University of North Texas
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Neuroprotective Effects of DHED Eyedrops Protects Visual Function Despite Elevated IOP in an Ocular Hypertension Animal Model
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Microbiology, Immunology & Genetics (Biochemistry & Cancer Biology) Award - 2nd PlacePurpose: Glaucoma remains the second leading cause of irreversible blindness and is often associated with chronically elevated intraocular pressure (IOP) leading to ocular hypertension (OHT). All of the currently accepted therapies attempt to reduce the elevated IOP. However, despite intervention, studies show progressive neuronal damage continues in the retina and may extend to the rest of the visual system, leading to additional neuropathologies. Interest in utilizing 17β-estradiol (E2) for its neuroprotective effects has become increasingly recognized; however, due to its side effects, such as cancer risk and feminization in males, its application as a therapy is limited. Our lab has developed the estrogen prodrug, 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), which remains inactive until its CNS-specific metabolism via short-chain reductase into the active compound E2. This study aims to elucidate the pleiotropic effects of E2 derived from DHED as a potential therapy for preserving the visual system under OHT. We hypothesize that topical application of DHED will prevent the neurodegenerative effects of chronic OHT on the retina and maintain visual function. Methods: OHT was induced in 8 to 10-month-old male Brown Norway rats via hypertonic saline injection into an episcleral vein. IOP was measured via a tonometer (Tonolab) to confirm sustained elevated IOP post-surgery and throughout the treatment period. DHED was topically delivered through eyedrops (20% 2-hydroxylpropyl-beta-cyclodextrin, 0.1% DHED, and saline) once per day. Visual acuity (VA) and contrast sensitivity (CS) were measured using the OptoMotry system with the OptoMotry 1.7 software (Cerebral Mechanics Inc). VA and CS were assessed using the "Rat" preset, and gratings were adjusted using a simple staircase progression. A fixed frequency of 0.272 c/D was chosen for the CS based on prior studies. Observers for the OptoMotry tests were blinded. The eyes and optic nerves were collected and fixed for RGC and axon counts, respectively. Seminal vesicles were collected and weighed to assess peripheral estrogenic effects. Results: The IOP was elevated by 53 % ± 15% and was sustained in both vehicle and DHED-treated groups with no differences between treatment groups. The vehicle-treated group gradually lost visual function, retaining only 60% ± 5% and 30% ± 4% of their VA and CS, respectively, by the end of the treatment period. However, the DHED-treated group maintained significantly better visual performance, retaining 91% ± 3% and 75% ± 7% of their VA and CS compared to the baseline. No differences in the mass of the seminal vesicles between treatment groups. Comparison of RGC and axon counts in the optic nerve are ongoing. Conclusion: This study demonstrates the neuroprotective effects of DHED-derived E2 on the visual system without peripheral side effects. Despite sustained OHT, the VA and CS of the topically administered DHED reduced the impact of injury compared to the vehicle control group. Future studies will investigate DHED administration's impact on the retina and visual cortex proteome.This study was supported by a grant (R01EY027005) from the National Institutes of Health (KPT) and by the Robert A. Welch Foundation (endowment BK-0031) (LP
Epigenetic Changes of Nuclear-Encoded Oxidative Phosphorylation Genes and Cognitive Function: A Study of Mexican Americans and Non-Hispanic Whites
No full textPurpose: There is a higher prevalence of metabolic disease and Alzheimer’s Disease (AD) in Mexican Americans (MA). Despite this data, there has been minimal research done on the methylation status of genes involved in mitochondrial oxidative phosphorylation (OXPHOS)/cellular metabolism and how this influences the risk for developing cognitive impairment (CI). Methods: Results were derived from 299 MAs and 252 non-Hispanic Whites (NHW), all of whom were participants of the Texas Alzheimer’s Research and Care Consortium (TARCC). Themethylation status of CpG sites was assessed by running peripheral blood samples on the InfiniumMethylationEPIC BeadChip array. Results: Based on a Bonferroni adjusted alpha of7.36485 x 10⁶, six differentially methylated sites were significant in MAs: cg07470503, cg10057295, cg13823120, cg26891598, cg21490662, and cg17904988. All the sites were hypomethylated in CI/AD cohorts compared to NC except for cg26891598. There were no sites of significance in NHWs. Conclusions: The strongest association with CI/AD within the MA cohort was at cg07470503, with a p-value of 1.00 x 10⁶ in MAs. This CpG site is found within the DGUOK gene. The DGUOK gene is responsible for making the enzyme deoxyguanosine kinase, which is needed to properly create mitochondrial DNA; a dysfunctional gene leads to impaired mitochondrial function that could decrease the efficiency of OXPHOS. The abnormal cellular metabolism that ensues could set up the foundation for neurodegeneration to occur. Moving forward, the cg07470503 site could serve as a marker to identify the risk of metabolic disease and consequent CI/AD in MA patients
Assessment of Food Insecurity Amongst HSC Patients Using the Hunger Vital Signs Screening Tool
No full textPurpose: The US Department of Agriculture (USDA) defines food insecurity (FI) as “lack of consistent access to enough healthy food for an active healthy life.” FI is associated with negative developmental and health outcomes in children and adults but is less often associated with the physical appearance of malnourishment in children. Because of this, the American Academy of Pediatrics recommends FI screening for all pediatric patients. The Hunger Vital Signs (HVS) screening tool was developed as an efficient and effective way to screen for FI in clinical settings. Since its development, the HVS has been found to be sensitive, specific, and valid as a screening tool for FI in all populations, as compared to the USDA’s 18-item Household Food Security Survey. This project aims to assess the prevalence and distribution of food insecurity within HSC’s patient population.
Methods: As part of the check-in process, patients or their caregivers completed an HVS screening at each clinic visit. HVS asks if within the past 12 months, patients “worried whether our food would run out before we got money to buy more,” and if “the food we bought just didn’t last and we didn’t have money to get more,” and allows patients to answer along a 4-point scale. Patients who screened positive for FI then received in person or mailed resources from the clinic Social Worker, including various local food resources. The results of these screenings along with various patient demographics were then analyzed for various trends and distributions via Excel. Additionally, patients who screened positive for food insecurity were then provided resources by the clinic social workers, and results of these patients’ subsequent HVS screenings were followed to assess effectiveness of these resources.
Results: Overall, 10.1% of patients screened positive for FI. Disparities across various factors were present, including percent FI amongst Asian patients of 6.1% compared to that of Native American patients of 15.5%. Additionally, patients from the UNT HSC Center for Older Adults showed only a 6.0% FI percentage. After intervention by the social work team, 40% of patients experiencing FI showed improvement on subsequent screenings.
Conclusions: This study shows that food insecurity is a prevalent issue in our clinic’s patient population. Disparities across various factors were present, including ethnicity and clinic location, suggesting important areas for improved interventions. While 40% of food insecure patients showed improvement following intervention, several challenges were met regarding validation of this improvement data, emphasizing important areas for future research
The Role of Parenting Behaviors and Their Influence on Adolescent Drunk and Drugged Driving: 2016-2019, USA
No full textDrugged driving, the act of driving a vehicle under the influence of illicit drugs, by adolescents is a serious public health concern. Many factors contribute to this risk behavior, but much less is known regarding the role of parenting behaviors in this phenomenon. The purpose of this study was to examine specific parenting behaviors and their influence among a nationally representative sample of adolescents. Pooled data from the 2016-2019 National Survey on Drug Use and Health (NSDUH) among 17,520 adolescents ages 16-17 years old were analyzed. Differences were found in specific parenting behaviors and adolescent drugged/drunk driving, with parents not checking homework and not telling their children they are proud of them being the most influential. Findings from the present study may inform drugged driving prevention programs for parents and adolescents and enhance road safety interventions.This research received no external funding
Effectiveness of AI Use in Qualitative Abstract Coding
No full textPurpose: As the field of qualitative research continues to evolve, the integration of artificial intelligence (AI) methods into data analysis has garnered increasing attention. This research paper presents a comparative analysis that evaluates the effectiveness, advantages, and disadvantages of utilizing AI methods for qualitative analysis of innovation characteristics of grant abstracts from the NIH RePORTER database, compared to traditional manual approaches. By comparing AI results to manual coding results, this project explores the potential transformative impact of AI on qualitative research.
Methods: As part of the NIH HEAL initiative, researchers manually coded over 700 HEAL abstracts to examine innovation characteristics of grants funded. Survey questions included the type of study, study innovation, primary goals, and expected outputs. To explore whether these abstracts, when prompted in ChatGPT v4.0 would yield the same results as a human coder, we will input 100 of the 700 coded abstracts into ChatGPT, entering the same instructions given to the human coders. A comparative analysis will then assess and score the output in terms of detail, depth, relevance, and completeness of the responses.
Results: We expect there to be no major differences between human and ChatGPT coding. This would suggest that AI can produce valid qualitative coding outcomes, potentially streamlining some research processes that involve abstracting themes from textual data and opening new possibilities for large-scale qualitative analysis.
Conclusions: Ultimately, the findings of this study have the potential to shape the direction of qualitative research, offering valuable guidance to researchers and practitioners on the feasibility and reliability of integrating AI methods into their work. This research will contribute to the ongoing discourse on the role of AI in qualitative research and provide a foundation for future investigations in this rapidly evolving field
Favre-Racouchot Syndrome Following Image-Guided Superficial Radiation Therapy
No full textBackground: Favre-Racouchot Syndrome (FRS) is a cutaneous disease characterized by nodules, cysts, and comedones located in sun-exposed areas of the face, such as the bilateral temporal and periorbital skin. FRS is associated with chronic sun exposure, cigarette smoking, and rarely with radiation therapy. Case Information: We present the first recorded cases of Favre-Racouchot Syndrome occurring in the setting of image-guided superficial radiation therapy (IG-SRT). A 68-year-old male with a history of nodular BCC on the forehead and right arm presented for a lesion on his forehead. The patient was being treated with IG-SRT #_msocom_1to the affected areas, and he initially noticed the lesion within the radiation treatment field during the 6th week of treatment (about 75% of the way through his treatments). Also, a 59-year-old female with a history of nodular BCC on the right nasal ala, that was treated with IG-SRT, presented for a lesion on her nose. The lesion was first noted during her 2-week follow-up visit after completing her IG-SRT treatments. Both of the patients in our cases were actively smoking tobacco products throughout their radiation treatments. Our cases differ from the prior reported cases due to the form of radiotherapy being used. It is important to note that the patient in Case 1 had additional NMSCs on the forearm and trunk. The forearm BCC was treated at the same time as the forehead lesion. The trunk lesion began treatment 6 months after the forehead and forearm lesions were treated. Neither of these treatment sites developed comedones. This shows that the location of the lesion may play a role in the development of FRS, especially in those actively smoking tobacco products during treatment. Conclusion: The combination of underlying chronic actinic damage, radiation, and tobacco use may increase the risk of developing FRS. Tobacco use in conjunction with radiation treatment may have a synergistic effect. As IG-SRT is becoming increasingly more prevalent as a treatment for non-melanoma skin cancers, it is important to monitor for adverse events and complications
Prevalence of Bilateral Frontal Sinus Absence in Cadaveric Specimens: A Cross-Sectional Study
No full textPurpose: The frontal sinus is one of four pairs of paranasal sinuses, developed early in gestation and continuing pneumatization into teenage years. Due to the differences in pneumatization, large variability exists in the size and dimensions of the frontal sinus, with the majority of radiologic studies showing prevalence of bilateral frontal sinus agenesis to be between 3-5%. While frontal sinus agenesis has not been identified as a frequent cause of patient complaints, it has contributed to worsening symptoms in certain diseases, and this anatomical variation may pose complicated risks to patient treatments, such as surgery. This study aims to demonstrate the prevalence of bilateral frontal sinus agenesis in a population of fixed cadavers from the United States.
Methods: The sagittally hemisected skulls of forty-eight cadavers donors of the HSC Willed Body Program were used for this study, and were not separated based on sex, race, or age. All donors were above the age of 35, allowing for complete pneumatization of the frontal sinuses at the time of hemisection. Initial gross observation of the frontal sinus was performed by the researchers at the midline site of hemisection. If the hollow frontal sinus was not identifiable, sagittal cuts with a bone shear were performed in the bilateral supraorbital regions laterally up to two centimeters from the site of midline hemisection in order to determine if the frontal sinus was present. This method was performed on each of the forty-eight cadaveric skulls. During gross observation and further dissection of the supraorbital regions of the skulls, bilateral presence or absence of the frontal sinuses was noted.
Results: Three of the forty-eight donors exhibited bilateral agenesis of the frontal sinus leaving forty-five to exhibit unilateral or bilateral presence of frontal sinuses. This correlates to a prevalence of bilateral frontal sinus absence in 6.25% of the population.
Conclusion: This study contributes valuable insights to variations and developmental sequences of the frontal sinus. Literature is consistent regarding prevalence of frontal sinus agenesis in various populations, ranging from 2% to 8% depending on the country of origin; the prevalence of bilateral frontal sinus absence in the sample population of this study was 6.25%. Our findings contribute to current data highlighting prevalence rates, which highlights the importance of noting radiologically determined frontal sinus abnormalities in patient histories, ensuring appropriate care during surgeries and future treatments of conditions such as chronic sinusitis and primary ciliary dyskinesia (PCD)
Methylation of IL-6 & TNF-α Associated Genes in Cognitive Impairment: A Texas Alzheimer's Research & Care Consortium (TARCC) Study
No full textPurpose: The Mexican American (MA) population poses one of the highest risk groups for the development of Alzheimer’s Disease (AD). Inflammatory biomarkers, such as IL-6 and TNF-a, have been associated with cognitive decline but most only in non-Hispanic Whites (NHWs). Epigenetic DNA methylation of CpG islands associated with inflammatory markers (IL-6 and TNF-a) have been studied and identified in other diseases but literature for its effects on cognitive impairment (CI), especially in MAs, is quite sparse. This study aims to determine if DNA methylation of CpG islands for IL-6 and TNF-a are associated with CI in a MA and NHW cohort. Methods: Utilizing the TARCC cohort (N = 551), participants within ethnic groups (N = 299 MAs, N = 252 NHWs) were stratified by cognitive status (normal cognition (NC) or CI). Methylation data at CpG sites were measured as beta values by array probes using the Illumina EPIC array. Linear regression analysis was performed in R comparing the beta value and cognitive diagnosis (NC or CI) for MA and NHW. Covariates include age, sex, education, CD8T cells, CD4T cells, B cells, monocytes, neutrophils, and the APOE gene. Result: The methylation sites cg04381957 and cg04583842 (both associated with IL-6) were significant within MAs. Those sites suggest hypomethylation and hypermethylation, respectively, in CI compared to the NC. Methylation site cg16411857 (associated with TNF-a) was not significant with CI in either MAs or NHWs. Conclusion: There was a stronger association with IL-6 related CpG sites and CI especially in MA at cg04381957 (p = 0.0035) within the RFTN1 gene. Future research plans to include inflammatory syndromes, such as diabetes, which could be a potential confounding variable affecting levels of IL-6 or TNF-a
New Insights into the Roles of Glutaredoxins in the Lens
Get PDFGlutaredoxins (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
Potential Developmental Impacts of the Lysine N-Methyltransferase 5B Mutation: A Case Report
No full textBackground: Lysine N-Methyltransferases (KMTs) play a crucial role in regulating chromatin modification. Specifically, deleterious heterozygous variants in Lysine N-Methyltransferase 5B (KMT5B) are linked to intellectual disability (ID) and/or autism spectrum disorder (ASD). Pathogenic variants in several of these genes have been identified in autosomal- dominant or X- linked neurodevelopmental disorders. Additional symptoms include seizures, crossed eyes, flexible joints, and low muscle tone. However, little is known about the effects of the KMT5B mutation on other organ systems as there are fewer than 50 reported cases in the literature. Case Information: This case report follows a 4-year-old male patient seen in the pediatric clinic for a well child visit. Data obtained from the electronic medical records through authorized providers showed the patient was previously diagnosed with a 17p12 deletion, hereditary neuropathy with pressure palsies (HNPP), and KMT5B de Novo mutation. During infancy, the patient had a history of staring off and eye rolling. Developmental delays prompted a genetic evaluation which revealed a maternally inherited 17p12 deletion involving the PMP22 gene, predisposing the patient to hereditary neuropathy with liability to pressure palsies and a de novo pathogenic variant in the KMT5B gene. The KMT5B mutation predisposed the patient to ID and ASD which manifested as missed developmental milestones. At 33 months, the patient began walking and at 36 months the patient exhibited limited speech (only 7-8 words). Additionally, the patient has a history of possible seizure activity, macrocephaly, hypotonia, and possible craniosynostosis although his last head CT scan did not confirm it. Currently, the patient has bilateral eustachian tube dysfunction requiring tympanostomy tube placement, pes planus requiring ankle foot orthotics, and recurrent croup infections with 6 episodes in the last 2 years. The patient is currently monitored by neurology, ENT, physical therapy, and speech therapy and attends special education at his public school. We are in the process of acquiring the patient's follow-up records from the specialty clinic to evaluate the ongoing status of the patient. Conclusions: The influence of the KMT5B mutation on human embryonic development beyond the brain remains poorly understood, as the existing studies emphasize its impact on intellectual disability. Mouse studies of the mutation have implicated its involvement in the embryonic development of organs such as the lungs, liver, heart, skin, and bone. The recurrent croup infections and eustachian tube dysfunction in our patient emphasizes the need to investigate potential developmental consequences in humans. Recurrent croup infections often stem from secondary causes such as congenital and acquired airway abnormalities. We propose that the KMT5B mutation may have contributed to our patient's eustachian tube dysfunction and potentially caused a congenital airway abnormality, increasing susceptibility to croup infections. This case offers unique insights into the potential association of airway and eustachian tube dysfunction with the KMT5B mutation, which is not previously documented. Given the limited number of reported cases and the demonstrated impact on the embryonic development of various organs in mice, further investigation is warranted to comprehensively assess potential complications associated with the KMT5B mutation in humans