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Articles 1 - 25 of 25
Full-Text Articles in Medicine and Health Sciences
A Mixed Methods Evaluation Of Patient And Provider Perspectives Of Chronic Illness Management Following Kidney Transplantation, Catherine Kelley Pantik
A Mixed Methods Evaluation Of Patient And Provider Perspectives Of Chronic Illness Management Following Kidney Transplantation, Catherine Kelley Pantik
Theses and Dissertations (ETD)
Introduction: Inconsistent, fragmented care coordination in kidney transplant recipients (KTRs)—whose management requires long-term, complex care, and multiple handoffs among providers—has been shown to result in suboptimal care and higher costs. In order to move forward in improving long-term outcomes, it is necessary to fully assess current practice patterns with appropriate measures. With a full and accurate picture of how elements of the management plan influence both KTR and the health care provider (HCP), it will be possible to implement changes that improve long-term outcomes.Methods: The Chronic Care Model (CCM) was the framework for the study. A mixed method research approach …
Cellular Corrosion Of Cocrmo Total Knee Implants: Understanding Underlying Mechanisms Through Retrieval Analysis And Simulated Inflammatory Conditions, Griffin Heise
Theses and Dissertations (ETD)
Introduction. Total joint arthroplasty is considered one of the most beneficial aspects of modern orthopedic surgery. Due to the increase in population, obesity rates, and medical advances, total joint replacements have become more commonplace in the United States. Recently, a unique type of damage has been investigated in cobalt-chrome (CoCr) implants that remains poorly understood and highly controversial. Originally, it was believed that this damage type was caused by inflammatory cells directly attacking the metal surface, leading to damage of the oxide layer. However, damage caused by electrocautery tools has shown identical characteristics, leading some to believe this is the …
Validation Testing Of A Synthetic Spine And Upgraded Protocol For A Biomechanical Evaluation Of A Lumbar Spinal Orthosis, Daniel Hoyer
Validation Testing Of A Synthetic Spine And Upgraded Protocol For A Biomechanical Evaluation Of A Lumbar Spinal Orthosis, Daniel Hoyer
Theses and Dissertations (ETD)
Low back pain (LBP) is highly prevalent in all walks of life. Standard conservative treatment methods may work for some, but others go on to have spinal injections, opioids, or surgical procedures to alleviate pain. The Distractive and Mobility-Enabling Orthosis (DMO) was developed to meet the need for a conservative, drug-free treatment method. In this research, the low back support test protocol for evaluating DMO success was upgraded with a new synthetic lumbar spine model. The latest generation of the DMO project was then evaluated using the new system in a laboratory setting and on a pilot physical therapy patient.First, …
The Discovery And Development Of Thienopyrimidines As Inhibitors Of Helicobacter Pylori, Alex Kagabo Mugengana
The Discovery And Development Of Thienopyrimidines As Inhibitors Of Helicobacter Pylori, Alex Kagabo Mugengana
Theses and Dissertations (ETD)
The rate of successful treatment for Helicobacter pylori infections, with the clarithromycin triple therapy, is only 75%. The triple therapy, which consists of a proton pump inhibitor and two broad-spectrum antibiotics such as clarithromycin and amoxicillin, is becoming less effective due to the rise of strains with resistance against these antibiotics. In the search for narrow spectrum drugs for the treatment of H. pylori infections, a high-throughput screen was performed to identify selective compounds against H. pylori. This screen revealed two selective and structurally related thienopyrimidines. Structure-activity relationship of the thienopyrimidines against H. pylori was examined through the synthesis of …
Delineating The Mechanisms Of Misfolded Endoplasmic Reticulum (Er) Luminal Protein Retrotranslocation For Er-Associated Degradation, Christina Oikonomou
Delineating The Mechanisms Of Misfolded Endoplasmic Reticulum (Er) Luminal Protein Retrotranslocation For Er-Associated Degradation, Christina Oikonomou
Theses and Dissertations (ETD)
Secreted, plasma membrane, and resident proteins of the secretory pathway are synthesized in the endoplasmic reticulum (ER) where they undergo post-translational modifications, oxidative folding, and subunit assembly in tightly monitored processes. An ER quality control (ERQC) system oversees protein maturation and ensures that only those reaching their native state will continue trafficking into the secretory pathway to reach their final destinations. Proteins that fail quality control must be recognized and eliminated to maintain ER proteostasis. The ER-associated degradation (ERAD) was discovered nearly 30 years ago and entails the identification of improperly matured secretory pathway proteins and their retrotranslocation to the …
An Update On Pharmaceutical Strategies For Oral Delivery Of Therapeutic Peptides And Proteins, Nirnoy Dan
An Update On Pharmaceutical Strategies For Oral Delivery Of Therapeutic Peptides And Proteins, Nirnoy Dan
Theses and Dissertations (ETD)
Peptides and proteins are imperative for the human body and play crucial roles in governing various bio-chemical processes. Recent advances in molecular biology and biochemistry helped in understanding the role of these endogenous macromolecules in different pathological and disease conditions. Currently, small molecule drugs (< 900dalton) in comparison to the therapeutic peptides and proteins-based drugs (TPP) dominate pharmaceutical market. However, the game is changing with the recent advances of biotechnological tools like recombinant DNA technology, solid phase protein synthesis etc., which enabled large-scale production of therapeutic peptides and proteins. The Success of Human Insulin, the first FDA approved commercial recombinant protein based therapeutic in 1982, revolutionized the field of TPPs. The number of FDA approved TPPs reached about to ~239 in 2017 compared to where it was only ~130 in 2008. Rapid progress in this sector can be attributed to several advantages of proteins and peptides over small molecule drugs both financially and clinically. From a clinical perspective, proteins and peptides are inherently more specific to the target site than the small molecules drugs, which lead to less interferences with normal biological system of the patient and caused minimal off-target side effects. A handful of proteins which are used for different clinical complications are less immunogenic because they are produced in the body naturally. Furthermore, proteins and peptides also take part in several complex and complicated biological processes, which is difficult to be to be mimicked by the small molecule drugs. From a financial standpoint, median total pre-market development times were shorter for biologics (10.6 years) than the small molecules drugs (12.6 years) estimated using Merck Index. In 2009, US Congress passed the Biologics Price Competition and Innovation Act (BPCIA) which gave new biologics 12 years of guaranteed exclusivity. The most commonly utilized routes for administering TPPs are I.V, I.P or I.M injections, which largely suffer from patient compliances. There are ~350 TPPs under clinical development and among them only 2 are given orally which is Interferon-α and Human growth hormone. Currently, most efforts in both industry and academia are centered around enhancing bioavailability of orally administered TPPs which typically are less than 1%. Oral administration is the non-invasive, most preferred route of drug administration for the patients. Furthermore, oral dosage forms are cheaper to manufacture as well as to administer, because they do not need to be produced under sterile conditions or administered in clinics. However, unfavorable physicochemical characteristics of TPPs like high molecular weight, hydrophilicity, poor stability in the physiological conditions, short biological half-life, low permeability through the epithelial barrier in the small intestine put up a massive barrier in the development of orally available dosage forms of TPPs. In this review, we will discuss the challenges associated with oral delivery of TPPs and the ongoing efforts to solve them.
Reverse Zoonosis Of Pandemic A(H1n1)Pdm09 Influenza Viruses At The Swine/Human Interface, Daniel Gene Darnell
Reverse Zoonosis Of Pandemic A(H1n1)Pdm09 Influenza Viruses At The Swine/Human Interface, Daniel Gene Darnell
Theses and Dissertations (ETD)
The 2009 pandemic influenza A(H1N1)pdm09 virus emerged from the swine population. Despite frequent zoonotic events, swine influenza viruses had not become established in humans previously and little is known about host-barriers which prevent swine influenza viruses from efficiently infecting humans. Thus, the emergence of the H1N1pdm09 viruses in humans and the subsequent reverse zoonoses back to swine offered an extremely valuable opportunity to expand current knowledge. We used our active swine farm surveillance platform in combination with viruses from the USDA surveillance program to look for evidence of interspecies transmission of H1N1pdm09 viruses in the US. We found phylogenetic evidence …
Antibiotic Drug Discovery Targeting Bacterial Metabolism, Miranda J. Wallace
Antibiotic Drug Discovery Targeting Bacterial Metabolism, Miranda J. Wallace
Theses and Dissertations (ETD)
Over the last century, the use of antibiotics has enabled many advances in modern medicine, making life as we know it possible. In recent years, however, emerging bacterial resistance to virtually all major antibiotic classes has resulted in a worldwide increase in morbidity, mortality, and financial burden associated with drug resistant infections. The antimicrobial resistance crisis presents an urgent need for new antimicrobials with distinct mechanisms of action from existing drugs. The current pharmaceutical pipeline of new antibiotics is limited due to three obstacles: a lack of understanding of resistance mechanisms, a dearth of novel mechanisms of action among new …
Fear Learning And The Olfactory Bulb: Neural Correlates Of Behavioral Fear Generalization, Jordan Marie Ross
Fear Learning And The Olfactory Bulb: Neural Correlates Of Behavioral Fear Generalization, Jordan Marie Ross
Theses and Dissertations (ETD)
The exploration of how learning alters neural coding to guide behaviors remains fundamental to neuroscience. At the most basic level, the ability for organisms to flexibly adapt to changing environments and situations is paramount to biological success and often manifests in behavioral responses controlled by neural activity. For example, organisms must modify their behavior to defensive responses in the face of biological threat. Neural circuitry is involved in coordinating an initial defensive behavioral response but must undergo reorganization in order to reliably employ defensive responses in subsequent encounters based on a cue that signals imminent danger. One such form of …
Investigation Of Riluzole’S Synaptic Protection Mechanism Through Hsf1-Bdnf Axis, Yi Zhang
Investigation Of Riluzole’S Synaptic Protection Mechanism Through Hsf1-Bdnf Axis, Yi Zhang
Theses and Dissertations (ETD)
The FDA-approved amyotrophic lateral sclerosis (ALS) drug Riluzole has great potential in treating Alzheimer’s disease (AD) based on promising animal data as well as its known action on modulating synaptic transmission. However, its detailed mechanism of action is not fully understood. Here, we proposed work aiming to address this aspect via focus- ing on the Heat Shock Factor 1 (HSF1)-dependent mechanisms. We found that Riluzole could increase HSF1 and BDNF (Brain-Derived Neurotrophic Factor) expression both at transcriptional and translational levels. CA1 (Cornu Ammonia, the first region in the hip- pocampal circuit), is its main target. We also demonstrated a protective …
Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery, Jesse Jones
Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery, Jesse Jones
Theses and Dissertations (ETD)
Background: Significant concerns are associated with the use of broad-spectrum antibacterial agents, including collateral eradication of beneficial bacteria from the human microbiome, the onset of antibacterial-associated infections, and continued emergence of antibacterial drug resistance. As such, a critical need for novel and selective antibacterial targets exists. The investigation of two such targets, each pertaining to the highly concerning infections caused by streptococcal species and Clostridioides difficile, are presented herein. Bacterial topoisomerase I represents a potentially promising narrow-spectrum target as studies have arisen demonstrating its essentiality in bacterial species lacking the only other type IA topoisomerase (topoisomerase III). Additionally, recent studies …
The Role Of Secretory Phospholipase A2 Group Iia In Obesity And Metabolism, Michael S. Kuefner
The Role Of Secretory Phospholipase A2 Group Iia In Obesity And Metabolism, Michael S. Kuefner
Theses and Dissertations (ETD)
Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases previously implicated in inflammation, atherogenesis, and antibacterial actions. These enzymes hydrolyze glycerophospholipids at the sn-2 position releasing lysophospholipids and fatty acids. Though studies have shown PLA2G2A is pro-inflammatory and promotes atherosclerosis, no research has analyzed the role of this enzyme in obesity and metabolism. Studies in the past 5-10 years utilizing various knock- out or over-expression mouse models have analyzed the role of different secretory phospholipase A2s (sPLA2) in metabolic diseases. From these studies, it is known that at least seven of the 11 sPLA2 …
Regulation Of Cyp3a5 In Pancreatic Ductal Adenocarcinoma, Jessica D. Hoyer
Regulation Of Cyp3a5 In Pancreatic Ductal Adenocarcinoma, Jessica D. Hoyer
Theses and Dissertations (ETD)
CYP3A5 is a drug metabolism enzyme that is polymorphically expressed in normal tissues and expressed in high amounts in some cancers, including pancreatic ductal adenocarcinoma (PDAC). There have been several published studies regarding CYP3A5 regulators, but there is still much to be discovered concerning CYP3A5 regulation in cancer. To further understand the regulation of CYP3A5, a high-throughput screen was performed in the AsPC-1 PDAC cell line. This screen employed small interfering RNA (siRNA) targeting transcription factors and chromatin-associated proteins. We identified siRNA that decreased CYP3A5 mRNA and protein levels in AsPC-1 cells and probed into the potential mechanisms. Taken together, …
Identification Of Novel Cyp2e1 Inhibitor To Investigate Cellular And Exosomal Cyp2e1-Mediated Toxicity, Mohammad Arifur Rahman
Identification Of Novel Cyp2e1 Inhibitor To Investigate Cellular And Exosomal Cyp2e1-Mediated Toxicity, Mohammad Arifur Rahman
Theses and Dissertations (ETD)
Cytochrome P450 2E1 (CYP2E1)-mediated hepatic and extra-hepatic toxicity is of significant clinical importance. Diallyl sulfide (DAS) has been shown to prevent xenobiotics such as alcohol- (ALC/ETH), acetaminophen- (APAP) induced toxicity and disease (e.g. HIV-1) pathogenesis. DAS imparts its beneficial effect by inhibiting CYP2E1-mediated metabolism of xenobiotics, especially at high concentration. However, DAS also causes toxicity at relatively high dosages and with long exposure times. The objective of the first project was to find potent DAS analogs which can replace DAS as a research tool or as potential adjuvant therapy in CYP2E1-mediated pathologies.
Roles Of Γδ T Cells In Influenza Infections And Methods For Tcr Expression And Characterization, Xizhi Guo
Roles Of Γδ T Cells In Influenza Infections And Methods For Tcr Expression And Characterization, Xizhi Guo
Theses and Dissertations (ETD)
"Influenza virus is a significant pathogen in humans and animals with the ability to cause extensive morbidity and mortality. Exuberant immune responses associated with immune cell migration/activation and cytokine/chemokine release, can be induced after infections. Recent studies have painted a complex picture of viral clearance and tissue repair in adults. The immune responses in neonatal influenza infections and the potential methods to engineer antigen-specific T cells for immunotherapy against cancers and infections will be the focus of this dissertation." "Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that …
Sex-Related Differences In Perception And Discrimination Of Different Speakers: An Analysis Of The Auditory Dorsal Stream Via Eeg, David Thornton
Sex-Related Differences In Perception And Discrimination Of Different Speakers: An Analysis Of The Auditory Dorsal Stream Via Eeg, David Thornton
Theses and Dissertations (ETD)
Growing evidence that speech perception tasks elicit sensorimotor activity, and that this activity varies due to context, sex, cognitive load, and cognitive ability. However, it is unknown as to whether the sex of the speaker and demands of the task differentially effect males and females during speech perception tasks. This study investigated whether speaker sex and task demands (i.e. passive listening or active discrimination) influence sensorimotor and auditory cortical activity in males and females differently. Raw EEG data were collected from 27 males and 29 females during passive listening to, and discrimination of /ba/ and /da/ syllable pairs spoken by …
Challenging The Paradigm Of Clinical Triazole Resistance In Aspergillus Fumigatus, Jeffrey Michael Rybak
Challenging The Paradigm Of Clinical Triazole Resistance In Aspergillus Fumigatus, Jeffrey Michael Rybak
Theses and Dissertations (ETD)
Invasive aspergillosis is a leading cause of morbidity and mortality among immunocompromised populations and is predicted to cause more than 200,000 life- threatening infections each year. Aspergillus fumigatus is the most prevalent pathogen isolated from patients with invasive aspergillosis, accounting for more than 60% of all cases. Currently, the only antifungal agents available with consistent activity against A. fumigatus are the mold-active triazoles and amphotericin B, of which the triazoles commonly represent both front-line and salvage therapeutic options. Unfortunately, the treatment of infections caused by A. fumigatus has recently been further complicated by the global emergence of triazole resistance among …
The Effect Of Motor Responses Versus Verbal Responses On Sound Localization Accuracy In Young Children With Normal Hearing, Karen Ann Martin
The Effect Of Motor Responses Versus Verbal Responses On Sound Localization Accuracy In Young Children With Normal Hearing, Karen Ann Martin
Theses and Dissertations (ETD)
Rationale. Sound localization is the ability to pinpoint the origin of a sound source within an auditory space. This ability is essential for safety, orientation, and communication. Poor sound localization abilities, especially in young children, can have a negative impact on academics and safety. This issue is exacerbated when there is a hearing loss. Young children do not localize as well as adults until age 6 or older. Data regarding sound localization accuracy in preschoolers and young children have been sparse. Recently, with the increasing numbers of cochlear implantation (especially in children) there have been more studies investigating sound localization …
Injectable Systems For Long-Lasting Insulin Therapy, Kumar Kulldeep Niloy
Injectable Systems For Long-Lasting Insulin Therapy, Kumar Kulldeep Niloy
Theses and Dissertations (ETD)
Diabetes mellitus is one of the major global health problems and the prevalence rate is ever increasing reaching to 48% increase by the year of 2040 causing significant economic burdens. Insulin therapy has been the mainstay of diabetes treatment since its discovery in 1922. However, insulin is an unstable peptide with a half-life of only 4-6 min which poses significant challenge in prolonging duration of action of insulin. Nevertheless, the advances in recombinant DNA technology and protein engineering have enabled the development of several long-acting insulin analogue products which show duration of action up to 42 h. However, these insulin …
Study Of Natural Killer Cells And Their Therapeutic Role In Pediatric Cancer, Hong Ha Rosa Nguyen
Study Of Natural Killer Cells And Their Therapeutic Role In Pediatric Cancer, Hong Ha Rosa Nguyen
Theses and Dissertations (ETD)
NK cells are known to play an important role in the natural defense against viral infections and tumor immune surveillance. Through complex interactions between NK cell receptors and target cell ligands, transformed or unhealthy cells are identified and rapidly eliminated. NK cells have been used for therapeutic purposes in pediatric oncology, for example by harnessing the mechanisms of NK cell surveillance in acute myeloid leukemia (AML) or intervention-augmented antibody-dependent cell-mediated cytotoxicity (ADCC) in neuroblastoma. However, the underlying cellular mechanisms in these processes are not fully understood. In my thesis research, I sought to gain a deeper understanding of the molecular …
An Investigation Into Clinically Relevant Determinants Of Azole Resistance In Candida Albicans, Andrew T. Nishimoto
An Investigation Into Clinically Relevant Determinants Of Azole Resistance In Candida Albicans, Andrew T. Nishimoto
Theses and Dissertations (ETD)
"Candida albicans is a commensal organism commonly colonizing the human gut and skin. As an opportunistic pathogen, it can cause persistent and serious infections in individuals with compromised immune systems, including the very young and elderly. Moreover, C. albicans can cause a wide spectrum of diseases ranging from superficial mucosal infections to life-threatening invasions of the organs and bloodstream. Candida species are the most common cause of invasive fungal disease, which is associated with high mortality and imposes a heavy toll on the healthcare system. Over the last 30 years, the azole antifungals have been a mainstay of antifungal therapy, …
Molecular Mechanisms Of Metabolic Reprogramming In Pancreatic Cancer, Sonam Kumari
Molecular Mechanisms Of Metabolic Reprogramming In Pancreatic Cancer, Sonam Kumari
Theses and Dissertations (ETD)
Pancreatic cancer ranks as third deadliest cancer worldwide in both men and women. The lack of diagnostic methods, chemo-resistance and invasiveness of the disease diminishes the overall survival rate in patients. Dysregulated glucose metabolism and several molecular determinants including oncogenic signaling pathways play pivotal roles in the development, progression and metastasis of pancreatic cancer. The aberrant glucose metabolism is the most prevalent key factor that influences pancreatic tumorigenesis. The cancer cells of pancreas utilize oxygen for the breakdown of glucose to lactate, which is known as Warburg effect. This phenotype of pancreatic cancer encourages proliferation, growth, migration and invasive phenotypes …
Investigation Of Cell-Type-Specific Effects And Synergistic Interactions Between Genes In Duplication 15q Syndrome, Kevin A. Hope
Investigation Of Cell-Type-Specific Effects And Synergistic Interactions Between Genes In Duplication 15q Syndrome, Kevin A. Hope
Theses and Dissertations (ETD)
Duplication 15q syndrome (Dup15q) is a genetic disorder caused by duplications of the 15q11.2-q13.1 region and is characterized by developmental delay, autism spectrum disorder, and treatment resistant epilepsy. Extra copies of the E3 ubiquitin ligase UBE3A and elevated levels of UBE3A expression in neurons are thought to be the primary cause of Dup15q phenotypes. However, animal models overexpressing UBE3A in neurons have not successfully recapitulated all aspects of Dup15q syndrome, especially epilepsy. Here, we used Drosophila melanogaster (fruit flies) to investigate Dup15q syndrome. In Chapter 2 we explored whether Dube3a, the Drosophila homolog of UBE3A, is imprinted in the fly …
Using Genetic Diversity To Understand Susceptibility To Cognitive Decline In Aging And Alzheimer’S Disease, Sarah M. Neuner
Using Genetic Diversity To Understand Susceptibility To Cognitive Decline In Aging And Alzheimer’S Disease, Sarah M. Neuner
Theses and Dissertations (ETD)
An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging and transition to dementia such as Alzheimer's disease (AD). Identifying the specific genetic variants that contribute to cognitive aging and AD may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we turned to genetically diverse mice from the BXD genetic reference panel (GRP) to overcome some of the …
Transcriptional Regulation Of Nlrc4 Inflammasome By Irf8, Ein Lee
Transcriptional Regulation Of Nlrc4 Inflammasome By Irf8, Ein Lee
Theses and Dissertations (ETD)
The NLRC4 inflammasome is a crucial part of the innate immune response against bacterial infections. We found that NLRC4 inflammasome activation in bone marrow-derived macrophages (BMDMs) is greatly dependent on interferon regulatory factor 8 (IRF8). NLRC4-mediated caspase-1 activation and subsequent production of the inflammasome-dependent cytokines IL-1β and IL-18 and cell death were impaired in IRF8-deficient cells. IRF8 mediated the transcription of genes encoding NAIPs, the receptors for NLRC4 inflammasome, which recognize bacterial flagellin and type III secretion system (T3SS) proteins. IRF8 was critical for host survival following infection with Salmonella Typhimurium or Burkholderia thailandensis. Furthermore, mice deficient in IRF8 were …