Vascular Function in Chronic Kidney Disease and in Renovascular Disease

Cardiovascular mortality is 15 to 30 times higher in patients with chronic kidney disease than in the age-adjusted general population. Even minor renal dysfunction predicts cardiovascular events and death in the general population. In patients with atherosclerotic renovascular disease the annual cardiovascular event and death rate is even higher. The abnormalities in coronary and peripheral artery function in the different stages of chronic kidney disease and in renovascular disease are still poorly understood, nor have the cardiac effects of renal artery revascularization been well characterized, although considered to be beneficial. This study was conducted to characterize myocardial perfusion and peripheral endothelial function in patients with chronic kidney disease and in patients with atherosclerotic renovascular disease. Myocardial perfusion was measured with positron emission tomography (PET) and peripheral endothelial function with brachial artery flow-mediated dilatation. It has been suggested that the poor renal outcomes after the renal artery revascularization could be due to damage in the stenotic kidney parenchyma; especially the reduction in the microvascular density, changes mainly evident at the cortical level which controls almost 80% of the total renal blood flow. This study was also performed to measure the effect of renal artery stenosis revascularization on renal perfusion in patients with renovascular disease. In order to do that a PET-based method for quantification of renal perfusion was developed. The coronary flow reserve of patients with chronic kidney disease was similar to the coronary flow reserve of healthy controls. In renovascular disease the coronary flow reserve was, however, markedly reduced. Flow-mediated dilatation of brachial artery was decreased in patients with chronic kidney disease compared to healthy controls, and even more so in patients with renovascular disease. After renal artery stenosis revascularization, coronary vascular function and renal perfusion did not improve in patients with atherosclerotic renovascular disease, but in patients with bilateral renal artery stenosis, flow-mediated dilatation improved. Chronic kidney disease does not significantly affect coronary vascular function. On the contrary, coronary vascular function was severely deteriorated in patients with atherosclerotic renovascular disease, possibly because of diffuse coronary artery disease and/or diffuse microvascular disease. The peripheral endothelial function was disturbed in patients with chronic kidney disease and even more so in patient with atherosclerotic renovascular disease. Renal artery stenosis dilatation does not seem to offer any benefits over medical treatment in patients with renovascular disease, since revascularization does not improve coronary vascular function or renal perfusion.

Quantification and Clinical Relevance of Cystatin C

An aging population and increasing rates of diabetes mellitus contribute to a high prevalence of kidney dysfunction – approximately 10 percent of adults in developed countries have chronic kidney disease (CKD). CKD is a progressive loss of kidney function and this remains permanent. Early recognition of this condition is important for prevention or impeding severe adverse cardiac and renal outcomes. Cystatin C is a low molecular weight cysteine protease inhibitor that has emerged as a biomarker of kidney function. The special potential of plasma cystatin C in this setting is related to its independency of muscle mass, which is a remarkable limitation of the traditional marker creatinine. Cystatin C is a sensitive marker in diagnosing mild and moderate CKD, especially in small children, in the elderly and in conditions where muscle mass is affected. Cystatin C is quantified with immunoassays, mainly based on particle-enhanced nephelometry (PENIA) or turbidimetry (PETIA). The aim of this study was to develop a rapid and reliable assay for quantification of human cystatin C in plasma or serum by utilizing time-resolved fluorescence-based immunoassay methods. This was accomplished by utilizing different antibodies, including polyclonal and 7 monoclonal antibodies against cystatin C. Different assay designs were tested and the best assay was further modified to a dry-reagent double monoclonal assay run on an automated immunonalyzer. This assay was evaluated for clinical performance in estimating reduced kidney function and in predicting risk of adverse outcomes in patients with non-ST elevation acute coronary syndrome. Of the tested assay designs, heterogeneous non-competitive assay had the best performace and was chosen to be developed further. As an automated double monoclonal assay, this assay enabled a reliable measurement of clinically relevant cystatin C concentrations. It also showed a stronger concordance with the reference clearance method than the conventional PETIA method in patients with reduced kidney function. Risk of all-cause mortality and combined events, defined by death and myocardial infarction, increased with higher cystatin C and cystatin C remained an independent predictor of death and combined events after adjustment to nonbiochemical baseline factors. In conclusion, the developed dry-reagent double monoclonal assay allows rapid and reliable quantitative measurement of cystatin C. As measured with the developed assay, cystatin C is a potential predictor of adverse outcomes in cardiac patients.

Cardiac Imaging in the Diagnosis of Coronary Artery Disease: The Value of Quantitative Imaging of Myocardial Perfusion and Deformation

Atherosclerosis is a chronic and progressive disease of the vasculature. Increasing coronary atherosclerosis can lead to obstructive coronary artery disease (CAD) or myocardial infarction. Computed tomography angiography (CTA) allows noninvasive assessment of coronary anatomy and quantitation of atherosclerotic burden. Myocardial blood flow (MBF) can be accurately measured in absolute terms (mL/g/min) by positron emission tomography (PET) with [15O] H O as a radiotracer. We studied the coronary microvascular dysfunction as a risk factor for future coronary calcification in healthy young men by measuring the coronary flow reserve (CFR) which is the ratio between resting and hyperemic MBF. Impaired vasodilator function was not linked with accelerated atherosclerosis 11 years later. Currently, there is a global interest in quantitative PET perfusion imaging. We established optimal thresholds of [15O] H O PET perfusion for diagnosis of CAD (hyperemic MBF of 2.3 mL/g/min and CFR of 2.5) in the first multicenter study of this type (Turku, Amsterdam and Uppsala). In myocardial bridging a segment of the coronary artery travels inside the myocardium and can be seen as intramural course (CTA) or systolic compression (invasive coronary angiography). Myocardial bridging is frequently linked with proximal atherosclerotic plaques. We used quantitative [15O] H O PET perfusion to evaluate the hemodynamic effects of myocardial bridging. Myocardial bridging was not associated with decreased absolute MBF or increased atherosclerotic burden. Speckle tracking allows quantitative echocardiographic imaging of myocardial deformation. Speckle tracking during dobutamine stress echocardiography was feasible and comparable to subjective wall motion analysis in the diagnosis of CAD. In addition, it correctly risk stratified patients with multivessel disease and extensive ischemia.

Determination of the critical activities of a public-private intermediary organization with the help of value chain analysis

Tämän diplomityön tavoitteena oli selvittää arvoketjuanalyysin avulla toiminnot, joilla voittoatavoittelemattoman, julkisen osakeyhtiön toimintaa voitaisiin kuvata. Tarkoituksena oli selvittää mainitut toiminnot yleisesti ja luoda malli kohdeyrityksen arvoketjusta ja sen toiminnoista. Tutkielma jakautuu teoreettiseen ja empiiriseen osaan. Ensimmäinen pohjautuu aikaisempaan tutkimukseen ja kirjallisuuteen sidosryhmistä, arvon muodostumisesta ja arvoketjuanalyysistä. Jälkimmäinen on laadullista tapaustutkimusta. Empiriassa mallinnettiin Lappeenranta Innovation Oy:nsisäisiä toimintoja ja sidosryhmien odotuksia. Empiirinen tutkimus perustui kohdeyrityksen omistajille ja henkilöstölle tehtyihin haastatteluihin sekä yrityksen toiminnan päivittäiseen seurantaan. Johtopäätöksenätodettiin, että julkisen, voittoa tavoittelemattoman yrityksen toiminnot on mahdollista kuvata arvoketjuanalyysin avulla. Alan ja yrityksen asettamat erityispiirteet toivat haasteita määrittelylle, mutta silti arvoketju antoi selkeän tavan kohdeyrityksen toimintojen mallintamiselle.

Challenges and Means for the Front End Activities of Software Development

The front end of innovation is regarded as one of the most important steps in building new software products or services, and the most significant benefits in software development can be achieved through improvements in the front end activities. Problems in the front end phase have an impact on customer dissatisfaction with delivered software, and on the effectiveness of the entire software development process. When these processes are improved, the likelihood of delivering high quality software and business success increases. This thesis highlights the challenges and problems related to the early phases of software development, and provides new methods and tools for improving performance in the front end activities of software development. The theoretical framework of this study comprises two fields of research. The first section belongs to the field of innovation management, and especially to the management of the early phases of the innovation process, i.e. the front end of innovation. The second section of the framework is closely linked to the processes of software engineering, especially to the early phases of the software development process, i.e. the practice of requirements engineering. Thus, this study extends the theoretical knowledge and discloses the differences and similarities in these two fields of research. In addition, this study opens up a new strand for academic discussion by connecting these research directions. Several qualitative business research methodologies have been utilized in the individual publications to solve the research questions. The theoretical and managerial contribution of the study can be divided into three areas: 1) processes and concepts, 2) challenges and development needs, and 3) means and methods for the front end activities of software development. First, the study discloses the difference and similarities between the concepts of the front end of innovation and requirements engineering, and proposes a new framework for managing the front end of the software innovation process, bringing business and innovation perspectives into software development. Furthermore, the study discloses managerial perceptions of the similarities and differences in the concept of the front end of innovation between the software industry and the traditional industrial sector. Second, the study highlights the challenges and development needs in the front end phase of software development, especially challenges in communication, such as linguistic problems, ineffective communication channels, a communication gap between users/customers and software developers, and participation of multiple persons in software development. Third, the study proposes new group methods for improving the front end activities of software development, especially customer need assessment, and the elicitation of software requirements.

Social media and public libraries : exploring information activities of library professionals and users

Social media has become a part of many people’s everyday lives. In the library field the adoption of social media has been widespread and discussions of the development of “Library 2.0” began at an early stage. The aim with this thesis is to study the interface between public libraries, social media, and users, focusing on information activities. The main research question is: How is the interface between public libraries and social media perceived and acted upon by its main stakeholders (library professionals and users)? The background of Library 2.0 is strongly associated with the development of the Web and social media, as well as with the public libraries and their user-centered and information technological development. The theoretical framework builds on the research within the area of Library and Information Science concerning information behavior, information practice, and information activities. Earlier research on social media and public libraries is also highlighted in this thesis. The methods survey and content analysis were applied to map the interface between social media and public libraries. A questionnaire was handed out to the users and another questionnaire was sent out to the library professionals. The results were statistically analyzed. In the content analysis public library Facebook pages were studied. All the empirical investigations were conducted in the area of Finland Proper. An integrated analysis of the results deepens the understanding of the key elements of the social media and public library context. These elements are interactivity, information activities, perceptions, and stakeholders. In this context seven information activities were distinguished: reading, seeking, creating, communicating, informing, mediating, and contributing. This thesis contributes to develop the research concerning information activities and draws a realistic picture of the challenges and opportunities in the social media and public library context. It also contributes with knowledge on library professionals and library users, and the existing differences in their perceptions of the interface between libraries and social media.

The early activities of front end of innovation in oem companies using a new fei platform as a framework for renewal

The main goal of this study is to create a seamless chain of actions and more detailed structure to the front end of innovation to be able to increase the front end performance and finally to influence the renewal of companies. The main goal is achieved through by the new concept of an integrated model of early activities of FEI leading to a discovery of new elements of opportunities and the identification of new business and growth areas. The procedure offers one possible solution to a dynamic strategy formation process in innovation development cycle. In this study the front end of innovation is positioned between a strategy reviews and a concept creation with needed procedures, tools, and frameworks. The starting point of the study is that the origins of innovation are not well enough understood. The study focuses attention on the early activities of FEI. These first activities are conceptualized in order to find out successful innovation initiatives and strategic renewal agendas. A seamless chain of activities resulting in faster and more precise identification of opportunities and growth areas available on markets and inside companies is needed. Three case studies were conducted in order to study company views on available theory doctrine and to identify the first practical experiences and procedures in the beginning of the front end of innovation. Successful innovation requires focus on renewal in both internal and external directions and they should be carefully balanced for best results. Instead of inside-out mode of actions the studied companies have a strong outside-in thinking mode and they mainly co-develop their innovation initiatives in close proximity with customers i.e. successful companies are an integral part of customers business and success. Companies have tailor-made innovation processes combined their way of working linked to their business goals, and priorities of actual needs of transformation. The result of this study is a new modular FEI platform which can be configured by companies against their actual business needs and drivers. This platform includes new elements of FEI documenting an architecture presenting how the system components work together. The system is a conceptual approach from theories of emergent strategy formation, opportunity identification and creation, interpretation-analysis-experimentation triad and the present FEI theories. The platform includes new features compared to actual models of FEI. It allows managers to better understand the importance of FEI in the whole innovation development stage and FEI as a phase and procedure to discover and implement emergent strategy. An adaptable company rethinks and redirects strategy proactively from time to time. Different parts of the business model are changed to remove identified obstacles for growth and renewal which gives them avenues to find right reforms for renewal.

The effects of congestion in the daily management of a trauma hospital

Today’s healthcare organizations are under constant pressure for change, as hospitals should be able to offer their patients the best possible medical care with limited resources and, at the same time, to retain steady efficiency level in their operation. This is challenging, especially in trauma hospitals, in which the variation in the patient cases and volumes is relatively high. Furthermore, the trauma patient's care requires plenty of resources as most the patients have to be treated as single cases. Occasionally, the sudden increases in demand causes congestion in the operations of the hospital, which in Töölö hospital appears as an increase in the surgery waiting times within the yellow urgency class patients. An increase in the surgery waiting times may cause the diminution of the patient's condition, which also raises the surgery risks. The congestion itself causes overloading of the hospital capacity and staff. The aim of this master’s thesis is to introduce the factors contributing to the trauma process, and to examine the correlation between the different variables and the lengthened surgery waiting times. The results of this study are based on a three-year patient data and different quantitative analysis. Based on the analysis, a daily usable indicator was created in order to support the decision making in the operations management. By using the selected indicator, the effects of congestion can be acknowledged and the corrective action can also be taken more proactively.

Erectile dysfunction in cardiovascular risk population

The inability to achieve and to maintain erection, erectile dysfunction, is a bothersome symptom of elderly men. Moreover, there is a high comorbidity between cardiovascular diseases and erectile dysfunction. However, very little is known concerning the risk factors of ED in apparently healthy men without comorbidities affecting the arteries. A cross-sectional population survey was conducted from August 2005 to September 2007 in two rural towns of Harjavalta and Kokemäki in Finland. Excluding those with previously diagnosed cardiovascular diseases, diabetes or chronic kidney disease, every community-dwelling inhabitant was invited to take part in the survey. Of the 2939 45- to 70-year-old men invited, 2049 responded. Selecting those at risk for cardiovascular diseases, 1000 eligible men were examined. According to the International Index of Erectile Function short form 57% of the studied men reported erectile dysfunction. Increasing age, smoking, depressive symptoms, decreasing pulmonary function, sedentary lifestyle, non-marital status and low education level were associated with increasing risk of erectile dysfunction. However, hypertension, diabetes, obesity, hypercholesterolemia were not associated with erectile dysfunction, although these associations have been described in numerous previous studies. Moreover, erectile dysfunction was not associated with increasing risk of pre-diabetes. In apparently healthy men, increasing age, smoking, depressive symptoms, decreasing pulmonary function, sedentary lifestyle, non-marital status, low education level but not hypertension, obesity, hypercholesterolemia, diabetes or pre-diabetes were associated with increasing risk of erectile dysfunction.

Genetics of inherited small vessel diseases – in search of a novel small vessel disease and modifiers of the clinical course of CADASIL

The genetic and environmental risk factors of vascular cognitive impairment are still largely unknown. This thesis aimed to assess the genetic background of two clinically similar familial small vessel diseases (SVD), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and Swedish hMID (hereditary multi-infarct dementia of Swedish type). In the first study, selected genetic modifiers of CADASIL were studied in a homogenous Finnish CADASIL population of 134 patients, all carrying the p.Arg133Cys mutation in NOTCH3. Apolipoprotein E (APOE) genotypes, angiotensinogen (AGT) p.Met268Thr polymorphism and eight NOTCH3 polymorphisms were studied, but no associations between any particular genetic variant and first-ever stroke or migraine were seen. In the second study, smoking, statin medication and physical activity were suggested to be the most profound environmental differences among the monozygotic twins with CADASIL. Swedish hMID was for long misdiagnosed as CADASIL. In the third study, the CADASIL diagnosis in the Swedish hMID family was ruled out on the basis of genetic, radiological and pathological findings, and Swedish hMID was suggested to represent a novel SVD. In the fourth study, the gene defect of Swedish hMID was then sought using whole exome sequencing paired with a linkage analysis. The strongest candidate for the pathogenic mutation was a 3’UTR variant in the COL4A1 gene, but further studies are needed to confirm its functionality. This study provided new information about the genetic background of two inherited SVDs. Profound knowledge about the pathogenic mutations causing familial SVD is also important for correct diagnosis and treatment options.