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Sex differences in the activation of central autonomic control regions and neuroinflammation in chronic intermittent hypoxia
No full textResearch Appreciation Day Award Winner - HSC College of Pharmacy, 2023 Pharmaceutical Science Research Award - 1st PlacePurpose: Obstructive sleep apnea (OSA) is an independent risk factor for hypertension. Chronic interment hypoxia (CIH), which models episodic hypoxemia of OSA, produces daytime hypertension, oxidative stress, and activation of central autonomic regions that regulate mean arterial pressure (MAP) in male Sprague Dawley (SD) rats. Unlike gonadally intact females, gonadectomized females and males develop CIH hypertension. Lesioning of median preoptic nucleus (MnPO) in males prevents CIH hypertension. We hypothesize that the sex difference observed in CIH hypertension is due sex differences in neuroinflammation and activation of central autonomic regions that support MAP in CIH. Methods: Gonadally intact adult male and female SD rats (250-300g) were continuously exposed to normoxia (CON) or CIH (10% O2 every 3mins cycling 21% O2 every 3mins, 8h/day) for 7 days. Radiotelemetry transmitters were implanted in rats to record MAP and heart rate (HR). After one week of baseline recording, the rats were exposed to either continuous normoxia or CIH and were euthanized (inactin 100 mg/kg ip) on the 8th day for immunohistochemistry and blood analysis. All forebrain sections were stained for FosB/ΔFosB and either neuronal nitric oxide synthase (NOS1) or IBA1 to identify active microglia. Results: CIH males exhibited significantly increased hematocrit indicating erythropoiesis compared to control males (CON 42.1% ± 0.6, n=10; CIH 44.6% ± 0.7, n = 10. P = 0.0173). CIH males exhibited an increase in the average number of FosB positive neurons (CON male 20 ± 2 cells/section, CIH male 35 ± 3; CON female 11 ± 1, CIH female 12 ± 2,) and colocalization of FosB and NOS1 (CON male 10 ± 1 cells/section, CIH male 18 ± 4; CON female 5 ± 1, CIH female 6 ± 1) in the MnPO. CIH females showed a trend for an increase in the average number of IBA1 immunoreactive microglial cells in MnPO (CON 187 ± 16, n = 2; CIH 218 ± 18, n = 4). Conclusion: CIH is associated with increased FosB staining in the MnPO of male rats as opposed to female rats which is consistent with our working hypothesis. In addition, FosB positive MnPO neurons also contained NOS1. In female rats, CIH is associated with a trend for an increase in the numbers of IBA1 positive microglia, indicating increased neuroinflammation in females that is independent of hypertension. CIH was associated with increased FosB staining in NOS1 positive MnPO neurons suggesting that they may be contributing to the sustained hypertension reported in male rats.
The research is funded by NIH grant RO1 HL155977.NIH grant RO1 HL15597
Assessing HSC Health Pediatric Clinic Adherence and Barriers to HealthySteps Screenings
No full textPurpose: HealthySteps is a program created to provide developmental support to patients aged up to three years old and their families. Children are monitored to make sure they are reaching developmental milestones. Implementation and adherence to the HealthySteps competencies are monitored yearly per clinic. Each clinic can self-assess through a Fidelity Implementation Checklist, where each indicator is graded as either: did not begin, does not meet fidelity, approaching fidelity, meets basic fidelity, or meets optimal fidelity. When the optimal goals of HealthySteps are followed, the program had nationwide significant benefits for the patients, parents, and pediatric care team. Methods: The UNT Health Science Center Pediatric Clinic was analyzed for its implementation and fidelity to HealthySteps developmental and autism screening competencies. Data was collected from Jan. 2017 – July 2022 beginning when HealthySteps was implemented at the clinic and analyzed yearly. The number of patients receiving at least one developmental screening a year and one autism screening by 28 months were calculated from the total number of patients 0 – 3 years of age. Results: Developmental screenings have improved from "Approached Fidelity” to "Meets Basic Fidelity,” while autism screenings have gone from "Approaching Fidelity” to "Does Not Meet Fidelity.” Conclusions: Barriers to patient screenings could include the following: patients coming late to appointments leading to a rushed visit, tablet technology failure, data entry issues from patient check-in to EHR, EMR content access, new staff not being aware of the HealthySteps program and its benefits, and staff forgetting to administer the screenings. To begin reaching for the "Meets Optimal Fidelity” target, the most attainable goal is to establish better communication between the clinic and HealthySteps specialists with more consistent scheduled meetings
Novel role of HIV-1 Nef in regulating the ubiquitination of cellular proteins
No full textOur recent data established that HIV-1 Nef is pivotal in determining the fate of cellular proteins by modulating ubiquitination. However, it is unknown which proteins are ubiquitinated in the presence of Nef, a question critical for understanding the proliferation/restriction strategies of HIV-1 in infected cells. To identify cellular proteins ubiquitinated by Nef, we conducted a proteomic analysis of cellular proteins in the presence and absence of Nef. Proteomic analysis in HEK293T cells indicated that 93 proteins were upregulated and 232 were downregulated in their ubiquitination status by Nef. Computational analysis classified these proteins based on molecular function, biological process, subcellular localization, and biological pathway. Of those proteins, we found a majority of molecular functions to be involved in binding and catalytic activity. With respect to biological processes, a significant portion of the proteins identified were related to cellular and metabolic processes. Subcellular localization analysis showed the bulk of proteins to be localized to the cytosol and cytosolic compartments, which is consistent with the known function and location of Nef during HIV-1 infection. As for biological pathways, the wide range of affected proteins was denoted by the multiple modes to fulfill function, as distinguished from a strictly singular means, which was not detected. Among these ubiquitinated proteins, six were found to directly interact with Nef, wherein two were upregulated and four downregulated. We also identified 14 proteins involved in protein stability through directly participating in the Ubiquitin Proteasome System (UPS)-mediated proteasomal degradation pathway. Of those proteins, we found six upregulated and eight downregulated. Taken together, these analyses indicate that HIV-1 Nef is integral to regulating the stability of various cellular proteins via modulating ubiquitination. The molecular mechanisms directing Nef-triggered regulation of cellular protein ubiquitination are currently under investigation.The research was supported by departmental resources to I-WP and KB. JP was supported in part by an F31 DA053151 fellowship from the National Institute on Drug Abuse. MG was supported by NIDA award R25DA0043225 to Harlan Jone
A Rare Case of Synchronous Familial Adenomatous Polyposis and Endometrial Carcinoma
No full textResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2023 Medical Student Government Association Best in Third Year ClassResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2023 Student Research Award - Best Case StudyFamilial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by numerous polyps in the colon. It is caused by a germline mutation of the adenomatous polyposis coli (APC) gene. Patients have a guaranteed risk of having colorectal cancer and can also develop multiple extra-intestinal manifestations, including cutaneous lesions, brain tumors, desmoid tumors, osteomas, and thyroid cancer. Thus, extensive screenings for both colorectal cancer and the manifestations mentioned above are recommended on a frequent basis. Ovarian and endometrial malignancies are not known to be associated with FAP. Here, we present a case of synchronous FAP and endometrial carcinoma.
A 51-year-old female with family history of autosomal-dominant-patterned colon cancer, subtotal colectomy at 17 due to multiple polyps, ileostomy with a J-pouch at 35, and recent upper endoscopy suspicious for ampullary adenoma, presented with one-month history of fatigue and night sweats. Review of system was positive for heartburn and easy bruising. The patient did not have formal genetic testing. She has close follow-ups with yearly surveillance upper GI endoscopy (EGD), flexible sigmoidoscopy, and thyroid ultrasound. At 44, she underwent dilation and curettage due to menorrhagia; samples revealed endometrial cancer, which led her to undergo a bilateral salpingo-oophorectomy.
Reports of endometrial and ovarian cancers in FAP are rare. In another case, a 57-year-old female with FAP was found to have bilateral ovarian microcystic stromal tumors (MCSTs), papillary thyroid carcinoma, and endometrial carcinoma. Histopathology from the MCSTs and thyroid was positive for beta-catenin, an important marker in FAP. MCST is a rare subtype of ovarian cancer that has been found concurrent with FAP on several occasions. Although our patient did not have genetic testing, the large number of polyps and autosomal dominant pattern of inheritance are consistent with FAP, rather than Lynch or MUTYH-associated polyposis (MAP) syndromes, which could present similarly. It would be important to look at histopathology in our patient to determine whether there is overlapping genetic expression with FAP. Nevertheless, our case represents another rare instance of co-occurrence of endometrial cancer and FAP. More research needs to be done to explore the potential association between endometrial/ovarian malignancies and FAP. Holistic care is an integral part of osteopathic medicine, thus it is important for osteopathic physicians to provide well-rounded care for every patient. This case gives evidence that there might be benefits in future screening of endometrial/ovarian cancer in patients with FAP that could potentially increase life expectancy in these patients.N
Characterization of Bilingual Mexican Americans among a Community Dwelling Cohort: An HABS-HD Study
No full textIntroduction: Bilingualism has been increasingly studied in the context of neuroprotection particularly as it relates to cognitive decline. Despite higher rates of English/Spanish bilingualism, Mexican Americans also experience a higher risk of cognitive decline related to Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRDs) as compared to Non-Hispanic Whites. Few studies to date have broadly examined the link between bilingualism and specific demographic, cognitive, and biomarkers among this ethnic group.The aim of this study is to examine the relationship between language status (monolingual/bilingual) on select demographic, cognitive, and AD specific blood biomarkers among this racial/ethnic group.
Methods: Data were analyzed on n=890 Mexican Americans from the The Health & Aging Brain Study - Health Disparities (HABS-HD) study. Participants completed a clinical interview, which includes a self-report of language status (monolingual/bilingual) as well as various neuropsychological tests and an informant interview in order for clinicians to determine cognitive and functional status. Plasma amyloid (A), tau (T), and neurofilament light chain [NfL](N) blood biomarkers were assayed using the ultra-sensitive Single molecule array (Simoa) technology. Demographic characteristics were generated utilizing independent t-tests or chi square analyses for continuous and/or categorical variables. ANCOVAs were conducted with covariates of age, sex, and education for cognitive test performance and A/T/(N) blood biomarkers split by language status (monolingual, bilingual) as well as by cognitive status (cognitively unimpaired, cognitively impaired).
Results: Of the n=890 Mexican Americans, n=393 self reported as monolingual and n=497 as bilingual. Among monolinguals, 70% were diagnosed as cognitively unimpaired, 20% with mild cognitive impairment (MCI), and 10% with Dementia while among bilinguals, 78% received a diagnosis of cognitively unimpaired, 17% with MCI, and 5% with Dementia. Regarding neuropsychological testing, bilingual individuals performed significantly better across measures of global cognition, attention, and processing speed (ps<0.001). While examining blood biased biomarkers, a trending significance of higher total tau was found among bilinguals compared to monolinguals. When separated by cognitive status, total tau was higher among bilingual Mexican Americans who were cognitively unimpaired (p=0.044). Higher Aβeta 40 levels were found to be significantly associated with reduced performance on measures of attention, processing speed, and executive functioning among bilinguals who were cognitively unimpaired (ps<0.001). Among bilinguals with cognitive impairment, higher total tau levels were associated with lower performance on a measure of working memory (p=0.001) and higher NfL levels were associated with lower performance on measures of global cognitive screening measure and working memory (ps=0.001).
Discussion: As rates of AD and ADRDs increase in Mexican Americans, their bilingualism may be advantageous in delaying this pathology. Bilingualism is differentially related to cognitive and AD biomarkers. Better understanding the relationship between bilingualism and these markers might be informative regarding potential protective effects for this at risk group
Relationship of Down Syndrome with Keratoconus and Gonadotropins
No full textPurpose: Down syndrome (DS), also known as trisomy 21, is a common genetic disorder of chromosomal nondisjunction. DS has been strongly associated with Keratoconus (KC); however, the exact pathobiology remains unexplored. KC is one of the most significant corneal disorders which is characterized by thinning, cone-shaped protrusion, and steepening of the cornea leading to a significant reduction of visual acuity and even blindness. The aim of this study was to investigate the relationship of DS with KC in the context of gonadotrophic hormones.
Methods: This study adhered to the declaration of Helsinki. Fifty-eight healthy controls (29 male, 29 female), one hundred and forty-nine KC (112 male, 37 female), and eighty DS (44 male, 36 female) patients were recruited for this study. Plasma samples were collected from all participants. We investigated the expression of Gonadotrophin-releasing hormone (GnRH) and Follicle stimulating hormone (FSH) using enzyme-linked immunosorbent assay (ELISA).
Results: Significant downregulation of GnRH expression was observed in KCs when compared with healthy (p = 0.0006) and DSs (p = 0.00249). GnRH was significantly downregulated in KC and DS males, compared to their healthy counterparts, while no significance was observed in females across all diseases. Significant upregulation of FSH levels was observed in DSs compared to both healthy and KCs (p < 0.0001). FSH expression was also significantly elevated in both DS males and females when compared to healthy and KCs.
Conclusions: Our results revealed downregulation of GnRH, but upregulation of FSH in DS participants as compared to KCs. These findings provide new insights into the potential association between DS and KC, and substantiate the role of gonadotropins. Further studies are warranted to further understand the underlying mechanisms and potential implications for the treatment and management of these conditions.NIH/NEI R21EY03232
The Role of Pregnancy Intention in the Choice of Contraception Among U.S. Women of Reproductive Age: 2017-2019 National Survey of Family Growth
No full textPurpose: Contraceptive use is an important aspect of women’s reproductive health. Long-acting reversible contraceptives (LARCs) such as the intrauterine device and hormonal implant, are known to be highly-effective methods to prevent an unintended pregnancy. Pregnancy intention may contribute to contraception use, and women who do not intend to get pregnant may opt for effective contraception methods. However, pregnancy intention is a behavioral factor that is subject to change based on circumstances. This study describes contraception use by pregnancy intention among a nationally representative sample of U.S. women aged 15-49 years.
Methods: The study sample included women aged 15-49 years from the 2017-2019 National Survey of Family Growth (n=3025). The dependent variable was current contraception method at the time of interview, operationalized into four categories: LARCs (reference category), pill/ring/patch/injectable, barrier methods, and no contraception. Pregnancy intention (in the future or after a current pregnancy) was operationalized as intending, not intending, and don’t know/refused. The relationship between pregnancy intention and current contraception method was examined using weighted, multinomial logistic regression analyses, adjusting for race, age group, and type of current health insurance coverage.
Results: The mean age of the women was 29.6 years (SD=8.4 years), and women identified as White (67.6%), Black (24.2%), and Other (8.2%). Less than a third (29.6%) of the women had a bachelor’s degree or higher, and a majority (58.4%) of women had private insurance. Overall, 22.1% were currently using LARCs and 15.7% were using no contraception. Compared to women intending to get pregnant, women not intending to get pregnant had lower odds of using pill/ring/patch/injectable (aOR=0.57; 95%CI=0.41, 0.80), barrier methods (aOR=0.54; 95%CI=0.40, 0.73), and no contraception (aOR=0.40; 95%CI=0.25, 0.64) versus LARCs. Women aged 20-29 years had lower odds of using pill/ring/patch/injectable (aOR=0.41; 95%CI=0.25, 0.67) and no contraception (aOR=0.43; 95%CI=0.24, 0.79) versus LARCs, compared with women aged 15-19 years. Older women within the age group 40-49 had higher odds of using barrier methods (aOR=1.98; 95%CI=1.05, 3.73) and significantly lower odds of using pill/ring/patch/injectable (aOR=0.32; 95%CI=0.18, 0.57) versus LARCs, compared with women aged 15-19 years. Compared to women with private insurance, women with public insurance (Medicaid/Children’s Health Insurance Program) had lower odds of using pill/ring/patch/injectable (aOR=0.50; 95%CI=0.35, 0.72) versus LARCs.
Conclusions: Overall, women not intending to get pregnant were less likely to use pill/ring/patch/injectable and barrier methods compared to LARCs. As such, women who desire to prevent unintended pregnancy may opt for LARCs. Findings also show that a proportion of women not intending to get pregnant were not using any method of contraception, which highlights the need to examine reasons for no contraceptive use among this group of women. Given that pregnancy intention can be dynamic, preconception care should be accessible to women to support them in making informed decisions about their reproductive health. Moreover, there is need to examine factors that impact decision-making on contraception methods while accounting for pregnancy intention
Geriatric Practice Leadership Institute (GPLI): An Age-Friendly Program
No full textPurpose
According to the Institute of Medicine, immediate steps must be taken to educate and train both the current and future health care workforce to work collaboratively in addressing the diverse needs of the growing older adult population. Most healthcare professionals had very little education or clinical training in the care of older adults nor the most effective ways to work as a clinical team.
Methods
The Geriatric Practice Leadership Institute (GPLI) is a collaboration between two universities providing interprofessional teams of early and mid-career professionals with the skills and knowledge needed to leverage leadership skills to effectively work within interdisciplinary teams to provide age-friendly care to older adults. The GPLI incorporates the Institute for Healthcare Improvement (IHI) Age-Friendly Health Systems 4Ms’ Framework into the training.
The GPLI is an on-line, team-based program which engages 5-7 teams each session. Module topics include Age-Friendly Health Systems, organizational culture, leading self, leading interprofessional teams, and quality improvement. Additionally, teams select and complete a quality improvement project based on the Age-Friendly Health Systems 4Ms and submit final report and presentation. The teams are also assigned a coach for support. Continuing education credits and a micro-credential are available to participants. Participants complete a survey following the completion of the program.
The GPLI has been funded by the Health Resources and Services Administration (HRSA) Geriatrics Workforce Enhancement Program grant (numberU1QHP2873), which currently covers all costs for participants.
Results
The GPLI has trained over 175 healthcare professionals during the past 7 years with teams representing ambulatory to emergency responder organizations. Participants were all asked to complete a survey to gauge the program's success. When asked about how valuable the information was in the program in a post-completion survey, 100% of participants answered 'very’ or 'extremely’ valuable. Additionally, all participants answered either 'very’ or 'extremely’ valuable when asked how useful their executive sponsor was in supporting their team's involvement and project.
Conclusion
After many years of offering the program, many lessons have been learned, and consistent themes have emerged from the teams who have been the most successful. These include team representation from all levels of the organization, a focus on culture change, and flexibility to change and adjust, especially during the COVID-19 pandemic.HRS
Association of Race and Receiving Mental Health Counseling in Patients Diagnosed with Depression
No full textContext: High prevalence of depression in the United States population is a rising issue, which warrants the need for understanding how to best target behavioral therapy as a treatment option for populations who are least likely to have received or to seek out such intervention.
Purpose: To determine if there is a significant relationship between race and frequency of mental health counseling as a treatment option in patients with depression.
Methods: This cross-sectional study included 949 patients diagnosed with depression, retrieved from the 2018 NAMCS (National Ambulatory Medical Care Survey) database. These patients were stratified by race as given in the NAMCS variable as "White”, "Black”, and "Others”. Of those 949 patients, 97 subjects sought out mental health counseling. We performed statistical analyses to determine if race was a predictor for seeking out mental health treatment.
Results: An ANOVA statistical analysis demonstrated a significant difference in those who sought out mental health counseling and race (p = .009) amongst those patients diagnosed with depression. Age (p <.001) was another significant factor affecting whether these patients sought mental health counseling. 12/42 "Other” subjects (9.1%, p <.001) with depression sought mental health treatment, followed by 9/69 Black subjects (13%, p = .024), followed by 76/838 White subjects (9.1%, p <.001).
Conclusions: The results contradicted our initial prediction, which anticipated that the white population would show higher rates of receiving mental health counseling than black and other race populations. We attribute these findings to the differences in severity and perception of depression symptoms among different races. Limitations to the study include sample size availability, inconsistencies in what each physician constitutes as mental health treatment, coding inaccuracies, and confounding variables including socioeconomic status and age
Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D(3)-Selective Antagonists
Get PDFPrevious studies have confirmed that the binding of D(3) receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D(3) receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D(3) receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D(3) receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D(3) receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D(2) receptor ranging from 22- to 180-fold. The beta-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC(50) = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D(3) receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT(3) receptors and TSPO. The results of this study revealed that a new class of selective D(3) receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.This work was supported by a grant from National Institute on Drug Abuse, grant number DA029840