2019

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3D-Printed Insert for Visualization of Liposomal Interactions with Collagen Fibers
(2019-03-05) Mishra, Ina; Kastellorizios, Michail; Curry, Stephen
Purpose: Nanoparticles, such as liposome, are commonly used as vehicles for drug delivery to target tissues such as tumors. However, relatively little research has focused on liposomal interactions with the tumor extracellular matrix (ECM), a huge hurdle in the process of perfecting dosage. To our knowledge, there is no method available that allows the observation liposomes against a whole collagen fiber. In order to better study these interactions, we have designed a 3D-printed frame that helps in visualizing liposome transport around a collagen fiber. Observation of our replicated microenvironment will allow us to shed more light on the movements of liposomes within the ECM of tumor cells. Methods: Collagen fiber was removed from adult rat tail and allowed to soak in phosphate-buffered saline (PBS) overnight. Primary design of the frame was done using SketchUp software. Printing of 12mm frame design was done using a Form 2 3D printer (Formlabs). Fiber-in-frame was placed in a glass bottom microwell dish (MatTek Corp.). Research-grade liposomes that mimic the clinical product Doxil (DoxomTM, Liposomics) were used in a background of 0.07mg/ml BSA solution, and added to the channel. Visualization of the interaction was done using confocal microscope (Nikon A1R-MP+ Multiphoton System). Results: As a proof-of-concept, we mounted a collagen fiber into our frame and filled channel with BSA solution. Observation indicates that liposomes prefer to accumulate on the collagen fiber surface. Multiple trial frames were needed to account for height requirements necessary for confocal microscopy. Our built-in sample well allowed for a maximum 20 uL of formulation to be added into the channel environment from one end of the fiber. Our next steps will focus on reducing height and volume of background and sample needed as well as removing the need for a dish or slide altogether. Future studies will focus on kinetic phenomena in this microenvironment. Conclusions: Using the methods described above, we observed that Doxom liposomes accumulated near the fiber surface. This suggests that liposomes can use collagen as a route of travel in the extracellular environment. Future experiments with this frame design and others will be used to study the liposomal interactions with collagen and other ECM components. In addition to new frame designs, instruments with higher intensity and resolution will provide more accurate data.
A Bigger View: US public TB prevention initiatives with a broader health systems perspective
(2019-03-05) Miller, Thaddeus; Grebennikov, Sarah; Stockbridge, Erica L.; Hussain, Anusha
Background: Tuberculosis (TB) is a complex disease and persists as a greater threat than most understand. Responsibility for TB treatment and control has generally fallen to public health agencies. Unfortunately, important limitations to the public health sector’s of TB control are beginning to show. UNTHSC recently hosted a “systems thinking symposium” with the goal of helping public health authorities view their work in broader context. This project presents an analysis of industry perspectives on public TB control initiatives drawn from symposium discussions. Purpose: We analyzed 36 hours of discussions to better understand how CDC’s messaging around TB prevention and managing latent TB infection (LTBI) in particular is heard, accepted, and potentially acted on in various health care sectors. Methods: Approximately 30 participants from across the US healthcare system discussed how incentives and disincentives within their industry might affect TB-related public health initiatives. Discussion sessions focused on how at-risk patients self-identify and seek care; how providers identify potentially at-risk patients; how clinical evaluation is initiated and conducted; treatment initiation; and treatment completion. We analyzed discussion transcripts to identify industry perspectives, opportunities and barriers, and potential gaps in TB control initiatives. The unit of study was the program or industry represented by responses, not individual respondents, and the North Texas Regional IRB determined the project not to be human subjects research. Results: We identified the 15 most commonly used context appropriate words from a 78,604 word transcript. These were mapped to broad themes such as improving screening target populations, continuity of care, and potential roles of the non-public health sector. Notable barriers were identified within the clinical and managed care sectors, including consistent questioning of TB prevention as a priority activity, including potential risks, benefits, and the value proposition. Conclusions: CDC’s promotion of targeted LTBI screening and treatment, and TB prevention in general, is not well reflected in the attitudes of the non-public healthcare sector in our sample. Most health care professionals would choose not to prioritize LTBI due to the logistics of insurance and more urgent and emergent diseases. It may be important for CDC to consider who and how they target TB elimination messaging in order to enhance impact.
A Case of Symptomatic Angiomyolipoma
(2019-03-05) Young, Todd; Eskildsen, Dane
Background: Renal angiomyolipoma (AML) are benign soft tissue neoplasms classically composed of blood vessels, smooth muscle cells and adipocytes. These masses are found in .3 to 2.1% of the population and can be strongly associated with genetic syndromes such as the Tuberous Sclerosis Complex. While most of these masses are found incidentally, they can, in rare cases, become symptomatic. Patients with symptomatic AML most commonly present with hematuria, flank pain and renal hemorrhage. Case Presentations: A.H. is a 51-year-old obese female who presented 7 months ago to the emergency department with sudden onset left upper quadrant pain, nausea and emesis. On admission, her hemoglobin was found to be 9.1. Due to continued anemia she was transfused with 2 units of blood. CT scan of the abdomen and pelvis showed massive hemorrhage in the retroperitoneum surrounding the left kidney and a focus of fatty tissue likely representing a large AML. After Urological consult, left renal pole artery embolization was performed by interventional radiology. Over the next several months, after resolution of the hemorrhage, subsequent scans found that the symptomatic mass measured 4 cm and another 1.2 cm AML was found in the ipsilateral kidney. 6 months’ post presentation it was determined that, due to size and history of hemorrhage that the patient would undergo a radical left nephrectomy. Upon surgical exploration of the abdomen the tissue around the kidney was found to still be incredibly inflamed and thick. Despite this, the surgery proceeded without complications. Conclusion: Classic AML are the only benign renal masses that can confidently be diagnosed using imaging. As such, confirmed asymptomatic AML are often left untreated and actively observed over time. The consensus in literature indicates a size 4 cm as the cutoff for when AML are suspicious for symptomatic manifestation. Indeed, the risk of significant symptoms directly increases with size of the mass. This same 4cm size cutoff is used as a guideline for when treatment is warranted. Modern first line treatment includes embolization, with partial or radical nephrectomy coming into play when embolization fails to control symptoms or with excessively large masses. In this case, although embolization initially controlled the bleeding, patient comorbidities and tumor size warranted definitive removal of the mass.
A Case Series Comparison of Treatment Techniques for Blount’s Disease
(2019-03-05) Mayfield, Matthew; DeRon, Nathan Jr.
Background: Blount’s disease is disordered growth at the proximal tibial physis of pediatric patients causing leg bowing known as genu vara. Diminished growth of the medial physis causes leg bowing without natural correction. The high prevalence of comorbid obesity in patients is thought to contribute to destruction of growth cells at the physis. There are two common treatments: hemiepiphysiodesis involves arresting the lateral proximal tibial physis to allow increased growth at the medial proximal tibia. Osteotomy includes realigning the tibia and fibula such that the lower extremity mechanical axis becomes increasingly linear. This case series analyzes the optimal treatment choice based on patient age. Case Descriptions: Case 1 A 10-year-old male presented with bilateral leg bowing, bilateral knee pain, and obesity (BMI = 53.8). Treatment was bilateral hemiepiphysiodesis at the lateral tibial physis using eight-plates. This correction was insufficient. Bilateral tibia-fibula osteotomies with external fixation (ex-fix) were then performed with successful correction. Case 2 An 8-year-old female presented with bilateral leg bowing, limp, knee pain, and obesity (BMI = 44.7). Treatment was bilateral hemiepiphysiodesis at the lateral tibial physis. The left hemiepiphysiodesis proved sufficient for correction, but the right hemiepiphysiodesis did not. A subsequent tibia-fibula osteotomy with ex-fix was performed and proved successful. Case 3 A 12-year-old male presented with leg bowing, knee pain, and obesity (BMI = 38.6). Treatment was bilateral hemiepiphysiodesis at the lateral tibial physis. This proved insufficient, and treatment proceeded to a left tibia-fibula osteotomy with ex-fix and a right tibial osteotomy with internal fixation. These osteotomies were sufficient for correction. Conclusion: This case series shows an indication for osteotomy as first-line treatment for Blount’s disease in patients at a relative advanced age. The study also identified further potential research targets. A retrospective look at success rates of treatments in various age groups may help determine the age at which each treatment is preferred. A retrospective analysis may be performed to determine the infection rates in both types of treatment. Finally, additional research may be performed to determine the obesity threshold required to increase risk for Blount’s disease. This data is potentially useful to pediatricians for patient education and prevention.
A Comparison of Autism Spectrum Disorder (ASD) and a dual diagnosis of ASD + Developmental Coordination Disorder (DCD): A Case Study
(2019-03-05) Kata, Karolina; Ganesh, Abhinaya; Mauk, Joyce; Bowman, Paul; Bailey, Laurie; Hamby, Tyler; Miller, Haylie; Chang, Shannon
Background: Autism Spectrum Disorder (ASD), Developmental Coordination Disorder (DCD), and the dual diagnosis of ASD+DCD often have longer diagnostic trajectories given the complexity of their symptom profiles and associated difficulty with differential diagnosis. While first concerns may originate from parents, schools, or medical professionals, it may take years of waiting and assessments to reach a final diagnosis. Patients with co-occurring disorders can undergo a lengthier process as symptoms of 1 disorder may mask symptoms of another and create confusions within a care team. By understanding differences in the lines of service visited, symptoms, and parent concerns exist for patients with and without a dual diagnosis, we aim to identify potential targets for improvement in the diagnostic process. Case Information: Patient 1 (ASD+DCD) is a Caucasian female who presented with first concerns at 2 years and reached an ASD diagnosis at 6.25 years and a DCD diagnosis at 2 years. She was recommended and utilized speech therapy (ST), occupational therapy (OT), and physical therapy (PT). She had 9 visits with professionals and was assessed with the Ages and Stages Questionnaire (ASQ), Modified Checklist for Autism in Toddlers (M-CHAT), and the Autism Diagnostic Observation Schedule (ADOS). Patient 2 (ASD) is a Hispanic male with first concerns at 2 years and reached a final diagnosis at 6.5 years. While he was recommended ST, OT, and PT, he only utilized ST. He had 10 visits with professionals before reaching his diagnosis and was assessed with the ASQ, ADOS, and Social Communication Questionnaire (SCQ). Both were first seen by Pediatrics and were given a final diagnosis at Child Study Center. Conclusions: The age when a reliable diagnosis for ASD or DCD can be made is 1.5 and 5 years, respectively. However, the average age of diagnosis for ASD or DCD is 4.9 and 7.8 years. While patient 1 reached her DCD diagnosis at 2 years, both patients received their ASD diagnoses later than average. Several factors, such as the physician’s knowledge, clinical resources, sex, socioeconomic status, cultural and language barriers, and co-occurrence with ADHD may play a role in explaining this delay in diagnosis.
A Comparison of Protocols for Simulating Hemorrhage in Humans: Step vs. Ramp Lower Body Negative Pressure
(2019-03-05) Kay, Victoria; Anderson, Garen; Sprick, Justin; Rickards, Caroline; Rosenberg, Alexander
Lower body negative pressure (LBNP) elicits central hypovolemia, and has been used to characterize the cardiovascular and cerebrovascular responses to simulated hemorrhage in humans. LBNP protocols traditionally employ a progressive stepwise reduction in pressure that is maintained for specific time periods. More recently, however, continuous ramp LBNP protocols have been utilized to simulate the continuous nature of most bleeding injuries. Purpose: The aim of this study was to compare tolerance and hemodynamic responses between a step LBNP protocol and a continuous ramp LBNP protocol until the onset of presyncope. Methods: Healthy human subjects (N=20; 8F, 12M) participated in two LBNP protocols to presyncope: 1) Step Protocol, where chamber pressure decreased every 5-min to -15, -30, -45, -60, -70, -80, -90 and -100 mmHg, and, 2) Ramp Protocol, where chamber pressure decreased 3 mmHg/min. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), middle and posterior cerebral artery velocity (MCAv and PCAv), muscle and cerebral oxygen saturation (SmO2 and ScO2), and end-tidal CO2 (etCO2) were measured continuously. Time to presyncope, the cumulative stress index (CSI; summation of chamber pressure*time at each pressure), and hemodynamic responses were compared between the two protocols. Results: Time to presyncope (Step: 1611.8 ± 80.5 s vs. Ramp: 1675.4 ± 68.3 s; P=0.17), and the ensuing magnitude of central hypovolemia (%Δ SV, Step: -54.3 ± 2.5 % vs. Ramp: -51.9 ± 2.7 %; P=0.31) were similar between protocols, despite a higher CSI for the step protocol (Step: 946.5 ± 98.4 mmHg*min vs. Ramp: 836.7 ± 81.6 mmHg*min; P=0.06). While there were no differences at presyncope between protocols for the maximum change in HR, MCAv, or SmO2 (P≥0.21), the reduction in MAP was slightly less (Step: -17.1 ± 1.8 % vs. Ramp: -20.0 ± 1.4 %; P=0.02) and the reductions in PCAv, ScO2,and etCO2 (P≤0.08) were slightly greater for the step protocol compared to the ramp protocol. Conclusion: These results suggest that step and continuous ramp LBNP protocols elicit relatively similar tolerance times, reductions in central blood volume, and subsequent reflex hemodynamic responses, despite a greater cumulative stress in young healthy adults.
A comparison of Social Responsiveness Scores in patients aged 0-24 with Autism Spectrum Disorder or schizophrenia.
(2019-03-05) Miller, Haylie; Shahub, Nur-Alhuda
Purpose: Autism Spectrum Disorder (ASD) and schizophrenia share common features; past research demonstrates that these features include pathophysiology, social-cognitive impairments, possible genetic underpinnings, and risk factors. In both disorders, social cognition presents a key barrier to quality of life. One measure of social cognition designed for use in ASD, the Social Responsiveness Score (SRS), is also commonly used to assess social cognition and plan interventions in schizophrenia. We aimed to determine whether people with ASD and schizophrenia differ in the mean and range of their SRS scores. Methods: We identified an age-matched sample of fifteen individuals with Autism Spectrum Disorder (Male = 13, Female = 2; MAge= 22.71, SDAge= 3.24) from the National Database of Autism Research and thirteen individuals with schizophrenia (Male = 10, Female = 3; MAge= 22.07, SDAge= 2.99) from the SchizConnect database. All individuals were between the ages of 0 and 24 years. Data were analyzed using Microsoft Excel and the Statistical Package for Social Sciences software. SRS T-scores Results: Mean SRS scores did not differ between the ASD (M = 80.50, SD = 14.32) and the schizophrenia (M = 89.78, SD = 39.37) groups (p = 0.22). Although the group means were not significantly different, the schizophrenia group had a notably wider range of SRS scores than the ASD group. Conclusions: Although our groups did not differ in their mean SRS scores, there was wide variability in the schizophrenia group. The SRS was designed for ASD, and may not be an adequate measure of social dysfunction in other populations. At minimum, this wide variability suggests that when using the SRS as a tool for assessing social-communication skills in schizophrenia, the influence of other factors (such as age, behavior, or language) must also be considered. Further study is required to fully assess the clinical utility of this tool for non-ASD populations.
A Computer-Based Approach to Developing Diagnostic Rules
(2019-03-05) Papa, Frank; Parikh, Tiraj
Purpose: In 2015, the National Academy of Medicine published a report revealing that diagnostic error may be America’s third leading cause of death and responsible for the majority of paid medical malpractice claims. Medical education researchers are now looking to the learning sciences for theories that might support improvements in the diagnostic performance of tomorrow’s health care providers. One such theory, called “Dual-Process Theory”, suggests that people utilize two distinct approaches to diagnostic reasoning: pattern recognition and analytical reasoning. To date, researchers have paid little attention to how we reason analytically. Dual-process theorists suggest that analytical reasoning is, in part, predicated upon a clinician’s knowledge of diagnostic rules. These rules encompass knowledge in the form of experientially-based, statistically-framed estimates of the frequency with which a given disease is associated with each of its characteristic findings. The purpose of this project is to produce a computer-based training tool which supports learners in how to analytically reason via the acquisition and application of conditional probability (CP) derived diagnostic rules. Methods: This tool will have four components: 1) a display of CP derived diagnostic rules associated with signs and symptoms most likely to be linked to a given clinical presentation 2) a set of interactive tools enabling learners to identify which of those rules are most robust in ruling in/out the various differentials, 3) a set of practice cases where learners are given multiple opportunities to apply these CP derived rules, and 4) interactive screen prompts designed to guide the students in developing a cognitive strategy to apply high-yield rules to diagnose a multitude of test cases. Results: The exhibitor will demonstrate a tool which: 1) displays disease by sign/symptom CPs, 2) enables their rearrangement (by history & physical, breadth by feature strength, and depth by selected differential) as the basis for formulating diagnostic rules, and 3) functions which support the construction of a diagnostic strategy. Conclusions: After completion of the described educational tool, the authors will execute an IRB approved study involving students in a year 2 systems course, and a treatment/control research design.
A DISCOVERY-DRIVEN LABEL-FREE PROTEOMICS BASED SURVEY OF ESTRADIOL-REGULATED PROTEIN NETWORKS AND ASSOCIATED BIOLOGICAL FUNCTION IN THE RAT RETINA
(2019-03-05) Rahlouni, Fatima; Nguyen, Vien; Prokai-Tatrai, Katalin; Prokai, Laszlo; Zaman, Khadiza
A DISCOVERY-DRIVEN LABEL-FREE PROTEOMICS BASED SURVEY OF ESTRADIOL-REGULATED PROTEIN NETWORKS AND ASSOCIATED BIOLOGICAL FUNCTION IN THE RAT RETINA Khadiza Zaman1, Fatima Rahlouni1,2, Vien Nguyen1, Katalin Prokai-Tatrai1 and Laszlo Prokai1 1 Department of Pharmacology & Neuroscience,University of North Texas Health Science Center, Fort Worth, TX. 2 Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX. Purpose: Previous studies have established the pleiotropic role of 17β-estradiol (the predominant human estrogen) as a potent neuroprotectant, but only recently it has gained attention for its therapeutic potential against ocular neurodegenerative diseases. Thus, this study was designed to perform a label free quantitative proteomics based survey to understand the impact of topical administration of E2 on the rat retina. This is one of the first reports elucidating E2-regulation of rat retinal proteins, networks and associated biological processes, thus providing us with more insights on topical hormone therapy. Methods: Ovariectomized (OVX) Brown Norway rats were given 0.1% w/v E2 eye drops in saline/2-hydroxypropyl-β-cyclodextrin vehicle and controls received vehicle daily for three weeks. Retina from euthanized animals were immediately isolated. Retinal proteins were extracted and analyzed using data-dependent nanoflow LC-ESI-MS/MS on Orbitrap EliteTM (Thermo) or Orbitrap Velos Pro. MS/MS data was searched against the UniProt rat protein database using Mascot (Matrix Science). Validations and label-free quantitation were performed using Scaffold (Proteome Software) by observing changes in protein abundances between treated and control using t test. Differentially expressed proteins were mapped to protein interaction networks and biological processes through Ingenuity Pathway Analysis® (Qiagen). Results: In our proteomics-based quantitation, we identified 66 E2 regulated proteins in the OVX rat retina among which 49 up-regulated and 17 down-regulated (p1.5-fold change between groups). Some of the most highly scored identified networks are associated with endocrine system disorders, organismal injury and abnormalities, and developmental disorder. Presence of nuclear estrogen receptor (ER) in our dataset also reinforces the intricate nature of E2 signaling conveying neuroprotection. Our network-based analysis emphasized on the role of E2 in neuroprotection through regulation of various stress-induced signaling cascades such as ERK/MAPK pathways. Conclusion: By using an OVX model with little or no endogenous E2, our study potentiates the neuroprotective role of E2 upon topical administration of the hormone. With this vast array of information on estrogen biology we seek to create foundations in basic science research regarding hormone therapy focusing on the “estrogenic retina.” Acknowledgement: This study was supported by the National Eye Institute and the Office of Research on Women’s Health (grant number EY027005 to K.P.-T.) and by the Robert A. Welch Foundation (endowment BK-0031 to L.P.).
A Liposomal Platform Using a Microfluidic Mixing Method for Drug Delivery and Targeting of Metastatic Prostate Cancer
(2019-03-05) Ranjan, Amalendu; Joshi, Rohan; Vishwanatha, Jamboor; Lampe, Jana B.
Purpose: The success rate for the treatment of localized prostate cancer (PCa) is very high. However, the overall survival rate for patients with metastatic PCa drops to 28%. Bone is the primary metastatic site in 90% of PCa patients, which not only shortens survival, but also causes a significant decrease in the quality of life. The objective of the project is to develop a dual-targeted nanotherapeutic for bone metastatic PCa. We will engineer liposomes composed of two lipids, DOPE and DOTAP. A bone-targeting moiety with a high affinity to the Ca2+ in bone will be conjugated to the outside of the liposome. This liposome will be loaded with a cabazitaxel-ligand conjugate that has a high affinity for the receptors that are upregulated in 95% of PCa cells. Methods: In this formulation we have used a lipid ratio between 40% and 60%. Then the size and polydispersity were optimized by selecting the best Flow Ratio (FR) and Total Flow Rate (TFR) settings in the NanoAssemblr. We also measured the zeta potential (ZP). Cellular uptake studies were performed using the PC3 cell line and DID dye-loaded, DOPE-DOTAP liposomes, then imaged with a Zeiss LSM 510 confocal microscope. Additionally, liposomes were loaded with curcumin to determine their % drug loading (DL) and encapsulation efficiency (EE). Results: The liposomes were optimized with a 50:50 mol% ratio, a 1:1 FR, and a 6 ml/min TFR. Size (~150 nm) and polydispersity index (0.2), were measured and found to be consistent over a 7-day period to show stability. The ZP (~+40 mV) was also measured. The cellular uptake studies showed that the liposomes were increasingly taken up by the cells over time. The EE was ~93% and DL was ~5%. Conclusion: By finding a desirable ratio of lipids, FR and TFR, we have optimized our liposomal formulation based on size, PDI, and ZP. Also, we have demonstrated that our liposome can easily be taken up by cancer cells and have shown excellent DL and EE. As a result, we are prepared to continue with the next steps of the project. In the next step we will attach the bone-targeting moiety to the liposome, conjugate cabazitaxel with the targeting ligand, and load the liposomes with the cabazitaxel-ligand. Fully functional liposomes will be tested for in vitro and in vivo functionality.
A Novel Mutation of APOB in Two Siblings with Hypercholesterolemia
(2019-03-05) Hamilton, Luke; Hamby, Tyler; Wilson, Don; Sprunger, Abigail
A Novel Mutation of APOB in Two Siblings with Hypercholesterolemia 1 Abigail Sprunger, BS; 2L. Hamilton, MS; 3T. Hamby, PhD; and 2D. P. Wilson, MD, FNLA 1University of North Texas Health Science Center, Ft Worth, TX, and the Departments of 2Pediatric Endocrinology and Diabetes and 3Research Administration, Cook Children’s Medical Center, Ft Worth, TX, USA. Abstract Background: Familial hypercholesterolemia (FH) is a common genetic disorder cause of premature atherosclerosis due to chronically elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. Individuals with FH experience an increased risk of premature cardiovascular disease (CVD), and lack of early identification and treatment increases the risk of CVD-related coronary events later in life. We report two siblings with FH caused by a novel mutation in APOB. Methods: Electronic medical records were reviewed for two patients with FH. Case Information: Two biologically related siblings (male age 9, female age 11) were found to have LDL-C levels [greater than] 95th centile for respective age and gender. Neither sibling had preexisting medical conditions nor a history of chronic medications. Both siblings were found to have the same missense variant in the APOB gene, a novel mutation causing hypercholesterolemia. Because of parental concerns regarding use of statins, both were treated with a cholesterol absorption inhibitor. Conclusions: Despite the benefits of early identification of those at moderate-to-severe risk, several knowledge gaps impede successful cholesterol screening of children: misunderstanding goals of screening, the best screening method, and ideal age for screening and for intervention. Current guidelines recommend universal cholesterol screening and selective screening starting at 10 and 2 years of age, respectively. Although not routinely preformed, identification of a genetic mutation helps to 1) confirm the diagnosis of FH; and 2) serves as an additional risk factor for CVD, aids risk stratification and clinical-decision making, and helps determine the timing and intensity of treatment that would provide the best long-term health benefits. In addition to lipid-lowering medications, treatment should include global reduction of all CVD risk factors through health education, and adoption of life-long, heart-healthy living with a goal to reduce LDL-C levels to
A peek into Tarrant County’s declining Tobacco Usage
(2019-03-05) Turnbow, Austin; Ali, Reiza; Lewis, Daeija; Arrigunaga, Jose; Wolstein, Austin
Background Smoking is the leading cause of preventable death in the United States. It is estimated that nearly half a million premature deaths can be attributed to smoking per year. Tarrant County has shown a steady decline in adult smokers in the past decade. In 2015, Fort Worth showed an adult smoking rate of 15.80%, compared to 16.70% in the state of Texas. This number dropped to 14% by 2017. To better understand future health implications, the contributing factors to this decline are discussed. Methods Through the use of data collection from a variety of community resources, a compilation of the most noteworthy efforts made towards combating tobacco addiction are identified and thoroughly evaluated. These resources are identified through tarrant211.org and the Tarrant Cares website. Results Many services use an evidence-based approach to reduce the likelihood of substance use through education, familial support, and acquiring the skills needed to live a tobacco free life. Setting goals, making good decisions, and developing a strong-willed mind set can help residents gain confidence and make healthy choices. Many of the substance abuse prevention services that are available include community coalition programs, youth prevention programs, partnership for success, and strategic prevention framework through prescriptions. Conclusions Based on the efficacy of the programs that were evaluated, it can be concluded that these resources have indeed led to a decrease in tobacco use amongst Tarrant County residents. With more widespread efforts towards combating tobacco use through various resources, Texas can become a healthier state as a whole. The resources available in Tarrant County are effective, and a tribute to local government leaders who have made it a priority to have these resources available to its residents. The returns on these investments should encourage expanded efforts, especially aimed at youth.
A Previously Unreported Combination of Mutations and its Unexpected Outcome in a Patient with Type 1a Rickets: A Case Study
(2019-03-05) Swanson, Larry MD; Sridhar, Swathi
Background: Type 1a rickets is a rare autosomal recessive condition in which the enzyme 1-alpha-hydroxylase is not fully active. The result of this mutated enzyme is the inability to convert vitamin D from 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. This form of rickets classically presents with low 1,25 (OH)2 vitamin D, hypocalcemia, elevated parathyroid hormone (PTH), and distinct radiographic findings such as bowing of the legs and widening of the growth plates1,2. There are a number of mutations of the CYPB27B1 gene that are known to cause impaired enzymatic activity. Individuals with homozygous and compound heterozygous mutations have been described. Correlations between specific mutations and varying degrees of enzymatic impairment have been made. Case Information: A 14-year-old male was referred to endocrinology after experiencing a pathologic femur fracture. His mobility was severely limited secondary to bowing of his legs and pain with weight bearing. He was 48.4” tall (z = -4.8). He had pronounced bowing of his extremities and wide wrists. Labwork revealed the following: serum Ca 6.3 mg/dL, serum Phos 4.4 mg/dL, PTH 265 pg/mL, 25-hydroxyvitamin D 29 ng/mL, and 1,25 (OH)2 vitamin D 33 pg/mL (19-83). He was then admitted to the inpatient endocrine service and treated with oral and IV calcium, ergocaliciferol, and calcitriol. Later, whole exome sequencing revealed compound heterozygous variants of the CYP27B1 gene: c1319_1325dupCCCACCC (p.P443fs) and c.1226C [greater than] T (p.T409l). The normal level of 1,25-(OH)2 vitamin D concentration was surprising, given that both of the mutations in this patient were previously believed to cause complete enzymatic inactivity. The P443fs variant has been found in combination with other mutations, resulting in phenotypic variability3. The T409l variant appears less frequently in the literature, but is also believed to cause complete enzymatic inactivity. The P443fs and T409l mutations, however, have not previously been described together. Conclusion: The normal 1,25 (OH)2 vitamin D concentration in this patient suggests that at least one of these two CYP27B1 variants does not universally cause complete enzymatic inactivity, which is a departure from the current evidence base. Further use of genetic testing in Type 1a Rickets may result in improved understanding of the connection between genotype and phenotype in this rare condition.
A rare case of primary germinoma in corpus callosum.
(2019-03-05) Anderson, Jenna; Ellis, Thomas; Kata, Karolina
Background Primary intracranial germinoma is a rare lesion which accounts for approximately 0.5–2% of all central nervous system (CNS) tumors. Generally, this neoplasm occurs in the midline structures with the majority located in the pineal and suprasellar regions. Germinoma presenting primarily in the corpus callosum is highly unusual and reportings of similar cases in scientific literature are limited. The aim of this case report is to describe clinical features, imaging findings, and management of a primary germinoma uniquely presenting in the corpus callosum. Case Information 21-year-old man with Parinaud syndrome, gait instability, altered mood, and remote history of orbital trauma presented initially for an ophthalmology evaluation of vision change. These symptoms prompted intracranial imaging, including MRI which revealed an enhancing lesion in the corpus callosum, evidence of obstructive hydrocephalus, and an arachnoid band in the region of the aqueduct of Sylvius. The lesion was believed to potentially represent either a primary CNS lymphoma, glioblastoma, anaplastic astrocytoma, or tumefactive demyelinating disease. The patient underwent a right frontal stereotactic brain biopsy and third ventriculostomy. Pathologic evaluation with immunohistochemistry and tumor marker analysis confirmed a diagnosis of primary germinoma. Post-operative plan included oncology consultation to establish chemotherapy and radiation treatment. Additional imaging showed corpus callosum mass with evidence of diffuse extension in the surrounding structures. Interestingly, in contrast to pre-operative imaging, enhancement of the pineal gland area was noted and provided additional rationale for development of obstructive hydrocephalus. Conclusion Primary germinoma of corpus callosum has not yet been extensively described in literature. The present case demonstrates that primary germinoma can occur in uncommon midline structures and present with unique imaging findings. This report contributes to improving recognition and further understanding of clinical presentation and course and potentially to optimize the treatment in similar future case.
A Robust Model for A Sustainable Diverse Healthcare Community - The Center for Diversity and International Programs, UNT Health Science Center
(2019-03-05) Jones, Harlan; Basha, Riyaz; Vishwanatha, Jamboor; Nair, Maya
About CDIP The Center for Diversity and International Program’s (CDIP) objectives are to broaden partnerships (local, national and international), unify institutional pipeline programs, innovate education and training, and lead diverse constituencies to opportunities in biomedical/behavioral science research and Health Professional career paths. CDIP’S programs A pipe line of programs from “K-12” to “healthcare professionals” are offered by CDIP K – 12 Outreach Stimulate and broaden student’s awareness of biomedical and health professional careers paths by exposing students to clinical and laboratory research environments at UNTHSC. Undergraduate Summer Research Internships Various undergraduate summer research programs at UNTHSC are funded through numerous sources. Participants are created with minority and non-minority-serving institution partners across USA. Graduate and Health Professional Student Training Programs Supports short term and dual degree research training for underrepresented students in health professions. Faculty Grant Writing and Professional Development Provide research and mentoring to underrepresented graduate and heath professional students, post-docs and junior faculty. CDIP’S structure The main pillars of CDIP are constituted with (1) Texas Center for Health Disparities (TCHD): A National Institute of Minority Health and Health Disparities (specialized Center of Excellence in Health Disparities (U54) was announced in 2017. (1) Research (2) Education and Training and (3) Outreach (2) National Research Mentoring Network (NRMN): Develop a culture of mentoring relationships, and more broadly the research workforce. (3) Diversity Training Programs: The plan includes a variety of programs that reach out to students from K-12, through college, and into graduate school and health care professions. (4) Texas Minority Health, Education Research and Outreach: Supports PhD scholars, junior faculty development and scholarship for senior faculty. Impact of CDIP CDIP has pioneered inter professional collaboration at institutional and national levels. 801 students and 201 faculty members from various colleges/schools at UNT Health Science Center and partnering institutions across the nation participated in various programs offered by CDIP and benefiting their educational or professional career. Such collaboration resulted in more than 200 publications and $24.76 Million in research funding. In summary, CDIP functions are in full alignment with the mission of ‘One University’.
A Student-Run Clinic as an Approach to Refugee Health
(2019-03-05) Miller, Dallas; Lin, Christine; Gee, Kelly; Chang, Shannon; Hughes, Jonathan
Background: Texas is one of the top U.S. states for refugee resettlement, receiving 9% of the country’s refugees from October 2018 to February 2019 alone. The Congolese and Burmese comprise most of the refugee populations in Texas, holding 57% and 21% of state arrivals, respectively. Within Texas, Tarrant county is currently one of the top counties where refugees are resettled. Before a refugee resettled in the U.S., they must undergo a tedious resettlement process that consists of biographical data collection, medical and security screenings, and interviews. Once approved, refugees are assigned to a non-governmental organization that aids in the often difficult transition to their new lives in the U.S. Many challenges during the resettlement process may prevent the individual from obtaining adequate medical care. Language, cultural beliefs, and socioeconomic factors are the major barriers to accessing health care services resulting in the underutilization of resources. Access to community health resources is often also hindered by I-485 form processing times approaching 2 years. As a result, many refugees do not seek out care until medical emergencies arise. Refugee Health Initiative’s goal is to establish continuity of care by connecting refugees seen at our health clinics with pertinent healthcare resources. Case Information: From October 2018 to February 2019, we have held 4 clinics at 2 locations and have seen a total of 67 refugees, of which, 23 were males and 44 were females. The average age of patients seen was 41.73 years. While all were seen for a general screening, common co-occurring complaints included cold and flu symptoms, blood glucose screening, abdominal pain, headache, and dysuria. Patient medical histories included diabetes, hypertension, nephrolithiasis, hyperlipidemia, and hypothyroidism. Conclusions: Refugee experiences in the clinic setting reveal problems in navigating the health care system. Language barriers prevent many from understanding diagnoses and medications, while those who are unsure of their insurance status are often lost to follow-up. Although breakthroughs are being made in outreach, continued innovation in approaching these populations is essential in developing a relationship of trust with Western health care methods. The Refugee Health Initiative’s clinic has the potential to become an entry point of care that can improve health promotion and deconstruct cultural misunderstandings of the healthcare system.
A Systematic Review of the Utility of Procalcitonin in Bacterial Meningitis
(2019-03-05) Gaviola, Dr. Marian; Mai, Steven
Purpose/Objective: To review the utility of procalcitonin (PCT) in the management of bacterial meningitis (BM). Methods: An English-language MEDLINE search from 1964 through June 20, 2018 was completed using the following search terms: calcitonin, calcitonin gene-related peptides, meningitis: bacterial/diagnosis, and meningitis, bacterial/blood. Primary literature that evaluated the diagnostic value of PCT in adult patients for separating BM from viral or aseptic meningitis and studies comparing PCT with other biomarkers were included. Studies that did not consider antibiotic pretreatment as an exclusion criterion were excluded. Results: A total of 15 studies were identified for inclusion in this review. Ten studies evaluated the utility of PCT in distinguishing BM from non-bacterial meningitis (NBM) in a total of 1022 patients. Eight of these were prospective studies and two were retrospective. All 10 studies showed that PCT is significantly elevated in cases of BM compared to NBM, with the average elevation ranging from 0.5 ng/mL to 4.714 ng/mL in the serum and 0.2 ng/mL to 1.88 ng/mL in the cerebrospinal fluid (CSF). Three studies compared the diagnostic value of serum PCT versus non-serum PCT. All three studies were prospective clinical studies and included a total 502 patients. Two studies showed that serum PCT had a higher diagnostic value compared to CSF PCT and only one showed that CSF PCT is superior. Finally, no studies reviewed the use of PCT in guiding antibiotic de-escalation and no studies reviewed whether to use PCT in parallels or in series. However, two studies considered the use of PCT in guiding antibiotic usage and one study examined the use of PCT in conjunction with lactate. These studies showed that there are higher levels of CSF PCT in patients with gram-negative infections compared to those with gram-positive infections and explored the possibility of using PCT in addition to glucose to guide antibiotic therapy. Lastly, one study showed that there is higher specificity when using PCT with lactate in series and higher sensitivity when used in parallel. Conclusions: PCT is a useful biomarker in identifying cases of BM and serum PCT may be better than CSF PCT in identifying BM. However, larger studies are necessary to confirm these results and identify a standardized threshold. Additionally, more studies are necessary to explore the best way to utilize PCT and in diagnosing BM and the utility of PCT in guiding antibiotic therapy for BM.
A Systems Approach to Postpartum Depression: Opportunities for Prevention and Treatment
(2019-03-05) Thompson, Erika; Adhikari, Sujita
A Systems Approach to Postpartum Depression: Opportunities for Prevention and Treatment Sujita Adhikari MPH Candidate, Erika L. Thompson, PhD, MPH, CPH Dept. of Health Behavior and Health Systems, UNT Health Science Center, Fort Worth TX,76107 Background Postpartum Depression (PPD) is a common mental health issue that occurs in women after childbirth. The depressive symptoms in affected mother are often manifested as a feeling of extreme sadness, guilt, helplessness, insomnia, excessive crying, extreme concern about child, fatigue and suicidal thoughts. Biological factors (e.g. hormonal changes) and psychological factors (e.g. stress, lack of social support, low socio-economic status, abusive relationships, greater work pressure, the occurrence of adverse life events, previous history of depression) are risk factors for PPD. In 2018, 14.7% of women in Texas who gave live birth experienced postpartum depression. Due to the complexity of this health issue, systems thinking is necessary to identify organizations aligned with addressing PPD, which can then help design effective interventions to minimize the potentially harmful effects of PPD. Objective The main objective is to identify organizations in the Fort Worth region that are involved in postpartum depression prevention or treatment and map organization connections. Methodology A web search was conducted in November 2018 to identify organizations and government bodies who address postpartum depression. Interconnection was established amongst these organizations to analyze using a system thinking approach. Results Three national-level organizations (e.g. Medicaid), four state-level organizations (e.g. Texas Department of Health and Human Services) and three local level organizations (e.g. MHMR of Tarrant County) were identified in the Fort Worth region. These organizations when analyzed were found connected with each other forming a system which operated to address PPD in this region. Conclusion These major ten organizations that are dedicated to working on postpartum depression are interconnected. The organizations operate at different levels to form a complex system. While organizations are making a positive impact on this issue, it is still necessary to dive deeper and understand the underlying factors for this problem. By understanding the complex system for PPD prevention and opportunities for integration, better mental health outcomes can be achieved.
Absolute and Relative Morphometric Differences in the Craniofacial Skeleton of OIM-/- Mice and Wild-Type Littermates
(2019-03-05) McBride, Alexandra H.; Organ, Jason; Menegaz, Rachel A.; Ladd, Summer
Purpose: Osteogenesis Imperfecta (OI, or “Brittle Bone Disease”) is a disorder caused by genetic point mutations in COL1A1/COL1A2 which affect the synthesis of type I collagen (Col1). Humans with the severe type III OI exhibit increased susceptibility to skeletal fractures and shortened stature, as well as cranial dysmorphologies and dental malocclusions. Mouse models of Col1 defects report postcranial phenotypes similar to those seen in humans, with a limited number of studies reporting alterations to cranial and dental integrity. This project tests the hypothesis that the reduced craniofacial dimensions reported in both humans and mice with Col1 defects are linked to an overall reduction in body size. Methods: The homozygous OI murine (OIM-/-) is a mouse strain with a nonlethal recessively inherited mutation of the COL1A2 gene. Wild-type (WT) and OIM-/- littermates were weaned at 21d and raised until adult (16 weeks). 3D morphometric landmarks were collected from serial in-vivo µCT scans at 4, 10, and 16 weeks using etdips software. Past 2.17 software was used to Procrustes-transform (rotate and translate) the landmark data, and to calculate interlandmark distances (ILDs) and centroid sizes. ILDs were scaled against skull/mandible centroid size and skull/mandible length to account for the effect of size. Mann-Whitney U tests (α=0.05) were used to compare centroid sizes and both absolute and relative (scaled) ILDs between the genotypes. Results: When comparing absolute morphometric distances, adult OIM-/- mice have shorter skulls, basicrania, palates, mandibles, and toothrows. However, OIM-/-mice are smaller overall than their WT littermates as measured by both body mass and craniomandibular centroid sizes. When the effects of size are accounted for, the trend for interlandmark distances in WT mice to be greater than those in OIM-/- mice is significantly reduced or even reversed. For example, when scaled to centroid size, no significant difference exists between WT and OIM-/- mice in skull, basicranial, or mandibular length. OIM-/- mice have a relatively short midface, short nasal bones, tall mandibular corpora and long mandibular toothrows. Conclusions: These findings underscore the importance of size and scaling in morphometric analyses. The deleterious effect of Col1 mutations on global skeletal dimensions, in combination with localized morphometric changes, may underlie the facial phenotype seen in human patients with OI type III. Attempts to identify these localized changes should first account for the restricted growth and small body sizes present in individuals with OI.
Activation of TRPV4 channels reduces IOP and improves outflow facility by regulating eNOS dependent nitric oxide release from the trabecular meshwork
(2019-03-05) Kasetti, Ramesh; Maddineni, Prabhavathi; Millar, J. Cameron; Zode, Gulab; Patel, Pinkal
Purpose: Nitric oxide (NO) is known to reduce intraocular pressure (IOP) by relaxation of the trabecular meshwork (TM) and distal vessels of the conventional outflow pathway. However, the intrinsic mechanisms by which outflow pathway tissues regulate NO production is yet to be elucidated. In vascular endothelium, activation of mechanosensory transient receptor potential vanilloid 4 (TRPV4) channels results in endothelial nitic oxide synthase (eNOS) mediated NO release, which in turn promotes vasodilation. Here, we determined whether activation of TRPV4 regulates IOP and conventional outflow via NO release in the TM. Methods: In wildtype (WT) and glucocorticoid-induced ocular hypertensive (OHT) C57BL/6J mice, the effect of TRPV4 agonist GSK1016790A on IOP and outflow facility was determined using rebound tonometry and constant-flow infusion method respectively. Effect of TRPV4 agonist on eNOS activation and NO production was determined using Western blot and fluorometric DAF-FM assay in primary human TM cells and ex vivo cultured human TM donor tissues. We report for the first time a method for electrochemical measurement of NO in human anterior segment donor tissues using NO microsensors. Results: Topical administration of TRPV4 agonist GSK1016790A significantly reduced IOP (Pin WT and OHT mice compared to contralateral control eyes. In OHT mice, treatment with GSK1016790A resulted in increased outflow facility (P=0.02)compared to contralateral vehicle treated eyes. We further demonstrate that TRPV4 activation by GSK1016790A resulted in increased eNOS phosphorylation in GTM3 cells, primary human TM cells, and cultured human TM donor tissues. Activation of TRPV4 in primary TM cells and ex vivocultured human TM donor tissues resulted in increased DAF-FM fluorescence, which signifies increase in TRPV4-mediated NO production. Treatment of human anterior segments with TRPV4 agonist resulted in increased production of NO as detected electrochemically using NO microsensors. Nonselective inhibition of NOS by L-NAME abrogated the IOP lowering effect of TRPV4 agonist in mice and reduced TRPV4-mediated NO production in outflow pathway cells and donor tissues. Conclusion: TRPV4 activation improves IOP and outflow facility, perhaps by regulation of eNOS dependent NO release.

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