Cardiovascular disease (CVD) is a complex combination of multiple conditions. The majority of deaths within CVD include heart attacks and strokes caused by atherosclerotic disease. The pathophysiological process for atherosclerotic disease occurs within the endothelial lining of the vessels of the body. This prolonged process occurs when cholesterol deposits form irregularity in luminal flow resulting in decreased blood flow and ischaemia. This unstable cholesterol plaque can rupture resulting in clot formation and artery occlusion. Within this thesis I aim to show background to the relevant pathophysiology of ischaemic heart disease (IHD) with the main emphasis on acute myocardial infarction (AMI), the history of its therapy to current therapy. I will discuss the theorised role of stem cell therapy within animal models and previous clinical trials within regenerative medicine and AMI. I will describe and discuss the method and the results of the REGENERATE-AMI trial (Clintrial.gov: NCT00765453), which will include the safety and efficiency of the therapy, and the possible cytokine mechanism by which this therapy may exert it effect. Additionally I will describe the potential for assessing myocardial oedema using 3-slice T2-STIR short axis stack imaging post AMI compared to the conventional 10-slice T2-STIR technique to assess its feasibility and clinical similarity to assess its use as a tool in translational research.

One of the most critical elements in empowering the patient, and ensuring concordance, is communication of the possible benefits and harms of different actions in health care. Risk assessment is a complex task due both to the different interpretations of the concept of risk, and the common lack of hard facts. Hormone, or hormone replacement, therapy (HT) is used by many women in, and after, the menopause. The benefits and possible harms associated with short and long term treatment with HT have been extensively discussed the last decade and the use of HT has decreased dramatically internationally the last few years. The aims of this thesis were to study the interaction between patient and physician when discussing risks and benefits of different treatment alternatives, and to suggest strategies to improve risk communication in clinical practice. The studies have focused on how risks and benefits with HT were communicated between women and physicians during firsttime consultations in 1999- 2000 on this subject (20 women, 5 gynaecologists), and through questionnaires how attitudes towards HT have changed between 1999 (n=1,760) and 2003 (n=1,733) among women entering the menopause (53-54 years). Through a qualitative analysis of the risk communication in the consultations a system was constructed to classify how risk is communicated in relation to benefits. This was used to assess and present differences in risk communication in the consultations. Different rhetorical strategies by the physicians were identified and the dominating tendency was a move from the woman’s current problems to the long-term effects of HT. The questionnaires showed a marked difference in attitudes towards HT between the years. In 2003 women perceived HT to be associated with higher risk and less benefits than in 1999. This correlated to a drastic reduction in the use of HT over the same period. Media was the most frequent source of information about HT during the last twelve months before the questionnaire in 2003. Possible explanations for the different attitudes towards HT between women entering the menopause and gynaecologist; how this difference might have influenced the results; and how they may have implications for future communication strategies are discussed. This thesis illustrates the importance of a deeper understanding in health care of the concept of risk in order to achieve an adequate communication of risk. This is important both in consultations and in campaigns to educate and inform the public. / Reprinted figure 1 on page 32 with permission from Science Ref # 05-17260-Revised. Copyright 2006 AAAS.

Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described. Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study. The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype. The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug. Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

<p>Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.</p>

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234

No description available.

No description available.

No description available.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234