Modulation of growth by aromatase inhibitor treatment in boys: Efficacy and safety

Without estrogen action, the fusion of the growth plates is postponed and statural growth continues for an exceptionally long time. Aromatase inhibitors, blockers of estrogen biosynthesis, have therefore emerged as a new potential option for the treatment of children with short stature. We investigated the efficacy of the aromatase inhibitor letrozole in the treatment of boys with idiopathic short stature (ISS) using a randomised, placebo-controlled, double-blind research setting. A total of 30 boys completed the two-year treatment. By decreasing estrogen-mediated central negative feedback, letrozole increased gonadotrophin and testosterone secretion in pubertal boys, whereas the pubertal increase in IGF-I was inhibited. Treatment with letrozole effectively delayed bone maturation and increased predicted adult height by 5.9 cm (P0.001), while placebo had no effect on either parameter. The effect of letrozole treatment on near-final height was studied in another population, in boys with constitutional delay of puberty, who received letrozole (n=9) or placebo (n=8) for one year, in combination with low-dose testosterone for six months during adolescence. The mean near-final height of boys randomised to receive testosterone and letrozole was significantly greater than that of boys who received testosterone and placebo (175.8 vs. 169.1 cm, P=0.04). As regards safety, treatment effects on bone health, lipid metabolism, insulin sensitivity, and body composition were monitored in boys with ISS. During treatment, no differences in bone mass accrual were evident between the treatment groups, as evaluated by dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck. Bone turnover and cortical bone growth, however, were affected by letrozole treatment. As indicated by differences in markers of bone resorption (U-INTP) and formation (S-PINP and S-ALP), the long-term rate of bone turnover was lower in letrozole-treated boys, despite their more rapid advancement in puberty. Letrozole stimulated cortical bone growth in those who progressed in puberty: the metacarpal index (MCI), a measure of cortical bone thickness, increased more in letrozole-treated pubertal boys than in placebo-treated pubertal boys (25% vs. 9%, P=0.007). The change in MCI correlated positively with the mean testosterone-to-estradiol ratio. In post-treatment radiographic evaluation of the spine, a high rate of vertebral deformities - mild anterior wedging and mild compression deformities - were found in both placebo and letrozole groups. In pubertal boys with ISS treated with letrozole, stimulated testosterone secretion was associated with a decrease in the percentage of fat mass and in HDL-cholesterol, while LDL-cholesterol and triglycerides remained unchanged. Insulin sensitivity, as evaluated by HOMA-IR, was not significantly affected by the treatment. In summary, treatment with the aromatase inhibitor letrozole effectively delayed bone maturation and increased predicted adult height in boys with ISS. Long-term follow-up data of boys with constitutional delay of puberty, treated with letrozole for one year during adolescence, suggest that the achieved gain in predicted adult height also results in increased adult height. However, until the safety of aromatase inhibitor treatment in children and adolescents is confirmed, such treatment should be considered experimental.

Growth and Modification of Cluster-Assembled Thin Films

Thin film applications have become increasingly important in our search for multifunctional and economically viable technological solutions of the future. Thin film coatings can be used for a multitude of purposes, ranging from a basic enhancement of aesthetic attributes to the addition of a complex surface functionality. Anything from electronic or optical properties, to an increased catalytic or biological activity, can be added or enhanced by the deposition of a thin film, with a thickness of only a few atomic layers at the best, on an already existing surface. Thin films offer both a means of saving in materials and the possibility for improving properties without a critical enlargement of devices. Nanocluster deposition is a promising new method for the growth of structured thin films. Nanoclusters are small aggregates of atoms or molecules, ranging in sizes from only a few nanometers up to several hundreds of nanometers in diameter. Due to their large surface to volume ratio, and the confinement of atoms and electrons in all three dimensions, nanoclusters exhibit a wide variety of exotic properties that differ notably from those of both single atoms and bulk materials. Nanoclusters are a completely new type of building block for thin film deposition. As preformed entities, clusters provide a new means of tailoring the properties of thin films before their growth, simply by changing the size or composition of the clusters that are to be deposited. Contrary to contemporary methods of thin film growth, which mainly rely on the deposition of single atoms, cluster deposition also allows for a more precise assembly of thin films, as the configuration of single atoms with respect to each other is already predetermined in clusters. Nanocluster deposition offers a possibility for the coating of virtually any material with a nanostructured thin film, and therein the enhancement of already existing physical or chemical properties, or the addition of some exciting new feature. A clearer understanding of cluster-surface interactions, and the growth of thin films by cluster deposition, must, however, be achieved, if clusters are to be successfully used in thin film technologies. Using a combination of experimental techniques and molecular dynamics simulations, both the deposition of nanoclusters, and the growth and modification of cluster-assembled thin films, are studied in this thesis. Emphasis is laid on an understanding of the interaction between metal clusters and surfaces, and therein the behaviour of these clusters during deposition and thin film growth. The behaviour of single metal clusters, as they impact on clean metal surfaces, is analysed in detail, from which it is shown that there exists a cluster size and deposition energy dependent limit, below which epitaxial alignment occurs. If larger clusters are deposited at low energies, or cluster-surface interactions are weaker, non-epitaxial deposition will take place, resulting in the formation of nanocrystalline structures. The effect of cluster size and deposition energy on the morphology of cluster-assembled thin films is also determined, from which it is shown that nanocrystalline cluster-assembled films will be porous. Modification of these thin films, with the purpose of enhancing their mechanical properties and durability, without destroying their nanostructure, is presented. Irradiation with heavy ions is introduced as a feasible method for increasing the density, and therein the mechanical stability, of cluster-assembled thin films, without critically destroying their nanocrystalline properties. The results of this thesis demonstrate that nanocluster deposition is a suitable technique for the growth of nanostructured thin films. The interactions between nanoclusters and their supporting surfaces must, however, be carefully considered, if a controlled growth of cluster-assembled thin films, with precisely tailored properties, is to be achieved.

Numerical approaches to new particle formation and growth in the atmosphere

Aerosols impact the planet and our daily lives through various effects, perhaps most notably those related to their climatic and health-related consequences. While there are several primary particle sources, secondary new particle formation from precursor vapors is also known to be a frequent, global phenomenon. Nevertheless, the formation mechanism of new particles, as well as the vapors participating in the process, remain a mystery. This thesis consists of studies on new particle formation specifically from the point of view of numerical modeling. A dependence of formation rate of 3 nm particles on the sulphuric acid concentration to the power of 1-2 has been observed. This suggests nucleation mechanism to be of first or second order with respect to the sulphuric acid concentration, in other words the mechanisms based on activation or kinetic collision of clusters. However, model studies have had difficulties in replicating the small exponents observed in nature. The work done in this thesis indicates that the exponents may be lowered by the participation of a co-condensing (and potentially nucleating) low-volatility organic vapor, or by increasing the assumed size of the critical clusters. On the other hand, the presented new and more accurate method for determining the exponent indicates high diurnal variability. Additionally, these studies included several semi-empirical nucleation rate parameterizations as well as a detailed investigation of the analysis used to determine the apparent particle formation rate. Due to their high proportion of the earth's surface area, oceans could potentially prove to be climatically significant sources of secondary particles. In the lack of marine observation data, new particle formation events in a coastal region were parameterized and studied. Since the formation mechanism is believed to be similar, the new parameterization was applied in a marine scenario. The work showed that marine CCN production is feasible in the presence of additional vapors contributing to particle growth. Finally, a new method to estimate concentrations of condensing organics was developed. The algorithm utilizes a Markov chain Monte Carlo method to determine the required combination of vapor concentrations by comparing a measured particle size distribution with one from an aerosol dynamics process model. The evaluation indicated excellent agreement against model data, and initial results with field data appear sound as well.

On measurements of formation, growth, hygroscopicity, and volatility of atmospheric ultrafine particles

Atmospheric aerosol particles affect the global climate as well as human health. In this thesis, formation of nanometer sized atmospheric aerosol particles and their subsequent growth was observed to occur all around the world. Typical formation rate of 3 nm particles at varied from 0.01 to 10 cm-3s-1. One order of magnitude higher formation rates were detected in urban environment. Highest formation rates up to 105 cm-3s-1 were detected in coastal areas and in industrial pollution plumes. Subsequent growth rates varied from 0.01 to 20 nm h-1. Smallest growth rates were observed in polar areas and the largest in the polluted urban environment. This was probably due to competition between growth by condensation and loss by coagulation. Observed growth rates were used in the calculation of a proxy condensable vapour concentration and its source rate in vastly different environments from pristine Antarctica to polluted India. Estimated concentrations varied only 2 orders of magnitude, but the source rates for the vapours varied up to 4 orders of magnitude. Highest source rates were in New Delhi and lowest were in the Antarctica. Indirect methods were applied to study the growth of freshly formed particles in the atmosphere. Also a newly developed Water Condensation Particle Counter, TSI 3785, was found to be a potential candidate to detect water solubility and thus indirectly composition of atmospheric ultra-fine particles. Based on indirect methods, the relative roles of sulphuric acid, non-volatile material and coagulation were investigated in rural Melpitz, Germany. Condensation of non-volatile material explained 20-40% and sulphuric acid the most of the remaining growth up to a point, when nucleation mode reached 10 to 20 nm in diameter. Coagulation contributed typically less than 5%. Furthermore, hygroscopicity measurements were applied to detect the contribution of water soluble and insoluble components in Athens. During more polluted days, the water soluble components contributed more to the growth. During less anthropogenic influence, non-soluble compounds explained a larger fraction of the growth. In addition, long range transport to a measurement station in Finland in a relatively polluted air mass was found to affect the hygroscopicity of the particles. This aging could have implications to cloud formation far away from the pollution sources.

Observations on the first steps of atmospheric particle formation and growth

Atmospheric aerosol particles have a significant impact on air quality, human health and global climate. The climatic effects of secondary aerosol are currently among the largest uncertainties limiting the scientific understanding of future and past climate changes. To better estimate the climatic importance of secondary aerosol particles, detailed information on atmospheric particle formation mechanisms and the vapours forming the aerosol is required. In this thesis we studied these issues by applying novel instrumentation in a boreal forest to obtain direct information on the very first steps of atmospheric nucleation and particle growth. Additionally, we used detailed laboratory experiments and process modelling to determine condensational growth properties, such as saturation vapour pressures, of dicarboxylic acids, which are organic acids often found in atmospheric samples. Based on our studies, we came to four main conclusions: 1) In the boreal forest region, both sulphurous compounds and organics are needed for secondary particle formation, the previous contributing mainly to particle formation and latter to growth; 2) A persistent pool of molecular clusters, both neutral and charged, is present and participates in atmospheric nucleation processes in boreal forests; 3) Neutral particle formation seems to dominate over ion-mediated mechanisms, at least in the boreal forest boundary layer; 4) The subcooled liquid phase saturation vapour pressures of C3-C9 dicarboxylic acids are of the order of 1e-5 1e-3 Pa at atmospheric temperatures, indicating that a mixed pre-existing particulate phase is required for their condensation in atmospheric conditions. The work presented in this thesis gives tools to better quantify the aerosol source provided by secondary aerosol formation. The results are particularly useful when estimating, for instance, anthropogenic versus biogenic influences and the fractions of secondary aerosol formation explained by neutral or ion-mediated nucleation mechanisms, at least in environments where the average particle formation rates are of the order of some tens of particles per cubic centimeter or lower. However, as the factors driving secondary particle formation are likely to vary depending on the environment, measurements on atmospheric nucleation and particle growth are needed from around the world to be able to better describe the secondary particle formation, and assess its climatic effects on a global scale.

A DISCURSIVE PERSPECTIVE ON LEGITIMATION STRATEGIES IN MULTINATIONAL CORPORATIONS

Few studies have examined legitimation in multinational corporations from a discursive perspective. To complement the existing institutional literature, we adopt a critical discourse analysis perspective that allows us to examine the microlevel processes of discursive legitimation. We provide an example of a media text— dealing with a production unit shutdown—to demonstrate how this perspective elucidates the various textual strategies used to legitimate multinational corporations’ actions and their controversial consequences.

Growth and Convergence: The case of China

Growth and Convergence: The Case of China Since the initiation of economic reforms in 1978, China has become one of the world’s fast-growing economies. The rapid growth, however, has not been shared equally across the different regions in China. The prominent feature of substantial differences in incomes and growth rates across the different Chinese regions has attracted the attention of many researchers. This book focuses on issues related to economic growth and convergence across the Chinese regions over the past three decades. The book has eight chapters. Apart from an introduction chapter and a concluding chapter, all the other chapters each deal with some certain aspects of the central issue of regional growth and convergence across China over the past three decades. The whole book is organized as follows. Chapter 1 provides an introduction to the basic issues involved in this book. Chapter 2 tests economic growth and convergence across 31 Chinese provinces during 1981-2005, based on the theoretical framework of the Solow growth model. Chapter 3 investigates the relationship between openness to foreign economic activities, such as foreign trade and foreign direct investment, and the regional economic growth in the case of China during 1981-2005. Chapter 4, based on data of 31 Chinese provinces over the period 1980-2004, presents new evidence on the effects of structural shocks and structural transformation on growth and convergence among the Chinese regions. Chapter 5, by building up an empirical model that takes account of different potential effects of foreign direct investment, focuses on the impacts of foreign direct investment on China’s regional economic performance and growth. Chapter 6 reconsiders the growth and convergence problem of the Chinese regions in an alternative theoretical framework with endogenous saving behavior and capital mobility across regions. Chapter 7, by building up a theoretical model concerning comparative advantage and transaction efficiency, focuses on one of the potential mechanisms through which China achieves its fast economic growth over the past few decades. Chapter 8 concludes the book by summarizing the results from the previous chapters and suggesting directions for further studies.

Knowledge Sharing in Multinational Corporations - A Social Captal Perspective (summary section only)

Multinational corporations (MNCs) are commonly perceived as networks of differentiated units, dependent for their competitive edge on the sharing of different kinds of internal resources. This ‘differentiated network’ view of the MNC strongly emphasizes the crucial role of interunit knowledge sharing, the topic of this thesis. The five essays presented here contribute to the research on interunit knowledge sharing in MNCs by focusing on the roles played by language, identity, and feedback seeking in the knowledge sharing process. While these factors have occasionally been brought up in previous research as potentially relevant for interunit knowledge sharing, they have so far been subject to limited empirical examination – an important omission which this thesis is an effort to redress. Furthermore, the treatment of the topic is anchored in a theoretical framework based on social capital. This perspective contributes to MNC research by providing a comprehensive framework for examining the significance of social relationships in interunit interaction. The findings can be summarized in two main points. Firstly, language skills and shared identity appear to promote the accumulation of interunit social capital. Secondly, high levels of interunit social capital seem to promote interunit knowledge sharing and feedback seeking. These observations raise a number of both theoretical and practical issues of considerable relevance for MNC management.

Increasing Knowledge Focus - a Means for Entrepreneurs to Remain on a Growth Path: Essays on the Role and Nature of Knowledge Management in Finnish SMEs (summary section only)

This study explores the role and nature of knowledge management (KM) in small and medium-sized companies (SMEs). Even though the role of knowledge as a competitive advantage is commonly recognized in the SME sector, almost no attention has been paid to the managing and developing of knowledge in SMEs. This thesis consists of three different sub-studies that were reported in four individual essays. The results of the questionnaire study indicate that nearly all companies that responded to the questionnaire (N = 108) found intangible assets, i.e. knowledge resources to be their main source of competitive advantage. However, only less than a third of the companies actively deal with knowledge management. The results also indicate a significant correlation between activity in knowledge management and sustainable organic growth of the company. The interview study (N = 10) explored the context and motives of the SMEs for managing their intangible assets, and the concrete practices of knowledge management. It turned out that KM facilitated change management, clarification of the vision and new strategy formulation. All the interviewed companies were aiming at improved innovation process, new ways of doing business and attaining an increased “knowledge focus” in their business. Nearly all also aspired to grow significantly. Thus, KM provides a strategy for these SMEs to guarantee their survival and sustainability in the turbulent markets. The action research was a process to assess and develop intangible resources in three companies. The experienced benefits were the clarification of future focus and strategy, creation of a common language to discuss strategic issues within the company, as well as improved balance of different categories of intangible assets. After the process all the case companies had developed in the chosen key areas. Thus, by systematic knowledge management the implementation of new strategic orientation (knowledge focusing) was facilitated. The findings can be summarized in two main points. First, knowledge management seems to serve the purpose of change, renewal and new strategic orientation in the SMEs. It also seems to be closely related to organic growth and innovation. All of these factors can be considered dimensions of entrepreneurship. Second, the conscious development of intangible assets can increase the balance of different categories of intangible assets and the overall knowledge focusing of business. In the case companies, this in turn facilitated the path to the improved overall performance.

Towards Explaining the Use of Control Mechanisms in Foreign Subsidiaries of MNCs (summary section only)

Control is central to management and there is already a considerable body of research on control. However, the emergence and growth of multinational corporations (MNCs) has renewed the interest in control, as MNCs are complex (often large) organizations that face circumstances beyond those of national business organizations. The geographical dispersion of MNC activities means that the headquarters controls subsidiaries that differ with regard to power and that are embedded in different cultural, political, legal and educational systems. Foreign subsidiary control also takes place across language boundaries and physical (i.e. geographical) distances. In face of these challenges, how are foreign subsidiaries controlled? The thesis explores different types of control mechanisms and attempts to explain the degree to which they are used to control foreign subsidiaries. It contributes to existing knowledge on control by exploring how five different control mechanisms are related to each other. Previous research has tended to focus only on one or two control mechanisms and seldom has their effect on each other been explored. The thesis also contributes by including two central aspects of the MNC that have been neglected in much of the research on foreign subsidiary control: language competence of subsidiary staff and physical distance between the headquarters and its subsidiaries. The findings indicate that specific control mechanisms should not be studied in isolation as there are intricate relationships among the different control mechanisms. Language competence of the subsidiary staff can furthermore affect the type and degree of control that the headquarters can exercise over a subsidiary. The findings also indicate that changes in the physical distance between subsidiaries and its headquarters (i.e. a relocation of the headquarters as part of a restructuring process) can have great consequences for the headquarters-subsidiary relationship.

Shareholder/Stakeholder Value Management, Company Growth and

There has been considerable discussion in the literature about the relative merits of shareholder value management and stakeholder value management, but relatively little empirical research has been reported concerning the relationship between these types of management and financial performance. The present study puts forward a hypothesis that true shareholder value management also encompasses stakeholder value management. This combination of shareholder/stakeholder value management is hypothesised to be associated with superior financial performance and sales growth. Using a sample of chief financial officers' ratings of the contemporary management accounting techniques economic value added and the balanced scorecard to represent the two management types, the study found evidence in support of the hypothesis.

Gender Divisions and Gender Policies in Top Finnish Corporations

The expansion of transnational corporations is a fundamental part of contemporary globalising processes. Through their activities, transnational corporations also have impacts on national and cultural gender relations, thus highlighting that gender relations are indeed amenable, to some extent, to social change. Accordingly, large transnational corporations have many effects and implications for gender relations in society, as well as having their own gender relations within them, characteristically in the form of men’s far greater presence in management than women’s. A key aspect in the functioning of transnational corporations is thus the way they organise and restructure gender relations within their own activities. The research presented here on gender divisions and gender policies in largest Finnish multinational and national corporations is part of a longer-term examination of the relations of gender relations in transnational corporations. It sets out the results of a survey of the largest 100 Finnish corporations with regard to the following main kinds of question: · general information on the corporation’s size, sector and economic activities; · the gender composition of their employment, middle management, top management, and board; · their gender equality plans and related policies. The human resources manager or their equivalent or delegate of 62 corporations responded to the survey. The general analysis of the data obtained from the survey is presented in this research report. Special attention is given to relations between the gender divisions and the gender policies of corporations. Interpretations of the data and more general theoretical implications are discussed in the report, with special attention to theoretical ways forward.