Repository logo

Browsing by Author "Fails, Anna, committee member"

Now showing 1 - 4 of 4
  • Thumbnail Image
    ItemOpen Access
    Evaluation of the pharmacodynamics and analgesic efficacy of two buprenorphine formulations in dogs
    (Colorado State University. Libraries, 2020) Bunnag, Nadhapat, author; Rezende, Marlis, advisor; Mama, Khursheed, advisor; Fails, Anna, committee member; MacPhail, Catriona, committee member
    Pain is an unpleasant and distressing experience. While it serves a protective function for a short period, untreated, ongoing pain has significant detrimental effects. Opioids are one of the most important analgesic agents used for pain management in human and veterinary medicine, with the µ opioid agonists being the most effective for moderate to severe pain. Traditional presentations of µ opioid agonists or partial agonists usually require frequent dosing, which can lead to significant stress due to frequent animal restraint, variability in the level of analgesia and can be labor intensive and time consuming for veterinary personal. Buprenorphine has been shown to be effective in the treatment of mild to moderate pain with minimal adverse effects in dogs. Despite having a longer dosing interval than most other mu agonists, buprenorphine still requires hospitalization of clinical patients or intermittent handling of research animals. In recent years, new formulations of buprenorphine have been introduced and have the potential to provide longer duration of action after a single subcutaneous injection. This dissertation presents the pharmacodynamics and analgesic efficacy of two long-lasting buprenorphine formulations in dogs. The first formulation evaluated is a sustained-release buprenorphine (buprenorphine HCL in a proprietary sustained release biodegradable liquid polymer matrix). The pharmacokinetics and selected behavioral, physiologic and antinociceptive effects of two doses of this sustained-release formulation was evaluated in dogs. The antinociceptive effects of this formulation were assessed using a mechanical nociceptive testing threshold device. The second formulation is a high-concentration buprenorphine, which has been approved for use in cats. Selected behavioral, physiologic and antinociceptive effects of two doses of this high-concentration formulation were evaluated in dogs undergoing neutering. The analgesic efficacy of this formulation was evaluated using 3 different pain-scoring systems. Both formulations showed promising results. Sustained-release buprenorphine provided significant increase in mechanical nociceptive thresholds for up to 84 hours after drug administration, while the high-concentration buprenorphine provided effective analgesia with minimal side effects in dogs undergoing neutering for at least 24 hours after drug administration. These findings suggest that both formulations have the potential to be an effective and practical alternative in providing long-lasting analgesia in dogs.
  • Thumbnail Image
    ItemOpen Access
    Musical neglect training for unilateral visual neglect in right hemispheric stroke patients
    (Colorado State University. Libraries, 2015) Kang, Kyurim, author; Thaut, Michael, advisor; LaGasse, Blythe, committee member; Fails, Anna, committee member
    The purpose of this study was to examine the immediate and longer-lasting effect of Musical Neglect Training (MNT) on unilateral visual neglect. A single-subject design was used, as participants served as their own control. Two individuals participated in this study. Participants underwent two weekly 30-minute individual sessions over a time period of three weeks, for a total of six MNT sessions for each participant. Two standardized assessments (Albert's and Line Bisection Test) were used. The assessments were administered immediately before and after each of the 6 MNT sessions to assess the immediate effect of MNT. During the training, participants played a set of horizontally arranged tone bars tuned to an ascending triads and scales. At the endpoint of each sequence a cymbal was positioned and played to give a strong audiovisual target in the left visual field for the participants. The experimenter provided a chordal accompaniment on the keyboard to provide harmonic-rhythmic pacing and to cue continuous playing to the end of the sequence. Follow-up testing was done one week after their 6th session to examine the longer-lasting effects of MNT. Paired t-tests were used to test for statistical improvement between pre- and post-test of interventions (immediate effects). Also, nonparametric statistics (Wilcoxon) was also calculated in parallel with the paired t-tests due to the small sample size and possible violations of normal distribution. For the longer-lasting effects, raw data were compared between the average of 6 sessions’ pre-test and follow-up test since there was only one follow-up test. Both participants showed statistical improvement with Albert's Test in the immediate effect (Participant 1: p=.02, Participant 2: p=.01). Results for the immediate effect of MNT on the Line Bisection Test were not significantly different, but means were lower for post-test (Participant 1: M=24.17%, Participant 2: M=9.16%) compared to pre-test (Participant 1: M=25.65%, Participant 2: M=10.39%), indicating positive improvement. Although not statistically significant for the longer-lasting effect, participant 2 had a lower score (score=7) compared to averaged pretest scores of the 6 treatment sessions (M=9.5), indicating a positive outcome, while participant 1 was unchanged at follow-up score (score=14) compared to the pretest average (M=14.5) in the Albert’s Test. Moreover, participant 1 showed increased deviation percentages from the averaged pre-test (M=25.65%) to follow-up test (deviation =27.18%), indicating no positive effect for the longer-lasting effect in the Line Bisection Test. Participant 2 showed a decreased deviation in follow-up score (deviation=7.70%) compared to averaged pre-test score (M=10.39%). The study indicates MNT as a potentially positive intervention for clients with unilateral visual neglect. Future research should employ this music-based intervention with clients in subacute recovery stages post stroke. Furthermore, developing the intervention protocol with increased duration and a higher number of sessions may result in stronger results. Based on the results from this study and previous studies, research focusing on the underlying neural mechanism and tailoring the intervention protocol appropriately to the clinical situation is warranted.
  • Thumbnail Image
    ItemOpen Access
    Prion strain adaptation: breaking and building species barriers
    (Colorado State University. Libraries, 2014) Reid, Crystal Meyerett, author; Zabel, Mark, advisor; Hoover, Edward, committee member; Spraker, Terry, committee member; Fails, Anna, committee member
    Prions have been an enigma to researchers and agricultural producers alike since their inception. The timing and order of prion disease discovery can be attributed to the scrutiny of the prion protein-only hypothesis. The characterization of bacteria, viruses, and the infectious qualities encoded by their genomes only confounded the hypothetical notion of protein as an infectious agent. Perhaps viral etiology theories could have been disregarded earlier if genetic prion diseases were not quickly overshadowed by experimental transmissibility of the putative infectious protein. Despite the discordant journey, mounting evidence suggests that prion pathogenesis is caused by the conversion of the normal cellular host protein, (PrPC) into a protease-resistant, abnormal disease-causing isoform devoid of nucleic acid (PrPRES). Importantly, no differences are observed in the primary sequence of PrPC as compared to PrPRES indicating that observable differences between the normal and disease-causing proteins must be conformational. Additionally, even in the absence of nucleic acid, prions are able to infect various hosts differently, suggesting the phenomenon of prion strains. Characteristically long incubation periods and incomplete attack rates, as consequence of primary passage of prion infected material between differing species, but often even within the same species, have been defined as the species and transmission barrier respectively. Conversion efficiency of infectious prions is most efficient when host and donor PrPC are identical leading some researchers to believe that heterologous PrP blocks conversion, extending the days to onset of clinical disease. Evidence also suggests that prion protein primary sequence predisposes PrPC to fold in an un-infectious normal conformation but interaction with a PrPRES conformer, enciphering biological strain characteristics, provides a template for misfolding PrPC into an infectious conformation. Protein misfolding cyclic amplification (PMCA) has provided additional evidence that PrPRES acts as a template that can convert normal prion protein (PrPC) into the infectious misfolded PrPRES isoform. PMCA utilizes sonication to break up PK resistant aggregates into smaller prion seeds that may interact and template PrPC substrate present in the uninfected brain homogenate. Uniquely, prion disease can be inherited, transmitted, or occur spontaneously. Recently, several investigators have reported spontaneous generation of infectious prions using in vitro methods such as PMCA. Additional investigations into host factors needed for efficient conversion and replication has led to the discovery of differences in the propensity of PrPC misfolding among different species. Several groups have recently suggested that cervid prion protein has a higher propensity for misfolding in vitro and in vivo as a result of a unique rigid loop identifiable in cervid PrPC secondary structure. It has been proposed that increased transmission efficiency of cervid prions can be attributed to the presence of this rigid loop. The principle interest in the current research of this dissertation is to gain deeper knowledge about what fundamental factors play a role in prion strain adaptation, to challenge current theories about prion strain fidelity and to assess species barriers and prion strain dynamics with the aid of differential mouse models of prion disease. The comprehensive hypothesis of this dissertation is that host factors, including but not solely PrPC, mediate prion strain adaptation and determine host range and strength of species barriers. We used PMCA, bioassay using transgenic mice expressing variable amounts of PrPC from mouse and cervid species, and cell culture lines expressing different host PrPC to address these questions. We challenged the efficiency and congruency of PMCA by characterizing strain properties of amplified material in parallel with mouse bioassay by: incubation period, PK resistance, glycoform ratios, lesion profiles, and conformational stability. We further wanted to test if PMCA de novo generated prions were infectious and what strain properties they would emulate. We hypothesized that the PK resistant material generated with PMCA was infectious and transmissible and possess strain properties reminiscent of other cervid prion strains. Finally, our lab hypothesized that PrPRES conformation enciphers prion strain properties by acting as a template for nascent PrPRES but that host factors also play a role in adapting prion strains derived from a different host and that species barriers can be overcome through this adaptation.
  • Thumbnail Image
    ItemOpen Access
    Sex-specific cardiometabolic responses to chronic stress and the impact of prefrontal-medullary regulation
    (Colorado State University. Libraries, 2024) Dearing, Carley, author; Myers, Brent, advisor; Smith, Bret, committee member; Fails, Anna, committee member; Hoke, Kim, committee member
    Globally, cardiovascular and metabolic disease are leading causes of death and years lived with disability. Chronic stress is an etiologic factor in both diseases and biologic sex plays an important role in the progression and prognosis of each. However, the neurobiological basis of how chronic stress exposure intersects with sex, cardiovascular, and metabolic function to impact systemic physiology is poorly understood. Prior studies from our group indicate that, in rats, the prefrontal infralimbic cortex (IL)-rostral ventrolateral medulla (RVLM) circuit inhibits sympathetic and endocrine responses to stress. Therefore, we aimed to address the overarching hypothesis that the IL-RVLM circuit is necessary for homeostatic function and mitigation of deleterious changes to metabolic, cardiac, and microvascular function following chronic stress. To this end, an intersectional genetic approach was used to induce Cre-dependent expression of tetanus toxin light chain and inhibit neurotransmitter release from RVLM-projecting IL neurons in male and female rats. Rats were then exposed to 2 weeks of chronic variable stress (CVS). Metabolic function was assessed with a fasted glucose tolerance test. Cardiovascular function was examined with echocardiography and non-invasive hemodynamics. Additionally, microvascular function was quantified via ex-vivo resistance arteriole pressure myography. Our results indicate that glucose tolerance, left ventricular structure, and vascular function are all impacted in a sex-dependent manner. Following chronic stress, circuit-intact females show glucodysregulation characterized by decreased glucose clearance, elevated corticosterone, and insulin insensitivity. Regardless of stress, circuit inhibition in females also impaired glucoregulation but was characterized by elevated glucagon with no compensatory insulin response. Circuit inhibition also increased relative heart size, increased endothelial-dependent vasodilation at both normotensive and hypertensive pressures, and increased myogenic tone and diastolic wall strain. These changes indicate that chronic stress in females leads to broad endocrine-autonomic dysregulation of glucose homeostasis and microvascular function that is exacerbated by IL-RVLM inhibition. While chronic stress in males resulted in an adaptive metabolic response and no changes in normotensive vasodilation, circuit inhibition in chronically-stressed males lead to glucodysregulation and increased endothelial-dependent vasodilation at hypertensive pressures. Additionally, these animals had reduced ventricular wall thickness in diastole. Broadly, these results support the hypothesis that the IL-RVLM circuit is necessary for appropriate glucose homeostasis and vascular function and that circuit inhibition and chronic stress lead to sex-specific responses that may differentially impact the progression of cardiovascular and metabolic disease.