CHRI sis at the NICU: The Medley with Midazolam

Approximately 1.5 million neonates undergo anesthesia for surgical procedures in the United States every year1. Midazolam is a commonly used anesthetic agent used in the Neonatal Intensive Care Unit (NICU). It is used to sedate neonates and facilitates complex procedures such as mechanical ventilation.2 The extensive use of midazolam has raised questions about whether it affects the cognitive development of infants. In 2014, the International Anesthesia Research Society released a statement saying, “Surgeries and procedures requiring anesthetic and sedative drugs that could reasonably be delayed should possibly be postponed because of the potential risk to the developing brain of infants, toddlers, and preschool children”. 3 Although some evidence shows that midazolam exposure could harm an infant’s cognitive development, little is known about what parts of the developing brain are directly affected by midazolam. Additionally, research has yet to uncover whether the effects of midazolam persist into adulthood. In order to examine the consequences of midazolam exposure, a holistic system biology approach should be implemented. Experimental data from four different levels ─ the molecular level, the physical trait level, the behavioral level, and “omics” level would help address these issues. Our objective is to investigate how prolonged exposure to midazolam affects cellular as well as behavioral functions. A rodent model was implemented to study the effects at infanthood, adolescence, and adulthood. Our molecular results revealed that midazolam could potentially cause disturbances in key brain protein levels. Additionally, midazolam could potentially contribute to social deficits as evidenced by behavioral results. Overall, the results all point to midazolam\u27s potential to delay proper neurodevelopment.https://digitalcommons.unmc.edu/surp2021/1028/thumbnail.jp

The Relationship Between Concussion History And Lower Extremity Biomechanics During A Land And Cut Task

In high impact landing tasks, athletes with a history of sports related concussion (SRC) have been found to demonstrate lower extremity (LE) biomechanics that are associated with elevated injury risk. However, the exact relationships between SRC history and LE biomechanics are inconclusive. PURPOSE: The purpose of this study was to investigate the relationship between SRC history and LE biomechanics during a cutting task. METHODS: A cohort of athletes with a history of SRC (n=20) and a control group of healthy athletes (n=20) were recruited for this study. The control group were matched by age, sex, and sport. Athletes performed an unanticipated land and cut task. Athletes stood on a 60 cm box and focused on a visual light positioned three meters away from them. The light displayed green, pink, blue, or red. Athletes were instructed to step off the box, land on both limbs, and perform a 45-degree cutting maneuver to left or right when they saw red or green light respectively. A point biserial correlation was conducted correlating group (0 = control, 1 = SRC) with the following dependent variables: dominant limb ground reaction force (D_GRF), dominant limb ankle dorsiflexion angle (D_DF), dominant limb knee flexion angle (D_KFA), dominant limb knee flexion moment (D_KFM), dominant limb knee abduction angle (D_KAA), and dominant limb knee abduction moment (D_KAM). A linear regression equation was obtained for any significant correlations. RESULTS: There was a small significant negative correlation between group and KFA (r = -.342, p \u3c .01). There were no other significant correlations between group and LE biomechanical variables (p \u3e .05). A linear regression analysis showed SRC history as a significant predictor of KFA (KFA = 60.24 - 6.16(group); R2 = 0.117, p = .03). CONCLUSION: The SRC group was associated with lower KFA. According to our regression analysis, athletes with an SRC history had predicted a 6.2 degree decrease in KFA compared to the control group during the land and cut task. Furthermore, approximately 12% of the variance in KFA can be explained by SRC. This suggests that previously concussed athletes may be at a higher risk for LE injury. Further research in this area is needed to confirm this relationship

Peritoneal Mouse as Detected on 18F-FDG PET-CT

We present the case of a 77-year-old male with a history of prostate cancer. Follow up PET-CT and contrast-enhanced CT demonstrated a small peritoneal loose body or “mouse” in the pelvis. This is an uncommon, benign, asymptomatic finding which is usually incidentally discovered. The significance of being aware of this entity is to distinguish it from metastasis, especially in patients with known abdominal and pelvic malignancies

Effect of Combined Methamphetamine and Oxycodone Use on the Synaptic Proteome in an In Vitro Model of Polysubstance Use

Polysubstance use (PSU) generally involves the simultaneous use of an opioid along with a stimulant. In recent years, this problem has escalated into a nationwide epidemic. Understanding the mechanisms and effects underlying the interaction between these drugs is essential for the development of treatments for those suffering from addiction. Currently, the effect of PSU on synapses-critical points of contact between neurons-remains poorly understood. Using an in vitro model of primary neurons, we examined the combined effects of the psychostimulant methamphetamine (METH) and the prescription opioid oxycodone (oxy) on the synaptic proteome using quantitative mass-spectrometry-based proteomics. A further ClueGO analysis and Ingenuity Pathway Analysis (IPA) indicated the dysregulation of several molecular functions, biological processes, and pathways associated with neural plasticity and structural development. We identified one key synaptic protein, Striatin-1, which plays a vital role in many of these processes and functions, to be downregulated following METH+oxy treatment. This downregulation of Striatin-1 was further validated by Western blot. Overall, the present study indicates several damaging effects of the combined use of METH and oxy on neural function and warrants further detailed investigation into mechanisms contributing to synaptic dysfunction

Identification of YWHAH as a Novel Brain-Derived Extracellular Vesicle Marker Post Long-Term Midazolam Exposure during Early Development

Recently, the long-term use of sedative agents in the neonatal intensive care unit (NICU) has raised concerns about neurodevelopmental outcomes in exposed neonates. Midazolam (MDZ), a common neonatal sedative in the NICU, has been suggested to increase learning disturbances and cognitive impairment in children. However, molecular mechanisms contributing to such outcomes with long-term MDZ use during the early stages of life remain unclear. In this study, we for the first time elucidate the role of brain-derived extracellular vesicles (BDEVs), including mining the BDEV proteome post long-term MDZ exposure during early development. Employing our previously established rodent model system that mimics the exposure of MDZ in the NICU using an increasing dosage regimen, we isolated BDEVs from postnatal 21-days-old control and MDZ groups using a differential sucrose density gradient. BDEVs from the control and MDZ groups were then characterized using a ZetaView nanoparticle tracking analyzer and transmission electron microscopy analysis. Next, using RT-qPCR, we examined the expression of key ESCRT-related genes involved in EV biogenesis. Lastly, using quantitative mass spectrometry-based proteomics, we mined the BDEV protein cargo that revealed key differentially expressed proteins and associated molecular pathways to be altered post long-term MDZ exposure. Our study characterized the proteome in BDEV cargo from long-term MDZ exposure at early development. Importantly, we identified and validated the expression of YWHAH as a potential target for further characterization of its downstream mechanism and a potential biomarker for the early onset of neurodevelopment and neurodegenerative diseases. Overall, the present study demonstrated long-term exposure to MDZ at early development stages could influence BDEV protein cargo, which potentially impact neural functions and behavior at later stages of development

Crisis in the NICU and the Medley with Midazolam

Epidemiologic studies of human patients have revealed a correlation between childhood exposure to general anesthetic and sedative agents and subsequent cognitive deficits. This association is supported by data from animal models, which shows that developmental exposure to both anesthetics and sedatives causes lasting impairments in learning. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative agent on neonates in the Neonatal Intensive Care Unit (NICU). However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations and neurobiological mechanisms. Elucidation of these mechanisms is of high clinical importance and may develop neuroprotective therapeutic strategies for optimizing outcomes for uniquely vulnerable NICU populations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen from postnatal day 3 (P3) pups until P21 to comprehensively characterize how early-life exposure to MDZ impacts neurodevelopment outcomes at different tiers ─ phenotypic, molecular, behavioral, and high throughput- “omics” levels. Our data demonstrated that repetitive exposure to MDZ at an early age stunts neurodevelopment during the early stages of life disrupts the blood-brain barrier, and alters the synaptic components and neurochemistry, which may be indicative of behavioral deficits at later development. Additionally, our bioinformatics analysis from purified synaptosome identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, upregulated in the MDZ group and whose expression was further validated by western blot. Our study has provided a comprehensive characterization of MDZ effects on development at multiple tiers yielding novel insights on how long-term exposure to MDZ impacts development. Notably, the identification of ADD1 as a potential target and further characterization of its downstream mechanisms can give additional insights into its role as a potential therapeutic for treating neurodevelopmental alterations associated with long-term MDZ use in neonates.https://digitalcommons.unmc.edu/chri_forum/1056/thumbnail.jp

The novel method to reduce the silica content in lignin recovered from black liquor originating from rice straw

Difficulties in the production of lignin from rice straw because of high silica content in the recovered lignin reduce its recovery yield and applications as bio-fuel and aromatic chemicals. Therefore, the objective of this study is to develop a novel method to reduce the silica content in lignin from rice straw more effectively and selectively. The method is established by monitoring the precipitation behavior as well as the chemical structure of precipitate by single-stage acidification at different pH values of black liquor collected from the alkaline treatment of rice straw. The result illustrates the significant influence of pH on the physical and chemical properties of the precipitate and the supernatant. The simple two-step acidification of the black liquor at pilot-scale by sulfuric acid 20w/v% is applied to recover lignin at pH 9 and pH 3 and gives a percentage of silica removal as high as 94.38%. Following the developed process, the high-quality lignin could be produced from abundant rice straw at the industrial-scale