No description available.

No description available.

Heart failure is an illness that requires life-long treatment and often affects everyday aspects of a person’s life. Self-care is a significant part of the treatment. Good self-care resources make it possible for people with heart failure to make the lifestyle changes they often need to maintain or improve their level of health. Self-care means having knowledge of and being able to recognize the symptoms and signs of deterioration that can occur with heart failure, so that the person can take appropriate measures – and it also means knowing when it is time to seek professional help. The significance of self-care for heart failure has increased and will increase even more in the future, when monitoring one’s condition will be left more and more to the people themselves and those who take care of them. The object of the study was to learn what self-care measures people with heart failure say they apply in everyday life. The quantitative method of a questionnaire study (The European Heart Failure Self-Care Behaviour Scale) was used. Of the 94 people registered at a heart failure unit who were asked to complete the questionnaire, 58 of them consented. The results showed that more than 95% of the people with heart failure applied the recommended self-care measure of taking the medicines prescribed by their doctor. Many also applied the self-care measures of taking a rest during the day (83%) and taking it easy when they felt out of breath (78%). On the other hand, the self-care measures of daily weight control were applied only by 41%, daily exercise by only 48% and salt and fluid restrictions by only 59%. The self-care measures of contacting a doctor/nurse when noticing problems or symptoms of deterioration were applied by only 36% of those who felt out of breath and by only 43% of those who felt increased fatigue. The conclusion is that there is a need to improve the knowledge about and confidence in self-care treatment for people with heart failure. One way of achieving this is to show that people with heart failure check for symptoms and apply measures in their homes as part of the treatment and that this leads to an increased quality of life.

Computer simulations are widely used in the truck industry in order to provide assistance in the product development. Bolt joints are common in trucks. A bolt fracture usually has a great influence on how a truck structure will behave in a crash. Therefore, when simulating truck crashes it is important to be able to predict when bolt fracture occurs. A material model for 10.9 bolts has been calibrated and validated by using the finite element software LS-DYNA. The material model consists of a failure strain surface, which depends on the triaxiality, Lode parameter and the element size. In this thesis, the calibrated material model is referred to as the bolt model. A good agreement to predict the force at fracture in bolts between simulation model results and physical test results has been obtained. Still, further validation is needed to evaluate the bolt model completely.

No description available.

Heart failure is a common and serious chronic condition, which can be as ‘malignant’ as most forms of cancer (Stewart, MacIntyre, Hole, Capewell, & McMurray, 2001). Recent estimates are that around 40,000 men and 45,000 women are living with heart failure in Scotland (Stewart, MacIntyre, Capewell, & McMurray, 2003). Heart failure is significantly influenced by socioeconomic factors, with people on lower incomes being more likely to develop, and die faster from, heart failure (McAlister et al, 2004). There is a growing body of research on the experience of living with heart failure, however, none provides serious consideration of the role of socioeconomic factors in impacting the experience of heart failure, and some qualitative research may actually obscure such factors. There were two main aims in this thesis. One was to explore how qualitative research methods can better consider the relationship between experience and broader context, such as the influence of socio-economic factors on health. The other aim was to examine the experiences of people as they live with and die from heart failure in ways that situate their accounts in the broader context of their lives. An initial research study, on which I was the main researcher, focused on the experiences of 30 people living with advanced heart failure. These people, their carers and key health professionals were interviewed, where possible, three times over a six months period. This thesis re-examines that study, focusing on 20 of those participants, for which a total of 122 interviews were conducted. I used a dialogical approach to see whether the socioeconomic context of heart failure for these respondents, could be captured through exploring experiences, performance, relationships, discourses and institutional practices, the social processes that mediate the relationship between socioeconomic disadvantage and chronic diseases were explored. This offers important learning in relation to the experience of living with heart failure, along with the experience of providing care. The findings highlight the need to broaden our view of chronic illness beyond biomedical approaches, and grow our methodological approaches along with that, in order to develop knowledge and practice that has relevance for people who live with and die from heart failure.

In this thesis I examined molecular mechanisms involved in acute and chronic liver injury, and also studied basic pathways mediating tumour promotion. Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen activated protein kinase family and is a key intracellular signaling molecule involved in the control of cell fate. Paracetamol induced hepatic JNK activation in both human and murine paracetamol hepatotoxicity, and in a murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity. In addition, delayed administration of JNK inhibitor was more effective than N-acetylcysteine following paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride or anti-Fas antibody mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic TNF-alpha production following paracetamol poisoning. These data demonstrate a central role for JNK in the pathogenesis of paracetamol induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity. Liver fibrosis with loss of tissue architecture and subsequent hepatic failure represents a massive healthcare burden worldwide. Expression of Galectin-3 (a beta-galactoside binding animal lectin) is upregulated in established human fibrotic liver disease, during the development of experimental liver fibrosis and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the gene encoding Galectin-3 blocks transdifferentiation of precursors to myofibroblasts in vitro and in vivo, markedly attenuating hepatic scarring in a murine model of liver fibrosis. Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduced myofibroblast activation and procollagen(I) expression. The reduction in hepatic fibrosis observed in the Galectin-3-/- mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with wild type hepatic stellate cells. However TGF-beta stimulated signaling via Smad-2 and 3 was equivalent in both Galectin-3-/- and wild type hepatic stellate cells indicating that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. This supports a novel and important mechanistic role for Galectin-3 in the regulation of myofibroblast activation and consequent liver fibrosis. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation following hepatic injury and may therefore provide a novel therapeutic approach to the prevention and treatment of liver fibrosis. CD98hc (a ligand for Galectin-3) constitutively and specifically associates with beta1 integrins and is highly expressed on the surface of human tumour cells irrespective of the tissue of origin. CD98hc promotes both anchorage- and serum-independent growth. Using chimeras of CD98hc and the type II membrane protein CD69 demonstrated that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumour promotion by integrins.

Methods: All patients (5606) with at least one serum creatinine ≥130μmol/L in females and ≥150μmol/L (Index creatinine) in males during a 6 month period in 2003 were grouped according to whether they had Acute Kidney Injury (AKI), Acute on chronic renal failure (ACRF) and chronic kidney disease (CKD). 1903 patients could  not be classified. After using all available creatinine data and identifying markers of kidney damage a further group of patients with CKD were identified. Case records were examined for the presence of co-morbidity, date of death, cause of death and whether they were known to a renal physician. Results: 1225 patients were identified as having CKD out of the 1903 “Unclassified” cohort (65%). The majority of CKD patients were elderly females with Stage 3 CKD. Hypertension and ischaemic heart disease were the two most common co-morbid conditions. Only 12% of CKD patients were referred to a nephrologists. 43% of CKD patients were dead at follow-up mostly from cardiovascular causes (31^st December 2005). The presence of proteinuria was independently associated with death. The age adjusted standardised prevalence of CKD, excluding those on RRT, was 20929 per million adult population. 3.6% went on to start RRT by the end of follow-up. Conclusions: CKD is predominantly a condition of elderly females, associated with considerable morbidity and mortality. However the majority of patients die from cardiovascular disease before progressing to ESRD. Therefore these patients may be appropriately managed in primary care without the need for specialist renal input allowing targeting of the specialist renal resources to the fewer patients who require them.

Le remodelage ventriculaire gauche (RVG) est un processus complexe qui intervient après un infarctus du myocarde chez 30% des patients en dépit des meilleurs traitements connus actuellement. Le but de mon travail de thèse consistait à identifier les déterminants moléculaires du RVG dans le but de mieux en comprendre les mécanismes physiopathologiques. Pour cela, nous avons étudié les modifications post-traductionnelles des protéines contractiles du VG et en particulier, la phosphorylation et la O-N-acétylglucosaminylation (O-GlcNAc). Nous nous sommes ensuite particulièrement intéressés à la troponine T (TnT) pour laquelle nous avons ainsi pu mettre en évidence une diminution de la phosphorylation au niveau de la sérine 208 au niveau du VG et du plasma chez le rat, suggérant que cela pourrait être un marqueur du RVG post-infarctus. Pour cette étude, nous avons travaillé en collaboration avec l’unité INSERM U644 de Rouen sur un modèle expérimental d’insuffisance cardiaque. L’infarctus du myocarde est induit chez le rat par ligature de la branche descendante de l’artère coronaire gauche, les rats témoins subissant l’intervention mais sans ligature. Dans un premier temps, nous avons réalisé une étude globale du phosphoprotéome du VG en phase tardive du RVG (2 mois post-ligature). Pour cela, les protéines extraites du VG ont été séparées par électrophorèse bidimensionnelle puis colorées au Pro-Q®Diamond (spécifique des protéines phosphorylées) puis au Sypro®Ruby (spécifique des protéines totales). Par analyse bioinformatique, nous avons mis en évidences 69 spots polypeptidiques présentant des modulations de phosphorylation. Nous avons donc analysé ces spots par spectrométrie de masse et avons identifié 30 protéines correspondant à 53 spots polypeptidiques présentant des modulations de phosphorylation. Parmi ces protéines, nous avons choisi de nous concentrer et d’étudier 6 protéines contractiles : la TnT, l’alpha-tropomyosine 1 (α-Tm 1), la desmine, l’αB-crystalline et les chaînes légères de myosine 1 et 2 (MLC). Pour chacune de ces protéines, nous avons identifié le type d’acide aminé responsable de la phosphorylation et quantifié les modulations de phosphorylation dans le VG des rats insuffisants cardiaques (IC). De manière intéressante, nous avons observé que le VG des animaux IC présentait une diminution significative de la phosphorylation sur les résidus sérine pour l’α-Tm 1, la TnT et la MLC-2 et sur les résidus de tyrosine pour l’αB-crystalline ainsi qu’une augmentation significative de la phosphorylation sur les résidus tyrosine pour la MLC-1 et sur les résidus de sérines pour la desmine, confirmant ainsi les résultats obtenus en électrophorèse bidimensionnelle. Afin de compléter l’analyse des modifications post-traductionnelles, nous avons étudié les modifications de O-GlcNAc pour chacune de ces protéines. Nous avons ainsi observé une diminution significative de la O-GlcNAcylation de l’α-Tm 1, de la desmine et l’αB crystalline ainsi qu’une augmentation de la O-GlcNAcylation de la MLC-3 et de la TnT. Par ailleurs, nous avons pu corréler ces modulations de phosphorylation et de O-GlcNAcylation avec des modulations de l’activité des enzymes impliquées dans ces modulations. En effet, par analyse bioinformatique de la séquence de la TnT et par recherche bibliographique nous avons mis en évidence que la protéine kinase C et la protéine phosphatase 2A pourrait être impliquées dans ces modulations de phosphorylation. Nous avons alors mis en évidence une diminution de l’activité de la protéine kinase C epsilon dans le VG des rats IC mais sans variation de l’activité de la protéine phosphatase 2A. Par ailleurs, nous avons mis en évidence une augmentation de l’activité de la O-GlcNAc transférase et une diminution de l’activité de la O-GlcNAcase dans le VG des rats IC. [...] / Despite significant improvements in management of myocardial infarction (MI), left ventricular remodelling (LVR) remains a major complication and a strong predictor of both heart failure (HF) and death after MI. Although several variables, such as MI size, have been identified as risk factors, LVR remains difficult to predict in clinical practice. Better prediction could allow an individualized approach with more intense therapy and follow-up for such high-risk patients. The aim of my work is to identify molecular determinants of LVR to have a better understanding of physiopathological mechanisms of LVR. For that purpose, we studied post-translational modifications of contractile proteins in particular, phosphorylation and O-N-acetylglucosaminylation (O-GlcNAc). Then, we studied particularly troponin T (TnT) for which we could highlight a decrease of phosphorylation of serine 208 in LV and plasma of MI-rats. These results suggest that the level of circulating phosphorylated troponin T could be new biomarker of LVR and may help to predict the development of heart failure after MI. For this study, we worked in collaboration with INSERM unit U644 at Rouen using an experimental model of HF. MI was induced in rat by left coronary ligation and, the control rats undergoing the surgery without ligation. Initially, we performed differential phosphoproteomic study of LV in the late phase of the LVR (2 months post-MI). For this purpose, LV proteins were extracted and separated by two-dimensional electrophoresis. Gels were first stained by Pro-Q®Diamond (specific of phosphorylated proteins) and then by Sypro®Ruby (specific of total proteins). By bioinformatic analysis, we showed that 69 polypeptidic spots were modulated for their phosphorylation levels. We analyzed these spots by mass spectrometry and identified 30 proteins corresponding to 53 spots with modulationof phosphorylation. Among these proteins, we have chosen to study 6 contractile proteins: TnT, alpha-tropomyosin 1 (Tm-α1), desmin, αB-crystallin and myosin light chains 1 and 2 (MLC). For each described proteins, we have validated the modulation of phosphorylation and determined the aminoacid involved in the phosphorylation modulation using immunoprecipitation techniques with specific antibodies against the proteins and phospho-Tyrosine, -Threonine and –Serine antibodies confirming the screening performed by 2D-electrophoresis for the detection of phosphoproteins. We observed a significant decrease of phosphorylation on serine for Tm-α1, TnT and MLC-2 and on tyrosine residues for αB-crystallin as well as a significant increase in phosphorylation on tyrosine for MLC-1 and on serine residues for desmin, thus confirming the results obtained in two-dimensional electrophoresis. In order to complete analysis of the post-translational modifications, we studied the modifications of O-GlcNAc for each one of these proteins. We thus observed a significant decrease in O-GlcNAcylation of Tm-α1, αB-crystallin and desmin as well as an increase in O-GlcNAcylation of the MLC-3 and TnT. In addition, we have correlated these modulations of phosphorylation and O-GlcNAcylation levels with modulations of the activity of enzymes implied in these modulations. Indeed, by bioinformatic analysis of the TnT sequence and literature review, we highlighted that the protein kinase C and the protein phosphatase 2A could be implied in these modulations. We observed a decrease of protein kinase C epsilon isoform expression in the LV of MI- rats without modulation of protein phosphatase 2A activity. In addition, we showed an increase in the activity of O-GlcNAc transferase and a decreaseof O-GlcNAcase activity in LV of MI rats. [...]

Heart failure (HF) is a complex, debilitating disease that affects approximately 6.5 million Americans (Ades et al., 2013). HF is a large reason for hospital readmissions, and subsequently, a major contributor to rising health care costs. Unfortunately, there is no cure for HF, but various interventions such as cardiac rehabilitation (CR) have been employed to help patients manage the symptoms. However, the lack of patients ever being referred to cardiac rehabilitation is disturbing. Healthcare providers play an essential role in providing education about heart failure and CR, and thus should be knowledgeable about these principles themselves. Therefore, the aim of this project is to evaluate data from a survey sent to nurse practitioners (NPs) regarding whether HF patients are being referred to CR appropriately, and if barriers are limiting use of CR programs. This was a descriptive, nonexperimental study with a survey design seeking to understand if NP providers are following evidence-based guidelines when treating HF patients and if providers consider CR programs to be an appropriate treatment tool. A survey questionnaire was distributed to NPs who are members of Coalition of Arizona Nurses in Advanced Practice (CAZNAP). Data from 27 surveys were used for analysis. Results showed that nurse practitioner respondents felt they had a good understanding of heart failure education and diagnosis. A majority also considered CR to be a useful tool for HF patients, and all agreed that health care providers affect CR enrollment and participation rates. A mere nine respondents (33%) reported being introduced to the outcomes and benefits of CR in their graduate education. Findings also confirmed previous work suggesting that providers are not adequately referring HF patients to CR, as 33% of NPs reported they have never referred a patient to CR. With respect to these findings, it is important to identify methods to assist providers with proper education about CR and its referral methods. As supported by the literature review, improved referral rates to CR can lead to better management and health outcomes for HF patients. Therefore, further research is needed to identify interventions that promote increased CR referral rates.