2022 VCOM Research Retreat Program

Abstracts

Severe Orthopedic Trauma, Suspected Drug Abuse, and Homelessness: A Forensic Death Investigation Highlights a Need for Better Support for Vulnerable Populations in Southern Alabama Presenter: Melinda Carter, PhD Co-Authors: Taylor Bush*; Drama Cumbie*; Palmer Ford*; John Sisson*; Edward A. Reedy,MD, PhD Decomposed human remains recovered from southern Alabama were transported to the Montgomery Medical Examiners’ Office for autopsy during summer, 2022. The advanced stage of decay required removal of soft tissue and examination by both a forensic pathologist (E.R.) and anthropologist (M.C.). Standard osteological analysis of the person’s biological profile determined that these were the remains of a young adult male of European ancestry (“white”). Examination of the skeletal remains identified numerous poorly healed fractures throughout the skeleton, including an orthopedic plate on the right proximal humerus. Extremely poor dental health in a relatively young individual strongly suggests chronic drug use, though preliminary toxicological analysis of the soft tissue was negative. The remains were positively identified by comparison of medical records provided for a missing person in the area with the postmortem examination of the remains. The goal of this presentation is to address how a single traumatic incident required orthopedic surgical intervention, yet the patient’s lifestyle contributed to poor healing, infection that required another surgery, and ultimately homelessness and an unattended death, the cause and manner of which are undetermined. We address signs and symptoms of poor oral health that herald a patient in any clinical setting who may need additional attention and social support. We examine how chronic drug use can affect skeletal health and post operative healing. We discuss how certain vulnerable populations can obtain mental health support, food, and nutritional counseling. We also consider how manipulative medicine by osteopathic physicians might play a critical role in helping vulnerable patients. We present the science and complexity of this unfortunate patient outcome to shine a light on how death investigation can contribute to an awareness among healthcare workers of how mind, body, and spirit impact systemic health to stimulate discussions of how to better serve such people in need. Presenter: Blaise Costa, PhD Co-Authors: Seth Boehringer; Patrick Rafael BS; Tullia Johnston BS, MPH; Alyssa Ingram BS; Nakia Philip BS; Pamela VandeVord, PhD The normal function of N-methyl D-aspartate receptors (NMDARs) plays a critical role in brain development and cognitive function. Children born with mutations in NMDAR subunits, that reduce glutamate potency, suffer from various neuropsychiatric disorders including epilepsy, major depression, developmental delay, and intellectual disability. In the current work, to validate the capability of CNS4, - a novel agonist concentration-dependent NMDAR modulator, to preferentially potentiate hypoactive receptors, two disease-causing GluN2A mutants that are known to reduce glutamate potency to 4.4 (A548T) and 126 (V685G) fold were generated, sequenced and assayed using two-electrode voltage clamp electrophysiology technique. The results obtained from this experiment indicate that CNS4 significantly increased glutamate potency in A548T [(Glu EC50 in µM; 4.68 ±0.7, n=11 vs 1.93 ±0.55, n=5, p<0.05) and V685G (91.67 ±25.35, n=18 vs 0.99 ±0.14, n=17, p<0.01)] mutant expressing 2A receptors when co-expressed with wild type GluN1. However, CNS4 did not alter glutamate potency [(Glu EC50 in µM): 1.89 ±0.11, n=12 vs 2.58 ±0.45, n=5, p>0.05] in the wild-type GluN1/2A receptors. These results reveal that the CNS4 selectively modulates the hypoactive NMDARs. Previous findings demonstrated that CNS4 potentiated NMDA receptor currents disproportionately higher levels when activated by sub-saturating concentration of glutamate. Therefore, we hypothesize that CNS4 or its analogs will be an appropriate lead candidate for the development of clinically useful compounds to treat drug-resistant neuropsychiatric disorders like anti-NMDA receptor encephalitis. CNS4 preferentially potentiates hypoglutamatergic disease-causing mutant GluN1/2A subtype of NMDA receptors

*VCOM Student