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  • Public defence: 2017-09-27 10:15 Hörsal 1, Uppsala
    Jans, Jenny
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Causes and Consequences of Early-life Conditions: Alcohol, Pollution and Parental Leave Policies2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay I: This paper studies the effect of air pollution on infant health in Sweden. Combining register panel data on birth outcomes and family characteristics with pollution data, I estimate the effect of particulate matter (PM10) on several birth outcomes that previously have been shown to be predictive of future outcomes. The results suggest that pollution adversely affects infant health (birth weight and gestational length). Moreover, quantile estimates suggests that the effects are larger in the lower tail of the health distribution. The effect is stronger both among children from low income households and among children born to mothers who smoke. I also find suggestive evidence of non-linearities in the relationship between PM10 and health at birth.

  • Public defence: 2017-09-28 09:15 Rosénsalen, Uppsala
    Pallangyo, Eunice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    "If really we are committed things can change starting from us providers" Improving postpartum care: A facilitation intervention at government-owned health institutions in a low-resource suburb in Dar es Salaam, Tanzania2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Globally, postpartum care is a neglected area in the continuum of maternal and newborn services. Facilitation interventions focusing on addressing local problems report positive results in improving the health of mothers and newborns in low-resource settings. 

    The aim of this thesis was to investigate a facilitation intervention to improve postpartum care at government-owned health institutions in a low-resource suburb of Dar es Salaam, Tanzania. A before-and-after study design was used to describe and evaluate the intervention in this thesis. Data were collected using mixed methods in the intervention group and the control group, before and after the intervention and were used for making comparisons.  

    The baseline studies showed that postpartum care practices were next to non-existent at the institutions, that most healthcare providers had high levels of knowledge, positive attitudes towards postpartum care and declared themselves ready to engage in its improvement. Mothers coming with their newborns for immunisation were satisfied with the services. 

    The intervention to improve postpartum care involved healthcare providers in six geographical clusters, each including 3–6 institutions, with one facilitator for each cluster. Using a participatory approach, they facilitated colleagues in identifying and addressing the provision of postpartum care at institutions. Data were collected among healthcare providers, facilitators and mothers using: focus group discussions; questionnaires; observations; and interviews, and by making field notes, written at each institution. 

    In the intervention, facilitators and healthcare providers used four strategies to improve postpartum care:increasing awareness and knowledge on postpartum care of healthcare providers and mothers; mobilising professional and material resources; improving care routines, communication and documentation; and promoting an empowering and collaborative work style. 

    The endline evaluation showed that postpartum care was conducted in the intervention group with some care items performed for 80% of observed mothers. The quality grading, which involved nine experts and was based on national guidelines, showed that none of the healthcare providers reached the level of good quality of care. In the comparison group, postpartum care continued to be next to non-existent. The healthcare providers’ knowledge increased in both groups but to a higher extent in the intervention group. The t-test indicated a significant difference in knowledge between the intervention and comparison groups and between before and after the intervention in both groups. The difference in differences for knowledge was 1.3. The attitudes showed no major difference between baseline and endline in the intervention and comparison groups. 

    This facilitation intervention was an acceptable and applicable approach and indicates promising results in improving the quality of postpartum care and in increasing mothers’ attendance.

    List of papers
    1. A baseline mixed methods study on postpartum care among health professionals in Tanzania
    Open this publication in new window or tab >>A baseline mixed methods study on postpartum care among health professionals in Tanzania
    2017 (English)In: African Journal of Midwifery and Women's Health, ISSN 1759-7374, Vol. 11, no 3, 115-122 p.Article in journal (Refereed) Published
    Abstract [en]

    Background: Globally, postpartum care (PPC) is a neglected part of maternal and neonatal health, despite 50% of maternal deaths occuring in the first weeks after childbirth.

    Aim: The study aimed to assess knowledge, attitudes and practices among providers of PPC in government institutions in two low-resource suburbs of Dar es Salaam: Ilala and Temeke.

    Methods: Health professionals ( n =149) at all levels of care completed a knowledge and attitudes questionnaire. A checklist was used to observe 25 health professionals at reproductive and child health units, and 38 mothers were interviewed on exit. χ 2 - and logistic regression tests were used to analyse the outcomes. Field notes were analysed qualitatively.

    Findings: Overall, 64% of health professionals had high knowledge and most had positive attitudes towards PPC. Level of education was found to be positively associated with positive attitudes towards PPC (OR=2.5 CI 95% 1.03–6.13). PPC consultations with mothers and newborns during the first week after childbirth were found to be few or nonexistent. Mothers who came with newborns for BCG immunisation were mostly satisfied with the services.

    Conclusion: Quality improvement is required at the structure and process levels of the health system in order to provide holistic PPC consultations.

    Keyword
    Postpartum care, knowledge, Practice, Tanzania
    National Category
    Health Sciences Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-327324 (URN)
    Available from: 2017-08-09 Created: 2017-08-09 Last updated: 2017-08-11Bibliographically approved
    2. "If really we are committed things can change, starting from us": Healthcare providers' perceptions of postpartum care and its potential for improvement in low-income suburbs in Dar es Salaam, Tanzania
    Open this publication in new window or tab >>"If really we are committed things can change, starting from us": Healthcare providers' perceptions of postpartum care and its potential for improvement in low-income suburbs in Dar es Salaam, Tanzania
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    2017 (English)In: Sexual & Reproductive HealthCare, ISSN 1877-5756, E-ISSN 1877-5764, Vol. 11, 7-12 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective

    To explore healthcare providers' perceptions of the current postpartum care (PPC) practice and its potential for improvement at governmental health institutions in low-resource suburbs in Dar es Salaam, Tanzania.

    Design

    Qualitative design, using focus group discussions (8) and qualitative content analysis.

    Setting

    Healthcare institutions (8) at three levels of governmental healthcare in Ilala and Temeke suburbs, Dar es Salaam.

    Participants

    Registered, enrolled and trained nurse-midwives (42); and medical and clinical officers (13).

    Results

    The healthcare providers perceived that PPC was suboptimal and that they could have prevented maternal deaths. PPC was fragmented at understaffed institutions, lacked guidelines and was organized in a top-down structure of leadership. The participants called for improvement of: organization of space, time, resources, communication and referral system; providers' knowledge; and supervision and feedback. Their motivation to enhance PPC quality was high.

    Key conclusions

    The HCP awareness of the suboptimal quality of PPC, its potential for promoting health and their willingness to engage in improving care are promising for the implementation of interventions to improve quality of care. Provision of guidelines, sensitization of providers to innovate and maximize utilization of existing resources, and supportive supervision and feedback are likely to contribute to the sustainability of any improvement.

    Keyword
    Focus group, HCP, Postpartum care, Quality of care, Tanzania
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-319552 (URN)10.1016/j.srhc.2016.09.001 (DOI)000394066700002 ()28159132 (PubMedID)
    Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2017-08-11Bibliographically approved
    3. Implementation of a facilitation intervention to improve postpartum care in a low resource suburb in Dar es Salaam, Tanzania
    Open this publication in new window or tab >>Implementation of a facilitation intervention to improve postpartum care in a low resource suburb in Dar es Salaam, Tanzania
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    Intervention, facilitation, knowledge translation, quality of care
    National Category
    Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-327348 (URN)
    Available from: 2017-08-09 Created: 2017-08-09 Last updated: 2017-08-11
    4. Improved postpartum care after a participatory facilitation intervention in Dar es Salaam, Tanzania: a mixed method evaluation
    Open this publication in new window or tab >>Improved postpartum care after a participatory facilitation intervention in Dar es Salaam, Tanzania: a mixed method evaluation
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    2017 (English)In: Global Health Action, ISSN 1654-9716, E-ISSN 1654-9880, Vol. 10, no 1, 1295697Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    In order to improve the health and survival of mothers/newborns, the quality and attendance rates of postpartum care (PPC) must be increased, particularly in low-resource settings.

    OBJECTIVE:

    To describe outcomes of a collegial facilitation intervention to improve PPC in government-owned health institutions in a low-resource suburb in Dar es Salaam, Tanzania.

    METHODS:

    A before-and-after evaluation of an intervention and comparison group was conducted using mixed methods (focus group discussions, questionnaires, observations, interviews, and field-notes) at health institutions. Maternal and child health aiders, enrolled nurse midwives, registered nurse midwives, and medical and clinical officers participated. A collegial facilitation intervention was conducted and healthcare providers were organized in teams to improve PPC at their workplaces. Facilitators defined areas of improvement with colleagues and met regularly with a supervisor for support.

    RESULTS:

    The number of mothers visiting the institution for PPC increased in the intervention group. Some care actions were noted in more than 80% of the observations and mothers reported high satisfaction with care. In the comparison group, PPC continued to be next to non-existent. The healthcare providers' knowledge increased in both groups but was higher in the intervention group. The t-test showed a significant difference in knowledge between the intervention and comparison groups and between before and after the intervention in both groups. The difference of differences for knowledge was 1.3. The providers perceived the intervention outcomes to include growing professional confidence/knowledge, improved PPC quality, and mothers' positive response. The quality grading was based on the national guidelines and involved nine experts and showed that none of the providers reached the level of good quality of care.

    CONCLUSIONS:

    The participatory facilitation intervention contributed to improved quality of PPC, healthcare providers' knowledge and professional confidence, awareness of PPC among mothers, and increased PPC attendance.

    Keyword
    Healthcare providers, Tanzania, facilitation, postpartum care, quality
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-322208 (URN)10.1080/16549716.2017.1295697 (DOI)000401284900001 ()28498737 (PubMedID)
    Available from: 2017-05-17 Created: 2017-05-17 Last updated: 2017-08-11Bibliographically approved
  • Public defence: 2017-09-29 09:15 A1:111a, Uppsala
    Dyakova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Flinders University.
    The processing of natural images in the visual system2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Any image can be described in terms of its statistics (i.e. quantitative parameters calculated from the image, for example RMS-contrast, the skewness of image brightness distribution, and slope constant of an average amplitude spectrum).

    It was previously shown that insect and vertebrate visual systems are optimised to the statistics common among natural scenes. However, the exact mechanisms of this process are still unclear and need further investigation.

    This thesis presents the results of examining links between some image statistics and visual responses in humans and hoverflies.

    It was found that while image statistics do not play the main role when hoverflies (Eristalis tenax and Episyrphus balteatus) chose what flowers to feed on, there is a link between hoverfly (Episyrphus balteatus) active behaviours and image statistics. There is a significant difference in the slope constant of the average amplitude spectrum, RMS contrast and skewness of brightness distribution between photos of areas where hoverflies were hovering or flying. These photos were also used to create a prediction model of hoverfly behaviour. After model validation, it was concluded that photos of both the ground and the surround should be used for best prediction of behaviour. The best predictor was skewness of image brightness distribution.

    By using a trackball setup, the optomotor response in walking hoverflies (Eristalis tenax) was found to be influenced by the slope constant of an average amplitude spectrum. 

    Intracellular recording showed that the higher-order neuron cSIFE (The centrifugal stationary inhibited flicker excited) in the hoverfly (Eristalis tenax) lobula plate was inhibited by a range of natural scenes and that this inhibition was strongest in a response to visual stimuli with the slope constant of an average amplitude spectrum of 1, which is the typical value for natural environments. 

    Based on the results of psychophysics study in human subjects it was found that sleep deprivation affects human perception of naturalistic slope constants differently for different image categories (“food” and “real world scenes”).

    These results help provide a better understanding of the link between visual processes and the spatial statistics of natural scenes.

    List of papers
    1. In situ modeling of multimodal floral cues attracting wild pollinators across environments
    Open this publication in new window or tab >>In situ modeling of multimodal floral cues attracting wild pollinators across environments
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    (English)In: Article in journal (Refereed) Submitted
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-328029 (URN)
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2017-08-16
    2. Predicting unconstrained field flight behaviour from image statistics
    Open this publication in new window or tab >>Predicting unconstrained field flight behaviour from image statistics
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-328030 (URN)
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2017-08-16
    3. A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes
    Open this publication in new window or tab >>A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes
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    2015 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, 8522Article in journal (Refereed) Published
    Abstract [en]

    Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons with limited bandwidth to encode challengingly large input ranges. Natural scenes are not random, and peripheral visual systems in vertebrates and insects have evolved to respond efficiently to their typical spatial statistics. The mammalian visual cortex is also tuned to natural spatial statistics, but less is known about coding in higher order neurons in insects. To redress this we here record intracellularly from a higher order visual neuron in the hoverfly. We show that the cSIFE neuron, which is inhibited by stationary images, is maximally inhibited when the slope constant of the amplitude spectrum is close to the mean in natural scenes. The behavioural optomotor response is also strongest to images with naturalistic image statistics. Our results thus reveal a close coupling between the inherent statistics of natural scenes and higher order visual processing in insects.

    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-264173 (URN)10.1038/ncomms9522 (DOI)000364930800007 ()26439748 (PubMedID)
    Funder
    Swedish Research Council, 2012-4740
    Note

    Supplementary information available for this article at http://www.nature.com/ncomms/2015/151006/ncomms9522/suppinfo/ncomms9522_S1.html

    Available from: 2015-10-06 Created: 2015-10-06 Last updated: 2017-08-16Bibliographically approved
    4. Sleep deprivation changes our perception of naturalness
    Open this publication in new window or tab >>Sleep deprivation changes our perception of naturalness
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    (English)In: Article in journal (Refereed) Submitted
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-328031 (URN)
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2017-08-16
  • Public defence: 2017-09-29 09:15 B/B22, Uppsala
    Martijn, Joran
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Exploration of microbial diversity and evolution through cultivation independent phylogenomics2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Our understanding of microbial evolution is largely dependent on available genomic data of diverse organisms. Yet, genome-sequencing efforts have mostly ignored the diverse uncultivable majority in favor of cultivable and sociologically relevant organisms. In this thesis, I have applied and developed cultivation independent methods to explore microbial diversity and obtain genomic data in an unbiased manner. The obtained genomes were then used to study the evolution of mitochondria, Rickettsiales and Haloarchaea.

    Metagenomic binning of oceanic samples recovered draft genomes for thirteen novel Alphaproteobacteria-related lineages. Phylogenomics analyses utilizing the improved taxon sample suggested that mitochondria are not related to Rickettsiales but rather evolved from a proteobacterial lineage closely related to all sampled alphaproteobacteria.

    Single-cell genomics and metagenomics of lake and oceanic samples, respectively, identified previously unobserved Rickettsiales-related lineages. They branched early relative to characterized Rickettsiales and encoded flagellar genes, a feature once thought absent in this order. Flagella are most likely an ancestral feature, and were independently lost during Rickettsiales diversification. In addition, preliminary analyses suggest that ATP/ADP translocase, the marker for energy parasitism, was acquired after the acquisition of type IV secretion systems during the emergence of the Rickettsiales.

    Further exploration of the oceanic samples yielded the first draft genomes of Marine Group IV archaea, the closest known relatives of the Haloarchaea. The halophilic and generally aerobic Haloarchaea are thought to have evolved from an anaerobic methanogenic ancestor. The MG-IV genomes allowed us to study this enigmatic evolutionary transition. Preliminary ancestral reconstruction analyses suggest a gradual loss of methanogenesis and adaptation to an aerobic lifestyle, respectively.

    The thesis further presents a new amplicon sequencing method that captures near full-length 16S and 23S rRNA genes of environmental prokaryotes. The method exploits PacBio's long read technology and the frequent proximity of these genes in prokaryotic genomes. Compared to traditional partial 16S amplicon sequencing, our method classifies environmental lineages that are distantly related to reference taxa more confidently.

    In conclusion, this thesis provides new insights into the origins of mitochondria, Rickettsiales and Haloarchaea and illustrates the power of cultivation independent methods with respect to the study of microbial evolution.

    List of papers
    1. Single-cell genomics of a rare environmental alphaproteobacterium provides unique insights into Rickettsiaceae evolution
    Open this publication in new window or tab >>Single-cell genomics of a rare environmental alphaproteobacterium provides unique insights into Rickettsiaceae evolution
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    2015 (English)In: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370, Vol. 9, no 11, 2373-2385 p.Article in journal (Refereed) Published
    Abstract [en]

    The bacterial family Rickettsiaceae includes a group of well-known etiological agents of many human and vertebrate diseases, including epidemic typhus-causing pathogen Rickettsia prowazekii. Owing to their medical relevance, rickettsiae have attracted a great deal of attention and their host-pathogen interactions have been thoroughly investigated. All known members display obligate intracellular lifestyles, and the best-studied genera, Rickettsia and Orientia, include species that are hosted by terrestrial arthropods. Their obligate intracellular lifestyle and host adaptation is reflected in the small size of their genomes, a general feature shared with all other families of the Rickettsiales. Yet, despite that the Rickettsiaceae and other Rickettsiales families have been extensively studied for decades, many details of the origin and evolution of their obligate host-association remain elusive. Here we report the discovery and single-cell sequencing of 'Candidatus Arcanobacter lacustris', a rare environmental alphaproteobacterium that was sampled from Damariscotta Lake that represents a deeply rooting sister lineage of the Rickettsiaceae. Intriguingly, phylogenomic and comparative analysis of the partial 'Candidatus Arcanobacter lacustris' genome revealed the presence chemotaxis genes and vertically inherited flagellar genes, a novelty in sequenced Rickettsiaceae, as well as several host-associated features. This finding suggests that the ancestor of the Rickettsiaceae might have had a facultative intracellular lifestyle. Our study underlines the efficacy of single-cell genomics for studying microbial diversity and evolution in general, and for rare microbial cells in particular.

    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-267117 (URN)10.1038/ismej.2015.46 (DOI)000365091700005 ()25848874 (PubMedID)
    Funder
    Swedish Research Council, 621-2009-4813Swedish Research Council, 621-2011-4669EU, European Research Council, 310039-PUZZLE_CELLEU, European Research Council, 281633-EvoChlamy
    Available from: 2015-11-18 Created: 2015-11-18 Last updated: 2017-08-08Bibliographically approved
    2. Deep mitochondrial origin outside the sampled alphaproteobacteria
    Open this publication in new window or tab >>Deep mitochondrial origin outside the sampled alphaproteobacteria
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    (English)Article in journal (Refereed) Submitted
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-327305 (URN)
    Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-08-16
    3. Amplicon sequencing of the 16S-ITS-23S rRNA operon with long-read technology for improved phylogenetic classification of uncultured prokaryotes
    Open this publication in new window or tab >>Amplicon sequencing of the 16S-ITS-23S rRNA operon with long-read technology for improved phylogenetic classification of uncultured prokaryotes
    (English)Manuscript (preprint) (Other academic)
    National Category
    Evolutionary Biology Microbiology
    Identifiers
    urn:nbn:se:uu:diva-327307 (URN)
    Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-08-08
    4. First genomes of Marine Group IV archaea enlighten the evolutionary origins of Haloarchaea
    Open this publication in new window or tab >>First genomes of Marine Group IV archaea enlighten the evolutionary origins of Haloarchaea
    (English)Manuscript (preprint) (Other academic)
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-327308 (URN)
    Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-08-08
    5. Deeply branching alphaproteobacteria illuminate early Rickettsiales evolution
    Open this publication in new window or tab >>Deeply branching alphaproteobacteria illuminate early Rickettsiales evolution
    (English)Manuscript (preprint) (Other academic)
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-327309 (URN)
    Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-08-08
  • Public defence: 2017-09-29 10:00 Föreläsningssalen, Falu lasarett, Falun
    Carlsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Healthcare and patient factors affecting sick leave: From a primary health care perspective2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: For indeterminate reasons, there have been major variations in sick leave in Sweden, and many physicians have perceived sick leave assignments as burdensome.

    Aim: To gain more knowledge and understanding, from a perspective of primary health care, about factors in health care and patients that affect sick leave. Thereby help patients in the best way, facilitate the work of physicians and other health professionals involved in the rehabilitation process, and use the health care resources optimally.

    Methods: This thesis is based on a randomised controlled trial (RCT) in a primary health care centre with participants on short-term sick leave, due to pain and/or mental illness, who received a multidisciplinary assessment. Qualitative focus-group discussions with physicians in primary health care centres. A cohort of women on very long-term sick leave due to pain and/or mental illness, who lost sickness benefits due to a new time limit on sickness insurance, were randomised to multidisciplinary assessment and multimodal intervention (TEAM), or to Acceptance and Commitment Therapy (ACT). In an extended cohort, including some men on very long-term sick leave due to pain and/or mental illness, the importance of the motivation for return to work (RTW) was investigated.

    Results. Very early multidisciplinary assessment increased days on sick leave in the first three month period. Physicians at primary health care centres perceived sick leave assignments as burdensome, but clearer rules and cooperation with other professionals have made sick leave assignments less burdensome. TEAM intervention resulted in an increase in working hours per week as well as an increase in work-related engagements, compared to control in the RCT. Motivation for RTW was associated with RTW or increased employability in the rehabilitation of patients

    Conclusions: Continued studies are needed to find those who are at risk of long-term sick leave, the time when rehabilitation efforts should be started, and the content of rehabilitation. Collaboration in teams facilitates sick leave assignments for physicians at primary care health centres. Motivation for RTW might be a factor of importance for the effect of rehabilitation and needs to be studied further.

    List of papers
    1. Early multidisciplinary assessment was associated with longer periods of sick leave: A randomized controlled trial in a primary health care centre
    Open this publication in new window or tab >>Early multidisciplinary assessment was associated with longer periods of sick leave: A randomized controlled trial in a primary health care centre
    2013 (English)In: Scandinavian Journal of Primary Health Care, ISSN 0281-3432, E-ISSN 1502-7724, Vol. 31, no 3, 141-146 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective

    To study the effects on sick leave from an early multidisciplinary assessment at a primary health care centre. Design. Randomized controlled trial.

    Setting

    Patients who saw GPs at a primary health care centre in mid-Sweden and asked for a sickness certificate for psychiatric or musculoskeletal diagnoses were invited to participate. Patients included were sick-listed for less than four weeks; 33 patients were randomized either to an assessment within a week by a physiotherapist, a psychotherapist, and an occupational therapist or to "standard care". The therapists used methods and tools they normally use in their clinical work.

    Main outcome measure

    Proportion of patients still sick-listed three months after randomization, total and net days on sick leave, and proportion who were on part-time sick leave.

    Results

    At follow-up after three months, in contrast to the pre-trial hypothesis, there was a trend toward a higher proportion of patients still sick-listed in the intervention group (7/18) as compared with the control group (3/15). The intervention group also had significantly longer sick-listing periods (mean 58 days) than the control group (mean 36 days) (p = 0.038). The proportion of patients who were part time sick-listed was significantly higher in the intervention group (10/18) than in the control group (2/15) (p = 0.027).

    Conclusions

    In this study an early multidisciplinary assessment was associated with longer periods on sick leave and more individuals on part-time sick leave.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-205930 (URN)10.3109/02813432.2013.811943 (DOI)000323243900005 ()23909930 (PubMedID)
    Available from: 2013-08-26 Created: 2013-08-26 Last updated: 2017-08-17Bibliographically approved
    2. General practitioners' perceptions of working with the certification of sickness absences following changes in the Swedish social security system: a qualitative focus-group study
    Open this publication in new window or tab >>General practitioners' perceptions of working with the certification of sickness absences following changes in the Swedish social security system: a qualitative focus-group study
    2015 (English)In: BMC Family Practice, ISSN 1471-2296, E-ISSN 1471-2296, Vol. 16, 21Article in journal (Refereed) Published
    Abstract [en]

    Background: Many physicians in Sweden, as well as in other countries, find the matter of certification of sickness absence (COSA) particularly burdensome. The issuing of COSAs has also been perceived as a work-environment problem among physicians. Among general practitioners (GPs) are the highest proportion of physicians in Sweden who experience difficulties with COSA. Swedish authorities have created several initiatives, by changing the social security system, to improve the rehabilitation of people who are ill and decrease the number of days of sick leave used. The aim of this study was to describe how GPs in Sweden perceive their work with COSA after these changes. Methods: A descriptive design with a qualitative, inductive focus-group discussion (FGD) approach was used. Results: Four categories emerged from the analysis of FGDs with GPs in Sweden: 1) Physicians' difficulties in their professional role; 2) Collaboration with other professionals facilitates the COSA; 3) Physicians' approach in relation to the patient; 4) An easier COSA process. Conclusions: Swedish GPs still perceived COSA to be a burdensome task. However, system changes in recent years have facilitated work related to COSA. Cooperation with other professionals on COSA was perceived positively.

    Keyword
    General practitioners, Primary health care, Focus group discussions, Sick leave, Certification of sickness absence, Social security system
    National Category
    Other Medical Sciences
    Identifiers
    urn:nbn:se:uu:diva-248186 (URN)10.1186/s12875-015-0238-5 (DOI)000350069200001 ()
    Available from: 2015-04-12 Created: 2015-03-30 Last updated: 2017-08-17Bibliographically approved
    3. Effectiveness of two vocational rehabilitation programmes in women with long-term sick leave due to pain syndrome or mental illness: 1-year follow-up of a randomized controlled trial
    Open this publication in new window or tab >>Effectiveness of two vocational rehabilitation programmes in women with long-term sick leave due to pain syndrome or mental illness: 1-year follow-up of a randomized controlled trial
    2017 (English)In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 49, no 2, 170-177 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective: Mental illness and chronic pain are common reasons for long-term sick leave, typically more so for women. This study investigated the effects on return to work of 2 vocational rehabilitation programmes. Methods: In this randomized controlled study, 308 women were allocated to treatment with acceptance and commitment therapy, to multidisciplinary assessment and individualized rehabilitation interventions, or to a control group. Return-to-work at 12 months was assessed as: (i) returning to health insurance; (ii) number of reimbursed health insurance days during follow-up; (iii) self-reported change in working hours; (iv) a composite measure of self-reported change in work-related engagement. Results: The mean age of the Swedish study population was 48.5 years (standard deviation (SD) 6.3 years) and the mean time on sick leave 7.5 years (SD 3.2 years). There were no significant differences in reimbursed days or returning to the health insurance at 12 months. The multidisciplinary assessment and individualized rehabilitation interventions group, compared with control, reported a significant increase in working hours per week, as well as a significant increase in work-related engagement. Conclusion: Multidisciplinary assessments and individual rehabilitation interventions may improve the chance of return-to-work in women with long-term sick leave due to pain condition or mental illness.

    Keyword
    return to work, vocational rehabilitation, multidisciplinary rehabilitation, acceptance and commitment therapy, chronic pain
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-317212 (URN)10.2340/1651977-2188 (DOI)28101560 (PubMedID)
    Available from: 2017-03-11 Created: 2017-03-11 Last updated: 2017-08-08Bibliographically approved
    4. Motivation for return to work and actual return to work among people on long-term sick leave due to pain syndrome or mental health conditions
    Open this publication in new window or tab >>Motivation for return to work and actual return to work among people on long-term sick leave due to pain syndrome or mental health conditions
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    Sick leave, motivation, return to work, sickness insurance, insurance medicine, public employment service, self-determination theory
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Research subject
    Family Medicine
    Identifiers
    urn:nbn:se:uu:diva-327288 (URN)
    Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-08-17Bibliographically approved
  • Public defence: 2017-09-29 10:00 Hambergsalen, Uppsala
    Rasmusson, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Modeling of geohydrological processes in geological CO2 storage – with focus on residual trapping2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Geological storage of carbon dioxide (CO2) in deep saline aquifers is one approach to mitigate release from large point sources to the atmosphere. Understanding of in-situ processes providing trapping is important to the development of realistic models and the planning of future storage projects. This thesis covers both field- and pore-scale numerical modeling studies of such geohydrological processes, with focus on residual trapping. The setting is a CO2-injection experiment at the Heletz test site, conducted within the frame of the EU FP7 MUSTANG and TRUST projects.

    The objectives of the thesis are to develop and analyze alternative experimental characterization test sequences for determining in-situ residual CO2 saturation (Sgr), as well as to analyze the impact of the injection strategy on trapping, the effect of model assumptions (coupled wellbore-reservoir flow, geological heterogeneity, trapping model) on the predicted trapping, and to develop a pore-network model (PNM) for simulating and analyzing pore-scale mechanisms.

    The results include a comparison of alternative characterization test sequences for estimating Sgr. The estimates were retrieved through parameter estimation. The effect on the estimate of including various data sets was determined. A new method, using withdrawal and an indicator-tracer, for obtaining a residual zone in-situ was also introduced.

    Simulations were made of the CO2 partitioning between layers in a multi-layered formation, and parameters influencing this were identified. The results showed the importance of accounting for coupled wellbore-reservoir flow in simulations of such scenarios.

    Simulations also showed that adding chase-fluid stages after a conventional CO2 injection enhances the (residual and dissolution) trapping. Including geological heterogeneity generally decreased the estimated trapping. The choice of trapping model may largely effect the quantity of the predicted residual trapping (although most of them produced similar results). The use of an appropriate trapping model and description of geological heterogeneity for a site when simulating CO2 sequestration is vital, as different assumptions may give significant discrepancies in predicted trapping.

    The result also includes a PNM code, for multiphase quasi-static flow and trapping in porous materials. It was used to investigate trapping and obtain an estimated trapping (IR) curve for Heletz sandstone.

    List of papers
    1. Analysis of alternative push-pull-test-designs for determining in situ residual trapping of carbon dioxide
    Open this publication in new window or tab >>Analysis of alternative push-pull-test-designs for determining in situ residual trapping of carbon dioxide
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    2014 (English)In: International Journal of Greenhouse Gas Control, ISSN 1750-5836, Vol. 27, 155-168 p.Article in journal (Refereed) Published
    Abstract [en]

    Carbon dioxide storage in deep saline aquifers is a promising technique to reduce direct emissions of greenhouse gas to the atmosphere. To ensure safe storage the in situ trapping mechanisms, residual trapping being one of them, need to be characterized. This study aims to compare three alternative single-well carbon dioxide push-pull test sequences for their ability to quantify residual gas trapping. The three tests are based on the proposed test sequence by Zhang et al. (2011) for estimating residual gas saturation. A new alternative way to create residual gas conditions in situ incorporating withdrawal and a novel indicator-tracer approach has been investigated. Further the value of additional pressure measurements from a nearby passive observation well was evaluated. The iTOUGH2 simulator with the EOS7C module was used for sensitivity analysis and parameter estimation. Results show that the indicator-tracer approach could be used to create residual conditions without increasing estimation uncertainty of S-gr. Additional pressure measurements from a passive observation well would reduce the uncertainty in the S-gr estimate. The findings of the study can be used to develop field experiments for site characterization.

    Keyword
    CO2, CCS, Site characterization, Field test, Residual saturation, Single-well test
    National Category
    Energy Systems
    Identifiers
    urn:nbn:se:uu:diva-232013 (URN)10.1016/j.ijggc.2014.05.008 (DOI)000340319600012 ()
    Available from: 2014-09-12 Created: 2014-09-12 Last updated: 2017-08-15Bibliographically approved
    2. Distribution of injected CO2 in a stratified saline reservoir accounting for coupled wellbore-reservoir flow
    Open this publication in new window or tab >>Distribution of injected CO2 in a stratified saline reservoir accounting for coupled wellbore-reservoir flow
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    2015 (English)In: Greenhouse Gases: Science and Technology, E-ISSN 2152-3878, Vol. 5, no 4, 419-436 p.Article in journal (Refereed) Published
    Abstract [en]

    Geological storage in sedimentary basins is considered a viable technology in mitigating atmospheric CO2 emissions. Alternating high and low permeability strata are common in these basins. The distribution of injected CO2 among such layers affects e.g. CO2 storage efficiency, capacity and plume footprint. A numerical study on the distribution of injected CO2 into a multi-layered reservoir, accounting for coupled wellbore-reservoir flow, was carried out using the T2Well/ECO2N code. A site-specific case as well as a more general case were considered. Properties and processes governing the distribution of sequestrated CO2 were identified and the potential to operationally modify the distribution was investigated. The distribution of CO2 was seen to differ from that of injected water, i.e. it was not proportional to the transmissivity of the layers. The results indicate that caution should be taken when performing numerical simulations of CO2 injection into layered formations. Ignoring coupled wellbore-reservoir flow and instead adopting a simple boundary condition at the injection well, such as an inflow rate proportional to the transmissivity of each layer, may result in significant underestimation of the proportion of CO2 ending up in the shallower layers, as not all relevant processes are accounted for. This discrepancy has been thoroughly investigated and quantified for several CO2 sequestration scenarios.

    Keyword
    CCS, flow distribution, geological storage, layered formation, wellbore model
    National Category
    Oceanography, Hydrology, Water Resources
    Identifiers
    urn:nbn:se:uu:diva-263036 (URN)10.1002/ghg.1477 (DOI)000360356800007 ()
    Funder
    EU, FP7, Seventh Framework Programme, 227286EU, FP7, Seventh Framework Programme, 309067
    Available from: 2015-09-30 Created: 2015-09-24 Last updated: 2017-08-15Bibliographically approved
    3. A simulation study of the effect of trapping model, geological heterogeneity and injection strategies on CO2 trapping
    Open this publication in new window or tab >>A simulation study of the effect of trapping model, geological heterogeneity and injection strategies on CO2 trapping
    2016 (English)In: International Journal of Greenhouse Gas Control, ISSN 1750-5836, E-ISSN 1878-0148, Vol. 52, 52-72 p.Article in journal (Refereed) Published
    Abstract [en]

    Industrial CO2 emissions to the atmosphere can be reduced through geological storage, where the gas is injected into the subsurface and trapped by several mechanisms. Residual and solubility trapping are two important processes providing trapping, and their effectiveness ultimately determines the feasibility of geological storage. By means of numerical modeling, a systematic analysis was made concerning the factors potentially affecting trapping, to guide the planned injection experiments at the Heletz test injection site. The effect of enhanced-trapping injection strategies along with the role of geological heterogeneity and the choice of trapping model (TM) were evaluated. The results showed that adding chase-fluid stages to a conventional CO2 injection enhanced the trapping. Taking into account the geological heterogeneity decreased trapping, as this retarded the buoyant migration, resulting in less imbibition and residual trapping. The choice of TM was significant, with the simplified Land TM producing the highest trapping, and the Aissaoui TM the lowest. The results stress the importance of using an appropriate TM as well as heterogeneity model for the site in question for any predictive modeling of CO2 sequestration, as different assumptions may lead to significant discrepancies in the predicted trapping.

    Keyword
    CCS, Capillary trapping, Hysteresis, Injection strategies, Residual trapping, Solubility trapping
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-303260 (URN)10.1016/j.ijggc.2016.06.020 (DOI)000381728300006 ()
    Funder
    EU, FP7, Seventh Framework Programme, 227286; 309067
    Available from: 2016-09-16 Created: 2016-09-15 Last updated: 2017-08-15Bibliographically approved
    4. Residual trapping of carbon dioxide during geological storage – insight gained through a pore-network modeling approach
    Open this publication in new window or tab >>Residual trapping of carbon dioxide during geological storage – insight gained through a pore-network modeling approach
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    (English)In: Article in journal (Other academic) Submitted
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-327991 (URN)
    Available from: 2017-08-15 Created: 2017-08-15 Last updated: 2017-08-15
  • Public defence: 2017-09-29 10:15 Hörsal 2, Uppsala
    Andersson, Josefine
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Insurances against job loss and disability: Private and public interventions and their effects on job search and labor supply2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay I: Employment Security Agreements, which are elements of Swedish collective agreements, offer a unique opportunity to study very early job search counselling of displaced workers. These agreements provide individual job search assistance to workers who are dismissed due to redundancy, often as early as during the period of notice. Compared to traditional labor market policies, the assistance provided is earlier and more responsive to the needs of the individual worker. In this study, I investigate the effects of the individual counseling and job search assistance provided through the Employment Security Agreement for Swedish blue-collar workers on job finding and subsequent job quality. The empirical strategy is based on the rules of eligibility in a regression discontinuity framework. I estimate the effect for workers with short tenure, who are dismissed through mass-layoffs. My results do not suggest that the program has an effect on the probability of becoming unemployed, the duration of unemployment, or income. However, the results indicate that the program has a positive effect on the duration of the next job.

    Essay II: The well-known positive relationship between the unemployment benefit level and unemployment duration can be separated into two potential sources; a moral hazard effect, and a liquidity effect pertaining to the increased ability to smooth consumption. The latter is a socially optimal response due to credit and insurance market failures. These two effects are difficult to separate empirically, but the social optimality of an unemployment insurance policy can be evaluated by studying the effect of a non-distortionary lump-sum severance grant on unemployment durations. In this study, I evaluate the effects on unemployment duration and subsequent job quality of a lump-sum severance grant provided to displaced workers, by means of a Swedish collective agreement. I use a regression discontinuity design, based on the strict age requirement to be eligible for the grant. I find that the lump-sum grant has a positive effect on the probability of becoming unemployed and the length of the completed unemployment duration, but no effect on subsequent job quality. My analysis also indicates that spousal income is important for the consumption smoothing abilities of displaced workers, and that the grant may have a greater effect in times of more favorable labor market conditions.

    Essay III: Evidence from around the world suggest that individuals who are awarded disability benefits in some cases still have residual working capacity, while disability insurance systems typically involve strong disincentives for benefit recipients to work. Some countries have introduced policies to incentivize disability insurance recipients to use their residual working capacities on the labor market. One such policy is the continuous deduction program in Sweden, introduced in 2009. In this study, I investigate whether the financial incentives provided by this program induce disability insurance recipients to increase their labor supply or education level. Retroactively determined eligibility to the program with respect to time of benefit award provides a setting resembling a natural experiment, which could be used to estimate the effects of the program using a regression discontinuity design. However, a simultaneous regime change of disability insurance eligibility causes covariate differences between treated and controls, which I adjust for using a matching strategy. My results suggest that the financial incentives provided by the program have not had any effect on labor supply or educational attainment.

  • Public defence: 2017-09-29 13:00 Fåhraeus Hall, Rudbecklaboratoriet, Uppsala
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Development of ADAPT-based tracers for radionuclide molecular imaging of cancer2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    ABD-Derived Affinity Proteins (ADAPTs) is a novel class of small engineered scaffold proteins based on albumin-binding domain (ABD) of streptococcal protein G. High affinity ADAPT  binders against various therapeutic targets can be selected.  In this thesis, we report a development of ADAPT-based radionuclide imaging agents providing high sensitivity and specificity of molecular imaging of HER2 expression in disseminated cancers.

    We investigated the feasibility of the use of ADAPTs as imaging agents and influence of molecular design and radiolabeling chemistry on in vivo targeting and biodistribution properties of the tracers.

    In Paper I we demonstrated the feasibility of the use of anti-HER2 ADAPT6 molecule as a high contrast imaging agent;

    In Paper II we evaluated the influence of composition of histidine-containing tag on in vivo biodistribution of ADAPT-based tracers labeled with 99mTc using 99mTc(CO)3 binding to histidine-containing tags and 111In using DOTA chelator at N-terminus;

    In Paper III we evaluated the influence of different aspects of N-terminus leading sequence on targeting including effect of sequence size on clearance rate and effect of the composition of the sequence on biodistribution profile;

    In Paper IV, we evaluated the influence of residualizing properties and positioning of the label on biodistribution and targeting; and

    In Paper V, we compared tumor-targeting properties of the ADAPT6 labeled at C-terminus with 99mTc using N3S chelator and 111In using DOTA chelator.

    In conclusion, ADAPTs constitute a very promising class of targeting probes for molecular imaging providing high contrast. Molecular design of the ADAPT proteins and chelators/linkers for labeling has an appreciable effect on their imaging properties.

    List of papers
    1. ADAPT, a novel scaffold protein-based probe for radionuclide imaging of molecular targets that are expressed in disseminated cancers
    Open this publication in new window or tab >>ADAPT, a novel scaffold protein-based probe for radionuclide imaging of molecular targets that are expressed in disseminated cancers
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    2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 20, 4364-4371 p.Article in journal (Refereed) Published
    Abstract [en]

    Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity ProTeins (ADAPT), have been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high affinity binders to various proteins. Further, ABD was engineered to rapidly purify ADAPT6, eradicate its binding to albumin and enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, 111In for SPECT imaging and 68Ga for PET imaging. Pharmacological studies in mice demonstrated that the fully engineered molecule 111In/68Ga-DOTA-(HE)3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET by one hour post-infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for non-invasive in vivo imaging.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-262291 (URN)10.1158/0008-5472.CAN-14-3497 (DOI)000365601900013 ()26297736 (PubMedID)
    Funder
    Swedish Cancer Society, 2012/354Swedish Research Council, 521-2012-2228Swedish Research Council, 621-2012-5088
    Note

    First two authors (Garousi and Lindbo) contributed equally

    Last two authors (Tolmachev and Hober) contributed eaually

    Available from: 2015-09-12 Created: 2015-09-12 Last updated: 2017-08-10
    2. Influence of Histidine-Containing Tags on the Biodistribution of ADAPT Scaffold Proteins.
    Open this publication in new window or tab >>Influence of Histidine-Containing Tags on the Biodistribution of ADAPT Scaffold Proteins.
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    2016 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 27, no 3, 716-726 p.Article in journal (Refereed) Published
    Abstract [en]

    Engineered scaffold proteins (ESP) are high-affinity binders that can be used as probes for radionuclide imaging. Histidine-containing tags enable both efficient purification of ESP and radiolabeling with (99m)Tc(CO)3. Earlier studies demonstrated that the use of a histidine-glutamate-histidine-glutamate-histidine-glutamate (HE)3-tag instead of the commonly used hexahistidine (H6)-tag reduces hepatic uptake of radiolabeled ESP and short peptides. Here, we investigated the influence of histidine-containing tags on the biodistribution of a novel type of ESP, ADAPTs. A series of anti-HER2 ADAPT probes having H6- or (HE)3-tags in the N-termini were prepared. The constructs, (HE)3-ADAPT6 and H6-ADAPT6, were labeled with two different nuclides, (99m)Tc or (111)In. The labeling with (99m)Tc(CO)3 utilized the histidine-containing tags, while (111)In was attached through a maleimido derivative of DOTA conjugated to the N-terminus. For (111)In-labeled ADAPTs, the use of (HE)3 provided a significantly (p < 0.05) lower hepatic uptake at 1 h after injection, but there was no significant difference in hepatic uptake of (111)In-(HE)3-ADAPT6 and H6-ADAPT6 at later time points. Interestingly, in the case of (99m)Tc, (99m)Tc(CO)3-H6-ADAPT6 provided significantly (p < 0.05) lower uptake in a number of normal tissues and was more suitable as an imaging probe. Thus, the influence of histidine-containing tags on the biodistribution of the novel ADAPT scaffold proteins was different compared to its influence on other ESPs studied so far. Apparently, the effect of a histidine-containing tag on the biodistribution is highly dependent on the scaffold composition of the ESP.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-286833 (URN)10.1021/acs.bioconjchem.5b00677 (DOI)000372478600026 ()26781756 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2015/350Swedish Research Council, 2015-02353, 621-2012-5088
    Note

    First two authors (Lindbo and Garousi) contributed equally

    Available from: 2016-04-21 Created: 2016-04-21 Last updated: 2017-08-10Bibliographically approved
    3. Influence of the N-Terminal Composition on Targeting Properties of Radiometal-Labeled Anti-HER2 Scaffold Protein ADAPT6
    Open this publication in new window or tab >>Influence of the N-Terminal Composition on Targeting Properties of Radiometal-Labeled Anti-HER2 Scaffold Protein ADAPT6
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    2016 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 27, no 11, 2678-2688 p.Article in journal (Refereed) Published
    Abstract [en]

    Radionuclide-imaging-based stratification of patients to targeted therapies makes cancer treatment more personalized and therefore more efficient. Albumin-binding domain derived affinity proteins (ADAPTs) constitute a novel group of imaging probes based on the scaffold of an albumin-binding domain (ABD). To evaluate how different compositions of the N-terminal sequence of ADAPTs influence their biodistribution, a series of human epidermal growth factor receptor type 2 (HER2)-binding ADAPT6 derivatives with different N-terminal sequences were created: GCH6DANS (2), GC(HE)3DANS (3), GCDEAVDANS (4), and GCVDANS(5). These were compared with the parental variant: GCSS(HE)3DEAVDANS (1). All variants were site-specifically conjugated with a maleimido-derivative of a DOTA chelator and labeled with (111)In. Binding to HER2-expressing cells in vitro, in vivo biodistribution as well as targeting properties of the new variants were compared with properties of the (111)In-labeled parental ADAPT variant 1 ((111)In-DOTA-1). The composition of the N-terminal sequence had an apparent influence on biodistribution of ADAPT6 in mice. The use of a hexahistidine tag in (111)In-DOTA-2 was associated with elevated hepatic uptake compared to the (HE)3-containing counterpart, (111)In-DOTA-3. All new variants without a hexahistidine tag demonstrated lower uptake in blood, lung, spleen, and muscle compared to uptake in the parental variant. The best new variants, (111)In-DOTA-3 and (111)In-DOTA-5, provided tumor uptakes of 14.6 ± 2.4 and 12.5 ± 1.3% ID/g at 4 h after injection, respectively. The tumor uptake of (111)In-DOTA-3 was significantly higher than the uptake of the parental (111)In-DOTA-1 (9.1 ± 2.0% ID/g). The tumor-to-blood ratios of 395 ± 75 and 419 ± 91 at 4 h after injection were obtained for (111)In-DOTA-5 and (111)In-DOTA-3, respectively. In conclusion, the N-terminal sequence composition affects the biodistribution and targeting properties of ADAPT-based imaging probes, and its optimization may improve imaging contrast.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-312075 (URN)10.1021/acs.bioconjchem.6b00465 (DOI)000388430700011 ()27740752 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2015/350Swedish Research Council, 2015-02353Swedish Research Council, 621-2012-5088
    Available from: 2017-01-04 Created: 2017-01-04 Last updated: 2017-08-10Bibliographically approved
    4. Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and residualizing properties of the label
    Open this publication in new window or tab >>Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and residualizing properties of the label
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    2017 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667Article in journal (Refereed) Accepted
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-327415 (URN)
    Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-08-11
    5. Comparative evaluation of tumor targeting using anti-HER2 ADAPT scaffold protein labeled at C-terminus with  indium-111 and technetium-99m
    Open this publication in new window or tab >>Comparative evaluation of tumor targeting using anti-HER2 ADAPT scaffold protein labeled at C-terminus with  indium-111 and technetium-99m
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-327416 (URN)
    Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-08-10
  • Public defence: 2017-09-29 13:00 Hedstrandsalen, Uppsala
    von Seth, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Oxygen delivery and mitochondrial dysfunction as assessed by microdialysis during interventions in experimental sepsis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Early administration of broad-spectrum antibiotics is the first goal in sepsis treatment. Besides from bacteriostatic/bactericidal effects, some antibiotics may also modify the host´s response to infection. The novel antibiotic tigecycline may exert such properties; however, this property has not been evaluated in large-animal trials. We compared tigecycline with doxycycline and placebo in relation to anti-inflammatory, circulatory and organ dysfunction effects in a sterile pig model of sepsis. Doxycycline, but not tigecycline, reduced the inflammatory response as manifested by tumor necrosis factor alpha levels in plasma. Tigecycline, however, had a stabilizing effect on the circulation not exerted by doxycycline or placebo.

    To achieve rapid restoration of the circulating blood volume - another major goal in sepsis treatment - fluid bolus administration of is some-times practiced. In addition to crystalloids, albumin-containing solutions are suggested. Yet, some animal-experimental data suggests that rapid bolus administration of albumin reduces albumin’s plasma-expanding effect. We compared a rapid intravenous bolus of radiolabeled albumin with a slow infusion in a sterile pig model of sepsis. Rapid bolus of administration did not reduce plasma levels of albumin following administration and did not increase the amount of albumin that left the circulation.

    Inadequate oxygen delivery (DO2) by the circulation to the tissues may cause increased plasma lactate, which is the most striking effect of sepsis on the metabolism. However, experimental data and clinical trials refute this link, instead, suggesting other mechanisms, including impaired oxygen extraction, mitochondrial dysfunction and accelerated aerobic glycolysis. We investigated the impact of DO2, oxygen consumption (VO2), hemodynamic parameters and inflammatory response on plasma lactate and organ dysfunction in two experimental sepsis models. In the most severe cases of shock, with DO2, there was an increase in plasma lactate, but without a decrease in VO2, invalidating the assumption that the increase in lactate is due to anaerobic metabolism.

    To identify critical steps in the sepsis-induced increase in lactate, we inhibited the major energy-producing step in the electron transport chain (ETC). The combination of sepsis and ETC inhibition led to a cellular energy crisis. This finding suggests that early sepsis induces a partial mitochondrial dysfunction.

    List of papers
    1. Effects of Tigecycline and Doxycycline on Inflammation and Hemodynamics in Porcine Endotoxemia: a Prospective, Randomized and Placebo Controlled Trial
    Open this publication in new window or tab >>Effects of Tigecycline and Doxycycline on Inflammation and Hemodynamics in Porcine Endotoxemia: a Prospective, Randomized and Placebo Controlled Trial
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    2015 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 43, no 6, 604-611 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Antibiotics might, apart from an antimicrobial effect, also exert anti-inflammatory effects. The novel antibiotic tigecycline, potentially useful in septic shock from Gram-negative multi-resistant bacteria, is structurally related to antibiotics with known anti-inflammatory properties. However, its anti-inflammatory effects have previously not been explored in vivo. Using a sterile integrative porcine sepsis model, we investigated the anti-inflammatory and circulatory effects of tigecycline in comparison to doxycycline and placebo.

    METHODS: Eighteen pigs were randomized to receive tigecycline 100 mg, doxycycline 200 mg or placebo and subjected to 6 h endotoxin infusion at 0.5 μg x kg x h. Markers of inflammation, nitric oxide (NO) production, vascular permeability, hemodynamics, organ dysfunction, tissue metabolism and acid-base parameters were monitored.

    RESULTS: Peak plasma tumor necrosis alpha (TNF-α) was lower in the doxycycline group (P=0.031) but not in the tigecycline group (P=0.86) compared to placebo with geometric mean plasma concentrations of 16, 79 and 63 ng x ml, respectively. Mean arterial pressure was higher 4-6 h in the tigecycline group with values at 6 h of 107± 9 mmHg compared to the placebo and doxycycline groups (85 ± 27 mmHg and 90 ± 32 mmHg, respectively) (P=0.025). The white blood cell and the neutrophil granulocyte counts were less reduced in the doxycycline group, but not in the tigecycline group at 4-6 h (P=0.009 and p=0.019, respectively). Other markers of inflammation, organ dysfunction, tissue metabolism and acid-base parameters were unaffected by tigecycline.

    CONCLUSIONS: Consistent with known anti-inflammatory properties, doxycycline yielded decreased TNF-α levels. Tigecycline did not affect cytokine levels but counteracted hypotension and hypoperfusion.

    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-244766 (URN)10.1097/SHK.0000000000000351 (DOI)000354734300013 ()25664982 (PubMedID)
    Available from: 2015-02-20 Created: 2015-02-20 Last updated: 2017-08-13Bibliographically approved
    2. Rapid Bolus Administration Does Not Increase the Extravasation Rate of Albumin: A Randomized Controlled Trial in the Endotoxemic Pig
    Open this publication in new window or tab >>Rapid Bolus Administration Does Not Increase the Extravasation Rate of Albumin: A Randomized Controlled Trial in the Endotoxemic Pig
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    2017 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 47, no 4, 514-519 p.Article in journal (Refereed) Published
    Abstract [en]

    Some experimental data suggest that rapid bolus administration of albumin causes less plasma-expanding effects than slow, continuous infusion. To determine whether rapid bolus administration, in comparison with slow infusion, results in greater extravasation of albumin in experimental septic shock we performed a randomized controlled trial with 32 endotoxemic pigs. The animals were monitored and ventilated with standard intensive care equipment and given 10 mL x kg 5% albumin labeled with Technetium-99m, either as a rapid 15-minute bolus (Bolus group, n = 16) or as a 2-hour (h) infusion (Infusion group, n = 16). Radioactivity was monitored in plasma, extracellular microdialysate and urine for 6 h. Physiological parameters were monitored hourly. Radioactivity in the liver, spleen, kidney and lung was analyzed post-mortem.The plasma area under the curve (AUC) activity0-6h was 4.4 ± 0.9 x 10 in the Bolus group and 4.4 ± 1.1 x 10 counts x min x mL x h in the Infusion group. Blood hemoglobin levels increased in both groups, suggesting severe capillary leakage. Yet, there were no group differences in albumin radioactivity in plasma, muscle tissue, urine or in the post-mortem analysis of the organs. Following albumin administration, circulatory and respiratory parameters were similar in the two groups.In conclusion, the present results suggest that albumin might be given as a bolus without leading to increased extravasation of albumin, in contrast to previous animal experiments in rodents.

    Keyword
    Albumin, animal models, capillary leak syndrome, endotoxin, fluid resuscitation, sepsis
    National Category
    Infectious Medicine Hematology Surgery
    Identifiers
    urn:nbn:se:uu:diva-305826 (URN)10.1097/SHK.0000000000000761 (DOI)000396226300016 ()27749758 (PubMedID)
    Available from: 2016-10-23 Created: 2016-10-22 Last updated: 2017-08-13Bibliographically approved
    3. The role of oxygen delivery and inflammatory response on plasma lactate and organ dysfunction in experimental septic shock
    Open this publication in new window or tab >>The role of oxygen delivery and inflammatory response on plasma lactate and organ dysfunction in experimental septic shock
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Elevated plasma lactate and organ dysfunction in septic shock may be due to insufficient oxygen delivery (DO2). However, other mechanisms, as mitochondrial dysfunction or adrenergic glycolysis may contribute to elevated lactate. We conducted a retrospective cohort analysis of 104 pigs in bacteremic and endotoxemic shock to investigate the impact of DO2, oxygen consumption (VO2), hemodynamics and inflammatory response on elevation in plasma lactate, tissue metabolism and organ dysfunction in experimental bacteremic and endotoxemic shock.

    Experimental septic shock was induced by continuous infusion of live bacteria and endotoxin for 6 hours (h). Hemodynamic parameters and DO2 were measured with pulmonary artery catheters and oximetry. Lactate, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were analyzed in plasma. Muscle metabolism was investigated with microdialysis. At 3 h, DO2 was 289±68 mL x min-1 x m-2 (mean±SD) and plasma lactate levels were 2.9±1.2 mmol x L-1. Elevated plasma lactate was dependent on DO2, but only at DO2 levels <250 mL x min-1 x m-2. Despite increased plasma lactate and decreased DO2, no decrease in VO2 was seen. Muscle pyruvate levels increased and lactate-to-pyruvate ratio decreased. Urinary output, but not static lung compliance, was DO2-dependent. In a multiple regression model DO2, mean arterial pressure and IL-6 were the strongest predictors of increased plasma lactate. Urinary output, but not static lung compliance, was DO2-dependent.

    In muscle accelerated glycolysis contributes to increased lactate. In addition, inflammatory response, manifested as plasma IL-6 but not as TNF-a, was associated with an elevation in plasma lactate levels. 

    National Category
    Anesthesiology and Intensive Care
    Research subject
    Anaesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-326784 (URN)
    Available from: 2017-08-12 Created: 2017-08-12 Last updated: 2017-08-13
    4. Mitochondrial stress in early experimental sepsis revealed by electron transport chain inhibition
    Open this publication in new window or tab >>Mitochondrial stress in early experimental sepsis revealed by electron transport chain inhibition
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Increased plasma lactate in sepsis may not be due to insufficient oxygen

    delivery, but accelerated glycolysis and mitochondrial dysfunction may also contribute. To

    assess critical pathophysiological steps in non-ischemic lactate increase we studied the muscle metabolism with microdialysis in a sepsis model in pigs submitted to continuous E. coli infusion (sepsis group, n=12) for 3 hours (h). A control group (sham group, n=4) underwent the same procedures but did not receive E. coli. Protocolized interventions were applied to normalize oxygen delivery (DO2) and blood pressure. Metabolism was intervened locally via microdialysis catheters with the electron-transport chain inhibitor sodium cyanide and the inhibitor of the major energy consuming enzyme Na+/K+-ATPase ouabain.

    Results: All pigs in the sepsis group had positive blood cultures at 1 h. Median (range) Sequential Organ Failure Assessment (SOFA) score at 0 h was 0 (0-1) in both groups. At 3 h, SOFA increased to 6 (3-6) in the sepsis group but remained virtually unchanged in the sham group. Plasma lactate increased in the sepsis group despite that protocolized interventions maintained DO2.

    Sepsis accelerated glycolysis with a decrease in glucose, maintained or increased in lactate and pyruvate with a virtually normal lactate-to-pyruvate ratio (LPR) in microdialysate from catheters without intervention. The local cyanide intervention produced a severe energy crisis as evidenced by a dramatically elevated LPR, a lowered pyruvate and an increased lactate in both the sepsis and sham group. During sepsis, when the cyanide effect gradually diminished, this energy crisis normalized in the sham group but partly persisted in the sepsis group.

    Conclusions: Our findings suggest a reduction in mitochondrial oxidative capacity induced by sepsis, as revealed by cyanide inhibition. Decreasing energy consumption with a local ouabain intervention did not impact glucose and fat metabolism in sepsis or sham animals.

    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-327928 (URN)
    Available from: 2017-08-12 Created: 2017-08-12 Last updated: 2017-08-13
  • Public defence: 2017-09-30 09:15 Gunnesalen, Uppsala
    Edvinsson, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Attention Deficit/Hyperactivity Disorder in Adults: Prevalence, Psychiatric Comorbidities and Long-term Outcome2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Attention Deficit/Hyperactivity Disorder (ADHD) was originally thought to occur only in children, but is increasingly recognised as causing functional impairment also in adulthood. The overall aim of this thesis was to achieve a comprehensive understanding of ADHD in adulthood.

    A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering and general assessment of functioning (GAF) was distributed to three samples: the general population (GP), outpatient psychiatry (OPP) and female prison inmates. Symptoms consistent with ADHD were more than three times higher in the OPP sample than in the GP sample (6.6 versus 2.1%). ADHD symptoms and related problems occurred in 50% of the prison inmates.

    A cohort of 168 patients diagnosed with ADHD in adulthood was interviewed about current ADHD symptoms and psychiatric comorbidity on axis I and II. The lifetime prevalence of psychiatric comorbidity on axis I was 92% and current comorbidity, including autism spectrum disorders and Tourette’s syndrome, was 47%. The sex-specific pattern of the comorbid disor-ders was similar to that in the general population. Forty-six per cent of the patients endorsed the specific criteria for at least one personality disorder.

    After a mean follow-up of six years, there was remission of adult ADHD in about 30% of the patients, regardless of whether there was ongoing medication or not. There were no differences in function and quality of life, except for global general improvement, which was better in patients currently on medication.

    The most prevalent long-term side effects of pharmacological treatment with mainly stimulants were decreased appetite, dry mouth, anxiousness/restlessness and an increase in pulse frequency. The discontinuation rate was about 50%: 29% discontinued because of a perceived lack of effect, followed by elevated mood or hypomania (11%). No detectable evidence of tolerance and increased need for dosage over time was observed.

    To conclude, Symptoms of ADHD is highly overrepresented in OPP and in female inmates compared with the GP. Furthermore, adults diagnosed with ADHD have a high lifetime prevalence of psychiatric comorbidity. Long-term pharmacological treatment with stimulants is safe with relatively mild and tolerable adverse effects. Continued medication, however, is not related to remission.

    List of papers
    1. ADHD-related symptoms among adults in out-patient psychiatry and female prison inmates as compared with the general population
    Open this publication in new window or tab >>ADHD-related symptoms among adults in out-patient psychiatry and female prison inmates as compared with the general population
    2010 (English)In: Uppsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 1, 30-40 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective. To compare the prevalence of symptoms consistent with attention deficit hyperactivity disorder (ADHD) and related problems in adults in the general population, out-patient psychiatry (where females are in majority), and female convicts. Method. A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering, and general assessment of functioning (GAF) was distributed to samples of the general population, open care psychiatry, and female prison inmates. Completed questionnaires were received from 517/1000, 349/400, and 50/65 of the three samples, respectively. Results. Symptoms consistent with ADHD were more than three times higher in out-patient psychiatry than in the general population (6.6% versus 2.1%), with a male-to-female ratio of 1.6-1.7. The severity of symptoms and frequencies of associated disabilities were similar in men and women. ADHD symptoms and related problems occurred in 50% of the female prisoners, which is similar to male prisoners according to the literature. Conclusion. The high prevalence of symptoms and disabilities of ADHD in women should lead to awareness of the disorder in both sexes and be addressed in terms of diagnostic work-up, treatment, and rehabilitation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-136943 (URN)10.3109/03009730903532333 (DOI)000275061700005 ()20085506 (PubMedID)
    Available from: 2010-12-15 Created: 2010-12-14 Last updated: 2017-09-07Bibliographically approved
    2. Gender differences of axis I and II comorbidity in subjects diagnosed with attention-deficit hyperactivity disorder as adults
    Open this publication in new window or tab >>Gender differences of axis I and II comorbidity in subjects diagnosed with attention-deficit hyperactivity disorder as adults
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    2013 (English)In: Acta Neuropsychiatrica, ISSN 0924-2708, E-ISSN 1601-5215, Vol. 25, no 3, 165-174 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective: To investigate gender differences in psychiatric comorbidity patients diagnosed with attention-deficit hyperactivity disorder (ADHD) as adults. Methods: Interviews about current ADHD symptoms and psychiatric comorbidity on axis I and II (Structured Clinical Interview for DSM-IV axis I and axis II) were conducted in a clinical cohort of 168 patients (78 women, 90 men). Independent information on childhood and current symptoms was collected from parents, partners and patient files. Results: The lifetime prevalence of psychiatric comorbidity on axis I reached 92%, and current comorbidity, including autism spectrum disorders and Tourette's syndrome, was 47%. Women had a higher lifetime prevalence of mood and eating disorders compared with men, where substance-use disorders were more frequent. Ten per cent of patients fulfilled diagnostic criteria for a personality disorder. When excluding the general diagnostic criteria, 46% of the patients endorsed the specific criteria for at least one personality disorder. Gender differences were identified with predominance of histrionic personality traits in women and conduct disorder in men. Conclusion: Patients diagnosed with ADHD as adults display an extremely high lifetime axis I comorbidity with a gender-specific pattern similar to the general population. No gender differences were identified with regard to personality disorders; however, an increased prevalence of deviant personality traits was confirmed. This study stresses the importance of evaluating comorbidity among patients diagnosed with ADHD as adults to secure optimal treatment.

    Keyword
    ADHD, adults, comorbidity, gender
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-204118 (URN)10.1111/j.1601-5215.2012.00682.x (DOI)000320550800006 ()
    Available from: 2013-07-22 Created: 2013-07-22 Last updated: 2017-09-07Bibliographically approved
    3. Six-Year Outcome in Subjects Diagnosed with Attention-Deficit/Hyperactivity Disorder as Adults
    Open this publication in new window or tab >>Six-Year Outcome in Subjects Diagnosed with Attention-Deficit/Hyperactivity Disorder as Adults
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Medical and Health Sciences Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-327890 (URN)
    Available from: 2017-08-11 Created: 2017-08-11 Last updated: 2017-09-07
    4. Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder
    Open this publication in new window or tab >>Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-327891 (URN)
    Available from: 2017-08-11 Created: 2017-08-11 Last updated: 2017-09-07
  • Public defence: 2017-10-06 09:15 A1:111a, BMC, Uppsala
    Källback, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Universitet.
    Development and Application of Software Tools for Mass Spectrometry Imaging2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mass spectrometry imaging (MSI) has been extensively used to produce qualitative maps of distributions of proteins, peptides, lipids, neurotransmitters, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. Moreover, during the last 10 years, there has been growing demand to quantify target compounds in tissue sections of various organs. This thesis focuses on development and application of a novel instrument- and manufacturer-independent MSI software suite, msIQuant, in the open access format imzML, which has been developed specifically for quantitative analysis of MSI data. The functionality of msIQuant facilitates automatic generation of calibration curves from series of standards that can be used to determine concentrations of specific analytes. In addition, it provides many tools for image visualization, including modules enabling multiple interpolation, low intensity transparency display, and image fusion and sharpening. Moreover, algorithms and advanced data management modules in msIQuant facilitate management of the large datasets generated following rapid recent increases in the mass and spatial resolutions of MSI instruments, by using spectra transposition and data entropy reduction (at four selectable levels: coarse, medium, fine or superfine) before lossless compression of the data. As described in the thesis, implementation of msIQuant has been exemplified in both quantitative (relative or absolute) and qualitative analyses of distributions of neurotransmitters, endogenous substances and pharmaceutical drugs in brain tissue sections. Our laboratory have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine, in histological tissue sections at high spatial resolution by matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI) MSI. Chemical derivatization by charge-tagging primary amines of analytes significantly increased the sensitivity, enabling mapping of neurotransmitters that were not previously detectable by MSI. The two MSI approaches have been used to directly measure changes in neurotransmitter levels in specific brain structures in animal disease models, which facilitates understanding of biochemical mechanisms of drug treatments. In summary, msIQuant software has proven potency (particularly in combination with the reported derivatization technique) for both qualitative and quantitative analyses. Further developments will enable its implementation in multiple operating system platforms and use for statistical analysis.

    List of papers
    1. Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections
    Open this publication in new window or tab >>Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections
    2012 (English)In: Journal of Proteomics, ISSN 1874-3919, Vol. 75, no 16, 4941-4951 p.Article in journal (Refereed) Published
    Abstract [en]

    MALDI MS imaging has been extensively used to produce qualitative distribution maps of proteins, peptides, lipids, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. There is growing demand to quantify the amount of target compounds in the tissue sections of different organs. We present a novel MS imaging software including protocol for the quantitation of drugs, and for the first time, an endogenous neuropeptide directly in tissue sections. After selecting regions of interest on the tissue section, data is read and processed by the software using several available methods for baseline corrections, subtractions, denoising, smoothing, recalibration and normalization. The concentrations of in vivo administered drugs or endogenous compounds are then determined semi-automatically using either external standard curves, or by using labeled compounds, i.e., isotope labeled analogs as standards. As model systems, we have quantified the distribution of imipramine and tiotropium in the brain and lung of dosed rats. Substance P was quantified in different mouse brain structures, which correlated well with previously reported peptide levels. Our approach facilitates quantitative data processing and labeled standards provide better reproducibility and may be considered as an efficient tool to quantify drugs and endogenous compounds in tissue regions of interest.

    Keyword
    Brain, Deuterated standard, MALDI, Neuropeptide, Lung, Standard curve
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-182525 (URN)10.1016/j.jprot.2012.07.034 (DOI)000308524400007 ()
    Note

    This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research.

    Available from: 2012-10-12 Created: 2012-10-11 Last updated: 2017-08-19Bibliographically approved
    2. msIQuant - Quantitation Software for Mass Spectrometry Imaging Enabling Fast Access, Visualization, and Analysis of Large Data Sets
    Open this publication in new window or tab >>msIQuant - Quantitation Software for Mass Spectrometry Imaging Enabling Fast Access, Visualization, and Analysis of Large Data Sets
    2016 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 8, 4346-4353 p.Article in journal (Refereed) Published
    Abstract [en]

    This paper presents msIQuant, a novel instrument- and manufacturer-independent quantitative mass spectrometry imaging software suite that uses the standardized open access data format imzML. Its data processing structure enables rapid image display and the analysis of very large data sets (>50 GB) without any data reduction. In addition, msIQuant provides many tools for image visualization including multiple interpolation methods, low intensity transparency display, and image fusion. It also has a quantitation function that automatically generates calibration standard curves from series of standards that can be used to determine the concentrations of specific analytes. Regions-of-interest in a tissue section can be analyzed based on a number of quantities including the number of pixels, average intensity, standard deviation of intensity, and median and quartile intensities. Moreover, the suite's export functions enable simplified postprocessing of data and report creation. We demonstrate its potential through several applications including the quantitation of small molecules such as drugs and neurotransmitters. The msIQuant suite is a powerful tool for accessing and evaluating very large data sets, quantifying drugs and endogenous compounds in tissue areas of interest, and for processing mass spectra and images.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-297908 (URN)10.1021/acs.analchem.5b04603 (DOI)000374706000026 ()27014927 (PubMedID)
    Funder
    Swedish Research Council, 2013-3105 2014-6215 2009-6050
    Available from: 2016-06-29 Created: 2016-06-28 Last updated: 2017-08-19
    3. A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging
    Open this publication in new window or tab >>A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging
    (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882Article in journal (Refereed) Submitted
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-328051 (URN)
    Available from: 2017-08-19 Created: 2017-08-19 Last updated: 2017-08-19
    4. Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections
    Open this publication in new window or tab >>Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections
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    2014 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 84, no 4, 697-707 p.Article in journal (Refereed) Published
    Abstract [en]

    Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. We have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, GABA, glutamate, acetylcholine, and L-alpha-glycerylphosphorylcholine, in histological tissue sections at high spatial resolutions. The method is employed to directly measure changes in the absolute and relative levels ofneurotransmitters in specific brain structures in animal disease models and in response to drug treatments, demonstrating the power of mass spectrometry imaging in neuroscience.

    National Category
    Medical Bioscience
    Identifiers
    urn:nbn:se:uu:diva-239353 (URN)10.1016/j.neuron.2014.10.011 (DOI)000345424900007 ()25453841 (PubMedID)
    Available from: 2014-12-29 Created: 2014-12-22 Last updated: 2017-08-19Bibliographically approved
    5. Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry
    Open this publication in new window or tab >>Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry
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    2016 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 136, 129-138 p.Article in journal (Refereed) Published
    Abstract [en]

    With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

    Keyword
    Neurotransmitter, Dopamine, Imaging, Mass spectrometry, Parkinson's disease, Serotonin
    National Category
    Neurology Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-299698 (URN)10.1016/j.neuroimage.2016.05.004 (DOI)000378048000012 ()27155126 (PubMedID)
    Funder
    Swedish Research Council, 2013-3105 2014-6215 2009-6050The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078EU, FP7, Seventh Framework Programme, 607517
    Available from: 2016-07-27 Created: 2016-07-26 Last updated: 2017-08-19Bibliographically approved
  • Public defence: 2017-10-06 09:15 Grönwallsalen, Uppsala
    Nyberg, Christoffer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Metabolic and Endocrine Response in the Acute Stage of Subarachnoid Hemorrhage2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The rupture of an aneurysm in subarachnoid hemorrhage (SAH) is a dramatic event causing a severe impact on the brain and a transient or permanent ischemic condition. Several types of responses to meet the challenges of SAH have been found in the acute phase, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, elevated levels of brain natriuretic peptide (BNP), and disturbances in cerebral and systemic metabolism.

    Cerebral metabolism and the endocrine stress response in the ultra-early phase was investigated in a novel porcine model of SAH in which autologous blood was injected to the anterior skull base. Early activation of the HPA axis was found with rapid elevation of adrenocorticotrophic hormone, cortisol and aldosterone. The peak values of these hormones were early and may be impossible to catch in patients. There were indications of a sympathetic nervous response with excretion of catecholamines in urine as well as plasma chromogranin-A elevation. Cerebral microdialysis suggested immediate substrate failure followed by hypermetabolism of glucose. The animal model seems suited for further studies of aneurysmal SAH.

    NT-proBNP was investigated in 156 patients with SAH, there was a dynamic course with increasing levels during the first 4 days of the disease. Factors predicting high NT-proBNP load included female sex, high age, high Troponin-I at admission, angiographic finding of an aneurysm and worse clinical condition at admission. High levels of NT-proBNP were correlated to factors indicating a more severe disease, suggesting the initial injury in aneurysmal SAH is an important factor in predicting high NT-proBNP during the acute stage of the disease.

    Measurements with indirect calorimetry were performed daily during the first week after SAH on 32 patients with SAH. There was a dynamic course with increasing energy expenditure (EE) the first week after SAH. Comparisons with three predictive equations indicated that measured EE generally is higher than predicted, but considerable variation exists within and between patients, indicating that prediction of EE in SAH is difficult.

    Altogether, the studies demonstrate a complicated response in acute SAH that needs to be further studied to increase possibility of good outcome in SAH patients.

    List of papers
    1. Metabolic Pattern of the Acute Phase of Subarachnoid Hemorrhage in a Novel Porcine Model: Studies with Cerebral Microdialysis with High Temporal Resolution
    Open this publication in new window or tab >>Metabolic Pattern of the Acute Phase of Subarachnoid Hemorrhage in a Novel Porcine Model: Studies with Cerebral Microdialysis with High Temporal Resolution
    2014 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 6, e99904- p.Article in journal (Refereed) Published
    Abstract [en]

    Background: Aneurysmal subarachnoid hemorrhage (SAH) may produce cerebral ischemia and systemic responses including stress. To study immediate cerebral and systemic changes in response to aneurysm rupture, animal models are needed. Objective: To study early cerebral energy changes in an animal model. Methods: Experimental SAH was induced in 11 pigs by autologous blood injection to the anterior skull base, with simultaneous control of intracranial and cerebral perfusion pressures. Intracerebral microdialysis was used to monitor concentrations of glucose, pyruvate and lactate. Results: In nine of the pigs, a pattern of transient ischemia was produced, with a dramatic reduction of cerebral perfusion pressure soon after blood injection, associated with a quick glucose and pyruvate decrease. This was followed by a lactate increase and a delayed pyruvate increase, producing a marked but short elevation of the lactate/pyruvate ratio. Glucose, pyruvate, lactate and lactate/pyruvate ratio thereafter returned toward baseline. The two remaining pigs had a more severe metabolic reaction with glucose and pyruvate rapidly decreasing to undetectable levels while lactate increased and remained elevated, suggesting persisting ischemia. Conclusion: The animal model simulates the conditions of SAH not only by deposition of blood in the basal cisterns, but also creating the transient global ischemic impact of aneurysmal SAH. The metabolic cerebral changes suggest immediate transient substrate failure followed by hypermetabolism of glucose upon reperfusion. The model has features that resemble spontaneous bleeding, and is suitable for future research of the early cerebral and systemic responses to SAH that are difficult to study in humans.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-229957 (URN)10.1371/journal.pone.0099904 (DOI)000338508200053 ()24940881 (PubMedID)
    Available from: 2014-08-18 Created: 2014-08-18 Last updated: 2017-08-17Bibliographically approved
    2. The Early Endocrine Stress Response in Experimental Subarachnoid Hemorrhage
    Open this publication in new window or tab >>The Early Endocrine Stress Response in Experimental Subarachnoid Hemorrhage
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    2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, e0151457Article in journal (Refereed) Published
    Abstract [en]

    Introduction In patients with severe illness, such as aneurysmal subarachnoid hemorrhage (SAH), a physiologic stress response is triggered. This includes activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The aim of this study was to investigate the very early responses of these systems. Methods A porcine animal model of aneurysmal SAH was used. In this model, blood is injected slowly to the basal cisterns above the anterior skull base until the cerebral perfusion pressure is 0 mm Hg. Sampling was done from blood and urine at -10, +15, +75 and +135 minutes from time of induction of SAH. Analyses of adrenocorticotropic hormone (ACTH), cortisol, aldosterone, catecholamines and chromogranin-A were performed. Results Plasma ACTH, serum cortisol and plasma aldosterone increased in the samples following induction of SAH, and started to decline after 75 minutes. Urine cortisol also increased after SAH. Urine catecholamines and their metabolites were found to increase after SAH. Many samples were however below detection level, not allowing for statistical analysis. Plasma chromogranin-A peaked at 15 minutes after SAH, and thereafter decreased. Conclusions The endocrine stress response after aneurysmal SAH was found to start within 15 minutes in the HPA axis with early peak values of ACTH, cortisol and aldosterone. The fact that the concentrations of the HPA axis hormones decreased 135 minutes after SAH may suggest that a similar pattern exists in SAH patients, thus making it difficult to catch these early peak values. There were also indications of early activation of the sympathetic nervous system, but the small number of valid samples made interpretation difficult.

    National Category
    Endocrinology and Diabetes Neurology
    Identifiers
    urn:nbn:se:uu:diva-296872 (URN)10.1371/journal.pone.0151457 (DOI)000372701200055 ()
    Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2017-08-17Bibliographically approved
    3. Predictors of increased cumulative serum levels of the N-terminal prohormone of brain natriuretic peptide 4 days after acute spontaneous subarachnoid hemorrhage
    Open this publication in new window or tab >>Predictors of increased cumulative serum levels of the N-terminal prohormone of brain natriuretic peptide 4 days after acute spontaneous subarachnoid hemorrhage
    2014 (English)In: Journal of Neurosurgery, ISSN 0022-3085, Vol. 120, no 3, 599-604 p.Article in journal (Refereed) Published
    Abstract [en]

    Object. The rupture of an intracranial aneurysm is followed by increased intracranial pressure and decreased cerebral blood flow. A major systemic stress reaction follows, presumably to restore cerebral blood flow. However, this reaction can also cause adverse effects, including myocardial abnormalities, which are common and can be serious, and increased levels of natriuretic peptides, especially brain natriuretic peptide (BNP). The association of BNP with fluid and salt balance, vasospasm, brain ischemia, and cardiac injury has been studied but almost exclusively regarding events after admission. Brain natriuretic peptide has also been measured at various time points and analyzed in different ways statistically. The authors approached BNP measurement in a new way; they used the calculated area under the curve (AUC) for the first 4 days to quantitatively measure the BNP load during the first critical part of the disease state. Their rationale was a suspicion that early BNP load is a marker of the severity of the ictus and will influence the subsequent course of the disease by disturbing the fluid and salt balance. Methods. The study included 156 patients with acute spontaneous subarachnoid hemorrhage (SAH). Mean patient age was 59.8 +/- 11.2 years, and 105 (67%) of the patients were female. An aneurysm was found in 138 patients. A total of 82 aneurysms were treated by endovascular coiling, 50 were treated by surgery, and 6 were untreated. At the time of admission, serum samples were collected for troponin-I analysis and for the N-terminal prohormone of BNP (NT-proBNP); daily thereafter, samples were collected for the NT-proBNP analysis. The cumulative BNP load was calculated as the AUC for NT-proBNP during the first 4 days. The following variables were studied in terms of their influence on the AUC for NT-proBNP: sex, age, World Federation of Neurosurgical Societies grade of SAH, Fisher grade, angiographic result, treatment of aneurysm,'clinical neurological deterioration, verified infections, vasospasm treatment, and 6-month outcome. Results. The AUC for NT-proBNP was larger when variables indicated a more severe SAH. These variables were higher Fisher and World Federation of Neurosurgical Societies grades, high levels of troponin-I at admission, an aneurysm, neurological deficits, and infections. The AUC for NT-proBNP was also larger among women, older patients, and patients with poor outcomes. Linear regression showed that the best predicting model for large AUC for NT-proBNP was the combination of the following: female sex, high levels of troponin-I, an aneurysm, neurological deficits, and advanced age. Conclusions. The cumulative BNP load during the first days after SAH can be predicted by variables describing the severity of the disease already known at the time of admission. This information can be used to identify patients at risk for an adverse course of the disease.

    Keyword
    subarachnoid hemorrhage, NT-proBNP, vascular disorders, brain natriuretic peptide, troponin-I
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-222748 (URN)10.3171/2013.8.JNS13625 (DOI)000332048800003 ()
    Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2017-08-17Bibliographically approved
    4. Daily Energy Expenditure in the Acute Phase of Aneurysmal Subarachnoid Hemorrhage
    Open this publication in new window or tab >>Daily Energy Expenditure in the Acute Phase of Aneurysmal Subarachnoid Hemorrhage
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Neurology Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-328119 (URN)
    Available from: 2017-08-17 Created: 2017-08-17 Last updated: 2017-08-17
  • Public defence: 2017-10-06 09:30 Polhemssalen, Ång/10134, Uppsala
    Guo, Meiyuan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Theoretical Chemistry.
    Electronic structure investigations of transition metal complexes through X-ray spectroscopy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Catalysts based on the first-row (3d) transition metals are commonly seen in chemical and biological reactions. To understand the role of the transition metal in the catalyst, the element specific technique core level spectroscopy is used to probe the electronic structure and geometric properties centered around the metal site. Different types of X-ray spectra can be applied to probe the metal 3d character orbitals involved in reactions, which make it possible to identify and characterize the reactive sites of samples in different forms. A detailed interpretation and understanding of the different X-ray spectra requires a unified method which can be used to model different types of X-ray spectra, e.g., soft and hard X-rays. In this thesis, theoretical investigations of the electronic structures of 3d transition metal complexes through X-ray spectroscopy are presented. The restricted active space method (RAS) is used to successfully reproduce different types of X-ray spectra by including all important spectral effects: multiplet structures, spin-orbit coupling, charge-transfer excitations, ligand field splitting and 3d-4p orbital hybridization. Different prototypes of molecules are adopted to test the applicability of the RAS theory.

    The metal L edge X-ray absorption (XAS) spectra of low spin complexes [Fe(CN)6]n and [Fe(P)(ImH)2]n in ferrous and ferric oxidation state are discussed. The RAS calculations on iron L edge spectra of these comparing complexes have been performed to fingerprint the oxidation states of metal ion, and different ligand environments. The Fe(P) system has several low-lying spin states in the ground state, which is used as a model to identify unknown species by their spectroscopic fingerprints through RAS spectra simulations. To pave the route of understanding the electronic structure of oxygen evolution complex of Mn4CaO5 cluster, the MnII(acac)2 and MnIII(acac)3 are adopted as prototypical Mn-complexes. The 3d partial fluorescence yield-XAS are employed on the Mn L-edge in solution. Combining experiments and RAS calculations, primary questions related to the oxidation state and spin state are discussed.

    The first application to simulate the metal K pre-edge XAS of mono-iron complexes and iron dimer using RAS method beyond the electric dipole is completed by implementing the approximate origin independent calculations for the intensities. The K pre-edge spectrum of centrosymmetric complex [FeCl6]n– ferrous state is discussed as s and a donor model systems. The intensity of the K pre-edge increases significantly if the centrosymmetric environment is broken, e:g:, when going from a six-coordinate to the four-coordinate site in [FeCl4]n. Distortions from centrosymmetry allow for 3d-4p orbital hybridization, which gives rise to electric dipole-allowed transitions in the K pre-edge region. In order to deliver ample electronic structure details with high resolution in the hard X-ray energy range, the two-photon 1s2p resonant inelastic X-ray scattering process is employed. Upon the above successful applications of one-photon iron L edge and K pre-edge spectra, the RAS method is extended to simulate and interpret the 1s2p resonant inelastic X-ray scattering spectra of [Fe(CN)6]n in ferrous and ferric oxidation states. The RAS applications on X-ray simulations are not restricted to the presented spectra in the thesis, it can be applied to the photon process of interest by including the corresponding core and valence orbitals of the sample.

    List of papers
    1. Restricted active space calculations of L-edge X-ray absorption spectra: From molecular orbitals to multiplet states
    Open this publication in new window or tab >>Restricted active space calculations of L-edge X-ray absorption spectra: From molecular orbitals to multiplet states
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    2014 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 141, no 12, 124116Article in journal (Refereed) Published
    Abstract [en]

    The metal L-edge (2p -> 3d) X-ray absorption spectra are affected by a number of different interactions: electron-electron repulsion, spin-orbit coupling, and charge transfer between metal and ligands, which makes the simulation of spectra challenging. The core restricted active space (RAS) method is an accurate and flexible approach that can be used to calculate X-ray spectra of a wide range of medium-sized systems without any symmetry constraints. Here, the applicability of the method is tested in detail by simulating three ferric (3d(5)) model systems with well-known electronic structure, viz., atomic Fe3+, high-spin [FeCl6](3-) with ligand donor bonding, and low-spin [Fe(CN)(6)](3-) that also has metal backbonding. For these systems, the performance of the core RAS method, which does not require any system-dependent parameters, is comparable to that of the commonly used semi-empirical charge-transfer multiplet model. It handles orbitally degenerate ground states, accurately describes metal-ligand interactions, and includes both single and multiple excitations. The results are sensitive to the choice of orbitals in the active space and this sensitivity can be used to assign spectral features. A method has also been developed to analyze the calculated X-ray spectra using a chemically intuitive molecular orbital picture.

    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-236075 (URN)10.1063/1.4896373 (DOI)000342844100021 ()25273421 (PubMedID)
    Note

    Correction in: Journal of Chemical Physics, vol. 141, issue 4, article number: 149905, DOI: 10.1063/1.4908043 ISI: 000349847000064

    Available from: 2014-11-12 Created: 2014-11-12 Last updated: 2017-08-16Bibliographically approved
    2. Cost and sensitivity of restricted active-space calculations of metal L-edge X-ray absorption spectra
    Open this publication in new window or tab >>Cost and sensitivity of restricted active-space calculations of metal L-edge X-ray absorption spectra
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    2016 (English)In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 37, no 5, 477-486 p.Article in journal (Refereed) Published
    Abstract [en]

    The restricted active-space (RAS) approach can accurately simulate metal L-edge X-ray absorption spectra of first-row transition metal complexes without the use of any fitting parameters. These characteristics provide a unique capability to identify unknown chemical species and to analyze their electronic structure. To find the best balance between cost and accuracy, the sensitivity of the simulated spectra with respect to the method variables has been tested for two models, [FeCl6](3-) and [Fe(CN)(6)](3-). For these systems, the reference calculations give deviations, when compared with experiment, of 1 eV in peak positions, 30% for the relative intensity of major peaks, and 50% for minor peaks. When compared with these deviations, the simulated spectra are sensitive to the number of final states, the inclusion of dynamical correlation, and the ionization potential electron affinity shift, in addition to the selection of the active space. The spectra are less sensitive to the quality of the basis set and even a double- basis gives reasonable results. The inclusion of dynamical correlation through second-order perturbation theory can be done efficiently using the state-specific formalism without correlating the core orbitals. Although these observations are not directly transferable to other systems, they can, together with a cost analysis, aid in the design of RAS models and help to extend the use of this powerful approach to a wider range of transition metal systems.

    Keyword
    transition metals; X-ray absorption spectroscopy; multiconfigurational wavefunction; spin-orbit coupling; charge transfer
    National Category
    Theoretical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-276263 (URN)10.1002/jcc.24237 (DOI)000369176900002 ()26502979 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), s00112-267 liu-2012-00060-46Carl Tryggers foundation Marcus and Amalia Wallenberg FoundationSwedish Research Council
    Available from: 2016-02-10 Created: 2016-02-10 Last updated: 2017-08-16Bibliographically approved
    3. Fingerprinting electronic structures of heme using theoretical modeling of L-edge X-ray absorption spectra
    Open this publication in new window or tab >>Fingerprinting electronic structures of heme using theoretical modeling of L-edge X-ray absorption spectra
    (English)Manuscript (preprint) (Other academic)
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-327409 (URN)
    Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-08-16
    4. Probing the oxidation state: A case study of Mn II (acac) 2 and Mn III (acac) 3 on how charge and spin densities determine Mn L-edge X-ray absorption energies
    Open this publication in new window or tab >>Probing the oxidation state: A case study of Mn II (acac) 2 and Mn III (acac) 3 on how charge and spin densities determine Mn L-edge X-ray absorption energies
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-327410 (URN)
    Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-08-16
    5. Simulations of iron K pre-edge X-ray absorption spectra using the core restricted active space method
    Open this publication in new window or tab >>Simulations of iron K pre-edge X-ray absorption spectra using the core restricted active space method
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    2016 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 4, 3250-3259 p.Article in journal (Refereed) Published
    Abstract [en]

    The intensities and relative energies of metal K pre-edge features are sensitive to both geometric and electronic structures. With the possibility to collect high-resolution spectral data it is important to find theoretical methods that include all important spectral effects: ligand-field splitting, multiplet structures, 3d-4p orbital hybridization, and charge-transfer excitations. Here the restricted active space (RAS) method is used for the first time to calculate metal K pre-edge spectra of open-shell systems, and its performance is tested against on six iron complexes: [FeCl6](n-), [FeCl4](n-), and [Fe(CN)(6)](n-) in ferrous and ferric oxidation states. The method gives good descriptions of the spectral shapes for all six systems. The mean absolute deviation for the relative energies of different peaks is only 0.1 eV. For the two systems that lack centrosymmetry [FeCl4](2-/1-), the ratios between dipole and quadrupole intensity contributions are reproduced with an error of 10%, which leads to good descriptions of the integrated pre-edge intensities. To gain further chemical insight, the origins of the pre-edge features have been analyzed with a chemically intuitive molecular orbital picture that serves as a bridge between the spectra and the electronic structures. The pre-edges contain information about both ligand-field strengths and orbital covalencies, which can be understood by analyzing the RAS wavefunction. The RAS method can thus be used to predict and rationalize the effects of changes in both the oxidation state and ligand environment in a number of hard X-ray studies of small and medium-sized molecular systems.

    National Category
    Theoretical Chemistry
    Research subject
    Chemistry with specialization in Quantum Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243571 (URN)10.1039/c5cp07487h (DOI)000369506000108 ()26742851 (PubMedID)
    Funder
    Marcus and Amalia Wallenberg FoundationSwedish Research CouncilCarl Tryggers foundation Knut and Alice Wallenberg Foundation, KAW-2013.0020Swedish National Infrastructure for Computing (SNIC), snic2013-1-317Swedish National Infrastructure for Computing (SNIC), snic2014-5-36
    Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2017-08-16Bibliographically approved
    6. Applications to metal K pre-edges of transitionmetal dimers illustrate the approximate origin independence for the intensities in the length representation
    Open this publication in new window or tab >>Applications to metal K pre-edges of transitionmetal dimers illustrate the approximate origin independence for the intensities in the length representation
    2017 (English)In: Molecular Physics, ISSN 0026-8976, E-ISSN 1362-3028, Vol. 115, no 1-2, 174-189 p.Article in journal (Refereed) Published
    Abstract [en]

    X-ray absorption spectroscopy (XAS) in the metal K pre-edge is a standard probe of electronic and geometric structure of transition metal complexes. Simulating the K pre-edge spectra requires contributions beyond the electric dipole, but if that term is non-zero, the second-order terms, e. g. electric quadrupoles, are no longer origin-independent. In the velocity representation, complete origin independence can be achieved by including all terms to the same order in the oscillator strength. Here, we implement that approach in the length representation and use it for restricted active space (RAS) simulations of metal K pre-edges of iron monomers and dimers. Complete origin independence is not achieved and the size of the remaining errors depends on the electric dipole oscillator strength and its ratio in length and velocity representations. The error in the origin independence is in the ANO basis sets two orders of magnitude smaller than the value of the individual contributions. For systemswith strong electric dipole contributions, the errors are not significant within 3 angstrom from a metal centre, far enough to handlemany multi-metal systems. Furthermore, we discuss the convergence of the multipole expansion, the possibility to assign spectral contributions, and the origin of negative absorption intensities. [GRAPHICS]

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2017
    Keyword
    Multiconfigurational wavefunction, oscillator strengths, quadrupole intensities, properties, X-ray spectroscopy
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-319774 (URN)10.1080/00268976.2016.1225993 (DOI)000396794700015 ()
    Funder
    Knut and Alice Wallenberg Foundation, KAW-2013.0020Swedish Research Council, 2012-3910 2012-3924
    Available from: 2017-04-12 Created: 2017-04-12 Last updated: 2017-08-16Bibliographically approved
    7. Molecular orbital simulations of metal 1s2p resonant inelastic X-ray scattering
    Open this publication in new window or tab >>Molecular orbital simulations of metal 1s2p resonant inelastic X-ray scattering
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    2016 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 120, no 29, 5848-5855 p.Article in journal (Refereed) Published
    Abstract [en]

    For first-row transition metals, high-resolution 3d electronic structure information can be obtained using resonant inelastic X-ray scattering (RIXS). In the hard X-ray region, a K pre-edge (1s -> 3d) excitation can be followed by monitoring the dipole-allowed K alpha (2p -> 1s) or K beta (3p -> 1s) emission, processes labeled 1s2p or 1s3p RIXS. Here the restricted active space (RAS) approach, which is a molecular orbital method, is used for the first time to study hard X-ray RIXS processes. This is achieved by including the two sets of core orbitals in different partitions of the active space. Transition intensities are calculated using both first- and second-order expansions of the wave vector, including, but not limited to, electric dipoles and quadrupoles. The accuracy of the approach is tested for 1s2p RIXS of iron hexacyanides [Fe(CN)(6)](n-) in ferrous and ferric oxidation states. RAS simulations accurately describe the multiplet structures and the role of 2p and 3d spin-orbit coupling on energies and selection rules. Compared to experiment, relative energies of the two [Fe(CN)(6)](3-) resonances deviate by 0.2 eV in both incident energy and energy transfer directions, and multiplet splittings in [Fe(CN)(6)](4-) are reproduced within 0.1 eV. These values are similar to what can be expected for valence excitations. The development opens the modeling of hard X-ray scattering processes for both solution catalysts and enzymatic systems.

    National Category
    Theoretical Chemistry
    Research subject
    Chemistry with specialization in Quantum Chemistry
    Identifiers
    urn:nbn:se:uu:diva-302165 (URN)10.1021/acs.jpca.6b05139 (DOI)000380730400008 ()27398775 (PubMedID)
    Funder
    Marcus and Amalia Wallenberg FoundationSwedish Research CouncilKnut and Alice Wallenberg Foundation, KAW-2013.0020
    Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-08-16Bibliographically approved
  • Public defence: 2017-10-06 10:00 Lindahlssalen, Uppsala
    Junkunlo, Kingkamon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Regulation of hematopoiesis in the freshwater crayfish, Pacifastacus leniusculus: role of transglutaminase2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The freshwater crayfish, Pacifastacus leniusculus, has been used as a model for studying hematopoiesis or blood cell production or hematopoiesis and immunity. The work of this thesis aims to investigate the impact of factors such as ROS signaling, Ast1, and the PVF/PVR signaling pathway in controlling stem cell behavior during hematopoiesis and specifically the role of the crosslinking enzyme transglutaminase (TGase) in regulation of hematopoiesis.

    The role of ROS in crayfish hematopoiesis was characterized by using the antioxidant named NAC to inhibit ROS production. Low ROS level resulted in a prolonged decrease in hemocyte numbers and a combined injection of LPS and NAC caused a slower rate of new hemocyte production. A low ROS level in cell cultures supplemented with crude Ast1 was found to inhibit cell spreading and a high extracellular TGase activity was detected on the surfaces of APC and HPT cells. We suggest that ROS serves as a prime signal to control proliferation and differentiation of progenitor cells by affecting extracellular TGase activity. We reported an inhibitory effect of Ast1 on TGase enzyme activity and on its crosslinking activity and consequently Ast1 affects the clot formation and thus coagulation by inhibiting the crosslinking activity of the TGase enzyme. Secretion of the clot protein (CP) and the production of CP filament network between spreading cells were observed in HPT cell cultures in vitro. In the presence of CP together with Ast1 in 3D-collagen-I cultures, HPT cells were found to be more elongated and they formed chains of cells throughout the surrounding matrix. In the HPT tissue, CP was located around the HPT cells or around the lobules of HPT, and thus, CP was demonstrated to be a part of ECM and to possibly function together with collagen in generating a suitable environment for HPT progenitor cells. The inhibition of PVF/PVR downstream signaling pathway by Sunitinib malate resulted in a dramatic change of cell morphology and induction of an increase cell surface area during cell culture. The addition of crude Ast1 into the cell cultures in vitro enhanced this effect. Consequently, cell migration was stimulated and a high extracellular TGase activity on HPT cell surface was found after this inhibition. In conclusion, the work in this thesis provides new insight in understanding the role of the extracellular matrix (ECM) and extracellular TGase activity in controlling stem cell activity.

    List of papers
    1. Reactive oxygen species affect transglutaminase activity and regulate hematopoiesis in a crustacean
    Open this publication in new window or tab >>Reactive oxygen species affect transglutaminase activity and regulate hematopoiesis in a crustacean
    2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 34, 17593-17601 p.Article in journal (Refereed) Published
    Abstract [en]

    Reactive oxygen species (ROS) serve as a prime signal in the commitment to hematopoiesis in both mammals and Drosophila. In this study, the potential function of ROS during hematopoiesis in the crayfish Pacifastacus leniusculus was examined. The antioxidant N-acetylcysteine (NAC) was used to decrease ROS in both in vivo and in vitro experiments. An increase in ROS was observed in the anterior proliferation center (APC) after LPS injection. In the absence of NAC, the LPS-induced increase in ROS levels resulted in the rapid restoration of the circulating hemocyte number. In the presence of NAC, a delay in the recovery rate of the hemocyte number was observed. NAC treatment also blocked the spread of APC and other hematopoietic tissue (HPT) cells, maintaining these cells at an undifferentiated stage. Extracellular transglutaminase (TGase) has been shown previously to play a role in maintaining HPT cells in an undifferentiated form. In this study, we show that extracellular TGase activity increased when the ROS level in HPT or APC cells was reduced after NAC treatment. In addition, collagen, a major component of the extracellular matrix and a TGase substrate were co-localized on the HPT cell surface. Taken together, the results of this study show that ROS are involved in crayfish hematopoiesis, in which a low ROS level is required to maintain hematopoietic progenitor cells in the tissue and to reduce hemocyte release. The potential roles of TGase in this process are investigated and discussed.

    Keyword
    extracellular matrix, hematopoiesis, invertebrate, reactive oxygen species (ROS), transglutaminase
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biology with specialization in Comparative Physiology
    Identifiers
    urn:nbn:se:uu:diva-305568 (URN)10.1074/jbc.M116.741348 (DOI)000383241300011 ()27339892 (PubMedID)
    Funder
    Swedish Research Council, VR 20114797, VR 621-2012-2418
    Available from: 2016-10-19 Created: 2016-10-19 Last updated: 2017-08-22
    2. Role of astakine 1 in regulating transglutaminase activity
    Open this publication in new window or tab >>Role of astakine 1 in regulating transglutaminase activity
    2017 (English)In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 76, 77-82 p.Article in journal (Refereed) Published
    Abstract [en]

    Transglutaminase (TGase) has been implicated in maintaining the undifferentiated stage of hematopoietic stem cells (HSC) in the crayfish Pacifastacus leniusculus. TGase activity has been reported to be regulated by astakine1, an essential crayfish cytokine for inducing new hemocyte synthesis in hematopoietic tissue (HPT). Here, the role of astakine1 in TGase activity regulation and clotting protein (CP) cross-linking was characterized. A reduction in TGase activity was observed by the addition of purified astakine1 in vitro for both endogenous crayfish TGase and a commercial purified guinea pig liver TGase. As a result, we observed that astakine1 inhibits TGase enzyme activity and acts as a non-competitive inhibitor for the TGase enzyme. Additionally, the clotting reaction was impaired in the presence of astakine1. A decrease in TGase-mediated crosslinking of ε(γ-glutamyl)-lysine bonds was also observed in the presence of astakine1. In conclusion, this study shows that astakine1 acts as an inhibitor of TGase activity and that it also affects CP cross-linking during crayfish hematopoiesis.

    Place, publisher, year, edition, pages
    Elsevier, 2017
    Keyword
    Astakine1, Clotting protein, Hematopoiesis, Transglutaminase activity
    National Category
    Developmental Biology Other Biological Topics
    Research subject
    Biology with specialization in Comparative Physiology
    Identifiers
    urn:nbn:se:uu:diva-327217 (URN)10.1016/j.dci.2017.05.015 (DOI)28528959 (PubMedID)
    Available from: 2017-08-07 Created: 2017-08-07 Last updated: 2017-08-22Bibliographically approved
    3. PDGF/VEGF-related receptor affects transglutaminase activity to control cell migration during crustacean hematopoiesis
    Open this publication in new window or tab >>PDGF/VEGF-related receptor affects transglutaminase activity to control cell migration during crustacean hematopoiesis
    (English)In: ISSN 1547-3287Article in journal (Refereed) In press
    Keyword
    PDGF/VEGF, hematopoiesis, Transglutaminase, Ast1, crayfish
    National Category
    Developmental Biology Cell Biology Immunology
    Research subject
    Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-327243 (URN)
    Available from: 2017-08-07 Created: 2017-08-07 Last updated: 2017-08-14
    4. Clotting protein - an extracellular matrix (ECM) protein involved in crustacean hematopoiesis
    Open this publication in new window or tab >>Clotting protein - an extracellular matrix (ECM) protein involved in crustacean hematopoiesis
    (English)In: ISSN 0145-305XArticle in journal (Refereed) Submitted
    Keyword
    clotting protein, ECM, hematopoiesis, crustacean
    National Category
    Immunology Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-327248 (URN)
    Available from: 2017-08-07 Created: 2017-08-07 Last updated: 2017-08-14
  • Public defence: 2017-10-06 10:15 Sal IX, Uppsala
    Elfversson, Emma
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Peace and Conflict Research.
    Central Politics and Local Peacemaking: The Conditions for Peace after Communal Conflict2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Under what conditions can peace be established after violent communal conflict? This question has received limited research attention to date, despite the fact that communal conflicts kill thousands of people each year and often severely disrupt local livelihoods. This dissertation analyzes how political dynamics affect prospects for peace after communal conflict. It does so by studying the role of the central government, local state and non-state actors, and the interactions between these actors and the communal groups that are engaged in armed conflict. A particular focus is on the role of political bias, in the sense that central government actors have ties to one side in the conflict or strategic interests in the conflict issue. The central claim is that political bias shapes government strategies in the face of conflict, and influences the conflict parties’ strategic calculations and ability to overcome mistrust and engage in conflict resolution. To assess these arguments, the dissertation strategically employs different research methods to develop and test theoretical arguments in four individual essays. Two of the essays rely on novel data to undertake the first cross-national large-N studies of government intervention in communal conflict and how it affects the risk of conflict recurrence. Essay I finds that conflicts that are located in an economically important area, revolve around land and authority, or involve groups with ethnic ties to central rulers are more likely to prompt military intervention by the government. Essay II finds that ethnic ties, in turn, condition the impact that government intervention has on the risk of conflict recurrence. The other two essays are based on systematic analysis of qualitative sources, including unique and extensive interview material collected during several field trips to Kenya. Essay III finds that government bias makes it more difficult for the conflict parties to resolve their conflict through peace agreements. Essay IV finds that by engaging in governance roles otherwise associated with the state, non-state actors can become successful local peacemakers. Taken together, the essays make important contributions by developing, assessing and refining theories concerning the prospects for communal conflict resolution.

    List of papers
    1. Providing security or protecting interests?: Government interventions in violent communal conflicts in Africa
    Open this publication in new window or tab >>Providing security or protecting interests?: Government interventions in violent communal conflicts in Africa
    2015 (English)In: Journal of Peace Research, ISSN 0022-3433, E-ISSN 1460-3578, Vol. 52, no 6, 791-805 p.Article in journal (Refereed) Published
    Abstract [en]

    What factors drive governments’ decisions to intervene in local conflicts within their borders? Communal conflict – that is, organized violence between non-state groups that are mobilized along a shared communal identity – kills thousands each year and severely impacts local livelihoods, at times threatening to spread and affect entire regions. Given the state’s assumed monopoly over the legitimate use of force, we should expect the concerned governments to be critical actors of the overall effort to restore peace in cases of local communal conflict, but empirical evidence indicates that central states tend to only intervene in some cases but not in others. This phenomenon has so far been understudied and the variations in states’ efforts to manage these conflicts remain unexplained. This article presents the first quantitative study of state intervention in communal conflicts. Building on existing scholarly work, I argue that state intervention is explained by a combination of strategic interests and state capacity, and that interests related to ethnic constituencies and land control play an important part in explaining governments’ strategies. These propositions find support in a statistical analysis covering sub-Saharan Africa from 1989 to 2010.

    Keyword
    Communal conflict, intervention, land control, non-state, non-state conflict, sub-Saharan Africa
    National Category
    Political Science
    Research subject
    Peace and Conflict Research
    Identifiers
    urn:nbn:se:uu:diva-265486 (URN)10.1177/0022343315597968 (DOI)000364164200007 ()
    Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2017-08-18Bibliographically approved
    2. Whose side are you on? Government bias, intervention and the recurrence of communal conflict
    Open this publication in new window or tab >>Whose side are you on? Government bias, intervention and the recurrence of communal conflict
    (English)Manuscript (preprint) (Other academic)
    National Category
    Political Science
    Research subject
    Peace and Conflict Research
    Identifiers
    urn:nbn:se:uu:diva-324925 (URN)
    Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2017-08-18
    3. The political conditions for local peacemaking: A comparative study of communal conflict resolution in Kenya
    Open this publication in new window or tab >>The political conditions for local peacemaking: A comparative study of communal conflict resolution in Kenya
    (English)Manuscript (preprint) (Other academic)
    National Category
    Political Science
    Research subject
    Peace and Conflict Research
    Identifiers
    urn:nbn:se:uu:diva-324926 (URN)
    Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2017-08-18
    4. Peace from below: Governance and peacebuilding in Kerio Valley, Kenya
    Open this publication in new window or tab >>Peace from below: Governance and peacebuilding in Kerio Valley, Kenya
    2016 (English)In: Journal of Modern African Studies, ISSN 0022-278X, E-ISSN 1469-7777, Vol. 54, no 3, 469-493 p.Article in journal (Refereed) Published
    Abstract [en]

    Under what circumstances can non-state actors become successful local peacemakers? A growing body of research documents the involvement of non-state actors in local conflict resolution in Africa. However, there is large variation in such actors' power, legitimacy, and ultimately their ability to contribute to conflict resolution. The ways in which contextual and dynamic factors at local and national levels, and in particular the relationship between non-state and state actors and institutions, affect local conflict resolution are not sufficiently understood. To address this gap, this paper analyses the peace process addressing a long-standing conflict in Kerio Valley, Kenya. The analysis illustrates how the failure of the state to provide security and basic services led non-state actors to fill important roles in governance. Through this process, they were endowed with legitimacy and power which enabled them to play key roles in a peace process that led to a mutually acceptable peace agreement.

    National Category
    Political Science
    Research subject
    Peace and Conflict Research
    Identifiers
    urn:nbn:se:uu:diva-300965 (URN)10.1017/S0022278X16000227 (DOI)000382379300005 ()
    Available from: 2016-08-16 Created: 2016-08-16 Last updated: 2017-08-18Bibliographically approved
  • Public defence: 2017-10-06 13:00 Sal MA624, Moas båge, Flemingsberg
    Andén, Lovisa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Philosophy.
    Litteratur och erfarenhet i Merleau-Pontys läsning av Proust, Valéry och Stendhal2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The aim of this thesis is to explore the relation between literary expression and experience in Merleau-Ponty’s philosophy. The principal focus is Merleau-Ponty’s investigations into literature, in two of his first courses at Collège de France, 1953- 1954: Sur le problème de la parole (On the Problem of Speech) and Recherches sur l’usage littéraire du langage (Research on the Literary Use of Language). While the former remains unpublished, the latter was finally published in 2013. At the time of his premature death, Merleau-Ponty left thousands of pages of working notes. They were supposed to contribute to a major philosophical work, the planned title of which was Être et monde (Being and world). Merleau-Ponty had planned to undertake an extensive examination of language in the last part of the work. However, in the absence of this text, the courses on literary language afford us the possibility of sketching the direction that this research might have taken.

    The examination of literary language use is, for Merleau-Ponty, made possible by an understanding of language found in Ferdinand de Saussure’s linguistics. Merleau-Ponty’s interpretation of Saussurean linguistics anticipates the structuralist reading that was later to dominate the intellectual scene. Instead of reading the linguistics of Saussure in opposition to phenomenology, he finds in the former an ally that allows him to think Husserlian phenomenology further.

    In the course notes, Merleau-Ponty explores the relation between sensible experience and linguistic expressions through close readings of Proust, Valéry and Stendhal. In the writing of Marcel Proust, he finds a writer that perpetually examines his experience, searching for expressions that are capable of bringing it forth. In Stendhal’s writing, Merleau-Ponty finds a literary method that makes the world appear through the “small true facts” that describe it. Finally, in Paul Valéry’s poetic writing he finds a writer superimposing words over other words, in order to create new significations. In their literary writing he finds a capacity to seize the world anew, beyond our habitual preconceptions of it, thus bringing us closer to the experience we already perceive.

  • Public defence: 2017-10-06 13:00 Ekmansalen, Uppsala
    Bremer, Oskar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Silurian vertebrates of Gotland (Sweden) and the Baltic Basin2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During the Silurian, the Swedish island Gotland was positioned close to the equator and covered by a shallow sea called the Baltic Basin. The sedimentary rocks (predominantly carbonates) comprising most of the island today were initially formed in this warm sea, and the relatively complete succession of rocks often contains fossil fragments and scales from early vertebrates, including heterostracans, anaspids, thelodonts, osteostracans, acanthodians, and a stem-osteichthyan. Fossils of early vertebrates become increasingly more common in younger Silurian rocks, but are mostly represented by fragmentary remains and rarer occurrences of articulated jawless vertebrates (agnathans). However, the record of articulated specimens and jawed vertebrates (gnathostomes) are more numerous in rocks of the following Devonian Period. Isolated peaks of agnathan diversity during the Silurian and disarticulated remains of gnathostomes from this period hint at a cryptic evolutionary history. A micropaleontological approach with broader sampling may provide a better understanding of early vertebrate distribution patterns and hopefully give some insights into this history. The objective of this study was to build upon previous sampling on Gotland and to use established frameworks for disarticulated remains with the aim of making comparisons with similar studies performed in the East Baltic. However, difficulties locating the collections from these previous works necessitated a different focus. Undescribed museum collections and newly sampled material enabled some taxonomical revisions and greatly improved the understanding of vertebrate distribution in the youngest part of the Gotland sequence. It also indicated that this interval may represent the early stages of the diversification of gnathostomes that become increasingly dominant toward the end of the Silurian. Furthermore, the description of samples from partly coeval sections in Poland enabled some preliminary comparisons outside of Gotland, and presented a striking example of restricted environmental occurrences for a thelodont taxon. This is encouraging for future sampling and investigations on Gotland. Together with the establishment of a facies-framework comparable to that developed in the East Baltic and correlations to other areas, this may prove fruitful for an increased understanding of early vertebrate distribution and evolution during the Silurian.

    List of papers
    1. An updated stratigraphic and environmental framework for the distribution of Silurian vertebrates on Gotland
    Open this publication in new window or tab >>An updated stratigraphic and environmental framework for the distribution of Silurian vertebrates on Gotland
    2015 (English)In: Estonian journal of earth sciences, ISSN 1736-4728, E-ISSN 1736-7557, Vol. 64, no 1, 13-18 p.Article in journal (Refereed) Published
    Keyword
    vertebrate distribution, stratigraphy, facies, Silurian events, Gotland, Sweden
    National Category
    Developmental Biology Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-251824 (URN)10.3176/earth.2015.03 (DOI)000351327700004 ()
    Available from: 2015-04-27 Created: 2015-04-24 Last updated: 2017-08-21
    2. End-Wenlock terminal Mulde carbon isotope excursion in Gotland, Sweden: Integration of stratigraphy and taphonomy for correlations across restricted facies and specialized faunas
    Open this publication in new window or tab >>End-Wenlock terminal Mulde carbon isotope excursion in Gotland, Sweden: Integration of stratigraphy and taphonomy for correlations across restricted facies and specialized faunas
    Show others...
    2016 (English)In: Palaeogeography, Palaeoclimatology, Palaeoecology, ISSN 0031-0182, E-ISSN 1872-616X, Vol. 457, 304-322 p.Article in journal (Refereed) Published
    National Category
    Earth and Related Environmental Sciences
    Research subject
    Earth Science with specialization in Historical Geology and Palaeontology
    Identifiers
    urn:nbn:se:uu:diva-299498 (URN)10.1016/j.palaeo.2016.06.031 (DOI)000380598800025 ()
    Available from: 2016-07-21 Created: 2016-07-21 Last updated: 2017-08-21
    3. Vertebrate remains and conodont biostratigraphy in the Ludlow Burgsvik Formation of Gotland, Sweden
    Open this publication in new window or tab >>Vertebrate remains and conodont biostratigraphy in the Ludlow Burgsvik Formation of Gotland, Sweden
    (English)Manuscript (preprint) (Other academic)
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-328226 (URN)
    Available from: 2017-08-20 Created: 2017-08-20 Last updated: 2017-08-25
    4. Vertebrate dermal remains and conodont distribution in the upper Silurian Hamra and Sundre formations of Gotland, Sweden
    Open this publication in new window or tab >>Vertebrate dermal remains and conodont distribution in the upper Silurian Hamra and Sundre formations of Gotland, Sweden
    (English)Manuscript (preprint) (Other academic)
    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-328227 (URN)
    Available from: 2017-08-20 Created: 2017-08-20 Last updated: 2017-08-21
    5. Vertebrate microremains from the upper Silurian Winnica Formation of the Holy Cross Mountains, Poland
    Open this publication in new window or tab >>Vertebrate microremains from the upper Silurian Winnica Formation of the Holy Cross Mountains, Poland
    Show others...
    2017 (English)In: Geological Magazine, ISSN 0016-7568, E-ISSN 1469-5081, 1-19 p., doi:10.1017/S0016756817000681Article in journal (Other academic) Epub ahead of print
    National Category
    Other Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-281657 (URN)10.1017/S0016756817000681 (DOI)
    Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2017-09-04
  • Public defence: 2017-10-06 13:00 Föreläsningssalen Biblioteket, Falun
    Hesselman, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Caesarean Section: Short- and long-term maternal complications2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Caesarean section is a common major surgical procedure and long-term complications have not been fully investigated. By longitudinal population based register studies, based on National health registers and medical data records, maternal complications after caesarean delivery at subsequent labour (N=7 683), among extremely preterm births (N=406), and at remote gynaecologic surgery (N=25 354) were explored.

    In Paper I, uterine closure was investigated in respect to uterine rupture in a subsequent delivery after caesarean section. Uterine rupture occurred in 1.3 % of women with a previous caesarean section. There was no increased risk of uterine rupture with single compared with double layers for closure of the uterus (adjusted Odds Ratio 1.17, 95 % CI 0.78-1.70). Modifiable risk factors of uterine rupture in a trial of labour after caesarean section included induction of labour and use of epidural analgesia.

    In Paper II, maternal outcomes and surgical aspects of caesarean section in the extremely preterm period were assessed. Maternal complications were more frequently reported in extremely preterm- compared with term caesarean delivery. No increase in short-term morbidity was observed at 22-24 compared with 25-27 gestational weeks, but uterine corporal incisions were performed more frequently (18.1 % vs. 9.6 %, p=0.02).

    Furthermore, risk factors for abdominal adhesions after caesarean section and organ injury in remote gynaecologic surgery were analysed (Paper III and IV). Numbers of prior caesarean sections were the most important factor for formation of adhesions. Advanced maternal age, obesity, infection and delivery year 1997-2013 were factors associated with adhesions in conjunction with caesarean section. Organ injury occurred in 2.2 % of women undergoing benign hysterectomy. A history of caesarean section increased the risk (adjusted Odds Ratio 1.74, 95 % CI 1.41-2.15), but was only partly explained by the presence of adhesions. The organ affected depended on medical history; prior caesarean predisposed for bladder injury, prior bowel/pelvic surgery for bowel injury and endometriosis was associated with ureter injury at time of hysterectomy. In conclusion; data from National health registers indicates that caesarean delivery is associated with long-term complications, although the absolute risk of severe complications for the woman is low.

    List of papers
    1. The risk of uterine rupture is not increased with single- compared with double-layer closure: a Swedish cohort study
    Open this publication in new window or tab >>The risk of uterine rupture is not increased with single- compared with double-layer closure: a Swedish cohort study
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    2015 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 122, no 11, 1535-1541 p.Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    To compare single- with double-layer closure of the uterus for the risk of uterine rupture in women attempting vaginal birth after one prior caesarean delivery.

    DESIGN:

    Cohort study.

    SETTING:

    Sweden.

    POPULATION:

    From a total of 19 604 nulliparous women delivered by caesarean section in the years 2001-2007, 7683 women attempting vaginal birth in their second delivery were analysed.

    METHODS:

    Data from population-based registers were linked to hospital-based registers that held data from maternity and delivery records. Logistic regression was used to estimate the risk of uterine rupture after single- or double-layer closure of the uterus. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs).

    MAIN OUTCOME MEASURE:

    Uterine rupture.

    RESULTS:

    Uterine rupture during labour occurred in 103 (1.3%) women. There was no increased risk of uterine rupture when single- was compared with double-layer closure of the uterus (OR 1.17; 95% CI 0.78-1.76). Maternal factors associated with uterine rupture were: age ≥35 years and height ≤160 cm. Factors from the first delivery associated with uterine rupture in a subsequent delivery were: infection and giving birth to an infant large for gestational age. Risk factors from the second delivery were induction of labour, use of epidural analgesia, and a birthweight of ≥4500 g.

    CONCLUSIONS:

    There was no significant difference in the rate of uterine rupture when single-layer closure was compared with double -layer closure of the uterus.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-232789 (URN)10.1111/1471-0528.13015 (DOI)000362752100020 ()25088680 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Society of Medicine
    Available from: 2014-09-25 Created: 2014-09-25 Last updated: 2017-08-18Bibliographically approved
    2. Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section
    Open this publication in new window or tab >>Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section
    Show others...
    2017 (English)In: Journal of Perinatal Medicine, ISSN 0300-5577, E-ISSN 1619-3997, Vol. 45, no 1, 121-127 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective: To investigate the maternal complications associated with cesarean section (CS) in the extremely preterm period according to the gestational week (GW) and to indication of delivery. Study design: This is a retrospective case-referent study with a review of medical records of women who delivered at 22-27 weeks of gestation (n = 647) at two level III units in Sweden. For abdominal delivery, gestational length was stratified into 22-24 (n = 105) and 25-27 (n = 301) weeks. For comparison, data on women who underwent a CS at term were identified in a register-based database. Results: The rate of CS in extremely preterm births was 62.8%. There was no difference in the complication rates, but types of incisions other than the low transverse incision were required more often at 22-24 (18.1%) weeks than at 25-27 GWs (9.6%) (P = 0.02). Major maternal complications occurred in 6.6% compared with 2.1% in the extremely preterm and term CS, respectively (P < 0.01). A maternal indication of extremely preterm CS increased the risk of complications. Conclusions: Almost two-thirds of the births at 22-27 GWs had an abdominal delivery. No increase in short-term morbidity was observed at 22-24 weeks compared to 25-27 weeks. CS performed extremely preterm had more major complications recorded than cesarean at term. The complications are driven by the underlying maternal condition.

    Keyword
    Cesarean section, extremely preterm birth, post-operative complications, pregnancy complications
    National Category
    Pediatrics Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-317691 (URN)10.1515/jpm-2016-0198 (DOI)000393201100016 ()27768584 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2017-08-18Bibliographically approved
    3. Abdominal adhesions in gynaecologic surgery after caesarean section: a longitudinal population-based register study.
    Open this publication in new window or tab >>Abdominal adhesions in gynaecologic surgery after caesarean section: a longitudinal population-based register study.
    Show others...
    2017 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    OBJECTIVE: The aim of the study was to evaluate the association between abdominal adhesions at the time of gynaecologic surgery and a history of caesarean delivery, and to investigate obstetric factors contributing to adhesion formation after caesarean section (CS).

    DESIGN: Longitudinal population-based register study.

    SETTING: Sweden.

    POPULATION: Women undergoing benign hysterectomy and/or adnexal surgery in Sweden, 2000-2014, with a previous delivery during 1973-2013 (n = 15 479).

    METHODS: Information about abdominal adhesions during gynaecological surgery, prior medical history, pregnancies and deliveries were retrieved from Swedish National Health and Quality registers.

    MAIN OUTCOME MEASURES: Adhesions.

    RESULTS: In women with previous CS, adhesions were present in 37%, compared with 10% of women with no previous CS [odds ratio (OR): 5.18, 95% confidence interval (CI): 4.70-5.71]. Adhesions increased with the number of caesarean sections: 32% after one CS; 42% after two CS and 59% after three or more CS (P < 0.001). Regardless of the number of CS, factors at CS such as age ≥35 years (aOR: 1.28, 95% CI: 1.05-1.55), body mass index (BMI) ≥30 [adjusted OR (aOR): 1.91, 95% CI: 1.49-2.45] and postpartum infection (aOR: 1.55, 95% CI: 1.05-2.30) increased the risk of adhesions.

    CONCLUSIONS: Presence of adhesions in abdominal gynaecological surgery is associated with women's personal history of caesarean delivery. The number of caesarean sections was the important predictor of adhesions; advanced age, obesity and postpartum infection further increased the incidence.

    TWEETABLE ABSTRACT: Repeat caesarean, age, obesity and infection increased the risk of pelvic adhesions after caesarean section.

    Keyword
    Adhesions, adhesive disease, caesarean section, gynaecologic surgery
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-327111 (URN)10.1111/1471-0528.14708 (DOI)28444984 (PubMedID)
    Available from: 2017-08-03 Created: 2017-08-03 Last updated: 2017-08-18
    4. Effect of remote cesarean delivery on complications during hysterectomy: a cohort study.
    Open this publication in new window or tab >>Effect of remote cesarean delivery on complications during hysterectomy: a cohort study.
    2017 (English)In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, S0002-9378(17)30863-3Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    BACKGROUND: Cesarean section is frequently performed worldwide, and follow-up studies reporting complications at subsequent surgery are warranted.

    OBJECTIVES: The aim of the study was to investigate the association between a previous abdominal delivery and complications during a subsequent hysterectomy, and to estimate the fraction of complications driven by the presence of adhesions.

    STUDY DESIGN: This was a longitudinal population based register study of 25354 women undergoing a benign hysterectomy at 46 hospital units in Sweden 2000-2014.

    RESULTS: Adhesions were found in 45 % of the women with a history of cesarean delivery. Organ injury affected 2.2 %. The risk of organ injury (aOR 1.74, 95 % CI 1.41-2.15) and post-operative infection (aOR 1.26, 95 % CI 1.15-1.39) was increased with prior cesarean section, irrespective of whether adhesions were present or not. The direct effect on organ injury by a personal history of cesarean delivery was estimated to 73 %, and only 27 % was mediated by the presence of adhesions. Previous cesarean was a predictor of bladder injury (aOR 1.86, 95 % CI 1.40-2.47) and bowel injury (aOR 1.83, 95 % CI 1.10-3.03) but not ureter injury. A personal history of other abdominal surgeries was associated with bowel injury (aOR 2.27, 95 % CI 1.37-3.78), and the presence of endometriosis increased the risk of ureter injury (aOR 2.15, 95 % CI 1.34-3.44).

    CONCLUSIONS: Prior cesarean delivery is associated with an increased risk of complications during a subsequent hysterectomy, but the risk is only partly attributable to the presence of adhesions. Previous cesarean delivery and presence of endometriosis were major predisposing factors of organ injury at the time of the hysterectomy whereas background and perioperative characteristics were of minor importance.

    Keyword
    Adhesive disease, adhesions, cesarean section, complications, endometriosis, hysterectomy
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-327110 (URN)10.1016/j.ajog.2017.07.021 (DOI)28735704 (PubMedID)
    Available from: 2017-08-03 Created: 2017-08-03 Last updated: 2017-08-18