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Characterization for In-situ Ocular Implant Formation
No full textPurpose
Different diseases of the eye require intravitreal injections for treatment. While intravitreal injections are quick procedures, their requirement for routine in-office visits makes them inconvenient. An alternative is intra-ocular implants, designed to stay within the eye, these allow controlled release of therapeutic drugs to the posterior segment of the eye. Intra-ocular implants require symmetrical shapes for even and steady release of the drug. To study how well in-situ implants form, vitreous humor substitutes were made using varying ratios of hyaluronic acid (HA) and polyvinyl alcohol (PVA) within phosphate-buffered saline (PBS). These substitutes have surface characteristics that can be used as a potential marker to predict how symmetrical the in-situ implant forms. Here, we use contact angles to help characterize their interaction.
Methods
Vitreous humor substitutes were made using 0.01 g/mL solutions of HA and PVA in PBS. These solutions were mixed to create the following ratios of HA:PVA: 1:3, 1:1, and 3:1. To make the implant, 1-Methyl-2-pyrrolidone was dissolved in polylactic-co-glycolic acid in a 1.96:1 ratio. Films were prepared on glass slides using the solutions to take contact angles of the implant. Contact angles were taken using an optical goniometer at 30.2 frames per second for 10 seconds, where it was set to dispense 2 µL each time. For in-situ implant formation, the implant was injected into 5 mL wells of each solution (PBS, HA, PVA, 1:3, 1:1, and 3:1) at a 90-degree angle using a 20 gauge needle at 1.2 cm deep. In-situ implant formation was repeated 4 times.
Results
The following contact angles were taken at frame 300 and are the average of at least 10 runs. The average contact angle for water on a plain glass slide and the implant on a plain glass slide, PVA film, 1:3 film, 1:1 film, 3:1 film, and on the HA film was 26.13 ± 3.79, 28.57 ± 2.29, 32.65 ± 5.75, 32.41 ± 4.21, 35.02 ± 3.03, 37.20 ± 4.92, and 40.71 ± 5.22 degrees respectively. In-situ implant formation was consistently the most symmetrical within HA and the 1:3 hybrid, though still in irregular yet compact shapes. In-situ implant formations within the other solutions were randomly shaped with tendrilous protrusions that would coil upon themselves.
Conclusions
Contact angles for all solutions were found to be statistically different using T-tests. The different contact angles allow us to manipulate the interactions by varying the ratio of HA and PVA to make an environment most suitable for intra-ocular implant formation. Interestingly, the 1:3 substitute did not follow the direct relationship found between the amount of HA present in each vitreous humor substitute and their contact angles. Despite having one of the least amounts of HA, it provided a better environment for implant formulation. Thus, there must be an interaction between HA, PVA, and the implant that is optimal at 1:3. More is to be done with the 1:3 hybrid and implant by repeating the experiment with serial dilutions to help us determine which patient populations may be most suitable to this type of treatment
Evaluating the Association of Gender as it Pertains to Health-Related Quality of Life Outcomes in Chronic Low Back Pain Patients
No full textBACKGROUND: 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
Cocaine Administration but Not Morphine Leads to Increases in Impulsivity as Measured in a Delay Discounting Task
No full textCocaine Administration but Not Morphine Leads to Increases in Impulsivity as Measured in a Delay Discounting Task
Jeri Keitzer, Olivia Anchondo, Kaylee Brunetti, Samia Shuchi, and Luis Colon-Perez
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107
Purpose: Inhibitory and cognitive control are mental process susceptible to repeated exposure to drugs of abuse. Specifically, impulsivity refers to the tendency to act prematurely without regard of the future. Substance use disorders patients (SUD) show impaired impulsivity; however, it is unclear whether psychostimulant use precedes impulsive behavior or vice versa. The delay discounting task is an assessment of impulsive choice used in behavioral neuroscience research. In this task, subjects are given a choice between an immediate small reward or a delayed large reward in which the time of delay increases across trials. Subjects that discount the delayed reward earlier are determined to act with more impulsivity. In this current study, we looked at impulsivity as it relates to performance in a delay discounting task before and after IP injection drug administration of either morphine or cocaine. We hypothesized that the subjects that were administered drugs would devalue the delayed reward earlier within the delay discounting task than control subjects.
Methods: For this study, we used Sprague Dawley rats split into 4 different groups: cocaine, morphine, saline, and naïve. All subjects were food restricted to increase motivation to obtain the reward food pellets. Rats began training on the delay discounting task after a training phase in which the rats were introduced to the behavioral chambers and exposed to the levers within the chambers in which they were trained to press to receive pellets. The delay discounting task consisted of a daily session in which the subject went through 5 phases (a total of 60 total trials) choosing between two levers to receive pellets. Each phase is characterized by two forced trials and ten choice trials. In the forced choice trials, the animal has only one option: either the immediate small reward or delayed choice reward. At each phase the delay increases from no delay to 4s, 8s, 16s, and 32s. During choice trials, rats choose between the immediate and delayed levers. Once a decision has been made, both levers retract until the next trial. First, baseline data of each subject’s impulsive choice was acquired, then the subjects underwent IP injection of either cocaine, morphine, or saline. A naïve group did not receive any injections. Rats were injected with drugs according to their weight (5 mg/kg) once per day for seven days, then they completed the delay discounting task again under experimental conditions.
Results: The cocaine drug group showed a significant decrease in delayed lever presses compared to all other groups during the delay discounting task following drug administration. No other significant differences were seen across any of the other groups.
Conclusion: The results of the study suggest that passive administration of cocaine in rats may lead to an increase in impulsivity but not morphine.BBRF Young Investigators Gran
Integration of psychosocial and medical factors in the care of a 17-year-old with GSW at T5 – a case study
No full textBackground: Rehabilitation psychology involves the application of psychological knowledge in the care of individuals with disabilities and chronic health conditions. This specialty involves ongoing evaluation of a patient’s mental and psychological status and the formation of positive coping skills and behaviors to help the patient achieve a satisfactory and productive life, as defined by the individual patient. Individuals with spinal cord injuries (SCIs) have an increased risk for poor physical, psychological, and social health. This trend is even more pronounced in vulnerable populations, including the poor, racial and ethnic minorities, older adults, and pediatric patients.
Case information: A 17-year-old male presented to Care Now with a gunshot wound (GSW) to the back. The patient was transferred to JPS. CXR showed that the bullet fractured T5 and remained lodged. The patient was diagnosed with incomplete SCI and paraplegia and treated for pulmonary and hepatic lacerations and diaphragm injury. The patient was transferred to Cook Children’s RCU for long-term management. Psychology was consulted to discuss patient’s dissatisfaction with catheterization and concerns on sexual functioning.
Conclusions: The incorporation of rehabilitation psychology in the care of patients with SCIs, particularly in vulnerable populations, has been shown to improve long-term success and independence. It is essential to implement a multi-factorial approach that considers both medical and psychosocial variables in a patient’s treatment plan. Emphasis must be placed on individual priorities of the patient to help the patient achieve acceptance and long-term satisfaction
An Evaluation of School-Based Health Centers' Program Elements
No full textPurpose: School-Based Health Centers (SBHCs) are being evaluated for their effectiveness worldwide. They consist of facilities providing health care services to children located on or near a school campus. SBHCs have a goal of advancing equity at the intersection of health and education, especially for students facing barriers to needed services. SBHCs use differing strategies that need to be assessed to identify which are most effective in implementing positive change for students. The purpose of this study is to analyze which aspects of SBHC mental and behavioral health services have been demonstrated to be successful in providing the best possible care to students. Three specific research questions were addressed: 1) what SBHC outcomes have been evaluated in the literature 2) what barriers to implementation are identified, 3) are there models that integrate on-site and telehealth service delivery.
Methods: This study was conducted in accordance with PRISMA guidelines for rapid systematic reviews using Covidence software. Key words were searched in PubMed, Scopus, Cinahl, and PsycINFO databases, and resulted in 436 articles being identified. After duplicates were removed, 230 studies remained. Titles and abstracts of these studies were screened using defined inclusion and exclusion criteria screen. Following the screening, 13 studies were included for complete review. Data extraction was performed addressing the three research questions above and included use of school-based health centers before and after the 2020 pandemic.
Results: 1) SBHC outcomes identified in the 13 studies included academic performance, tardiness, attendance, discipline, school connectedness, and commitment to educational future. 2) Two studies examined barriers to implementation and identified high turnover among staff and patients, insufficient buy-in, and insufficient time for training and planning. 3) Two studies were identified that examined hybrid models combining telehealth and on-site care
Conclusions: SBHC use is significantly associated with increases in GPA over time and these effects are moderated by the types of services used. SBHC use indirectly impacts academic performance by improving health and emotional well-being, but the association with attendance was variable. Tardiness was increased in SBHC users, but SBHC users reported higher scores relating to school bonding. This implied that the users reported happiness at school and looked forward to going to school. While these outcomes are of importance to school stakeholders, students, and families, the measurement of mental health outcomes in existing studies is limited. Implementation of school-based health centers had its challenges, including high turnover among staff, lack of buy-in and leadership among staff, and insufficient time for planning and training. Integrating educators and school-based health clinics could create more buy-in as staff would be more aware and potentially more supportive of school-based mental health clinics overall. There was limited evidence that met inclusion criteria regarding the hybrid model, however, the evidence showed that the hybrid model increased access to care. Studies also found that SBHC use increased significantly following the pandemic of 2020, due to increased health awareness and mental health struggles that occurred during this time
Sex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apnea
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Pharmacology & Neuroscience Award - 1st PlaceBackground: Obstructive sleep apnea (OSA) is a highly prevalent sleeping disorder in the USA with known sex differences in prevalence and severity. Men have a higher incidence and experience greater severity of OSA than women. However, recent reports indicate the incidence of OSA in women, particularly mild cases of OSA, may be under-reported and left untreated. OSA is characterized by elevated oxidative stress and inflammation, mechanisms that involve mitochondrial function. This study addressed the role of 1) sex and 2) mitochondrial oxidative stress in OSA induced circulatory oxidative stress and inflammatory cytokines.
Methods: Adult Sprague-Dawley male and female rats were implanted (s.c.) with an osmotic pump containing either MitoTEMPOL (mitochondrial oxidative stress inhibitor; MT) or saline vehicle and then exposed to a model of OSA, chronic intermittent hypoxia (CIH), or normoxic room-air for 14 days. The CIH protocol consisted of 10 CIH cycles/hour/8 hrs/day, in which each CIH cycle was composed of 3 minutes of normoxia at 21% O2 and 3 minutes of hypoxia at 10% O2. This protocol replicates an apnea-hypopnea index (AHI) of 10, which is consistent with mild OSA in humans. At the conclusion of the CIH protocol, rats were sacrificed and plasma was collected to quantify markers of oxidative stress (Advanced Oxidized Protein Products, AOPP) and inflammation (pro-inflammatory IL-6, anti-inflammatory IL-10, IL-6/IL-10 ratio). To determine statistical significance, ANOVA followed by Tukey’s post-hoc test was used. Significance level was set a p<0.05.
Results: We found circulating oxidative stress was dependent on CIH and sex. Sex differences were observed in control normoxic rats, in which females had higher oxidative stress than males. Interestingly, the impact of CIH on oxidative stress was dependent on sex, wherein CIH decreased oxidative stress in females but increased oxidative stress in males. Inhibiting mitochondria-associated oxidative stress reduced oxidative stress in vehicle females, but only blocked the effect of CIH-induced oxidative stress in males. In contrast to oxidative stress, CIH increased the level of IL-6 only in females. Further, CIH overall induced a pro-inflammatory state as measured by an elevated IL6/IL10 ratio in females. The inflammatory effects of CIH in females were blocked by inhibiting mitochondrial-associated oxidative stress, despite no effect on circulating oxidative stress in CIH. Neither CIH nor MT impacted inflammatory markers in males.
Discussion: These results indicate CIH-induced mechanisms underlying oxidative stress and inflammation are dependent on sex. Specifically, males experience a mitochondria-associated oxidative stress phenotype and females experience a mitochondria-associated inflammatory phenotype. These findings indicate that the OSA phenotype is sex-dependent, which may be related to the under-reported OSA incidence in women compared to men. Further, these data indicate that women may be at unique risk from OSA, particularly when AHIs are mild. Interestingly, inhibition of mitochondrial oxidative stress may be a potential drug target for both men and women with OSA.NIH R01 NS0091359; AHA 22PRE-900431; AHA 22POST-903250; NIH T32 AG02049
Variant Blood Supply of the Superficial Face: A Case Report
No full textIntroduction: The facial and transverse facial arteries provide the major arterial supply for the superficial face. The facial artery arises from the external carotid artery, in the carotid triangle of the neck, and crosses the angle of the mandible as it ascends the anterolateral face. Following a distinctive course, it continues by running along the oral commissure where it gives off the superior and inferior labial branches. Continuing its trajectory, the artery ascends along the nasolabial sulcus, providing the lateral nasal branch, and concludes its course by terminating as the angular branch near the medial aspect of the eye. The transverse facial artery, which arises from the superficial temporal artery, has a significant role in lateral face vascularization by supplying blood to the parotid gland, masseter, and integument and terminating near the buccal area.
Case Presentation: During a unilateral dissection of a previously hemisected head of a 78-year-old donor from the UNTHSC Willed Body program, variations of the facial and transverse facial arteries were observed. The superficial and deep structures of the face were subsequently dissected and cleaned to expose arterial origins and terminations. The variant anatomical structures were then noted and photographed. The facial artery arose from the external carotid between the lingual and occipital arteries. After crossing the angle of the mandible, the variant facial artery terminated below the oral fissure, supplying blood to the lower face only. The transverse facial artery arose from the superficial temporal, running deep to the parotid gland extending across the lateral face. It then continued in the typical path of the facial artery, following the nasolabial sulcus supplying the muscles and tissues above the oral fissure. It was observed that this variant transverse artery supplied blood to the superficial face instead of the facial artery. Conclusion: The face, like the rest of the human body, has a variety of documented anatomical variations. The observed anatomical variations of the facial and transverse facial arteries highlight the complexity and diversity regarding the vascular supply of the face. The documentation of such variations serves as vital information in clinical and surgical practice to yield the best patient outcomes during treatment
The Effect of 0.1 Hz Blood Flow Oscillations on Microvascular Blood Flow Responses Following Severe Ischemia
No full textBackground: We have shown that inducing 10 second (0.1 Hz) oscillations in arterial pressure and blood flow protects against reductions in tissue oxygenation during ischemia, independent of changes in macrovascular blood flow. However, it is unknown whether 0.1 Hz hemodynamic oscillations impacts microvascular function and vasodilatory capacity following severe ischemia. To examine this question, we assessed the reactive hyperemic response following a prolonged peripheral limb ischemia protocol with and without induced 0.1 Hz hemodynamic oscillations.
Hypothesis: 0.1 Hz oscillations in blood pressure and blood flow will increase microvascular blood flow, assessed via reactive hyperemia following a 10-min period of ischemia.
Methods: Thirteen healthy human participants (6M, 7F; 27.3 ± 4.2 y) completed two experimental protocols separated by ≥48 h. In both conditions, ischemia of the forearm was induced with a pneumatic cuff on the upper arm to decrease brachial artery blood velocity by ~70-80% from baseline. In the oscillation condition (OSC), 0.1 Hz oscillations in mean arterial pressure (MAP) and brachial artery blood flow were induced by inflating and deflating bilateral thigh cuffs every 5-s (10-s cycles; 0.1 Hz) throughout the forearm ischemia period. In the control condition (CON), the thigh cuffs were in place, but were inactive throughout the forearm ischemia period. Beat to beat arterial pressure was measured via finger photo plethysmography, and brachial artery diameter and blood velocity were measured via duplex Doppler ultrasound during baseline, ischemia, and the reperfusion period. The maximum mean brachial artery blood velocity, and 3-min area under the curve (AUC) of mean brachial artery blood velocity were used to determine the reactive hyperemia response.
Results: The magnitude of forearm ischemia, indexed by the reduction in brachial artery conductance, was matched between conditions (CON: -74.8 ± 10.4% vs. OSC: -75.6 ± 6.7%, p=0.39). Reactive hyperemia was not different between conditions as indexed by maximum mean brachial artery blood velocity (CON: 36.4 ± 12.4 cm/s vs. OSC: 39.3 ± 11.2 cm/s, p=0.53) or 3-min brachial artery blood velocity AUC (CON: 1495 ± 744 (cm/s)2 vs. OSC: 1596 ± 804 (cm/s)2, p=0.74).
Conclusion: Inducing 0.1 Hz hemodynamic oscillations during severe ischemia does not affect microvascular function, indexed by reactive hyperemia following release of the ischemic stimulus. A more direct measure of microvascular blood flow is needed to examine whether 0.1 Hz hemodynamic oscillations improves microvascular perfusion during ischemia.NIH Neurobiology of Aging & Alzheimer’s Disease Training Grant (T32 AG02049; KAD); American Heart Association Predoctoral Fellowship (23PRE1018469; KAD); American Heart Association Transformational Project Award (19TPA34910743; CAR); UNTHSC Physiology and Anatomy Seed Grant 2021 (CAR
Targeting Sp1 in Ewing Sarcoma: A multi-approach method for the utilization of Mithramycin
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Microbiology, Immunology & Genetics (Biochemistry & Cancer Biology) Award - 1st PlacePurpose: Ewing Sarcoma (ES) is a bone and soft tissue cancer affecting young adults and children. ES mostly occurs in the bones or soft tissue of the arms, legs, and pelvis. Localized ES presents with 5-year survival rate of 70%, but metastatic 5-year survival rate is between 15% and 30%. Our laboratory is interested in combination treatments using less toxic agents to induce sensitization to chemotherapy in ES. The anti-cancer activity of an antineoplastic antibiotic, Mithramycin, against ES cells has been shown. Mithramycin inhibits Specificity protein 1 (Sp1) a marker associated with aggressive cancer cell growth and resistance to chemo/radiation therapies. However, its mechanistic effects on other oncogenic proteins have yet to be elucidated in ES. The purpose of this study is to evaluate the effectiveness of Mithramycin and various combinations with other chemotherapeutic agents, Etoposide and Vincristine, to inhibit ES cell growth and assess the effect on key cancer related proteins regulated by Sp1. Future studies will include expanding upon Mithramycin’s mechanism of action in Ewing Sarcoma utilizing proteomics and various computational methods. Methods: Cell lines were obtained from Children’s Oncology Group (COG). Anti-proliferative activity of Mithramycin and/or Vincristine and Etoposide against ES cell lines, TC205 and CHLA10, was evaluated using CellTiterGlo kit. Dose curves were plotted and IC50 values were determined by Sigma-Plot software. The expression of Sp1 was determined by Western blot analysis. The specific type of effect (additive/antagonistic/ synergistic) of the combination treatments were determined by analyzing the combination index obtained via Calcusyn software. Nude mice were injected with TC205 cells and treated over two weeks with either Mithramycin (1mg/kg per week) and/or Etoposide (5mg/kg per week) and tumor volume was compared. Protein models were obtained from UnitProtKB and PDB and molecular dynamics simulations were run in the Schrödinger platform. Results: Mithramycin, etoposide, and vincristine decreased ES cell line viability in TC205 and CHLA10 cells as monotherapies, but more effectively in combination. Tumor volume was greatly attenuated upon Mithramycin and/or etoposide introduction, but more significantly when used in combination. Decreases in viability upon chemotherapeutic and Mithramycin introduction were drastically increased when used in combination and this effect was mirrored in further decreases in Sp1 expression. Synergistic drug responses were shown in the combination of Mithramycin with both Vincristine and Etoposide (CI <1). Sp1, Sp3, and survivin protein models were established and binding scoring and identification of key residues in Mithramycin protein interactions were identified. Conclusions: Mithramycin may effectively sensitize ES cells and improve the response of chemotherapy while lowering necessary effective dosages. Studies to understand the mechanism of action of Mithramycin on Sp1, Sp3, survivin, and other proteins involved in Ewing Sarcoma are underway.Cancer Prevention and Research Institute of Texas (Award#: RP210046