Theses and Dissertations

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21598

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A Retrospective Analysis of Outcomes with Pulmonary Artery Catheter Use in Patients Diagnosed with Cardiogenic Shock
(2024-08) Hollinger, Tess S.; Bunnell, Bruce A.; Liu, Ran; Felius, Joost
The primary goal of this study is to observe which timing variable of pulmonary artery catheter (PAC) insertion, or no PAC insertion is related to better in-hospital outcomes of patients with cardiogenic shock. Furthermore, additional variables like sex and health history are tested to see if they affect the relationship of PAC timing and inhospital outcomes. Data were retrospectively collected from the CSWG registry at a single center, BUMC. All variables collected were redacted and combined to form a dataset. From here I used the PAC timing and cardiogenic shock diagnosis variables to manually place patients into groups for analysis. The groups used were Prior (PAC placement before cardiogenic shock diagnosis), Early (PAC placement within 6 hours or less of cardiogenic shock diagnosis), Delay (PAC placement after 6 hours of diagnosis), None (no PAC use). 227 patients' data was collected and used for analysis. The only groups that were observed to have a significant difference in in-hospital outcomes were the Prior and Delay groups that have a significant decrease in in-hospital mortality in comparison to the Early group. The results of the analyses support that PAC timing groups Prior and Delay have less in-hospital mortality when compared to the Early group. There were no other findings to draw statistically significant conclusions from.
ADAM19 and ADAMTS4 expression in Human Optic Nerve Head Astrocytes
(2024-05) Easo, Tony; Tovar-Vidales, Tara; Inman, Denise; Rosales, Armando
Summary: Glaucoma is characterized by the degeneration and death of retinal ganglion cells (RGCs) and their axons, causing irreversible blindness. Various risk factors contribute to glaucoma onset, including intraocular pressure (IOP), age, and family history (1). In glaucoma, the primary site of damage is the optic nerve head (ONH), specifically the lamina cribrosa (LC) region. The ONH undergoes significant stress and structural changes in response to elevated IOP, leading to the death of RGCs (2). ONH astrocytes, a major cell type in the LC, are believed to play a significant role in the pathological remodeling of the extracellular matrix (ECM) during glaucoma. These cells respond notably to biomechanical stresses and increased levels of the fibrotic cytokine transforming growth factor beta 2 (TGFβ2), which is commonly found in the aqueous humor, trabecular meshwork, and optic nerve head (ONH) of glaucoma patients (2). Our lab has previously shown that ONH tissues treated with TGFβ2 show an increase in proteins that could be involved in glaucoma pathology. In this study, we primarily investigated the expression and regulation by TGFβ2 of A Disintegrin and Metalloproteinase (ADAM19) and ADAM with thrombospondin motifs (ADAMTS4) in ONH astrocytes. Hypothesis: IOP and remodeling of the ECM in the LC of the ONH are hallmarks of the pathogenesis of glaucoma. TGFβ2 is a profibrotic cytokine known to induce the synthesis and deposition of ECM. TGFβ2 increases ECM synthesis and deposition by ONH astrocytes within the LC, and RNA sequencing showed disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTS) were significantly dysregulated with TGFβ2 treatment compared to controls. Our lab has previously demonstrated that human ONH cells derived from glaucoma donors or treated with exogenous TGFβ2 increase profibrotic miRNAs and decrease anti-fibrotic miRNAs. MiR29c specifically, has been predicted to regulate members of the ADAM family proteins. Given that ADAMs and ADAMTS4 influence cell phenotype by modulating the ECM through cell adhesion, migration, proteolysis, and signaling pathways (19), we hypothesize that ONH astrocytes express ADAM19 and ADAMTS4 and that TGFβ2 and miR29c regulates ADAM19 and ADAMTS4 expression in ONH astrocytes. Significance: The existing treatments for glaucoma primarily focus on reducing IOP, which has proven effective in slowing the progression of the condition in many cases; however, it falls short of halting vision loss. To fully comprehend the intricacies of glaucoma pathology, investigating the expression of ADAM proteins in response to treatment with or without TGFβ2 in ONH astrocytes can provide insights that contribute to a better understanding of the disease and, potentially, the development of more holistic therapeutic approaches.
The Functional Role of Lectin-like Transcript 1 (LLT1) in Hepatocellular Carcinoma
(2023-08) Perkins, Joshua; Mathew, Stephen O.; Sankpal, Umesh; Basha, Riyaz; Chaudhary, Pankaj; Jones, Harlan P.
Hepatocellular carcinoma (HCC) is a global leading cause of cancer-related deaths. Current treatments for HCC are ineffective. Transplantation and surgical resection are the only curative options, however, only an approximate 3% of HCC patients are eligible. Without transplantation or resection, the 5-year, overall survival (OS) rates remain <10%, with death 6-18 months from diagnosis. Cancer immunotherapy provides an avenue to investigate potential treatments as immunotherapies can promote immune-mediated tumor lysis, while sparing patients from some of the toxic effects of radiation and chemotherapy. Prior research suggests the inhibitory mechanisms underlying the LLT1/NKR-P1A interaction attributes to cancer growth as it allows the cancer to evade immune surveillance. Studies demonstrate improved NK cell activity and NK cell-mediated tumor lysis upon applying LLT1 blockades in prostate, breast, and hematological cancers. The goal of this project was to similarly evaluate the role of LLT1 in HCC.
MECHANISM OF ACTION AND DRUG DELIVERY OF HYBRID NITRIC OXIDE DONATING AND ANTIOXIDANT SMALL MOLECULES IN EXPERIMENTAL MODEL OF OCULAR HYPERTENSION
(2024-05) Amankwa, Charles E.; Acharya, Suchismita; Krishnamoorthy, Raghu R.; Stankowska, Dorota L.; Karamichos, Dimitrios; Ellis, Dorette Z.; Mathis, Michael
Primary open angle glaucoma (POAG) belongs to a group of optic neuropathies characterized by the damage to the optic nerve head, and the slow progressive deterioration of retinal ganglion cells (RGCs). POAG is predominantly asymptomatic in its early phases, and the leading cause of irreversible blindness globally. The underlying mechanisms of POAG include but not limited to; elevated intraocular pressure (IOP), excitotoxicity, and oxidative stress. Additionally, reduced trabecular meshwork (TM) cellularity, viability and decreases in antioxidant enzymes have been reported to be implicated in the pathogenesis of POAG. Currently, IOP reduction remains the mainstay for slowing down the progression of RGC degeneration and TM cell death. However, IOP lowering alone does not eliminate the progressive neurodegeneration events. Therefore, the development of novel therapeutic strategies that can reduce IOP and simultaneously provide neuroprotective benefits is essential for the effective management of POAG. To this end, we designed and synthesized novel hybrid nitric oxide donor and antioxidant small molecules (SA-2, SA-9, and SA-10) with the goal of lowering IOP and providing neuroprotection in experimental models of glaucoma. In the present study, we evaluated the in-vitro efficacy of SA-analogs in protecting TM cells from oxidative stress induced cell death. Additionally, we aimed at understanding the mechanism of action of SA-2 and assessed its in-vivo IOP lowering efficacy and toxicity profile in PLGA encapsulated nanoparticles after topical administration. Considering that less than 5% of a topically applied drug reaches intraocular tissues due to limited ocular absorption, rapid precorneal drug elimination, and the corneal epithelial barrier, our overarching goal was to provide a sustained and prolonged IOP lowering effect to reduce the frequency of dosing and potential adverse effects to ocular tissues. We demonstrated the utility of SA-2, SA-9, and SA-10 as novel strategies to promote survival of TM cells by scavenging reactive oxygen species. We found that SA-2 and the second-generation sulfur containing hybrid NO donor-antioxidants: SA-9 and its active metabolite SA-10 scavenged broad-spectrum ROS while maintaining NO bioavailability. We observed significant improvement in antioxidant enzymes following treatment with SA-2. Notably, catalase, glutathione peroxidase and total antioxidant enzyme levels were increased with SA-2 treatment along with increased TM mitochondrial respiration. Our studies showed that the SA-2 encapsulated in PLGA polymer was readily bioavailable to both the anterior segment and posterior regions of the eye. This observation reflected in the sustained IOP reduction of SA-2 lasting for 6 days with no overt toxicity and functional decline in C57BL6/J mice eyes. In summary, this dissertation project provides an alternate therapeutic strategy in the management of POAG. Our modified formulation of SA-2NPs is a promising candidate for a sustainably reducing IOP while providing neuroprotection to the RGCs and TM.
Evaluating the Association of Gender as it Pertains to Health-Related Quality of Life Outcomes in Chronic Low Back Pain Patients
(2024-05) Slater, Madeline L.; Cunningham, Mark W., Jr.
BACKGROUND: Six hundred and nineteen million individuals worldwide are affected by low back pain, with this number estimated to increase to 850 million by the year 20501. Low back pain is also the leading cause of disability worldwide2 and contributes to the limitation of activities and needing leave from work resulting in severe medical burdens and economic costs3,4. Males and females (referred to as gender throughout this project based on variables in the NIH Minimum Dataset form for Chronic Low Back Pain) have recorded differences in chronic low back pain outcomes including, but not limited to, treatment outcomes and psychosocial outcomes. Individuals with female sex traditionally take on the female gender with associated norms and roles, and those with male sex often take on male gender and associated roles. Previous literature on this topic varies by location and typically reports on local patients. The PRECISION Pain Research Registry differs from other research projects because the participants involved in this study are from locations within the continental United States. This diversity in terms of location, ethnicity, and race of study participants allows a larger and more applicable representation of the U.S. population in terms of chronic low back pain management. Discrepancies on whether gender has an effect on health-related quality of life outcomes in chronic low back pain patients in the literature is controversial. Thus the link between gender and chronic low back pain outcome is unknown and is the focus of this study, in which we will use the PRECISION Pain Research Registry to examine the relationship. HYPOTHESIS: We hypothesize that males and females with chronic low back pain have different health-related quality of life outcomes and these differences are correlated to pain catastrophizing and pain-self efficacy scores. The specific aims of the project include (1) analyzing the association between gender and pain catastrophizing in chronic low back pain patients, (2) analyzing the association between gender and pain self-efficacy scores in chronic low back pain patients, and (3) using repeated measures to assess differences between males and females in chronic low back pain outcomes pertaining to health-related quality of life over a 12-month period. METHODS: Data from 1,478 patients in the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION) were analyzed using factors such as gender, age, race, ethnicity, smoking habits, low back pain duration, opioid use for low back pain treatment, occurrence of low back pain surgery, education level, comorbidities, non-pharmacological treatments, and body mass index (BMI). Importantly, this project conducted analysis to determine the association between gender and pain catastrophizing, pain self-efficacy, and health-related chronic low back pain outcomes. The health-related quality of life outcomes of sleep disturbance, pain interference, anxiety, depression, and energy levels are taken from the negative outcomes from the Patient-Reported Outcomes Measurement Information System (PROMIS) scale. RESULTS: Overall, there were no statistically significant associations between gender and pain catastrophizing scores with males having slightly higher scores compared to females. No association was seen between gender and pain self-efficacy. Male patients once again had slightly higher scores but the mean score difference was not significant. Results from interaction term analysis showed that pain catastrophizing and pain self-efficacy scores on their own have an effect on SPADE health-related quality of life outcomes but upon the introduction of gender, the effect becomes negligible.
Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats
(2023-08) Siyang, Lin; Jin, Kunlin; Sumien, Nathalie; Yang, Shaohua; Schreihofer, Derek A.
Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD), plaguing the elderly population. Although there is no definitive pathological definition of VCI, it is generally accepted that VCI results in global and/or local cerebral hypoperfusion, leading to cortical and subcortical infarcts and white matter lesions (WMLs). The integrity of white matter is critical in regulating efficient neuronal communication and maintaining cognitive function. Chronic cerebral hypoperfusion-induced WMLs are now considered a key mechanism leading to VCI and dementia. However, the mechanism underlying WMLs in response to hypoperfusion has not yet been fully clarified. Recent studies have shown that the dysfunction of pericytes is related to diverse vascular disorders, such as stroke and AD. Yet, the pathological event bridging pericyte dysfunction and cognitive impairment in VCI is unexplored. In this study, we aimed to investigate whether pericyte dysfunction could affect WMLs and cognitive impairment in a rat VCI model. Using a rat model of chronic cerebral hypoperfusion-induced VCI by two-vessel occlusion (2VO), we confirmed that 2VO could induce WMLs and cognitive impairment. We found that the number of pericytes in the brain was significantly altered after 2VO. Furthermore, we found that the capillary constrictions at pericyte bodies were significantly increased in the brain after 2VO compared to sham-operated rats, along with reduced cerebral blood flow (CBF). We then asked whether manipulating pericyte function could affect WMLs and cognitive impairment in VCI rats. CGS21680, a specific adenosine A2A subtype receptor agonist, has previously shown the effect of vasodilation. We intranasally administered CGS21680 twice per day for 7 days and found that the rats treated with CGS21680 showed a significant CBF increase at 7 and 14 days after 2VO, compared to the vehicle group, along with an increase in capillary lumens beneath pericytes after the treatment. Importantly, WMLs and cognitive impairment were significantly improved after CGS21680 treatment compared to the vehicle group. Our data suggest that pericyte dysfunction plays a critical role in WMLs and cognitive impairment in the rat model of VCI, which will help us further understand the pathogenesis and develop targeted interventions for VCI.
Examining the Impact of Multiple Clinical Profiles on Recovery Time in Pediatric Patients with Sports-related Concussion
(2024-05) Varghese, Merin M.; Gregory, Paula; Driver, Simon; Anderson, Jessica; Gwirtz, Patricia A.
Purpose: The primary objective is to identify potential relationships between primary clinical profiles (cognitive/fatigue, vestibular, ocular, migraine, anxiety/mood) and secondary clinical profiles, exploring how these interactions influence the duration of recovery in pediatric (SRC) patients. This study aims to provide valuable insights that can be used to create tailored and more effective treatment strategies, ultimately enhancing recovery outcomes. Hypothesis: There is a positive association between primary clinical profile and secondary clinical profile in pediatric patients with SRC (sports related concussion), which is related to patient recovery time. Methods: The study employs a retrospective design, utilizing data from the Concussion Registry at Baylor Scott & White Sports Concussion program to explore associations between variables. Statistical analyses, including chi-squared tests, odds ratio, t-test, ANOVA, and negative binomial regression models, will be conducted. The population consists of pediatric patients aged 12-18 diagnosed with SRC at the BSW Concussion Clinic. Results: We found significant associations between primary and secondary clinical profiles, particularly between cognitive/fatigue and migraine, migraine and ocular, migraine and vestibular, ocular and cognitive/fatigue, and ocular and migraine profiles. However, no substantial correlation was observed between these profile combinations and recovery time. Conclusion: This study emphasizes the need for a multidimensional approach to assessment and management of SRC in pediatric patients. While clinical profiles are associated, they do not significantly impact recovery time. Personalized care plans and treatment strategies can be developed by considering both primary and secondary clinical profiles to enhance recovery outcomes. Further research is required to better understand SRC in this population and address the study's limitations.
Store-Operated Calcium Entry and Podocyte Injury in Diabetic Nephropathy
(2024-05) Tao, Yu; Ma, Rong; Cunningham, J. Thomas; Mallet, Robert T.; Mathis, Keisa W.; Yan, Liang-Jun
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Proteinuria/albuminuria is not only the early clinical manifestation of DN, but also exacerbates kidney injury in DN and is associated with the mortality and cardiovascular event of DN. Podocytes are one of the major components of glomerular filtration barrier, and podocyte injury is the primary cause of proteinuria. Hyperglycemia is the major initiator of podocyte injury in DN. However, the underlying molecular mechanisms remain poorly understood. Store-operated calcium entry (SOCE) is a multifunctional calcium signaling in both excitable cells and non-excitable cells. Recent studies imply the pivotal roles of calcium signaling pathway in maintaining podocyte integrity, metabolism, and survival. However, the role of SOCE in podocytes in the setting of diabetes is not known. The present study aimed to determine the role of SOCE in podocytes in diabetic settings and the underlying molecular mechanisms. Our first specific aim was to determine that enhanced SOCE contributes to high glucose (HG)-induced podocyte injury. We first identified that the Orai1-mediated SOCE was enhanced in HG-treated podocytes. We further discovered that pharmacological and genetic inhibition of SOCE prevented nephrin protein loss and cytoskeleton disorganization in HG-treated human podocytes, suggesting a detrimental effect of exaggerated SOCE in podocytes. The second specific aim was to determine that the calpain signaling mediated HG/SOCE-induced podocyte injury. In immortalized human podocytes, HG treatment enhanced calpain activity, which was blunted by an SOCE inhibitor (BTP2). Furthermore, a calpain-1 and calpain-2 inhibitor (calpeptin) significantly attenuated podocyte nephrin protein loss induced by HG treatment. Theses results suggest that the calpain signaling pathway participates in HG/SOCE-induced podocyte injury. The last specific aim was to identify that SOCE contributed to podocyte injury in DN by impairing mitochondrial function. Using cultured immortalized human podocytes, we found that the SOCE inhibitor (BTP2) suppressed HG-induced depolarization of the mitochondria membrane potential, reduced ATP production, and impaired mitochondria respiration function. In addition, angiotensin II (Ang II), a known SOCE activator and a podocyte injury inducer in DN, also induced mitochondrial dysfunction in podocytes. Consistent with the results from HG treatment, inhibition of SOCE by BTP2 significantly attenuated the Ang II-induced podocyte mitochondria damage, suggesting the mitochondrial mechanism underlying the SOCE-induced podocyte injury. In conclusion, our present study suggests that enhanced SOCE is a new detrimental mechanism contributing to HG-induced podocyte injury by upregulating the calpain signaling pathway and impairing mitochondrial function. Therefore, suppressing SOCE and its downstream pathways would potentially slow down the development of DN.
Cancer Incidences And Outcomes In Adolescent And Young Adult Patients Living In Food Deserts - A Retrospective Study At Cook Children's Medical Center
(2024-05) Miller, Whitney N.; Basha, Riyaz
Food Deserts, as classified by the USDA, are areas of low access to nutritious foods. Access to nutritious food is inhibited by resources such as income, transportation, and/or distance to stores with healthy food options. The areas classified as food deserts are most commonly found in minority communities. Living in a food desert has been associated with several chronic diseases such as hypertension, coronary heart disease, chronic obstructive pulmonary disease, kidney disease, and cancer. This study evaluates adolescent and young adult data from the Cook Children's Cancer Registry for food desert status and its relationship between demographics and survival. The AYA oncology population is a growing area of research but remains understudied. Research looking into the health disparities caused by food deserts can impact future care by improving health and disease outcomes in the AYA community.
Biopsychosocial Factors Related to Weight Loss for Adults with Acquired Brain Injury Individuals in the Diabetes Prevention Program Group Lifestyle Balance
(2024-05) Alrawi, Shahad K.; Hodge, Lisa M.; Patterson, Rita M.; Driver, Simon; Quilico, Enrico
Purpose: The goal of this study was to combine data from two 12-month Diabetes Prevention Program Group Lifestyle Balance (DPP-GLB) randomized control trials (RCT)s among adult participants with acquired brain injury (ABI; i.e., traumatic brain injury and cerebrovascular accident [CVA; i.e., stroke] ) to identify the profiles of program responders ( ≥ 5% weight-loss at 12 months) and non-responders (< 5% weight-loss at 12 months) at 3, 6, and 12 months across biopsychosocial variables, including demographic, injury-related, self-report, and physiological factors. Hypothesis 1.1: Based on previous findings, we anticipate that age [22], body mass index (BMI) [27], and type of injury [22, 26] will be significantly different between groups. Also, it is anticipated that there will be differences in biological waist circumference, hemoglobin A1C, blood pressure, and 8-year diabetes risk) between responders and nonresponders. Methods: Data was collected from two RCTs examining the effect of the DPP-GLB program on people with ABI. Participants with TBI were 18-64 years of age, had a moderate to severe brain injury, were at least 6 months post-injury, and had a BMI ≥25kg/m2. Participants with CVA/Stroke were 18-85 years of age, had any type of stroke (e.g., hemorrhagic, anoxic), were at least 12 months post-injury, and had a BMI ≥25kg/m2. All participants were recruited from Baylor Scott & White Institute for Rehabilitation (BSWIR) system through flyers, calls, and emails, as well as through outpatient CVA/TBI support groups. Results: Sixty-nine (45 CVA, 24 TBI) participants completed 12-month follow-up in their respective studies with 33 (78%) [18 (38%) CVA, 16 (67%) TBI] classified as responders. There was a greater proportion of responders with a TBI diagnosis (p=0.02), but no additional statistically significant differences were detected (all p>0.05). Conclusion: Results indicate that biopsychosocial variables do not have a significant correlation to weight-loss in participants who responded and didn't respond to the GLB-TBI and GLB-CVA.
Carvedilol, an alternative for lowering liver stiffness in patients with cirrhosis and portal hypertension
(2024-05) Guriginjakunta, Niharika; Sankpal, Umesh; Heck, Amber J.
Liver cirrhosis, often associated with portal hypertension, presents a significant health burden globally. Carvedilol, a non-selective beta-blocker, has emerged as a promising therapeutic option for managing portal hypertension in patients with liver cirrhosis. This retrospective analysis assessed the effect of Carvedilol treatment on patients with liver cirrhosis and clinically suspected portal hypertension, focusing on its effects on liver function parameters, non-invasive fibrosis scores, and liver stiffness measurements. A total of 130 patients from the Liver Center of Texas were included in this retrospective analysis, comprising 65 patients in the treatment group receiving Carvedilol and 65 patients in the control group. Statistical analyses, including t-tests, were conducted to assess the differences between groups. Carvedilol treatment led to significant improvements in liver function parameters, including a reduction in AST levels, indicative of improved liver function. Non-invasive fibrosis scores, such as FIB-4, AGILE 3, AGILE 4, and APRI, showed notable improvements after Carvedilol treatment in the treatment group, suggesting a reduction in liver fibrosis and improved prognosis. Liver stiffness measurements using eKpa and CAP scores demonstrated significant reductions after Carvedilol treatment within the treatment group, indicating improved liver stiffness. The study suggests that Carvedilol is effective in managing portal hypertension in patients with liver cirrhosis. Further research is needed to confirm these findings in larger cohorts and evaluate the long-term efficacy, and safety of Carvedilol treatment. Additionally, addressing disparities in liver disease diagnosis and treatment is crucial for improving outcomes and reducing the burden of liver-related morbidity and mortality.
Comparative Patient Outcome Analysis Between Two Radiation Therapies for Head and Neck Cancers
(2023-05) Stein, Maggie J.; Ranjan, Amalendu P.; Basha, Riyaz; Neufeld, Sarah; Desai, Kajal
The Interaction Between Arterial Stiffness, Amplitude of Cerebral Blood Flow Oscillations, and Cerebral Tissue Oxygenation
(2024-05) Hudson, Lindsey M.; Rickards, Caroline A.; Tune, Johnathan D.; Dick, Gregory M.
Inducing 0.1 Hz (10-s cycle) oscillations in cerebral blood flow attenuates the reduction in cerebral tissue oxygenation during simulated hemorrhage in humans. Our laboratory has developed a potential therapeutic technique called pulsatile perfusion therapy (PPT) which induces 0.1 Hz oscillations in cerebral blood flow. It is unknown, however, how stiffness of the arteries influences the magnitude of cerebral blood flow oscillations, and/or the protection of cerebral tissue oxygenation. When 0.1 Hz oscillations are induced during simulated hemorrhage, we hypothesized that: 1) arterial stiffness of the internal carotid artery (ICA) and common carotid artery (CCA) would increase from rest; 2) the amplitude of 0.1 Hz oscillations in cerebral blood flow would be higher in individuals with stiffer arteries, and; 3) the reduction in cerebral tissue oxygenation would be smaller with higher amplitude of cerebral blood flow oscillations. Two studies using two different techniques of PPT were performed to investigate these hypotheses. Study 1: In a retrospective analysis, 8 healthy human participants (age: 30.1±7.6 y) underwent a 10-min hypovolemic oscillatory lower body negative pressure (OLBNP) protocol, where chamber pressure oscillated every 5-s between -30 mmHg and -90 mmHg (i.e., 0.1 Hz). ICA β-stiffness index was calculated from measurements of ICA diameter (via ultrasound imaging), and arterial pressure (via finger photoplethysmography). Middle cerebral artery velocity (MCAv) was measured using transcranial doppler ultrasound, and cerebral tissue oxygenation (ScO2) was measured with near infrared spectroscopy. Fast Fourier transformation was used to quantify oscillations in mean MCAv at ~0.1 Hz. While mean MCAv 0.1 Hz oscillations increased from baseline to OLBNP (N=8, 34.0±33.9 (cm/s)2 vs. 104.7±58.1 (cm/s)2, p=0.01), ICA β stiffness did not increase (N=5, 6.1±0.7 au vs. 8.2±2.7 au, p=0.21). There was no relationship between baseline ICA β-stiffness and the percent change in mean MCAv 0.1 Hz oscillations (N=5; r=0.44, p=0.46). ScO2 decreased from baseline to OLBNP (N=8, 66.5±2.9 % vs. 64.8±2.9 %, p=0.03), but there was also no relationship between the percent change in mean MCAv 0.1 Hz oscillations and the decrease in ScO2 (r=0.28, p=0.50). Study 2: In a prospective pilot study, 3 participants underwent a 10-min LBNP protocol to a chamber pressure of -60 mmHg, and hemodynamic oscillations were simultaneously induced with bilateral thigh cuffs inflating for 5-s to 230 mmHg then deflating for 5-s in a 10-s cycle (i.e., 0.1 Hz). β-stiffness index of the CCA was measured. In this pilot study, insufficient data were collected to perform statistics for each of the three aims, so descriptive results are presented. Adequate ultrasound measurements were made for assessment of CCA β- stiffness in two participants; in the control condition, CCA β-stiffness was 6.7 ± 2.4 au during baseline and increased to 7.4 ± 1.1 au during LBNP (N=2). With PPT, CCA β-stiffness was 6.6 ± 1.6 au during baseline and increased to 7.8 ± 2.2 au during LBNP (N=2). The amplitude of MCAv 0.1 Hz oscillations increased from 7.9 (cm/s)2 at baseline of the control condition to 179.8 (cm/s)2 (i.e., a ~23-fold increase) during LBNP. The amplitude of MCAv 0.1 Hz oscillations increased from 25.8 (cm/s)2 during baseline of PPT to 210.2 (cm/s)2 (~8-fold increase) during LBNP (N=1). ScO2 decreased from 75.0% to 71.3% during LBNP in the control condition, and from 73.4% to 71.6% in the PPT condition (N=1). Based on the results of Study 1, 0.1 Hz OLBNP does not increase ICA stiffness, and there is no relationship between ICA stiffness, amplitude of induced 0.1 Hz cerebral blood flow oscillations, and the reduction in cerebral tissue oxygenation during simulated hemorrhage. However, as this analysis was performed retrospectively, and arterial stiffness was not initially an outcome measure, there were limited data available for analysis. For Study 2, we were successfully able to induce 0.1 Hz oscillations in cerebral blood flow by combining LBNP with bilateral thigh cuff inflations. However, insufficient data were available to make definitive conclusions about the role of PPT on CCA β-stiffness, 0.1 Hz oscillations in cerebral blood flow, or the relationship in 0.1 Hz oscillations in cerebral blood flow and protection of cerebral tissue oxygenation. This study is currently ongoing, and additional data will provide further insight into these relationships.
Assessment of Digit Skin Temperatures Via Infrared Thermography Under Different Climatic Conditions
(2024-05) Boettger, Chloe E.; Maddux, Scott D.; Cho, Elizabeth; Romero, Steven A.
The responsiveness of the manual/pedal digits (i.e., finger/toes) to temperature changes makes them valuable indicators of thermoregulatory function. Further, while infrared thermography is used in many medical settings, its utility in assessing acute changes in digit skin temperatures remains poorly established. Accordingly, this research investigated the use of forward-looking infrared (FLIR) imaging as a methodological tool for analyzing digital skin temperatures across varying climatic conditions. A Teledyne FLIR E76 camera and associated FLIR Studio software were used to assess peripheral digit skin temperatures in a sample of 10 living human subjects (3 female, 7 male). Images of each hand and foot were captured every 5 minutes over a 45-minute period during exposure to four controlled climatic conditions in an environmental chamber. These experimental conditions included a control (22°C and 50% humidity), hot-humid (37°C and 85% humidity), hot-dry (44°C and 15% humidity), and cold-dry (5°C and 80% humidity) exposures. All images were taken at a perpendicular angle from the skin surface at a distance of 0.45 mm, as measured using the camera's laser-guided range finder function. Baseline images were similarly taken during a preliminary rest period prior to each experimental exposure. This resulted in a total of 2,200 images collected from the left hand and left foot of the 25 participants. Following theoretical expectations, preliminary findings indicate peripheral digit temperatures predictably decrease during the cold-dry exposure, while the hot-dry and hot-humid exposures induce increases in digit temperatures. These preliminary results suggest that infrared thermography likely provides an expedient mechanism for accurately assessing peripheral skin temperatures in humans under different climatic conditions. Infrared thermography may thus have valuable applications for assessing thermoregulatory function in both clinical and research settings.
New Insights into the Roles of Glutaredoxins in the Lens
(2024-05) Zhang, Jinmin; Wu, Hongli; Ellis, Dorette Z.; Green, Kayla; Prokai-Tatrai, Katalin; Yan, Liang-Jun
Glutaredoxins (Grxs) play a crucial role in reversing protein glutathionylation. Glutaredoxin 1 (Grx1) and Glutaredoxin 2 (Grx2) are two main members of Grxs. Our prior studies have demonstrated that the Grx1 and Grx2 double knockout (DKO) mice develop cataracts prematurely at three months of age, and they are more susceptible to UV radiation. Therefore, these findings have highlighted the importance of Grx1 and Grx2 in preserving the transparency of the lens. However, the precise mechanisms underlying the faster development of cataracts in response to simultaneous deletion of Grx1 and Grx2 remain unknown. Lens epithelial cells (LECs) are pivotal for preserving lens transparency and overall lens functionality. Consequently, a comprehensive understanding of the antioxidant defenses and cell repair mechanisms in LECs is vital for cataract prevention and treatment strategies. We hypothesized that the absence of Grx1 and Grx2 could alter LECs function, triggering cataractogenesis. To test the hypothesis, we isolated primary LECs from WT and DKO mice and conducted a range of in vitro experiments to assess the effects of Grxs deletion on the epithelial phenotype, cellular proliferation, apoptosis, and mitochondrial function in LECs. We also conducted histology analysis of lens tissues using hematoxylin and eosin (H&E) staining. Our results revealed that Grx1 and Grx2 deficiency altered epithelial phenotype, reduced proliferation rate, and aberrant cell cycle distribution of DKO LECs compared to WT LECs. The deficiency also induced cellular senescence in cultured DKO LECs, which is consistent with our H&E staining data showing that LECs in the lens tissue from DKO mouse had accelerated senescence. Additionally, DKO LECs displayed compromised mitochondrial function and a compensatory metabolic shift towards glycolysis, indicating an adaptive response to Grx deficiency. Importantly, we also found that the OHPy2N2 activated Grxs and prevented the lens from H2O2-induced lens opacification. In conclusion, the findings in this study indicate that Grxs are important in regulating the aging process in the lens. Compounds that can activate Grxs may be promising candidates for preventing cataracts.
Isolation and characterization of a novel bacteriophage for Pseudomonas aeruginosa
(2023-05) Serralta, John E.; Allen, Michael S.; Zhang, Yan; Hughes, Lee
Pseudomonas aeruginosa is a frequent nosocomial pathogen with emergent strains that display increasing resistance to a wide range of antibiotics including carbapenems. The goal of our study was to isolate and characterize novel bacteriophages with lytic activity against multidrugresistant (MDR) strains of P. aeruginosa. Isolation of wastewater phages was achieved through a series of plaque assays on a control strain (P. aeruginosa BAA-31). The host range of phage isolates was evaluated in vitro with MDR strains from the CDC Antibiotic-Resistance Isolate Bank. To prepare and sequence a library of phage genomes, we used Illumina's TruSeq® Nano DNA Library Prep Kit and MiSeq® system with reagent kit v2. The Center for Phage Technology's Galaxy platform was used for genome processing and annotation. We report the isolation of the novel Pseudomonas phage Jes517. Host range screening revealed 12 of 55 tested strains (21.8%) were at least partially susceptible to Jes517 with 3 showing consistently strong growth reduction in its presence. The ten closest relatives of Jes517 are in the genus Bruynoghevirus with percent identities ranging from 88.7% to 92.8%. Jes517 has a linear dsDNA genome of 45,608 bp encoding 76 open reading frames (ORFs) including three tRNAs. No known integrases, toxins, or resistance factors were identified during gene annotation. Based on its strong growth suppression of MDR P. aeruginosa and predicted lack of virulence genes, phage Jes517 makes a compelling candidate for further investigation and possible therapy.
A Novel Scanning and Staining Methodology for Visualizing Skeletal and Soft Tissue Using Micro-CT
(2023-05) Stalls, Javan A.; Menegaz, Rachel A.; Gonzales, Lauren A.; Lesciotto, Kate M.
While there are many forms of radiological imaging that can be used to gather anatomical data from biological specimens, micro-computed tomography (micro-CT) imaging has been the standard for visualizing dense tissue, such as bone, with detailed resolution. However, this imaging modality is not well suited for soft tissues due to their decreased tissue density. This inability to distinguish between soft tissues in CT scans limits our ability to investigate bone-muscle interactions that are thought to stimulate and direct bone modeling during early postnatal development. The goal of this project was to develop a novel CT protocol that incorporates at least two new methods for visualizing soft tissue in CT imaging: iodine staining intended to capture muscle, and ruthenium red staining intended to capture cartilage. The ultimate goal is to enable the creation of an anatomical model that shows the development of both skeletal and soft tissue structures in the crania of neonatal mice from birth to weaning.
Impact of Endoscopic Vacuum-Assisted Closure on Quality of Life in Patients After Treatment of Gastrointestinal Leaks
(2023-05) Rana, Rashmeen K.; Malaer, Joseph D.; Preskitt, John T.; Farmer, George
Endoscopic Vacuum Assisted Wound Closure (EVAC) is an effective therapeutic option to treat Gastrointestinal (GI) leaks after the surgery. Prior to EVAC, conventional approaches to treat leaks included surgical intervention or endoscopic stents. Even though EVAC has been in use for more than a decade and has proven to be successful in treating GI leaks, the long-term quality of life impact of this treatment is uncertain. With the use of a short form (SF-36) survey, a validated questionnaire to assess both physical and mental health, the long-term impact of EVAC on the quality of life was evaluated. When assessing the long-term quality of life for patients who are at least 2 years out from their sentinel surgery, the EVAC group scored higher in all 8 quality of life domains with 4 domains reaching statistical significance as compared with conventional therapy group which received other treatments for leak management.
The Role of Mitochondrial Respiration in Müller Glia Survival and Function Under Normal and Glaucomatous Conditions In Vivo
(2023-05) Nsiah, Nana Yaa; Inman, Denise M.; Stankowska, Dorota L.; Zode, Gulab S.; Yang, Shaohua
Several markers of mitochondrial dysfunction have been observed in the retinas of glaucoma patients and experimental animal models. However, these studies have primarily focused on retinal neuron cells even though glial cells too contain significant amounts of mitochondria. Thus, little is known about how glial cell mitochondrial dysfunction contributes to glaucoma pathology. As the principal macroglial cells of the retina, Müller glia (MG) function is essential to maintaining homeostasis in the retina. However, very little is known about how MG generate energy to support their function in vivo. In this study, we address the role of mitochondrial respiration in MG using an inducible Cox10 knockout transgenic mouse model. Cox10 (protoheme IX farnesyltransferase) encodes a component of cytochrome c oxidase (COX), complex IV, of the electron transport chain. Cox10 deficient cells lack functional COX. Disruption of COX function in MG did not affect MG survival nor retinal structure but impaired visual function and upregulated glycolysis pathway protein expression in the retina. These data suggest that MG-specific mitochondrial respiration is essential for whole retinal energy metabolism and visual processing. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be upregulated in the glaucomatous retina and optic nerve, yet its role in glaucoma pathogenesis remains unexplored. HIF-1α is a transcription factor that promotes glycolysis and metabolic adaptation during hypoxia. By blocking HIF-1α degradation through pharmacologic inhibition, we found that prolonged HIF- 1α stabilization led to retinal glycolysis and oxidative phosphorylation (OXPHOS) protein downregulation and AMP-activated protein kinase (AMPK) activation, indicating low energy status. These changes were accompanied by impaired retinal ganglion cell (RGC) function and glial cell activation. Taken together, these results demonstrate the essential role of MG-specific OXPHOS in the retina, as well as pointing to a role for HIF-1α in neurodegeneration in the retina.
MRI Detected EMVI Post-Neoadjuvant Therapy for Rectal Cancer: Retrospective Chart Review, Recurrence, and Clinical Implications
(2023-05) Piña, Emerald M.; Mathew, Stephen O.; Malaer, Joseph D.; Preskitt, John T.
There is limited and conflicting data on the value of EMVI status on post-neoadjuvant therapy MRI reports as a prognostic indicator. The study conducted was an IRB approved retrospective chart review to assess the relationship of EMVI status on post-neoadjuvant therapy MRI reports with recurrence and survival. Data collection was conducted on Baylor University Medical Center patients that were enrolled in a multi-disciplinary tumor board for rectal cancer from 2013 to 2021. Descriptive and statistical analysis was performed that showed statistically significant differences between EMVI status on post-neoadjuvant therapy MRI reports and age, recurrence, metastasis, survival probability, and tumor regression grade.

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