Browsing by Author "Basaraba, Randall J., committee member"
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Item Open Access Antimicrobial resistance surveillance in feedlot cattle(Colorado State University. Libraries, 2011) Benedict, Katharine M., author; Morley, Paul S., advisor; Booker, Calvin W., committee member; Van Metre, David C., committee member; Basaraba, Randall J., committee memberObjectives: To develop and validate methodological components of a model for surveillance of antimicrobial use and resistance in feedlot cattle. Methods: A web-based survey of participants knowledgeable and interested in antimicrobial use in beef feedlots was used to solicit responses regarding appropriate metrics for quantifying, analyzing, and reporting antimicrobial exposures. The accuracies of two susceptibility tests commonly recommended for surveillance programs were determined using stochastic latent class analysis. Multivariable logistic and linear regression was used to investigate associations between exposures to antimicrobial drugs and antimicrobial resistance. Results: When reporting antimicrobial use in the context of antimicrobial resistance, survey participants believed that the Animal Defined Daily Dose metric was the most accurate. The two susceptibility tests investigated had comparable accuracies for the antimicrobial drugs tested. Exposure to parenteral tetracycline in the study feedlots was associated with resistance to tetracycline; however, exposures to all other classes of antimicrobials were not associated with antimicrobial resistance. Conclusions: Appropriate metrics for reporting and analyzing antimicrobial resistance are necessary to accurately investigate associations between use and resistance, though clarity of what the metric represents may be lost. Testing of susceptibility in surveillance programs is equally valid by way of disk diffusion testing. Multivariable logistic regression was an appropriate and useful method to investigate associations between use and resistance. Parenteral exposures to antimicrobials did not drive antimicrobial resistance at mid-feeding period.Item Open Access Novel therapeutics, associated adverse effects, and changes in immune responses during pulmonary infection with Mycobacterium tuberculosis(Colorado State University. Libraries, 2024) Ali, Malik Zohaib, author; Gonzalez-Juarrero, Mercedes, advisor; Basaraba, Randall J., committee member; Moreno, Julie A., committee member; Chen, Chaoping, committee memberPatients diagnosed with multidrug resistant (MDR) or extensively drug resistant (XDR) tuberculosis (TB) have limited treatment options. The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral-drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) collectively termed as BPaL for the treatment of TB. This regimen achieved remarkable results as almost 90% of the participants suffering from MDR- or XDR-TB had favorable outcomes. Despite the extraordinary outcomes, many patients also developed severe adverse effects (AEs) which were associated with the long-term administration of the oxazolidinone protein synthesis inhibitor linezolid. Spectinamide 1599 (S) is also a potent protein synthesis inhibitor of Mycobacterium tuberculosis (Mtb) with an excellent safety profile, but which lacks oral bioavailability. In chapter 2, we hypothesized that inhaled spectinamide 1599, combined with BPa ––BPaS regimen ––, has similar efficacy to that of BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c (permissive resistant) and C3HeB/FeJ (permissive susceptible) murine chronic TB efficacy models. Both regimens promoted similar bactericidal effects in lung and spleen of both models after 4 weeks. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL treatment also decreased myeloid to erythroid ratio and increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. During therapy both regimens improved the lung lesion burden, reduced neutrophil and cytotoxic T cell counts while increased the number of B and helper and regulatory T cells. This combined data suggests that inhaled spectinamide 1599 combined with BPa is an effective TB therapy that avoids L-associated AEs. The granuloma formation is the pathological hallmark of TB, and several studies suggest that there are temporal and spatial changes in their distinct immune responses. These changes differ not only from one granuloma to another in a single individual but also depend on the severity of the disease. In chapter 3, we attempted to understand longitudinal changes in immune cells, their relationships, and their spatial distribution in granulomas of Mtb infected BALB/c and C3HeB/FeJ mouse models using a novel technique of multispectral imaging microscopy. Multiplex fluorescence immunohistochemistry (mfIHC) is unique in its ability to provide both expression and location of several immune cells along with their co-localization in a single tissue section while preserving tissue architecture and spatial context. The results showed that as the infection progresses, there are also dynamic changes in the immune phenotypes forming the granulomas and those located within the parenchymal tissue. Moreover, the histologically similar granulomas manifested complexity in their immune cell composition mainly due to the presence of adaptive immune responses. The advanced cellular granulomas in BALB/c TB model were mainly predominated by CD4 and CD8 T cells, Ly6G stained neutrophils, B220 B cells and all these were surrounded by F4/80 macrophages. With time post infection, there was an increased uniform recruitment of CD4 and Foxp3 T cells, F4/80 macrophages and Ly6G neutrophils within granulomas compared to parenchymal tissue where IFNγ and IL-10 secreting cells were in abundance. Moreover, B220 B cells and CD8 T cells also showed increased but heterogeneous distribution among the advancing granulomas especially B220 B cells formed clusters. The spatial analysis showed an increased median distance for Ly6G neutrophils, whereas this distance was decreased for B220 B cells when measured from CD4 and CD8 cells. In summary, combining the spatial and temporal data in addition to the mere cell counts helps to uncover interactions and relationships between different immune cells within the granuloma.Item Open Access Targeting protein kinase C in an autoimmune diabetes mouse model(Colorado State University. Libraries, 2020) DiLisio, James E., author; Podell, Brendan K., advisor; Basaraba, Randall J., committee member; Lark, Daniel S., committee memberProtein kinase C, a family of intracellular signal transducing proteins, are critical for a myriad of cellular actions with implications in both diabetes and its complications. The isoform PKCθ is enriched in T lymphocytes and functions to mediate signal transduction during T cell receptor stimulation. PKCθ has been shown to play a role in T cell mediated autoimmunity, whereby its activation increases autoimmune T cell function and suppresses that of regulatory T cells. We hypothesize that specific inhibition of PKCθ in autoimmune diabetes will enhance islet tolerance, increase regulatory T cell phenotypes, and delay the onset of overt diabetes in the NOD mouse model. A cell permeable, pseudo-substrate peptide inhibitor was shown to inhibit T cell receptor activation, in both in vitro T cell stimulations and ex vivo isolated T cells from treated mice. Pre-diabetic NOD mice treated daily with the peptide inhibitor for 4 weeks exhibited increased glucose tolerance at 15 weeks of age as well as increases in regulatory T cell phenotypes and reduced insulitis at 17 weeks of age in comparison to controls. Through long term diabetes onset studies, the peptide inhibitor slightly reduced the incident rate and delayed the onset of diabetes in a subset of animals. The moderate effects observed in preventing disease may be attributed to low efficacy or stability of the peptide inhibitor in vivo, which might be remedied by either genetic or pharmacological ablation of PKCθ activity. However, our data demonstrate the potential for targeting PKCθ in autoimmune diabetes as an immunotherapy to prevent or delay disease by increasing tolerance through the expansion of protective regulatory T cells.Item Open Access The processes for determining the risk factors involved with the morbidity and mortality of the Southern stingray, Dasyatis americana, at an aquarium(Colorado State University. Libraries, 2016) Grant, Krystan R., author; Campbell, Terry W., advisor; Basaraba, Randall J., committee member; Gloeckner, Gene W., committee member; Hill, Ashley E., committee memberTo view the abstract, please see the full text of the document.