Graduation date: 1997

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

published_or_final_version / abstract / Pharmacology / Master / Master of Philosophy

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

The major objective of this project was to examine the potential for mediators of IgE-mediated allergic reactions to alter neural activity. The project was divided into three parts. In Part I, the ability of endogenously released chemical mediators to alter neural activity in vitro was assessed by measuring isometric contractile responses to electrical field stimulation (EFS) (2-128 Hz, 20 V, 0.5 msec. duration) of sensitized rabbit bronchi before and after exposure to the antigen horseradish peroxidase (HRP). Antigen enhanced bronchial responses to EFS with low frequencies: mean log (± S.E.) frequency which produced 20% of maximum response decreased from 1.04 (± 0.05) to 0.90 (± 0.07) Hz (p < 0.05). Responses of unsensitized bronchi were not enhanced by antigen. Chlorpheniramine, an H₁ antagonist, abolished the antigen effect. Antigen did not enhance the responses to exogenous acetylcholine. Hence, the antigen is apparently modulating neural activity and not smooth muscle per se. In Part II, the capacity for histamine to modulate vagally-induced bronchoconstriction in anesthetized, vagotomized, mechanically-ventilated rabbits was examined in vivo. Changes in pulmonary resistance induced by electrically stimulating the cut ends of the vagi (2-32 Hz, 20 V, 0.5 msec. duration) were assessed before and 10 minutes after histamine aerosolization (10 breaths of 10 mg/ml). Histamine inhalation potentiated vagally-induced bronchoconstriction at low frequencies: mean log (± S.E.) frequency producing a 20% change in pulmonary resistance decreased from 0.88 (± 0.09) to 0.56 (± 0.15) (p < 0.05). Chlorpheniramine abolished this effect. In Part III, the dependence on IgE antibodies of the in vitro modulation of neurally-induced contraction of sensitized bronchi was investigated. Rabbits were passively immunized with fractions enriched with HRP-specific IgE, IgG, or IgM antibodies. After 72 hours, rabbits were sacrificed and the responses of bronchi to EFS were assessed before and after antigen challenge. Antigen enhanced the responses to EFS only of bronchi passively sensitized with IgE. Therefore, antigen enhancement of neural activity was dependent on IgE. These studies demonstrate that the interaction between antigen and IgE antibodies can induce the release of chemical mediators which can alter neural activity.

Bibliography: leaves 234-314. Examines the role of vascular endothelial cells in inflammation with particular reference to their participation in the immune response directed against a vascularised allograft (kidney)

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Dentistry / 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.

Copies of author's previously published articles inserted. / Bibliography: leaves 190-225. / vi, 225 leaves, [66] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the time course and degree of neutrophil polarisation in plasma and compares this response with those induced by FMLP, purified plasma proteins (particularly immunoglobulin type G) and chemotactic imflammatory mediators. In addition, the possible roles of extracellular divalent cations (Ca2+ and Mg2+), intracellular Ca2+ ions and actin microfilament distribution during responses to each stimulus are examined. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1993