No description available.

Alpha1-proteinase inhibitor (alpha1-PI) has been shown to be a useful marker of gastrointestinal protein loss in some species. The objectives of this study were, first, to develop and analytically validate an ELISA for the measurement of alpha1-PI in feces and serum from cats, and, second, to evaluate fecal alpha1-PI concentrations in healthy cats and cats with chronic gastrointestinal disease. The lower detection limits of the ELISA were 0.02 g/L for serum and 0.04 microgram/gram for feces. The observed-to-expected (O/E) ratios for serial dilutions of serum and fecal samples ranged from 100.0 to 129.7% (mean +/- SD: 112.2 +/- 9.9%) and 103.5 to 141.6% (115.6 +/- 12.8%), respectively. The O/E ratios for samples spiked with seven known concentrations of alpha1-PI ranged from 82.3 to 107.8% (94.7 +/- 7.6%) for serum and 78.5 to 148.7% (96.8 +/- 18.2%) for feces. The coefficients of variation for intra-assay and inter-assay variability were <7.9% and &lt;12.1% for serum, and 5.3%, 11.8%, and 14.2% and 7.7%, 10.2%, and 20.4% for feces, respectively. Reference intervals were 0.6 to 1.4 g/L for serum and up to 1.6 microgram/g for feces. We conclude that this ELISA is sufficiently linear, accurate, precise, and reproducible. For the clinical evaluation, twenty cats with clinical signs of chronic gastrointestinal disease and 20 healthy control cats were enrolled. The diseased cats were grouped into two groups: mild to moderate idiopathic inflammatory bowel disease (IBD) (Group A; n=8) and severe IBD or neoplastic disease (Group B; n=12), based on histopathology results of endoscopic biopsies. Fecal alpha1-PI concentrations and serum concentrations of total protein, albumin, globulin, cobalamin, folate, pancreatic lipase immunoreactivity, and trypsin-like immunoreactivity were determined. Nineteen of the 20 diseased cats had increased fecal alpha1-PI concentrations, ranging from 1.9 to 233.6 microgram/g (normal range: <= 1.6 microgram/g). Fecal alpha1-PI concentrations were statistically significantly different between healthy cats and cats of Group A (median: 3.9 microgram/g, range: 1.3 to 9.2 microgram/g, P<0.001) or cats of Group B (median: 20.6 microgram/g, 4.3 to 233.6 microgram/g; P<0.001), and also between cats of Groups A and B (P<0.01). Hypoalbuminemia, hypoproteinemia, and hypocobalaminemia were detected in 88%, 83%, and 56% of the diseased cats, respectively. Our study suggests that increased fecal alpha1-PI concentrations in association with hypoalbuminemia may be a common finding in cats with IBD or GI neoplasia. Furthermore, alpha1-PI concentrations appear to be higher in cats with severe IBD or confirmed GI neoplasia when compared to cats with mild to moderate IBD.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and is a risk factor for lung cancer development. COPD encompasses both emphysema and chronic bronchitis, the pathogenesis of which are unclear. In this dissertation, I leveraged genome-wide gene-expression studies of emphysema and lung cancer to investigate pathogenesis and carcinogenesis in COPD. Tobacco smoke is the primary cause of emphysema. The most severe form is also associated with alpha1-antitrypsin deficiency (AATD) resulting from a mutation. In this study, I leveraged multiple lung samples from patients with emphysema, with or without AATD. While genes involved in tissue repair decreased with emphysema severity, the unfolded protein response (UPR) was uniquely changed in AATD lungs. AATD may play multiple roles in emphysema and UPR activation suggests AAT replacement therapy may be insufficient to treat this form of emphysema. Emphysema is a progressive disease, and the mean linear intercept (Lm) can serve as a surrogate of progression. I evaluated whether Lm increases in non-diseased lungs may represent similar processes to those occurring in emphysema, and could offer insight into early stages of disease or homeostasis. Genes involved in tissue repair increased with Lm in controls but decreased in disease. Tissue repair processes may be active in even the non-insulted lung, suggesting their activity is necessary for lung homeostasis and their deficiency may drive emphysema progression. Finally, COPD patients are at increased lung cancer risk, and transcriptomic changes common to both diseases could explain this risk. In both COPD and lung cancer, I discovered that H3K27Me3 regulated genes are repressed, and that the methyltransferase responsible for H3K27me3, EZH2, is induced. H3K27Me3, an oncogenic histone modification, may drive carcinogenesis and pathogenesis in COPD. Though usual and AATD emphysema share transcriptomic signatures associated with tissue repair, which may be active in the normal homeostatic lung, the UPR changes in AATD emphysema only; successful therapeutic strategies in emphysema will need to account for this difference. In COPD, H3K27Me3 may play a role in both pathogenesis and carcinogenesis, making it an attractive target for therapeutic interventions, but one that would need further augmentation in AATD. / 2019-11-01T00:00:00Z

Die in den letzten Jahren erhobenen genetischen Befunden untermauern das Konzept, daß ein Ungleichgewicht von Proteasen und ihren Inhibitoren wesentlich an der Pathogenese der chronischen Pankreatitis beteiligt ist. Die Identifizierung von Mutationen im kationischen Trypsinogen bei Patienten mit hereditärer Pankreatitis hat das Verständnis der Erkrankung entscheidend beeinflußt. Der Nachweis von SPINK1-, CFTR- und PRSS1-Mutationen bei Patienten ohne Familienanamnese für eine Pankreatitis deutet darauf hin, daß auch die idiopathische Pankreatitis genetisch determiniert ist. Die bisher durchgeführten Studien legen nahe, daß die erblich bedingte chronische Pankreatitis eine genetisch heterogene Erkrankung ist, die in Abhängigkeit von den defekten Genen bzw. den zugrundeliegenden Mutationen einem autosomal dominanten, einem autosomal rezessiven oder einem komplexen Erbgang folgt. Das gehäufte Auftreten von SPINK1-Mutationen bei alkoholischer chronischer Pankreatitis ist ein Hinweis darauf, daß genetische Faktoren auch zur Suszeptibilität von primär nicht erblichen Formen der chronischen Pankreatitis beitragen. Im weiteren konnte gezeigt werden, daß genetische Dispositionsfaktoren auch bei der Pathogenese der tropischen Pankreatitis einen wesentlichen Stellenwert besitzen. Diese Daten stellen das Konzept der tropischen Pankreatitis als eigene, tropenspezifische Krankheitsentität in Frage. In der vorliegenden Arbeit wurde die Bedeutung genetischer Faktoren bei der Entstehung der hereditären und idiopathischen wie der alkoholischen Pankreatitis untersucht. Die vollständige Aufklärung der genetischen Ursachen wird vermutlich die Unterscheidung zwischen hereditärer und idiopathischer bzw. tropischer chronischer Pankreatitis obsolet werden lassen. Nach Ausschluß sekundärer Ursachen sollte auch bei Patienten ohne Familienanamnese eine Genanalyse auf Mutationen in den obengenannten Genen veranlaßt werden. / The recent discoveries of trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) mutations in patients with hereditary and idiopathic chronic pancreatitis support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma initiates the inflammatory process. Thus, pancreatitis may be the result of an imbalance of proteases and their inhibitors within the pancreatic parenchyma. Since the first description of inherited pancreatitis reported an autosomal dominant trait, hereditary CP was defined as an rare dominant inherited disease. Subsequently, the fact of familial clustering in one generation only, which indicates other inheritance pattern such as recessive or complex trait, was blinded out in the disease concept of hereditary CP for a long time. The Identification of PRSS1, SPINK1 and CFTR mutations in patients with so-called idiopathic chronic pancreatitis, however, shows that inherited cases of CP are much more frequent and that different mutations in different genes might lead to different inheritance pattern. Evaluation of patients with CP without an obvious predisposing factor should include genetic testing for mutations in the above mentioned genes even in the absence of a family history of pancreatitis. The finding of SPINK1 mutations in alcohol-induced pancreatitis indicates that genetic factors genetic factors may increase disease susceptibility to primary non-hereditary CP types. This work summarises the significance of genetic factors in the pathogenesis of hereditary and idiopathic as well as alcoholic chronic pancreatitis. Thus, the identification of further genes involved into the pathogenesis of inherited CP probably will also enhance our knowledge about more common types of CP such as alcoholic or tropical CP.

Chronic pulmonary diseases include a wide range of illnesses that differ in etiology, prevalence, symptomatology and available therapy. A common link among these illnesses is their impact on patients’ vital function of breathing, high symptom burden and significantly impaired quality of life. This dissertation research evaluates disease severity, symptom burden and health behaviors of patients with three different chronic pulmonary conditions. First, alpha-1 antitrypsin deficiency (AATD) is an inherited condition that typically is associated with an increased risk of early onset pulmonary emphysema. This study examines differences in demographic, health, and behavioral characteristics and compares clinical outcomes and health related behaviors and attitudes between two severe genotypes of AATD - ZZ and SZ. The findings of the study suggest that patients with SZ genotype and less severe form of deficiency report higher number of exacerbations, comorbidities, as well as unhealthy behaviors such as lack of exercise and current smoking. In addition, individuals with the more severely deficient ZZ genotype are more adherent to disease management and prevention program recommendations and maintain a healthier lifestyle than individuals with SZ genotype. Second chronic lung disease examined in this research was chronic obstructive pulmonary disease (COPD), the fourth leading cause of death and second leading cause of disability in the United States. Prevalence and burden of cough and phlegm, two of the most common symptoms of the COPD, were assessed among participants of the COPD Foundation’s Patient-Powered Research Network (COPD PPRN). In addition, association between patient-reported levels of phlegm and cough, clinical outcomes and patients’ quality of life were evaluated. Participants’ quality of life was assessed using Patient Reported Outcome Measurement Information System instrument PROMIS-29. Association between changes in symptom severity over time and patient-reported quality of life were examined. Findings of this study indicated that severity of cough and phlegm were associated with higher number of exacerbations, greater dyspnea, and worsened patient-reported quality of life including physical and social functioning. Improvement in cough and phlegm severity over time was associated with better patient-reported quality of life. Third pulmonary illness described in this dissertation is non-cystic fibrosis bronchiectasis (NCFB), a rare and etiologically diverse condition characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Association between presence of Pseudomonas aeruginosa (PA), one of the most frequently isolated pathogens in patients with NCFFB, and disease severity was assessed utilizing enrollment data from the Bronchiectasis and NTM Research Registry (BRR). NCFB disease severity was evaluated using modified versions of validated in large international cohorts instruments, the Bronchiectasis Severity Index (BSI) and FACED. The findings of this study indicate that PA infection is common in NCFB patients, and presence of PA in patients’ sputum is associated with having moderate and high severity of bronchiectasis. In addition, the results of this study suggest that the two severity assessment instruments classify patients with NCFB differently which may be attributed to a greater number of severity markers utilized in the calculation of the BSI compared to FACED. In conclusion, the proposed dissertation aims to enhance understanding of differences in health outcomes between genotypes of AATD within AlphaNet registry, and to guide future health-promoting behaviors. It highlights the burden of common symptoms such as cough and phlegm in patients with COPD within COPD PPRN and their association with patients’ quality of life. In addition, it introduces modified indices of NCFB severity and emphasizes high burden of the disease in patients with presence of PA within the US BRR.

Katecholamine beeinflussen durch direkte Stimulation über adrenerge Rezeptoren die Funktion von Immunzellen. Ziel der Untersuchungen an Patienten mit Rheumatoider Arthritis war es, das Expressionsprofil unterschiedlicher adrenerger Rezeptorsubtypen in CD4(+)T-Lymphozyten dieser Patienten zu bestimmen. Zur Quantifizierung der Expression wurden semiquantitative RT-PCR-Analysen durchgeführt. Die Untersuchung zeigte, dass alpha1-adrenerge Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten exprimiert werden. Es scheint eine Korrelation zwischen bestimmten extraartikulären Organmanifestationen (z.B. Sicca-Sydrom und Tenosynovitis) und der Expression alpha1-adrenerger Rezeptoren zu bestehen. Die gefundene differenzielle Expression der Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten legen vertiefende Untersuchungen zur Relevanz des adrenergen Systems bei der Lymphozytenfunktionsmodulation nahe.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / "May 2007" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

Depuis quelques années, l’étude du code neuronal impliqué dans la perception des signaux de communication acoustique est devenue un domaine de recherche considérable. La littérature récente de ce domaine suggère que la discrimination entre ces signaux reposerait plutôt sur une organisation des décharges neuronales en motifs temporels que sur des variations globales de taux de décharge. Ma thèse a eu pour objectif de déterminer dans quelle mesure une régulation des inhibitions corticales peut (i) changer les motifs temporels déclenchés par des vocalisations conspécifiques et hétérospécifiques et (ii) modifier l’information portée par ces motifs sur l’identité des vocalisations. Nous avons enregistré l’activité neuronale dans le cortex auditif de cobayes anesthésiés en 16 sites corticaux lors de la présentation d’un jeu de vocalisations, et avons partiellement bloqué les inhibitions corticales par des applications de Gabazine (4minutes, 10µm). Dans ces conditions, les réponses évoquées sont plus fortes et les motifs temporels plus marqués. L’information mutuelle quantifiée au niveau de chaque site cortical est augmentée mais l’information populationnelle au niveau de l’ensemble des 16 sites enregistrés n’est pas modifiée, un effet qui peut s’expliquer par le fait que la redondance entre les sites corticaux est augmentée. Nous avons ensuite évalué dans quelle mesure une modulation noradrénergique était susceptible de mimer les effets d’un blocage partiel des inhibitions. Bien que les agonistes utilisés (α1, α2 et ) aient tous induit des modifications des réponses évoquées et de la reproductibilité des motifs temporels, aucun d’entre eux n’a induit de changements importants de l’information portée par les réponses neuronales aux vocalisations. En revanche, les effets induits par la phenylephrine, un agoniste α1, sont vraisemblablement sous-tendus par une action sur les inhibitions intra-corticales, ce qui rend plausible l’hypothèse d’une modulation noradrénergique des inhibitions corticales. Il est donc envisageable que l’action coordonnée de plusieurs systèmes neuromodulateurs puisse moduler les inhibitions corticales et ainsi changer la quantité d’information portée par les neurones corticaux sur l’identité des stimuli à discriminer. / Over the last 10 years, the neural code involved in the perception of acoustic communication signals has become a large area of researches. The recent literature suggests that the discrimination between these signals relies more on the temporal organization of neuronal discharges rather than on global changes of firing rate. My PhD thesis aimed at determining to what extent the regulation of cortical inhibition may (i) change the temporal patterns triggered by conspecific and heterospecific vocalizations and (ii) modify the information carried by these patterns on the vocalization identity. Neuronal activity was recorded in the auditory cortex of anesthetized guinea pigs in 16 cortical sites during presentation of a set of vocalizations, and a partial blockage of intra-cortical inhibition was performed by Gabazine application (4 minutes, 10μm). Under these conditions, evoked responses were stronger and the temporal patterns were reinforced. Mutual information quantified at each cortical site was increased but the information computed at the populationnal level did not change, an effect that could be explained by the fact that the redundancy between cortical sites was increased. We then assessed to which extent the noradrenergic modulation can mimic the effects of a partial blockage of inhibitions. Although all the tested drugs modulated both the evoked responses and the spike-timing reliability, none of the noradrenergic agonists used here (α1, α2 and ) induced significant changes in the information carried by neuronal responses. However, the effects induced by phenylephrine, an α1 agonist, seemed to involve an action on the intra-cortical inhibition, which suggests that a noradrenergic modulation of cortical inhibition can operate in the auditory cortex. It is therefore possible to envision that the coordinated action of several neuromodulatory systems modulates cortical inhibition and thus changes the information carried by cortical neurons on the stimuli identity.

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on January 5, 2010). Vita. Thesis advisor: Habib Zaghouani. Includes bibliographical references.

Katecholamine beeinflussen durch direkte Stimulation über adrenerge Rezeptoren die Funktion von Immunzellen. Ziel der Untersuchungen an Patienten mit Rheumatoider Arthritis war es, das Expressionsprofil unterschiedlicher adrenerger Rezeptorsubtypen in CD4(+)T-Lymphozyten dieser Patienten zu bestimmen. Zur Quantifizierung der Expression wurden semiquantitative RT-PCR-Analysen durchgeführt. Die Untersuchung zeigte, dass alpha1-adrenerge Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten exprimiert werden. Es scheint eine Korrelation zwischen bestimmten extraartikulären Organmanifestationen (z.B. Sicca-Sydrom und Tenosynovitis) und der Expression alpha1-adrenerger Rezeptoren zu bestehen. Die gefundene differenzielle Expression der Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten legen vertiefende Untersuchungen zur Relevanz des adrenergen Systems bei der Lymphozytenfunktionsmodulation nahe.