published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Die vorliegende Querschnittstudie untersuchte Serumkonzentrationen pro- und antiinflammatorischer Zytokine und deren Modulation durch körperliche Aktivität bei Patienten mit Adipositas, definiert durch einen Body Mass Index (BMI)≥ 30 kg/m², im Vergleich zu nicht-adipösen Probanden (BMI< 30 kg/m²). Weiterhin war der spezifische Einfluss der zentralen (viszeralen) Adipositas auf diese Zytokine Gegenstand dieser Studie. Dazu wurden die Serumkonzentrationen von Interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, Granulozyten-Makrophagen-Kolonie stimulierendem Faktor (GM-CSF), Interferon (IFN)-γ und Tumornekrosefaktor (TNF)-α bei adipösen und zentral-adipösen Patienten sowie bei nicht-adipösen Probanden bestimmt und zwischen den einzelnen Gruppen verglichen. Weiterhin wurden Korrelationen der Zytokinserumkonzentrationen mit Adipositas-relevanten Körpermaßen berechnet. Durch objektive Aktivitätsaufzeichnung mittels Aktometrie wurde darüber hinaus der Einfluss physischer Betätigung auf die Zytokinspiegel untersucht. Es zeigten sich signifikant erhöhte pro- und antiinflammatorische Zytokinkonzentrationen bei adipösen und zentral-adipösen Patienten. Weiterhin war eine geringere körperliche Aktivität mit höheren Konzentrationen bestimmter Zytokine assoziiert. Die Konzentrationen mehrerer Zytokine korrelierten darüber hinaus mit bestimmten adipometrischen Daten. Diese Ergebnisse zeigen, dass die Adipositas mit inflammatorischen Prozessen assoziiert ist, die eine Veränderung der Produktion pro- und antiinflammatorischer Zytokine zur Folge haben, und sie weisen darauf hin, dass diese inflammatorischen Prozesse durch physische Aktivität abgemildert werden könnten. Einschränkend ist jedoch zu bedenken, dass eine Querschnittstudie nur Hinweise auf mögliche Kausalzusammenhänge, aber keine Belege hierfür bieten kann.

The Best M.Phil Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize, 2001-2003. / published_or_final_version / abstract / toc / Medicine / Master / Master of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / toc / Surgery / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy

Epithelial cells lining the upper airways are characterized by low sodium absorption and elevated chloride secretion. Together, the movement of these ions creates the osmotic drive to hydrate the airways. Recent studies indicate that influenza is capable of directly modulating the vectorial transport of sodium and chloride ions. However, the direct impact of influenza has not been studied with respect to potassium channels. This is significant because potassium conductance creates the driving force for chloride secretion. Disruptions to this process leads to edema formation in the lungs and can subsequently cause Acute Respiratory Distress Syndrome. Additionally, it has been demonstrated that the induction of pro-inflammatory cytokines in infected cells may contribute to altered ion channel function, further exacerbating edema formation. The purpose of this study was to assess the direct and indirect effects of influenza virus infection on potassium and chloride ion channel function in a secretory epithelial cell model. In order to assess the direct effects we exposed polarized epithelial cell monolayers to varying doses of H1N1 virus. Potassium and chloride channel function was measured by means of short-circuit current in an Ussing chamber. The immune response to viral infection was determined by RT-qPCR and Bioplex suspension array. Virus conditioned media (CM), and IL-8 were used to characterize the indirect effects on non-infected cells. We observed an increase in chloride secretion, consistent with edema formation, when 60% of the epithelium was infected, and after CM treatment. This observation correlated with increased potassium channel conductance through the calcium-activated (KCNN4) and cAMP-activated potassium channels (KCNQ1), which was ameliorated upon specific inhibition of these channels. The data suggest that the mixture of pro-inflammatory cytokines induced by viral infection directly up-regulate these potassium channels. However, treatment with IL-8 also appears to increase chloride secretion, although the underlying mechanism remains to be determined, as it is not mediated through KCNN4 and KCNQ1. We conclude that the strong induction of cytokines in infected cells act in a paracrine manner on non-infected cells to increase potassium channel conductance. This up-regulation of potassium channels subsequently drives an increase in chloride secretion, leading to fluid build-up in the lungs and edema formation.

This early phase study examined the effects of a series of ten standard-protocol acupuncture treatments over four weeks in 12 healthy, but symptomatic, menopausal women. Two biologic markers, heart rate variability to evaluate effects of acupuncture on the autonomic nervous system as it relates specifically to the heart, and interleukin 6, a proinflammatory cytokine, to capture physiologic impact of acupuncture on the immune-inflammatory response, were collected.Women who exhibited significant menopausal symptoms, as measured by a minimum score of 22 out of a possible 44 points on the Menopause Rating Scale (MRS), underwent 10 sessions of a standard acupuncture point protocol intervention over a four-week period. Symptoms were evaluated for 28 days using the MRS. After the intervention was complete, one final open-ended question was asked of each participant to explore subjective experiences not captured by the validated instrument. Physiologic measurements included a 30-minute continuous measure of electrocardiogram data before and during acupuncture, as well as pre and post acupuncture measures of serum interleukin 6 at the first and final acupuncture treatment. Heart rate variability was assessed using spectral analysis, and interleukin 6 changes were measured using ELISA. Analysis included linear regression, Wilcoxon Signed Ranks test and Spearman correlation coefficients.After the acupuncture intervention, menopausal symptoms improved significantly. Heart rate variability did not show consistent or predictable intra or inter-subject changes, however several components of HRV, interleukin 6 and symptoms were found to have significant correlations.A larger study was deemed feasible. Menopause symptoms improved. Heart rate variability showed no consistent changes or trends. Interleukin 6 decreased in seven subjects, between the first and tenth acupuncture treatment, but did not reach statistical significance.This small project suggests that heart rate variability, when measured at each acupuncture treatment, does not change in a consistent or predictable manner. Rather, acupuncture may provide a modulating influence that depends on the body's functional state at each treatment.

No description available.

Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from rupture of a blood vessel in the brain. Tissue inside the hematoma is irreversibly damaged soon after ICH onset and when this thesis research began, there was a dearth of information regarding pathological changes outside the hematoma. Inflammation is often proposed as a mechanism of injury, but very little information was available to show that inflammatory cells were in the right place at the right time to cause secondary brain injury. Using the collagenase-induced model of ICH, this work sought to better define spatial and temporal relationships between secondary brain injury and the inflammatory response after ICH. To test the hypothesis that reducing inflammation can protect the brain from secondary injury, minocycline, an antibiotic with established anti-inflammatory effects, was administered 6 hours after ICH onset. A small number of neurons die in the parenchyma bordering the hematoma between 6 hours and 3 days after ICH onset. This area was not associated with neutrophil infiltration, and most activated microglia/macrophages did not accumulate until after most neuron death had occurred. Despite a pronounced microglial response and prolonged increase in expression of many inflammatory genes, including complement receptor-3, interleukin-1 beta, interleukin-6, and interleukin-1 converting enzyme, no dying neurons were observed further outside the hematoma at any time. Interestingly, less early neuron death was observed in aged than in young animals, without a concomitant difference in the amount of tissue lost at 28 days. However, aged animals had less early microglial activation and a larger residual lesion, which might have resulted from impaired phagocytosis by activated microglia/macrophages. Minocycline was less effective in reducing microglial activation in aged animals, and did not reduce neuron death in either young or aged animals. Edema and BBB disruption was associated with degradation of the basal lamina protein, collagen type IV, and that damaged vessels are associated with tumor necrosis factor-alpha (TNFα)-positive neutrophils and active matrix metalloprotease-12 (MMP-12), all of which were reduced by delayed minocycline treatment. In contrast to ischemic stroke, there is a limited ‘penumbra’ outside the hematoma. Nevertheless, BBB damage in this region appears to be a potential target for protection. Furthermore, the prominent inflammatory response that continues for days after ICH does not appear to be associated with damage to other areas of the brain. Minocycline appears to protect the BBB by reducing neutrophil infiltration and the MMP-12 mediated basal lamina degradation. Future studies should investigate other targets for protection (i.e., white matter injury), and seek drugs that modulate the inflammatory response in aged animals and promote lesion resolution.