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.

Sosiaalipalveluja kaikille ja kaiken ikää? : Tutkimus suomalaisten mielipiteistä ja kokemuksista sosiaalipalveluista sekä niiden suhteesta legitimiteettiin

This research analyses opinions on the system of social welfare services from the point of view of clients and the public in general in Finland. The approach is quantitative, drawing on theories of the welfare-state tradition. The data used comes from the comprehensive Welfare and Services in Finland survey compiled by STAKES. While previous research on the welfare state has predominantly focused on surveying public opinion on social protection, this research focuses on social welfare services. The main focus of this research is on publicly funded care provided by municipal social welfare services. In this research, social welfare services include child day care, services for people with disabilities, home-help services, counselling by social workers and social assistance. The research considered in particular whether the clients or the population has different opinions towards social welfare services or social benefits. In addition, the research partly covers areas of informal care provided by family and friends. The research material consisted of the STAKES Welfare and Services in Finland survey. The data was compiled in 2004 and 2006 by Statistics Finland. The research comprises five articles. Additional data have been extracted from social welfare statistics and registers. Multiple approaches were applied in the survey on welfare and services the methods in this research included interviews by phone and mail, and register data. The sample size was 5 810 people in 2004 and 5 798 in 2006. The response rates were 82.7% and 83.7%, respectively. The results indicate that a large majority (90%) of the Finnish population is of the opinion that the public sector should bear the main responsibility for organising social and health services. The system of social welfare services and its personnel have strong public support 73% and 80% respectively. However, new and even negative tones have emerged in the Finnish debate on social welfare services. Women are increasingly critical of the performance of social welfare services and the level of social protection. Furthermore, this study shows that women more often than men wish to see an increase in the amount of privately organised social welfare services. Another group critical of the performance of social welfare services are pensioners. People who had used social welfare services were more critical than those who had not used them. Thus, the severest criticism was received from the groups who use and gain most from public services and benefits. However, the education and income variables identified in earlier studies no longer formed a significant dividing line, although people with higher education tend to foster a more positive view of the performance of social welfare services as well as the level of social protection. Income differences did not bear any significance, that is, belonging to a high or low income group was not a determining factor in the attitude towards social welfare services or social benefits. According to the research, family and friends still form an informal yet significant support network in people's everyday lives, and its importance has not been diminished by services provided by the welfare state. The Finnish public considers child day care the most reliable form of social welfare services. Indeed, child day care has become the most universal sector of our system of social welfare services. Other services that instil confidence included counselling by social workers and services for people with disabilities. On the other hand, social assistance and home-help services received negative feedback. The negative views were based on a number of arguments. One argument contends that the home-help service system, which was originally intended for universal use, is crumbling. The preventive role of home-help services has been reduced. These results mirror the increasingly popular opinion that social welfare services are not produced for all those who need them, but to an increasing extent for a select few of them. Municipalities are struggling with their finances and this, combined with negative publicity, has damaged the public's trust in some municipal social welfare services. A welfare state never achieves a stable condition, but must develop over time, as the world around it changes. Following the 1990's recession, we are now in a position where we can start to develop a system that responds to the needs of the next generation. Study results indicating new areas of dissatisfaction reflect the need to develop and improve the services provided. It is also increasingly essential that social welfare services pay attention to the opinions of clients and the public. Should the gap between opinions and actual activities increase, the legitimacy of the whole system would be questioned. Currently, the vast majority of Finns consider the system of social welfare services adequate, which provides us with the continuity required to maintain and improve client-oriented and reasonably priced social welfare services. Paying attention to the signals given by clients and the general public, and reacting to them accordingly, will also secure the development and legitimacy of the system in the future.

The function and regulation of the U11-48K protein in U12-dependent splicing

The removal of noncoding sequences, or introns, from the eukaryotic messenger RNA precursors is catalyzed by a ribonucleoprotein complex known as the spliceosome. In most eukaryotes, two distinct classes of introns exist, each removed by a specific type of spliceosome. The major, U2-type introns account for over 99 % of all introns, and are almost ubiquitous. The minor, U12-type introns are found in most but not all eukaryotes, and reside in conserved locations in a specific set of genes. Due to their slow excision rates, the U12-type introns are expected to be involved in the regulation of the genes containing them by inhibiting the maturation of the messenger RNAs. However, little information is currently available on how the activity of the U12-dependent spliceosome itself is regulated. The levels of many known splicing factors are regulated through unproductive alternative splicing events, which lead to inclusion of premature STOP codons, targeting the transcripts for destruction by the nonsense-mediated decay pathway. These alternative splice sites are typically found in highly conserved sequence elements, which also contain binding sites for factors regulating the activation of the splice sites. Often, the activation is achieved by binding of products of the gene in question, resulting in negative feedback loops. In this study, I show that U11-48K, a protein factor specific to the minor spliceosome, specifically recognizes the U12-type 5' splice site sequence, and is essential for proper function of the minor spliceosome. Furthermore, the expression of U11-48K is regulated through a feedback mechanism, which functions through conserved sequence elements that activate alternative splicing and nonsense-mediated decay. This mechanism is conserved from plants to animals, highlighting both the importance and early origin of this mechanism in regulating splicing factors. I also show that the feedback regulation of U11-48K is counteracted by a component of the major spliceosome, the U1 small nuclear ribonucleoprotein particle, as well as members of the hnRNP F/H protein family. These results thus suggest that the feedback mechanism is finely tuned by multiple factors to achieve precise control of the activity of the U12-dependent spliceosome.

Achievement and Social Strategies and the Cumulation of Positive and Negative Experiences During Young Adulthood

These longitudinal studies focused on investigating young adults during transition into a new educational environment. The aims were to examine: (1) what kinds of achievement and social strategies young adults deploy, (2) whether the deployment of these strategies predicts people's success in their studies, their life events, their peer relationships, and their well-being, (3) whether young adults' success in dealing with educational transition (e.g. success in studies, life events, peer relationships and well-being) predict changes in their strategies and well-being, and (4) the associations between young adults' social strategies, interpersonal behaviour, person perception, and their peer relationships and satisfaction with them. The participants were students from Helsinki university and from two vocational institutes (the numbers ranging between 92 and 303). The results revealed that achievement and social strategies contributed to individuals' success in dealing with both the academic and interpersonal challenges of a new environment. Social strategies were also associated with online interpersonal behaviour and person perception, which mediated their impact on peer relationships. Achievement and social strategies changed as a result of environmental feedback. However, they also showed high stability, forming reciprocal and cumulative associations with the feedback the individuals received about their success in dealing with educational transition: the use of functional strategies, such as optimistic, defensive-pessimistic and planning-oriented strategies, increased their success, which in turn enhanced their well-being and further deployment of functional strategies. The opposite was true in the case of dysfunctional strategies, such as self-handicapping and avoidance. Key words : Achievement strategies, social strategies, transition, young adults, life events, sociometric status, social behaviour, person perception, well-being.

Sekä että : Ironia koherenssina ja inkoherenssina

The interpretation of irony in this study is seen as being crucially dependent on the notion of coherence. Coherence depends on a complex interplay of contextual features, which is why all interpretations must be seen as socio-cultural processes. An utterance is perceived as coherent if it makes sense and if it hangs together. Incoherent utterances can result in an ironic interpretation; however, the incoherence must also be perceived as being intentional, and intentionality in turn is a sign of the ironist's rejecting stance. The study does not encompass the notion of irony of fate nor situational irony that is unintentional. Irony is defined in this study as a combination of five components. It is seen as (1) a negative attitude that reflects (2) the intention of the ironist, and (3) has a target and most often (4) a victim too. Essential to irony is its fifth component, the fact that one or more of these four components must be inferred from co- or context. The componential definition of irony is crucial in deciding whether an interpretation is ironic or not, and the definition makes it possible to discern the differences as well as the similarities between different kinds of irony. The method of the study is experimental: 12 Finnish newspaper texts that could be considered to be ironic were interpreted by 107 informants. The interpretation of one of the texts was based on unelicited feedback given by readers of a weekly magazine. The responses were analyzed to determine (a) whether the texts were perceived as being coherent or incoherent and (b) whether the informants appealed to any of the five components of irony. The results of the analyses of the informants' responses indicate that differences between the ironic and non-ironic interpretations of the texts can be explained in terms of whether or not the informant regarded the text as being coherent. The thesis also discusses the shortcomings of other accounts of irony: the Gricean theory of conversational implicature, speech act theory, irony as rhetoric, irony as pretense, irony as echoic mention, and irony as framing. In contrast to these other accounts, the study focuses on irony as a textual phenomenon and underlines the importance of socio-cultural context in the interpretation of irony. Key words: irony, coherence, incoherence, the componential definition of irony, interpretation of linguistic utterances.

Weakening of the Gram-negative bacterial outer membrane - A tool for increasing microbiological safety

Gram-negative bacteria are harmful in various surroundings. In the food industy their metabolites are potential cause of spoilage and this group also includes many severe or potential pathogens, such as Salmonella. Due to their ability to produce biofilms Gram-negative bacteria also cause problems in many industrial processes as well as in clinical surroundings. Control of Gram-negative bacteria is hampered by the outer membrane (OM) in the outermost layer of the cells. This layer is an intrinsic barrier for many hydrophobic agents and macromolecules. Permeabilizers are compounds that weaken OM and can thus increase the activity of antimicrobials by facililating entry of hydrophobic compounds and macromolecules into the cell where they can reach their target sites and inhibit or destroy cellular functions. The work described in this thesis shows that lactic acid acts as a permeabilizer and destabilizes the OM of Gram-negative bacteria. In addition, organic acids present in berriers, i.e. malic, sorbic and benzoic acid, were shown to weaken the OM of Gram-negative bacteria. Organic acids can poteniate the antimicrobial activity of other compounds. Microbial colonic degradation products of plant-derived phenolic compounds (3,4-dihydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 3,4-dihydroxyphenylpropionic acid, 4-hydroxyphenylpropionic acid, 3-phenylpropionic acid and 3-hydroxyphenylpropionic acid) efficiently destabilized OM of Salmonella. The studies increase our understanding of the mechanism of action of the classical chelator, ethylenediaminetetra-acetic acid (EDTA). In addition, the results indicate that the biocidic activity of benzalkonium chloride against Pseudomonas can be increased by combined use with polyethylenimine (PEI). In addition to PEI, several other potential permeabilizers, such as succimer, were shown to destabilize the OM of Gram-negative bacteria. Furthermore, combination of the results obtained from various permeability assays (e.g. uptake of a hydrophobic probe, sensitization to hydrophobic antibiotics and detergents, release of lipopolysaccharide (LPS) and LPS-specific fatty acids) with atomic force microscopy (AFM) image results increases our knowledge of the action of permeabilizers.

Stiffer Optical Tweezers through Real-Time Feedback Control

This thesis integrates real-time feedback control into an optical tweezers instrument. The goal is to reduce the variance in the trapped bead s position, -effectively increasing the trap stiffness of the optical tweezers. Trap steering is done with acousto-optic deflectors and control algorithms are implemented with a field-programmable gate array card. When position clamp feedback control is on, the effective trap stiffness increases 12.1-times compared to the stiffness without control. This allows improved spatial control over trapped particles without increasing the trapping laser power.

The Population Consequences of Sex and Conflict

Natural selection generally operates at the level of the individual, or more specifically at the level of the gene. As a result, individual selection does not always favour traits which benefit the population or species as a whole. The spread of an individual gene may even act to the detriment of the organism in which it finds. Thus selection at the level of the individual can affect processes at the level of the organism, group or even at the level of the species. As most behaviours ultimately affect births, deaths and the distribution of individuals, it seems inevitable that behavioural decisions will have an impact on population dynamics and population densities. Behavioural decisions can often involve costs through allocation of energy into behavioural strategies, such as the investment into armaments involved in fighting over resources or increased mortality due to injury or increased predation risk. Similarly, behaviour may act o to benefit the population, in terms of higher survival and increased fecundity. Examples include increased investment through parental care, choosing a mate based on the nuptial gifts they may supply and choosing territories in the face of competition. Investigating the impact of behaviour on population ecology may seem like a trivial task, but it is likely to have important consequences at different levels. For example, antagonistic behaviour may occasionally become so extreme that it increases the risk of extinction, and such extinction risk may have important implications for conservation. As a corollary, any such behaviour may also act as a macroevolutionary force, weeding out populations with traits which, whilst beneficial to the individuals in the short term, ultimately result in population extinction. In this thesis, I examine how behaviours, specifically conflict and competition over a resource and aspects of behaviour involved in sexual selection, can affect population densities, and what the implications are for the evolution and ecology of the populations in question. It is found that both behaviours related to individual conflict and mating strategies can have an effect at the level of the population, but that various factors, such as a feedback between selection and population densities or macroevolution caused by species extinctions, may act to limit the intensity of conflicts that we observe in nature.

Evaluation of Vestibular Function with Visual Feedback Posturography and Motorized Head Impulse Test.

Objectives: To evaluate the applicability of visual feedback posturography (VFP) for quantification of postural control, and to characterize the horizontal angular vestibulo-ocular reflex (AVOR) by use of a novel motorized head impulse test (MHIT). Methods: In VFP, subjects standing on a platform were instructed to move their center of gravity to symmetrically placed peripheral targets as fast and accurately as possible. The active postural control movements were measured in healthy subjects (n = 23), and in patients with vestibular schwannoma (VS) before surgery (n = 49), one month (n = 17), and three months (n = 36) after surgery. In MHIT we recorded head and eye position during motorized head impulses (mean velocity of 170º/s and acceleration of 1 550º/s²) in healthy subjects (n = 22), in patients with VS before surgery (n = 38) and about four months afterwards (n = 27). The gain, asymmetry and latency in MHIT were calculated. Results: The intraclass correlation coefficient for VFP parameters during repeated tests was significant (r = 0.78-0.96; p < 0.01), although two of four VFP parameters improved slightly during five test sessions in controls. At least one VFP parameter was abnormal pre- and postoperatively in almost half the patients, and these abnormal preoperative VFP results correlated significantly with abnormal postoperative results. The mean accuracy in postural control in patients was reduced pre- and postoperatively. A significant side difference with VFP was evident in 10% of patients. In the MHIT, the normal gain was close to unity, the asymmetry in gain was within 10%, and the latency was a mean ± standard deviation 3.4 ± 6.3 milliseconds. Ipsilateral gain or asymmetry in gain was preoperatively abnormal in 71% of patients, whereas it was abnormal in every patient after surgery. Preoperative gain (mean ± 95% confidence interval) was significantly lowered to 0.83 ± 0.08 on the ipsilateral side compared to 0.98 ± 0.06 on the contralateral side. The ipsilateral postoperative mean gain of 0.53 ± 0.05 was significantly different from preoperative gain. Conclusion: The VFP is a repeatable, quantitative method to assess active postural control within individual subjects. The mean postural control in patients with VS was disturbed before and after surgery, although not severely. Side difference in postural control in the VFP was rare. The horizontal AVOR results in healthy subjects and in patients with VS, measured with MHIT, were in agreement with published data achieved using other techniques with head impulse stimuli. The MHIT is a non-invasive method which allows reliable clinical assessment of the horizontal AVOR.

Service firms´ action upon negative incidents in high touch services: A narrative study

The study concerns service management, and specifically the action service firms take with regard to customer dissatisfaction, customer complaints and complaining customers in high touch services. Customer dissatisfaction, customer complaints and complaining customers are called negative incidents in the study. The study fills a research gap in service management studies by investigating negative incidents as a part of an open service system. In contrast to main stream service management studies defining service quality as how the customer as a consumer defines it, in the present study, the concept of interactive service quality is adopted. The customer is considered as a co-producer of service who thus has a role to play in service quality and productivity. Additionally, the study juxtaposes the often opposed perspectives of the manager and the customer as well as the often forgotten silent voices of service employees and supervisors. The study proposes that the service firm as an entity does not act but it is the actors at the different hierarchical layers who act. Additionally, it is acknowledged in the study that the different actors at the different hierarchical layers have different knowledge of the service system and different objectives for service encounters. Therefore, they interpret the negative incidents from different perspectives and their actions upon negative incidents are subsequently guided by their interpretations. The research question is: how do service firms act upon negative incidents in high touch services? In order to answer to the research question a narrative research approach was chosen. The actors at the different hierarchical layers acted as informants of the study and provided stories about customer dissatisfaction, customer complaining and complaint handling in high touch services. Through storytelling, access to the socially constructed reality of service firms’ action was achieved. Stemming from the literature review, analysis of empirical data and my theoretical thinking, a theory about service firms’ action upon negative incidents in high touch services was developed and the research question was answered. The study contributes to service recovery and complaint management studies as well as to studies on customer orientation and its implementation in service firms. Additionally, the study has a methodological contribution to service management studies since it reflects service firms’ action with narratives from multiple perspectives. The study is positioned in the tradition of the Nordic School of Marketing Thought and presents service firms’ action upon negative incidents in high touch services as a complex human-centered phenomenon in which the actors at the different hierarchical layers have crucial roles to play. Ritva Höykinpuro is associated with CERS, the Centre for Relationship Marketing and Service Management at Hanken School of Economics.

The Negative News Threshold - an Explanation for Negative Skewness in Stock Returns

A vast literature documents negative skewness and excess kurtosis in stock return distributions on several markets. We approach the issue of negative skewness from a different angle than in previous studies by suggesting a model, which we denote the “negative news threshold” hypothesis, that builds on asymmetrically distributed information and symmetric market responses. Our empirical tests reveal that returns for days when non-scheduled news are disclosed are the source of negative skewness in stock returns. This finding lends solid support to our model and suggests that negative skewness in stock returns is induced by asymmetries in the news disclosure policies of firm management.

Bovine mastitis caused by coagulase-negative staphylococci : host response and bacterial factors

Coagulase-negative staphylococci (CNS) are the most common bacteria isolated in bovine subclinical mastitis in many countries, and also a frequent cause of clinical mastitis. The most common species isolated are Staphylococcus (S) chromogenes, S. simulans, S. epidermidis, and S. xylosus. One half of the intramammary infections (IMI) caused by CNS persist in the udder. The pathogenesis of IMI caused by CNS is poorly understood. This dissertation focuses on host response in experimental intramammary infection induced by S. chromogenes, S. epidermidis and S. simulans. Model for a mild experimental CNS infection was developed with S. chromogenes (study I). All cows were infected and most developed subclinical mastitis. In study II the innate immune response to S. epidermidis and S. simulans IMI was compared in eight cows using a crossover design. A larger dose of bacteria was used to induce clinical mastitis. All cows became infected and showed mild to moderate clinical signs of mastitis. S. simulans caused a slightly stronger innate immune response than S. epidermidis, with significantly higher concentrations of the interleukins IL-1beta and IL-8 in the milk. The spontaneous elimination rate of the 16 IMIs was 31%, with no difference between species. No significant differences were recorded between infections eliminated spontaneously or remaining persistent, although the response was stronger in IMIs eliminated spontaneously, except the concentration of TNF-α, which remained elevated in persistent infections. Lactoferrin (Lf) is a component of the humoral defence of the host and is present at low concentrations in the milk. The concentration of Lf in milk is high during the dry period, in colostrum, and in mastitic milk. The effect of an inherent, high concentration of Lf in the milk on experimental IMI induced with S. chromogenes was studied in transgenic cows that expressed recombinant human Lf in their milk. Human Lf did not prevent S. chromogenes IMI, but the host response was milder in transgenic cows than in normal cows, and the former eliminated infection faster. Biofilm production has been suggested to promote persistence of IMI. Phenotypic biofilm formation and slime producing ability of CNS isolates from bovine mastitis was investigated in vitro. One-third of mastitis isolates produced biofilm. Slime production was less frequent for isolates of the most common mastitis causing species S. chromogenes and S. simulans compared with S. epidermidis. No association was found between the phenotypic ability to form biofilm and the persistence of IMI or severity of mastitis. Slime production was associated with persistent infections, but only 8% of isolates produced slime.