Browsing by Subject "pathology"
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Item An inhalation model of acute Q fever in guinea pigs(2009-05-15) Russell-Lodrigue, Kasi ElizabethCoxiella burnetii is an intracellular pathogen that can cause both acute and chronic disease (Q fever) in humans and infects many animals with varying clinical illness and persistence. A guinea pig aerosol-challenge model of acute Q fever was developed using infection with C. burnetii across a 5-log range of challenge doses. Clinical signs included fever, weight loss, respiratory difficulty, and death, with degree and duration of response corresponding to dose of organism delivered. Histopathologic evaluation revealed coalescing panleukocytic bronchointerstitial pneumonia 7 days after a high-dose challenge, resolving to multifocal lymphohistiocytic interstitial pneumonia by 28 days. Clinical and pathologic changes noted in these guinea pigs were comparable to those seen in human acute Q fever, making this an accurate and valuable animal model. This model was used to compare the relative virulence of eight isolates from four different genotypic groups: I (RSA493, RSA334, and RSA270), IV (Q177 and Q173), V (Q212 and Q217), and VI (5J108-111). Guinea pigs infected with group I acute-diseaseassociated isolates had severe respiratory disease, while no to moderate clinical illness was observed in animals given group IV or V chronic-disease-associated isolates. 5J108- 111 appeared avirulent. These data suggest that C. burnetii isolates have a range of disease potentials and support a distinction in strain virulence between established genotypic groups, though isolates within the same genomic group cause similar pathologic responses. Heterologous protection was confirmed by cross vaccination and challenge with RSA493 and Q217. A marked non-specific suppression of lymphoproliferation was noted at 14 and 28 days post infection with RSA493; similar suppression was seen after infection with Q173 and Q212 but not 5J108-111. Proinflammatory cytokines IFN-? and TNF-? were produced during early C. burnetii infection, at which time anti-inflammatory cytokines TGF-? and IL-10 were repressed. A vaccine made from phase I C. burnetii was found to be completely protective against lethal infection in the guinea pig model, while vaccination with killed phase II organisms conferred only partial protection, preventing death and reducing but not precluding fever and respiratory illness. Protective vaccination significantly stimulated cell-mediated immunity and elicited increases in IFN-?, TNF-?, and IL-12p40 mRNA levels.Item Stented Artery Biomechanics: A Computational and In Vivo Analysis of Stent Design and Pathobiological Response(2011-08-08) Timmins, Lucas HowardVascular stents have become a standard for treating atherosclerosis due to distinct advantages in trauma and cost with other surgical techniques. Unfortunately, the therapy is hindered by the risk of a new blockage (termed restenosis) developing in the treated artery. Clinical studies have indicated that stent design is a major risk factor for restenosis, with failure rates varying from 20 to 40% for bare metal stents. Subsequently, there has been a significant effort devoted to reducing failure rates by covering stents in polymer coatings in which anti-proliferative drugs are embedded, however complications have arisen (e.g. incomplete endothelization, lack of success in peripheral arteries, lack of long-term follow-up studies) that have limited the success of this technology. It has been thought that restenosis is directly related to the mechanical conditions that vascular stents create. Moreover, it has been hypothesized that stents that induce higher non-physiologic stresses result in a more aggressive pathobiological response that can lead to restenosis development. In this study, a combination of computational modeling and in vivo analysis were conducted to investigate the artery stent-induced wall stresses, and subsequent biological inflammatory response. In particular, variations in stent design were investigated as a means of examining specific stent design criteria that minimize the mechanical impact of stenting. Collectively, these data indicate that stent designs that subject the artery wall to higher stress values result in significantly more neointimal tissue proliferation, therefore, confirming the aforementioned hypothesis. Moreover, this work provides valuable insight into the role that biomechanics can play in improving the success rate of this percutaneous therapy and overall patient care.Item Studies on the molecular epidemiology, pathogenesis, diagnosis and treatment of avian mycobacteriosis(2009-05-15) Saggese, Miguel DanielWe investigated the molecular epidemiology, differential susceptibility to infection and disease, pathogenesis, diagnosis and treatment of avian mycobacteriosis in captive ringneck doves (Streptopelia risoria) and in the endangered white-winged duck (Cairina scutulata), both naturally infected with Mycobacterium a. avium. Our studies in doves demonstrated lower susceptibility to infection and less severity of lesions in the white color morph compared with the non-white. Genetic mechanisms of immunity to mycobacteriosis may be contributing or determining these differences. Given that the genes that code for white coloration are sex linked in birds, it is very likely that the gene or genes modulating this different immune response to M. a. avium infection in these doves could be associated to these loci or at least located in the same sexual (Z) chromosome, as the association with white color suggest. In the same birds, spleen biopsies followed by liver biopsies had the greatest potential for the diagnosis of mycobacteriosis by the demonstration of acid-fast organisms. Additional culturing of spleen or liver biopsies significantly increased the diagnosis of mycobacteriosis. The use of polymerase chain reaction (PCR) was the less sensitive techniques. Uneven distribution and low number of organisms in the liver, spleen and bone marrow may have contributed with the low diagnostic value of PCR. In a second group of sixteen doves with mycobacteriosis from the same flock, the combination of azithromycine, ethambutol and rifampin for 180 days was well tolerated but failed to cure them. Furthermore, this study demonstrated the inefficacy of liver biopsy to evaluate treatment as well the presence of antibiotic resistance in two isolates. These results highlight that erradication of mycobacteriosis in birds is not easy to achieve. Together with the possible emergence of antibiotic resistance in potentially zoonotic mycobacteria our results suggest that the treatment of mycobacteriosis in birds should not be recommended. Finally, the last study shows that white-winged ducks are highly susceptible to at least two sequevars of M. a. avium and that mycobacteriosis is a major threat to the ex situ conservation program. The minimal heterozygosis previously shown in these ducks could be contributing to this apparently ineffective immune response.