published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / Microbiology / Master / Master of Philosophy

published_or_final_version / abstract / toc / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

The Best PhD Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize / published_or_final_version / abstract / toc / Microbiology / Doctoral / Doctor of Philosophy

In recent years, increased focus has been placed on the role of intrauterine infection and inflammation in the pathogenesis of fetal brain injury leading to neurodevelopmental disorders such as cerebral palsy. At present, the mechanisms by which inflammatory processes during pregnancy cause this effect on the fetus are poorly understood. Our previous work has indicated an association between experimentally-induced intrauterine infection, increased proinflammatory cytokines, and increased white matter injury in the guinea pig fetus. In order to further elucidate the pathways by which inflammation in the maternal system or the fetal membranes leads to fetal impairment, a number of studies investigating aspects of the disease process have been performed. These studies represent a body of work encompassing novel research and results in a number of human and animal studies. Using a guinea pig model of inflammation, increased amniotic fluid proinflammatory cytokines and fetal brain injury were found after a maternal inflammatory response was initiated using endotoxin. In order to more closely monitor the fetal response to chorioamnionitis, a model using the chronically catheterized fetal ovine was carried out. This study demonstrated the adverse effects on fetal white matter after intrauterine exposure to bacterial inoculation, though the physiological parameters of the fetus were relatively stable throughout the experimental protocol, even when challenged with intermittent hypoxic episodes. The placenta is an important mediator between mother and fetus during gestation, though its role in the inflammatory process is largely undefined. Studies on the placental role in the inflammatory process were undertaken, and the limited ability of proinflammatory cytokines and endotoxin to cross the placenta are detailed herein. Neurodevelopmental disorders can be monitored in animal models in order to determine effective disease models for characterization of injury and use in therapeutic strategies. Our characterizations of postnatal behaviour in the guinea pig model using motility monitoring and spatial memory testing have shown small but significant differences in pups exposed to inflammatory processes in utero. The data presented herein contributes a breadth of knowledge to the ongoing elucidation of the pathways by which fetal brain injury occurs. Determining the pathway of damage will lead to discovery of diagnostic criteria, while determining the vulnerabilities of the developing fetus is essential in formulating therapeutic options. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2008-03-06 20:24:03.417

Background: Downhill running involves eccentric contractions of the gluteal, quadriceps, hamstring and calf muscles and the lengthening of muscle fibres as they contract. Several studies have demonstrated that this type of prolonged eccentrically biased exercise induces tissue damage and subsequent enhancement of an inflammatory response. Traumeel® S (Heel GmbH, Baden-Baden, Germany) is a homeopathic-complex used to treat trauma and inflammatory processes that is sold as an over the counter remedy in pharmacies. Although the antiinflammatory and analgesic effects of Traumeel® S have been demonstrated in selected clinical trials as well as in in vitro experimental models, little is known of its scientific mechanisms of action. Aim: The aim of this study was to establish whether administration of Traumeel® S five days before and three days after a 90-minute downhill treadmill run at 75% V02 peak significantly changes systemic markers of the inflammatory response. These are to include blood-borne concentrations of Cortisol and examples of selected T-helperrcell cytokines, T-helper2-cell cytokines, chemokines and pro-inflammatory cytokines during the three days following the 90-minute downhill run. Method: This study was designed as a double-blinded, placebo-controlled clinical trial in which matched subjects were randomised to Traumeel (TRAU) and Placebo (PLAC) pairs and exposed to two 90-minute downhill running trials. Twenty subjects (12 men, 8 women) aged between 20 and 50 years, fully complied with all inclusion criteria set for the study. Following baseline laboratory and field testing, they were matched according to gender, body mass index (BMI), training age, training status, peak running performance and foot-strike patterns and randomized into TRAU and PLAC groups. One Traumeel® S tablet was ingested three times per day for five days prior to and three days following a 90-minute downhill run on a treadmill at a -6% gradient and at a speed eliciting 75% V02 peak on a level gradient. Blood samples were obtained immediately before the 90-minute trial (PRE), immediately after the trial (IPE) and 24 hours (24 PE), 48 hours (48 PE) and 72 hours (72 PE) following the trial. Each subject was also requested to complete a training record prior to the trial and keep a record of the daily symptoms of delayed onset muscle soreness (DOMS) both at rest (general pain) and while walking (daily living). Full blood counts, serum creatine kinase (CK) and Cortisol concentrations were determined using standard haematological laboratory procedures. A sandwich ELISA was used to determine plasma interleukin-6 (IL-6) concentrations. A commercial bead-array kit was used to conduct flow cytometric analysis of Interleukin-8 (IL-8), Interleukin-10 (IL-10), Tumour Necrosis Factor alpha (TNFa), and Interleukin-12p70 (IL-12p70) concentrations. Results: Paired student Mests indicate that the mean ± SEM of the two groups was not significantly different (p < 0.05) in terms of age, BMI, percentage body fat, training age, foot strike patterns, running performance, FVC, FEV1; baseline heart rate and blood pressure, RERmax, V02 peak, VEmax, or training status. Although the TRAU group completed the 90-minute downhill running trial at a significantly faster speed (13.3 ± 2.1 vs. 12.8 ±0.3 km.hr; p = 0.02) and covered a greater distance (20.1 ± 0.3 vs. 19.34 ± 0.4; p = 0.03), mean and maximum heart rate and RPE did not differ between trials in the TRAU and PLAC groups. The downhill running protocol resulted in significant increases in neutrophil counts and creatine kinase, Cortisol, IL-6, IL-8 and IL-10 concentrations in the circulation (n = 20; p < 0.001). When comparing the TRAU (n = 10) and PLAC (n = 10) groups, blood neutrophil counts, creatine kinase, Cortisol, and IL-6 concentrations over the 5 time points and PRE, IPE and 24 PE plasma TNF, IL-8, EL-10 and EL-12p70 concentrations did not differ significantly (p > 0.05). Blood creatine kinase was, however, significantly higher in the TRAU group at 24PE (p < 0.05). The post-trial DOMS scores reported by the TRAU group over the 3-day post-exercise recovery period were also significantly lower in the TRAU group at 24PE (p = 0.03). Conclusion: Despite a faster running speed and higher post trial CK concentration in the TRAU group following the 90-minute downhill run, statistically significant differences in circulating stress hormone, and cytokine concentrations (IL-6, IL-8, IL-10, TNFa and IL-12p70) between the TRAU and PLAC groups, were not identified. Delayed onset muscle soreness was also significantly lower in the TRAU group at 24 hours post trial (p = 0.03). While these findings would support attenuation of the post-exercise inflammatory response by Traumeel® S, further work is required to verify this possibility. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, 2008.

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<p>A growing number of studies have investigated the role of exercise both during and after a breast cancer diagnosis. Observational data suggests that regular endurance exercise is associated with a 20-50% reduction in cancer-specific mortality in women diagnosed with early stage breast cancer, compared to inactive women; however it is unclear whether there is a differential association across breast cancer subtypes. As a pre-requisite to guide future large phase II/III clinical trials, there is a critical need to confirm the biological plausibility of the exercise association in breast cancer patients as well as elucidate the underlying mechanisms of action via utilization of preclinical models. </p><p>In the present study we investigated the systemic effects of prescribed aerobic training in cancer patients and the direct impact on breast cancer cell subtype phenotypes. In order to test the in vivo significance, we interrogated aerobic training effects on breast cancer progression and tumor biology using syngeneic breast cancer mouse models. </p><p>Our results suggest that aerobic training may alter the host availability of pro-inflammatory and growth factor cytokines in patients with solid tumors. Modulation of systemic effectors in breast cancer patients compared to controls causes a differential phenotypic response on breast cancer cell subtypes. In vivo, aerobic training has a differential response on breast tumor progression compared to controls that is mediated by Hif1-&#945; and metabolic reprogramming of breast cancer cells.</p> / Dissertation

Es konnte bisher vielfach gezeigt werden, dass Zytokine im Zusammenhang mit depressiven Störungen stehen. Darauf aufbauend untersuchten wir die Expression mehrerer Zytokine bei depressiv Erkrankten. Wir verglichen die Serumkonzentrationen der Interleukine (IL) IL-2, IL-4, IL-5, IL-10, IL-12 und IL-13, des Granulozyten-Makrophagen-Koloniestimulierenden Faktors (GM-CSF), des Interferons-gamma (IFN-) und des Tumornekrosefaktors-alpha (TNF-) bei 64 Probanden mit einer akuten depressiven Symptomatik und bei 206 nicht-depressiven Probanden. Depressive Patienten wiesen im Vergleich zu den nicht-depressiven Probanden erhöhte Konzentrationen von IL-2, IL-5, IL¬¬-12, IL-13, GM-CSF, IFN- und TNF- auf. Bei Aufteilung der Gruppen in nicht-adipöse (BMI < 30) und adipöse (BMI ≥ 30) Probanden zeigten nicht-adipöse Depressive (n = 40) erhöhte Konzentrationen von IL-5, IL-12, IL-13, GM-CSF, IFN- und TNF- im Vergleich zu den nicht-adipösen Probanden ohne eine Depression (n=85). Adipöse Depressive (n = 24) zeigten erhöhte Konzentrationen von IL-5, IL-12 und IFN- verglichen mit adipösen Probanden ohne eine Depression (n = 121). Verschiedene Zytokinkonzentrationen waren in Abhängigkeit von körperlicher Aktivität, Berufstätigkeit und Schlafverhalten verändert, was eine Assoziation der Zytokinproduktion mit Verhaltensaspekten nahelegt. Die Ergebnisse unterstützen die Annahme einer Überexpression pro-inflammatorischer Zytokine bei der Depression und erweitern das Spektrum der Zytokine, die möglicherweise mit Depressionen assoziiert sind, um GM-CSF, IL-5 und IL-13. Veränderungen dieser Zytokine könnten zur Erklärung beitragen, warum allergische und asthmatische Erkrankungen häufig mit einer Depression einhergehen.

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