Browsing by Author "Ortega, Sterling"
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Item Evaluation of a bi-modal therapy in a model of cerebral ischemia(2024-03-21) Hernandez, Katherine; Jones, Nathan; Ortega, SterlingPurpose: Ischemic strokes are a significant contributor to cardiovascular-related deaths in the U.S. Currently, pharmacological interventions are limited to alteplase, an FDA-approved thrombolytic agent, or a surgical procedure known as a thrombectomy. However, their effectiveness is limited by a narrow therapeutic window and incomplete reperfusion rates. Our research explores an alternative strategy centered around PNU-120596 (PNU), a positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (a7 nAChR), which has shown promise in previous studies in a male rat stroke model. The a7 nAChR is expressed in various central nervous system cells, and studies suggest that PNU directly promotes neuroprotection in these cells. Furthermore, research indicates increased expression of the a7 nAChR in immune cells, specifically in activated inflammatory CD4 T-cells, a cell crucial in stroke studies. We hypothesize that PNU is a bi-modal therapeutic agent, addressing neuronal loss and inflammatory responses, presenting a unique advantage. Methods: This study aims to provide insight into PNU's efficacy and regulatory role in stroke-induced inflammatory CD4 T-cells. The study will assess PNU treatment's efficacy in promoting stroke recovery in transient middle cerebral artery (tMCAO) mice, a murine stroke model, and investigate how PNU modulates stroke-induced inflammatory CD4 T-cells, examining their suppression, neuronal survival, and alleviation of the disease using mixed cortical cultures. Mice that had undergone the tMCAO procedure were administered 20mg/kg of PNU immediately after reperfusion, and brain tissue was collected 24 and 72 hours post-tMCAO for infarct analysis. Spleen and cervical lymph nodes were collected at the same time points for flow cytometry analysis. Results: PNU reduces stroke infarct when administered immediately after tMCAO, and brain tissue is collected 24 hours post-tMCAO. However, protection is lost when the same dose is administered, and brain tissue is collected 72 hours post-tMCAO. No significant changes in levels of CD4 T-cell percentages were seen in the spleen or cervical lymph nodes at both time points. Conclusion: This study suggests that PNU reduces infarct volume immediately 24 hours post-tMCAO, but the protection is lost at 72 hours post-tMCAO. However, subsequent studies are necessary to assess the efficacy of PNU at longer time points with different dosages.Item In-Vitro Assessment of Cortical Repair Induced by Branched-chain Amino Acid Treatment(2024-03-21) Mathew, Ezek; Jones, Nathan; Dickerman, Rob; Ortega, SterlingPurpose: Traumatic Brain Injury (TBI) refers to a constellation of pathologies resulting from mechanical damage to cortical tissue. The neurological sequala of such injuries can be devastating, and definitive treatment does not exist at this time. Branched-chain Amino Acid (BCAA) treatment has demonstrated neuroprotective effects in clinical literature and in various animal models of TBI. However, there is a lack of in-vitro literature referencing the repair capacity of BCAA administration after neuronal injury, particularly in the context of TBI. To fill this gap in knowledge, a scratch assay was repurposed for use in cortical culture, to assess the repair capacity of BCAA treatment. Methods: Mouse-derived Mixed Cortical Culture (MCC) cells were extracted and seeded in 24 well plates. A scratch assay was performed, where a vertical scratch was drawn across each well in a reproducible manner with a 200 uL pipette tip. This procedure is meant to recapitulate aspects of mechanical damage induced by TBI on cortical tissue. Subsequently, images were taken immediately post-injury (0 hour time point), at 24 hour, and at 48 hour time points post-scratch to quantify the area of scratch unfilled by cells. Various dose concentrations of BCAA were tested in comparison to control (media only) and vehicle control (water). Test conditions included the customary BCAA ratio, which is a 2:1:1 mix of leucine, isoleucine, and valine; additionally, a 1:1:1 ratio of leucine, isoleucine, and valine was also tested. Results: At 48 hours post-scratch, significant differences were found in open wound area when comparing the media only control to 10 uM (p < 0.01), 30 uM (p < 0.01), 300 uM (p < 0.001), and 1000 uM (p < 0.01) of the 2:1:1 BCAA dose. Significant differences were also found in the wound area when comparing the water vehicle control to 10 uM (p < 0.05), 30 uM (p < 0.01), 300 uM (p < 0.01), and 1000 uM (p < 0.01) of the 2:1:1 BCAA dose. No significant differences were found in the open wound area when comparing the controls and BCAA doses, at the 24 hour time point. Of note, no significant differences were found between control and treatment with the 1:1:1 ratio of leucine, isoleucine, and valine at any time point. Conclusion: BCAA treatment at the 2:1:1 ratio was seen to accelerate injury recovery at various dose concentrations, as quantified by open wound area after scratch injury was induced. This cell culture model demonstrates the importance of BCAA ratios. While this aligns with animal models and clinical literature, this is the first in-vitro assessment of BCAA repair capacity, in the context of cortical culture. Future studies will be undertaken to further elucidate the constituents of the repair mechanism.Item Investigating an early source of IFN-gamma production post large vessel occlusion in mice(2024-03-21) Sharif, Safia; Hernandez, Katherine; Jones, Nathan; Ortega, SterlingIn the United States, strokes are one of the leading causes of death- with ischemic strokes being the most common. The etiology by which ischemic strokes occur may be due to large vessel occlusion. Typically, this process occurs by which a thrombus or embolus occludes a major vessel within the brain leading to reduced blood flow (ischemia) precipitating damage to brain tissue. Large vessel occlusion is a critical event, in which a rapid response is required to ensure the survival of brain tissue. It is understood that IFN-gamma is involved in the production of various inflammatory mediators, however, in the context of the stroke, it is not known where the IFN-gamma production is sourced from early in the stroke cascade. This study investigates the production of IFN-gamma in the context of a large vessel occlusion in mice. In vitro and in vivo studies were utilized to (1) compare the production of IFN-gamma amongst large vessel pre-occlusion, large vessel post-occlusion, and a distal vascular site (2) examine the direct relationship between oxygen-glucose deprivation applied to mixed cortical cultures and naïve lymphocytes (3) investigate the source of IFN-gamma production. Collected data was analyzed by utilizing flow cytometry. Findings revealed that in comparison to the pre-occlusion, the post-occlusion sample of blood contained increased levels of IFN-gamma. Mixed cortical cultures were examined under ischemic-like conditions and demonstrated increased IFN-gamma production from naïve cells. Evidence also suggested that the most likely source of IFN-gamma production stems from macrophages. IFN-gamma could potentially be an important modulator in the exacerbation of brain parenchymal damage, especially in the context of post-large vessel occlusion.Item Predictors of Chronic Kidney Disease During Childhood in Neonates with Bronchopulmonary Dysplasia(2022-08) Wallace, Samantha W.; Mathew, Stephen O.; Ortega, Sterling; Fudala, Rafal; Starr, MichellePremature infants are more likely to survive at earlier gestational ages today than ever before. However, many of these infants face long-term complications associated with their prematurity, as their organs have not had sufficient time to develop. This is particularly notable in the kidney and the lung. Due to physiological similarities, injury of one of these systems can lead to the injury of another, a phenomenon known as kidneylung crosstalk. Furthermore, infants who experience acute kidney injury are also at increased risk of experiencing chronic kidney disease in the future. Therefore, early identification and management of kidney and lung injuries is key for effective prevention of future chronic disease. This study addresses the frequency of kidney disease in a population of neonates with bronchopulmonary dysplasia, a chronic lung disease which is common in premature neonates.Item Sigma-1 Receptors and and their Effects on Mice with rmTBI(2023-05) Kuo, Aaron, J.; Schreihofer, Derek A.; Sumien, Nathalie; Ortega, SterlingRepetitive mild traumatic brain (rmTBI) injury is common in contact sports, yet there are no specific treatments to mitigate the potential long-term detrimental effects of such injuries. Retrospective studies have observed athletes in contact sports such as American football, boxing, rugby, soccer, and martial arts have higher rates of Chronic Traumatic Encephalopathy (CTE), mood and behavior disturbance, motor and dementia-related diseases, and other neuropathological diseases. We propose that activation of S1R can mitigate detrimental behavioral and biochemical consequences of repetitive mild head injury in a mouse model. Sigma-1 receptors (S1R) are intracellular chaperone proteins that are involved in numerous cell processes. Among their diverse actions, activation of the S1R has been observed to reduce neurodegeneration in experimental models of stroke, Alzheimer's disease, Parkinson's disease and others. This wide range of effectiveness suggests that targeting S1R could also be beneficial for other neurological injuries including traumatic brain injury. In this short-term study of rmTBI in male mice, we observed only minor behavioral deficits 5 weeks after the last of 7 closed head injuries that may be mitigated by treatment with the prototypical S1R agonist PRE-084. However, PRE-084 itself had basal effects on cognition, making firm conclusions premature. Continued observation of these mice will help to determine whether there are additional long-term effects of the injury modelItem Single-Center Analysis of Cardiogenic Shock Outcomes in the Cardiac ICU and Non-Cardiovascular ICU Setting(2023-12) Chenamsetty, Maneesha R.; Millar, J. Cameron; Ortega, SterlingCardiogenic shock (CS) is a complicated condition characterized by reduced cardiac output. Treatment methods for CS depend on the etiology and severity of CS. Despite the advanced treatment options CS still has a high mortality rate. In this project, we investigated the effect of intensive care unit (ICU) type on patients' CS clinical outcomes. A total of 133 patients were included from 2021-2023 admissions at Baylor University Medical Center (BUMC) hospital. The in-hospital mortality rate was higher in the non-cardiovascular ICU (NCICU) (48%) when compared to the cardiac ICU (CICU) (28%), and the difference was statistically significant (p<0.001). Patients admitted into the NCICU have highly unfavorable discharge locations (p= 0.03). The median duration of days spent in the CICU is significantly longer (p<0.001). These results may not conclude the effect of ICU type on outcomes, but it does influence the CS clinical outcomes.Item Single-Center Analysis of the Off-Hour Effect in Cardiogenic Shock Outcomes(2022-12) Harrison, Caroline R.; Berg, Rance E.; Ortega, SterlingThe off-hours effect is a phenomenon where patients admitted during nights and weekends have poorer outcomes than those admitted during weekdays. This observation is often more pronounced in emergent conditions such as cardiogenic shock. Few studies have investigated the presence of an off-hour effect in patients with cardiogenic shock. In my thesis project, I explored the existence of an off-hour effect in 155 cardiogenic shock cases at a major urban hospital by evaluating patient outcomes. Patients admitted during off-hours had higher complication rates (OR=2.66, 95% CI, 1.29 to 5.49; p=0.01). I also found that patients admitted during on-hours waited longer to receive mechanical circulatory support devices after being admitted; however, this did not appear to negatively effect on-hour patient outcomes. While it appears that admission time does influence patient outcomes, the underlying cause for this effect is not yet understood.Item Unilateral to Bilateral Progressive Sciatic Neuropathy After Radiotherapy: A Case Report(2024-03-21) Mathew, Ezek; Drown, Mariah; Abarquez, Angela; Shivnani, Anand; Ortega, Sterling; Dickerman, RobBackground: Radiation therapy is often an adjunct treatment for prostate cancer. However, this procedure is not without risks; as the lumbosacral plexus is not routinely contoured during radiotherapy treatment plans, this raises potential for unintended consequences. As this case, especially this particular presentation, is an extremely rare occurrence, we will examine relevant literature and discuss the challenging diagnosis. Case Presentation: In this report, we detail the case of a 66-year-old male patient who suffered from unilateral sciatic neuropathy. Unfortunately, this unilateral neuropathy became bilateral, and was deemed idiopathic at the time, causing the patient severe distress. However, further workup which consisted of examination of patient history, scrutinizing imaging, and electromyography (EMG), painted a different picture. The onset of the patient’s complaints appeared to be initiated by adaptive radiotherapy, which the patient underwent during his treatment regimen for prostate cancer. Conclusions: As radiation-induced lumbosacral plexopathy (RILSP) may present in a delayed fashion after treatment, diagnosis could become difficult. While radiculopathy was the differential diagnosis which initially led to neurosurgical consultation, the patient’s presentation did not align with this diagnosis. Further workup, especially strategic usage of EMG, allowed for discernment of a neuropathic condition, versus a mechanically induced radiculopathy. While RILSP appears to be an underreported phenomenon subsequent to pelvic radiation, there exists only one other case of such neuropathy after prostate radiotherapy. Knowledge of this case will enable clinicians to modify their workup and avoid spine surgery in cases where it may cause harm.