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  • Disputas: 2017-10-20 09:00 Gustavianum, Auditorium Minus, 753 10 Uppsala
    Bergman, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Cerebral biomarkers in women with preeclampsia2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Preeclampsia and eclampsia are among the most common causes of maternal and fetal mortality and morbidity worldwide. There are no reliable means to predict eclampsia or cerebral edema in women with preeclampsia and knowledge of the brain involvement in preeclampsia is still limited. S100B and neuron specific enolase (NSE) are two cerebral biomarkers of glial- and neuronal origin respectively. They are used as predictors for neurological outcome after traumatic brain injuries and cardiac arrest but have not yet been investigated in preeclampsia.

    This thesis is based on one longitudinal cohort study of pregnant women (n=469, Paper I and III), one cross sectional study of women with preeclampsia and women with normal pregnancies (n=53 and 58 respectively, Paper II and IV) and one experimental animal study of eclampsia (Paper V).

    In Paper I and III, plasma concentrations of S100B and NSE were investigated throughout pregnancy in women developing preeclampsia (n=16) and in women with normal pregnancies (n=36) in a nested case control study. Plasma concentrations were increased in women developing preeclampsia in gestational week 33 and 37 for S100B and in gestational week 37 for NSE compared to women with normal pregnancies.

    In Paper II and IV, increased plasma concentrations of S100B and NSE were confirmed among women with preeclampsia compared to women with normal pregnancies. Furthermore, increased plasma concentrations of S100B correlated to visual disturbances among women with preeclampsia (Paper II) and plasma concentrations of S100B and NSE remained increased among women with preeclampsia one year after delivery (Paper IV).

    In Paper V, an experimental rat model of preeclampsia and eclampsia demonstrated increased serum concentrations of S100B after seizures in normal pregnancy (n=5) and a tendency towards increased plasma concentrations of S100B in preeclampsia (n=5) compared to normal pregnancy (n=5) without seizures. Furthermore, after seizures, animals with magnesium sulphate treatment demonstrated increased serum concentrations of S100B and NSE compared to no treatment.

    In conclusion; plasma concentrations of S100B and NSE are increased in preeclampsia during late pregnancy and postpartum and S100B correlates to visual disturbances in women with preeclampsia. The findings are partly confirmed in an animal model of eclampsia.

    Delarbeid
    1. Plasma levels of S100B during pregnancy in women developing pre-eclampsia
    Åpne denne publikasjonen i ny fane eller vindu >>Plasma levels of S100B during pregnancy in women developing pre-eclampsia
    Vise andre…
    2012 (engelsk)Inngår i: Pregnancy Hypertension, ISSN 2210-7789, E-ISSN 2210-7797, Vol. 2, nr 4, 398-402 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective

    S100B is suggested to be a peripheral biomarker of central nervous system injury with increased blood–brain barrier permeability. The aim of this study was to investigate if there is a difference in plasma levels of S100B throughout pregnancy between women developing pre-eclampsia and those who did not.

    Study design

    A nested case-control study within a longitudinal study cohort was performed. Healthy pregnant women were enrolled and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. Levels of S100B throughout pregnancy were analyzed with an ELISA assay.

    Results

    The levels of S100B did not change between gestational weeks 10 and 37 (0.047 vs. 0.052; p = 0.71) in the healthy controls, but the S100B levels increased between corresponding weeks in women who developed pre-eclampsia (0.052 vs. 0.075; p < 0.05). In gestational weeks 33 and 37 women who developed pre-eclampsia had higher levels of S100B than the controls (p = 0.047 and p = 0.010, respectively).

    Conclusion

    S100B levels increase during pregnancy in women who develop pre-eclampsia and there is an increased S100B level in women who develop pre-eclampsia compared with healthy pregnancies several weeks before clinical symptoms of the disease. The increased amount of plasma S100B in women developing pre-eclampsia might be secondary to cerebral vascular damage and S100B is a potential peripheral biomarker reflecting cerebral involvement in pre-eclampsia.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-185093 (URN)10.1016/j.preghy.2012.03.001 (DOI)000209446000010 ()26105610 (PubMedID)
    Forskningsfinansiär
    Swedish Society of MedicineStiftelsen Olle Engkvist Byggmästare
    Tilgjengelig fra: 2012-11-20 Laget: 2012-11-20 Sist oppdatert: 2017-09-01bibliografisk kontrollert
    2. Plasma Levels of S100B in Preeclampsia and Association With Possible Central Nervous System Effects
    Åpne denne publikasjonen i ny fane eller vindu >>Plasma Levels of S100B in Preeclampsia and Association With Possible Central Nervous System Effects
    Vise andre…
    2014 (engelsk)Inngår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, nr 8, 1105-1111 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND:

    S100B is supposed to be a peripheral biomarker of central nervous system (CNS) injury. The purpose of this study was to compare levels of S100B in women with preeclampsia with levels in healthy pregnant control subjects and furthermore to analyze levels of S100B in relation to possible CNS effects.

    METHODS:

    A cross-sectional case-control study in antenatal care centers in Uppsala, Sweden, was performed. Fifty-three women with preeclampsia and 58 healthy pregnant women were recruited at similar gestational length; women with preeclampsia were recruited at time of diagnosis, and control subjects were recruited during their routine visit to an antenatal clinic. Plasma samples were collected, and levels of S100B were analyzed with an enzyme-linked immunosorbent assay. Information about demographic and clinical characteristics, including symptoms related to CNS affection, was collected from the medical records. The main outcome measures were plasma levels of S100B and possible CNS effects.

    RESULTS:

    Levels of S100B were significantly higher among women with preeclampsia than among control subjects (0.12 µg/L vs. 0.07 µg/L; P < 0.001). In preeclampsia, there was a significant association between high levels of S100B and visual disturbances (P < 0.05).

    CONCLUSIONS:

    S100B is increased among women with preeclampsia, and high levels of S100B associate with visual disturbances, which might reflect CNS affection in women with preeclampsia.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-221882 (URN)10.1093/ajh/hpu020 (DOI)000342237900022 ()24610883 (PubMedID)
    Tilgjengelig fra: 2014-04-07 Laget: 2014-04-07 Sist oppdatert: 2017-09-01bibliografisk kontrollert
    3. Plasma Levels of the Cerebral Biomarker, Neuron-Specific Enolase, are Elevated During Pregnancy in Women Developing Preeclampsia
    Åpne denne publikasjonen i ny fane eller vindu >>Plasma Levels of the Cerebral Biomarker, Neuron-Specific Enolase, are Elevated During Pregnancy in Women Developing Preeclampsia
    2016 (engelsk)Inngår i: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 23, nr 3, 395-400 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objectives: Neuron-specific enolase (NSE) is considered to be a peripheral biomarker of central nervous system injury. The aim of this study was to compare levels of NSE throughout pregnancy, in healthy pregnant women and in women developing preeclampsia. Methods: A nested case-control study within a longitudinal study cohort was performed. Four hundred sixty nine healthy pregnant women were enrolled, and plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. Levels of NSE were analyzed in 16 women with preeclampsia and 36 controls throughout pregnancy with an enzyme-linked immunosorbent assay. Results: In gestational week 37, women who developed preeclampsia had significantly higher plasma levels of NSE than healthy pregnant controls (P < .001). The levels of NSE did not change between gestational weeks 10 and 37 in women who developed preeclampsia, but the levels decreased significantly in healthy pregnant controls (P < .001). Conclusion: In pregnant women developing preeclampsia, the levels of NSE remained high throughout pregnancy, whereas in healthy women, these tended to decline over time, especially at the 2 last time points. The result might be confounded in early pregnancy by extracerebral sources of NSE, such as the corpus luteum. Findings need to be confirmed in a larger prospective study.

    Emneord
    eclampsia, NSE, preeclampsia
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-281488 (URN)10.1177/1933719115604732 (DOI)000370719100015 ()26355117 (PubMedID)
    Tilgjengelig fra: 2016-03-30 Laget: 2016-03-24 Sist oppdatert: 2017-09-01bibliografisk kontrollert
    4. Cerebral Biomarkers in Women With Preeclampsia Are Still Elevated 1 Year Postpartum
    Åpne denne publikasjonen i ny fane eller vindu >>Cerebral Biomarkers in Women With Preeclampsia Are Still Elevated 1 Year Postpartum
    Vise andre…
    2016 (engelsk)Inngår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 29, nr 12, 1374-1379 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND There is evidence of cerebral involvement among women with preeclampsia. Levels of the cerebral biomarkers neuron-specific enolase (NSE) and S100B are elevated during pregnancy in women developing preeclampsia. It is although not known if these biomarkers return to normal range postpartum. The aim with this study was to compare levels of S100B and NSE during pregnancy and 1 year postpartum in women who have had preeclampsia to women with normal pregnancies. METHODS This study was a longitudinal study of cases (n = 53) with preeclampsia and controls (n = 58) consisted of normal pregnant women in matched gestational weeks. Plasma samples were collected at inclusion during pregnancy and 1 year postpartum. Plasma samples were analyzed for levels of S100B and NSE by enzyme-linked immunosorbent assays kits. RESULTS Levels of NSE and S100B in women with preeclampsia were higher during pregnancy than in women with normal pregnancies. One year postpartum, women who have had preeclampsia still had a higher median level of both NSE (5.07 vs. 4.28 mu g/l, P < 0.05) and S100B (0.07 vs. 0.06 mu g/l, P < 0.05) compared to women with previous normal pregnancies. High levels of NSE and S100B postpartum remained associated with previous preeclampsia after adjustment for confounding factors. Levels of NSE correlated to S100B during pregnancy and postpartum. CONCLUSIONS Levels of NSE and S100B are still elevated 1 year postpartum in women who have had preeclampsia in contrast to women with previous normal pregnancies. We hypothesize that there might be a persistent cerebral involvement among women with preeclampsia even 1 year postpartum.

    Emneord
    blood pressure, hypertension, Neurological dysfunction, NSE, preeclampsia, S100B
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-316434 (URN)10.1093/ajh/hpw097 (DOI)000392732700009 ()27653032 (PubMedID)
    Forskningsfinansiär
    Swedish Society of MedicineSwedish Research Council, 2014-3561 D0277901
    Tilgjengelig fra: 2017-03-01 Laget: 2017-03-01 Sist oppdatert: 2017-09-01bibliografisk kontrollert
    5. Effect of Experimental Preeclampsia, Seizure and MgSO4 Treatment in a Rat Model on Serum Levels of S100B and Neuron Specific Enolase
    Åpne denne publikasjonen i ny fane eller vindu >>Effect of Experimental Preeclampsia, Seizure and MgSO4 Treatment in a Rat Model on Serum Levels of S100B and Neuron Specific Enolase
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    eclampsia; neurological dysfunction; neuron specific enolase; preeclampsia; S100B
    HSV kategori
    Forskningsprogram
    Obstetrik och gynekologi
    Identifikatorer
    urn:nbn:se:uu:diva-328757 (URN)
    Konferanse
    RCOG world congress 2017 20th-22nd of March 2017
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-09-01
  • Disputas: 2017-10-20 09:15 Polhemsalen, 10134, Uppsala
    Sjökvist, Linnea
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Elektricitetslära.
    Wave Loads and Peak Forces on Moored Wave Energy Devices in Tsunamis and Extreme Waves2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Surface gravity waves carry enormous amounts of energy over our oceans, and if their energy could be harvested to generate electricity, it could make a significant contribution to the worlds power demand. But the survivability of wave energy devices in harsh operating conditions has proven challenging, and for wave energy to be a possibility, peak forces during storms and extreme waves must be studied and the devices behaviour understood. Although the wave power industry has benefited from research and development in traditional offshore industries, there are important differences. Traditional offshore structures are designed to minimize power absorption and to have small motion response, while wave power devices are designed to maximize power absorption and to have a high motion response. This increase the difficulty of the already challenging survivability issue. Further, nonlinear effects such as turbulence and overtopping can not be neglected in harsh operating conditions. In contrast to traditional offshore structures, it is also important to correctly account for the power take off system in a wave energy converter (WEC), as it is strongly coupled to the devices behaviour.

    The focus in this thesis is the wave loads and the peak forces that occur when a WEC with a limited stroke length is operated in waves higher than the maximum stroke length. The studied WEC is developed at Uppsala University, Sweden, and consists of a linear generator at the seabed that is directly driven by a surface buoy. A fully nonlinear CFD model is developed in the finite volume software OpenFOAM, and validated with physical wave tank experiments. It is then used to study the motion and the forces on the WEC in extreme waves; high regular waves and during tsunami events, and how the WECs behaviour is influenced by different generator parameters, such as generator damping, friction and the length of the connection line. Further, physical experiments are performed on full scale linear generators, measuring the total speed dependent damping force that can be expected for different loads. The OpenFOAM model is used to study how the measured generator behaviour affects the force in the connection line.

    Delarbeid
    1. Numerical models for the motion and forces of point-absorbing wave energy converters in extreme waves
    Åpne denne publikasjonen i ny fane eller vindu >>Numerical models for the motion and forces of point-absorbing wave energy converters in extreme waves
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot elektricitetslära
    Identifikatorer
    urn:nbn:se:uu:diva-328485 (URN)
    Forskningsfinansiär
    Natural‐Disaster Science
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-08-24
    2. Buoy geometry and its influence on survivability for apoint absorbing wave energy converter: Scaleexperiment and CFD simulations
    Åpne denne publikasjonen i ny fane eller vindu >>Buoy geometry and its influence on survivability for apoint absorbing wave energy converter: Scaleexperiment and CFD simulations
    Vise andre…
    2017 (engelsk)Konferansepaper, Oral presentation with published abstract (Fagfellevurdert)
    Abstract [en]

    For wave energy to be an economically viable energysource, the technology has to withstand power levelsduring storms that can be close to 50 times higher thanduring normal operating conditions, and withstandmany years of wear. The impact of high wave loads isstudied not only within the field of wave energy, buthas long been a subject of study for ships, platformsand other offshore structures.To model the force on the device under extreme and/orovertopping waves is a difficult task. Experiments areexpensive and difficult to implement, and numerical meth-ods are either very computationally demanding CFD-methods, or less accurate approximative methods. Inaddition, the performance and experienced forces during extreme waves are model dependent, and differentoffshore structures must be studied independently.Here, a 1:20 scale model of the Uppsala Universitypoint-absorber type wave energy converter (WEC) has been tested in extreme wave conditions at the COASTLaboratory Ocean Basin at Plymouth University. The WEC consists of a linear generator connected to a buoyat the sea surface, and performance of two differentbuoys is studied: a cylinder and cylinder with moon-pool. Two types of wave sets have been used: focusedwaves embedded into regular waves, and irregular waves. The focus of this paperis on comparing the performance of the two buoys, and on analysing the experimental data using a numerical model. A fully non-linear computational fluid dynamics(CFD) model based on OpenFOAM is presented and validated.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-321807 (URN)
    Konferanse
    Marine Energy Technology Symposium, WATERPOWER WEEK IN WASHINGTON
    Tilgjengelig fra: 2017-05-11 Laget: 2017-05-11 Sist oppdatert: 2017-08-24
    3. The Effect of Overtopping Waves on Peak Forceson a Point Absorbing WEC
    Åpne denne publikasjonen i ny fane eller vindu >>The Effect of Overtopping Waves on Peak Forceson a Point Absorbing WEC
    2016 (engelsk)Konferansepaper, Publicerat paper (Fagfellevurdert)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-313253 (URN)
    Konferanse
    Asian Wave and Tidal Energy Conference Series, AWTEC, October 24-28 2016, Singapore, Singapore
    Merknad

    Title in Book of Abstracts: OpenFOAM Modelling of Point-absorbing WECs with Different Buoy Topologies

    Tilgjengelig fra: 2017-01-18 Laget: 2017-01-18 Sist oppdatert: 2017-08-24bibliografisk kontrollert
    4. Peak Forces on a Point Absorbing Wave Energy Converter Impacted by Tsunami Waves
    Åpne denne publikasjonen i ny fane eller vindu >>Peak Forces on a Point Absorbing Wave Energy Converter Impacted by Tsunami Waves
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot elektricitetslära
    Identifikatorer
    urn:nbn:se:uu:diva-328486 (URN)
    Forskningsfinansiär
    Natural‐Disaster Science
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-08-24
    5. Survivability of a Point Absorbing Wave Energy Converter Impacted by Tsunami Waves
    Åpne denne publikasjonen i ny fane eller vindu >>Survivability of a Point Absorbing Wave Energy Converter Impacted by Tsunami Waves
    2017 (engelsk)Inngår i: 12th European Wave and Tidal Energy Conference Series, Cork, Ireland, 27 August - 1 September, 2017, 2017Konferansepaper, Oral presentation only (Fagfellevurdert)
    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot elektricitetslära
    Identifikatorer
    urn:nbn:se:uu:diva-328487 (URN)
    Konferanse
    EWTEC2017
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-09-11
    6. Peak forces on wave energy linear generators in tsunami and extreme waves
    Åpne denne publikasjonen i ny fane eller vindu >>Peak forces on wave energy linear generators in tsunami and extreme waves
    2017 (engelsk)Inngår i: Energies, ISSN 1996-1073, E-ISSN 1996-1073, energies-210620Artikkel i tidsskrift (Fagfellevurdert) Accepted
    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot elektricitetslära
    Identifikatorer
    urn:nbn:se:uu:diva-328490 (URN)
    Forskningsfinansiär
    Natural‐Disaster Science
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-09-11
    7. Line Force and Damping at Full and Partial Stator Overlap in a Linear Generator for Wave Power
    Åpne denne publikasjonen i ny fane eller vindu >>Line Force and Damping at Full and Partial Stator Overlap in a Linear Generator for Wave Power
    2016 (engelsk)Inngår i: Journal of Marine Science and Engineering, ISSN 2077-1312, Vol. 4, nr 4, 81Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A full scale linear generator for wave power has been experimentally evaluated bymeasuring the line force and translator position throughout the full translator stroke. The measuredline force, in relation to translator speed, generator damping and stator overlap, has been studied bycomparing the line force and the damping coefficient, γ, for multiple load cases along the translatorstroke length. The study also compares the generator ’s behavior during upward and downwardmotion, studies oscillations and determines the no load losses at two different speeds. The generatordamping factor, γ, was determined for five different load cases during both upward and downwardmotion. The γ value was found to be constant for full stator overlap and to decrease linearly witha decreasing overlap, as the translator moved towards the endstops. The decline varied with theexternal load case, as previously suggested but not shown. In addition, during partial stator overlap,a higher γ value was noted as the translator was leaving the stator, compared to when it was enteringthe stator. Finally, new insights were gained regarding how translator weight and generator dampingwill affect the translator downward motion during offshore operation. This is important for powerproduction and for avoiding damaging forces acting on the wave energy converter during operation.

    Emneord
    wave power, force measurement, line force, power take-off, damping
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-313254 (URN)10.3390/jmse4040081 (DOI)
    Merknad

    Liselotte Ulvgård and Linnea Sjökvist contributed equally to this work.

    Tilgjengelig fra: 2017-01-18 Laget: 2017-01-18 Sist oppdatert: 2017-09-21bibliografisk kontrollert
    8. Speed Dependent PTO Damping in a Linear Generator for Wave Power - Measured Damping and Simulated WEC Behaviour
    Åpne denne publikasjonen i ny fane eller vindu >>Speed Dependent PTO Damping in a Linear Generator for Wave Power - Measured Damping and Simulated WEC Behaviour
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328494 (URN)
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-09-21
    9. Experimental study of generator damping at partial stator overlap in a linear generator for wave power
    Åpne denne publikasjonen i ny fane eller vindu >>Experimental study of generator damping at partial stator overlap in a linear generator for wave power
    Vise andre…
    2017 (engelsk)Inngår i: 12th European Wave and Tidal Energy Conference Series, Cork, Ireland, 27 August - 1 September, 2017, 2017Konferansepaper, Oral presentation only (Fagfellevurdert)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328496 (URN)
    Konferanse
    EWTEC2017
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-09-21
    10. On the Optimization of Point Absorber Buoys
    Åpne denne publikasjonen i ny fane eller vindu >>On the Optimization of Point Absorber Buoys
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-218218 (URN)
    Tilgjengelig fra: 2014-02-10 Laget: 2014-02-10 Sist oppdatert: 2017-08-24bibliografisk kontrollert
    11. Calculating Buoy Response for a Wave Energy Converter - a Comparsion Between Two Computational Methods and Experimental Results
    Åpne denne publikasjonen i ny fane eller vindu >>Calculating Buoy Response for a Wave Energy Converter - a Comparsion Between Two Computational Methods and Experimental Results
    Vise andre…
    2017 (engelsk)Inngår i: Theoretical and Applied Mechanics Letters, ISSN 2095-0349Artikkel i tidsskrift (Fagfellevurdert) In press
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328498 (URN)10.1016/j.taml.2017.05.004 (DOI)
    Forskningsfinansiär
    Natural‐Disaster Science
    Tilgjengelig fra: 2017-08-24 Laget: 2017-08-24 Sist oppdatert: 2017-09-11
  • Disputas: 2017-10-20 10:15 Sal IX, Uppsala
    Lindberg Bromley, Sara
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för freds- och konfliktforskning.
    Keeping Peace while Under Fire: The Causes, Characteristics and Consequences of Violence against Peacekeepers2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Peacekeepers are widely viewed as being at growing risk of direct and deliberate violence. Attacks are recorded in many and diverse contexts, targeting interventions deployed by both the United Nations and other organisations. This dissertation seeks to advance the understanding of such violence, studying its causes, characteristics and consequences. The impact of deliberate violence against peacekeepers can be severe; it often extends past those immediately affected and impacts interveners’ ability to accomplish their aims. As a topic of scientific inquiry, however, violence against peacekeepers has only recently seen a growth in interest, and systematic study has so far been sparse. This dissertation makes a number of theoretical and empirical contributions to this emerging area of research. The dissertation contains four individual essays. To set the stage and provide foundations for further studies, Essay I specifies key concepts and maps the research field to date. It promotes a wider, and arguably more theoretically appropriate, conceptualisation of violence against peacekeepers than used in earlier studies. Essay II presents new, systematically collected event data on violence against UN and non-UN peacekeepers deployed to conflict-affected countries in sub-Saharan Africa between 1989 and 2009. Patterns from the data demonstrate that, while widely prevalent, violence against peacekeepers is not ubiquitous to peacekeeping and displays considerable variation within and across interventions. Drawing on this novel data, Essay III provides one of the first systematic studies on the time-varying determinants of rebel attacks on peacekeepers, showing its occurrence to be closely linked to rebel performance on the battlefield. Finally, Essay IV explores how operating in a challenging security environment can affect peacekeepers’ ability to perform core mission functions, drawing on the case of the UN Multidimensional Integrated Stabilization Mission in Mali (MINUSMA). The analysis illustrates how such an environment may expose and further constrain already limited capabilities and willingness for robust and armed action in UN peacekeeping operations. Taken together, the essays advance our understanding of the causes, characteristics and consequences of violence against peacekeepers.

    Delarbeid
    1. Violence against Peacekeepers: Key Concepts and Causes
    Åpne denne publikasjonen i ny fane eller vindu >>Violence against Peacekeepers: Key Concepts and Causes
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Freds- och konfliktforskning
    Identifikatorer
    urn:nbn:se:uu:diva-328647 (URN)
    Tilgjengelig fra: 2017-08-29 Laget: 2017-08-29 Sist oppdatert: 2017-08-31
    2. Introducing the UCDP Peacemakers at Risk Dataset, Sub-Saharan Africa 1989-2009
    Åpne denne publikasjonen i ny fane eller vindu >>Introducing the UCDP Peacemakers at Risk Dataset, Sub-Saharan Africa 1989-2009
    (engelsk)Inngår i: Journal of Peace Research, ISSN 0022-3433, E-ISSN 1460-3578Artikkel i tidsskrift (Fagfellevurdert) Accepted
    sted, utgiver, år, opplag, sider
    Sage Publications
    HSV kategori
    Forskningsprogram
    Freds- och konfliktforskning
    Identifikatorer
    urn:nbn:se:uu:diva-328672 (URN)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2017-08-29 Laget: 2017-08-29 Sist oppdatert: 2017-08-31
    3. Offsetting Losses: Bargaining Power and Rebel Attacks on Peacekeepers
    Åpne denne publikasjonen i ny fane eller vindu >>Offsetting Losses: Bargaining Power and Rebel Attacks on Peacekeepers
    2016 (engelsk)Inngår i: International Studies Quarterly, ISSN 0020-8833, E-ISSN 1468-2478, Vol. 60, nr 4, 611-623 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In recent years, international third parties have increasingly sought to manage the dire consequences of civil war, often by deploying peacekeeping operations. However, peacekeepers sometimes face deliberate attacks by armed groups. These attacks hamper efforts to provide humanitarian relief and security. This raises a critical question: what factors lead rebel groups to target peacekeepers? We argue that internal conflict dynamics are important for explaining this phenomenon. Rebels attack peacekeepers as an alternative strategy to undermine incumbent regimes. They adopt this strategy as the balance of power turns against them in their struggle against governments. We evaluate our argument using a novel event data set on violent attacks on peacekeepers in sub-Saharan Africa from 1989 to 2009. We find a positive relationship between rebel losses and violent attacks on peacekeepers. These findings hold when controlling for mission-specific characteristics, time-invariant unobserved heterogeneity, and across different model specifications.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-314273 (URN)10.1093/isq/sqw017 (DOI)000392925300003 ()
    Tilgjengelig fra: 2017-02-01 Laget: 2017-02-01 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    4. MINUSMA and Mali's Precarious Peace: Current-day United Nations Peacekeeping in Contexts of Insecurity
    Åpne denne publikasjonen i ny fane eller vindu >>MINUSMA and Mali's Precarious Peace: Current-day United Nations Peacekeeping in Contexts of Insecurity
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Freds- och konfliktforskning
    Identifikatorer
    urn:nbn:se:uu:diva-328671 (URN)
    Tilgjengelig fra: 2017-08-29 Laget: 2017-08-29 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-20 12:15 B/A1:111a, Uppsala
    Andersén, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Self-efficacy, Vocational Rehabilitation and Transition to Work2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The overall aim of this thesis was to examine the relationship between self-efficacy, individually tailored vocational rehabilitation and transition to work or studies.

    Study I was a cross-sectional study based on questionnaire- and registry data, investigating whether factors related to sick leave predict self-efficacy in women on long-term sick leave (n= 337) due to pain and/or mental illness. General self-efficacy was low. Anxiety and depression were the strongest predictors for low self-efficacy.

    Study II used longitudinal data from a randomised controlled trial, comprising partly the same women (n=401) as in Study I. Participants were allocated to either 1) assessment of multidisciplinary team and multimodal intervention (TEAM), 2) acceptance and commitment therapy (ACT), or 3) control group. Self-efficacy increased in the TEAM group in comparison with the control group.

    Study III had a descriptive qualitative design with individual interviews, studying participants’ (n=14) experiences with an individually tailored vocational rehabilitation project, and encounters with professionals working in it. The participants, who were on long-term sick leave due to mental illness or pain reported overall positive experiences with the project. The project was based on collaboration between authorities and motivational interviewing. The positive experiences were based on four categories: Opportunities for receiving various dimensions of support, Good overall treatment by the professionals, Satisfaction with the working methods of the project, and Opportunities for personal development.

    Study IV was a prospective cohort study investigating perceived self-efficacy in unemployed young adults (n= 249) aged 19-29 year with disabilities, and the association between self-efficacy and transition to work or studies. The study used questionnaire- and registry data from a vocational rehabilitation project. Higher levels of self-efficacy were associated with increased odds for ‘transition to work’. General self-efficacy was low, and young adults with lower self-efficacy reported worse self-rated health compared with those with higher self-efficacy.

    This thesis showed that multidisciplinary assessment with a multimodal intervention had positive effects on self-efficacy. Individually tailored vocational rehabilitation, based on cooperation and motivational interviewing, may be beneficial for individuals on long-term sick leave and the interactions between participants and the professionals may affect participants’ self-efficacy positively. Mental health needs to be considered when targeting self-efficacy in vocational rehabilitation. Furthermore, research is needed to a) clarify which components in the multidisciplinary team intervention can increase self-efficacy, b) study the effects of vocational rehabilitation based on an individual design, cooperation and motivational interviewing on self-efficacy, health and transition to work, and c) develop interventions that can increase self-efficacy and support transition to work/ studies in young adults with disabilities.

    Delarbeid
    1. Predictors of self-efficacy in women on long-term sick leave
    Åpne denne publikasjonen i ny fane eller vindu >>Predictors of self-efficacy in women on long-term sick leave
    Vise andre…
    2015 (engelsk)Inngår i: International Journal of Rehabilitation Research, ISSN 0342-5282, E-ISSN 1473-5660, Vol. 38, nr 4, 320-326 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Self-efficacy has been shown to be related to sick leave and to be a predictor of return to work after sickness absence. The aim of this study was to investigate whether factors related to sick leave predict self-efficacy in women on long-term sick leave because of pain and/or mental illness. This cross-sectional study uses baseline data from 337 Swedish women with pain and/or mental illness. All included women took part in vocational rehabilitation. Data were collected through a sick leave register and a baseline questionnaire. General self-efficacy, sociodemographics, self-rated health, anxiety, depression, view of the future, and social support were measured and analyzed by univariate and multivariate linear regression analyses. The full multivariate linear regression model, which included mental health factors together with all measured factors, showed that anxiety and depression were the only predictive factors of lower self-efficacy (adjusted R-2 = 0.46, P < 0.001) and explained 46% of the variance in self-efficacy. The mean scores of general self-efficacy were low, especially in women born abroad, those with low motivation, those with uncertainties about returning to work, and women reporting distrust. Anxiety and depression are important factors to consider when targeting self-efficacy in vocational rehabilitation.

    Emneord
    anxiety, depression, self-efficacy, sick leave, vocational rehabilitation, women
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-268763 (URN)10.1097/MRR.0000000000000129 (DOI)000364627800006 ()26258448 (PubMedID)
    Tilgjengelig fra: 2015-12-15 Laget: 2015-12-09 Sist oppdatert: 2017-08-31
    2. Strengthened general self-efficacy with multidisciplinary vocational rehabilitation in women on long-term sick leave: A randomised controlled trial
    Åpne denne publikasjonen i ny fane eller vindu >>Strengthened general self-efficacy with multidisciplinary vocational rehabilitation in women on long-term sick leave: A randomised controlled trial
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Purpose To investigate the effects of two vocational rehabilitation interventions on self-efficacy for women on long-term sick leave ≥1 year due to chronic pain and/or mental illness. Methods This study uses data from a randomised controlled trial consisting of two phases and comprising 401 women on long-term sick leave. They were allocated to either 1) assessment of a multidisciplinary team and a multimodal intervention (TEAM), 2) Acceptance and commitment therapy (ACT), or 3) a control group. Data were collected through repeated measurements from self-reported questionnaires before intervention, 6 and 12 months later and registry data. Data from measurements of general self-efficacy, sociodemographics, anxiety and depression were analysed with linear regression analyses. Results During the time for the intervention, the women in the TEAM group increased their self-efficacy mean value from 2.29 to 2.74. The adjusted linear regression model, which included group allocation, sociodemographics, self-efficacy pre-treatment, anxiety and depression showed that TEAM intervention increased self-efficacy at 12 months (B=0.25, 95% CI, 0.10 to 0.41). ACT intervention had no effect on self-efficacy at 12 months (B=0.02, 95% CI, -0.16 to 0.19). The results in the adjusted model also showed that higher self-efficacy at pre-treatment was associated with a higher level of self-efficacy at 12 months (B=0.68, 95% CI, 0.54 to 0.81). Conclusion This study implies that an assessment of a multidisciplinary team with a multimodal intervention almost normalised the level of self-efficacy in women on long-term sick leave. Self-efficacy needs to be taken into consideration in vocational rehabilitation.

    Emneord
    Sick leave • Vocational rehabilitation •Self-efficacy • Women • Multidisciplinary rehabilitation Chronic pain • Mental illness
    HSV kategori
    Forskningsprogram
    Socialmedicin
    Identifikatorer
    urn:nbn:se:uu:diva-328789 (URN)
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
    3. Positive experiences of a vocational rehabilitation intervention for individuals on long-term sick leave, the Dirigo project. A qualitative study
    Åpne denne publikasjonen i ny fane eller vindu >>Positive experiences of a vocational rehabilitation intervention for individuals on long-term sick leave, the Dirigo project. A qualitative study
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Background: The process of returning to work after long-term sick leave can sometimes be complex. Many factors, (e.g. cooperation between different authorities and the individual as well as individual factors such as health, emotional well-being and self-efficacy) may have an impact on an individual’s ability to work. The aim of this study was to investigate clients’ experiences with an individually tailored vocational rehabilitation, the Dirigo project, and encounters with professionals working on it. The Dirigo project was based on collaboration between rehabilitation authorities, individually tailored interventions and a motivational interviewing approach. 

    Methods: A descriptive qualitative design was used with data collected through interviews. Fourteen individuals on long-term sick leave took part in individual semi-structured interviews. The interviews were analysed using content analysis.

    Results: The analysis showed overall positive experience of methods and encounters with professionals in a vocational rehabilitation project. The positive experiences were based on four key factors: 1. Opportunities for receiving various dimensions of support.  2. Good overall treatment by the professionals. 3. Satisfaction with the working methods of the project, and 4. Opportunities for personal development.

    Conclusions: The main result showed that the clients had an overall positive experience of a vocational rehabilitation project and encounters with professionals who used motivational interviewing as a communication method. The overall positive experience indicated that their interactions with the different professionals may have affected their self-efficacy in general and in relation to transition to work. The knowledge is essential for the professionals working in the area of vocational rehabilitation. However, vocational rehabilitation interventions also need a societal approach to be able to offer clients opportunities for job training and real jobs.

    Emneord
    Sick leave, vocational rehabilitation, motivational interviewing, cooperation, return-to-work, qualitative study
    HSV kategori
    Forskningsprogram
    Socialmedicin
    Identifikatorer
    urn:nbn:se:uu:diva-328791 (URN)
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
    4. The relationship between self-efficacy and transition to work or studies in young adults with disabilities
    Åpne denne publikasjonen i ny fane eller vindu >>The relationship between self-efficacy and transition to work or studies in young adults with disabilities
    Vise andre…
    (engelsk)Inngår i: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905Artikkel i tidsskrift (Fagfellevurdert) Accepted
    Abstract [en]

    Abstract Aim: To investigate perceived self-efficacy in unemployed young adults with disabilities and the association between self-efficacy and transition to work or studies. Methods: This prospective cohort study collected data through self-report questionnaires and registry data from a vocational rehabilitation project with young adults, aged 19-29 years. The Swedish Social Insurance Agency, the Swedish Public Employment Service and the participating municipalities identified potential participants to the study. A total of 531 participants were included in the study, of which 249 (47%) were available for analysis. Multinomial logistic regression models were carried out to estimate the associations between self-efficacy, demographic, health and employment status. The latter was coded as: “no transition to work or studies”, “transition to studies”, and “transition to work”. Results: A higher level of self-efficacy was associated with increased odds for “transition to work” (OR=2.37, p<0.05). This finding remained consistent when adjusting for possible confounders. The mean value of self-efficacy was low, and participants with lower self-efficacy reported worse self-rated health (p<0.001) compared with participants with higher self-efficacy. Conclusions: The results from this study suggest that self-efficacy should be addressed in vocational rehabilitation of young adults with disabilities in order to support their transition and integration into the labour market.

    Emneord
    self-efficacy ∙ young adults ∙ disability ∙ employment
    HSV kategori
    Forskningsprogram
    Socialmedicin
    Identifikatorer
    urn:nbn:se:uu:diva-328794 (URN)
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-20 13:00 Häggsalen Ångströmlaboratoriet, Uppsala
    Sun, Fengzhen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad mekanik.
    Mechanical Properties and Deformation Behaviour of Polymer Materials during Nanosectioning: Characterisation and Modelling2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Research in local fracture processes and micro-machining of polymers and polymer-based composites has attracted increasing attention, in development of composite materials and miniaturisation of polymer components. In this thesis, sectioning (machining) of a glassy polymer and a carbon nanotube based composite at the nanoscale was performed by an instrumented ultramicrotome. The yield stresses and fracture toughness of these materials were determined by analysing the sectioning forces. Fractographic analysis by atomic force microscopy was conducted to characterise the topographies and elastic properties of the sectioned surfaces to explore the deformation and fracture behaviour of the polymer during nanosectioning. The study reveals that a transition from homogenous to shear localised deformation occurred as the uncut chip thickness (depth of cut) or sectioning speed increased to a critical value. Analytical and finite element methods were used to model the nanosectioning process. The shear localised deformation was caused by thermal softening due to plastic dissipation. Although not considering sectioning, the tensile properties of a polymer nanocomposite were additionally investigated, where the degree of nanofibrillation and polyethylene glycol (PEG) content had significant effects.

    Delarbeid
    1. Polymer fracture and deformation during nanosectioning in an ultramicrotome
    Åpne denne publikasjonen i ny fane eller vindu >>Polymer fracture and deformation during nanosectioning in an ultramicrotome
    2017 (engelsk)Inngår i: Engineering Fracture Mechanics, ISSN 0013-7944, E-ISSN 1873-7315, Vol. 182, 595-606 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The fracture and deformation behaviour of a thermoplastic in the nanosectioning process is investigated by using an ultramicrotome instrumented with force transducers. For sections with thickness values in the order of 10–100 nm, the specific work of surface formation of polymethyl methacrylate is found to be 6.3 J m−2, which is considerably smaller to macroscopic fracture toughness, but relatively close to the theoretical specific surface energy of 1.5 J m−2 of breaking the covalent bonds. Periodic transverse features, spaced a few hundred nanometres on the sectioned surfaces, are observed by atomic force microscopy for sections above a critical thickness. It reveals that a transition of the deformation mode occurs at a certain thickness, which is in concert with sectioning experiments for other materials showing adiabatic shear bands.

    Emneord
    NanosectioningFractureLocalized deformationPeriodic featuresAdiabatic shearing
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328893 (URN)10.1016/j.engfracmech.2017.05.044 (DOI)
    Tilgjengelig fra: 2017-09-04 Laget: 2017-09-04 Sist oppdatert: 2017-09-04
    2. Rate effects on localized shear deformation during nanosectioning of an amorphous thermoplastic polymer
    Åpne denne publikasjonen i ny fane eller vindu >>Rate effects on localized shear deformation during nanosectioning of an amorphous thermoplastic polymer
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    To investigate the effects of loading rate on the thermomechanical behavior of thermoplastic polymer, polymethyl methacrylate (PMMA) sections with a thickness below 100 nm were made at different sectioning speeds by an instrumented ultramicrotome and the sectioning forces were measured. Atomic force microscopy was used to characterize the topographical features of the sectioned surfaces. Periodic structures of shear localizations were observed to form when the sectioning speed exceeded a critical value. With the measured sectioning parameters and other parameters determined based on previous studies, the effects of sectioning speed on the thermomechanical response of this polymer were analyzed using an existing adiabatic shearing model and a suitable constitutive law. A sectioning speed for the onset of shear localization was predicted, agreeing with the experimental results. The method presented in this work provides an approach to analyze the formation of shear localizations in polymers at the nanometer scale deformation. 

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328887 (URN)
    Tilgjengelig fra: 2017-09-04 Laget: 2017-09-04 Sist oppdatert: 2017-09-04
    3. Effect of nanosectioning on surface features and stiffness of an amorphous glassy polymer
    Åpne denne publikasjonen i ny fane eller vindu >>Effect of nanosectioning on surface features and stiffness of an amorphous glassy polymer
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    Sectioning of a glassy polymer, poly(methyl methacrylate), at the nanoscale was carried out by means of an ultramicrotome. The effects of sectioning thickness and speed on the topography and stiffness over the surface were then investigated by atomic force microscopy. A critical section thickness and speed were identified, below which a flat and smooth cut surfaces were created, with homogeneous elasticity. Above the critical thickness or speed, localized periodic bands were formed on the sectioned surfaces oriented perpendicular to the cutting direction with a nonhomogeneous distribution of the mapped elasticity. Finite-element simulations based on a constitutive model of the polymer reproduced the periodic shear bands observed in the experiments. The influence of sectioning speed on the elastic modulus was predicted by a damage mechanics model and was found to correlate with results obtained by atomic force microscopy. The results lend confidence that critical machining conditions, such as sectioning thickness and speed, can be predicted to avoid undesirable shear localizations and damage formation in manufacture of e.g. small scale optical and photonic applications. 

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328888 (URN)
    Tilgjengelig fra: 2017-09-04 Laget: 2017-09-04 Sist oppdatert: 2017-09-04
    4. Finite element modeling of nanosectioning of a glassy polymer based on an elastic-viscoplastic model
    Åpne denne publikasjonen i ny fane eller vindu >>Finite element modeling of nanosectioning of a glassy polymer based on an elastic-viscoplastic model
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Finite element modelling of nanosectioning of poly(methyl methacrylate) (PMMA) is conducted in this work. The modified Mulliken-Boyce model including adiabatic heating was used to depict the elastic-viscoplastic behavior of PMMA during nanosectioning. The simulated results were compared with the experimental results obtained by ultramicrotome nanosectioning. The simulation can capture the basic features of the shear bands formed during nanosectioning, which indicates that the adiabatic heating play a important role in controlling the chip formation. 

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328889 (URN)
    Tilgjengelig fra: 2017-09-04 Laget: 2017-09-04 Sist oppdatert: 2017-09-04
    5. Assessing local yield stress and fracture toughness of carbon nanotube poly(methyl methacrylate) composite by nanosectioning
    Åpne denne publikasjonen i ny fane eller vindu >>Assessing local yield stress and fracture toughness of carbon nanotube poly(methyl methacrylate) composite by nanosectioning
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    A nanosectioning (cutting) method was used to test the local shear yield stress and fracture toughness of multiwall carbon nanotube (MWCNT) poly(methyl methacrylate) (PMMA) composites, and the effect of MWCNT content on the stress and toughness were investigated. The composites were prepared by a solution casting method, with MWCNT content varying from 0.05-1.0 wt%. A critical MWCNT content was found at 0.1 wt%; below such a critical content the shear yield stress increases by the incorporation of MWCNTs, while above this content the yield stress reduces. The fracture toughness of the composite was effectively enhanced by the addition of MWCNTs, from 17 J/m2 for the neat PMMA to 25 J/m2 for the 1.0 wt% composite. The shear yield stresses obtained by nanosectioning were correlated to nanoindentation measurement, and possible contributions from the MWCNTs to the fracture toughness of the composite were analysed.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328890 (URN)
    Tilgjengelig fra: 2017-09-04 Laget: 2017-09-04 Sist oppdatert: 2017-09-04
    6. Mechanical characteristics of nanocellulose-PEG bionanocomposite wound dressings in wet conditions
    Åpne denne publikasjonen i ny fane eller vindu >>Mechanical characteristics of nanocellulose-PEG bionanocomposite wound dressings in wet conditions
    Vise andre…
    2017 (engelsk)Inngår i: Journal of The Mechanical Behavior of Biomedical Materials, ISSN 1751-6161, E-ISSN 1878-0180, Vol. 69, 377-384 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Wood nanocellulose has been proposed for wound dressing applications partly based on its capability to form translucent films with good liquid absorption capabilities. Such properties are adequate for non-healing and chronic wounds where adequate management of exudates is a requirement. In addition, the translucency will allow to follow the wound development without the necessity to remove the dressing from the wound. Understanding the mechanical properties of nanocellulose films and dressings are also most important for tailoring optimizing wound dressing structures with adequate strength, conformability, porosity and exudate management. Mechanical properties are usually assessed in standard conditions (50% relative humidity, RH), which is not relevant in a wound management situation. In this study we have assessed the mechanical properties of three nanocellulose grades varying in the degree of nanofibrillation. The effect of nanofibrillation and of polyethylene glycol (PEG) addition, on the tensile strength, elongation and elastic modulus were assessed after 24 h in water and in phosphate-buffered saline (PBS). The results reveal the behavior of the nanocellulose dressings after wetting and shed light into the development of mechanical properties in environments, which are relevant from a wound management point of view.

    Emneord
    CNF, Nanocellulose, Bionanocomposites, Plasticizer, Mechanical properties
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-323443 (URN)10.1016/j.jmbbm.2017.01.049 (DOI)000400199600041 ()28171794 (PubMedID)
    Tilgjengelig fra: 2017-07-06 Laget: 2017-07-06 Sist oppdatert: 2017-09-04bibliografisk kontrollert
  • Disputas: 2017-10-20 13:15 A1:107, Uppsala
    Emanuelsson, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Steroids and steroid-metabolizing enzymes in the nervous system: Special focus on cell survival and sex hormone synthesis2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Some steroids in the brain and peripheral nervous system have been shown to have neuroprotective effects but the knowledge is limited. The present study examines the effects of steroids including oxysterols, vitamin D and vitamin D analogs on cell viability/growth and steroidogenesis in the nervous system.

    Both 24- and 27-hydroxycholesterol reduced staurosporine-induced toxicity in human neuroblastoma SH-SY5Y cells. In addition, 27-hydroxycholesterol decreased the staurosporine-mediated induction of caspases, known to be important in apoptotic events. From the findings it may be concluded that effects of oxysterols on cellular viability are dependent on the concentration and on the type of oxysterol. 24-Hydroxycholesterol was also found to attenuate oxidative stress both in SH-SY5Y cells and astrocytes. The results indicate that during some conditions, oxysterols may have neuroprotective effects.

    The vitamin D analogs tacalcitol and calcipotriol strongly reduced proliferation, cell viability and migration of human glioblastoma T98G cells, similarly as 1,25(OH)2D3 , the physiological form of vitamin D. Glioblastoma is the most lethal type of primary tumors in the CNS. These findings suggest that vitamin D analogs are potential candidates in treatment of brain tumors, most likely in combination with other therapies.

    Astrocytes were found to be a major site for expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) whereas expression of CYP17A1 was found in both astrocytes and neurons. 3β-HSD and CYP17A1 are important steroidogenic enzymes. Vitamin D inhibited both CYP17A1- and 3β-HSD -mediated activity and mRNA levels, with a stronger effect on mRNA expression than on enzyme activity. This indicates that 1,25(OH)2D3 could affect the production of sex hormones in the brain.

    In summary, results from this thesis contribute to the knowledge on the effects of oxysterols on cell viability and oxidative stress in cells from the CNS. Also the results provide data on the effects of vitamin D in the brain and suggest that vitamin D analogs may be promising candidates for treatment of certain brain tumors.

    Delarbeid
    1. Protective effects of 27-and 24-hydroxycholesterol against staurosporine-induced cell death in undifferentiated neuroblastoma SH-SY5Y cells
    Åpne denne publikasjonen i ny fane eller vindu >>Protective effects of 27-and 24-hydroxycholesterol against staurosporine-induced cell death in undifferentiated neuroblastoma SH-SY5Y cells
    2012 (engelsk)Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 525, nr 1, 44-48 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Alterations in cholesterol metabolism have been linked to several neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis and Parkinson's disease. Brain cholesterol is metabolized to the oxysterols 24-hydroxycholesterol and 27-hydroxycholesterol. Disturbed levels of these oxysterols are found in neurodegenerative conditions. In the current study we examined the effects of 27- and 24-hydroxycholesterol on viability of human neuroblastoma SH-SY5Y cells treated with staurosporine, a toxic substance that induces apoptosis. Analyses using MTT assay and measurement of lactate dehydrogenase release showed that presence of 27-hydroxycholesterol counteracted the toxic effects of staurosporine on these cells. Also, 27-hydroxycholesterol significantly decreased the staurosporine-mediated induction of caspase-3 and -7, known to be important in apoptotic events. 24-Hydroxycholesterol had similar effects on viability as 27-hydroxycholesterol in low concentrations, although in higher concentrations this oxysterol exacerbated the toxic effects of staurosporine. From these findings it may be concluded that effects of oxysterols on cellular viability are strongly dependent on the concentration and on the type of oxysterol. Previous studies on oxysterols have reported that these compounds are pro-apoptotic or trigger pathological changes that result in neurodegeneration. The present data indicate that, during some conditions, oxysterols may have neuroprotective effects.

    Emneord
    Oxysterol, Cholesterol metabolism, Cell viability, Neuroprotection, Neurodegeneration, Apoptosis
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-183219 (URN)10.1016/j.neulet.2012.07.057 (DOI)000308520900009 ()
    Tilgjengelig fra: 2012-10-26 Laget: 2012-10-23 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    2. Vitamin D analogs tacalcitol and calcipotriol inhibit proliferation and migration of T98G human glioblastoma cells
    Åpne denne publikasjonen i ny fane eller vindu >>Vitamin D analogs tacalcitol and calcipotriol inhibit proliferation and migration of T98G human glioblastoma cells
    2017 (engelsk)Inngår i: Neuroscience, ISSN 0306-4522Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Forskningsprogram
    Biokemi
    Identifikatorer
    urn:nbn:se:uu:diva-328769 (URN)
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
    3. Expression and regulation of CYP17A1 and 3β-hydroxysteroiddehydrogenase in cells of the nervous system: potential effects of vitamin D on brain steroidogenesis
    Åpne denne publikasjonen i ny fane eller vindu >>Expression and regulation of CYP17A1 and 3β-hydroxysteroiddehydrogenase in cells of the nervous system: potential effects of vitamin D on brain steroidogenesis
    Vise andre…
    2017 (engelsk)Inngår i: Neurochemistry International, ISSN 0197-0186Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Forskningsprogram
    Biokemi
    Identifikatorer
    urn:nbn:se:uu:diva-328770 (URN)
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
    4. Effects of 24-hydroxycholesterol on oxidative stress in human neuroblastoma SH-SY5Y cells and primary rat astrocytes
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of 24-hydroxycholesterol on oxidative stress in human neuroblastoma SH-SY5Y cells and primary rat astrocytes
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Biokemi
    Identifikatorer
    urn:nbn:se:uu:diva-328776 (URN)
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-20 13:15 Vårdskolans aula, Västerås
    Olofsdotter, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Anxiety among Adolescents: Measurement, Clinical Characteristics, and Influences of Parenting and Genetics2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Anxiety is the most commonly reported mental health problem among adolescents. Still, many adolescents in need of treatment are not detected and the clinical characteristics and etiological pathways of adolescent anxiety are under-researched topics. This thesis examined the clinical utility of the Swedish versions of the Spence Children’s Anxiety Scale (SCAS) and the clinical characteristics of multiple anxiety disorders among psychiatrically referred adolescents, and the influence of parenting and oxytocin gene (OXT) variants on anxiety among adolescents in the general population.  Studies employed cross-sectional and longitudinal designs and were based on questionnaire, interview, and genotype data.

    Support for the reliability and validity of both SCAS and SCAS-P was obtained. The overall ability to predict anxiety among referred adolescents ranged from fair to excellent for both scales. 

    Among adolescents psychiatrically referred for any reason, the prevalence of any anxiety disorder was 46%. Homotypic comorbidity was observed in 43%, and heterotypic comorbidity in 91%.

    Early adolescent anxiety influenced homotypic anxiety in late adolescence independent of parental rejection and control. The mediating role of parenting was small with indirect effect sizes no larger than one-tenth the size of direct effects, irrespective of the informant on parenting behavior.

    Significant interaction effects with positive and negative parenting were observed for OXT variants rs4813625 and rs2770378 in relation to social anxiety. The nature of the interactions was in line with the differential susceptibility framework for rs4813625, whereas for rs2770378, results indicated a diathesis–stress type of interaction.

    The findings suggest that psychiatrically referred adolescents with anxiety disorders are best characterized as a highly complex patient group and call attention to the necessity of structured assessment. For this purpose, this thesis provides evidence for the clinical utility of the SCAS; routine utilization of this questionnaire can improve detection of adolescents in need of anxiety treatment. Findings of this theses further suggest that the influence of positive and negative parenting behaviors on anxiety may be of greater importance among some adolescents than others, depending on individual differences in sensitivity to parenting. The etiology of anxiety among adolescents may therefore involve differential susceptibility effects of the interplay between genes and parenting behaviors.

    Delarbeid
    1. Assessing Adolescent Anxiety in General Psychiatric Care: Diagnostic Accuracy of the Swedish Self-Report and Parent Versions of the Spence Children's Anxiety Scale
    Åpne denne publikasjonen i ny fane eller vindu >>Assessing Adolescent Anxiety in General Psychiatric Care: Diagnostic Accuracy of the Swedish Self-Report and Parent Versions of the Spence Children's Anxiety Scale
    Vise andre…
    2016 (engelsk)Inngår i: Assessment (Odessa, Fla.), ISSN 1073-1911, E-ISSN 1552-3489, Vol. 23, nr 6, 744-757 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    This study examined the psychometric properties and diagnostic accuracy of the Swedish translations of the Spence Children's Anxiety Scale, self- and parent report versions, in a sample of 104 adolescents presenting at two general psychiatric outpatient units. Results showed high informant agreement and good internal reliability and concurrent and discriminant validity for both versions and demonstrated that this scale can distinguish between adolescents with and without an anxiety disorder in a non-anxiety-specific clinical setting. The relative clinical utility of different cutoff scores was compared by looking at the extent to which dichotomized questionnaire results altered the pretest probability of the presence of a diagnosis as defined by the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Optimized for screening and diagnostic purposes in Sweden, cutoff scores obtained in the current study outperformed a previously identified cutoff score derived from an Australian community sample. The Spence Children's Anxiety Scale is a useful clinical instrument for the assessment of anxiety in adolescents.

    Emneord
    anxiety disorders, adolescents, Spence Children's Anxiety Scale, test validity, diagnostic accuracy
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-252419 (URN)10.1177/1073191115583858 (DOI)000388676500008 ()25934162 (PubMedID)
    Tilgjengelig fra: 2015-05-06 Laget: 2015-05-06 Sist oppdatert: 2017-08-14bibliografisk kontrollert
    2. Anxiety disorders among adolescents referred to general psychiatry for multiple causes: clinical presentation, prevalence, and comorbidity
    Åpne denne publikasjonen i ny fane eller vindu >>Anxiety disorders among adolescents referred to general psychiatry for multiple causes: clinical presentation, prevalence, and comorbidity
    Vise andre…
    2016 (engelsk)Inngår i: Scandinavian Journal of Child and Adolescent Psychiatry and Psychology, E-ISSN 2245-8875, Vol. 4, nr 2, 55-64 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Reports of anxiety disorder characteristics among youth in clinical settings typically include descriptions of patients who have been specifically referred for anxiety treatment. At odds with a large body of evidence which demonstrates these disorders to be most common among young people, prevalence studies in samples referred to general psychiatry for multiple causes are scarce and report highly discrepant estimates.

    For this study and regardless of their presenting symptoms, 125 adolescents (57.6% girls) between the ages of 12 and 18 years who were consecutively referred to two child and adolescent general psychiatry clinics in Sweden were assessed for anxiety disorders and comorbidity using the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Self-ratings of anxiety symptoms and difficulties with family, school, friends, sleep, and body aches were also obtained.

    At least one anxiety disorder was found in 46% of participants. Among anxious adolescents, homotypic comorbidity (concurrent anxiety) was observed in 43%, and heterotypic comorbidity (concurrent non-anxiety psychiatric disorders) was observed in 91%. No comorbidity was observed in 5%. Trauma, ache, and difficulties making friends were more common among anxious adolescents as compared with psychiatrically referred adolescents without anxiety.

    The finding that only 21% of adolescents diagnosed with anxiety disorders were referred for anxiety further supports the routine use of standardized and structured instruments—irrespective of referral cause—to improve both precision and detection rates in the clinical setting. Comprehensive assessments are of utmost importance to fully address the complexity of the symptoms in this patient group.

    HSV kategori
    Forskningsprogram
    Barn- och ungdomspsykiatri
    Identifikatorer
    urn:nbn:se:uu:diva-323571 (URN)10.21307/sjcapp-2016-010 (DOI)
    Tilgjengelig fra: 2017-06-08 Laget: 2017-06-08 Sist oppdatert: 2017-08-14bibliografisk kontrollert
    3. The mediating role of parenting behaviors in the relationship between early and late adolescent levels of anxiety: specificity and informant effects
    Åpne denne publikasjonen i ny fane eller vindu >>The mediating role of parenting behaviors in the relationship between early and late adolescent levels of anxiety: specificity and informant effects
    (engelsk)Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    HSV kategori
    Forskningsprogram
    Barn- och ungdomspsykiatri
    Identifikatorer
    urn:nbn:se:uu:diva-323576 (URN)
    Tilgjengelig fra: 2017-06-08 Laget: 2017-06-08 Sist oppdatert: 2017-08-14
    4. Differential susceptibility effects of oxytocin gene (OXT)polymorphisms and perceived parenting on social anxiety among adolescents
    Åpne denne publikasjonen i ny fane eller vindu >>Differential susceptibility effects of oxytocin gene (OXT)polymorphisms and perceived parenting on social anxiety among adolescents
    Vise andre…
    (engelsk)Inngår i: Development and psychopathology (Print), ISSN 0954-5794, E-ISSN 1469-2198Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
    sted, utgiver, år, opplag, sider
    New York:
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-323574 (URN)10.1017/S0954579417000967 (DOI)
    Tilgjengelig fra: 2017-06-08 Laget: 2017-06-08 Sist oppdatert: 2017-08-14
  • Disputas: 2017-10-20 13:30 B21, Uppsala
    Sollert, Carina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    New Arylation Strategies Based on Organomain Group Reactivity2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The work in this thesis describes the development of new heteroarylation methodology based on transition metal-catalysed C-H functionalisation and the properties of organomain group compounds. The underlying reaction mechanisms and reactivity patterns of the (hetero)arene substrates are also investigated. The selective C2-H arylation indoles, which are key pharmaceutically-relevant units, was achieved using N-pyrimidyl directing groups, RuII catalysis and arylboronic acids as the coupling reagents (paper I). The use of this set of conditions enabled a remarkable functional group tolerance, highlighted by the preservation of halide substituents on both coupling partners. Mechanistic experiments suggest that cleavage of the C2-H bond occurs through an electrophilic aromatic substitution type pathway. The dehydrogenative C2-H silylation of unprotected gramine and tryptamine alkaloids and other related heteroarenes using hydrosilanes under Ru0 catalysis is described in paper II. The protocol does not require protecting groups and undirected C2-H silylation of heteroarenes is possible at higher temperatures. Significantly, H/D-exchange studies revealed deuterium incorporation at the C4 and C7 positions of the indole unit, apart from C2-H silylation. This study represents the first account of C4-H activation using an electron-rich metal catalyst. Paper III describes an unexpected and profound influence of boronate substituents on the regioselectivity of aryne trapping reactions. The boronates may be introduced easily to the backbone of established fluoride-activated precursors via Ir-catalysed C-H functionalisation. Optimisation and mechanistic studies on the unprecedented level of regioselectivity control these substituents permit using external additives is presented.

    Delarbeid
    1. Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
    Åpne denne publikasjonen i ny fane eller vindu >>Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
    Vise andre…
    2015 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 14, 5380-5386 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The Ru-catalysed C2-H arylation of indoles and pyrroles by using boronic acids under oxidative conditions is reported. This reaction can be applied to tryptophan derivatives and tolerates a wide range of functional groups on both coupling partners, including bromides and iodides, which can be further derivatised selectively. New indole based ruthenacyclic complexes are described and investigated as possible intermediates in the reaction. Mechanistic studies suggest the on-cycle intermediates do not possess a para-cymene ligand and that the on-cycle metalation occurs through an electrophilic attack by the Ru centre.

    Emneord
    catalysis, C-H activation, heterocycles, reaction mechanisms, ruthenium
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-252711 (URN)10.1002/chem.201405931 (DOI)000352504500017 ()25689052 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2015-05-18 Laget: 2015-05-11 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    2. Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners
    Åpne denne publikasjonen i ny fane eller vindu >>Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners
    2016 (engelsk)Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, nr 34, 5868-5871 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Selective Ru-catalysed C2–H silylation of heteroarenes is presented. The transformation works with or without directing group assistance and requires no protecting groups. Gramines and tryptamines may be converted efficiently whilst avoiding deleterious elimination side-reactions. Mechanistic studies reveal an unusual activation of the indole C4–H bond by an electron-rich metal.

    sted, utgiver, år, opplag, sider
    Royal Society of Chemistry, 2016
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-286545 (URN)10.1039/C6CC00803H (DOI)000374396500022 ()27050747 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2016-04-20 Laget: 2016-04-20 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    3. Distal Fluoroboronate Substituents for Remote Control of Aryne Distortion and Regioselectivity
    Åpne denne publikasjonen i ny fane eller vindu >>Distal Fluoroboronate Substituents for Remote Control of Aryne Distortion and Regioselectivity
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328748 (URN)
    Tilgjengelig fra: 2017-08-30 Laget: 2017-08-30 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-21 13:00 Auditorium Minus, Uppsala
    Högberg, Dominika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Screening for asymptomatic carotid atherosclerosis2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ischemic stroke is the most common cause of handicap in adults and the third most common cause of death in Sweden. Internal carotid artery atherosclerosis is an important cause and accounts for 20% of ischemic strokes. Screening for carotid atherosclerosis has been debated over the past two decades.

    The aims of this thesis were (I) to study the prevalence of and risk factors associated with carotid artery atherosclerosis among 65 year old men, (II) to evaluate a simplified ultrasound protocol (the grayscale/mosaic method) for the exclusion of significant carotid artery stenosis for screening purpose, (III) to evaluate the required effect of primary preventive therapy in reducing risk of stroke among patients with asymptomatic carotid disease in order for screening to be cost-effective and (IV) to study natural history of carotid atherosclerosis and outcome five years after screening in 65-year old men.

    The prevalence of atherosclerotic plaques was high (25%), while the prevalence of >50% stenosis was relatively low (2.0%). Smoking, hypertension, diabetes mellitus and coronary artery disease were independent risk factors and individuals with several risk factors had a higher prevalence of stenosis. Most of those at risk were not on any preventive medication. A simplified grayscale/mosaic method was found to have a high negative predictive value for significant carotid stenosis. The minimum stroke risk reduction effect required for preventive intervention to be cost effective was 22%. Carotid atherosclerotic plaque and stenosis 50-79% has a relatively benign development during five years if treated with BMT and risk factor adjustment. Very few progressed to symptomatic disease. More severe stenosis (80-99%) had higher rate of neurological events, and may benefit from additional intervention.

    In conclusion, prevalence of silent atherosclerotic disease in carotid arteries was common among 65-year-old men. Most of those at risk had no secondary prevention. There is a simple DUS method that could be used for screening purpose. Screening for carotid disease is only cost-effective if the preventive strategy lowers the risk of stroke by 22%. Men with plaques and moderate stenosis have a good prognosis, but among those with severe stenosis there is a need for further intervention.

    Delarbeid
    1. Carotid Artery Atherosclerosis Among 65-year-old Swedish Men: A Population-based Screening Study
    Åpne denne publikasjonen i ny fane eller vindu >>Carotid Artery Atherosclerosis Among 65-year-old Swedish Men: A Population-based Screening Study
    Vise andre…
    2014 (engelsk)Inngår i: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 48, nr 1, 5-10 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective: There are limited contemporary epidemiological data on the prevalence of carotid atherosclerosis in the general population. The aim was to determine the prevalence of and risk factors associated with carotid artery atherosclerosis among 65-year-old men. Methods: This was a population-based screening study. All 65-year-old men in the County of Uppsala, Sweden, who attended screehing for abdominal aortic aneurysm (AAA) 2007-2009, were invited for duplex scanning of the carotid arteries. Results: Of 4801 men invited, 4657 (97%) accepted. Carotid plaques (>2 x 6 mm) were observed in 1169 (25%) men, 94 (2.0%) had carotid stenoses (50-99%), and 15 (0.3%) had occluded carotid arteries. In a multivariate logistic regression model, smoking (OR 1.7, 95% CI 1.5-1.9), hypertension (1.5, 95% CI 1.3-1.7), diabetes mellitus (1.2, 95% CI 1.0-1.5), and coronary artery disease (1.5, 95% CI 1.3-1.8) were associated with prevalence of carotid atherosclerosis (plaque and/or stenosis). The use of antiplatelet agents and statins in participants with a carotid plaque was 20% and 29%, respectively. The corresponding figures in participants with a stenosis were 42% and 41%. Conclusions: This study offers contemporary data on the prevalence of carotid atherosclerosis in a population-based cohort of 65-year-old men. Most of those at risk had no other clinical manifestation of atherosclerosis, and therefore had no secondary prevention.

    Emneord
    Carotid stenosis, Atherosclerotic plaque, Prevalence, Screening
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-229726 (URN)10.1016/j.ejvs.2014.02.004 (DOI)000338820900003 ()24631197 (PubMedID)
    Tilgjengelig fra: 2014-08-16 Laget: 2014-08-12 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    2. Simplified ultrasound protocol for the exclusion of clinically significant carotid artery stenosis
    Åpne denne publikasjonen i ny fane eller vindu >>Simplified ultrasound protocol for the exclusion of clinically significant carotid artery stenosis
    Vise andre…
    2016 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, nr 3, 165-169 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objectives: To evaluate a simplified ultrasound protocol for the exclusion of clinically significant carotid artery stenosis for screening purposes. Material and methods: A total of 9,493 carotid arteries in 4,748 persons underwent carotid ultrasound examination. Most subjects were 65-year-old men attending screening for abdominal aortic aneurysm. The presence of a stenosis on B-mode and/or a mosaic pattern in post-stenotic areas on colour Doppler and maximum peak systolic velocity (PSV) in the internal carotid artery (ICA) were recorded. A carotid stenosis was defined as The North American Symptomatic Carotid Endarterectomy Trial (NASCET) >20% and a significant stenosis as NASCET >50%. The kappa (kappa) statistic was used to assess agreement between methods. Sensitivity, specificity, positive predictive (PPV), and negative predictive (NPV) values were calculated for the greyscale/mosaic method compared to conventional assessment by means of PSV measurement. Results: An ICA stenosis was found in 121 (1.3%) arteries; 82 (0.9%) were graded 20%-49%, 16 (0.2%) were 50%-69%, and 23 (0.2%) were 70%-99%. Eighteen (0.2%) arteries were occluded. Overall, the greyscale/mosaic protocol showed a moderate agreement with ICA PSV measurements for the detection of carotid artery stenosis, x=0.455. The sensitivity, specificity, PPV, and NPV for detection of >20% ICA stenosis were 91% (95% CI 0.84-0.95), 97% (0.97-0.98), 31% (0.26-0.36), and 97% (0.97-0.97), respectively. The corresponding figures for >50% stenosis were 90% (0.83-0.95), 97% (0.97-0.98), 11% (0.08-0.15), and 100% (0.99-1.00). Conclusion: Compared with PSV measurements, the simplified greyscale/mosaic protocol had a high negative predictive value for detection of >50% carotid stenosis, suggesting that it may be suitable as a screening method to exclude significant disease.

    Emneord
    Carotid stenosis, screening, ultrasound
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-304440 (URN)10.1080/03009734.2016.1201177 (DOI)000381958400002 ()27379448 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, K2013-64X-20406-07-3
    Tilgjengelig fra: 2016-10-05 Laget: 2016-10-05 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    3. Clinical effect and cost effectiveness of screening for asymptomatic carotid stenosis – A Markov model
    Åpne denne publikasjonen i ny fane eller vindu >>Clinical effect and cost effectiveness of screening for asymptomatic carotid stenosis – A Markov model
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objectives:   Screening for asymptomatic carotid artery stenosis (ACAS) is controversial. The cost-effectiveness of screening depends on screening cost, ACAS prevalence, and the potential stroke reducing effect of best medical treatment (BMT). The aim of the study was to determine the threshold values for these parameters in order for screening for ACAS to be cost-effective.

    Material and methods: The clinical effect and cost-effectiveness of ultrasound-screening for ACAS with subsequent initiation of BMT versus not screening, was assessed in a Markov model with a life-time perspective. Key parameters; including stroke risk, all-cause mortality, and costs were based on contemporary published data, population statistics and ongoing screening programs. Prevalence of ACAS and rate of ongoing BMT was based on data from a population recently screened for ACAS. Minimum required stroke-risk reduction from BMT, incremental cost-efficiency ratio (ICER), absolute risk reduction for stroke (ARR), number needed to screen (NNS) were calculated. 

    Results: Screening was cost-effective at an ICER of €5744 per incremental quality adjusted life-year (QALY) gained. ARR was 135 per 100000 screened, NNS was 741 and QALYs gained were 6700 per 100000 invited. At a willingness-to-pay (WTP) threshold of €50,000 per QALY the minimum required stroke risk reduction from BMT was 22%. The assumed degree of stroke risk reduction was the most important determinant of cost-efficiency.  

    Conclusion: A moderate (22%) reduction in the risk of stroke from BMT was required for an ACAS screening strategy to be cost-effective at WTP of €50,000/QALY. Targeting populations with higher prevalence of ACAS could improve cost-efficiency.

    Emneord
    cost-eefectiveness, carotid stenosis, screening, preventive treatment
    HSV kategori
    Forskningsprogram
    Kirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-328785 (URN)
    Prosjekter
    Screening for asymptomatic carotid atherosclerosis
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
    4. Five-year outcomes in men screened for carotid artery stenosis at 65 years of age - a population-based cohort study.
    Åpne denne publikasjonen i ny fane eller vindu >>Five-year outcomes in men screened for carotid artery stenosis at 65 years of age - a population-based cohort study.
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objectives: The aim was to determine the prognosis of 65-year old men five years after carotid ultrasound screening, as well as risk factors for disease progression.

    Material and methods: All 65-year-old men living in the county of Uppsala 2007-2009 were invited to an ultrasound examination of both carotid arteries and re-invited at age 70. The cohort was grouped into: normal carotids, plaque without significant stenosis, moderate stenosis (50-79%), and severe stenosis (80-99%). The rates of disease progression to death, significant stenosis, and neurological events were assessed, as well as risk factors and medication.

    Results: Among men participating in carotid screening at age 65, 3057 were re-screened at age 70. In those with normal carotids (n=2318), 23 (1.0%) progressed to a moderate, and four (0.2%) developed a symptomatic severe stenosis. Among those with plaque (n=696), 25 (3.6%) progressed to moderate, and eight (1.1%) to severe stenosis, of whom four (0.6%) had symptoms. Of 31 with 50-79% stenosis, four (12.9%) had progressed to a severe stenosis, of whom two (6.5%) developed symptoms. Five of twelve subjects (42%) with 80-99% stenosis developed symptoms. Disease regression was present among 306 (41.4%) men. In multivariable analysis, smoking, coronary artery disease and hypercholesterolemia were associated with disease progression. The proportions of antiplatelet, statin and antihypertensive treatment in the population at age 70 were 22%, 29% and 55% respectively.

    Conclusion: Men with plaques and moderate stenosis have a good prognosis, but in those with severe stenosis there was a high risk of neurological events.

    Emneord
    carotid stenosis, atherosclerotic plaque, natural history, mortality, stroke rate
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328800 (URN)
    Prosjekter
    Screening for carotid atherosclerosis
    Tilgjengelig fra: 2017-08-31 Laget: 2017-08-31 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-23 09:00 Seminarierum klinisk neurofysiologi, Uppsala
    Salah, Heba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Critical care has undergone several developments in the recent years leading to improved survival. However, acquired muscle weakness in the intensive care unit (ICU) is an important complication that affects severely ill patients and can prolong their ICU stay. Critical illness myopathy (CIM) is the progressive decline in the function and mass of the limb muscles in response to exposure to the ICU condition, while ventilator-induced diaphragm dysfunction (VIDD) is the time dependent decrease in the diaphragm function after the initiation of mechanical ventilation. Since the complete underlying mechanisms for CIM and VIDD are not completely understood, there is a compelling need for research on the mechanisms of CIM and VIDD to develop intervention strategies targeting these mechanisms. The aim of this thesis was to investigate the effects of several intervention strategies and rehabilitation programs on muscle wasting associated with ICU condition. Moreover, muscle specific differences in response to exposure to the ICU condition and different interventions was investigated. Hence, a rodent ICU model was used to address the mechanistic and therapeutic aspects of CIM and VIDD. The effects of heat shock protein 72 co-inducer (HSP72), BGP-15, on diaphragm and soleus for rats exposed to different durations of ICU condition was investigated. We showed that 5 and 10 days treatment with BGP-15 improved diaphragm fiber and myosin function, protected myosin from posttranslational modification, induced HSP72 and improved mitochondrial function. Moreover, BGP-15 treatment for 5 days improved soleus muscle fibers function, improved mitochondrial structure and reduced the levels of some ubiquitin ligases. In addition to BGP-15 treatment, passive mechanical loading of the limb muscles was investigated during exposure to the ICU condition. We showed that mitochondrial dynamics and mitophagy gene expression was affected by Mechanical silencing while mechanical loading counteracted these effects. Our investigation for other pathways that can be involved in muscle wasting associated with ICU condition showed that the Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is differentially activated in plantaris, intercostals and diaphragm. However, further studies are required with JAK2/STAT3 inhibitors to fully examine the role of this pathway in the pathogenesis of CIM and VIDD prior to translation to clinical research.

    Delarbeid
    1. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
    Åpne denne publikasjonen i ny fane eller vindu >>The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
    Vise andre…
    2016 (engelsk)Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, nr 350, 350ra103Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-303060 (URN)10.1126/scitranslmed.aaf7099 (DOI)000380780000005 ()
    Eksternt samarbeid:
    Forskningsfinansiär
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research Council, 8651; 4423; 4870; 3074EU, European Research Council, CT-223756; COST CM1001The Karolinska Institutet's Research FoundationStockholm County CouncilNovo Nordisk, 100193
    Tilgjengelig fra: 2016-09-14 Laget: 2016-09-14 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    2. Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
    Åpne denne publikasjonen i ny fane eller vindu >>Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328594 (URN)
    Tilgjengelig fra: 2017-08-28 Laget: 2017-08-28 Sist oppdatert: 2017-08-31
    3. Mechano-signalling pathways in an experimental intensive critical illness myopathy model
    Åpne denne publikasjonen i ny fane eller vindu >>Mechano-signalling pathways in an experimental intensive critical illness myopathy model
    Vise andre…
    2016 (engelsk)Inngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-322821 (URN)
    Tilgjengelig fra: 2017-08-21 Laget: 2017-08-21 Sist oppdatert: 2017-08-31
    4. Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328592 (URN)
    Tilgjengelig fra: 2017-08-28 Laget: 2017-08-28 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-23 09:15 Zootissalen, Uppsala
    Viereckel, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    United in Diversity: A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this doctoral thesis aimed at characterizing restricted subpopulations of neurons in the Basal Ganglia circuitry and their importance in the wider function of the network. To this end, we identified subpopulations of neurons in the subthalamic nucleus (STN), substantia nigra (SN) and ventral tegmental area (VTA), characterized their molecular profile and investigated their physiological role in the circuitry.

    Within the mouse STN, reduction of glutamatergic neurotransmission in a subpopulation expressing Paired-like homeodomain transcription factor 2 (Pitx2) led to structural alterations in the nucleus as well as biochemical alterations of the dopaminergic system in the Nucleus accumbens (NAc) and changes in reward-related behavior. In the ventral midbrain, we identified and characterized novel marker genes selective to the VTA or SN. Of these, transient receptor potential cation channel subfamily V member 1 (TrpV1) marks a population of mainly glutamatergic neurons in the VTA which project to the NAc, while gastrin releasing peptide (Grp) is expressed in a population of dopaminergic neurons neuroprotected in Parkinson's disease. Furthermore, we discovered that disruption of glutamatergic co-release of dopaminergic neurons expressing dopamine transporter (DAT), diminishes fast EPSCs and glutamate release but does not affect the acquisition of reward-related behavioral tasks. To selectively quantify glutamate release from specific subpopulations, we devised a technique combining glutamate-amperometry and optogenetics. This was used to measure glutamate released from Pitx2-expressing synaptic terminals in the Globus pallidus as well as DAT- or TrpV1-expressing terminals in the NAc.

    In summary, this doctoral thesis has furthered understanding of the function and importance of specific subpopulations within the Basal Ganglia circuitry and provides a novel means to investigate glutamate in the intact rodent brain within clearly defined, restricted cell populations.

    Delarbeid
    1. Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption
    Åpne denne publikasjonen i ny fane eller vindu >>Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption
    Vise andre…
    2016 (engelsk)Inngår i: ENEURO, ISSN 2373-2822, Vol. 3, nr 5, UNSP e0264Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.

    Emneord
    dopamine, dynorphin, glutamate, rearing, reward, self-administration
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-315932 (URN)10.1523/ENEURO.0264-16.2016 (DOI)000391930400042 ()
    Forskningsfinansiär
    Swedish Research Council, Vetenskapsradet 2013-4657 2014-3804 2011-4423 2015-4870 2012-2304The Swedish Brain FoundationÅke Wiberg Foundation
    Tilgjengelig fra: 2017-02-22 Laget: 2017-02-22 Sist oppdatert: 2017-09-05bibliografisk kontrollert
    2. Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease
    Åpne denne publikasjonen i ny fane eller vindu >>Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease
    Vise andre…
    2016 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 35203Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-307529 (URN)10.1038/srep35203 (DOI)000385768100001 ()27762319 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 2013-4657 2014-3804The Swedish Brain FoundationÅke Wiberg Foundation
    Tilgjengelig fra: 2016-11-17 Laget: 2016-11-17 Sist oppdatert: 2017-09-05bibliografisk kontrollert
    3. Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation
    Åpne denne publikasjonen i ny fane eller vindu >>Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation
    Vise andre…
    2017 (engelsk)Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, nr 11, 2584-2591 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.

    Emneord
    glutamate co-transmission, intracranial self-stimulation, mesolimbic dopamine system, nucleus accumbens, reinforcement learning, reward, ventral striatum
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-318762 (URN)10.1016/j.celrep.2017.02.062 (DOI)28297663 (PubMedID)
    Forskningsfinansiär
    NIH (National Institute of Health)Swedish Research Council, 2013-4657 2014-3804The Swedish Brain Foundation
    Tilgjengelig fra: 2017-03-28 Laget: 2017-03-28 Sist oppdatert: 2017-09-05bibliografisk kontrollert
    4. A Physiological Insight into Real-Time Glutamate Release upon Optogenetic Stimulation in vivo
    Åpne denne publikasjonen i ny fane eller vindu >>A Physiological Insight into Real-Time Glutamate Release upon Optogenetic Stimulation in vivo
    2017 (engelsk)Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328036 (URN)
    Tilgjengelig fra: 2017-08-16 Laget: 2017-08-16 Sist oppdatert: 2017-09-05
  • Disputas: 2017-10-23 10:00 B/C8:305, Uppsala
    Hoeber, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi.
    Neural progenitors for sensory and motor repair2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Injury and neurodegenerative conditions of the spinal cord can lead to paralysis and loss of sensation. Cell therapeutic approaches can restore sensory innervation of the spinal cord following injury and protect spinal cord cells from degeneration. This thesis primarily focuses on the restoration of deaffarented sensory fibres following injury to the dorsal root and spinal cord. These injuries lead to the formation of a non-permissive glial scar that prevents sensory axons from reinnervating spinal cord targets. It takes advantage of a dorsal root injury model that closely mimics spinal root avulsion injuries occurring in humans. In the first part of the thesis, three different neural progenitor types from human or murine sources are tested for their regenerative properties following their transplantation to the site of dorsal root avulsion injury. In the second part, the ability of murine neural progenitors to protect spinal motor neurons from a neurodegenerative process is tested.

    In the first original research article, I show that human embryonic stem cell derived neural progenitors are able to restore sensorimotor functions, mediated by the formation of a tissue bridge that allows ingrowth of sensory axons into the spinal cord. In the second research article, I present that murine boundary cap neural crest stem cells, a special type of neural progenitor that governs the entry of sensory axons into the spinal cord during development, are unable to form a permissive tissue bridge. This is possibly caused by the contribution of transplant derived ingrowth non-permissive glial cells. In the third research article, I show that human neural progenitors derived from foetal sources are capable of stimulating sensory ingrowth and that they ameliorate the glial scar. When this approach is combined with the delivery of sensory outgrowth stimulating neurotrophic factors, these cells fail to form a permissive tissue bridge and fail to modify the glial scar. In the final research article, murine boundary cap neural crest stem cells are shown to protect motor neurons, which harbor an amyotrophic lateral sclerosis causing mutation, from oxidative stress. Oxidative stress is a pathological component of amyotrophic lateral sclerosis in human patients.

    Taken together, this thesis provides first evidence that sensory regeneration following a spinal root avulsion injury can be achieved by transplantation of human neural progenitors. In addition, it introduces murine boundary cap neural crest stem cells as interesting candidates for the cell therapeutic treatment of amyotrophic lateral sclerosis.

    Delarbeid
    1. Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
    Åpne denne publikasjonen i ny fane eller vindu >>Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
    Vise andre…
    2015 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, Vol. 5, 10666Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-251488 (URN)10.1038/srep10666 (DOI)000356063500001 ()26053681 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 5420, 20716
    Tilgjengelig fra: 2015-04-20 Laget: 2015-04-20 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    2. Sensory regeneration in dorsal root avulsion
    Åpne denne publikasjonen i ny fane eller vindu >>Sensory regeneration in dorsal root avulsion
    2015 (engelsk)Inngår i: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, nr 11, 1739-1740 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-275487 (URN)10.4103/1673-5374.170296 (DOI)000367332800011 ()
    Forskningsfinansiär
    Swedish Research Council, 5420Swedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
    Tilgjengelig fra: 2016-02-04 Laget: 2016-02-04 Sist oppdatert: 2017-08-31bibliografisk kontrollert
    3. Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar.
    Åpne denne publikasjonen i ny fane eller vindu >>Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar.
    Vise andre…
    2017 (engelsk)Inngår i: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 12, nr 4, 339-351 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.

    MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.

    RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration.

    CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.

    Emneord
    calcium-binding protein, glia, nerve degeneration, neural stem cell, sensory neuron, spinal cord
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328589 (URN)10.2217/rme-2016-0163 (DOI)28621171 (PubMedID)
    Tilgjengelig fra: 2017-08-28 Laget: 2017-08-28 Sist oppdatert: 2017-08-31
    4. A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord.
    Åpne denne publikasjonen i ny fane eller vindu >>A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord.
    Vise andre…
    2017 (engelsk)Inngår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, nr 14, 1065-1077 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

    Emneord
    biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)28562227 (PubMedID)
    Tilgjengelig fra: 2017-08-28 Laget: 2017-08-28 Sist oppdatert: 2017-08-31
    5. Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons.
    Åpne denne publikasjonen i ny fane eller vindu >>Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons.
    Vise andre…
    2017 (engelsk)Inngår i: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, nr 3, 773-783 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

    Emneord
    Amyotrophic lateral sclerosis, Neurodegeneration, Neuroglia, Oxidative stress, Transplantation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328588 (URN)10.1007/s13311-016-0505-8 (DOI)28070746 (PubMedID)
    Tilgjengelig fra: 2017-08-28 Laget: 2017-08-28 Sist oppdatert: 2017-08-31
  • Disputas: 2017-10-26 09:00 Rudbecksalen, Uppsala
    Fletcher, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Antibody- and Peptide-based Immunotherapies: Proof-of-concept and safety considerations2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The aim of cancer immunotherapy is to eradicate tumours by inducing a tumour-specific immune response. This thesis focuses on how antibodies and peptides can improve antigen presentation and the subsequent tumour-specific T cell response. Tumour recognition by the immune system can be promoted through delivery of antigen in the form of a vaccine. One example is the development of a therapeutic peptide vaccine containing both CD4+ and CD8+ T cell epitopes. So far, peptide vaccinations have shown limited success in clinical trials and further improvements are needed, such as choice of adjuvant and T cell epitopes, as well as targeted delivery of peptides and adjuvants to the same DC.

    In paper I, we describe the development of a peptide-peptide conjugate (with a tumour T cell epitope) that, via immune complex formation and FcγR binding, enhance antigen uptake and activation of DCs. The conjugate consists of three tetanus toxin-derived linear B cell epitopes (MTTE) that were identified based on specific IgG antibodies in human serum. Three MTTE peptide sequences were conjugated to a synthetic long peptide (SLP) that consists of a T cell epitope derived from the desired target tumour.

    In paper II, the conjugate was evaluated in a modified Chandler loop model containing human blood, mimicking blood in circulation. The conjugate was internalised by human monocytes in an antibody-dependent manner. A conjugate containing the model CMV-derived T cell epitope pp65NLV generated recall T cell responses dependent on MTTE-specific antibodies and the covalent conjugation of the three MTTE with the SLP.

    In paper III, a CD40-specific antibody was characterised for local treatment of solid tumours. The antibody eradicated bladder tumours in mice and induced T cell-mediated immunological memory against the tumour.

    In paper IV, we characterised the Chandler loop model (used in paper II) for its potential use in predicting cytokine release syndrome (CRS) in response to monoclonal antibodies (mAbs). Superagonistic antibodies (e.g., OKT3) induced rapid cytokine release whereas no cytokine release was induced by antibodies (e.g., cetuximab) associated with low incidence of CRS in the clinic.

    In conclusion, this thesis work demonstrates proof-of-concept of improved strategies for antibody- and peptides-based cancer immunotherapies and their potential use in multiple cancer indications.

    Delarbeid
    1. Linking T cell epitopes to a common linear B cell epitope; a targeting and adjuvant strategy to improve T cell responses: Targeting antigen to DCs via IC formation
    Åpne denne publikasjonen i ny fane eller vindu >>Linking T cell epitopes to a common linear B cell epitope; a targeting and adjuvant strategy to improve T cell responses: Targeting antigen to DCs via IC formation
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Immune complexes are potent mediators of cellular immunity and have been extensively studied for their disease mediating properties in humans and for their role in anti-cancer immunity. However, a viable approach to use antibody-complexed antigen as vehicle for specific immunotherapy has not yet reached clinical use. Since virtually all people have endogenous antibodies against tetanus toxoid (TTd), such commonly occurring antibodies are promising candidates to utilize for immune modulation. As an initial proof-of-concept we investigated if anti-tetanus IgG could induce potent cross-presentation of a conjugate of a long peptide harboring SIINFEKL, a MHC class I presented epitope of ovalbumin (OVA), to TTd. This protein conjugate enhanced OVA-specific CD8+ T cell responses when administrated to seropositive mice. Since a peptide-protein conjugate with TTd is poorly defined, we next investigated whether a synthetic peptide-peptide conjugate, with a chemically defined linear B cell epitope of tetanus toxin (TTx) origin, could improve cellular immune responses. Herein we identify one linear B cell epitope, here after named MTTE, thru a screening of overlapping peptides from the alpha and beta region of TTx, and by assessment of the binding of pooled IgG, or individual human IgG from high-titer TTd vaccinated donors, to these peptides. Subsequently, we developed a chemical protocol to synthesize defined conjugates containing multiple copies of MTTE covalently attached to one or more T cell epitopes of choice. To demonstrate the potential of the above approach we show that immune complexes of anti-MTTE antibodies with such MTTE-containing conjugates are able to induce DC and T cell activation when using a model antigen.

    Emneord
    immune complex, FcgRs, dendritic cells, peptide conjugate
    HSV kategori
    Forskningsprogram
    Immunologi
    Identifikatorer
    urn:nbn:se:uu:diva-329037 (URN)
    Tilgjengelig fra: 2017-09-06 Laget: 2017-09-06 Sist oppdatert: 2017-09-07
    2. Formation ofimmune-complexes by a defined linear tetanus toxin-derived B cell epitope boosts human T cell responses to long peptides: ICs boost specific-T cells
    Åpne denne publikasjonen i ny fane eller vindu >>Formation ofimmune-complexes by a defined linear tetanus toxin-derived B cell epitope boosts human T cell responses to long peptides: ICs boost specific-T cells
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Enhancing T cell responses against both viral and tumor antigens requires efficient co-stimulation and directed delivery of peptide antigens into APCs. As short peptides can lead to T cell tolerance and can only be used in a specific set of patients, long peptides are considered favourable vaccine moieties from a clinical perspective as they can harbor more than one immunogenic epitope enabling a broader target population. In addition, longer peptides are not bound unselectively to MHC class I on any cell, but rather require processing and will thereby be presented to T cells in secondary lymphoid organs. However, as peptides are not actively targeted to and taken up by APCs, and the standard non-conjugated adjuvant-peptide mixtures do not ensure co-targeting of the two to the same APC. We have identified a linear tetanus-toxin derived B cell epitope that can mediate the formation of immune-complexes by the presence of circulating antibodies. Herein, we show that these complexes, improve both antigen uptake by APCs (blood monocytes and CD1c+ DCs) and thereby CD8+ T cell recall responses in a human ex-vivo blood loop system. The uptake of the peptide conjugate by blood monocytes is dependent on antibodies and the complement component C1q.  The defined linear peptide steers the immune-complex formation to a monoclonal-like complex and as a consequence we show that the number of linear tetanus sequences per T cell epitope determines the outcome of the response. We envision that this strategy can be used to facilitate active uptake of antigens into antigen-presenting cells to improve T cell responses against pathogens or cancer.

    Emneord
    peptide conjugate, therapeutic vaccine, whole blood, immune complexes
    HSV kategori
    Forskningsprogram
    Immunologi; Immunologi; Idé- och lärdomshistoria
    Identifikatorer
    urn:nbn:se:uu:diva-328860 (URN)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2017-09-06 Laget: 2017-09-06 Sist oppdatert: 2017-09-07
    3. The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity
    Åpne denne publikasjonen i ny fane eller vindu >>The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity
    Vise andre…
    2015 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, nr 5, 1115-1126 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-239514 (URN)10.1158/1078-0432.CCR-14-0913 (DOI)000351982800025 ()25316820 (PubMedID)
    Tilgjengelig fra: 2014-12-29 Laget: 2014-12-29 Sist oppdatert: 2017-09-07bibliografisk kontrollert
    4. Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanisms-of-action of immunotherapeutics: CRS prediction in human whole blood
    Åpne denne publikasjonen i ny fane eller vindu >>Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanisms-of-action of immunotherapeutics: CRS prediction in human whole blood
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    First infusion reactions along with severeanaphylactic responses can occur as a result of systemic administration oftherapeutic antibodies. The underlying mechanisms by which monoclonal antibodiesinduce cytokine release syndrome (CRS) can involve direct agonistic effects viathe drug target, or a combination of target-engagement along with innatereceptor interactions. Despite the wide variety of pathways and cells that canplay a role in CRS, many currently used assays are devoid of one or morecomponents that must be present for these responses to occur. To date, oneassay that has not been used for studying CRS is the Chandler loop model. Thismodel is commonly used to study surface/blood interface interactions and has alsobeen used to study the instant blood-mediated inflammatory reaction (IBMIR). Herein we use a modified Chandler loopmodel with a heparin conjugate lining the inner surface of the loops to studyCRS. This allows for an assay harboring immune cells, intact cascade systemsalong with endogenous antibodies. Here, we evaluated a plethora of commerciallyavailable monoclonal antibodies to assess the capacity of the Chandler loopmodel for CRS prediction. We demonstrated that in a 4-hour loop assay both thesuperagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), displayed aclear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induced TNFα and IFN-g release in 20 out of23 donors tested, whereas ANC28.1 induced TNF-α, IL-2 and IFN-g release in all donors tested (n=18-22). On theother hand, non-agonistic antibodies associated with no or low infusionreactions in the clinic, namely cetuximab and natalizumab, neither induced cytokinerelease nor caused false positive responses. A TGN1412-like antibody alsodisplayed a clear cytokine release with an adaptive cytokine profile (IFN-g and IL-2) and all donors (n=9) inducing adistinct IL-2 response. Additionally, the value of an intact complement systemin the assay was highlighted by the possibility to dissect out themechanism-of-action (MOA) of alemtuzumab and rituximab. The loop assay can eithercomplement lymph node-like assays or stand-alone to investigate drug/bloodinteractions during preclinical development, or for individual safety screeningprior to a first-in-man clinical trial.

    Emneord
    Cytokine release syndrome, Chandler loop, TGN1412, alemtuzumab
    HSV kategori
    Forskningsprogram
    Immunologi
    Identifikatorer
    urn:nbn:se:uu:diva-328816 (URN)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2017-09-06 Laget: 2017-09-06 Sist oppdatert: 2017-09-07
  • Disputas: 2017-10-26 09:15 Rosénsalen, Uppsala
    Henriksson, Dorcus Kiwanuka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Health systems bottlenecks and evidence-based district health planning: Experiences from the district health system in Uganda2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In low-income countries where maternal and child mortality remains high, there is limited use of context-specific evidence for decision making and prioritization of interventions in the planning process at the sub-national level, such as the district level. Knowledge on the utility of tools and interventions to promote use of district-specific evidence in the planning process is limited, yet it could contribute to the prioritization of high-impact interventions for women and children.

    This thesis aims to investigate, in the planning process, the use of district-specific evidence to identify gaps in service delivery in the district health system in Uganda in order to contribute to improving health services for women and children.

    Study I evaluated the use of the modified Tanahashi model to identify bottlenecks for service delivery of maternal and newborn interventions. Study II and III used qualitative methods to document the experiences of district managers in adopting tools to facilitate the utilization of district-specific evidence, and the barriers and enablers to the use of these tools in the planning process. Study IV used qualitative methods, and analysis of district annual health work plans and reports.

    District managers were able to adopt tools for the utilization of district-specific evidence in the planning process. Governance and leadership were a major influence on the use of district-specific evidence. Limited decision space and fiscal space, and limited financial resources, and inadequate routine health information systems were also barriers to the utilization of district-specific evidence.

    Use of district-specific evidence in the planning process is not an end in itself but part of a process to improve the prioritization of interventions for women and children. In order to prioritize high impact interventions at the district level, a multifaceted approach needs to be taken that not only focuses on use of evidence, but also focuses on broader health system aspects like governance and leadership, the decision and fiscal space available to the district managers, limited resources, and inadequate routine health information systems.

    Delarbeid
    1. Bottleneck analysis at district level to illustrate gaps within the district health system in Uganda
    Åpne denne publikasjonen i ny fane eller vindu >>Bottleneck analysis at district level to illustrate gaps within the district health system in Uganda
    Vise andre…
    2017 (engelsk)Inngår i: Global Health Action, ISSN 1654-9716, E-ISSN 1654-9880, Vol. 10, nr 1, 1327256Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Poor quality of care and access to effective and affordable interventions have been attributed to constraints and bottlenecks within and outside the health system. However, there is limited understanding of health system barriers to utilization and delivery of appropriate, high-impact, and cost-effective interventions at the point of service delivery in districts and sub-districts in low-income countries. In this study we illustrate the use of the bottleneck analysis approach, which could be used to identify bottlenecks in service delivery within the district health system.

    METHODS: A modified Tanahashi model with six determinants for effective coverage was used to determine bottlenecks in service provision for maternal and newborn care. The following interventions provided during antenatal care were used as tracer interventions: use of iron and folic acid, intermittent presumptive treatment for malaria, HIV counseling and testing, and syphilis testing. Data from cross-sectional household and health facility surveys in Mayuge and Namayingo districts in Uganda were used in this study.

    RESULTS: Effective coverage and human resource gaps were identified as the biggest bottlenecks in both districts, with coverage ranging from 0% to 66% for effective coverage and from 46% to 58% for availability of health facility staff. Our findings revealed a similar pattern in bottlenecks in both districts for particular interventions although the districts are functionally independent.

    CONCLUSION: The modified Tanahashi model is an analysis tool that can be used to identify bottlenecks to effective coverage within the district health system, for instance, the effective coverage for maternal and newborn care interventions. However, the analysis is highly dependent on the availability of data to populate all six determinants and could benefit from further validation analysis for the causes of bottlenecks identified.

    Emneord
    Tanahashi model, bottleneck analysis, demand-side determinants, district health systems, maternal and newborn care, supply-side determinants
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-329444 (URN)10.1080/16549716.2017.1327256 (DOI)28581379 (PubMedID)
    Tilgjengelig fra: 2017-09-15 Laget: 2017-09-15 Sist oppdatert: 2017-09-15bibliografisk kontrollert
    2. Improving child survival through a district management strengthening and community empowerment intervention: early implementation experiences from Uganda
    Åpne denne publikasjonen i ny fane eller vindu >>Improving child survival through a district management strengthening and community empowerment intervention: early implementation experiences from Uganda
    Vise andre…
    2015 (engelsk)Inngår i: BMC Public Health, ISSN 1471-2458, Vol. 15, 797Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: The Community and District Empowerment for Scale-up (CODES) project pioneered the implementation of a comprehensive district management and community empowerment intervention in five districts in Uganda. In order to improve effective coverage and quality of child survival interventions CODES combines UNICEF tools designed to systematize priority setting, allocation of resources and problem solving with Community dialogues based on Citizen Report Cards and U-Reports used to engage and empower communities in monitoring health service provision and to demand for quality services. This paper presents early implementation experiences in five pilot districts and lessons learnt during the first 2 years of implementation. Methods: This qualitative study was comprised of 38 in-depth interviews with members of the District Health Teams (DHTs) and two implementing partners. These were supplemented by observations during implementation and documents review. Thematic analysis was used to distill early implementation experiences and lessons learnt from the process. Results: All five districts health teams with support from the implementing partners were able to adopt the UNICEF tools and to develop district health operational work plans that were evidence-based. Members of the DHTs described the approach introduced by the CODES project as a more systematic planning process and very much appreciated it. Districts were also able to implement some of the priority activities included in their work plans but limited financial resources and fiscal decision space constrained the implementation of some activities that were prioritized. Community dialogues based on Citizen Report Cards (CRC) increased community awareness of available health care services, their utilization and led to discussions on service delivery, barriers to service utilization and processes for improvement. Community dialogues were also instrumental in bringing together service users, providers and leaders to discuss problems and find solutions. The dialogues however are more likely to be sustainable if embedded in existing community structures and conducted by district based facilitators. U report as a community feedback mechanism registered a low response rate. Conclusion: The UNICEF tools were adopted at district level and generally well perceived by the DHTs. The limited resources and fiscal decision space however can hinder implementation of prioritized activities. Community dialogues based on CRCs can bring service providers and the community together but need to be embedded in existing community structures for sustainability.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-262578 (URN)10.1186/s12889-015-2129-z (DOI)000359690800008 ()26286146 (PubMedID)
    Tilgjengelig fra: 2015-09-16 Laget: 2015-09-16 Sist oppdatert: 2017-09-07
    3. Enablers and barriers to evidence based planning in the district health system in Uganda; perceptions of district health managers
    Åpne denne publikasjonen i ny fane eller vindu >>Enablers and barriers to evidence based planning in the district health system in Uganda; perceptions of district health managers
    Vise andre…
    2017 (engelsk)Inngår i: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 17, 103Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: The District Health System was endorsed as the key strategy to achieve 'Health for all' during the WHO organized inter-regional meeting in Harare in 1987. Many expectations were put upon the district health system, including planning. Although planning should be evidence based to prioritize activities, in Uganda it has been described as occurring more by chance than by choice. The role of planning is entrusted to the district health managers with support from the Ministry of Health and other stakeholders, but there is limited knowledge on the district health manager's capacity to carry out evidence-based planning. The aim of this study was to determine the barriers and enablers to evidence-based planning at the district level.

    Methods: This qualitative study collected data through key informant interviews with district managers from two purposefully selected districts in Uganda that have been implementing evidence-based planning. A deductive process of thematic analysis was used to classify responses within themes.

    Results: There were considerable differences between the districts in regard to the barriers and enablers for evidence-based planning. Variations could be attributed to specific contextual and environmental differences such as human resource levels, date of establishment of the district, funding and the sociopolitical environment. The perceived lack of local decision space coupled with the perception that the politicians had all the power while having limited knowledge on evidence-based planning was considered an important barrier.

    Conclusion: There is a need to review the mandate of the district managers to make decisions in the planning process and the range of decision space available within the district health system. Given the important role elected officials play in a decentralized system a concerted effort should be made to increase their knowledge on evidence-based planning and the district health system as a whole.

    Emneord
    District, Planning, Health systems, Evidence, Managers, Decentralization, Politicians, Uganda
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-317589 (URN)10.1186/s12913-017-2059-9 (DOI)000393277300001 ()28148251 (PubMedID)
    Tilgjengelig fra: 2017-03-24 Laget: 2017-03-24 Sist oppdatert: 2017-09-07bibliografisk kontrollert
    4. Decision making in district health planning in Uganda: Does use of local evidence matter?
    Åpne denne publikasjonen i ny fane eller vindu >>Decision making in district health planning in Uganda: Does use of local evidence matter?
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction

    In a decentralized health system, district health managers are tasked with planning for health service delivery which should be evidence-based. However, planning in low-income countries such as Uganda, has been described as ad hoc. A systematic approach to the planning process using district-specific evidence was introduced to district health managers in Uganda. However, little is known about how the use of district-specific evidence does inform the planning process. In this study we further investigate how the use of this evidence affects the annual planning process.

    Methodology

    The study was conducted in two districts that were introduced to the systematic approach of using district-specific evidence in the planning process. District annual health work plans for financial years 2012/13; 2013/14; 2014/15 and 2015/16 and bottleneck analysis reports for 2012, 2013, 2014 and 2015 were reviewed. Semi-structured interviews with key informants from the districts were also conducted.

    Results

    District managers reported that they were able to produce more robust district annual work plans when they used district-specific evidence. About half of the priority activities that were identified using district-specific evidence were included in the annual work plans. Procurement and logistics, training and support supervision activities were the most prioritized. Use of local evidence was viewed positively by the health managers. However, there was a lack of clarity on what activities should be incorporated in the annual work plans and district managers considered the lack of autonomy or decision space as a constraint to the use of district-specific evidence.

    Conclusion

    District-specific evidence and a structured process for its use to prioritize activities and make decisions in the planning process at the district level helped systematize the planning process. Health managers were able to articulate and advocate for priorities related to child survival. However, the reported limited decision and fiscal space, human resource gaps, inadequate funding and high dependency on donor funding did not always allow for use of district-specific evidence in the planning process. 

    Emneord
    District health planning, evidence, district health systems
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-329080 (URN)
    Tilgjengelig fra: 2017-09-07 Laget: 2017-09-07 Sist oppdatert: 2017-09-07
  • Disputas: 2017-10-26 13:15 Room 10132, Ånströmlaboratoriet, Uppsala
    Wang, Shujiang
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Insights into dynamic covalent chemistry for bioconjugation applications2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Dynamic covalent chemistry (DCC) is currently exploited in several areas of biomedical applications such as in drug discovery, sensing, molecular separation, catalysis etc. Hydrazone and oxime chemistry have several advantages, such as mild reaction conditions, selectivity, efficiency, and biocompatibility and therefore, have the potential to be for bioconjugation applications. However, these reactions suffer from major drawbacks of slow reaction rate and poor bond stability under physiological conditions. In this regard, the work presented in this thesis focuses on designing novel bioconjugation reactions amenable under physiological conditions with tunable reaction kinetics and conjugation stability.

    The first part of the thesis presents different strategies of dynamic covalent reactions utilized for biomedical applications. In the next part, a detailed study related to the mechanism and catalysis of oxime chemistry was investigated in the presence of various catalysts. Aniline, carboxylate and saline were selective as target catalysts and their reaction kinetics were compared under physiological conditions (Paper I and II). Then we attempted to explore the potential of those chemistries in fabricating 3D hydrogel scaffolds for regenerative medicine application. A novel mild and regioselective method was devised to introduce an aldehyde moiety onto glycosaminoglycans structure. This involved the introduction of amino glycerol to glycosaminoglycans, followed by regioselective oxidation of tailed flexible diol without affecting the C2-C3 diol groups on the disaccharide repeating unit. The oxidation rate of the tailed flexible diol was 4-times faster than that of C2-C3 diol groups of native glycosaminoglycan. This strategy preserves the structural integrity of the glycosaminoglycans and provides a functional aldehyde moiety (Paper III). Further, different types of hydrazones were designed and their hydrolytic stability under acidic condition was carefully evaluated. The hydrazone linkage with the highest hydrolytic stability was utilized in the preparation of extracellular matrix hydrogel for delivery of bone morphogenetic proteins 2 in bone regeneration (Paper IV) and studied for controlled release of the growth factor (Paper III).

    In summary, this thesis presents a selection of strategies for designing bioconjugation chemistries that possess tunable stability and reaction kinetics under physiological conditions. These chemistries are powerful tools for conjugation of biomolecules for the biomedical applications.

    Delarbeid
    1. Insights into the Mechanism and Catalysis of Oxime Coupling Chemistry at Physiological pH
    Åpne denne publikasjonen i ny fane eller vindu >>Insights into the Mechanism and Catalysis of Oxime Coupling Chemistry at Physiological pH
    2015 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 15, 5980-5985 s.Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The dynamic covalent-coupling reaction involving alpha-effect nucleophiles has revolutionized bioconjugation approaches, due to its ease and high efficiency. Key to its success is the discovery of aniline as a nucleophilic catalyst, which made this reaction feasible under physiological conditions. Aniline however, is not so effective for keto substrates. Here, we investigate the mechanism of aniline activation in the oxime reaction with aldehyde and keto substrates. We also present carboxylates as activating agents that can promote the oxime reaction with both aldehyde and keto substrates at physiological pH. This rate enhancement circumvents the influence of alpha-effect by forming H-bonds with the rate-limiting intermediate, which drives the reaction to completion. The combination of aniline and carboxylates had a synergistic effect, resulting in a similar to 14-31-fold increase in reaction rate at pD 7.4 with keto substrates. The biocompatibility and efficiency of carboxylate as an activating agent is demonstrated by performing cell-surface oxime labeling at physiological pH using acetate, which showed promising results that were comparable with aniline.

    Emneord
    ketones, kinetics, coupling reaction, oxime, reaction mechanisms
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-252690 (URN)10.1002/chem.201406458 (DOI)000352506500042 ()25737419 (PubMedID)
    Tilgjengelig fra: 2015-05-25 Laget: 2015-05-11 Sist oppdatert: 2017-09-06bibliografisk kontrollert
    2. Saline catalyse oxime reaction at physiological pH: overcoming a major limitation of bioorthogonal reaction
    Åpne denne publikasjonen i ny fane eller vindu >>Saline catalyse oxime reaction at physiological pH: overcoming a major limitation of bioorthogonal reaction