Im klinischen Alltag stellt die Diagnosestellung der Sepsis bei Schwerbrandverletzten eine Herausforderung dar. Ursächlich sind pathophysiologische Besonderheiten der Verbrennungskrankheit, die in ihrer klinischen Präsentation dem Bild einer Sepsis ähnelt und somit die differentialdiagnostische Abgrenzung erschwert. Es existieren aktuell keine Parameter, Scores, oder Sepsiskriterien, die mit ausreichender Kompetenz eine Sepsis bei Brandverletzten feststellen können. Traditionelle Infektionsparameter (WBC, CRP, Fieber) gelten als zu unspezifisch. Das in der allgemeinen Intensivmedizin weithin etablierte Procalcitonin wird bei Brandverletzten ebenfalls kontrovers diskutiert. Für die Sepsis-3-Definition unter Verwendung des SOFA-Scores konnten bislang keine ausreichende Sensitivität und Spezifität nachgewiesen werden. IL-6 ist ein etablierter Marker der Inflammation mit sehr rascher Induktion bei einer Sepsis. Während das Ergebnis von Blutkulturen häufig erst nach 24-48 Stunden vorliegt, ist die Bestimmung des IL-6 innerhalb weniger Stunden möglich. Der diagnostische Wert des IL6 in der Frühphase der Sepsis bei Brandverletzten ist bislang ungeklärt. Das Ziel unserer Studie war es, die mögliche Beziehung zwischen positiven Blutkulturen und Il- 6-Serumspiegel bei schwerbrandverletzten Patienten mit klinischem Verdacht auf eine Sepsis zu überprüfen und den prädiktiven Wert des IL-6 mit dem anderer Parameter (PCT, WBC, Tmax und SOFA Score) zu vergleichen. In einer retrospektiven Studie wurden über einen 7-Jahreszeitraum alle Patienten eingeschlossen, bei denen bei klinischem Verdacht auf eine Sepsis Blutkulturen abgenommen sowie IL6, PCT und WBC bestimmt wurden. Die Patienten mit vollständigen Daten wurden gemäß Blutkultur in zwei Gruppen eingeteilt: Blutkultur-positive (BSI) und Blutkultur-negative Gruppe (Non-BSI). Die Gruppen wurden für alle gemessenen Biomarker, SOFA-Score und die maximale Körpertemperatur (T max) verglichen. Insgesamt wurden 101 Patienten eingeschlossen (BSI= 39, non-BSI= 62). Beide Gruppen waren hinsichtlich demographischer Daten und der Verletzungsschwere vergleichbar. IL-6 war bei den Patienten der BSI-Gruppe signifikant höher [1047 (339,9; 9000,5) vs. 198,5 (112,43; 702,52) ng/ l; p = 0,001]. In einer ROC-Analyse ergab sich eine AUC von 0,7 (59; 80,8 %). Somit ist IL-6 ein Biomarker mit moderater Aussagekraft. Als optimaler Cut-Off Wert erwies sich ein IL-6-Serumspiegel von 312,8 ng/ l (Sensitivität 79,5 %, Spezifität 56,5 %). Hinsichtlich der PCT, WBC und der Tmax zeigten die Gruppen keine signifikanten Unterschiede. Der SOFA-Score in der BSI-Gruppe war signifikant höher, allerdings wurde ein Anstieg um mindestens 2 Punkte im Vergleich zum Vortag nicht erreicht. Unsere Ergebnisse deuten darauf hin, daß IL-6 bei klinischem Verdacht auf eine Sepsis bereits frühzeitig eine positive Blutkultur vorhersagen kann. In diesem Kontext sind andere getestete Parameter (WBC, T max, PCT, SOFA-Score) weniger geeignet. Der frühe Anstieg des IL-6 könnte im klinischen Alltag hilfreich sein, da die Ergebnisse der IL-6-Bestimmung im Gegensatz zur Kultivierung von Blutkulturen innerhalb weniger Stunden vorliegen. Insbesondere in unklaren Fällen und Situationen, bei denen ein Zuwarten bezüglich der Einleitung einer Antibiotikatherapie möglich erscheint (z.B. fehlende Organdysfunktion) kann IL-6 einen Beitrag bei der Diagnosestellung leisten und einen Hinweis geben, ob differentialdiagnostische Überlegungen weiter verfolgt werden müssen. Die Bestimmung des IL-6 könnte somit zur Vermeidung eines zu liberalen, unkritischen Antibiotikaeinsatzes und den damit assoziierten Folgen beitragen. Das retrospektive Design und die Fallzahl sind relevante Limitationen unserer Studie. Eine Aussage zu möglichen Unterschieden zwischen grampositiven und gramnegativen Keimen kann daher nicht sicher getroffen werden. Weitere prospektive Untersuchungen mit einer höheren Patientenzahl sind daher unbedingt zu empfehlen.:Inhaltsverzeichnis 1. Einleitung…………………………………………………………………………..2 1.1 Epidemiologie der Schwerbrandverletzungen in Deutschland…...……..2 1.2 Pathophysiologie………………..……..…………………………….……….2 1.2.1 Verbrennungskrankheit………………………………….....…………….3 1.2.2 Schockphase……………....………………………………………..…….3 1.2.3 Phase der Ödemrückresorption…………………….………………..….4 1.2.4 Phase der Inflammation/ Infektion und des Hypermetabolismus…....4 1.2.5 Spätphase………………………………………………………......…..…4 1.3 Sepsis bei schwerbrandverletzten Patienten…………...…………………5 1.4 Stellenwert von Infektionsparametern und Scores in der Sepsis bei schwerbrandverletzten brandverletzten Patienten………………………..….6 1.5 Interleukin 6…………………………………..……………………………….7 1.5.1 Zelluläre Mechanismen und die Rolle von Interleukin 6 in der Verbrennungskrankheit……………..……………………………...………….7 1.5.2 Interleukin 6 in der Sepsis……………………...……………………….8 1.6 Material und Methoden………………...…………………...………………..9 1.7 Fragestellung und Zielsetzung des Forschungsvorhabens…………..…12 2. Publikation…………………………………………………………… ………….13 3. Zusammenfassung der Arbeit..…………………………..……………………..22 4. Literaturverzeichnis…………...……………….…………………………………25 5. Anlagen……………………………………………….…………………………...29 5.1 Erklärung über den wissenschaftlichen Beitrag des Promovenden zur Publikation………………………………………..……………………………….29 5.2 Erklärung über die eigenständige Abfassung der Arbeit…….……………….30 5.3 Lebenslauf…………………………….......………………………………...……31 5.4 Danksagung………………………………………......………………………….32

Nuclear factor kappa B (NFκB) is an inflammatory transcription factor that plays an important role in the host immune response to infection. The potential for chlamydiae to activate NFκB has been an area of interest, however most work has focused on chlamydiae impacting human health. Given that inflammation characteristic of chlamydial infection may be associated with severe disease outcomes or contribute to poor overall fitness in farmed animals, we evaluated the ability of porcine chlamydiae to induce NFκB activation in vitro. C. pecorum infection induced both NFκB nuclear translocation and activation at 2 hours post infection (hpi), an effect strongly enhanced by suppression of host de novo protein synthesis. C. suis and C. trachomatis showed less capacity for NFκB activation compared to C. pecorum, suggesting a species-specific variation in NFκB activation. At 24 hpi, C. pecorum induced significant NFκB activation, an effect not abolished by penicillin (beta lactam)-induced chlamydial stress. C. pecorum-dependent secretion of interleukin 6 was also detected in the culture supernatant of infected cells at 24 hpi, and this effect, too, was unchanged by penicillin-induced chlamydial stress. Taken together, these results suggest that NFκB participates in the early inflammatory response to C. pecorum and that stressed chlamydiae can promote inflammation.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and chronic hepatitis B virus (HBV) infection is the major risk factor of HCC. The virus encodes HBV X (HBx) protein that plays a critical role in the development of HCC. Studies have revealed numerous HBx-altered genes and signalling pathways that heavily contribute to tumourigenesis of non-tumour hepatocytes. However, the role of HBx in regulating other critical gene regulators such as microRNAs is poorly understood, which impedes the exploration of a complete HBx-associated carcinogenic network. Besides, critical microRNAs that drive the transformation of non-tumour hepatocytes are yet to be identified. Here, we overexpressed C-terminal truncated HBx protein in a non-tumour hepatocyte cell line MIHA, and measured a panel of cancer-associated miRNAs. We observed that oncogenic miR-21 was upregulated upon ectopic expression of this viral protein variant. HBx-miR-21 pathway was prevalent in HCC cells as inhibition of HBx in Hep3B and PLC/PRF/5 cells significantly suppressed miR-21 expression. Subsequently, we showed that the upregulation of miR-21 was mediated by HBx-induced interleukin-6 pathway followed by activation of STAT3 transcriptional factor. The high dependency of miR-21 expression to HBx protein suggested a unique viral oncogenic pathway that could aberrantly affect a network of gene expression. Importantly, miR-21 was essential in the HBx-induced transformation of non-tumour hepatocytes. Inhibition of miR-21 effectively attenuated anchorage-independent colony formation and subcutaneous tumour growth of MIHA cells. Our study suggested that overexpression of miR-21 was critical to promote early carcinogenesis of hepatocytes upon HBV infection.

Background: Inflammation is proposed to play a role in the development of Alzheimer's disease, and may also be involved in the pathogenesis of mild cognitive impairment (MCI). This study examined the association of inflammatory markers in serum or plasma with prevalent MCI and MCI subtypes in a population-based sample. Methods: Olmsted County, MN, residents aged 70-89 years on October 1, 2004, were evaluated using the Clinical Dementia Rating Scale, a neurological evaluation, and neuropsychological testing. Information ascertained for each participant was reviewed by an expert panel of neuropsychologists, physicians, and nurses, and a diagnosis of normal cognition, MCI, or dementia was made by consensus. C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis alpha (TNFα), and adiponectin were measured at baseline. Results: Among 313 subjects with MCI and 1570 cognitively normal subjects, a CRP level in the upper quartile (>3.3 mg/L) was significantly associated with MCI (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.00-2.01) and with nonamnestic MCI (OR, 2.05; 95% CI, 1.12-3.78) after adjusting for age, sex, and years of education. However, there was no association with amnestic MCI (OR, 1.21; 95% CI, 0.81-1.82). No association was observed with the other inflammatory markers. Conclusions: Plasma CRP is associated with prevalent MCI and with nonamnestic MCI in elderly, nondemented persons in a population-based setting. These findings suggest the involvement of inflammation in the pathogenesis of MCI.

Exposure to traumatic events can lead to many varied psychological and physiological difficulties, including an increased risk for chronic physical health problems and chronic pain disorders, which are thought to be mediated through the three major biological systems involved in the human stress response. The objective of the present study was to examine the relationships between psychological symptoms and proinflammatory immune markers, Interleukin-1β (IL-1β) and Interleukin-6 (IL-6), which are thought to be related to many of the physical health problems associated with posttraumatic psychopathology. Female participants (N=12) were recruited from a trauma specialty clinic and participated in approximately one research session per month for up to one year of psychotherapy. Five participants had at least three data points and were further examined for longitudinal correlations. Baseline measurements of urinary IL-1β were associated with self-report measures of trait anxiety and dissociative symptoms. One participant, who completed nine research sessions over nearly 12 months, showed improvements in depressive symptoms, state and trait anxiety, and dissociative symptoms that seemed to correspond with decreases in IL-6. IL-1β did not seem to be related to any of her symptom measures. A second participant, with five data points over almost four months, showed less marked change in symptomatology, but her IL-6 levels seemed to correspond with depressive and dissociative symptoms, and her IL-1β levels seemed to be associated with trends in state anxiety and dissociative symptoms. Three other participants had between three and four data points, and the trends obtained were inadequate to determine whether any true relationship existed among the longitudinal variables. These results provide preliminary evidence that it may be possible to reduce chronic pro-inflammatory dysregulation through psychotherapy-facilitated symptom reduction.

Graft Versus Host Disease (GVHD) is a major inflammatory complication of hematopoietic stem cell transplantation (HSCT). Such transplantations are lifesaving in treating certain conditions, such as acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, aplastic anemia, and thalassemia. However, the subsequent presentation of GVHD can pose a lethal threat, placing the patient’s life at risk, once again. The inflammatory response of the graft’s adaptive immunity towards the host’s native cells in GVHD is said to trigger a cytokine storm. Despite its widespread use both colloquially and in the medical field, criteria for “cytokine storms” do not exist. For this reason, a meta-analysis is being conducted that examines various cytokine levels of several different disease conditions, including acute respiratory distress syndrome, chimeric antigen receptor T cells, Crohn’s disease, SARS CoV-2, rheumatoid arthritis, sepsis, and graft versus host disease. The purpose of this study is to analyze a subset of data within this larger meta-analysis, specifically interleukin-6 (IL-6) levels in GVHD. Herein, I discuss the role of IL-6 in the pathogenesis of GVHD, examine the levels of IL-6 in varying stages of GVHD, and propose future directions for using IL-6 inhibition as a treatment for GVHD.

No description available.

Cortisol, a hormone produced by a hormone produced by the adrenal gland, is responsible for many regulatory functions in the body. Cortisol release is mediated by adrenocorticotrophic hormone, or ACTH, through the hypothalamus-pituitary-adrenal or HPA axis. This HPA axis is the major release pathway used during acute stress, during which the levels of ACTH parallel those of cortisol. However, in states of chronic stress, the level of ACTH drops dramatically, while cortisol remains high. This study focuses on the pathway of cortisol release during these chronic stress states, specifically examining the role of IL-6 with respect to STATs and the Jak/STAT pathway. It has been shown that IL-6 increases cortisol levels, and that IL-6 utilizes the Jak/STAT pathway. Also, the steroidogenic acute regulatory (StAR) promoter contains multiple STAT binding sites. Thus, STATs could be mediating the effects of IL-6 in the chronic release of cortisol by inducing expression of StAR. Experiments were performed to identify whether IL-6 has a direct effect on StAR promoter activity, StAR mRNA and StAR protein levels. Electromobility Shift Assays (EMSA) were performed to show that STATs bind to the full STAT site within the StAR promoter region. Various experiments were also carried out in the presence of IL-6 alone or, congruently with either a Jak (AG490) or STAT3 (Piceatannol) inhibitor, to show the effects of STATs and the Jak/STAT pathway on StAR. Luciferase assays were performed in order to observe the effects on induction of the StAR promoter. RT-PCR and western blots were also performed to observe the effect of Jak/STAT inhibition on both StAR mRNA levels and StAR protein levels. These experiments showed a marked decrease in the IL-6-stimulated StAR promoter activity, mRNA and protein expression when treated with wither Jak or STAT inhibitor. Therefore, IL-6 regulates expression of StAR through utilization of the Jak/STAT pathway; which phosphorylates and subsequently dimerizes STAT, allowing STAT to translocate to the nucleus and bind to the StAR promoter, thus increasing StAR expression and thereby inducing synthesis of cortisol.

Aim: Fatigue during team sports requiring multiple sprints can result from the combined effects of metabolic, mechanical, neurological, and immune factors. The purpose of this study was to investigate the influence of capsaicin on performance of and the physiological response to an exercise test simulating the fitness demands of team sport game conditions. Methods: This study was a placebo-controlled, crossover design. Nineteen healthy male experienced athletes age 18-30 yr consumed either 3 g/d cayenne (25.8 mg/d capsaicin) or placebo for 1 wk. Directly following the supplementation period, they completed a repeated sprint test consisting of 15 30 m maximal effort sprints on 35 s intervals. Sprint times were recorded via electronic dual-beam timing system. Fasted blood draws for interleukin-6 (IL-6) were taken at baseline prior to supplementation, 45-min pretest, and immediately post test. Heart rate (HR), blood pressure (BP), rate of perceived exertion (RPE), muscle soreness (MS), and gastrointestinal distress (GD) were measured 1-min pretest, during, posttest, and 1-min posttest. MS was also measured for 3 d posttest. Results: Relative to the placebo, capsaicin significantly reduced maximum HR by 9.3%, total average HR by 8.5%, and sprinting average HR by 6.0% (P<0.05). Capsaicin caused GD of at least 2/5 in 24.5% of subjects. There was no difference between treatments in fastest or mean sprint time, fatigue, percent change or difference in IL-6, BP, RPE, sprint or posttest MS. Conclusion: Capsaicin did not influence repeated sprint performance or the inflammatory response, but reduced HR during intense activity and causes substantial GD. / Master of Science

This thesis explores the pathogenesis of calciphylaxis, a rare and potentially fatal complication of chronic kidney disease (CKD) characterized by calcification and thrombosis of small- to medium-sized arteries. A range of bench techniques, including cell culture, genetic analysis, and immunofluorescence, were utilized in combination with human samples from patients with calciphylaxis and healthy controls. The results revealed a pathway that may modulate the thrombotic phenotype in these patients and, in turn, may serve as a targetable therapeutic axis. This work provides a foundation for further research and clinical advances in the field of calciphylaxis. Moreover, this study has the potential to inform the development of therapeutic interventions that could greatly improve the outcomes of CKD patients suffering from calciphylaxis. / 2026-03-05T00:00:00Z