DiVA - Academic Archive On-line

Protection and treatment of hypothermia in prehospital trauma care : with emphasis on active warming

Peter Lundgren — Tue, 24 Apr 2012 14:59:00 +0200

Background: In prehospital trauma care active warming is recommended to aid in protection from further cooling. However, scientific evidence of the effectiveness of active warming in a clinical setting is scarce. Also, evaluating the effectiveness of active warming, especially in harsh ambient conditions, by objective measures, is difficult.

Objective: To evaluate the effectiveness of field applicabe heat sources (I) and to evaluate active warming intervention in a prehospital clinical setting (II and III).

To evaluate reliability and validity of the Cold Discomfort Scale (CDS), a subjective judgement scale for assessment of the thermal state of patients in a cold environment (IV).

Methods: In a laboratory trial, non-shivering hypothermic subjects (n=5), were cooled in 8 ºC water followed by spontaneous warming, a charcoal heater, two flexible hot-water bags or two chemical heat pads, all applied to the chest and upper back (I). Oesophageal temperature, skin temperature, heat flux, oxygen consumption, respiratory rate and, heart rate were measured.

In two clinical randomized trials, shivering patients during road and air ambulance transport (II) and during field treatment (III) were randomized to either passive warming alone (n=22 and n=9) or to passive warming with the addition of a chemical heat pad (n=26 and n=11). Body core temperature, respiratory rate, heart rate, blood pressure (II) and the patients’ subjective sensation of thermal comfort (II and III) were measured.

In a laboratory trial, shivering subjects were exposed to – 20 ºC (n=22). The CDS was evaluated regarding reliability, defined as test-retest stability, and criterion validity, defined as the ability to detect changes in cold discomfort due to changes in cumulative cold stress (IV).

Results: In non-shivering hypothermic subjects postcooling afterdrop was significantly less for the chemical heat pads, but not for the hot water bags and the charcoal heater, compared to spontaneous warming (I). Temperature drop during the entire warming phase was significantly less for all the heat sources respectively, compared to spontaneous warming (I).

During road and air ambulance transport, ear canal temperature was significantly increased and cold discomfort significantly decreased, both in patients assigned to passive warming only, and in patients assigned to additional active warming (II). During field treatment, cold discomfort was significantly reduced in patients assigned to additional active warming, but remained the same in patients assigned to passive warming only (III).

Weighted kappa coefficient, describing test-retest stability, was 0.84 (IV). CDS ratings were significantly increased during each 30 minutes interval (IV).

Conclusion: In non-shivering hypothermic subjects, heat sources were effective to attenuate afterdrop, when providing high heat content over a large surface area and effective to continue to increase body core temperature when providing sustained high heat content. In shivering trauma patients, adequate passive warming were sufficient treatment to prevent afterdrop, to slowly increase body core temperature, and to reduce cold discomfort. If inadequate passive warming, additional active warming was required to reduce cold discomfort. The CDS, a subjective judgement scale for assessment of the thermal state of patients in a cold environment seemed to be reliable regarding test-retest stability and valid regarding ability to detect change in cumulative cold stress.

Here and now : Foundations and practice of human-experiential design

Kei Hoshi — Wed, 25 Apr 2012 10:00:00 +0200

The thesis claims that an experiential approach to design really does promise the possibility of scientific design of everyday life. The purpose of this thesis is to show the promise. René Descartes conceptualized the classical formulation of a mind-body dichotomy. Various resulting and unbalanced dichotomies, such as subjective-objective, internal-external, experiential-practical and so on, raise serious concerns surrounding the concept of design. The thesis raises a crucial issue about the imbalance between technological and human concerns in the context of human-computer interaction, an imbalance that has been caused partly by the mechanistic aspect of informatics and its impact on designing human computer interaction. The thesis first explores the origin of design as a distinct activity during the industrial revolution, and reviews the tide of design history from then until today. The brief review of design history indicates that design is not merely the skill of making things or presentations. This gives direction to how design can be positioned in our modern information society. Second, the author starts a critical discussion about ordinary design approaches that, it is suggested, may have hindered true human-centred design, and then introduces an alternative approach to design and research, which the author calls Human-Experiential Design. Third, the notion of Tangible Presence in Blended Reality Space is introduced. The conceptual grounding that illustrates the experiential approach to interaction design is discussed. Fourth, the thesis presents use cases and provides examples of Human-Experiential Design in specific practical contexts. The concrete examples suggest that the emphasis on ‘balance’ or appropriate blending is very important in the development of better interactive systems for health, capitalizing on seamless combinations of the virtual and the physical in Blended Reality Space. As exemplified in the thesis, the human-experiential approach, striving for optimal combinations of tangibility and evoked presence, offers a promising tool in designing for special needs groups such as elderly people with some cognitive weaknesses, and children undertaking physical rehabilitation programmes. It is suggested that such virtual-physical blends will release human beings from the strain that existing perceived dichotomies bring. Finally, the author concludes by offering a way forward, a way that is neither subjective nor objective but rather a meaningfully integrated blend of the dichotomies, which responds to the question of what it means to be human.

Molecular population genetics of inducible defense genes in Populus tremula

Carolina Bernhardsson — Wed, 25 Apr 2012 10:30:00 +0200

Plant-herbivore interactions are among the most common of ecological interactions. It is therefore not surprising that plants have evolved multiple mechanisms to defend themselves, using both constitutive chemical and physical barriers and by induced responses which are only expressed after herbivory has occurred. Herbivores, on the other hand, respond to these plant defenses by evolving counter-adaptations which makes defenses less effective or even useless. Adaptation can occur at different geographical scales, with varying coevolutionary interactions across a spatially heterogenous landscape. By looking at the underlying genes responsible for these defensive traits and herbivore related phenotypic traits, it is possible to investigate the coevolutionary history of these plant- herbivore interactions. Here I use molecular population genetic tools to investigate the evolutionary history of several inducible defense genes in European Aspen (Populus tremula) in Sweden. Two genes, belonging to the Polyphenol oxidase gene-family (PPO1 and PPO2), show skews in their site frequency spectrum together with patterns of diversity and divergence from an outgroup which correspond to signatures of adaptive evolution (Paper II). 71 single nucleotide polymorphisms (SNPs) from seven inducible defense genes (PPO1-PPO3, TI2-TI5) show elevated levels of population differentiation compared to control genes (genes not involved in plant defense), and 10 of these defense SNPs show strong signatures of natural selection (Paper III). These 71 defense SNPs also divides a sample of Swedish P. tremula trees into three distinct geographical groups, corresponding to a Southern, Central and Northern cluster, a patterns that is not present in control SNPs (Paper III). The same geographical pattern, with a distinct Northern cluster, is also observed in several phenotypic traits related to herbivory in our common garden in Sävar (Paper IV). These phenotypic traits show patterns of apparent local maladaptation of the herbivore community to the host population which could indicate the presence of “information coevolution” between plants and herbivores (Paper IV). 15 unique defense SNPs also show significant associations to eight phenotypic traits but the causal effects of these SNP associations may be confounded by the geographic structure found in both the underlying genes and in the phenotypic traits. The co-occurrence of population structure in both defense genes and herbivore community traits may be the result from historical events during the post-glacial recolonization of Sweden.

A follow-up of patients with chronic musculoskeletal pain, focusing on multimodal rehabilitation

Daniel Merrick — Wed, 25 Apr 2012 09:09:00 +0200

Chronic pain is usually defined as pain of more than three months duration. The prevalence of chronic pain among the general population in Sweden is 18%. Compared with the general population, these patients report lower life satisfaction, decreased activity in daily life and higher levels of depression with decreased work ability, and increased sick leave. Research indicates that multimodal rehabilitation (MMR) programmes, including cognitive behavioural approaches for patients disabled by chronic pain, are effective for return to work.

The primary aim of this thesis was to assess outcomes by a long-term follow-up of patients with chronic musculoskeletal pain. Furthermore, the aim was to evaluate two different rehabilitation strategies regarding impact on pain intensity, activity, depression, life satisfactions, and sick leave.

Two groups, comprising 255 (between the years 1999-2002) and 296 (between 2007-2008) patients respectively, from the Pain Rehabilitation Clinic at Umeå University Hospital, Sweden, were all assessed by interdisciplinary teams. They completed questionnaires regarding pain intensity, disability, life satisfaction, anxiety and depression, and sick leave, before intervention, immediately after intervention (only the first group; n=255), and at one-year follow-up, after participating in a MMR programme in a specialist clinic, or after receiving a rehabilitation plan (RP) with follow-up in primary care. Allocation to either of the two groups was based on the initial interdisciplinary team assessment. Furthermore, a five-year follow-up of 158 patients with whiplash injury was conducted.

Pain intensity decreased and life satisfaction increased significantly regarding somatic health in both groups, at follow-up. In addition, depression improved and disability decreased to a higher extent after participating in the MMR programme as compared to RP and subsequent follow-up in primary care. Patients’ positive beliefs about recovery, and positive expectations about work correlated with favourable rehabilitation outcomes. Sick leave at one year follow-up decreased in both groups.

Regarding whiplash injury, patients who reported moderate or severe disability also reported significantly higher pain intensity, depression and post-traumatic stress scores and lower perception of general health compared with patients who reported mild or no disability.

In conclusion, MMR programmes seem to be beneficial by decreasing pain intensity, depression, disability and sick leave among patients with chronic musculoskeletal pain. Furthermore, patients’ positive beliefs correlate with more favourable long-term outcomes. An interdisciplinary team assessment based on a biopsychosocial approach may be of value for selection of rehabilitation strategy.

Protection against cold in prehospital trauma care

Otto Henriksson — Wed, 25 Apr 2012 16:15:00 +0200

Background: Protection against cold is vitally important in prehospital trauma care to reduce heat loss and prevent body core cooling.

Objectives: Evaluate the effect on cold stress and thermoregulation in volunteer subjects byutilising additional insulation on a spineboard (I). Determine thermal insulation properties of blankets and rescue bags in different wind conditions (II). Establish the utility of wet clothing removal or the addition of a vapour barrier by determining the effect on heat loss within different levels of insulation in cold and warm ambient temperatures (III) and evaluating the effect on cold stress and thermoregulation in volunteer subjects (IV).

Methods: Aural canal temperature, sensation of shivering and cold discomfort was evaluated in volunteer subjects, immobilised on non-insulated (n=10) or insulated (n=9) spineboards in cold outdoor conditions (I). A thermal manikin was setup inside a climatic chamber and total resultant thermal insulation for the selected ensembles was determined in low, moderate and high wind conditions (II). Dry and wet heat loss and the effect of wet clothing removal or the addition of a vapour barrier was determined with the thermal manikin dressed in either dry, wet or no clothing; with or without a vapour barrier; and with three different levels of insulation in warm and cold ambient conditions (III). The effect on metabolic rate, oesophageal temperature, skin temperature, body heat storage, heart rate, and cold discomfort by wet clothing removal or the addition of a vapour barrier was evaluated in volunteer subjects (n=8), wearing wet clothing in a cold climatic chamber during four different insulation protocols in a cross-over design (IV).

Results: Additional insulation on a spine board rendered a significant reduction of estimated shivering but there was no significant difference in aural canal temperature or cold discomfort (I). In low wind conditions, thermal insulation correlated to thickness of the insulation ensemble. In greater air velocities, thermal insulation was better preserved for ensembles that were windproof and resistant to the compressive effect of the wind (II). Wet clothing removal or the use of a vapour barrier reduced total heat loss by about one fourth in the cold environment and about one third in the warm environment (III). In cold stressed wet subjects, with limited insulation applied, wet clothing removal or the addition of a vapour barrier significantly reduced metabolic rate, increased skin rewarming rate, and improved total body heat storage but there was no significant difference in heart rate or oesophageal temperature cooling rate (IV). Similar effects on heat loss and cold stress was also achieved by increasing the insulation. Cold discomfort was significantly reduced with the addition of a vapour barrier and with an increased insulation but not with wet clothing removal.

Conclusions: Additional insulation on a spine board might aid in reducing cold stress inprolonged transportations in a cold environment. In extended on scene durations, the use of a windproof and compression resistant outer cover is crucial to maintain adequate thermal insulation. In a sustained cold environment in which sufficient insulation is not available, wet clothing removal or the use of a vapour barrier might be considerably important reducing heat loss and relieving cold stress.

Cell-to-cell communication and virulence in Vibrio anguillarum

Kristoffer Lindell — Fri, 27 Apr 2012 10:00:00 +0200

Quorum sensing (QS) is a type of cell-to-cell communication that allows the bacteria to communicate via small molecules to coordinate activities such as growth, biofilm formation, virulence, and stress response as a population. QS depends on the accumulation of signal molecules as the bacterial population increases. After a critical threshold of the signal molecules are reached, the bacteria induce a cellular response allowing the bacteria to coordinate their activities as a population.

In Vibrio anguillarum, three parallel quorum-sensing phosphorelay systems channels information via three hybrid sensor kinases VanN, VanQ, and CqsS that function as receptors for signal molecules produced by the synthases VanM, VanS, and CqsA, respectively. The phosphorelay systems converge onto a single regulatory pathway via the phosphotransferase VanU, which phosphorylates the response regulator VanO. Together with the alternative sigma factor RpoN, VanO activates the expression of a small RNA, Qrr1 (Quorum regulatory RNA), which in conjunction with the small RNA chaperone Hfq, destabilizes vanT mRNA, which encode the major quorum-sensing regulator in V. anguillarum. This thesis furthers the knowledge on the quorum-sensing phosphorelay systems in V. anguillarum.

In this study, three additional qrr genes were identified, which were expressed during late logarithmic growth phase. The signal synthase VanM activated the expression of the Qrr1-4, which stands in contrast to Qrr regulation in other vibrios. Moreover, in addition to VanO, we predict the presence of a second response regulator which can be phosphorylated by VanU and repress Qrr1-4 expression. Thus, VanU functions as a branch point that can regulate the quorum-sensing regulon by activating or repressing VanT expression. Furthermore, VanT was shown to directly activate VanM expression and thus forming a negative regulatory loop, in which VanM represses VanT expression indirectly via Qrr1-4. In addition, VanM expression was negatively regulated post-transcriptionally by Hfq. Furthermore, a universal stress protein UspA repressed VanM expression via the repression of VanT expression. We showed that UspA binds Hfq, thus we suggest that UspA plays a role in sequestering Hfq and indirectly affect gene expression.

This thesis also investigated the mechanism by which V. anguillarum can attach to and colonize fish skin tissue. We show unequivocally that fish skin epithelial cells can internalize bacteria, thus keeping the skin clear from pathogens. In turn, V. anguillarum utilized the lipopolysaccharide O-antigen to evade internalization by the fish skin epithelial cells. This study provides new insights into the molecular mechanism by which pathogen interacts with marine animals to cause disease.

Patient and health care delays in malignant melanoma

Senada Hajdarevic — Wed, 2 May 2012 14:48:00 +0200

Background: Unlike other cancers, malignant melanoma (MM) is generally visible and can be easily and effectively cured if treated in time. Optimal cure of MM requires early detection, diagnosis, and treatment, which improves prognosis. However, patients as well as the health care organization and its professionals contribute to delayed treatment in various ways.

Aims and objectives: The general aim of this PhD thesis was to explore reasons for delay in care seeking, diagnosis, and treatment of malignant melanoma. The specific objectives to be addressed were

To explore patients’ decision making about seeking care for malignant melanoma
To identify specific patterns in the decision-making process to seek care for suspect melanoma, as narrated by women and men
To compare self-reported decision making coping styles between men and women in various ages, who live with or without a partner and are diagnosed with various stages of malignant melanoma in northern Sweden.
To describe and compare patients diagnosed with MM, depending on their initial contact with care, and with regard to age, sex, and MM type and thickness, and to explore pathways and time intervals between clinics from the initial contact to diagnosis and treatment.

Methods: In studies I and II, 21 and 30 patients, respectively, were interviewed about their decision making to seek care for MM. Study II focused on gender patterns in this decision making. The interviews were analysed using Grounded Theory (I) and qualitative content analysis (II). Study III included 270 people with MM who completed a translated questionnaire (Melbourne Decision Making Questionnaire) about coping styles in decision making. In study IV the pathways and time delay in health care for 71 people with MM were explored. Studies I and II were qualitative, whereas studies III and IV were quantitative.

Results: In study I, the insights into severity and feelings of fear and existential threat were identified as key motivators for patients to decide to seek care for a suspected melanoma. Results in study II showed that gender constructions influenced the care-seeking behaviour. Women acknowledged the skin changes and attempted self-care first. They delayed care seeking due to family responsibilities. Men seldom acknowledged the suspicious skin change, but sought care immediately after prompting, and most often complied with relatives’ advice to seek care. Study III showed that men generally scored higher in buck-passing, while women and those living without a partner scored higher in hypervigilance. Participants with nodular melanoma (NM), a rapid-growing form of MM, scored higher in vigilance than those diagnosed as in situ melanoma. No correlation was found between tumour thickness and coping styles. Some differences concerning treatment of MM were found in study IV between people who initially had sought care at primary health care centres (PHC) and those who had sought care at dermatological and specialist clinics (Derm). Thicker tumours as well as NM were more common in the PHC group. A larger proportion of patients from PHCs were primarily excided within the primary health care; however, almost all of them were later referred to surgical clinics for wide excision. Patients within the PHC group also had to wait longer for the registered results of histopathological assessments. In general, women waited a shorter time for primary excision, and older people waited longer for wide excision.

Conclusions: Time delay of diagnosis and treatment of MM is still common, and crucial to decrease. Future interventions should include gender aspects to influence people to seek care earlier. In health care, time delay could be decreased by facilitating access for patients with suspected skin melanomas, but also by reducing unnecessary referrals. Moreover, organizational changes whereby general practitioners and primary health care nurses are supported in using new technology for faster diagnoses and management of MM in collaboration with specialist clinics should be considered. Easy access and frequently used guidelines for MM could further decrease delay. Lastly, more efficient transfer and registration of laboratory results and referrals could decrease delay and improve patient safety.

Metastatic spinal cord compression in prostate cancer : clinical and morphological studies

Sead Crnalic — Fri, 27 Apr 2012 13:26:00 +0200

Background: Bone metastases occur in most patients with advanced hormone-refractory prostate cancer causing pain, pathologic fractures, and spinal cord compression. Few studies specifically address surgical treatment of metastatic spinal cord compression (MSCC) in prostate cancer. Criteria for identifying patients who may benefit from surgery are poorly defined. Most of the current knowledge regarding tumor biology in prostate cancer is based on studies of primary tumors or soft tissue metastases. The mechanisms regulating growth of bone metastases are not fully established.

Aims: a) to evaluate outcome after surgery for MSCC in prostate cancer and to identify prognostic factors for survival and functional recovery; b) to evaluate current practice for referral of prostate cancer patients with MSCC; c) to analyze expression of androgen receptor (AR), cell proliferation, apoptosis, and prostate-specific antigen (PSA) in bone metastases with regard to survival after surgery for complications of bone metastases.

Patients and Methods: We retrospectively evaluated the hospital records of 68 consecutive patients operated for metastatic spinal cord compression. Tumor tissue from bone metastases was obtained on spinal surgery (54 patients), fracture surgery (4 patients) and biopsy (2 patients), and analyzed by immunohistochemistry.

Results:

Study I: Mortality and complication rate after surgery was high. Patients with hormone-naïve disease and those with hormone-refractory disease with good performance status and without visceral metastases had more favorable survival. The ability to walk after surgery was related to better survival.

Study II: A new score for prognosis of survival after surgery for spinal cord compression includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The score is simple, tumor specific, and easy to apply in clinical practice.

Study III: Our results suggest that delays in diagnosis and treatment may have negative impact on functional outcome. Pretreatment ability to walk, hormone status of prostate cancer, and time from loss of ambulation influenced neurological recovery after surgery for spinal cord compression.

Study IV: High nuclear AR immunostaining in bone metastases and high preoperative serum PSA were associated with a poor outcome after metastasis surgery in patients with hormone-refractory prostate cancer. Short-term effect of castration therapy disclosed that nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected.

Conclusion: Prostate cancer patients with metastatic spinal cord compression represent a heterogeneous group. We identified prognostic factors for survival and functional outcome, which may help clinicians in making decisions about treatment. Our results also implicate the need for development of local and regional guidelines for treatment of patients with spinal cord compression, as well as the importance of information to patients at risk.

Simplified Routines for Sample Preparation and Analysis of Chemical Warfare Agent Degradation Products

Raja Subramaniam — Fri, 4 May 2012 10:00:00 +0200

The thesis describes the development of new and improved methods for analyzing degradation markers from organophosphorus Chemical Warfare Agents (CWAs).

Paper I and II describes an innovative and significantly improved method for the enrichment, derivatization (trimethysilylation) and GC-MS analysis of a broad range of organophosphorus CWAs degradation markers, namely the alkylphosphonic acids and a zwitterionic compound. That was achieved using solid phase disc extraction in combination with solid phase derivatization. The new method overcomes most limitations observed with existing techniques: it offers almost 100 % recoveries, requires no elution or evaporation steps, facilitates miniaturization of the solid sorbent and reagent, is compatible with in-vial derivatization, and minimizes the chromatographic background due to the use of a highly selective anion exchange sorbent disc.

Paper III describes the development of new fluorinated diazomethane derivatization reagents and their evaluation for rapid and high sensitivity screening and identification of nerve agent degradation markers. The reagents are water-tolerant to some extent, which simplifies the derivatization step. The best reagent identified was 3,5-bis(trifluoromethyl)benzyl diazomethane, which outperformed the other reagent isomers tested and also the established commercial alternative, pentafluorobenzylbromide, allowing for the rapid (5 min) and direct derivatization of a 25 μL aqueous sample in acetonitrile. The spectra of the formed derivatives (high-energy collision induced fragmentation MS/MS) were used to construct a database (Paper IV) that proved to be superior in terms of match factor and probability compared to EI data gathered for trimethylsilyl derivatives. The study also focused on efforts towards achieving detailed structure information on the alkyl chains of the compounds in question using diagnostic ion interpretation.

The final paper (paper V) describes the first rapid direct derivatization method for analyzing nerve agent metabolites in urine at trace levels. The method is based on the derivative from the paper III and the unambiguous identification was proven using a combination of low resolution and high resolution negative ion chemical ionization selected ion monitoring techniques.

Novel results presented in these papers include: the first in-situ derivatization of alkylphosphonic acids on an SPE disc; the first direct derivatization of nerve agent markers in water and biomedical samples; the first high sensitivity GC-MS screening for these markers; and the first highly reproducible high-energy isomer specific CID MS/MS library. Overall, the results presented in this thesis represent significant contributions to the analysis of nerve agent degradation products.

Mellan frihet och trygghet : personalgemensamt förhållningssätt i psykiatrisk omvårdnad

Per Enarsson — Fri, 4 May 2012 13:53:00 +0200

Background: The common staff approach in psychiatric care has not been studied explicitly before. Earlier studies in related areas of social processes in psychiatric care highlight the importance of the interaction between the patient and the carer to understanding communication patterns and attitudes. Other studies on social order and power in psychiatric care shows carers and patients as taking part in a hierarchical system in which patients are subordinate to carers.

Aim: The overall aim of this thesis is to study the phenomenon of the common staff approach in psychiatric care, how it emerges, and how it is used and experienced by both carers and patients.

Method: In the first study, grounded theory was applied to data from observations and interviews carried out with carers and clients in two psychiatric care group dwellings. In the second and third studies, a phenomenological hermeneutic method was used to analyse narrative interviews conducted with nine careers working on psychiatric wards and nine patients with experience of psychiatric in-care, respectively. In the fourth study, qualitative content analysis was used to analyse data obtained by a vignette method from interviews with 13 carers with experience of working in psychiatric in-care.

Results: A common staff approach can be understood as a social process in municipality-level group dwellings and psychiatric in-care, imposed by carers on clients or patients with the aim of restoring a predetermined order desired by the carers. When the order is disturbed the carers try to restore it by adopting a common and consistent approach towards the single patient perceived as the threat to order.

Barriers to the success of a common staff approach, from the point of view of the carers, include the likelihood that colleagues will interpret situations differently, the chance that patients might succeed in dividing carers into “good” and “bad” camps, and the knowledge that the patient suffers under a common staff approach.

The patients’ experiences partly confirm those of the carers – the dominant picture is that the patient feels persecuted and suffers under a common staff approach. However in some situations, patients can perceived the common approach as supportive and aimed to promote their recovery.

Carers’ ethical reasoning about the common staff approach is usually applied on an individual basis; it can change depending upon the patient, the situation, and the proposed approach, as well as upon how the approach might affect other patients, staff members, or the carers themselves.

Conclusions: The overall results from the four studies show that the common staff approach may meet carers’ needs, which under the approach take precedence over those of patients, but that the approach is more an exercise in asserting power and maintaining control than it is a therapeutic technique; that it is a difficult choice for the single carer to choose between the interests of the patient and the approval of colleagues; that the patient often suffers when a common staff approach is used; and that carers are seldom aware of the suffering experienced by the patient being managed by such an approach. A common staff approach has no part in a care-strategy; it is not an intentional care-plan; instead it appears to be a way for carers who feel vulnerable and under pressure to maintain order by controlling particular patients.

Host-pathogen interactions between Francisella tularensis and Drosophila melanogaster

Malin Vonkavaara — Fri, 4 May 2012 08:22:00 +0200

Francisella tularensis is a highly virulent Gram-negative bacterium causing the zoonotic disease tularemia. Arthropod-borne transmission plays an important role in transferring the disease to humans. F. tularensis induces very low amounts of pro-inflammatory cytokines during infection, due to inhibition of immune signaling pathways and an unusual structure of its lipopolysaccharide (LPS). To date, there is no vaccine available that is approved for public use, although an attenuated live vaccine strain (LVS) is commonly used as a model of the more infectious Francisella strains. To produce an effective vaccine it is important to understand the lifecycle of F. tularensis, including the interaction with the arthropod hosts. Drosophila melanogaster is a widely used model organism, which is increasingly being used in host-pathogen interaction studies as the immune pathways in flies are evolutionary conserved to the immune pathways in humans. An important part of the immune defense of D. melanogaster as well as of arthropods in general is the production of antimicrobial peptides. These peptides primarily target the bacterial membrane, inhibiting bacterial proliferation or directly killing the bacteria.

The aim of this thesis was to establish D. melanogaster as a model for F. tularensis infection and as a model for arthropod vectors of F. tularensis. Also, to use D. melanogaster to further study the interaction between F. tularensis and arthropod vectors, with specific regard to the host immune signaling and arthropod antimicrobial peptides.

F. tularensis LVS infects and kills D. melanogaster in a dose-dependent manner. During an infection, bacteria are found inside fly hemocytes, phagocytic blood cells, similar as in human infections. In mammals genes of the intracellular growth locus (igl) are important for virulence. In this work it is shown that the igl genes are also important for virulence in flies. These results demonstrate that D. melanogaster can be used as a model to study F. tularensis-host interactions.

LVS induces a prolonged activation of several immune signaling pathways in the fly, but seem to interfere with the JNK signaling pathway, similarly as in mammals. Overexpression of the JNK pathway in flies has a protective effect on fly survival.

Relish mutant flies, essentially lacking a production of antimicrobial peptides, succumb quickly to a F. tularensis infection, however, F. tularensis is relatively resistant to individual D. melanogaster antimicrobial peptides. Overexpressing antimicrobial peptide genes in wildtype flies has a protective effect on F. tularensis infection, suggesting that a combination of several antimicrobial peptides is necessary to control F. tularensis. The production of numerous antimicrobial peptides might be why D. melanogaster survives relatively long after infection. An intact structure of the lipid A and of the Kdo core of Francisella LPS is necessary for resistance to antimicrobial peptides and full virulence in flies. These results are similar to previous studies in mammals. In contrast to studies in mammals, genes affecting the O-antigen of F. tularensis LPS are not necessary for virulence in flies.

In conclusion, this thesis work shows that D. melanogaster can be used as a model for studying F. tularensis-host interactions. LVS activates several immune pathways during infection, but interfere with the JNK pathway. Overexpressing the JNK pathway results in increased survival of flies infected with LVS. Despite rather high resistance to individual antimicrobial peptides, exposure to a combination of several D. melanogaster antimicrobial peptides reduces the virulence of F. tularensis.

Mentalitet, pedagogik, historiskt minne : Om utbildningens samtida villkor och processer

Maude Morssy Berglund — Fri, 4 May 2012 10:30:00 +0200

This thesis attempts to highlight the contemporary conditions and processes of education in order to define what kind of education dominates the 21st century School. What mentality and pedagogy are governing the design of the 21st century School? How can the historical perspective help to explain the conditions and processes in contemporary education? This thesis studies these questions by analyzing and interpreting active educational discourses from the beginning of the 21st century. The study is based on critical hermeneutics. The concepts are mentality, inherent pedagogy and historical memory. The material underlying the study consists of 351 news articles about education in the Swedish newspaper Västerbottens-Kuriren. The interpretation process has been carried out at different stages, in order to describe, explain and understand active educational discourses. This interpretation applies three complementary methods - text analysis, hermeneutic interpretation and critical discourse analysis. The findings indicate a mentality containing three main trends – equal togetherness, independent learning and independent freedom of choice, which arises from an inherent pedagogy containing two main trends - competence-developing and a performance-enhancing process. The contemporary mentality and pedagogy are emerging in the gap between Piaget´s and Skinner's educational ethos. At a shorter historical perspective, mentalities in the 1990s bear major structural similarities to the mentalities formed in the 21st century. In parallel, inherent pedagogy in the 1990s shares less structural similarities to the pedagogy formed in the 21st century. At a longer historical perspective, one will notice major structural similarities between the 18th century and the 21st century. What distinguishes one period from another is that the 18th century was a class society with teachers who had low ambitions, whereas the 21st century is a democratic society with teachers who have high ambitions. What unites the periods is that both the 18th and the 21st centuries witnessed great spatial and economic change. They are centuries of coercion and competition as well as centuries of freedom. In addition, they share the qualities of distance and control, and they both treat children as adults. Finally both centuries face unfinished policies with contradictory trends. From a media perspective, the debates from the 1990s and the editorials and facts from the 21st century news articles bear no similarities in terms of ideological positions on education.

Shedding Light on Shade- and Dark-Induced Leaf Senescence

Bastiaan Brouwer — Fri, 4 May 2012 11:00:00 +0200

Leaf senescence is the final stage of leaf development, during which the leaf relocates most of itsvaluable nutrients to developing or storing parts of the plant. As this process progresses, leaves losetheir green color and their capacity to perform photosynthesis. Shade and darkness are well-knownas factors inducing leaf senescence and it has been proposed that senescence can be initiated byreductions in photosynthesis, photomorphogenesis and transpiration. However, despite the fact thatthe signaling mechanisms regulating each of these processes have been extensively described,particularly in seedlings, their contribution to the initiation of senescence in mature leaves stillremains unclear. Furthermore, the use of different experimental systems to study shade-inducedleaf senescence has yielded several divergent results, which altogether complicate the overallunderstanding of leaf senescence.

To address this, darkened plants and individually darkened leaves, which show different rates of leafsenescence, were studied. Comparing the transcriptome and metabolome of these two darktreatmentsrevealed that they differed distinctly with regard to their metabolic strategies. Wholedarkened plants were severely carbohydrate-starved, accumulated amino acids and slowed downtheir metabolism. In contrast, individually darkened leaves showed continued active metabolismcoupled to senescence-associated degradation and relocation of amino acids.

This knowledge was used to set up a new system to study how shade affects leaf senescence in themodel plant Arabidopsis thaliana. Use of this system revealed that different senescence-associatedhallmarks appeared in response to different intensities of shade. Some of these hallmarks werefurther shown to be part of both leaf senescence and photosynthetic acclimation to low light.

Finally, using this system on phytochrome mutants revealed that loss of phytochrome A increasedthe loss of chlorophyll under shade, without increasing the expression of senescence-associatedgenes.

Together, these findings suggest that shade-induced leaf senescence, which is generally perceived asa single process, is actually an intricate network of different processes that work together tomaintain an optimal distribution of nutrients within the plant.

Hypertension in Vietnam : from community-based studies to a national targeted programme

Pham Thai Son — Fri, 11 May 2012 15:12:00 +0200

Background: In the context of transitional Vietnam, hypertension has been shown to be one of the ten leading causes of morbidity and mortality in hospitals. However, population-based data on hypertension are to a large extent lacking. This thesis aims to characterise the current epidemiology of hypertension in the adult Vietnamese population and provide preliminary evidence for developing effective community-based hypertension management programmes nationwide.

Methods: The study was conducted during 2002-2010. It includes two national surveys of the adult population aged 25 years and older, randomly selected in eight provinces in different regions of Vietnam, as well as a community-based programme on hypertension management in two communes of Bavi district. The survey on hypertension and associated risk factors, which included 9,832 adults, applied the WHO STEP-wise approach. The survey on hypertension-related knowledge and health seeking behaviour included 31,720 adults, using a structured questionnaire. For the community-based study, three-year follow-up data on 860 hypertensives was used to assess the effectiveness of the hypertension control model.

Main findings: Hypertension prevalence was high (overall 25.1%, 28.3% in men and 23.1% in women). The proportions of hypertensives aware, treated and controlled were unacceptably low (48.4%, 29.6% and 10.7% respectively). Most Vietnamese adults (82.4%) had good knowledge about high blood pressure. People received their information on hypertension from mass media (newspapers, radio, and especially television). Most people would choose a commune health station (75%) if seeking health care for hypertension. The programme on hypertension control was able to run independently at the commune health station. Severity of hypertension and effectiveness of treatment were the main factors influencing people’s adherence to the programme. The hypertension control programme successfully reduced blood pressure (systolic blood pressure: -2.2 mmHg in men and -7.8 mmHg in women; diastolic blood pressure: -4.3 mmHg in men and -6.8 mmHg in women), the estimated CVD 10-year risk (-2.5% in women), and increased the proportions of treatment (22% in men and 13.6% in women) and control (11% in men and 17.3% in women) among hypertensive people.

Suggestions for hypertension control: (1) Address the general population by developing community interventions, particularly salt reduction; (2) Provide interventions to individuals at high risk of a CVD event, including multi-drug treatment within patient-centred primary health care. (3) Set up a hypertension care network based in the existing health care system; (4) Improve and strengthen capacity and skills of medical staff in cardiac care, particularly staff at primary care level.

Female urinary incontinence : impact on sexual life and psychosocial wellbeing in patients and partners, and patient-reported outcome after surgery

Margareta Nilsson — Fri, 11 May 2012 15:26:00 +0200

Background: Urinary incontinence (UI) and urgency are common conditions and can have a profound influence on many aspects of life. Approximately one in four women has UI and one in ten has daily symptoms. Knowledge is lacking, however, on the impact of UI and urgency on the lives of affected women and their partners and on the situation of women with urinary leakage one year postoperatively.

Aims: To study the consequences of female UI and urgency for patients and their partners on quality of life (QoL), the partner relationship, and their sexual lives. Also to evaluate the success rates of three operation methods: tension-free vaginal tape (TVT), tension-free vaginal tape-obturator (TVT-O), and transobturator tape (TOT) for stress urinary incontinence (SUI), with a particular focus on women who still have urinary leakage one year after surgery.

Methods: Women seeking healthcare for UI and/or urgency and their partners were invited to answer questionnaires. The women completed disease-specific questionnaires and both the women (n = 206) and their partners (n = 109) answered questions about their psychosocial situation, partner relationship, and sexual life. Patient-reported outcomes one year after surgery with TVT, TVT-O, or TOT (n = 3334) were derived from the Swedish National Quality Register for Gynaecological Surgery.

Results: Most of the women reported that their urinary problems negatively affected their physical activities, and almost half reported negative consequences for their social life. Women aged 25–49 years were less satisfied with their psychological health, sexual life, and leisure than women aged 50–74 years. One third of both the women and their partners (all the partners were men) experienced a negative impact on their relationship, and sexual life was negatively affected in almost half of the women and one in five of their men. Coital incontinence was reported in one third of the women. Most of their men did not consider this a problem, but the majority of the affected women did.

Satisfaction with outcome of the operation did not differ between TVT, TVT-O, and TOT, but TVT showed a higher success rate for SUI than TOT did. Higher age, higher body mass index, a diagnosis of mixed urinary incontinence, and a history of urinary leakage in combination with urgency each constitute a risk for a lower operation success rate. After one year, 29% of the women still had some form of UI, but half of these were satisfied with the outcome and most reported fewer negative impacts on family, social, working, and sexual life than before the operation.

Conclusions: Female UI and/or urgency impaired QoL, particularly in young women, and had negative effects on partner relationships and on some partners’ lives. Sexual life was also affected, more often in women with UI and/or urgency than in their partners. At one-year follow-up after surgery, about one third of the women still had some form of UI, but the negative impact on their lives was reduced. A challenge for health care professionals is to initiate a dialogue with women with urinary symptoms about sexual function and what surgery can realistically be expected to accomplish.

Characterization of FtsH proteases in the annual plant Arabidopsis thaliana

Harald Aigner — Fri, 11 May 2012 10:00:00 +0200

Background FtsH is an ATP-dependent membrane-bound metalloprotease. A. thaliana contains 12 FtsH proteases localized in membranes of chloroplasts and mitochondria where they form homo- or hetero-hexameric complexes. FtsH11 – the main subject of this thesis – is located in the chloroplast envelope.

Methods

Field studies with A. thaliana to determine Darwinian fitness. A growth under outdoor conditions often allows discovering of phenotypes that are unascertainable in the controlled environment of growth chambers.
Proteomic methods to discover fragments of substrate proteins (limited proteolysis) and changes in the proteome of FtsH protease deficient mutants.

Results ftsh11 has increased amount of: RuBisCO activase, several Calvin cycle enzymes, two enzymes involved in starch synthesis and some chaperons. Some of those enzymes have been identified as possible substrates of FtsH11. Under long photoperiods ftsh11 develops a chlorotic phenotype accompanied by decreasing NADP⁺/NADPH ratio and increase of ROS damaged proteins.

Understanding and managing cardiovascular disease risk factors in Vietnam : integrating clinical and public health perspectives

Quang Ngoc Nguyen — Fri, 11 May 2012 15:00:00 +0200

Background: Vietnam, like other low-income countries, is facing an epidemic burden of cardiovascular disease risk factors (CVDRFs). The magnitude and directions of CVDRF progression are matters of uncertainty.

Objectives: To describe the epidemiological progression of CVDRFs and the preventive effects of community lifestyle interventions, with reference to the differences in progression of CVDRF patterns between men and women.

Methods: The study was conducted during 2001-2009 in nationally representative samples and in a local setting of rural areas of Ba-Vi district, Ha-Tay province. Both epidemiological and interventional approaches were applied: (i) a population-based cross-sectional survey of 2,130 people aged ≥25 years in Thai-Binh and Hanoi; (ii) an individual participant-level meta analysis of 23,563 people aged 24-74 years from multiple similar surveys in 9 provinces around Vietnam; (iii) a 17-month cohort study of 497 patients in a hypertension management programme; (iv) a quasi-experimental trial on community lifestyle promotion integrated with a hypertension management programme, evaluated by surveys of 4,645 people in both intervention and reference communes before and after a 3-year intervention.

Main findings: (i) in the general adult population ≥25 years, CVDRFs were common, often clustered within individuals, and increased with age; (ii) the Vietnamese population is facing a growing epidemic of CVDRFs, which are generally not well managed; (iii) it is possible to launch a community intervention in low-resource settings within the scope of a commune-based patient-targeted programme on hypertension management; (iv) community health intervention with comprehensive healthy lifestyle promotion improves blood pressure and some behavioural CVDRFs.

Conclusion: Alarming increases in CVDRFs in the general population need comprehensive multi-level prevention strategies, which combine both individual high-risk and population health approaches. The commune-based hypertension-centred management programmes integrated with community health promotion are the initial but essential steps towards comprehensive and effective management of CVDRFs and should be part of an integrated and co-ordinated national program on the prevention and control of chronic diseases in low-resource settings like Vietnam.

Individual placement and support (IPS) i en socialpsykiatrisk kontext : en väg till arbete för personer med psykiskt funktionshinder?

Ulla Nygren — Fri, 11 May 2012 15:34:00 +0200

Introduktion

Delaktighet i arbete är för de allra flesta människor en önskad och viktig aktivitet av många olika anledningar, men för personer med en psykisk sjukdom är inklusionen i arbetslivet begränsad. I Sverige är en psykiatrisk diagnos den vanligaste orsaken till sjukskrivning och värst är situationen för unga personer (2011). Det finns ett mycket stort behov av rehabilitering till arbete för personer med en psykisk sjukdom. En metod för detta är Individual Placement and Support (IPS), som internationellt betraktas som den mest effektiva insatsen för att hjälpa dessa personer till anställning. Syftet med denna avhandling är att undersöka IPS i en socialpsykiatrisk kontext med avseende på arbetsrelaterade och icke arbetsrelaterade utfall, prediktorer för anställning och deltagarnas uppfattning om kompetens i vardagen. Ett ytterligare syfte var att beskriva det kvalitativa innehållet i IPS-insatsen ur klienternas och IPS-coachernas perspektiv.

Metod

Forskningsprojektets kontext utgjordes av två IPS-verksamheter, vilka var organiserade i respektive kommuns socialtjänst som tidsbegränsade projekt. Sextiofem män och kvinnor med olika psykiska sjukdomar som deltog i verksamheternas IPS-program inkluderades i studien. Arbetsrelaterade data rapporterades varannan månad av IPS-coacherna under två års uppföljning och innefattade: typ av sysselsättning och omfattning, typ och omfattning av IPS-insats, samt beskrivningar av vad som underlättat respektive försvårat i arbetet med klienterna. Icke arbetsrelaterade data samlades in vid baseline, vid 12 månader och vid 24 månader: psykiatriska symtom, självkänsla, livskvalitet, generellt psykosocialt fungerande, aktivitetskompetens och aktivitetsvärdering, samt delaktighet. Deltagarna intervjuades också vid 12 och 24 månader. Data analyserades i olika kombinationer i de fyra delstudier som är inkluderade i avhandlingen. Mest användes icke-parametrisk statistik, men också Rasch-analyser. I den sista delstudien tillämpades en kvalitativ fallstudiemetodik.

Resultat

Tjugofem procent var vid något tillfälle under det första året i anställning och ytterligare 14 procent var engagerade i reguljära studier. Alla utom fyra av deltagarna var vid något tillfälle i sysselsättning i någon form, mestadels i arbetsträning på vanlig arbetsplats. Omfattningen av anställning, studier och arbetsträning under det första året varierade mellan endast en vecka till 41 veckor. En liknande variation fanns i antalet timmar i sysselsättning. Deltagare i någon form av sysselsättning vid 12 månader visade positiva förändringar över tid med avseende på psykiatriska symtom (p=0.000) och psykosocialt fungerande (p=0.000). Dessa personer var också mer tillfredsställda med sin sysselsättningssituation (p=0.009). Tre potentiella prediktorer för anställning kunde identifieras, men bara psykiatriska symtom kvarstod som signifikant på en nivå av p<0.05. En lägre grad av psykiatriska symtom ökade oddset med 5.5 för att uppnå anställning under ett år. Generellt skattade deltagarna värdet av att kunna utföra olika aktiviteter i vardagen högre än hur de skattade sin förmåga att utföra dessa. Kliniskt meningsfulla glapp återfanns bland de mest värderade som handlade om att kunna sköta sin ekonomi och sina grundläggande behov, samt att kunna göra det man tycker om att göra. Flera av de aktiviteter som uppfattades som svårast att utföra är relaterade till förmågor av betydelse för att uppnå anställning. Fallstudien illustrerade komplexa processer i IPS-interventionen. En av dessa visade på betydelsen av reflekterade erfarenheter för klienters omkonstruktion av sina aktivitetsidentiteter och betydelsen av kontinuitet för att kunna göra det.

Diskussion

Deltagandet i IPS-programmen resulterade i sysselsättningsförändringar för de allra flesta av deltagarna, men proportionen i anställning var låg i jämförelse med de allra flesta internationella resultat. Komplexa processer uppstod på vägen i riktning mot arbete och både i de framgångsrika och mindre framgångsrika fallen, avseende anställning, förändrades personernas upplevelse av sig själva som aktörer. IPS är betraktad som evidensbaserad för personer med allvarlig psykisk sjukdom, vilket vanligen inkluderar personer med schizofreni och andra psykossjukdomar, men den undersökta gruppen av deltagare dominerades av personer med olika tillstånd av ångest och depression och relativt många personer hade neuropsykiatriska diagnoser. I kontrast till många andra studier av IPS, identifierades en lägre grad av psykiatriska symtom utgöra en prediktor för att bli anställd. Deltagarnas uppfattning om aktivitetskompetens och värdering av kompetens visade att det fanns glapp däremellan, som är viktiga att uppmärksamma när insatser ges i syfte att främja utvecklingen av värderad kompetens bland personer med psykiskt funktionshinder.

Slutsats

Denna avhandling representerar ett av de första försöken att studera IPS i en svensk kontext som kännetecknas av att det är socialtjänsten som är delvis ansvarig för psykiatrisk rehabilitering. Interventionen kan betraktas som användbar, men designen på denna studie tillåter inte att dra slutsatser om dess effektivitet. Genom att samla mer detaljerad information från klienters och IPS-coachers erfarenheter är det möjligt att få syn på processer som uppstår i en IPS-intervention och några av de komponenter som är av speciell betydelse för denna. Konsekvenserna av att ha högre grad av psykiatriska symtom tycks vara en barriär mot att bli anställd. En viktig förutsättning för att kunna förverkliga IPS uppfattas vara koordinerade samarbeten mellan de involverade aktörerna.

Pedagogisk ledning för en pedagogisk verksamhet? : Om den kommunala förskolans ledningsstruktur

Maria Styf — Tue, 15 May 2012 13:00:00 +0200

This thesis is a total coverage survey of the municipal preschool management structure. In the late 90's the preschool in Sweden became the first step in the overall educational system. It became a pedagogical activity similar to school with respect to form and content. Although the focus was on education, political voices reclaimed the unique nature of preschool i.e. educare. It became a preschool in transition between its own tradition and modernization. The idea is that the educational management structure should support a pedagogical leadership that directs the pedagogical activity towards preschool objectives. The local authority sets the structure for management in pre-school; a municipality that in itself is an institution with its own goals and objectives. These objectives can place the municipalities in the cross pressure between their own objectives and the ones for preschool. The question in this respect is; How is the management structure formed and why? Is it a structure formed with the intention of creating educational management for the local preschool or are there other factors that guide the design? A framework based on the historical background of the preschools and theoretical terms such as steering, leading, management, pedagogical leadership, educational activity, etc. was constructed. Results are based on an online questionnaire survey. 180 municipalities out of 290 answered the questionnaire, which gives a response rate at 62 %. The response rate is evenly distributed across municipal categories, categories that the municipalities were aggregated into, formed by The Swedish Association of Local Authorities and Regions. The categories were handled as survey units, to support a part of the analysis and to allow a comparison between the municipalities by municipality size, both demographic and geographic. The material was analysed using the SPSS statistical program and compiled and reported with descriptive statistics. Descriptive statistics were used to demonstrate the material's characteristics and the central tendency. The results show that the municipalities’ structure of management is varied. Different municipal categories do not change this varied picture of the management landscape significantly. Although the management structure varies regarding how many levels with formal titles and which positions and functions they should have, there is a consistency in which title that the formal leader for the preschool have. The municipalities primarily utilisea principalship with mixed responsibility for both preschool and school. In light of these results, do municipalities mould a structure for the educational management for the pedagogical activities in preschool? Yes and no: the municipalities do not form a structure for preschool alone. Results show that the municipalities' main purpose is not to create a line of management specifically for the preschool. The municipalities form a management structure for educational purposes dealing with an educational activity from preschool to elementary school. The new Education Act (2010:800), is a step toward distinguishing preschool leadership from school leadership and turns the leadership of preschools into a title solely for the position and function of preschool educational activities.

Closure of midline abdominal incisions with small stitches : studies on wound complications and health economy

Daniel Millbourn — Tue, 15 May 2012 09:58:00 +0200

Background A midline incision inflicts minimal damage to muscles, nerves and blood supply. Postoperative complications cause patients suffering and costs for society. Midline incisions should be closed with a continuous single-layer technique and a suture length (SL) to wound length (WL) ratio over 4. It has been recommended to place stitches at least 10 mm from the wound edge. Recent studies, taking the SL to WL ratio into account, have shown that a stronger wound is produced with small stitches placed closer to the wound edge.

Aims The aims were to study the rate of surgical site infection (SSI) and incisional hernia in relation to the use of small or large stitches; to study the effect of the SL to WL ratio and other risk factors for SSI and incisional hernia in relation to the size of stitches; and to study if the use of small stitches generates cost savings.

Materials and methods In a non-randomised study, 1991 to 1993, the patients having their midline incisions closed with an SL to WL ratio over 4 were selected. The rate of SSI and incisional hernia was analysed in relation stitch length (SL/number of stitches). In a randomised trial, 2001 to 2006, patients were randomised to closure of midline incisions with small stitches, placed 5 to 8 mm from the wound edge, or large stitches placed at a distance of at least 10 mm. Patient and operative characteristics were recorded. The rate of SSI and incisional hernia was studied and risk factors were analysed. The proportion of patients subjected to an incisional hernia repair was identified. The mean cost for a hernia repair during 2010 was calculated. A cost analysis was performed.

Results In the non-randomised study 368 patients were analysed. The lowest rate of SSI and incisional hernia was with a short stitch length. In the randomised trial, 356 patients were closed with small stitches and 381 with large. With small stitches SSI occurred in 17 of 326 patients (5.2%) and with large stitches in 35 of 343 (10.2%) (p=0.02). With small stitches incisional hernia was present in 14 of 250 patients (5.6%) and with large stitches in 49 of 272 (18.0%) (p<0.001). With small stitches, no risk factors could be identified. The rate of incisional hernia was lower with an SL to WL ratio over 4. A very high ratio did not affect the complication rates. With small stitches there was a cost for a longer suturing time, but a cost reduction of 1339 SEK was generated from the societal perspective for each closure compared with large stitches.

Conclusions In midline abdominal incisions closed with a continuous single-layer technique the rate of SSI and incisional hernia is lower with small stitches than with large. The rate of incisional hernia is lower with an SL to WL ratio over 4 and increasing the ratio very much above 4 does not increase the rate of complications. With small stitches no risk factors for the development of SSI and incisional hernia can be identified and cost savings are generated. The previous recommendation to use large stitches should be changed to recommend small stitches.

Insights into the effect of myocardial revascularisation on electrical and mechanical cardiac function

Ihab S Ramzy — Wed, 16 May 2012 08:25:00 +0200

Background: Acute coronary syndrome is known for its effect on cardiac function and can lead to impaired segmental and even global myocardial function. Evidence exists that myocardial revascularisation whether pharmacological, interventional or surgical results in improvement of systolic and diastolic left ventricular (LV) function, particularly that of the long axis which represents the sub-endocardial function, known as the most sensitive layer to ischaemia.

Objective: We sought to gain more insight into the early effect of pharmacological and interventional myocardial revascularisation on various aspects of cardiac function including endocrine, electrical, segmental, twist, right ventricular (RV) and left atrial (LA) function. In particular, we aimed to assess the response of ventricular electromechanical function to thrombolysis and its relationship with peptides levels. We also investigated the behaviour of RV function in the setting of LV inferior myocardial infarction (IMI) during the acute insult and early recovery. In addition, we aimed to assess in detail LA electrical and mechanical function in such patients. Finally, we studied the early effect of surgical revascularisation on the LV mechanics using the recent novel of speckle tracking echocardiography technology to assess rotation, twist and torsion and the strain deformation parameters as a tool of identifying global ventricular function.

Methods: We used conventionally Doppler echocardiographic transthoracic techniques including M-mode, 2-Dimentional, myocardial tissue Doppler, and speckle tracking techniques. Commercially available SPSS as a software was used for statistical analysis.

Results: 1-The elevated peptide levels at 7 days post-myocardial infarction correlated with the reduced mechanical activity of the adjacent non-infarcted segment thus making natriuretic peptides related to failure of compensatory hyperdynamic activity of the non-infarcted area rather than the injured myocardial segments. 2-RV segmental and global functions were impaired in acute IMI, and recovered in 87% of patients following thrombolysis. In the absence of clear evidence for RV infarction the disturbances in the remaining 13% may represent stunned myocardium with its known delayed recovery. 3-LA electromechanical function was impaired in acute inferior STEMI and improved after thrombolysis. The partial functional recovery suggests either reversible ischaemic pathology or a response to a non-compliant LV segment. The residual LA electromechanical and pump dysfunction suggest intrinsic pathology, likely to be ischaemic in origin. 4-LV function was maintained in a group of patients with multivessel coronary artery disease who underwent coronary artery bypass graft (CABG) surgery. Surgical myocardial revascularisation did not result in any early detectable change in the three functional components of the myocardium, including twist and torsion, as opposite to conventional percutaneous coronary intervention (PCI).

Conclusion: The studied different materials in this thesis provide significant knowledge on various aspects of acute ischaemic cardiac pathology and early effect of revascularisation. The use of non-invasive imaging, particularly echocardiography with its different modalities, in studying such patients should offer immediate thorough bed-side assessment and assist in offering optimum management.

Stereotactic imaging in functional neurosurgery

Hidehiro Hirabayashi — Wed, 16 May 2012 08:33:00 +0200

Background: The birth of stereotactic functional neurosurgery in 1947 was to a great extent dependent on the development of ventriculography. The last decades have witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders. Initially, these procedures were largely based on the same imaging technique that had been used since the birth of this technique, and that is still used in some centers. The introduction of new imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provided new potentials, but also new challenges for accurate identification and visualisation of the targets in the basal ganglia and the thalamus with an urge to thoroughly evaluate and optimize the stereotactic targeting technique, as well as evaluate accurately in stereotactic space the location and extent of stereotactic Radiofrequency (RF) lesions and the position of deep brain stimulation (DBS) electrodes.

Aims: To study the differences between CT and MRI regarding indirect atlas coordinates in thalamic and pallidal procedures and to evaluate and validate visualisation of the pallidum and the subthalamic nucleus in view of direct targeting irrespective of atlas-derived coordinates. Furthermore, to evaluate the contribution of RF parameters on the size of stereotactic lesions, as well as the impact of size and location on clinical outcome.

Method: The coordinates in relation to the landmarks of the 3^rd ventricle of the targets in the pallidum and ventrolateral thalamus were compared between CT and MRI in 34 patients. In another 48 patients direct visualization of the pallidum was evaluated and compared to indirect atlas based targeting. The possibility and versatility of visualizing the Subthalamic Nucleus (STN) on short acquisition MRI were evaluated in a multicentre study, and the use of alternative landmarks in identification of the STN was demonstrated in another study. In 46 patients CT and MRI were compared regarding the volume of the visible RF lesions. The volume was analysed with regard to coagulation parameters, and the location and size of the lesions were further evaluated concerning the clinical outcome.

Results:Minor deviations were seen between MRI and CT coordinates of brain targets. The rostro-caudal direction of these deviations were such that they would be easily accounted for during surgery, why MRI can obviate the need for CT in these procedures. MRI using a proton density sequence provided detailed images of the pallidal structures, which demonstrated considerable inter-individual variations in relation to the landmarks of the 3^rd ventricle. By using a direct visualization of the target, each patient will act as his or her own atlas, avoiding the uncertainties of atlas-based targeting. The STN could be visualized on various brands of MRI machines in 8 centers in 6 countries with good discrimination and with a short acquisition time, allowing direct visual targeting. The same scanning technique could be used for postoperative localization of the implanted electrodes. In cases where the lateral and inferior borders of the STN cannot be easily distinguished on MRI the Sukeroku sign and the dent internal-capsule-sign signs might be useful. The volume of a stereotactic RF lesion could be as accurately assessed by CT as by MRI. The lesion´s size was most strongly influenced by the temperature used for coagulation. The lesions´ volumes were however rather scattered and difficult to predict in the individual patient based solely on the coagulation parameters. For thalamotomy, the results on tremor was not related to the lesion´s volume. For pallidotomy, larger and more posterior-ventral lesions had better effect on akinesia while effects on tremor and dyskinesias were not related to size or location of the lesions.

Conclusions: The minor deviations of MRI from CT coordinates can be accounted for during surgery, why MRI can obviate the need of CT in these procedures. Direct visualized targeting on MRI of the pallidum is superior to atlas based targeting. The targets in the pallidum and the STN, as well as the location of the electrodes, can be well visualized with short acquisition MRI. When borders of the STN are poorly defined on MRI the Sukeroku sign and the dent internal-capsule-sign signs proved to be useful. The volumes of RF lesions can be accurately assessed by both stereotactic thin slice CT and MRI. The size of these lesions is most strongly influenced by the temperature of coagulation, but difficult to predict in the individual patient based on the coagulation parameters.

Within certain limits, there were no clear relationships between lesions´ volume and location and clinical effects of thalamotomies and pallidotomies.

Oral lichen planus : studies of factors involved in differentiation, epithelial mesenchymal transition and inflammation

Karin Danielsson — Wed, 16 May 2012 12:27:00 +0200

Background: Lichen planus is a chronic inflammation of skin and mucosa with unknown cause. Oral Lichen Planus, OLP, affects around 2% of the population. Autoimmunity has been suggested as a possible cause as the disease has autoimmune features such as female predominance, cyclic nature and cytotoxic T-cell infiltrate. It has been suggested that the intense inflammatory response seen in OLP is caused by factors on the keratinocyte surface triggering the immune system. Chronic inflammation is one of the hallmarks of oral lichen planus and chronic inflammation is connected to increased risk of tumor development. WHO classifies OLP as a potentially malignant condition with increased risk of developing Squamous cell carcinoma of head and neck, SCCHN, but malignant transformation of OLP is a matter of controversy. The aim of these studies was to further elucidate the autoimmune and premalignant character of OLP. Factors involved in malignant transformation, autoimmunity and inflammation were analyzed in normal oral mucosa, OLP and SCCHN. Factors studied were the signal transducers of Transforming growth factor-β the Smad proteins, microRNAs, COX-2, the receptor CXCR-3 and its ligands CXCL-10 and -11 and ELF-3.

Material and methods: In the study on Smad protein expression formalin fixed and paraffin embedded biopsies from normal oral mucosa, OLP and SCCHN was used. For the remaining studies fresh frozen biopsies from OLP and normal controls was used. All of the fresh frozen OLP samples and their controls were micro dissected to be able to analyze the epithelial part only as well as sections of the whole biopsy. Methods used are immunohistochemistry, qRT-PCR and Western blot.

Results: Analyses of smad proteins expression showed a clear increase of smad3 and smad7 in OLP compared to normal oral mucosa. The expressions of smad proteins in the tumors were more heterogeneous. Some of the SCCHN samples showed a similar expression as OLP while others did not. Micro RNA analyzes showed that miR-21 and miR-203 was significantly increased in OLP epithelium compared to normal oral epithelium while the expression of miR-125b and their potential targets p53 and p63 was decreased in OLP. The presence of COX-2 was significantly higher in OLP than normal controls. At the same time the expression of miR-26b, a suggested repressor of COX-2 was decreased in OLP compared to normal mucosa. The receptor CXCR-3 and its ligands CXCL-10 and -11 were increased in OLP. Expressions of the differentiation involved factor ELF-3 mRNA as well as protein were decreased in OLP.

Conclusion: The factors studied are involved in differentiation, malignant transformation and inflammation. Some of the results in these studies indicate a similar expression pattern for OLP and SCCHN. Several of the factors studied are involved in differentiation and their deregulation suggests a disturbed differentiation pattern and this could indicate a premalignant character of OLP but malignant transformation of OLP lesions are relative rare. A lot of these factors are also involved in inflammatory processes and connected to autoimmune diseases and their deregulation in OLP could also support an autoimmune cause of the disease. Based on our studies a suggestion is that the disturbed differentiation pattern triggers the intense immune response directed against the epithelial cells seen in OLP.

Cerebral blood flow and intracranial pulsatility studied with MRI : measurement, physiological and pathophysiological aspects

Anders Wåhlin — Wed, 16 May 2012 11:26:00 +0200

During each cardiac cycle pulsatile arterial blood inflates the vascular bed of the brain, forcing cerebrospinal fluid (CSF) and venous blood out of the cranium. Excessive arterial pulsatility may be part of a harmful mechanism causing cognitive decline among elderly. Additionally, restricted venous flow from the brain is suggested as the cause of multiple sclerosis. Addressing hypotheses derived from these observations requires accurate and reliable investigational methods. This work focused on assessing the pulsatile waveform of cerebral arterial, venous and CSF flows. The overall aim of this dissertation was to explore cerebral blood flow and intracranial pulsatility using MRI, with respect to measurement, physiological and pathophysiological aspects.

Two-dimensional phase contrast magnetic resonance imaging (2D PCMRI) was used to assess the pulsatile waveforms of cerebral arterial, venous and CSF flow. The repeatability was assessed in healthy young subjects. The 2D PCMRI measurements of cerebral arterial, venous and CSF pulsatility were generally repeatable but the pulsatility decreased systematically during the investigation.

A method combining 2D PCMRI measurements with invasive CSF infusion tests to determine the magnitude and distribution of compliance within the craniospinal system was developed and applied in a group of healthy elderly. The intracranial space contained approximately two thirds of the total craniospinal compliance. The magnitude of craniospinal compliance was less than suggested in previous studies.

The vascular hypothesis for multiple sclerosis was tested. Venous drainage in the internal jugular veins was compared between healthy controls and multiple sclerosis patients using 2D PCMRI. For both groups, a great variability in the internal jugular flow was observed but no pattern specific to multiple sclerosis could be found.

Relationships between regional brain volumes and potential biomarkers of intracranial cardiac-related pulsatile stress were assessed in healthy elderly. The biomarkers were extracted from invasive CSF pressure measurements as well as 2D PCMRI acquisitions. The volumes of temporal cortex, frontal cortex and hippocampus were negatively related to the magnitude of cardiac-related intracranial pulsatility.

Finally, a potentially improved workflow to assess the volume of arterial pulsatility using time resolved, four-dimensional phase contrast MRI measurements (4D PCMRI) was evaluated. The measurements showed good agreement with 2D PCMRI acquisitions.

In conclusion, this work showed that 2D PCMRI is a feasible tool to study the pulsatile waveforms of cerebral blood and CSF flow. Conventional views regarding the magnitude and distribution of craniospinal compliance was challenged, with important implications regarding the understanding of how intracranial vascular pulsatility is absorbed. A first counterpoint to previous near-uniform observations of obstructions in the internal jugular veins in multiple sclerosis was provided. It was demonstrated that large cardiac- related intracranial pulsatility were related to smaller volumes of brain regions that are important in neurodegenerative diseases among elderly. This represents a strong rationale to further investigate the role of excessive intracranial pulsatility in cognitive impairment and dementia. For that work, 4D PCMRI will facilitate an effective analysis of cerebral blood flow and pulsatility.

Biomechanical and neural aspects of eccentric and concentric muscle performance in stroke subjects : Implications for resistance training

Mattias Hedlund — Wed, 16 May 2012 15:00:00 +0200

Muscle weakness is one of the major causes of post-stroke disability. Stroke rehabilitation programs now often incorporate the same type of resistance training that is used for healthy subjects; however, the training effects induced from these training strategies are often limited for stroke patients. An important resistance training principle is that an optimal level of stress is exerted on the neuromuscular system, both during concentric (shortening) and eccentric (lengthening) contractions. One potential problem for post-stroke patients might be difficulties achieving sufficient levels of stress on the neuromuscular system. This problem may be associated with altered muscular function after stroke. In healthy subjects, maximum strength during eccentric contractions is higher than during concentric contractions. In individuals with stroke, this difference in strength is often increased. Moreover, it has also been shown that individuals with stroke exhibit alteration with respect to how the strength varies throughout the range of motion. For example, healthy subjects exhibit a joint specific torque-angle relationship that normally is the same irrespective of contraction mode and contraction velocity. In contrast, individuals with stroke exhibit an overall change of the torque-angle relationship. This change, as described in the literature, consists of a more pronounced strength loss at short muscle length. In individuals with stroke, torque-angle relationships are only partially investigated and so far these relationships have not been analysed using testing protocols that include eccentric, isometric, and concentric modes of contraction.

This thesis investigates the torque-angle relationship of elbow flexors in subjects with stroke during all three modes of contractions – isometric, concentric, and eccentric – and the relative loading throughout the range of movement during a resistance exercise. In addition, this thesis studies possible central nervous system mechanisms involved in the control of muscle activation during eccentric and concentric contractions.

The torque-angle relationship during maximum voluntary elbow flexion was examined in stroke subjects (n=11), age-matched healthy subjects (n=11), and young subjects (n=11) during different contraction modes and velocities. In stroke subjects, maximum torque as well as the torque angle relationship was better preserved during eccentric contractions compared to concentric contractions. Furthermore, the relative loading during a resistance exercise at an intensity of 10RM (repetition maximum) was examined. Relative loading throughout the concentric phase of the resistance exercise, expressed as percentage of concentric torque, was found to be similar in all groups. However, relative loading during the eccentric contraction phase, expressed as the percentage of eccentric isokinetic torque, was significantly lower for the stroke group. In addition, when related to isometric maximum voluntary contraction, the loading for the stroke group was significantly lower than for the control groups during both the concentric and eccentric contraction phases.

Functional magnetic resonance imaging was used to examine differences between recruited brain regions during the concentric and the eccentric phase of imagined maximum resistance exercise of the elbow flexors (motor imagery) in young healthy subjects (n=18) and in a selected sample of individuals with stroke (n=4). The motor and premotor cortex was less activated during imagined maximum eccentric contractions compared to imagined maximum concentric contraction of elbow flexors. Moreover, BA44 in the ventrolateral prefrontal cortex, a brain area that has been shown to be involved in inhibitory control of motor activity, was additionally recruited during eccentric compared to concentric conditions. This pattern was evident only on the contralesional (the intact hemisphere) in some of the stroke subjects. On the ipsilesional hemisphere, the recruitment in ventrolateral prefrontal cortex was similar for both modes of contractions.

Compared to healthy subjects, the stroke subjects exhibited altered muscular function comprising a specific reduction of torque producing capacity and deviant torque-angle relationship during concentric contractions. Therefore, the relative training load during the resistance exercise at a training intensity of 10RM was lower for subjects with stroke. Furthermore, neuroimaging data indicates that the ventrolateral prefrontal cortex may be involved in a mechanism that modulates cortical motor drive differently depending on mode of the contractions. This might partly be responsible for why it is impossible to fully activate a muscle during eccentric contractions. Moreover, among individuals with stroke, a disturbance of this system could also lie behind the lack of contraction mode-specific modulation of muscle activation that has been found in this population. The altered neuromuscular function evident after a stroke means that stroke victims may find it difficult to supply a sufficient level of stress during traditional resistance exercises to promote adaptation by the neuromuscular system. This insufficiency may partially explain why the increase in strength, in response to conventional resistance training, often has been found to be low among subjects with stroke.

Blir du anställningsbar lille/a vän? : Diskursiva konstruktioner av framtida medborgare i gymnasiereformer 1971-2011

Sara Carlbaum — Tue, 15 May 2012 09:00:00 +0200

School is one of the most important institutions society has for fostering its future citizens. Education policy can be seen as an important arena for the discursive struggle over the meaning of education, not only what it is for, its goals and purposes, but also its deficiencies. Education policies are not mirrors of reality but include a power dimension in describing the problems to be solved. Thus, a specific question or a particular phenomenon is given a certain value and meaning. The different articulations involved in representations of problems construct certain subject positions of citizenship which are not open for everyone. This makes it essential to deconstruct these gendered, racialized and classed subject positions. In the same way as in the beginning of the 1990s, the Swedish school system is currently facing changes. The most recent reform of upper secondary education, implemented in 2011, needs to be viewed in a historical perspective.

This thesis analyses discursive continuity and change with regard to representations of the problems, goals and purposes of upper secondary education during the period 1971-2011. Focus is also placed on changes and continuities in how the good future citizen is constructed and in what ways gender, class and ethnicity are produced in these constructions.

The theoretical framework is inspired and informed by discourse theory, feminist theory and theories on citizenship. Adopting this approach, I analyse government policy documents concerning upper secondary education reforms. The analysis shows not only changes, but also the importance of continuities in the dominating discourses of a school for all (1971-1989); a school for lifelong learning (1990-2005); and a school for the labour market (2006-2011). A shift from integration to differentiation is revealed in which the silencing of signifiers, such as democracy, equality and multiculturalism, lead to a risk of unequal opportunities for people to politicize their experience and situation. The previous demands for retraining and flexibility, for emancipation and lifelong learning are marginalised in favour of employability, skill supply and entrepreneurship. The constructions of good future citizens as consumers become instead constructions of citizens as products for business and growth. A male productive worker and male entrepreneur are constructed, privileging a white middle class. Neo-liberal and neo-conservative influences, reinforce the individual’s responsibility to become included in what is constructed as a desired citizenship.

Målsättning riksdagen : Ett aktörsperspektiv på nya partiers inträde i det nationella parlamentet

Niklas Bolin — Tue, 15 May 2012 09:00:00 +0200

During much of the 20th century, the national party systems of Western Europe remained largely unchanged. However, beginning in the 1970s, these frozen party systems slowly started to melt. As the number of parties has increased, the question of what explains new party entrance has also attracted more scholarly interest.

Despite this increased attention, the study of new political parties still suffers from a structuralist bias. The implication is that the fates of new parties are decided almost exclusively by external factors. Some scholars focus on the institutional environment; others emphasize sociological explanations, such as the formation of new cleavages in society.

Yet such non-actor-centred perspectives risk being excessively deterministic. They also struggle to explain why some parties succeed in gaining entrance to legislatures while others, seemingly under the same external circumstances, fail. In this thesis, therefore, a new way to study parties and their path to parliament is proposed. Starting with the notion that external conditions alone cannot explain new party entrance, the thesis takes an agency-based perspective. Three sets of strategies are identified as being important means for a party to influence its chances of getting into parliament. They concern the party's resources, its political project and its external relations. In what ways can supply and management of resources, policies and relations with other parties affect the potential for becoming a parliamentary party?

Through four in-depth case studies of new entrants into the Swedish national parliament, the Riksdag, the thesis concludes that there are some important commonalities in their paths to parliament. Especially with regard to their resources and their political project, the empirical evidence supports the initial premise: new party entrance is unthinkable without successful strategic behaviour.

OnPLS : Orthogonal projections to latent structures in multiblock and path model data analysis

Tommy Löfstedt — Wed, 16 May 2012 11:00:00 +0200

The amounts of data collected from each sample of e.g. chemical or biological materials have increased by orders of magnitude since the beginning of the 20th century. Furthermore, the number of ways to collect data from observations is also increasing. Such configurations with several massive data sets increase the demands on the methods used to analyse them. Methods that handle such data are called multiblock methods and they are the topic of this thesis.

Data collected from advanced analytical instruments often contain variation from diverse mutually independent sources, which may confound observed patterns and hinder interpretation of latent variable models. For this reason, new methods have been developed that decompose the data matrices, placing variation from different sources of variation into separate parts. Such procedures are no longer merely pre-processing filters, as they initially were, but have become integral elements of model building and interpretation. One strain of such methods, called OPLS, has been particularly successful since it is easy to use, understand and interpret.

This thesis describes the development of a new multiblock data analysis method called OnPLS, which extends the OPLS framework to the analysis of multiblock and path models with very general relationships between blocks in both rows and columns. OnPLS utilises OPLS to decompose sets of matrices, dividing each matrix into a globally joint part (a part shared with all the matrices it is connected to), several locally joint parts (parts shared with some, but not all, of the connected matrices) and a unique part that no other matrix shares.

The OnPLS method was applied to several synthetic data sets and data sets of “real” measurements. For the synthetic data sets, where the results could be compared to known, true parameters, the method generated global multiblock (and path) models that were more similar to the true underlying structures compared to models without such decompositions. I.e. the globally joint, locally joint and unique models more closely resembled the corresponding true data. When applied to the real data sets, the OnPLS models revealed chemically or biologically relevant information in all kinds of variation, effectively increasing the interpretability since different kinds of variation are distinguished and separately analysed.

OnPLS thus improves the quality of the models and facilitates better understanding of the data since it separates and separately analyses different kinds of variation. Each kind of variation is purer and less tainted by other kinds. OnPLS is therefore highly recommended to anyone engaged in multiblock or path model data analysis.

Anaplastic Lymphoma Kinase mutations and downstream signalling

Christina Schönherr — Wed, 16 May 2012 14:00:00 +0200

The oncogene Anaplastic Lymphoma Kinase (ALK) is a Receptor Tyrosine Kinase (RTK) and was initially discovered as the fusion protein NPM (nucleophosmin)-ALK in a subset of Anaplastic Large Cell Lymphomas (ALCL). Since then more fusion proteins have been identified in a variety of cancers. Further, overexpression of ALK due to gene amplification has been observed in many malignancies, amongst others neuroblastoma, a pediatric cancer. Lately, activating point mutations in the kinase domain of ALK have been described in neuroblastoma patients and neuroblastoma cell lines. In contrast, the physiological function of ALK is still unclear, but ALK is suggested to play a role in the normal development and function of the nervous system.

By employing cell culture based approaches, including a tetracycline-inducible PC12 cell system and the in vivo D. melanogaster model system, we aimed to analyze the downstream signalling of ALK and its role in neuroblastoma. First, we wished to analyze whether ALK is able to activate the small GTPase Rap1 contributing to differentiation/proliferation processes. Activated ALK recruits a complex of the GEF C3G and CrkL and activates C3G by tyrosine phosphorylation. This activated complex is able to activate Rap1 resulting either in neurite outgrowth in PC12 cells or proliferation of neuroblastoma cells suggesting a potential role in the oncogenesis of neuroblastoma driven by gain-of-function mutant ALK. Next, we could show that seven investigated ALK mutations with a high probability of being oncogenic (G1128A, I1171N, F1174L, F1174S, R1192P, F1245C and R1275Q), are true gain-of-function mutations, respond differently to ALK inhibitors and have different transforming ability. Especially the F1174S mutation correlates with aggressive disease development. However, the assumed active germ line mutation I1250T is in fact a kinase dead mutation and suggested to act as a dominant-negative receptor. Finally, ALK mutations are most frequently observed in MYCN amplified tumours correlating with a poor clinical outcome. Active ALK regulates mainly the initiation of MYCN transcription in human neuroblastoma cell lines. Further, ALK gain-of-function mutants and MYCN synergize in transforming NIH3T3 cells.

Overall, somatic mutations appear to be more aggressive than germ line mutations, implying a different impact on neuroblastoma. Further, successful application of ALK inhibitors suggests a promising future for the development of patient-specific treatments for neuroblastoma patients.