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Spectrum of interferonopathies with features of vasculitis
No full textDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Novel Roles for BET Bromodomain Protein 4 (BRD4) in Cardiac Physiology and Disease
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.Bromodomain (BRD) protein of the BET (Bromodomain and Extra-Terminal) family are epigenetic reader proteins that have emerged as novel therapeutic targets in cardiovascular disease as well as in a variety of cancers. Small molecule BET inhibitors, such as JQ1, have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BRD proteins in the heart have not been conducted to validate pharmacological findings and unveil potential side effects. Focusing on BRD4, we tested the hypothesis that cardiomyocyte BRD4 drives pathological cardiac remodeling in the setting of disease-related stress. To facilitate these studies, we engineered a cardiomyocyte-specific BRD4 knockout mouse.
Using this model, we investigated the role of BRD4 in cardiac physiology and disease. To our surprise, loss of BRD4 protein triggered a spontaneous and progressive decline in myocardial contractile performance, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse hearts showed early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria confirmed that BRD4 ablation results in specific changes in protein levels and activity of the mitochondrial electron transport chain. Comparative analysis of the JQ1-altered transcriptome suggests that a BRD4-dependent effect of BET inhibition includes changes in transcription of nucleus-encoded mitochondrial genes, raising concerns for cardiotoxicity with potent pharmacological BET inhibition.
Furthermore, we tested the roles of BRD4 isoforms, BRD4-L and BRD4-S(a), in cardiomyocyte biology. Isoform-specific knockdown of BRD4 using siRNAs in primary cardiomyocyte culture demonstrated that BRD4-S(a) is required for cardiomyocyte hypertrophy. BRD4-S(a) expression was low in naïve hearts, but it increased significantly in remodeling and failing hearts. Moreover, transgenic over-expression revealed that the BRD4-S(a) isoform is sufficient to induce hypertrophic remodeling and heart failure. In contrast, restoring BRD4-L expression partially rescued systolic dysfunction in animals with a cardiomyocyte specific deletion of BRD4.
In conclusion, present study provides evidence that BRD4 regulates cardiomyocyte mitochondrial homeostasis, and that it is required for maintaining normal cardiac function in rodents. Moreover, we demonstrated that the BRD4 short isoform is a driver of pathological cardiac hypertrophy, whereas the long isoform may have a homeostatic role. In aggregate, we have identified novel roles of BRD4 in cardiomyocyte biology, unveiling critical insights - as well as caveats - regarding the therapeutic targeting of BRD proteins in heart failure
Breakfast in Bed with Cat
No full textI like being whimsical and having fun with words.. especially when it comes to one of my favorite subjects- cats. I hope it brings a smile to your face as you read it (even if you don't have a cat)
Development of Ex Vivo Femoral Head Deformity Model to Test Restorative Surgical Techniques
Get PDFThe 60th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, February 1, 2022, 3-6 p.m., Microsoft Teams)Legg-Calve-Perthes disease (LCPD) is a childhood ischemic hip disorder which produces femoral head deformity due to weakened bone structure. The femoral head deformity causes pain, stiffness, and debilitating osteoarthritis; if left untreated, a total hip replacement is eventually required. Currently there is no reliable ex-vivo deformity model to develop and test the efficacy of new surgical devices and methods to improve the deformity and to restore the round shape. We hypothesize that a reliable model of deformity comparable to LCPD can be created using porcine cadaver bone by applying compressive force methods. Due to the availability of porcine humeral heads in the lab, we performed our preliminary studies using the humeral heads.
We tested four mechanical approaches. Our first approach involved the application of static and cyclic compressions to mature humeral heads. However, the method failed to deform the heads due the high compressive strength of the mature bone. Our second approach involved drilling into the mature heads to create stress risers before applying the compression forces. This resulted in undesirable fracture of the bone. Our third approach used juvenile porcine humeral heads with cyclic compressions which resulted in deformity, but was inconsistent in the number of cycles required to achieve the appropriate deformity.
Finally, we successfully achieved a reliable deformity model resembling LCPD by mounting juvenile humeral heads in a specific orientation and applying successive increases in static compression force at 50, 100, 150, 200, and 250 lbs using a Bose Electroforce 3330 test instrument. The amount of collapse after each static compression was measured using calipers. Identical measurements were taken after each compression test, up to 250lbs of force. This method created a 2 mm collapse of the humeral head which was reproducible.
In summary, we developed a novel ex-vivo model of deformity which will facilitate the development of new restorative surgical devices and techniques to improve the femoral head deformity of LCPD.Southwestern Medical Foundatio
Approaching gliomas through a translational research lens
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Number 7
Get PDFIf you're lucky enough to find love, holding onto it can be difficult and often seems unfair
Defining Cardiac Conduction System Gene Regulatory Networks
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.The cardiac conduction system initiates and propagates each heartbeat. Specialized conducting cells are a well-conserved phenomenon across vertebrate evolution, although mammalian and avian species harbor specific components unique to organisms with four-chamber hearts. Early histological studies in mammals provided evidence for a dominant pacemaker within the right atrium and clarified the existence of the specialized muscular axis responsible for atrioventricular conduction. Building upon these seminal observations, contemporary genetic techniques in a multitude of model organisms has characterized the developmental ontogeny, gene regulatory networks, and functional importance of individual anatomical compartments within the cardiac conduction system. Cis-regulatory DNA elements mediate transcriptional control (called enhancers in cases of transcriptional activation and silencers in cases of repression) by recruiting TFs. These collectively determine spatio-temporal regulation of each gene during development. Thus, determining the evolutionary history of participating enhancers provides key information on the origins of morphological trait diversity. My dissertation describes the development of novel genetic models, sensitive biochemical assays, and consistent genomic methodologies complemented with bioinformatics to highlight the gene regulatory networks that act during cardiac conduction system development and homeostasis with a particular emphasis on networks implicated in human electrical variation by large genome-wide association studies. As part of future directions of my doctoral work, I have also outlined some ongoing studies on determining the ontogeny of the cardiac pacemaker cells. I finally conclude with the translational impact of my research whereby we have made an impressive headway towards interrogating the development of the cardiac conduction system and onset of cardiomyopathies in human heart specimens
The infected, the infectious, and the investigation: transmitting lessons from infectious diseases to bioethics
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Decision Fatigue in Primary Care Opioid Prescribing
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.BACKGROUND: Decision fatigue -- a psychological phenomenon describing the depletion of mental resources as one makes a series of decisions -- affects primary care physicians as they treat patients and prescribe medications throughout the course of the clinical day. This results in more inappropriate treatments being ordered as the day goes on. Because the United States faces an unprecedented epidemic of opioid abuse, we must understand the extent to which decision fatigue affects opioid prescribing, as the prescription of these drugs has been associated with both long-term use and overdose deaths. Additionally, we are unaware of the effect various national interventions to stem the tide of the opioid epidemic have had on decision fatigue in opioid prescribing.
LOCAL PROBLEM: We are unaware of whether decision fatigue is playing a role in opioid prescribing, and if it is, how great the variation in prescription likelihood is throughout the clinical day in UT Southwestern's primary care clinics. The aim of this study is to measure PCPs' varying likelihoods of prescribing opioids throughout the clinical day, before and after major interventions were implemented to combat the epidemic, as this can serve as an indication of both the presence of decision fatigue and the impact of concerted interventions.
METHODS: We used the years 2014 and 2017 to represent the pre- and post-intervention periods for study, as many major interventions to combat the opioid epidemic took place in 2016. Next, we analyzed the percentage of appointments in which opioids were prescribed in each hour of physicians' clinical days, at three exclusively primary care clinics at UT Southwestern. Scheduled appointment times were used as substitutes for visit times. We then excluded patients with cancer and those who had surgery within six weeks of an appointment, in order to minimize the number of appointments in which opioids may be prescribed by clear clinical indication. Finally, we employed logistic regression analysis to determine the predictive relationship between appointment time and opioid prescriptions, using physicians' prescription rates in their first clinic hour as the reference for calculating hourly odds ratios in each year.
INTERVENTIONS: New legislation, updated healthcare guidelines, and national media coverage in 2016, including: the CDC's "Guideline for Prescribing Opioids for Chronic Pain—United States", the FDA's "General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products: Guidance for Industry, 2016", the Comprehensive Addiction and Recovery Act of 2016, the Surgeon General's call to providers to end the opioid crisis, and the opioid crisis becoming top health news story of 2016.
RESULTS: 34,972 clinic visits in 2014 and 42,313 clinic visits in 2017 met our inclusion criteria. In 2014, patients were prescribed an opioid at 5.34% of all primary care appointments, while in 2017, they were prescribed at a rate of 4.34% (2014 vs 2017 OR=1.290; 95% CI, 1.217-1.367). While the overall rates of opioids decreased from 2014 to 2017, the hourly likelihoods of patients being prescribed opioids steadily increased throughout the clinical day in both years (p<0.01 in 2014 and 2017). In fact, each year had hours in which physicians' opioid prescription odds ratio was over 1.6, when compared to their first clinical hour.
DISCUSSION: While there was a significant decrease in the overall likelihood of being prescribed opioids in 2017 compared to 2014, the variation in hourly prescription likelihoods is similar in both years. The results show that while interventions to combat the opioid epidemic were successful in reducing the overall amount of opioids prescribed, they had minimal impact on the effect of decision fatigue. Clinical decision support tools, integrated into the electronic medical record, have been proven to reduce the clinical variation that indicates the presence of decision fatigue. In light of this, this project should be continued, and decision fatigue measured, after implementation of such tools