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

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.

Yes / Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor–binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance. / Funded by a British Heart Foundation Clinical Research Training Fellowship for A.A. R.M.C. holds a British Heart Foundation Intermediate Clinical Research Fellowship. M.T.K. holds a British Heart Foundation Chair in Cardiology. S.B.W. holds a European Research Council Starting Grant.

"December 2004" / Includes bibliographical references (leaves 342-379) / xiii, 379 leaves : ill. (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2005

Bibliography: leaves 175-203. / xxix, 203 leaves, [14] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates whether cytokines influence the development of the embryo prior to implantation. / Thesis (Ph.D.)--University of Adelaide, Depts. of Obstetrics and Gynaecology and Microbiology and Immunology, 1993