| 31. |
- Aarnio, Mikko
(författare)
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Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.
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| 32. |
- Aarnio, Riina
(författare)
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Self-sampling for HPV testing in primary cervical screening : Including clinical and health economic aspects
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Persistent infection with high-risk human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. HPV testing has higher sensitivity for high-grade cervical intraepithelial neoplasia (CIN2+) than cytology, resulting in more effective screening. As HPV testing also offers an opportunity for self-sampling, it could serve as an even more effective and cost-effective method of cervical screening.First, we compared repeated self-sampling for HPV testing with Pap smear cytology in detection of CIN2+ in primary cervical screening for women aged 30–49 years (n=36 390). We found a more than twofold higher detection rate of CIN2+ and a fourfold higher detection rate of CIN2 with self-sampling compared with cytology. However, no difference was seen between the arms in the detection rate of CIN3+. It thus seems that CIN is detected at an earlier stage with self-sampling than with cytology, but the impact of this needs to be further explored.Second, as management of HPV-positive women with normal cytology results is a challenge, we wanted to evaluate the proportion of cases of histological CIN2+ in these women. In this prospective study we performed LEEP and found that 15% (6/40) of the women had undetected CIN2+. These findings can be used in counseling women about the risk of cervical cancer and helping clinicians in decisions on management.Third, we performed a cost-effectiveness analysis on the same study population as in Study I. Self-sampling for HPV testing resulted in a higher participation rate and more detected cases of CIN2+ at a lower cost and was regarded as more cost-effective than Pap smear cytology in cervical screening. These results can guide policy-makers when planning future screening programs.Fourth, we compared self-sampling with sampling by medical professionals for HPV testing in detection of CIN2+, using a combination of an FTA card as storage medium and a PCR-based HPV test (hpVIR) in women aged 30–60 years (n=11 951). No difference in the detection rates of histological CIN2+ was found between the arms.Taken together, self-sampling resulted in a higher participation rate than sampling by medical professionals in cervical screening and that triage with repeated self-sampling resulted in high compliance and detection rate of CIN2+. As repeated self-sampling for HPV testing was also cost-effective, it could serve as an attractive alternative in the development of future cervical screening programs. More research is needed on how to refine the management of HPV-positive women by self-sampling only.
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| 33. |
- Aaro Jonsson, Catherine
(författare)
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Long-term cognitive outcome of childhood traumatic brain injury
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is limited knowledge of cognitive outcome extending beyond 5 years after childhood traumatic brain injury, CTBI. The main objectives of this thesis were to investigate cognitive outcome at 6-14 years after CTBI, and to evaluate if advancements in the neurosurgical care, starting 1992, did influence long-term outcome and early epidemiology. An additional aim was to study the relationship between early brain injury parameters and early functional outcome. Study 1 evaluated cognitive progress during 14 years after CTBI, over three neuropsychological assessments in 8 patients with serious CTBI. Study 2 used patient records to investigate early epidemiology, received rehabilitation and medical follow up in two clinical cohorts, n=82 and n=46, treated neurosurgically for CTBI before and after 1992. An exploratory cluster analysis was applied to analyse the relation between early brain injury severity parameters and early functional outcome. In Study 3, participants in the two cohorts, n=18 and n=23, treated neurosurgically for CTBI before and after 1992, were subject to an extensive neuropsychological assessment, 13 and 6 years after injury, respectively. Assessment results of the two cohorts were compared with each other and with controls. Data were analysed with multivariate analyses of variance. Results and discussion. There were significant long-term cognitive deficits of similar magnitude and character in the two cohorts with CTBI, treated before and after the advancements in neurosurgical care. At 6-14 years after injury, long-term deficits in verbal intellectual and executive functions were found, and were discussed in terms of their late maturation and a decreased executive control over verbal memory-functions after CTBI. Visuospatial functions had a slightly better long-term recovery. The amount of rehabilitation received was equally low in both cohorts. The length of time spent in intensive care and the duration of care in the respirator may have a stronger relationship to early outcome than does a single measure of level of consciousness at admission. Main conclusions are that cognitive deficits are apparent at long-term follow up, 6-13 years after neurosurgically treated CTBI, even after advancements in the neurosurgical care in Sweden. Measures of verbal IQ, verbal memory and executive functions were especially low while visuospatial intellectual functions appear to have a better long-term recovery.
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| 34. |
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| 35. |
- Aarsand, Pål André, 1970-
(författare)
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Around the Screen : Computer activities in children’s everyday lives
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present ethnography documents computer activities in everyday life. The data consist of video recordings, interviews and field notes, documenting (i) 16 students in a seventh grade class in a computer room and other school settings and (ii) 22 children, interacting with siblings, friends and parents in home settings. The thesis is inspired by discourse analytical as well as ethnographic approaches, including notions from Goffman (1974, 1981), e.g. those of activity frame and participation framework, which are applied and discussed.The thesis consists of four empirical studies. The first study focuses on students’ illegitimate use, from the school’s point of view, of online chatting in a classroom situation. It is shown that the distinction offline/online is not a static one, rather it is made relevant as part of switches between activity frames, indicating the problems of applying Goffman’s (1981) notions of sideplay, byplay and crossplay to analyses of interactions in which several activity frames are present, rather than one main activity. Moreover, it is shown that online identities, in terms of what is here called tags, that is, visual-textual nicknames, are related to offline phenomena, including local identities as well as contemporary aesthetics. The second study focuses on placement of game consoles as part of family life politics. It is shown that game consoles were mainly located in communal places in the homes. The distinction private/communal was also actualized in the participants’ negotiations about access to game consoles as well as negotiations about what to play, when, and for how long. It is shown that two strategies were used, inclusion and exclusion, for appropriating communal places for computer game activities. The third study focuses on a digital divide in terms of a generational divide with respect to ascribed computer competence, documenting how the children and adults positioned each other as people ‘in the know’ (the children) versus people in apprentice-like positions (the adults). It is shown that this generation gap was deployed as a resource in social interaction by both the children and the adults. The forth study focuses on gaming in family life, showing that gaming was recurrently marked by response cries (Goffman, 1981) and other forms of blurted talk. These forms of communication worked as parts of the architecture of intersubjectivity in gaming (cf. Heritage, 1984), indexing the distinction virtual/‘real’. It is shown how response cries, sound making, singing along and animated talk extended the virtual in that elements of the game became parts of the children’s social interaction around the screen, forming something of an action aesthetic, a type of performative action for securing and displaying joint involvement and collaboration. As a whole, the present studies show how the distinctions master/apprentice, public/private, virtual/real and subject/object are indexicalized and negotiated in computer activities.
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| 36. |
- Aarts, Clara
(författare)
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Exclusive breastfeeding-Does it make a difference? : A longitudinal, prospective study of daily feeding practices, health and growth in a sample of Swedish infants
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The concept of exclusive breastfeeding in relation to daily feeding practices and to health and growth of infants in an affluent society was examined. In a descriptive longitudinal prospective study 506 mother-infant pairs were followed from birth through the greater part of the first year. Feeding was recorded daily, and health and growth were recorded fortnightly. Large individual variations were seen in breastfeeding patterns. A wide discrepancy between the exclusive breastfeeding rates obtained from "current status" data and data "since birth" was found.Using a strict definition of exclusive breastfeeding from birth and taking into account the reasons for giving complementary feeding, the study showed that many exclusively breastfed infants had infections early in life, the incidence of which increased with age, despite continuation of exclusive breastfeeding. However, truly exclusively breastfed infants seem less likely to suffer infections than infants who receive formula in addition to breast milk. Increasing formula use was associated with an increasing likelihood of suffering respiratory illnesses. The growth of exclusively breastfed infants was similar to that of infants who were not exclusively breastfed. The health of newborn infants during the first year of life was associated with factors other than feeding practices alone. Some of these factors may be prenatal, since increasing birth weight was associated with an increasing likelihood of having respiratory symptoms, even in exclusively breastfed infants. However, exclusive breastfeeding was shown to be beneficial for the health of the infant even in an affluent society.
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| 37. |
- Aarum, Johan
(författare)
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Interactions between mouse CNS cells : microglia and neural precursor cells
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mammalian central nervous system (CNS) contains a variety of cells, all specialized to perform different functions. Most numerous are the three types of glia cells, whose basic role is to support the signaling units of the CNS, the neurons. The perspective of this thesis is from the glia cells; particularly the microglia cells, a non-neural population of cells that are spread throughout the CNS. In the healthy CNS these cells are resting, but as a consequence of various CNS disturbances they rapidly become activated, frequently together with astrocytes, the second type of glia cells (oligodendrocytes being the third). This can happen slowly, as in neurodegenerative diseases, or quickly as in acute CNS lesions such as stroke. Both processes involve microglia cells, and sometimes macrophages from the circulation. These latter cells are difficult to distinguish from the microglia cells. In an effort to generate microglia specific markers we used phage display technology to select microglia specific peptides from a random peptide library displayed on the phage surface. Two sets of selection strategies were compared with regard to phage-clone enrichment. The first strategy was based on phage binding to monolayers of primary microglia fixed to a solid surface, while the second strategy was based on fluorescence activated cell sorting (FACS) of microglia cells with bound phages. The latter protocol was found to be superior. Five phage-clones that preferentially bound to microglia cells were isolated. One of the selected clones was shown to be microglia specific by free peptide inhibition and selective in binding to microglia cells, as compared to blood-derived monocytes. Much of our current knowledge in neurobiology derives from studies of cells in culture, a less complex substitute for in vivo studies. As a bridge between monolayer CNS cell cultures and in vivo animal models we set up a three-dimensional culture system, so called aggregate cultures from mouse CNS cells. These aggregates were characterized in detail regarding cellular composition and dynamics, as well as the expression of several neuropeptides and neurotransmitters. All the principle brain cells were present in the aggregates and their numbers changed over time, neurons being the most numerous. The cells appeared to mature as judged by their morphology and, in the case of neurons, the increased expression of synapse specific proteins. Among the investigated neuropeptides, enkephalin and dynorphin were the most abundant followed by galanin, approximating their expression in CNS development. We also found that neural precursor cells, capable of self-renewal and differentiation into neurons, astrocytes and oligodendrocytes, were maintained in the aggregates, even after more than two months of culturing. Treating the aggregates with EGF led to the formation of an outer layer of nestin-positive precursor cells. Using the aggregate culture in part, we found that factor(s) secreted from microglia cells attracts neural precursor cells in a chemotactic manner. This finding may explain the preferred migration of precursor cells to sites of CNS injury. Furthermore, microglia derived factors could affect the differentiation of neural precursor cells, such that more neurons were formed. Together these results suggest important functions of microglia cells in CNS development and pathology. It is reasonable to believe that the migration of neural precursor cells is directed both by attractant and repellant cues. Reactive astrocytes are well known to inhibit growing axons and recently also suggested to inhibit the migration of neural precursor cells. We show that astrocytes in culture repel neural precursor cells and that this effect is mediated by secreted Slit proteins. This conclusion is based on several observations; astrocytes produce Slit and the astrocyte-repellant effect was blocked by the ectodomain of the Slit receptor, and finally, recombinant Slit could substitute for astrocyte derived Slit. Knowledge about the interplay between attractive and repulsive cues may be important for the manipulation of neural precursor cells for medical purposes.
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| 38. |
- Aas, Erik, 1990-
(författare)
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A Markov Process on Cyclic Words
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The TASEP (totally asymmetric simple exclusion process) studied here is a Markov chain on cyclic words over the alphabet{1,2,...,n} given by at each time step sorting an adjacent pair of letters chosen uniformly at random. For example, from the word 3124 one may go to 1324, 3124, 3124, 4123 by sorting the pair 31, 12, 24, or 43.Two words have the sametype if they are permutations of each other. If we restrict TASEP to words of some particular type m we get an ergodic Markov chain whose stationary distribution we denote by ζm. Soζm (u) is the asymptotic proportion of time spent in the state u if the chain started in some word of type m. The distribution ζ is the main object of study in this thesis. This distribution turns out to have several remarkable properties, and alternative characterizations. It has previously been studied both from physical, combinatorial, and probabilitistic viewpoints.In the first chapter we give an extended summary of known results and results in this thesis concerning ζ. The new results are described (and proved) in detail in Papers I - IV.The new results in Papers I and II include an explicit formula for the value ofζat sorted words and a product formula for decomposable words. We also compute some correlation functions for ζ. In Paper III we study of a generalization of TASEP to Weyl groups. In Paper IV we study a certain scaling limit of ζ, finding several interesting patterns of which we prove some. We also study an inhomogenous version of TASEP, in which different particles get sorted at different rates, which generalizes the homogenous version in several aspects. In the first chapter we compute some correlation functions for ζ
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| 39. |
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| 40. |
- Aas, Randi Wågö
(författare)
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Workplace-based sick leave prevention and return to work : exploratory studies
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Earlier research have revealed risk factors for sick leave in the workplace, and thus the workplace has become an important arena for sick leave prevention and return to work (RTW). Despite that, some of these aspects have received little attention in exploratory studies. Simultaneously, there is a need to translate and implement the growing knowledge base in this field in order to develop evidence-based practice (EBP). Aim: The aim of the present research was to explore some aspects of workplace-based sick leave prevention and RTW, such as workplace interventions (studies III, IV, and the appendix), leadership qualities (study I), and work demands (study II), and also to reveal challenges to translating scientific knowledge into intervention decisions in the RTW process, and possible solutions to these challenges (study III). Methods: Content analysis methods were applied on data from interview transcripts and documents. In addition, a Cochrane systematic review of the literature was conducted. Results: Study I identified 78 distinct leadership qualities and seven leadership types (n = 345 meaning units) perceived by 30 employees on long-term sick leave and their immediate supervisors. The three most valued leadership qualities were “ability to make contact”, “being considerate”, and “being understanding”. The three most valued leadership types were the Protector, the Problem-Solver, and the Contact-Maker. The subordinates gave more descriptions of the Encourager and the Recognizer, whereas the supervisors most often described the Responsibility-Maker and the Problem-Solver. The combination of leadership types reported most frequently was the Protector together with the Problem-Solver. In study II, eight employees on long-term sick leave due to musculoskeletal diseases and disorders described 51 work demands they had experienced. The demands were perceived in some cases as having only a negative or a positive impact on work performance, but in others as both. Only seven of the demands were physical in nature, and most involved emotional and cognitive challenges in mastering the work tasks. It was also experienced that most demands came from the employee (n = 36) and only a few from the employer/work environment (n = 7) or both those sources (n = 8). Study III was a hypothetical case study aimed at revealing the challenges associated with translating scientific evidence into intervention decisions in the RTW process. This investigation was performed according to EBP frameworks. The evidence seemed to differ depending on whether it came from preventive, curative, or rehabilitative interventions. Moreover, it appeared that evidence in some cases originated from “good-for-all” interventions but in others from “tailored-type” interventions. Thus, a need to differentiate the roles of evidence was revealed in terms of whether it inspired, challenged, enlightened, informed, or determined the intervention decision. In general, the evidence-based framework seemed to construct a confined decision process. Possible solutions, and revised EBP steps were suggested. In study IV, 15 workplace interventions were identified (n = 306 meaning units), which were intended to reduce sick leave rates in 12 municipalities. The interventions were divided into two groups according to their targets in the organizations: nine organizational-workplace interventions targeted structures, processes, and culture (n = 220 descriptions, 72%); six employee-workplace interventions targeted persons (n = 86 descriptions, 28%). Examples of organizational-workplace interventions were developing routines/systems, establishing cooperation/ collaboration, providing information/education, building culture/anchoring, and recruiting/staffing. Employee-workplace interventions involved well-being/lifestyle interventions, physical activity/exercise, redeployment, adaptation, follow-up of employees on sick leave, and RTW programmes. The intervention profiles varied considerably between the municipalities. In the appendix (study V), a Cochrane systematic review of the literature was conducted to reveal the content and effectiveness of workplace interventions for employees with neck pain. Of 1,995 references found, 10 randomized controlled trials (RCTs) were included. Two of the RCTs had low risk of bias, and eight of them examined office workers. Few were on sick leave. Only three of the ten studies assessed the outcome of sick leave. The workplace interventions varied considerably regarding complexity and content. Overall, evidence was of low quality and showed no significant impact of workplace interventions on pain reduction (seven RCTs, 2,368 workers). Furthermore, one RCT, with 415 workers revealed that workplace interventions were significantly more effective in reducing sick leave in the intermediate term (OR 0.56, 95% CI 0.33–0.95), but not in the short or the long term. Conclusions: The results reported in this thesis revealed a variety of terminology related to workplace interventions, leadership qualities, and work demands, which might contribute to more in-depth understanding of sick leave prevention and RTW at workplaces. It was a challenge to trying to use evidence from randomized controlled trials in the RTW process, and the results call for new EBP approaches to translate evidence into decisions concerning complex workplace interventions. The current research also revealed that knowledge about the effectiveness of workplace interventions is still limited.
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