing the total cost. The results presented here provide an alternative to conventional methods …

Acquired Cytogenetic Changes In Adult Twins Discordant For A History Of Childhood Sexual Abuse, Jenni Brumelle

Theses and Dissertations

The primary study aim was to evaluate the latent biological effect of childhood sexual abuse (CSA) on adults by quantifying acquired cytogenetic changes and cortisol levels in identical twins who were discordant (N=22) or concordant (N=2) for a history of CSA. Although the difference scores for cortisol values between discordant identical co-twins were not significantly different from zero, a trend was observed for the twins exposed to intercourse, the most severe form of CSA, to have a blunted cortisol awakening response. Acquired cytogenetic changes were assessed by scoring telomere lengths and somatic cell abnormality frequencies via a cytokinesis-block micronucleus (MN) …

Transdermal And Oral Dl-Methylphenidate-Ethanol Interactions In C57bl/6j Mice, Guinevere Hannah Bell

MUSC Theses and Dissertations

The persistence of attention-deficit/hyperactivity disorder (ADHO) into adulthood has been increasingly recognized over the past few decades and the stimulant drug dl-methylphenidate (MPH) has remained a first-line pharmacotherapeutic agent in the treatment of ADHD. Many adult ADHD patients who are prescribed MPH report concomitant use with ethanol. In humans, coadministration of dl-MPH and ethanol results in pharmacokinetic and pharmacodynamic drug - drug interactions. Ethanol elevates biological concentrations of the pharmacologically active d-MPH isomer and yields the metabolic transesterification product ethylphenidate (EPH). EPH appears to be formed through the actions of carboxylesterase 1 (CES1) which exhibits I-MPH substrate enantioselectivity in both …

Role Of Angiotensin Converting Enzyme 2 (Ace2) In Obesity-Associated Hypertension, Manisha Gupte

University of Kentucky Doctoral Dissertations

The purpose of this research was to determine whether adipocytes express ACE2 and its role in obesity-associated hypertension with diet-induced obesity.

To determine if ACE2 was expressed in adipose tissue and its regulation in the setting of diet-induced obesity, we fed male mice either a low fat (LF) or high fat (HF) diet acutely (1 week) or chronically ( 4 months). We demonstrated that ACE2 was regulated specifically in adipose tissue with consumption of a HF diet. However, with chronic HF feeding adipose ACE2 was dysregulated resulting in activation of the systemic RAS and increased blood pressure.

To determine the …

Androgen Increases Angiotensin Receptor Type 1a On Smooth Muscle Cells To Promote Angiotensin Ii-Induced Abdominal Aortic Aneurysms, Xuan Zhang

University of Kentucky Doctoral Dissertations

The purpose of this study was to determine whether androgen promotes AT1aR expression on smooth muscle to confer high prevalence of AngII-induced AAAs in hyperlipidemic mice. In addition, we also investigate the role of androgen in the progression of established AngII-induced AAAs.

First, we sought to examine the role of endogenous androgen in the growth of established AngII-induced AAAs. By castrating male mice, we demonstrated that removal of endogenous androgen significantly decreased the progressive lumen dilation of established AngII-induced AAAs in male ApoE-/- mice, but had no effect on external AAA diameters. These results suggest that androgen contributes to the …

Identification Of Activities Involved In Cag/Ctg Repeat Instability, Nelson Lap Shun Chan

University of Kentucky Doctoral Dissertations

CAG/CTG repeat instability is associated with at least 14 neurological disorders, including Huntington’s disease and Myotonic dystrophy type 1. In vitro and in vivo studies have showed that CAG/CTG repeats form a stable hairpin that is believed to be the intermediate for repeat expansion and contraction.

Addition of extra DNA is essential for repeat expansion, so DNA synthesis is one of the keys for repeat expansion. In vivo studies reveal that 3’ CTG slippage with subsequent hairpin formation (henceforth called the 3’ CTG slippage hairpin) occurs during DNA synthesis. It is proposed that hairpin tolerance machinery is activated because prolonged …

Associatioin Of Plasma Aβ Peptides With Blood Pressure In The Elderly, Jean-Charles Lambert, Jean Dallongeville, Kathryn A. Ellis, Susanna Schraen-Maschke, James Lui, Simon Laws, Julie Dumont, Florence Richard, Dominque Cottel, Claudine Berr, David Ames, Colin L. Masters, Christopher C. Rowe, Cassandra Szoeke, Christophe Tzourio, Jean-Francois Dartigues, Luc Buee, Ralph Martins, Philippe Amouyel

Research outputs 2011

Background Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). Methodology/Principal Findings Plasma Aß1-40 and Aß1-42 levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) …

Internet Use And Its Impact On Secondary School Students In Chiang Mai, Thailand, Kesaraporn Wanajak

Theses: Doctorates and Masters

Internet addiction (IA) is a relatively new field of academic inquiry. Empirical studies suggest that IA, like other well researched addictive behaviours, has an effect on many aspects of a person‟s life, including academic/work performance, relationships, and physical and mental health (Goldberg, 1996; Young, 1996, 1998). Evidence of IA has been suggested by the findings that some Internet users spend increasingly longer periods of time online and experience withdrawal symptoms when offline. Those preoccupied with Internet-related activities may neglect exercise, family and social activities (Kim et al., 2010; Nalwa & Anand, 2003; Seo, Kang, & Yom, 2009; S. Yang & …

Yeast As A Model For Studying Aβ Aggregation, Toxicity And Clearance, Prashant R. Bharadwaj

Theses: Doctorates and Masters

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterised by acute memory loss and behavioural symptoms. The AD brain is characterized by the presence of senile amyloid plaques associated with degenerating neurites and inflammatory processes. The major protein component of these amyloid deposits is the amyloid beta (Aβ) protein. The Aβ protein is a 40 or 42 amino acid cleavage product of APP (Amyloid Precursor Protein) which is produced in low levels in the normal ageing brain. Although senile amyloid plaques is the major pathological hallmark of AD brains, accumulating evidence has been presented to …

Microbial Community Analysis Of Lake Chillisquaque, A Small Water System In Central Pennsylvania, Allison Mayhew

Honors Theses

Cyanobacteria are photosynthetic organisms that require the absorption of light for the completion of photosynthesis. Cyanobacteria can use a variety of wavelengths of light within thevisible light spectrum in order to harvest energy for this process. Many species of cyanobacteria have light-harvesting proteins that specialize in the absorption of a small range of wavelengths oflight along the visual light spectrum; others can undergo complementary chromatic adaptation and alter these light-harvesting proteins in order to absorb the wavelengths of light that are mostavailable in a given environment. This variation in light-harvesting phenotype across cyanobacteria leads to the utilization of environmental niches …

The Dynamics Of Integrate-And-Fire: Mean Vs. Variance Modulations And Dependence On Baseline Parameters, Joanna R. Wares, Todd W. Troyer

Department of Math & Statistics Faculty Publications

The leaky integrate-and-fire (LIF) is the simplest neuron model that captures the essential properties of neuronal signaling. Yet common intuitions are inadequate to explain basic properties of LIF responses to sinusoidal modulations of the input. Here we examine responses to low - and moderate-frequency modulations of both the mean and variance of the input current and quantify how these responses depend on baseline parameters. Across parameters, responses to modulations in the mean current are low pass, approaching zero in the limit of high frequencies. For very low baseline firing rates, the response cutoff frequency matches that expected from membrane integration. …

The Cardiac Atlas Project--An Imaging Database For Computational Modeling And Statistical Atlases Of The Heart, Carissa G. Fonseca, Michael Backhaus, David A. Bluemke, Randall D. Britten, Jae Do Chung, Brett R. Cowan, Alan H. Kadish

Office of the President Publications and Research

MOTIVATION: Integrative mathematical and statistical models of cardiac anatomy and physiology can play a vital role in understanding cardiac disease phenotype and planning therapeutic strategies. However, the accuracy and predictive power of such models is dependent upon the breadth and depth of noninvasive imaging datasets. The Cardiac Atlas Project (CAP) has established a large-scale database of cardiac imaging examinations and associated clinical data in order to develop a shareable, web-accessible, structural and functional atlas of the normal and pathological heart for clinical, research and educational purposes. A goal of CAP is to facilitate collaborative statistical analysis of regional heart shape …

Serum Monocyte Chemoattractant Protein-1 In Pancreatic Cancer., Jennifer Sullivan, Qiaoke Gong, Terry Hyslop, Harish Lavu, Galina Chipitsyna, Charles Yeo, Hwyda A Arafat

Department of Surgery Faculty Papers

Background/Aims. Pancreatic ductal adenocarcinoma (PDA) has etiological association with chronic inflammation. Elevated circulating levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), are found in obese individuals. We hypothesized that serum MCP-1 levels are elevated in obese PDA patients. Methods. ELISA was used to analyze MCP-1 serum levels in PDA (n = 62) and intraductal papillary mucinous neoplasms (IPMN) (n = 27). Recursive partitioning statistical analysis investigated the relationship between log MCP-1 and clinicopathological parameters. Results. Log MCP-1 values were significantly (P < 0.05) elevated in patients with BMI ≥ 37.5. In patients with BMI < 37.5, average log MCP-1 values were significantly elevated in PDA patients when compared to IPMN patients. Within the IPMN group, higher log MCP-1 levels correlated with increased age. Recursive partitioning analysis of IPMN versus PDA revealed a strategy of predicting characteristics of patients who are more likely to have cancer. This strategy utilizes log MCP-1 as the primary factor and also utilizes smoking status, gender, and age. Conclusion. MCP-1 is a promising biomarker in pancreatic cancer. The potential of using MCP-1 to distinguish PDA from IPMN patients must be studied in larger populations to validate and demonstrate its eventual clinical utility.

Strategies For Targeting Lentiviral Vectors, Christopher Matthew Trimby

University of Kentucky Doctoral Dissertations

Lentiviral gene therapy has held great promise for treating a wide range of neurological disorders due to its ability to stably integrate into the genome of nondividing cells like neurons, in addition to dividing cells. The nervous system is a complex and highly heterogeneous system, and while a therapeutic intervention may have beneficial effects in one population of cells it may have severe side effects in another. For this reason, specific targeting of lentiviral vectors is crucial for their ultimate utility for research and clinical research use.

Two different approaches for focusing the targeting of lentiviral vectors were employed in …

Role Of Pi3k-Akt Pathway In The Age Associated Decline In Tlr Mediated Activation Of Innate And Adaptive Immune Responses, Mosoka Papa Fallah

University of Kentucky Doctoral Dissertations

Immunosenescence results in reduced immune response to infections with Streptococcus pneumoniae as well as to pneumococcal polysaccharide vaccines. The antibody response to the capsular polysaccharide (CPS) provides protection against S. pneumoniae infection. CPS immunoresponse is T cell independent and needs the macrophage-derived cytokines such as IL-12, IL-6 and IL-1β to elicit an antibody response. We showed a cytokine dysregulation, i.e. a decrease in IL-12, IL-6 and TNF-α but an increase in IL-10, in the aged (18-24 months old comparable to >65 years in human) compared to young adult mouse (8-12 weeks less than 65 years old) splenic macrophages (SM) or …

The Role Of Olfactory Cues In The Sequential Radiation Of A Gall-Boring Beetle, Bradley Rhodes

Master’s Theses

Species diversity itself may cause additional species diversity. According to recent findings, some species modify their environment in such a way that they facilitate the creation of new niches for other species to evolve to fill. Given the vast speciesdiversity of insects, the occurrence of such sequential radiation of species is likely common among herbivorous insects and the species that depend on them, many of them being insects as well. Herbivorous insects often have close associations with specific host plants and their preferences for mating and ovipositing on a specific host-plant species can reproductively isolate host-specific populations, facilitating speciation. Previous …

Hibernacula Microclimate And White-Nose Syndrome Susceptibility In The Little Brown Myotis (Myotis Lucifugus), Laura Grieneisen

Master’s Theses

The objective of this project was to determine the relationship between hibernacula microclimate and White-nose Syndrome (WNS), an emerging infectious disease in bats. Microclimate was examined on a species scale and at the level of the individual bat to determine if there was a difference in microclimate preference between healthy and WNS-affected little brown myotis (Myotis lucifugus) and to determine the role of microclimate in disease progression. There is anecdotal evidence that colder, drier hibernacula are less affected by WNS. This was tested by placing rugged temperature and humidity dataloggers in field sites throughout the eastern USA, experimentally determining the …

Is Chronic Use Of Bacopa Monnieri An Effective Treatment To Improve Memory Performance In Healthy And Aging Adults?, Brian M. Kairalla

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of the systematic review is to determine whether or not chronic use of Bacopa monnieri is an effective treatment to improve memory performance in healthy and aging adults.

Effects Of Managed Care On The Health And Health-Care Of The Non-Elderly With Diabetes, Meihua Lu

Wayne State University Dissertations

This dissertation attempts to examine the quality effect of managed care plans (as compared with traditional fee-for-service plans, or FFS) on the health outcome and health care use of patients with diabetes. As the number of diabetics is growing rapidly with many of them are relying on managed care plans, knowing better the effects of different plans on health status and health care utilization is of great interest and significance to consumers, employers, and policymakers, especially at a time that universal health care is under being implemented.

Using up-to-date data from MEPS, a nationally representative survey, I compared 484 HMO …

Frazzled And Abelson Interact To Regulate The Actin Cytoskeleton In Drosophila, Bridget Elsa Varughese

Wayne State University Dissertations

Guidance receptors such as Frazzled affect cell shape and motility by directly or indirectly modulating the cytoskeleton. Fra is particularly needed for the formation of the posterior commissures in a developing Drosophila embryo. The cytoplasmic tyrosine kinase, Abelson Kinase (Abl) enhances the loss of commissures observed in fra mutant. Abl physically interacts with Frazzled to help guide commissural axons across the midline. Furthermore, the loss of commissural axons is only seen when the actin dynamics are perturbed. Abl is also known to regulate actin-dependent processes underlying formation of filopodia, microspikes and membrane ruffles. So, we established a Drosophila S2 cell …

Mechanisms Of Translation Arrest Following Focal Brain Ischemia, Monique K. Lewis

Wayne State University Dissertations

MECHANISMS OF TRANSLATION ARREST FOLLOWING FOCAL BRAIN

ISCHEMIA

by

MONIQUE K. LEWIS

August 2011

Advisor: Dr. Donald DeGracia

Major: Physiology

Degree: Doctor of Philosophy

The loss of blood flow to the brain is termed ischemia and the subsequent resumption of blood flow is termed reperfusion. Brain ischemia and reperfusion (I/R) occurs primarily following resuscitation from cardiac arrest and stroke and presents one of the most significant clinical challenges. At present, there are no clinically effective pharmacologic interventions to halt brain damage following I/R. The major Aim of this dissertation will be to investigate possible mechanisms involved in neuron death following …

Axogial Communication Mediated By Soluble Neuregulin-1 And Bdnf, Zhenzhong Ma

Wayne State University Dissertations

During peripheral nervous system development, successful communication between axons and glial cells including Schwann cells in peripheral nervous system and oligodendrocytes in central nervous system, is required for the proper functions of both neurons and glia. Three types of alternatively-spliced proteins belonging to the neuregulin1 (NRG1) gene family of growth and differentiation factors are essential for Schwann cell survival and peripheral nerve development. While membrane-bound NRG1 forms (type III) has been strongly implicated in the regulation of myelination process at late stage of Schwann cell development, little is known about the role of soluble, heparin-binding forms of NRG1 (type I/II) …