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  • Public defence: 2017-01-19 09:00 Hörsal E04 Farmakologihuset, Norrlands universitetssjukhus, Umeå
    Fridriksson, Jon Örn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Fridriksson, Jon Örn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Adverse effects of curative treatment of prostate cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Screening for prostate cancer is debated, there is conflicting data on the net benefit of screening. Men who consider screening need to be informed on the pros and cons. Rehospitalization after surgery can be used as an indicator of general quality of care. For radical prostatectomy, little is known on the readmission rate after surgery. Men diagnosed with low- and intermediate-risk prostate cancer have low prostate-cancer specific mortality. However, adverse effects after curative treatment can be severe and decrease quality of life. Curative treatments for prostate cancer differ mainly in the pattern of adverse effects but detailed analysis of long-term adverse effects is lacking.

    The aim of this thesis was to assess the perioperative quality of radical prostatectomy and the risk of adverse effects after curative treatment for prostate cancer.

    Material and Methods In this thesis, data from the National Prostate Cancer Register (NPCR) and other nationwide Swedish registers were used. By use of the Swedish personal identity number, NPCR was cross-linked to other registers creating Prostate Cancer data Base Sweden (PCBaSe), a large dataset for research.

    Results The proportion of men who had received information on the pros and cons of screening for prostate cancer with PSA testing was low (14%) indicating that the majority of men who were screened did not make an informed decision. The risk of rehospitalization within 90 days after radical prostatectomy was approximately 10% and similar after retropubic and robot-assisted radical prostatectomy. Compared to controls, there was an increased risk of adverse effects after both radiotherapy and radical prostatectomy up to twelve years after treatment and the overall risk was quite similar after retropubic and robot-assisted radical prostatectomy.

    Conclusion Improved information to men on the pros and cons of PSA screening is warranted. The risk of adverse effects was elevated up to 12 years after curative treatment for prostate cancer. The pattern of adverse effects was different after radiotherapy and radical prostatectomy but quite similar after retropubic and robot-assisted radical prostatectomy.

  • Public defence: 2017-01-20 09:00 Room E04_R1, Umeå
    Upadhyay, Arunkumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Upadhyay, Arunkumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Viperin, a multifunctional radical SAM enzyme: biogenesis and antiviral mechanisms2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) is an interferon-induced antiviral protein. It has three distinct functional domains: the N-terminal domain, the radical SAM (S-adenosylmethionine) domain for binding iron-sulphur cluster, and the C-terminus domain. Viperin has a broad antiviral effect, and is also involved in the immune response signalling. However, the function and antiviral mechanism of viperin are still not well characterized. Thus the overall aim of the thesis was to investigate and better understand the function of viperin and its antiviral mechanism by identifying the cellular network of interaction partners. Affinity purification and mass spectrometry analysis were used to identify cellular proteins that interact with viperin.

    CIA1 (also known as CIAO1), a factor involved in loading of iron-sulphur (Fe/S) cluster was identified and confirmed to interact at the C-terminus of viperin. It was also seen that the C-terminal domain and the functional SAM domain of viperin was essential for loading the Fe/S cluster onto viperin. On a closer look at the biogenesis of viperin, we identified and confirmed viperin interaction with CIA2A, CIA2B, (also known as FAM96A and FAM96B respectively) and MMS19, which are other factors involved in the transfer of Fe/S clusters onto cytosolic Fe/S apo-proteins. Surprisingly, MMS19, which has been shown to act as an adapter protein for other Fe/S proteins, only interacted indirectly and was not required for transferring the Fe/S cluster. Similarly, the interaction of viperin with both the isoforms of CIA2 was interesting, but the role they play in viperin biogenesis and antiviral function is still not clear and requires further investigation.

    Study of the antiviral action of viperin against tick-borne encephalitis virus (TBEV) showed that the activity of the SAM domain is essential for the strong inhibition of genome replication of TBEV. Furthermore, viperin also affects the assembly and release of TBEV. Viperin interacts with GBF1 and downregulates its activity, thus preferentially inducing the secretion of viral capsid protein from the cell, and therefore disrupting the formation of infectious virus particles. The N-terminal domain of viperin is important for its effect on assembly and release.

    In summary, this work contributes to our general understanding of viperin biogenesis in the cell regarding the loading of Fe/S cluster onto viperin. It also addresses the importance of the different domains for its antiviral function against TBEV. Finally, mass spectrometry and viperin interactome analysis implicate many other interesting cellular pathways or processes that might give us a better understanding of viperin’s function and antiviral mechanism. 

    The full text will be freely available from 2018-01-20 00:00
  • Public defence: 2017-01-20 09:00 Vårdvetarhusets aula, Umeå
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Blood pressure in very old age: determinants, adverse outcomes, and heterogeneity2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: High blood pressure (BP) is the leading risk factor for disease and mortality worldwide. However, risks associated with high BP in very old age (≥ 80 or ≥ 85 years) are not entirely understood, as the majority of scientific studies have been performed with younger populations and existing scientific knowledge about very old individuals is sometimes contradictory. Results of previous studies of very old individuals suggest that the associations of BP with mortality and stroke differ with levels of physical and cognitive function. More studies that are representative of very old individuals, including individuals with multimorbidity, that are of adequate size, involve proper adjustment, and investigate non-linear associations, are needed to investigate these issues.

    Systolic blood pressure (SBP) decline is common among very old individuals and has been shown to precede adverse events. Previous studies have shown that SBP change is associated with baseline SBP, age, and health-related factors, but determinants of SBP change have not been investigated using comprehensive, multivariate models.

    The three main aims of this thesis were to investigate, in a sample of individuals aged ≥ 85 years, 1) determinants of SBP change, 2) the association of BP with mortality risk and whether this association differs with respect to gait speed and/or Mini-Mental State Examination (MMSE) score, and 3) the association of BP with stroke risk and whether this association differs with respect to the Barthel Activities of Daily Living (ADL) index and/or MMSE score.

    Methods: The studies conducted for this thesis were based on data from the population-based Umeå 85+/Gerontological regional database study, which provided cross-sectional and longitudinal data on socioeconomic factors, medical conditions, drug prescriptions, and health-related assessments from 2000 to 2015. Participants were aged 85, 90, and ≥ 95 years, and lived in Västerbotten, Sweden, and Österbotten/Pohjanmaa, Finland. Follow-up assessments were conducted after 5 years. Mortality data were collected after 2 and 5 years, and stroke data were collected after 5 years, from death certificates, medical records, population registers, and the inpatient diagnosis register. Comprehensive multivariate models were developed to investigate determinants of SBP change using multiple linear regression, and to investigate associations of mortality and stroke risks with BP using Cox proportional-hazard regression models.

    Results: Average (± standard deviation) baseline SBP was 146 ± 23 mm Hg, and average diastolic blood pressure (DBP) was 74 ± 11 mm Hg. Within 5 years, 61% of participants had died and 10% had had incident strokes. Among participants followed for 5 years, the average annual SBP decline was 2.6 ± 5.4 mm Hg.

    In a multivariate model, SBP decline was associated with later investigation year (p = .009), higher baseline SBP (p < .001), baseline antidepressant drug use (p = .011), incident acute myocardial infarction during follow-up (p = .003), use of a new diuretic drug during follow-up (p = .044), and declining Barthel ADL index scores during follow-up (p < .001).

    In an age- and sex-adjusted analysis of the total sample, mortality risk was decreased in higher (vs. lower) BP categories (SBP ≥ 165 vs. ≤ 125 mm Hg: hazard ratio [HR] .50, p < .001; DBP 70–74 vs. 75–80 mm Hg: HR 1.32, p = .031). In a comprehensively adjusted analysis of the total sample, SBP was not associated significantly with mortality risk. The associations of SBP with mortality in the gait speed < .5 m/s subcohort corresponded with those found in the total sample. In comprehensively adjusted analyses in the gait speed ≥ .5 m/s subcohort, mortality risk increased independently with higher (vs. lower) BP (SBP ≥ 165 vs. 126–139 mm Hg: HR 2.13, p = .048; DBP > 80 vs. 75–80 mm Hg: HR 1.76, p = .026). In comprehensively adjusted analyses in the MMSE score subcohorts, SBP was associated significantly with mortality risk only in the 0–10 MMSE score subcohort; high and low SBP categories were associated independently with increased mortality risk, compared with an intermediary SBP category (SBP ≥ 165 vs. 126–139 mm Hg; HR 4.54, p = .007; SBP ≤ 125 vs. 126–139 mm Hg: HR 2.23, p = .023). Higher BP was associated significantly with increased stroke risk in multivariate models (SBP per 10 mm Hg increment: HR 1.19, p < .001; DBP per 10 mm Hg increment: HR 1.26, p = .013). SBP was not associated with stroke risk in participants with SBP < 140 mm Hg.

    Interaction effects on the association with mortality were significant between SBP and gait speed (age- and sex-adjusted model: p = .031) but not between SBP and MMSE score. No interaction in the association with stroke was found between any BP measure and Barthel ADL index or MMSE score.

    Conclusion: The decline in BP in very old age may be explained by health-related factors. Low BP may be a risk marker for short life expectancy, due to morbidity, in the general very old population and among very old individuals with low gait speeds. High BP seems to be an independent risk factor for mortality only in certain groups, which may be distinguished by high gait speed or very severe cognitive impairment. High SBP and DBP seem to increase stroke risk in very old age. These findings may contribute to a better understanding of the risks of adverse outcomes in very old individuals with different BP levels, the importance of comorbidity for these risks, and the etiology of SBP change. 

    The full text will be freely available from 2018-01-20 00:00
  • Public defence: 2017-01-20 13:00 Sal A, Tandläkarhögskolan 9 trappor, byggnad 1D, Umeå
    Vågberg, Mattias
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vågberg, Mattias
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brain parenchymal fraction in healthy individuals and in clinical follow-up of multiple sclerosis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Multiple sclerosis (MS) is an autoimmune disease characterised by inflammatory damage to the central nervous system (CNS). Accumulated CNS injury can be quantified as brain atrophy, definable as a reduction in brain parenchymal fraction (BPF). BPF correlate with disability in MS and is used routinely as an endpoint in clinical trials. In 2009/2010, a new MS clinical care program, that includes follow-up of BPF, was introduced at Umeå University Hospital (NUS). Levels of neurofilament light polypetide (NFL) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) are markers of axonal and astrocytic injury, respectively, and also potential surrogate biomarkers for BPF decline. The goals of this thesis were to establish age-adjusted values of BPF in healthy individuals and to relate these to the BPF values from individuals with MS as well as to the levels of NFL and GFAP in CSF. Another goal was to investigate if expanded disability status scale (EDSS)-worsening could be predicted in a clinical MS cohort and if BPF measurements could contribute to such predictions. Methods A group of 111 healthy individuals volunteered to participate in the studies. A total of 106 of these underwent MRI with BPF measurements, 53 underwent lumbar puncture (LP) with measurement of NFL and GFAP and 48 underwent both MRI and LP. Three different automatic and one manual method were utilised to determine BPF. A literature search on BPF in healthy individuals was performed for the purpose of a systematic review. For studying disability progression in MS, all individuals with MS followed at NUS and included in the Swedish MS registry were included if they had matched data on BPF, EDSS and lesion load as part of clinical follow-up (n=278). Results BPF as well as NFL and GFAP levels in CSF were all associated with age. NFL was associated with BPF and GFAP, but only the association with GFAP was retained when adjusting for age. Significant differences were found between different methods for BPF determination. In the MS population, BPF was associated with EDSS. Only progressive disease course could predict EDSS worsening. Conclusion The data on BPF and levels of NFL and GFAP in CSF of healthy individuals can aid in the interpretation of these variables in the setting of MS. Knowledge on differences in BPF data from different methods for BPF determination can be useful in comparing data across studies, but also highlights the need for a commonly accepted gold standard. The correlation between GFAP and NFL levels in CSF may indicate an association between glial and axonal turnover that is independent of the aging effect on the brain. However, the low number of volunteers for LP precluded clear conclusions. An association between BPF and EDSS was seen in the MS group. The ability to predict EDSS worsening in the clinical MS cohort was limited.

  • Public defence: 2017-01-20 13:00 Sal 933, byggnad 3A, 9tr, Norrlands Universitetssjukhus, Umeå
    Rydvall, Anders
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Rydvall, Anders
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Withhold  or  withdraw  futile  treatment in  intensive  care: arguments supported by physicians and the general public2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Since the 60s and with increasing intensity a discussion have continued about balance between useful and useless/harmful treatment. Different attempts have been done to create sustainable criteria and recommendations to manage the situations of futile treatment near the end of life. Obviously, to be able to withhold (WH) or withdraw (WD) treatment which is no longer appropriate or even harmful and burdensome for the patient, other processes than strict medical (or physiological) assessments are necessary.

    Aim. To shed light on the arguments regarding to WH or WD futile treatment we performed two studies of physicians’ and the general populations’ choice and prioritized arguments in the treatment of a 72-year-old woman suffering from a large intra-cerebral bleeding with bad prognosis (Papers I and II) and a new born boy with postpartum anoxic brain damage (Papers III and IV).

    Methods. Postal questionnaires based on two cases presented above involving severely ill patients were used. Arguments for and against to WH or WD treatment, and providing treatment that might hasten death were presented. The respondents evaluated and prioritized arguments for and against withholding neurosurgery, withdrawing life-sustaining treatment and providing drugs to alleviate pain and distress. We also asked what would happen to physicians’ own trust if they took the action described, and what the physician estimated would happen to the general publics’ trust in health services (Paper IV).

    Results. Approximately 70% of the physicians and 46% of the general public responded in both surveys. The 72-year-old woman: A majority of doctors (82.3%) stated that they would withhold treatment, whereas a minority of the general public (40.2%) would do so; the arguments forwarded and considerations regarding quality of life differed significantly between the two groups. Quality-of-life aspects were stressed as an important argument by the majority of both neurosurgeons and ICU-physicians (76.8% vs. 54.0%); however, significantly more neurosurgeons regarded this argument as the most important. A minority in both groups, although more ICU-physicians, supported a patient’s previously expressed wish of not ending in a persistent vegetative state as the most important argument. As the case clinically progressed, a consensus evolved regarding the arguments for decision making.

    The new born child: A majority of both physicians [56 % (CI 50–62)] and the general population [53 % (CI 49–58)] supported arguments for withdrawing ventilator treatment. A large majority in both groups supported arguments for alleviating the patient’s symptoms even if the treatment hastened death, but the two groups display significantly different views on whether or not to provide drugs with the additional intention of hastening death, although the difference disappeared when we compared subgroups of those who were for or against euthanasia-like actions.

    Conclusions. There are indeed considerable differences in how physicians and the general public assess and reason in critical care situations, but the more hopelessly ill the patient became the more the groups' assessments tended to converge, although they prioritized different arguments. In order to avoid unnecessary dispute and miscommunication, it is important that health care providers are aware of the public's views, expectations, and preferences. Our hypothesis—physicians’ estimations of others’ opinions are influenced by their own opinions—was corroborated. This might have implications in research as well as in clinical decision-making.

  • Public defence: 2017-01-20 13:15 Hörsal C, Lindellhallen, Umeå
    Eriksson, Max
    Umeå University, Faculty of Social Sciences, Department of Political Science.
    Eriksson, Max
    Umeå University, Faculty of Social Sciences, Department of Political Science.
    Changing Attitudes to Swedish Wolf Policy: wolf Return, Rural Areas, and Political Alienation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In 1966, the grey wolf was listed as a protected species in Sweden. Since then, the Swedish wolf population has increased in size, making human-wolf encounters more common, particularly in rural areas. Previous qualitative research has shown that segments of the rural population perceive the wolf to be incompatible with traditional rural life. Some also believe that the return of the wolf was orchestrated by urban interests, and perceive the wolf policy as a vehicle for the consolidation of urban power in rural areas. Thus, the return of the wolf can be assumed to aggravate pre-existing urban-rural tensions, resulting in conflicts over wolf policy, which Swedish wolf governance could be ill-equipped to handle. In view of this, this thesis is an examination of,

    how environmental, socio-political, and institutional factors affect varia-tions in public attitudes to the Swedish wolf policy over time, and discuss their policy implications.

    Drawing on extensive survey material collected in Sweden in 2004, 2009, and 2014, the wolf policy is approached from a political science perspective. This thesis is an attempt to bridge a number of existing gaps in literature related to wolves and policy, individual and collective level explanatory factors, and attitude change. The underlying assumption is that environmental, socio-political and institutional factors are likely to impact attitudes to wolf policy. Environmental change is found to be relevant, as direct experiences with wolf have increased over time, a development that was also associated with an increase of support for a more restrictive wolf policy (Paper I). Regarding socio-political change, politically alienated individuals were less likely to support the current wolf policy, and more likely to favor either more, or less restrictive policy options compared to other individuals. Rural areas displayed higher levels of political alienation than urban areas, and people living in rural areas were more likely to favor a more restrictive wolf policy (Paper II). Furthermore, individuals living in municipalities in which a high proportion of residents had grown up in a rural area, tended to favor a more restrictive wolf policy, an effect which could also be associated with political alienation (Paper III). Finally, institutional change was examined through an analysis of public support for the actors within the Wildlife Management Delegations (WMDs). In general, the interest groups represented in WMDs where found to reflect the representation preferred by the public. However, findings show a fundamental value divide in relation to natural resources, among the Swedish public, which is also reflected within the WMDs (Paper IV).

    The return of the wolf has caused part of the general public to want fewer wolves in Sweden. This attitudinal change is related to a growing divide between urban-rural areas in Sweden, and associated with a general pattern of political alienation. Thus, the wolf policy has become a symbolic issue around which rural citizens rally their fight against urban interests for political autonomy.

  • Public defence: 2017-01-25 13:00 Flexhallen, Umeå
    Peeters, Jeroen
    Umeå University, Faculty of Social Sciences, Department of Informatics. RISE Interactive.
    Peeters, Jeroen
    Umeå University, Faculty of Social Sciences, Department of Informatics. RISE Interactive.
    Perpetual perspectives: on designing for aesthetic engagement2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This dissertation investigates aesthetics of engagement in -interaction. Aesthetic refers to the aesthetic experience, based on a phenomenological and pragmatist understanding: dynamic and personal, appealing mutually to - and formed inseparably by - our bodily, emotional, as well as intellectual faculties. Engagement signifies this experience as forming a deeply involved relationship between people and an artefact in interaction. The theoretical background upon which this work is based, asserts that we perceive the world in terms of how we can act in it. Action, through the body, is how we make sense of the world around us. To be congruent with these foundations and the topic at hand means that the research program was investigated through a constructive design research process. The research program anchors and outlines the goal of this investigation: to contribute shareable knowledge of how to design for aesthetic engagement in interaction by leveraging a first-person -perspective. The findings of this research form two contributions to the overlapping fields of Human-Computer Interaction and (Interaction) Design Research.

    The main contribution is methodological and is concerned with generating knowledge through design. The methodological structure of this dissertation builds on a programmatic approach that centres on the first-person perspective of the designer, who learns from experience by reflecting on design action. Such an approach is fundamental to the design tradition, but its dependency on subjectivity is also a source of epistemological conflict since design, as mode of inquiry, matures and comes in contact with more established disciplines that have their own academic traditions. For design research, to develop its own intellectual culture, alternative and bidirectional relationships between theory and practice need to be further shaped, articulated, and debated in the field. This dissertation contributes to this discussion around designerly ways of knowing by exposing how skillful coping and intuition, through mechanisms of reflection-on-action, generate a multitude of perspectives on a complex design space. These perspectives reveal parts of the complexity of designing for aesthetic engagement, while leaving it intact. Exposing and consolidating the first-person (design) knowledge embedded in these perspectives allows this knowledge to be articulated as a shareable academic knowledge contribution.

    This shareable knowledge forms the second contribution of this dissertation. Reflections on the process and results of eight constructive design research projects describe a design space around aesthetic engagement. Individual reflections are consolidated into themes that describe how a design may elicit aesthetic engagement in interaction. These themes are experiential qualities: conceptual values that can be leveraged for a design to appeal to both mind and body in ways that are rich, open-ended and ambiguous. The findings propose strategies for interactions with digital technologies to open up the complexity of relations in the world between artefacts and people. Designing for aesthetics of engagement proposes ways to respect people’ skills in making sense of the complexity of the lived world. In respecting the uniqueness of their body and the subjectivity of their experiences, to design for aesthetic engagement is to support the expression of personal points of view in interaction. This points to ways in which designers can open up interactions with digital technologies to be more beautiful, respectful, and liveable, as it touches what makes us human: our personal being in the world.

  • Public defence: 2017-01-27 09:00 Sal E04, målpunkt R-1 (by 6E), Biomedicin, Umeå
    Farooqi, Nighat
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Farooqi, Nighat
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Nutrition and energy expenditure in women with chronic obstructive pulmonary disease2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aim

    The overall objective of this thesis was to increase the knowledge and validate methods for assessment of total daily energy expenditure (TEE), energy requirement and energy intake (EI) in women with COPD. We also investigated the relationship of BMI with clinical characteristics of COPD in a population-based study. Due to the substantial and increasing morbidity in women with COPD, special attention was given to this group.

    Methods

    Resting metabolic rate (RMR) was measured by indirect calorimetry (IC). TEE was measured by criterion method, doubly labeled water (DLW) (Paper I-III) during a 14-day period. TEE was simultaneously assessed by SenseWear Armband, software version 5.1 and 6.1 (SWA5 respectively SWA6), and ActiHeart (paper I). EI was assessed by diet history interview and 7-day food diary (paper II), and energy requirement was predicted using pedometer-determined physical activity level (paper III). Energy requirement data was also acquired from studies concerning TEE measured by DLW in patients with COPD (paper IV). BMI and other characteristics in subjects with COPD were compared with non-COPD subjects in a population-based study, Obstructive Lung disease in Norrbotten study (OLIN) (paper V).

    Results

    There was a large variation in RMR and TEE measured by DLW in this group of women with COPD. The results of energy expenditure study showed that the SWA5 assessed TEE with good accuracy over a 14-day period in free-living women with COPD. However, the SWA6 and ActiHeart methods tend to underestimate TEE. A higher proportion of women were within ± 5% of the TEE individually measured with the DLW method using SWA5 than SWA6 and AH (63%, 47%, 37% respectively). The agreement between the TEE measured by DLW and SWA5 was strong, and with SWA6 and ActiHeart it was lesser. Bland-Altman plots revealed no systematic bias for TEE. The reported EI was underestimated by 28% respectively 20 % when assessed by diet, and the 7-day food diary compared with the criterion method, DLW. More women were identified as valid-reporters based on their 7- day food diaries than on their diet histories (63% vs 32%). The accuracy of reported EI was only related to BMI. The agreement between the DLW and the EI methods was weak. The Bland-Altman plots revealed a slight systematic bias for both methods. The energy requirement predicted by pedometer-determined PAL multiplied by six different RMR equations was within a reasonable accuracy (±10%) of the measured TEE for all equations except one. The agreement between the DLW and four of six predicted TEE methods was strong. The Bland– Altman plots revealed no systematic bias for predicted energy requirement except for one. Estimated PAL from the pedometer was lower by 14 % than the measured criterion PAL. The energy requirement calculation based on available TEE data measured by DLW varied by BW and FFM. Compared to men, women had a lower RMR and TEE/kg BW/day, and higher RMR and TEE/kg FFM/day. The correlates of RMR/kg BW were gender and forced expiratory volume in 1st second (FEV1) % of predicted value, of TEE/ kg BW the correlates were age and gender, and of TEE/kg FFM were age and FEV1 % predicted. BMI decreased significantly with increase in disease severity and correlated significantly to forced expiratory volume in 1st second % predicted. In the population-based study (OLIN), subjects with COPD had lower BMI and a higher prevalence of underweight than in non-COPD, and its sub-groups namely, normal lung function and restrictive spirometry pattern subjects. There was an independent association between COPD and low BMI. Fewer COPD subjects were obese than in the non-COPD, normal lung function and restrictive spirometry pattern groups. Among the subjects with COPD, women had a lower mean BMI and a higher proportion were under-weight than men. In COPD women with under-weight, FEV1 % predicted values increased with an increase in BMI.

    Conclusion

    Compared with the gold standard DLW method, the total daily energy expenditure can be assessed reliably by SenseWear Armband 5 in women with COPD, while other devices underestimated TEE. The energy intake was underestimated by diet history and 7-day food diary methods, and energy requirement was predicted with reasonable accuracy using pedometer-determined PAL and common RMR equations, compared with DLW. Furthermore, the energy requirement was determined per kg BW/day and per kg FFM/day, using DLW based TEE data in patients with COPD. In the population-based study (OLIN), subjects with COPD had lower BMI and higher prevalence of under-weight than subjects without COPD. There was a gender difference, which was particularly significant in COPD, for women to have lower mean BMI and a higher prevalence of under-weight. The present findings indicate that low BMI is common in COPD and needs to be intervened. For a successful nutritional treatment, it is imperative to assess the patient’s ener

  • Public defence: 2017-01-27 09:00 N350, Vån 3, Umeå
    Tjust, Anton
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Tjust, Anton
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Extraocular Muscles in Amyotrophic Lateral Sclerosis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of motor neurons characterized by muscle paralysis and death within 3-5 years of onset. However, due to unknown mechanisms, the extraocular muscles (EOMs) remain remarkably unaffected. The EOMs are highly specialized muscles that differ from other muscles in many respects, including innervation and satellite cells (SCs). Understanding whether these factors play a role in the relative sparing of EOMs in ALS could provide useful clues on how to slow down the progression of ALS in other muscles.

    The EOMs and limb muscles from terminal ALS patients and age-matched controls as well as the commonly used SOD1G93A ALS mouse model were studied with immunofluorescence. Antibodies against neurofilament and synaptophysin were used to identify nerves and neuromuscular junctions (NMJs); against Pax7, NCAM, MyoD, myogenin, Ki-67, dystrophin and laminin, to identify SCs and their progeny in EOMs and limb muscles. The proportion and fiber size of myofibers containing myosin heavy chain (MyHC) slow tonic and MyHC slow twitch were also determined in human EOMs.

    The abundance of SCs differed extensively along the length of control human EOMs, being twice as abundant in the anterior portion. Pax7-positive cells were also detected in non-traditional SC positions. EOMs from terminal ALS patients showed similar numbers of resting and activated SCs as the controls. In limb muscles of ALS patients, the number of resting and activated SCs ranged from low (similar to normal aged, sedentary individuals) to high numbers, especially in muscles with long duration of disease and varied between the upper and lower limbs. The EOMs maintained a high degree of innervation compared to hindlimb muscles of symptomatic SOD1G93A mice. MyHC slow tonic fibers were less abundant in ALS patients than in controls. The change seemed more pronounced in bulbar onset patients, and in this group of subjects only, there was a strong association between decline in MyHC slow tonic fibers and age of death. Notably, the decline in MyHC slow tonic fibers was unrelated to disease duration.

    Our data suggested that SCs play a minor role in the progression of ALS in general and in the sparing of the EOMs in particular. The generally preserved innervation in the EOMs of G93A mice may reflect distinct intrinsic properties relevant for sparing of the oculomotor system.  Even though the EOMs are relatively spared in ALS, MyHC slow tonic myofibers were selectively affected and this may reflect differences in innervation, as these fibers are multiply innervated.

  • Public defence: 2017-01-27 09:00 S213H, Umeå
    Salimi Sofla, Amin
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE).
    Salimi Sofla, Amin
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE).
    Lead auditors, their client portfolios and performances2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on lead auditors’ differences in terms of client portfolios and  performances. First, lead auditors are surveyed and their responses on professional scepticism linked to their performances. Second, survey and archival data are combined to check whether self-control is related to performance. Third, lead auditors’ client portfolios are examined with regard to industry similarity, portfolio dispersion and client grouping. Finally, auditors’ independence is tested in the  private firm setting. Overall, the findings indicate that performance is not homogenous across lead auditors in the same (tier) audit firm(s), and that the characteristics of lead auditors and accounting firms are determinants that partly explain the differences.

  • Public defence: 2017-01-27 09:00 N200, Naturvetarhuset, Umeå
    Ekestubbe, Sofie
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ekestubbe, Sofie
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Timing and targeting of Type III secretion translocation of virulence effectors in Yersinia2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The Type III secretion system (T3SS) is an important virulence mechanism that allows pathogenic bacteria to translocate virulence effectors directly into the cytoplasm of eukaryotic host cells to manipulate the host cells in favor of the pathogen. Enteropathogenic Yersinia pseudotuberculosis use a T3SS to translocate effectors, Yops, that prevent phagocytosis by immune cells, and is largely dependent on it to establish and sustain an infection in the lymphoid tissues of a mammalian host. Translocation into a host cell requires specific translocator proteins, and is tightly controlled from both the bacterial and host cell cytoplasm. We aimed to investigate two of the regulatory elements, YopN and LcrV, to gain more insight into the translocation mechanism. Two separate regulatory complexes regulate expression and secretion of Yops, however, the processes are linked so that expression is induced when secretion is activated. A complex, including YopD, prevents expression of Yops, while YopN-TyeA and LcrG block secretion. LcrV is required to relieve the secretion block, by sequestering LcrG. We verified that LcrG binds to the C-terminal part of LcrV, which is consistent with what has been shown in Y. pestis. In addition to their regulatory roles, both LcrV and YopD are translocators and are assumed to interact at the bacterial surface, where LcrV promotes insertion of YopB and YopD into the host cell membrane. However, here we show that purified YopD failed to interact with LcrV, instead YopD solely interacted with a complex of LcrV-LcrG. This indicates that LcrV and YopD interact in the bacterial cytosol, which may be important for regulation of Yop expression and secretion. The established role of YopN is to block secretion prior to host cell contact. We found that deleting the central region (amino acids 76-181) had no effect on the regulatory role of YopN in expression and secretion of Yops. Interestingly, we found that, even though the YopN∆76-181 mutant secreted the translocators with similar kinetics as the wild type strain, translocation of the effector YopH, into HeLa cells, was significantly reduced. Consequently, the YopN∆76-181 mutant was unable to block phagocytosis, almost to the same level as the ∆lcrV mutant which is completely unable to translocate YopH. Our results indicate that YopN is involved in the translocation step in addition to its role in regulating secretion. Further, we show that the amino terminal of LcrV, in the context of translocation, is involved in the early intracellular targeting of YopH in order to block phagocytosis efficiently and sustain an in vivo infection. LcrV mutants that failed to efficiently target YopH intracellularly were severely attenuated also for in vivo virulence. All together, we show that LcrV and YopN are involved in more steps in the regulation of translocation, than what was known before. Our studies also highlight that early translocation is essential for Yersinia to block phagocytosis, which in the end is essential for in vivo virulence.

  • Public defence: 2017-01-27 10:15 S205H, Samhällsvetarhuset, Umeå
    Liljenfeldt, Johanna
    Umeå University, Faculty of Social Sciences, Department of Geography and Economic History, Economic and social geography.
    Liljenfeldt, Johanna
    Umeå University, Faculty of Social Sciences, Department of Geography and Economic History, Economic and social geography.
    Where the Wind Blows: the socio-political geography of wind power development in Finland, Norway and Sweden2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis analysis the planning process for large-scale wind power development in Finland, Norway and Sweden. The aim is to explore the emerging power relations and socio-economic dynamics of the negotiation, planning and realization of this new development. The thesis employs an energy justice framework to capture the opportunities different stakeholders have to take part in and influence wind power development processes (‘procedural justice’), and how the potential benefits and burdens of wind power development are divided between stakeholders (‘distributional justice’). The study’s setup is an embedded sequential mixed methods research design, which includes analysis of policy documents, in-dept interviews, observations, as well as register based population data.

    The thesis shows how power relations on both a structural level and an actor level are used to exert power and influence over the planning process for wind power development. On a structural level, the results indicate that transformations in EU directives and national planning laws and guidelines in Finland, Norway and Sweden in recent years have been more focused on speed and efficiency in planning processes than on legitimacy issues. The changes that have been implemented seem to point to diminishing opportunities for broad participation and debate in wind power planning processes, in favour of more top-down processes with a specific, sectoral focus on developing wind power. On the actor level, perceived improper behaviour by different actors within the planning process can further limit the possibilities for participation. People refrain from participating in planning processes, for instance, if they feel that they are treated disrespectfully or if there have occurred procedural errors that undermine the legitimacy of the formal planning process. However, participation in formal planning processes is not the only way to influence planning processes. There are a number of more informal channels, such as using the media or the Internet, lobbying, or rallying local support, that can and have been used by stakeholders to tap into the formal planning process to try to affect its outcomes. Such informal activities have a considerable spatial and scalar reach, the importance of which is that stakeholders utilizing such measures have the possibility to affect not only the local wind power project under debate, but also developments in other places and attitudes towards wind power more generally.

    As concerns distributional issues, the results of the thesis show that the evidence of distributional inequality concerning wind power development on the national scale in Sweden is not very strong; but if such inequalities exist, there are possibilities to redistribute the benefits from wind power to those who are burdened by the developments. Distributional injustice related to wind power development is thus not an evident problem, generally speaking, in Sweden today. However, if this state is to remain, procedural aspects related to the continued development of wind power need to be kept in mind, as procedural and distributional inequalities are intimately related. Of specific concern is the need to address formal and informal procedures that marginalize stakeholder participation in planning processes, but it is equally important to also consider who is to be included in or excluded from negotiations and the distribution of local economic benefits connected to specific wind power projects.

  • Public defence: 2017-01-27 13:15 Hörsal B, Samhällsvetarhuset, Umeå
    Babri, Maira
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Business Administration.
    Babri, Maira
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Business Administration.
    The Corporate Code of Ethics at Home, Far Away and in Between: Sociomaterial Translations of a Traveling Code2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Corporate codes of ethics (CCEs) have become increasingly prevalent as overarching ethical guidelines for multinational corporations doing business around the globe. As formal documents, governing corporations’ work, policies, and ways of doing business, CCEs are meant to guide all business activities and apply to all of the corporation’s employees, suppliers, and business partners. In multinational corporations, this means that diverse countries, cultures, and a myriad of heterogeneous actors are expected to abide by the same standards and guidelines, as stipulated in the CCE. Despite this empirical reality, CCEs have previously been approached by academics mainly as passive company documents or as marketing or management tools, in the contexts of their country of origin. Building on Actor-Network Theory this thesis applies an interactionist ontology, and relational epistemology, seeing the code as a sociomaterial object with both material and immaterial characteristics, and moving in a global arena. Furthermore, the CCEs are assumed to be susceptible to change, i.e. translations. With these assumptions, the CCE of a multinational corporation is followed as it travels between its country of origin (Sweden) and another country (China) and goes to work in different contexts. Heterogeneous empirical materials such as interviews, company documents, observations, shadowing, and emails are used to present stories from different contexts where the CCE is at work. The overall purpose of the thesis is to contribute to the theorizing of CCEs, thereby providing further understanding of the possible consequences of CCEs in contextually diverse settings. By following traces of a CCE, this study posits the need for a simultaneous understanding of three dimensions of CCEs for CCEs to be understood in contextually dispersed settings. The three dimensions are a) material translations of the code, b) enactments of these translations, and c) ideas associated with the material and enacted code.  The study contributes to the understanding of CCEs by highlighting a specific country-context (China), by putting together knowledge from codes in various contexts, and the overarching contribution lies in highlighting codes as different kinds of objects and adding to the existing literature – specifically, contextualizing the CCE as a vaporous object.

  • Public defence: 2017-02-03 09:00 Föreläsningssal A, Psykiatriska kliniken, Målpunkt F, Plan O, Umeå
    Rajalin, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Rajalin, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Distal risk factors, interpersonal functioning & family skills training in attempted suicide2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Suicidal behavior is an important global health problem affecting also significant others. Both genetic and environmental influences play an important role in the development of suicidal behavior. There is a need of interventions for family and friends after a suicide attempt. The aim of this thesis was to assess the impact of family history of suicide (FHS) and early life adversity (ELA) on severity of suicidal behavior and on level of interpersonal problems in suicide attempters. Furthermore it aimed to evaluate a DBT-based skills training program, Family Connections (FC), for relatives and friends of suicide attempters.

    Methods Studies I and II included 181 suicide attempters. FHS was assessed with the Karolinska Self-Harm History Interview or in patient records. ELA was assessed with the Karolinska Interpersonal Violence Scale (KIVS) measuring exposure to interpersonal violence in childhood. Suicide intent was measured with the Freeman scale. Interpersonal problems were assessed with the Inventory of Interpersonal Problems (IIP).

    Study III, a pilot study evaluating the effect of FC for family members of suicide attempters, included 13 participants who completed the program with pre- and post-questionnaires. The experience of burden was assessed with the Burden Assessment Scale (BAS), general wellbeing with Brief Symptom Inventory (BSI) and level of depression was assessed with Beck Depression Inventory (BDI). The Swedish scale Questions About Family Members (QAFM) was used to explore the quality of the participants’ relationship with the patient and the Quality of Life Inventory (QOLI) was used to measure satisfaction with life situation.

    Study IV included 132 family members, and investigated the feasibility and preliminary efficacy of FC in psychiatric care. Participants were assessed pre- and post-intervention with the following self-report questionnaires: BAS, QAFM and Five Facet Mindfulness Questionnaire.

    Results Male suicide attempters with FHS made more serious and well planned suicide attempts and had higher suicide risk. FHS and exposure to interpersonal violence as a child were independent predictors of suicide in male suicide attempters. Regarding interpersonal problems, suicide attempters with FHS had significantly more often an intrusive personal style, indicating that they might have an impaired ability to create stable, long-lasting relationships. In the pilot study the participants reported a significant reduction in burden, an improved psychic health and an improvement in the relationship with the patient after completing FC. In the fourth study, FC showed to be feasible and effectively implemented in a psychiatric outpatient services clinic. Regarding burden, results were in line with the pilot study, with a significant reduction in all subscales in BAS.

    Conclusions High-risk patients call for a consideration of both ELA and FHS in clinical suicide risk assessment. In suicide attempters at biological risk, suicide might be prevented with the early recognition of environmental risks. Further, the interpersonal problems associated with FHS may cause difficulties for suicide attempters to accept or benefit from treatment, and caregivers should take into account the characteristics of the suicide attempter´s interpersonal functioning. The results from the pilot study provide support for the need and importance of an educational program addressed specifically to family members of suicide attempters. Preliminary results support the feasibility and potential value of an implementation of FC in psychiatric open care clinics.

  • Public defence: 2017-02-03 10:00 Stora hörsalen (KB.E3.03), Umeå
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The majority of drugs are small organic molecules, so-called ligands, that influence biochemical processes by interacting with proteins. The understanding of how and why they interact and form complexes is therefore a key component for elucidating the mechanism of action of drugs. The research presented in this thesis is based on studies of acetylcholinesterase (AChE). AChE is an essential enzyme with the important function of terminating neurotransmission at cholinergic synapses. AChE is also the target of a range of biologically active molecules including drugs, pesticides, and poisons. Due to the molecular and the functional characteristics of the enzyme, it offers both challenges and possibilities for investigating protein-ligand interactions. In the thesis, complexes between AChE and drug-like ligands have been studied in detail by a combination of experimental techniques and theoretical methods. The studies provided insight into the non-covalent interactions formed between AChE and ligands, where non-classical CH∙∙∙Y hydrogen bonds (Y = O or arene) were found to be common and important. The non-classical hydrogen bonds were characterized by density functional theory calculations that revealed features that may provide unexplored possibilities in for example structure-based design. Moreover, the study of two enantiomeric inhibitors of AChE provided important insight into the structural basis of enthalpy-entropy compensation. As part of the research, available computational methods have been evaluated and new approaches have been developed. This resulted in a methodology that allowed detailed analysis of the AChE-ligand complexes. Moreover, the methodology also proved to be a useful tool in the refinement of X-ray crystallographic data. This was demonstrated by the determination of a prereaction conformation of the complex between the nerve-agent antidote HI-6 and AChE inhibited by the nerve agent sarin. The structure of the ternary complex constitutes an important contribution of relevance for the design of new and improved drugs for treatment of nerve-agent poisoning. The research presented in the thesis has contributed to the knowledge of AChE and also has implications for drug discovery and the understanding of biochemical processes in general.