University of Nebraska Medical Center
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The Optimized Parameters of Red Blood Cell Exchange by Apheresis in Transfusion-Dependent Thalassemia, a Small Case Series
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Education and Simulation Outcomes of Death and Dying Perceptions of RT Students
Get PDFThis is a published abstract from the UNMC Spotlight on Scholarship 2024
Perceptions of Medical Residents of Interprofessional Staffing with a Physician and a Clinical Pharmacist in a Primary Care Clinic Setting
Get PDFThis is a published abstract from the UNMC Spotlight on Scholarship 2024
Novel Mechanisms for the Neural Control of Breathing in Acute Lung Injury
Get PDFAcute lung injury (ALI) triggers inflammation that disrupts the normal alveolar-capillary endothelial barrier, impairing gas exchange and causing hypoxemia, which reflexively increases respiration. An elevated respiratory rate (fR) usually develops within hours to days following ALI. This acute respiratory failure disorder affects approximately 200,000 new cases annually in the US and accounts for 10% of ICU admissions, with high morbidity and mortality. The neural mechanisms underlying respiratory dysfunction post-ALI are not fully understood. My doctoral dissertation aimed to investigate the mediators of abnormal ventilation during ALI. Systemic hypoxia stimulates the carotid body (CB) chemoreflex, a crucial protective reflex that maintains oxygen homeostasis. This dissertation explores 1) chemoreflex changes post-ALI during early and recovery phases, examining both moderate (low-dose bleomycin, 1.25 mg/kg) and severe (high-dose bleomycin, 2.5 mg/kg) ALI in male rats, 2) sex-based differences in ALI, 3) the role of the superior cervical ganglion (SCG) in chronic chemoreflex sensitization, and 4) the potential neuroprotective effects of ProGel-Dex on chemoreflex sensitivity post-ALI.
In the initial study, chemoreflex responses to hypoxia and normoxic-hypercapnia were assessed. Moderate ALI rats displayed activated but not significantly different chemoreflex responses compared to controls at week 1 (W1) post-ALI. Conversely, severe ALI rats exhibited a blunted response. A 90% hyperoxia challenge ruled out a ceiling effect, as no changes in resting fR were observed. Both ALI severities resulted in sensitized chemoreflex activation at Week 4 (W4) post-ALI.
The second study focused on sex differences post-ALI, revealing that male rats had a more pronounced increase in resting fR during the ‘early’ phase of ALI. However, chemoreflex sensitivity during the ‘recovery’ phase of ALI (W4 post-ALI) was consistent across the sexes. Subsequent studies were conducted on male rats.
The third study explored the SCG\u27s involvement in chronic chemoreflex sensitization. Bilateral SCG ganglionectomy before bleomycin administration did not alter resting ventilatory parameters but significantly reduced chemoreflex activation in ganglionectomy bleo rats compared to sham-operated bleo rats.
The final study investigated the effects of ProGel-Dex (10µl/CB), 20 w/v%), a novel thermoresponsive drug on chronic chemoreflex sensitivity post-ALI. Although a single, local injection of ProGel-Dex did not significantly impact chemoreflex sensitization during the ‘recovery’ phase of ALI (W4 post-ALI), it effectively reduced the increase in resting fR at the ‘early’ phase of ALI (W1 post-ALI).
Collectively, these studies elucidate the impact of ALI on chemoreflex function, highlight sex-based differences in ALI, and identify SCG involvement in chronic sensitization post-ALI. They also explore therapeutic interventions, such as ProGel-Dex, aiming to improve the quality of life for ALI patients
Translational Pathways for Ultra Long-Acting Medicines for Chronic Disease: From HIV to Substance Use Disorders
No full textHuman immunodeficiency virus (HIV) and opioid use disorder (OUD) are among the top global public health challenges, with a significant overlap in the number of cases and higher mortality risks compared to the general population. Treatment and recreational opioid use lead to addictive disorders. Both conditions require repeated dosing of therapy where adherence to a strict lifelong regimen remains a major challenge. Notably, people living with HIV/AIDS (PLWHA) and struggling with opioid use disorders (OUD) show suboptimal adherence to antiretroviral drugs (ARVs). Also, the risk of transmitting HIV and other blood-borne infections through the sharing of needles and other injection equipment is high in patients with OUD. Recent studies have demonstrated that initiation of long-acting treatments among HIV and OUD patients is not only associated with decreased risk for opioid-related adverse events but also improved viral suppression. We hypothesized that the creation of ultra-long-acting (ULA) prodrug formulations could further improve treatment outcomes. We, therefore, sought to develop ultra-long-acting formulations of a broadly used integrase strand transfer inhibitor called dolutegravir (DTG) and mu-opioid receptor (MOR) partial agonist called buprenorphine (BUP), which has demonstrated a significant advantage in reducing opioid overdose deaths. For DTG, a library of monomeric and dimeric prodrug nanoformulations was synthesized and subjected to in vitro and preclinical pharmacokinetic (PK) screening studies that led to the identification of the lead 18-carbon chain-modified ester prodrug nanocrystal candidate (coined NM2DTG) with the potential to sustain therapeutic drug concentrations for over six months after a single intramuscular (IM) dose. Ideal physiochemical and PK properties facilitated slow DTG release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injections. Significant plasma drug levels were recorded for up to a year in rodents following a single injection of NM2DTG. Tissue sites for prodrug hydrolysis were dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affected an extended NM2DTG apparent half-life recorded by PK parameters. Similarly, a single IM injection of the lead BUP nanoformulations in Sprague Dawley rats sustains plasma BUP levels at or above the target mu-opioid receptor occupancy concentrations for over three months in ongoing PK studies. We hypothesize that BUP prodrugs will prolong the drug’s apparent half-life and allow for creation of organic solvent free ULA formulations. In summary, the development of ultra-long-acting DTG and BUP injectable formulations can improve treatment of HIV and OUD by enhancing adherence and delivery of the two broadly used drugs into sites of action
Transcription and 3D Chromatin Organization Interplay at Sub-Kilobase Scale
Get PDFNuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF’s RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted