Biomedical Sciences electronic theses and dissertations (MU)

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The items in this collection are the theses and dissertations written by students of the Department of Biomedical Sciences. Some items may be viewed only by members of the University of Missouri System and/or University of Missouri-Columbia. Click on one of the browse buttons above for a complete listing of the works.

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Modeling spatiotemporal patterns of chronic wasting disease using surveillance data
(University of Missouri--Columbia, 2024) Mosley, Joseph; Raghavan, Ram
Chronic wasting disease (CWD) is a neurodegenerative disease of cervids that has spread in North America uncontrollably since the late 1960s. This disease has no cure or effective prevention strategies, and its spread has wildlife disease management concerns as well as concerns for rural economies as many in the Midwestern states depend on big game hunting revenues. Surveillance of this disease by state wildlife health departments is done through nonprobabilistic sampling and it is often used for understanding the spatiotemporal distribution of the disease and its background prevalence in different areas. Making interpretations based on such surveillance data is problematic. In this study, I fit progressively complex Generalized Additive Models with a surveillance dataset collected in Kansas between 2005 - 2023 that was balanced spatially and spatiotemporally while comparing different ratios of negatively diagnosed data records to the positively diagnosed data sets. The best fitting model, with spatiotemporal smoothing functions and a tensor product interaction effect, produced a spatiotemporal probability map with an Area Under the Curve of 0.95, and a deviance explained of 65 percent. The prediction map reveals the potential spatiotemporal distribution of CWD in the state of Kansas and the spatiotemporal progression over the years. The northwestern, central, and southcentral portions of the state have progressively higher probability of cervids that could test positive for CWD. The potential spread of the disease to the eastern side of the state is also minimally evident.
Salivary analysis in dogs undergoing definitive radiation therapy for head and neck cancer
(University of Missouri--Columbia, 2024) Wyatt, Whitney Lee; Maitz, Charles
Xerostomia ("dry mouth") is one of the most common side effects of radiotherapy of head and neck tumors (HNT) in people and can significantly impact a patient's quality of life post-treatment. Aside from causing dry mouth, this condition may affect chewing, swallowing, and oral health. There are numerous diagnostic tools that have been utilized to diagnose and monitor xerostomia which include assessing salivary flow rates, proteomics, questionnaires, advanced imaging with CT and/or MRI, and videofluoroscopy. There is limited literature describing the incidence of radiation-induced xerostomia on canine patients. This study seeks to characterize the effect of radiation therapy on saliva composition and production, swallowing kinetics, and the clinical impact on canine patients with HNT. Dogs undergoing definitive-intent radiation therapy for HNT were prospectively enrolled in a clinical trial. Sixteen dogs were enrolled in the study, 14 dogs had nasal tumors and two dogs had oral tumors. Patients received timed saliva collection, saliva composition analysis, video/audio recordings of free feeding, and videofluoroscopic swallow study (VFSS) before and 1-, 3-, 6-, 9-, and 12-months post-treatment. Clients were also given a questionnaire to complete at each recheck. Saliva components were assessed in nine healthy dogs to establish baseline levels of lactate dehydrogenase (LDH), calcium, amylase, and phosphorus; mean values comparable to previously published data. The control and study group were similar, aside from a significant difference in phosphorus levels. The only significant finding, when assessing the study patients' components from baseline to 6-months post treatment, was a significant increase in the phosphorus level (P=0.03). Six study dogs had their saliva collection time recorded and there was a statistically significant increase in the saliva collection time across the 12-month recheck period (P=0.019). The significantly increased saliva collection time suggests that dogs with HNT experience radiation-induced xerostomia in the post-treatment period. Standardized client questionnaires were used to assess patients' eating and drinking behaviors. Results were variable, but most patients had abnormalities noted in the post-treatment setting and the majority of these coincided with prolonged saliva collection times. Interestingly, two patients were noted to develop severe calculus and gingivitis and required a dental cleaning in the post-treatment period. The absorbed radiation dose to the zygomatic, mandibular, and parotid glands was assessed. The highest mean dose was received by the zygomatic salivary glands, most notably the ipsilateral zygomatic gland (34.72 Gy). The volume of the zygomatic glands in the pre-treatment and post-treatment CT were assessed and there was a 58 percent volume reduction of the ipsilateral zygomatic gland. These patients were noted to have prolonged saliva collection times at this 6-month recheck period. Two methods were used to assess swallowing in the patients: VFSS and standard video/audio recordings during free feeding. Two patients were included in the VFSS portion of the study and five were included in the video/audio recordings. The video/audio analysis is underway. The results from VFSS are variable. The Lick-Swallow-Rate (LSR) and Inter-Swallow-Interval (ISI) were almost doubled at either the 1-month or 3-month recheck study. The time to maximum hyolaryngeal excursion (HLE) and pharyngeal transit time (PTT) were also elevated in the post-treatment period. These findings correlated with a prolonged saliva collection time in these dogs at these timepoints. The combination of these results demonstrate that canine patients can develop radiation-induced xerostomia and this side effect may impact the patients eating and drinking behaviors and oral health. These changes may impact a patient's quality of life and strategies to limit xerostomia and manage these clinical signs should be explored.
An evaluation of intramammary infection status in dairy heifers
(University of Missouri--Columbia, 2024) Novo, Alyssa; Adkins, Pamela
Contrary to expectation, IMI are prevalent in prepartum heifers. Though awareness of the problem has increased, there are still many questions surrounding the etiology and epidemiology of heifer IMI. For example, there is a paucity of studies evaluating IMI status in heifers prior to late gestation. Therefore, it is not known when heifers become susceptible to IMI or when the greatest risk of IMI occurs during the heifer life cycle. Furthermore, persistence of IMI identified during early lactation has been recently evaluated; however, data on the persistence of species first isolated from prepartum IMI, into early lactation, is lacking. Additionally, it is difficult to compare results between studies since there is no gold standard sampling method in primigravid and nulligravid heifers, no universally accepted IMI definition in heifers, and the methods that have been utilized for bacterial speciation vary in their reliability. The first study of this thesis, Chapter 2, addresses the knowledge gaps surrounding IMI prevalence in primigravid and nulligravid dairy heifers through the evaluation of 4 sampling techniques, including a teat canal swab, mammary secretions collected through the teat end, mammary secretion samples collected by cisternal puncture, and fine needle aspiration of the mammary tissue. Our second study (Chapter 3) aims to access the occurrence of IMI within 8 d postpartum and its relationship to the prepartum prevalence found in the first study. Results of these studies suggest that heifers are potentially susceptible to IMI by 6mo of age and, therefore, investigations are warranted to determine the prevalence and incidence of IMI in primigravid and nulligravid heifers. Furthermore, the IMI occurrence in heifers remained relatively constant between midgestation and 8d post-calving, whereas the IMI occurrence increased between initial sampling and 8d postpartum for the animals initially sampled as mature nulligravid heifers (ages 11-16mo). Therefore, while the focus of many treatment and prevention investigations have been primarily focused on late gestation, earlier treatments may be more effective in reducing the IMI prevalence in early lactation. Overall, diagnostic methods utilizing mammary sampling techniques that bypass the teat canal, such as a cisternal puncture or FNA technique, for prepartum IMI diagnosis may aid in developing a more comprehensive analysis of the etiology and epidemiology of IMI in nulligravid and periparturient heifers.
Elucidating the role of LARP6 in cardiovascular remodeling
(University of Missouri--Columbia, 2024) Russell, Jacob Jeffrey; Bender, Shawn B.; Bysani, Chandrasekar
Heart failure remains the leading cause of death in the United States, and always progresses despite currently available treatments and therapeutics. Of note, structural remodeling of the heart precedes the onset of overt symptoms that diminish a patient's quality of life. Many factors contribute to the adverse remodeling and dysfunction observed in heart failure. Of note, obesity, excess sympathetic drive, elevated angiotensin II and aldosterone signaling, and fluid overload create a distinct milieu of cardiac stressors. To compensate, the heart undergoes a period of necessary structural remodeling. However, chronic/excess remodeling disrupts tissue homeostasis and creates an environment that can exacerbate cardiac dysfunction. Therefore, identifying novel, effective therapeutic targets that prevent structural cardiac remodeling and delay the appearance of symptoms is of immense importance. One such molecular target is the La ribonucleoprotein 6, translational regulator (LARP6), which is an mRNA binding protein described for its contributions to fibrotic remodeling. This is achieved through the interaction between LARP6 and the 5' stem loop (5'SL) of collagen I and III mRNA, which increases their half-life and initiates their translation. However, the role of LARP6 in cardiac remodeling has yet to be described. To elucidate its role in cardiovascular remodeling, we genetically manipulated the function of LARP6 in two mouse models and exposed them to clinically relevant cardiac stressors. For the first aim, we utilized the 5'SL mutant mice which possess a mutation within the 5'SL of collagen I transcripts that prevent LARP6 from binding and is reported to decrease fibrotic remodeling. This study was conducted in response to high fat high sucrose (HFHS) feeding in male mice for 28 weeks. Endpoint cardiac assessment revealed increased diastolic dysfunction in WT mice fed a HFHS diet, which was prevented by the 5'SL mutation. Interestingly, fibrosis was not induced by the diet, therefore the protective effect of the 5'SL mutation was mediated through collagen independent effects. To increase focus on the role of LARP6 in cardiac fibrosis, we used a model of Ang II infusion (1000 ng/kg/min) to induce hypertension and cardiac remodeling. This second aim was conducted in male 5'SL mice. Ang II infusion significantly increased blood pressure, cardiac hypertrophy, and fibrosis remodeling in both WT and 5'SL mice. Therefore, in contrast to published data in different organs, LARP6 is dispensable in hypertension-induced fibrotic remodeling. Our final aim was to investigate the role of LARP6 within cardiomyocytes, a cell type not typically associated with fibrotic remodeling. To do this, we generated a transgenic mouse line overexpressing LARP6 in a cardiomyocyte-specific manner. We performed baseline longitudinal studies on male and female mice from 16-40 weeks of age. During this time, WT and LARP6 Tg mice were assessed for changes in blood pressure via tail-cuff plethysmography, as well as cardiac function and cardiac morphology by magnetic resonance imaging (MRI). At 40 weeks of age, mice were euthanized and tissue collected for additional molecular assays. We found that the LARP6 transgenic mice had increased Larp6 gene expression and protein expression localized to cardiomyocytes within the heart. Further, this increase in baseline LARP6 was associated with -increased ColIa1 gene expression, and significantly increased fibrotic remodeling at 40 weeks of age as assessed by picrosirius red (PSR) staining. However, MRI revealed that there were no significant differences in baseline cardiac function. Therefore, we wanted to challenge these mice with hypertensive insult. We expected that the male and female LARP6 Tg mice would have exacerbated cardiac fibrosis and dysfunction with Ang II infusion (1000 ng/kg/min). Unexpectedly, LARP6 prevented the Ang II-mediated systolic dysfunction that was observed in WT mice. Further, LARP6 prevented Ang II-induced interstitial, but not perivascular, fibrosis. This reduction in interstitial fibrosis was associated with reduced myofibroblasts activation as assessed by the number of interstitial cells expressing periostin. RNA sequencing revealed widespread changes to the cardiac transcriptome in response to LARP6 overexpression. Overall, cardiomyocyte-derived LARP6 is a multifunctional protein that exerts cardioprotective effects in the setting of hypertension.
Objective assessment of computed tomographic attenuation of inspiratory and expiratory series in dogs with and without bronchomalacia
(University of Missouri--Columbia, 2024) Gerhard, Charlotte; Reinero, Carol R.
Paired inspiratory:expiratory breath-hold computed tomographic scans (I:E-BH CT) capture thoracic images with control of respiratory phase, important with dynamic airway collapse. Radiomics allows assessment of objective metrics of lung attenuation. Hypothesis/Objectives: Dogs with bronchomalacia (BM) would have significantly different objective metrics of attenuation on I:E-BH CT reflecting changes in airway caliber and impaired downstream parenchymal aeration versus dogs without BM (NoBM). The objectives of this study were to document objective metrics of attenuation of the pulmonary parenchyma on I:E-BH CT in dogs with BM and NoBM using automated software analysis. Metics included mean lung attenuation (MLA), percent low attenuation area -856 Hounsfield units (HU; LAA percent-856), percentage high attenuating areas -700 HU (HAA percent-700), and percent attenuation area between -600 and -250 HU (HAA percent-600--250). Participants included client-owned dogs with BM (n=123) and NoBM (n=20). This retrospective study utilized 3D Slicer software to assess CT attenuation. Analysis used Spearman correlation and 2-way ANOVA with beta regression. When comparing the difference between inspiratory/expiratory phases, there was a significantly greater increase in MLA (p=0.001), a significant reduction in LAA percent-856 (p=0.016), and a significant increase in HAA percent-700 and HAA percent-600-250 (p [less than] 0.001 and p [less than] 0.0001, respectively) in BM versus NoBM dogs. In conclusion, a higher lung attenuation in BM dogs supports presence of impaired downstream parenchymal aeration to segmental and subsegmental airway collapse. Quantitative imaging holds promise for objectively evaluating changes with BM.

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