Influence of the genetic background on the jejunal pathology following oral infection with Yersinia enterocolitica in mice

Deckblatt-Impressum persönlicher Dank Inhalt Abkürzungen Abbildungen Tabellen Einleitung Literaturübersicht Eigene Arbeiten Diskussion Zusammenfassung Summary Literatur Anhang Danksagung SelbständigkeitserklärungZur Verwendung von Mausmodellen in der biomedizinischen Forschung ist die Erfassung von umfangreichen Basiskenntnissen über die Inzucht-Mausstämme notwendig. In Infektionsversuchen konnte festgestellt werden, dass der genetische Hintergrund Ursache für die unterschiedlichen Reaktionen der Mausstämme war. Dies ließ vermuten, dass auch auf histologischer Ebene Unterschiede in der Art und Ausprägung der Immunantwort zwischen den Mausstämmen existieren. Ziel der vorliegenden Studie war einerseits eine Vervollständigung der Basisdaten, andererseits sollte der histologische Nachweis qualitativer und quantitativer Unterschiede von Inzucht-Mausstämmen unter Infektionsbedingungen erfolgen. Weiterhin sollte eine Reihung der beurteilten Mausstämme in Bezug auf ihre Resistenz gegenüber Y. enterocolitica erstellt werden. Erstmals konnte im Zuge der Untersuchungen eine differenzierte Betrachtung von Resistenz und Immunität erfolgen. In der vorliegenden Studie wurden die vier ingezüchteten Wildtyp-Mausstämme (C57BL/6OlaHsd, BALB/cOlaHsd, C3H/HeNHsd und 129P2/OlaHsd) mit einem wenig pathogenen Stamm von Y. enterocolitica oral infiziert. Drei und neun Tage p.i. wurde eine umfassende, histopathomorphologische Untersuchung des aboralen Drittels des Dünndarmes durchgeführt. Im Mittepunkt stand die Feststellung der Yersinienkoloniezahl und -lokalisation sowie der unterschiedlichen Fähigkeit der Mausstämme, eine effektive Entzündungsreaktion mit Defektheilung auszubilden. Dazu wurde der unterschiedliche Charakter der Gewebeschädigungen sowie der entzündlichen Reaktionen beurteilt. Yersinienkolonien sowie die mit der Infektion assoziierten Gewebeveränderungen konnten sowohl bei allen untersuchten Mausstämmen in den PP als auch in der Schleimhaut nachgewiesen werden. Es waren qualitative und quantitative Unterschiede der Immunantwort, der Kolonieverteilungen und der Verläufe der Koloniezahlen bei den verschiedenen Inzucht-Mausstämmen zu beobachten. Erstmals war bei den untersuchten Mausstämmen histopathologisch ein unterschiedlicher Charakter der entzündlichen Veränderungen nachweisbar. C57BL/6OlaHsd wurde in der vorliegenden Studie wegen der zu Beginn relativ hohen Koloniezahlen als intermediär suszeptibel und als Stamm mit der effektivsten Immunität eingestuft. Die Bakterien wurden im Verlauf der Infektion anhand einer starken Immunantwort erfolgreich reduziert. Bereits früh waren Makrophagen nachweisbar, und eine Defektheilung war durch Granulationsgewebe sowie perivaskuläre Plasmazellinfiltrate im histoSummary Literatur Anhang Danksagung <a logischen Bild zu erkennen. Der Stamm BALB/cOlaHsd besaß eine hohe Resistenz und die in dieser Studie schwächste Immunität. Drei Tage p.i. traten zwar relativ geringe Koloniezahlen auf, jedoch setzte keine Reifung der Immunantwort ein. Die Zahl der Bakterienkolonien und der veränderten PP nahm sogar im Verlauf der Infektion zu. Zu beiden Untersuchungszeitpunkten waren ähnliche, akute, eitrige Veränderungen des Gewebes zu beobachten. Eine Organisation der Alterationen war kaum und eine signifikante Zunahme der Plasmazellinfiltration in die PP war nicht vorhanden. Die Tiere dieses Stammes waren damit nicht in der Lage, die Infektion zu begrenzen. Der Mausstamm C3H/HeNHsd wurde als empfänglichster Stamm mit intermediärer Immunität eingestuft. Zu Beginn der Infektion hatte bei diesem Stamm die stärkste Immunantwort eher destruktive Folgen. Makrophagen und Granulationsgewebe waren drei Tage p.i. kaum zu beobachten. Die Bakterien infizierten gleichermaßen PP und die Schleimhaut. Trotz einsetzender, verzögerter Organisation der Defekte, Infiltration der PP mit Plasmazellen und Reduzierung der Bakterienkolonien traten neun Tage p.i. immer noch relativ hohe Koloniezahlen auf. Die 129P2 /OlaHsd-Tiere konnten aufgrund Ihrer geringen Koloniezahlen drei Tage p.i. als resistent eingeordnet werden. Bei dem Stamm 129P2/OlaHsd waren nur relativ wenige PP von Veränderungen und der Kolonisation mit Yersinienkolonien betroffen. Die Einzeltiere zeigten eine sehr unterschiedlich erfolgreiche Immunantwort, weshalb die Immunität dieses Stammes als intermediär eingestuft wurde. Der eine Teil der Tiere ähnelte in seinem histologischen Bild dem der C57BL/6OlaHsd-Tiere, der andere Teil glich BALB/cOlaHsd. Verschiedene Faktoren werden in der vorliegenden Arbeit für die abweichende Resistenz und Immunität der Inzucht-Mausstämme verantwortlich gemacht. Eine unterschiedlich schnelle Ausbildung der TH1-Immunantwort mit der damit verbundenen, abweichenden Bildung von TH1-Cytokinen kann auch in dieser Arbeit die unterschiedlichen, histopathologisch nachweisbaren Reaktionen erklären. Besonders die Spiegel von IFN-γ und TNF-α und die Vermittlung ihrer biologischen Aktivität sind von großer Bedeutung für die Effektivität der Immunantwort. Eine unterschiedliche Anzahl der für die Yersinieninfektion essentiellen Makrophagen bzw. deren abweichende Aktivierung oder Funktionalität führen ebenfalls zu einer verminderten Bakterienreduktion. Die frühe Aktivierung der T-Lymphozyten zur Auslösung der TH1-Antwort spielt dabei eine entscheidende Rolle und ist in den verschiedenen Mausstämmen unterschiedlich ausgeprägt. Die unterschiedliche Bildung der CD4+ und CD8+ T-Zellen und Plasmazellen sowie jeweils deren Einwandern in die PP als auch die verschiedene Fähigkeit der Organisation des alterierten Gewebes tragen zur abweichenden Immunität bei. Weiterhin können unterschiedliche Expressionen und Beantwortungen von Chemokinen, Chemokinrezeptoren, Integrinen und Adhäsionsmolekülen bei den verschiedenen Inzucht-Mausstämmen für den abweichenden Influx der Immunzellen verantwortlich sein. Ebenfalls ist denkbar, dass die bakteriellen Pathogenitätsfaktoren (z.B. LcrV, rovA, Yops, etc.) in den verschiedenen Mausstämmen in unterschiedlicher Effektivität Angriffspunkte finden, um die Immunantwort zu modulieren und damit die Invasion und ihr Überleben im Wirt zu sichern. In der vorliegenden Arbeit konnte ein Beitrag zur Vervollständigung der Basisdaten von Inzucht- Mausstämmen unter Infektionsbedingungen geleistet und aufgezeigt werden, dass zwischen ihnen auf histologischer Ebene sowohl qualitative als auch quantitative Unterschiede bestanden. Mithilfe dieser Ergebnisse war es anschließend möglich, eine differenzierte Reihung der Mausstämme bezüglich ihrer abweichenden Resistenz und Immunität aufzustellen.Extensive basic knowledge on inbred mouse strains and specific mouse mutants is essential to use mouse models in biomedical science. The specific genetic background of the different inbred mouse strains is known to be responsible for the considerable variations in the reaction of mice to infections, such as Yersinia infections. This observation indicated that differences in intensity and characteristics of the immune response between mouse strains should also exist on histological level. On the one hand, this study aimed at adding to the data on basic knowledge of inbred mouse strains. On the other hand, histological evidence was to be provided of qualitative and quantitative differences in the examined inbred mouse strains reaction to an infection with Y. enterocolitica. Subsequently, an order of susceptibility and, for the first time, also of the immunity of the studied mouse strains was established. In the present study, four inbred wild-type mouse strains (C57BL/6OlaHsd, BALB/cOlaHsd, C3H/HeNHsd and 129P2/OlaHsd) were orally infected with a low- virulence strain of Y. enterocolitica. A systematic histopathomorphological analysis of the aboral small intestine was performed three and nine days p.i. The main focus was the characterization of the type and degree of inflammatory reactive patterns and the number and distribution of Yersinia colonies. Specifically, the influences of genetic backgrounds, gender and time point after infection were assessed. Yersinia colonies and the changes in the tissue associated with the Yersinia infection were detected in all mouse strains in the mucosa as well as in the PP. Qualitative and quantitative differences in the inflammatory response, the colonies distribution and the course of colony number were recorded between the different inbred mouse strains. For the first time, this study could demonstrate histopathologically that the inbred mouse strains studied differed in the character of the inflammatory changes. In the present study, C57BL/6OlaHsd was classified as intermediate susceptible because of its high number of colonies and as strain with the best immunity. The bacteria were eliminated by a strong, effective immune response during infection. Macrophages could be detected very early. Furthermore, a partial recovery by granulation tissue and perivascular plasma cell infiltrates was observed histologically. The strain BALB/cOlaHsd showed high resistance to the initial infection and the least effective immunity of the present study. Three days p.i., there were relatively low colony numbers but the strain did not show any maturation of the inflammatory response. The number of bacterial colonies and altered PP even increased during the infection. Similar purulent changes of the tissue were observed at both time points of examination. Organisation of the alterations hardly occured, and the plasma cell infiltration into the PP did not increase significantly. The animals of this strain were thus not able to confine the infection. The strain C3H/HeNHsd was classified as the most susceptible strain with an intermediate, delayed immunity. At the beginning, the strong immune response was rather destructive. Three days p.i. macrophages and granulation tissue were hardly observed. The bacteria infected the mucosa and the PP to a similar extent. Despite an early organisation of the defects, an infiltration of the PP with plasma cells and a reduction of the bacterial colonies, the number of colonies was still relatively high nine days p.i. The strain 129P2/OlaHsd was classified as rather resistant because of the low number of colonies three days p.i. All in all, only relatively few PP were affected and colonized by Yersinia. The success of the individuals' immune responses varied to a great extent, and the immunity of this strain was classified as intermediate. The histological appearance of some of the animals was comparable to the C57BL/6OlaHsd animals, others were similar to BALB/cOlaHsd. In the present study, several factors were discussed as possible causes for resistance and immunity of inbred mouse strains. Developing a TH1 immune response at different intensities and the corresponding delayed formation of TH1 cytokines might explain the different histopathologically detectable reactions in this study, too. In this context, IFN-γ and TNF-α levels and the mediation of their biological activity are of outstanding importance for the efficicacy of the inflammatory response. A differing number of macrophages which are essential for the confinement of Yersinia infection, or their delayed activation or reduced functionality might lead to a decreased reduction of bacteria and consequently to a persistence or even an exacerbation of the infection. An early activation of the T-lymphocytes to trigger the TH1 immune response may play a decisive role and is exhibited at varying degrees in the inbred mouse strains. Different proliferation of CD4+ and CD8+ T cells and their homing in the PP as well as the different organisation ability of the altered tissue might be additional factors contributing to the differing immune responses of the investigated mouse strains. Differences in the expression or response of a multitude of chemokines, chemokine receptors and adhesion molecules in the mouse strains might lead to the different influxes of immune cells. It is, furthermore, conceivable that factors of bacterial virulence (e.g. LcrV, rovA, Yops, etc.) are differently effective in the different mouse strains in finding their receptors or target structures to modulate the immune response and to consequently establish survival in the host. In the present study, basic data on inbred mouse strains in term of their reaction to an infection with Y. enterocolitica were established and qualitative as well as quantitative differences were detected on the histological level. Finally, a differentiated order of susceptibility and, for the first time, also of the immunity of the studied mouse strains was established based on histological evidence

Analysis of the compression ratio and quality in aerial images

In modern photomap systems, images are stored in centralized storage. Choosing a proper compression format for the storage of an aerial image is an important problem. This paper analyses aerial image compression in popular compression formats. For the comparison of compression formats, an image quality evaluation algorithm based on the calculation of the mean exponent error value is proposed. An image quality evaluation experiment is presented. The distribution of errors in aerial images and explanation of the causes for worse than usual compression effect are analysed. An integrated solution for the aerial image compression problem is proposed and the compression format most suitable for aerial images is specified. First published online: 14 Oct 201

Fallen Angel Bonds Investment and Bankruptcy Predictions Using Manual Models and Automated Machine Learning

The primary aim of this research was to find a model that best predicts which fallen angel bonds would either potentially rise up back to investment grade bonds and which ones would fall into bankruptcy. To implement the solution, we thought that the ideal method would be to create an optimal machine learning model that could predict bankruptcies. Among the many machine learning models out there we decided to pick four classification methods: logistic regression, KNN, SVM, and NN. We also utilized an automated methods of Google Cloud's machine learning. The results of our model comparisons showed that the models did not predict bankruptcies very well on the original data set with the exception of Google Cloud's machine learning having a high precision score. However, our over-sampled and feature selection data set did perform very well. This could likely be due to the model being over-fitted to match the narrative of the over-sampled data (as in, it does not accurately predict data outside of this data set quite well). Therefore, we were not able to create a model that we are confident that would predict bankruptcies. However, we were able to find value out of this project in two key ways. The first is that Google Cloud's machine learning model in every metric and in every data set either outperformed or performed on par with the other models. The second is that we found that utilizing feature selection did not reduce predictive power that much. This means that we can reduce the amount of data to collect for future experimentation regarding predicting bankruptcies.Comment: 8 pages, 3 figure

Growth of Oxide Compounds under Dynamic Atmosphere Composition

Commercially available gases contain residual impurities leading to a background oxygen partial pressure of typically several 10^{-6} bar, independent of temperature. This oxygen partial pressure is inappropriate for the growth of some single crystals where the desired oxidation state possesses a narrow stability field. Equilibrium thermodynamic calculations allow the determination of dynamic atmosphere compositions yielding such self adjusting and temperature dependent oxygen partial pressures, that crystals like ZnO, Ga2O3, or Fe{1-x}O can be grown from the melt.Comment: 4 pages, 3 figures, talk on CGCT-4 Sendai, May 21-24, 200

Heart rate variability in non-apneic snorers and controls before and after continuous positive airway pressure

BACKGROUND: We hypothesized that sympathetic nervous system activity (SNSA) is increased and parasympathetic nervous system activity (PNSA) is decreased during non-rapid eye movement (NREM) sleep in non-apneic, otherwise healthy, snoring individuals compared to control. Moreover, we hypothesized that these alterations in snoring individuals would be more evident during non-snoring than snoring when compared to control. METHODS: To test these hypotheses, heart rate variability was used to measure PNSA and SNSA in 11 normotensive non-apneic snorers and 12 control subjects before and 7-days after adapting to nasal continuous positive airway pressure (nCPAP). RESULTS: Our results showed that SNSA was increased and PNSA was decreased in non-apneic snorers during NREM compared to control. However, these changes were only evident during the study in which snoring was eliminated with nCPAP. Conversely, during periods of snoring SNSA and PNSA were similar to measures obtained from the control group. Additionally, within the control group, SNSA and PNSA did not vary before and after nCPAP application. CONCLUSION: Our findings suggest that long-lasting alterations in autonomic function may exist in snoring subjects that are otherwise healthy. Moreover, we speculate that because of competing inputs (i.e. inhibitory versus excitatory inputs) to the autonomic nervous system during snoring, the full impact of snoring on autonomic function is most evident during non-snoring periods

Ventilatory responses after major surgery and high dependency care

BACKGROUND: Disturbed breathing during sleep, with episodic upper airway obstruction, is frequent after major surgery. Ventilatory responses to hypercapnia and hypoxia during episodes of airway obstruction are difficult to investigate because the usual measure, that of ventilation, has been attenuated by the obstruction. We simulated the blood gas stimulus associated with obstruction to allow investigation of the responses. METHODS: To assess ventilatory responses, we studied 19 patients, mean age 59 (19–79), first at discharge from high dependency care after major abdominal surgery and then at surgical review, ∼6 weeks later. Exhaled gas was analysed and inspired gas adjusted to simulate changes that would occur during airway obstruction. Changes in ventilation were measured over the following 45–70 s. Studies were done from air breathing if possible, and also from an increased inspired oxygen concentration. RESULTS: During simulated obstruction, hypercapnia developed similarly in all the test conditions. Arterial oxygen saturation decreased significantly more rapidly when the test was started from air breathing. The mean ventilatory response was 5.8 litre min(−2) starting from air breathing and 4.5 litre min(−2) with oxygen breathing. The values 6 weeks later were 5.9 and 4.3 litre min(−2), respectively (P=0.05, analysis of variance). There was no statistical difference between the responses starting from air and those on oxygen. CONCLUSIONS: After major surgery, ventilatory responses to hypercapnia and hypoxaemia associated with airway obstruction are small and do not improve after 6 weeks. With air breathing, arterial oxygen desaturation during simulated rebreathing is substantial

An Improved Dynamic Model for the Respiratory Response to Exercise

ABSTRACT: Respiratory system modeling has been extensively studied in steady-state conditions to simulate sleep disorders, to predict its behavior under ventilatory diseases or stimuli and to simulate its interaction with mechanical ventilation. Nevertheless, the studies focused on the instantaneous response are limited, which restricts its application in clinical practice. The aim of this study is double: firstly, to analyze both dynamic and static responses of two known respiratory models under exercise stimuli by using an incremental exercise stimulus sequence (to analyze the model responses when step inputs are applied) and experimental data (to assess prediction capability of each model). Secondly, to propose changes in the models’ structures to improve their transient and stationary responses. The versatility of the resulting model vs. the other two is shown according to the ability to simulate ventilatory stimuli, like exercise, with a proper regulation of the arterial blood gases, suitable constant times and a better adjustment to experimental data. The proposed model adjusts the breathing pattern every respiratory cycle using an optimization criterion based on minimization of work of breathing through regulation of respiratory frequency