Serum C-reactive protein (CRP) is used as a marker of inflammation in several diseases including autoimmune disease and cardiovascular disease. CRP, a member of the pentraxin family, is comprised of five identical subunits. CRP has diverse ligand-binding properties which depend upon different structural states of CRP. However, little is known about the molecular dynamics and interaction properties of CRP. In this study, we used SAPS, SCRATCH protein predictor, PDBsum, ConSurf, ProtScale, Drawhca, ASAView, SCide and SRide server and performed comprehensive analyses of molecular dynamics, protein-protein and residue-residue interactions of CRP. We used 1GNH.pdb file for the crystal structure of human CRP which generated two pentamers (ABCDE and FGHIJ). The number of residues involved in residue-residue interactions between A-B, B-C, C-D, D-E, F-G, G-H, H-I, I-J, A-E and F-J subunits were 12, 11, 10, 11, 12, 11, 10, 11, 10 and 10, respectively. Fifteen antiparallel β sheets were involved in β-sheet topology, and five β hairpins were involved in forming the secondary structure. Analysis of hydrophobic segment distribution revealed deviations in surface hydrophobicity at different cavities present in CRP. Approximately 33 % of all residues were involved in the stabilization centers. We show that the bioinformatics tools can provide a rapid method to predict molecular dynamics and interaction properties of CRP. Our prediction of molecular dynamics and interaction properties of CRP combined with the modeling data based on the known 3D structure of CRP is helpful in designing stable forms of CRP mutants for structure-function studies of CRP and may facilitate in silico drug design for therapeutic targeting of CRP.

Serum C-reactive protein (CRP) is used as a marker of inflammation in several diseases including autoimmune disease and cardiovascular disease. CRP, a member of the pentraxin family, is comprised of five identical subunits. CRP has diverse ligand-binding properties which depend upon different structural states of CRP. However, little is known about the molecular dynamics and interaction properties of CRP. In this study, we used SAPS, SCRATCH protein predictor, PDBsum, ConSurf, ProtScale, Drawhca, ASAView, SCide and SRide server and performed comprehensive analyses of molecular dynamics, protein-protein and residue-residue interactions of CRP. We used 1GNH.pdb file for the crystal structure of human CRP which generated two pentamers (ABCDE and FGHIJ). The number of residues involved in residue-residue interactions between A-B, B-C, C-D, D-E, F-G, G-H, H-I, I-J, A-E and F-J subunits were 12, 11, 10, 11, 12, 11, 10, 11, 10 and 10, respectively. Fifteen antiparallel β sheets were involved in β-sheet topology, and five β hairpins were involved in forming the secondary structure. Analysis of hydrophobic segment distribution revealed deviations in surface hydrophobicity at different cavities present in CRP. Approximately 33 % of all residues were involved in the stabilization centers. We show that the bioinformatics tools can provide a rapid method to predict molecular dynamics and interaction properties of CRP. Our prediction of molecular dynamics and interaction properties of CRP combined with the modeling data based on the known 3D structure of CRP is helpful in designing stable forms of CRP mutants for structure-function studies of CRP and may facilitate in silico drug design for therapeutic targeting of CRP.

Periodontitis is a disease primarily affecting tooth attachment, i.e. concerning oral cavity, however, its connection to a number of systemic diseases is apparent nowadays. Oral microorganisms and their interaction with the immune system of their host play a significant part in the etiology of this multifactorial disease. Rapid development of DNA-based diagnostic methods in the last 15 years dramatically increased the spectrum of identified oral microorganisms and promoted understanding of how particular taxons correlate with periodontal health or disease. Moreover, next generation sequencing methods also bring new possibilities to study the relationship between periodontitis and other diseases such as diabetes mellitus, cardiovascular diseases (CVD), stroke, lung infection or kidney diseases, etc. The presented work focuses on the use of sequencing methods to compare the taxonomic composition of microbiomes within oral cavity and the tissues of aortic valves in patients suffering from CVD. The characterisation of taxonomic composition of microbiome in the analysed tissues was performed using the method of 454 pyrosequencing of variable region IV-V of the bacterial 16S rDNA. The present taxons were determined by comparing the obtained sequences with the Human Oral Microbiome Database. The common...

Verfasser: Gerald Stumpf Titel: Feldstudie zu fieberhaften Erkrankungen des Pferdes unter besonderer Berücksichtigung der Ehrlichiose und freien Endotoxins Institut: Institut für Bakteriologie und Mykologie der Veterinarmedizinischen Fakultät der Universität Leipzig Eingereicht im Dezember 2005 Bibliographische Daten: 92 Seiten, 13 Abbildungen, 15 Tabellen, 134 Quellenangaben Schlüsselworte: Pferd – Fieber – Ehrlichiose – Endotoxin – CRP – Neopterin – PCR Die vorliegende Arbeit beschäftigt sich mit den in der ambulanten Praxis vorkommenden fieberhaften Erkrankungen des Pferdes. Ein Ziel bestand in der Analyse und Verifizierung der klinischen Beobachtungen in der Praxis und der routinemäßigen Laborparameter. Durch die Verwendung zusätzlicher Parameter wurde deren diagnostische Bedeutung am erkrankten Pferd untersucht, um so den diagnostischen Rahmen bei der ätiopathogenetischen Aufklärung des Fiebers unbekannter Genese zu erweitern. Anhand eigener Untersuchungen von Erkrankungen mit Fieber unbekannter Genese im Vergleich zu anderen fieberhaften Krankheiten des Pferdes wurde die Bedeutung des Fiebers unbekannter Genese beim Pferd herausgestellt und das Krankheitsgeschehen charakterisiert. In die Laboruntersuchungen wurden die Entzündungsparameter Neopterin und CRP zusätzlich einbezogen. Mittels Antikörpernachweisen wurde die Beteiligung von Endotoxinen an der Entstehung von Fieber unbekannter Genese untersucht. Außerdem wurde die PCR zum Nachweis von Ehrlichiose bei spontan fieberhaft erkrankten Pferden eingesetzt. Bei 195 (50,9%) von insgesamt 383 Patienten wurde Fieber unbekannter Genese (Fiebertyp 1) registriert, im Jahresdurchschnitt waren es 65 (56 - 72) Pferde (Tab. 2). Dieser Fiebertyp hatte demnach die größte Bedeutung (p0,05). Es tritt in den Herbst und Wintermonaten am häufigsten auf. Rasse- und Altersprädispositionen ist nicht feststellbar. Es handelt sich um ein mit Fieber einhergehendes Krankheitsgeschehen mit geringer Kontagiosität. Der CRP-Wert liegt bei den Patienten mit Fieber unbekannter Genese im Normbereich. Das bedeutet, in Übereinstimmung mit OKIN et al. (2005), AGRAWAL (2005) und DE MAAT (2004), dass es nicht zu den entsprechenden mit Gewebszerfall einhergehenden Entzündungsreaktionen gekommen war. Das Neopterin wurde hier erstmals bei Pferden mit Fieber unbekannter Genese. Dieser Wert war erhöht (x=7,29). Es ist ein unspezifischer Parameter für den negative Korrelation (r=0,33, p0,05) mit Anti-Endotoxin-IgG festgestellt wurde. Die Erhöhung der Immunglobuline der Klasse IgG (Antiendotoxin-IgM: x=1,18 und Anti-Lipid-A-IgM: x=1,5) weist auf eine Beteiligung freier Endotoxine an der Entstehung von Fieber unbekannter Genese beim Pferd hin. Das Vorkommen von Anaplasma phagocytophilum (Ehrlichia equi) wurde erstmals in Deutschland beim Pferd molekulargenetisch nachgewiesen. Obwohl die ätiologische Diagnosestellung in dieser Studie nur begrenzt erweitert werden konnte, ergeben sich nach der hier vorgenommenen Charakterisierung des Fiebers unbekannter Genese beim Pferd für die Zukunft gute Ansatzpunkte für den gezielten Einsatz der PCR mit selektiv ausgewählten Primern, um den diagnostischen Rahmen zu erweitern. / Author: Gerald Stumpf Titel: Fieldstudy of febrile diseases in the horse in particular condition of ehrlichiosis and free endotxin Institute: Institute of Bacteriology and Mycology, Faculty of Veterinary Medicine, University of Leipzig Submitted in December 2005 Bibliographic data: 92 pages, 13 figures, 15 tables, 134 references Key words: Horse – Fever – Ehrlichiosis – Endotoxin – CRP – Neopterin - PCR The importance and prevalence of fever of unknown origin in horses was investigated, characterised and compared with other febrile conditions in horses. Inflammatory and stress parameters such as neopterin and CRP were included in the investigated laboratory profile. The level of IgG was investigated by an immunological approach for checking the involvement of endotoxins in the genesis of fever. PCR was used for the detection of ehrlichiosis in horses with spontaneous fever. In total, 383 horses with febrile conditions were examined within a period of 3 years. In 195 horses (50.9%) fever of unknown origin was diagnosed (fever type 1) indicating that this is the most important fever type in horses (p0.05) mainly seen in autumn and winter. In contrast, an age or race predispostion could not be detected. Typically, this fever type is characterised by a low contagiosity. The horses with fever of unknown oigin showed CRP values within the physiological range. This is indicative for the lack of tissue damage and respective inflammatory processes and supports the findings of OKIN et al. (2005), AGRAWAL (2005) und DE MAAT (2004). To the knowledge of the author, this is the first report on investigations of neopterin in horses with fever of unknown origin. Neopterin is an unspecific parameter and showed a negative correlation (r=0.33, p0.05) with anti-endotoxin IgG. The mean neopterin value in horses with fever of unknown oigin was increased (7.29). The observed increase of anti-endotoxin-IgM and anti-Lipid A-IgM indicates the involvement of endotoxins in the genesis of fever of unknown origin in horses. Moreover, this is the first report about the molecular genetic detection of Anaplasma phagocytophilum (Ehrlichia equi) in horses in Germany. In conclusion, the characterisation of fever of unknown origin in this thesis may stipulate further targeted investigations using PCR with selective primers to improve the etiological diagnosis of this disease.

ABSTRACT Background: Cardiovascular diseases (CVD) can be a risk factor for periodontitis, but periodontitis can also be a marker for an increased risk of cardiovascular diseases. In addition, the infectious biological effects may also be risk factors, such as increased number of cytokines or periodontal bacteria in the circulation. Aim of study:  1. To find systemic risk markers associated with an increased risk for CVD. 2. To study change of the selected biomarkers after periodontal treatment. Methods: Using articles from PubMed showing different risk markers that associate strongly with an increased risk for cardiovascular diseases (CVD). Inclusion criteria for the studies, the patients having periodontitis at baseline which has been clinically significant improved after treatment and that the risk markers have been measured before and after treatment. Additionally, these studies have contained enough individuals to be able to answer our question. We found 11 articles which fulfilled the criteria described above. Results: According to different studies, we have observed that there are significant risk markers associating with both periodontitis and CVD, and they have decreased after periodontal treatment. The most common risk markers are cholesterol, LDL, HDL, CRP and cytokines. All 11 studies showed significant decrease of at least one of the selected risk markers after periodontal treatment, while 2 of them also showed increased levels of several risk markers. Conclusion: We have found that successful treatment of periodontitis decreases systemic risk markers that are associated with increased risk for CVD. The clinical parameters for definition of periodontitis has been significantly improved.

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Type-2 diabetes has become a common disease. The complications associated with thedisease are often cardiovascular. Platelets are important components in hemostasis, one function is platelet adhesion. Platelet adhesion is the first step to form a platelet plug, together with subendothelial proteins. Blood lipids contribute to membrane structure of cells and has an important role in different signaling pathways. They have a key role in platelet activation and is associated with the changes in membrane lipids. C-reactive protein (CRP) is an acute phase protein and increases during inflammation. The physiological role is not fully known but increasing levels of CRP increases the risk for cardiovascular complications. The aim of this study was to analyze the correlation between platelet adhesion with blood lipids and high sensitivity CRP in type-2 diabetics. 69 patients with type-2 diabetes participated in this study. Lipids, CRP and platelet adhesion were analyzed, the values were used to perform correlation analysis. The results show statistically significant positive correlations between ApoA-1, HDL and platelet adhesion as well as significant negative correlations between LDL, ApoB/ApoA-1-ratio, LDL/HDL-ratio and platelet adhesion. ApoA-1 and platelet adhesion with collagen showed statistically significant correlations with r-values 0,299-0,436. ApoA-1/ApoB-quota showed statistically significant correlations with r-values from -0,492 to -0,268. Majority of correlations between totalcholesterol, ApoB, triglycerides, hsCRP and platelet adhesionshowed no statistically significant correlations. / Typ-2 diabetes har blivit en vanligare sjukdom. De komplikationer som kan uppstå vid diabetes, särskilt obehandlad diabetes, är ofta kardiovaskulära komplikationer. Trombocyter är viktiga komponenter i hemostasen, en av deras funktioner är trombocytadhesion. Trombocytadhesionen är första steget vid bildandet av en trombocytpropp, tillsammans med subendoteliala proteiner så kan trombocyterna fästa till kärlväggen och hemostasen påbörjas. Blodlipider bidrar till cellmembraners struktur, energiförvaring och har en viktig roll vid olika typer av signalering. De har en nyckelroll vid trombocytaktivering eftersom trombocytaktivering är associerad med förändringar som sker hos membranlipiderna. C-reaktivt protein (CRP) är ett akutfasprotein och ökar vid inflammation. Fysiologiska rollen är inte helt känd men stegring av CRP ökar risken för kardiovaskulära komplikationer. Syftet med denna studie är att analysera korrelationen mellan trombocytadhesion med blodlipider och högkänsligt CRP hos typ 2 diabetiker. Det medverkade 69 patienter med typ-2 diabetes i studien. Blodlipider, högkänsligt CRP och trombocytadhesion analyserades ochvärdena för respektive analyt användes för korrelationsanalyser.Resultaten visar statistiskt signifikanta positiva korrelationer mellan ApoA-1, HDL och trombocytadhesion samt signifikanta negativa korrelationer mellan LDL, ApoB/ApoA-1-kvot, LDL/HDL-kvot och trombocytadhesion. ApoA-1 och trombocytadhesion med kollagen som proteinyta uppvisade statistiskt signifikanta korrelationsintervall med r-värden på 0,299-0,436. ApoA-1/ApoB-kvoten visade statistiskt signifikanta korrelationsintervall med r-värdenmellan -0,492 till -0,268. Majoriteten av korrelationerna för variablerna: totalkolesterol, ApoB, triglycerider, högkänsligt CRP och trombocytadhesion visade inga statistiskt signifikanta korrelationer.

Les cytokines, produites lors de l’activation du système immunitaire, ont la capacité d’agir au niveau du système nerveux central et d’induire diverses altérations comportementales. Lorsque l’activation du système de l’immunité innée devient chronique, ces altérations comportementales peuvent évoluer en véritables symptômes neuropsychiatriques. La physiopathologie des symptômes neuropsychiatriques qui se développent dans un contexte d’inflammation chronique à bas bruit, c’est-à-dire caractérisé par une activation chronique des processus immunitaires mais à un niveau relativement faible, est peu connue et reste à déterminer. L’implication de l’inflammation chronique à bas bruit dans les symptômes de fatigue et les altérations cognitives constitue l’élément d’étude principal de ce travail de thèse. Les troubles métaboliques, tels que l’obésité et le diabète de type 2, sont de bons modèles pour une telle étude. Ces deux pathologies sont en effet caractérisées par une inflammation chronique à bas bruit qui proviendrait, au moins en partie, du tissu adipeux. De plus, la fatigue et les altérations cognitives sont fréquentes chez les patients souffrant de troubles métaboliques. Compte tenu du rôle connu de l’inflammation dans la physiopathologie de ces altérations comportementales, leur développement dans des contextes de troubles métaboliques pourrait également être lié à l’activation chronique à bas bruit de processus inflammatoires. Différents objectifs ont été définis pour tester cette hypothèse : 1) caractériser et spécifier les symptômes de fatigue et les altérations cognitives chez des patients diabétiques ou obèses ; 2) évaluer la relation entre inflammation systémique et état inflammatoire du tissu adipeux ; 3) étudier l’association de l’inflammation chronique à bas bruit avec les symptômes de fatigue et les altérations cognitives des patients souffrant de troubles métaboliques. Nos résultats indiquent que la fatigue, en particulier la fatigue générale et physique, représente une caractéristique fondamentale des troubles métaboliques. Des perturbations cognitives, se traduisant par un ralentissement psychomoteur dans un test de temps de réaction ainsi qu’une altération de performance dans une tâche de planification spatiale, ont également été décelées chez les patients diabétiques de type 2, particulièrement ceux sous insulinothérapie, et chez les patients obèses. Des altérations mineures étaient également mesurées dans une tâche d’empan spatial rétrograde chez les patients obèses. En ce qui concerne les données biologiques, nos résultats indiquent diverses associations entre l’inflammation systémique et l’expression des marqueurs inflammatoires (cytokines inflammatoires, dont le MCP1, et marqueurs des cellules T) dans le tissu adipeux viscéral des patients obèses. De façon intéressante, l’inflammation systémique à bas bruit était associée aux dimensions de fatigue (générale, mentale, réduction des activités et de la motivation) et aux altérations de performance dans les tests ciblant les fonctions exécutives. Dans l’ensemble, ces résultats supportent l’hypothèse de l’implication des macrophages et des lymphocytes T du tissu adipeux dans l’état inflammatoire systémique associé à l’obésité. Il suggère en outre que l’inflammation systémique à bas bruit pourrait participer au développement de la fatigue et des altérations cognitives chez les patients souffrant de troubles métaboliques. Ce travail de thèse offre une caractérisation précise des symptômes de fatigue et des altérations cognitives associées aux troubles métaboliques. En outre, ce travail apporte d’importantes informations sur les relations de l’inflammation chronique à bas bruit avec ces symptômes, et permet d’affiner les hypothèses relatives à l’implication de processus inflammatoires dans la physiopathologie de ces altérations. / Cytokines produced during the activation of the immune system have the ability to act within the central nervous system and to induce a large number of behavioral alterations. When the activation of immune system becomes chronic and unregulated, these behavioral alterations may lead to the development of neuropsychiatric symptoms. The pathophysiology of neuropsychiatric symptoms that develop in conditions of chronic low-grade inflammation context (i.e., characterized by a chronic but low activation of inflammatory processes), remains unknown. The main aim of this thesis was to investigate the involvement of low-grade inflammation in the development of fatigue symptoms and cognitive alterations in patients with metabolic disorders including obesity and type 2 diabetes. These conditions are characterized by a chronic low-grade inflammatory state, manifesting by higher blood concentrations of inflammatory factors. This inflammatory state would originate, at least partially, from the adipose tissue. Moreover, fatigue symptoms and cognitive alterations are common in metabolic disorders. Given the role of inflammation in the physiopathology of these symptoms, their development could also rely on chronic low-grade inflammatory processes. Several objectives were defined to test this hypothesis: 1) to characterize fatigue symptoms and cognitive alterations in obese and diabetic patients; 2) to assess the relationship of systemic inflammation with the inflammatory state of the adipose tissue; and 3) to investigate the association of low-grade inflammation with fatigue symptoms and cognitive alterations in patients with metabolic disorders. Fatigue symptoms and cognitive function were respectively assessed using the multidimensional fatigue inventory (MFI) and the neuropsychological tests automated battery CANTAB in diabetic patients (type 1 and type 2) and in obese patients before and after bariatric surgery. A control group was included for each model (obesity and type 2 diabetes). Circulating concentrations of inflammatory markers, as well as expression of inflammatory markers in the visceral adipose tissue of obese patients, were measured. Our results indicate that fatigue symptoms, especially in the dimensions of general and physical fatigue, represent fundamental characteristics of patients suffering from metabolic disorders. In addition, cognitive alterations (psychomotor slowing and alterations in spatial planning performance) were measured in type 2 diabetic patients, more particularly those under insulin treatment, and in obese patients. Slight alterations in the test of backward spatial span were measured in obese patients. With respect to biological data, our results indicate significant relationships between systemic inflammation and inflammatory markers (inflammatory cytokines, including MCP1, and T-cell markers) in the visceral adipose tissue of obese patients. Interestingly, chronic low-grade inflammation was associated with fatigue symptoms (general fatigue, mental fatigue, reduced activity and motivation) and performance alterations in tests assessing executive functions. Altogether, these data support the hypothesis of the involvement of the adipose macrophages and T lymphocytes in the systemic inflammatory state associated with obesity. Moreover, these results suggest that systemic low-grade inflammation associated with metabolic disorders may contribute to the physiopathology of fatigue and cognitive alterations in these conditions. In conclusion, these studies provide a precise characterization of fatigue symptoms and cognitive alterations associated with metabolic disorders, such as obesity or type 2 diabetes. In addition, this thesis work gives interesting information about the relationships of chronic low-grade inflammation and fatigue and cognitive symptoms, and refines hypotheses regarding the involvement of inflammatory processes in the physiopathology of these symptoms in patients with diabetes or obesity.

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