| 1. |
- Boij, Roland, 1952-
(författare)
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Aspects of inflammation, angiogenesis and coagulation in preeclampsia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18 (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.
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| 2. |
- Persson, Marie
(författare)
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Immune regulation during pregnancy in relation to allergy and in women undergoing in vitro fertilization
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During pregnancy, the fetus expresses both maternal and paternal antigens. To the mother, the paternal antigens are foreign, providing her immune system with an interesting challenge. The fact that the fetus is not normally attacked and rejected implies that mechanisms of tolerance must exist. Pregnancy has long been considered to cause a redirection of the maternal immune responses towards a less aggressive type. Allergic disease has also been associated with that same redirection of immune responses, suggesting that this deviation may be more pronounced in allergic women during pregnancy. Several observations support the concept of a role of the immune system in the etiology of unexplained infertility, associating a redirection of the immune responses towards a more aggressive type with pregnancy loss and pregnancy failure.The aim of this thesis was to investigate the immune responses during pregnancy in allergic and non-allergic women, and in infertile women undergoing IVF treatment. We hypothesized that allergic women would have a more pronounced Th2-deviation than non-allergic women towards paternal antigens during pregnancy and that an unsuccessful outcome of IVF treatment would be associated with aberrations in circulating leukocyte populations and a paternal antigen-specific Th1 and Th17 bias.An increased number of both spontaneous and paternal antigen-induced Th2-like cytokine-secreting cells in peripheral blood was associated with pregnancy in 54 women with pregnancies defined as normal. The allergic pregnant women did not have a more pronounced Th2-deviation than the non-allergic women, as measured by numbers of cytokine-secreting cells. However, when analyzing cytokine levels in cell supernatants, we did observe lower Th1 responses towards paternal antigens in the allergic compared with non-allergic women. Additionally, allergy was associated with a reduced capacity to induce anti-inflammatory IL-10 responses towards paternal antigens.In 25 infertile women undergoing IVF, the peak levels of the majority of paternal antigen-induced cytokines and leukocyte populations investigated coincided with the maximal levels of gonadotropins administered during IVF treatment, suggesting that controlled ovarian hyper-stimulation has a general stimulatory effect on the immune system and that it may be regarded as an inflammatory state. During the treatment, no differences were found regarding cytokine responses to paternal antigens in peripheral blood or the numbers or proportions of circulating leukocyte populations between women with a successful or unsuccessful outcome of IVF. We did see higher numbers of Th2-associated cytokine secreting cells and a lower proportion of lymphocytes in the pregnant compared with the non-pregnant women four weeks after embryo transfer, however, in line with previous findings of immune modulation during pregnancy.In conclusion, normal pregnancy seems to be characterized by a less aggressive type of immune responses, possibly more pronounced in allergic women. This may be of importance for the in utero influences on childhood allergy development. An unsuccessful outcome of IVF does not appear to be associated with a more aggressive type of immune responses towards paternal antigens or aberrations in circulating leukocyte populations, although this should be confirmed in a larger study. The results in this thesis also indicate that the hormonal therapy during IVF treatment has a stimulatory effect on the immune system, generating an inflammatory state.
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| 3. |
- Svensson-Arvelund, Judit, 1982-
(författare)
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Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A successful pregnancy requires that the maternal immune system adapts to tolerate the semi-allogeneic fetal-placental unit. This adaptation mainly occurs locally, i.e. at the fetal-maternal interface, where fetal-derived tissues come into close contact with maternal cells in the uterine endometrium (called decidua during pregnancy). Macrophages and regulatory T (Treg) cells are maternal immune cells that are enriched in the decidua and they likely play a central role in promoting fetal tolerance. However, the precise function of decidual macrophages and the factors regulating both macrophages and Treg cells in humans are unknown. The aim of this thesis was to characterize the phenotype and function of decidual macrophages from first trimester human pregnancy and to identify factors responsible for inducing tolerogenic properties in both decidual macrophages and Treg cells. CD14+ decidual macrophages showed characteristics of immune suppressive or homeostatic macrophages (expression of CD163, CD206 and CD209), mainly produced immunosuppressive cytokines, like IL-10 and IL-35, while levels of inflammatory cytokines, for instance IL-12 and IL-23, were low. Decidual macrophages also induced the expansion of CD25highFoxp3+ Treg cells, but not of Th1, Th2 and Th17 cells, in vitro. In addition, decidual macrophages preferentially secreted the monocyte- and Treg cell-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. These results suggest that decidual macrophages contribute to create the unique decidual cell composition and a tolerogenic immune environment that is compatible with fetal development. Further, by comparing decidual macrophages with different in vitro macrophage subsets, we showed that M-CSF and IL-10, but not GM-CSF, Th1 or Th2 stimuli, induced macrophages that resemble decidual macrophages in terms of cell surface marker expression, cytokine andchemokine production and gene expression profile. First trimester placental tissue, in particular placental trophoblast cells, was identified as an important source of M-CSF and IL-10. We also demonstrated that human fetal-derived placental tissue can induce the characteristics of decidual macrophages (CD163+CD206+CD209+IL-10+CCL18+) and the selective expansion of functionally suppressive CD25highFoxp3+ Treg cells, the latter partly mediated through IL-10, TGF-β and TRAIL. The placenta also limited activation of Th cells, for instance by generally reduced cytokine production. Our data show that the placenta has a unique ability to induce tolerogenic immune cells with a reduced inflammatory potential, which is essential for maintaining tissue integrity and preventing inflammation-induced fetal loss.
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| 4. |
- Mjösberg, Jenny, 1980-
(författare)
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Regulatory T cells in human pregnancy
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During pregnancy, fetal tolerance has to be achieved without compromising the immune integrity of the mother. CD4+CD25highFoxp3+ regulatory cells (Tregs) have received vast attention as key players in immune regulation. However, the identification of human Tregs is complicated by their similarity to activated nonsuppressive T cells. The general aim of this thesis was to determine the antigen specificity, frequency, phenotype and function of Tregs in first to second trimester healthy and severe early-onset preeclamptic human pregnancy. Regarding antigen specificity, we observed that in healthy pregnant women, Tregs suppressed both TH1 and TH2 reactions when stimulated with paternal alloantigens but only TH1, not TH2 reactions when stimulated with unrelated alloantigens. Hence, circulating paternal-specific Tregs seem to be present during pregnancy. Further, by strictly defining typical Tregs (CD4dimCD25high) using flow cytometry, we could show that as a whole, the Treg population was reduced already during first trimester pregnancy as compared with non-pregnant women. This was in contrast to several previous studies and the discrepancy was most likely due to the presence of activated non-suppressive cells in pregnant women, showing similarities to the suppressive Tregs. Although deserving confirmation in a larger sample, severe early-onset preeclampsia did not seem to be associated with alterations in the circulating Treg population. The circulating Treg population was controlled by hormones which, alike pregnancy, reduced the frequency of Foxp3 expressing cells. Yet, in vitro, pregnancy Tregs were highly suppressive of pro-inflammatory cytokine secretion and showed an enhanced capability of secreting immune modulatory cytokines such as IL-4 and IL-10, as well as IL-17, indicating an increased plasticity of pregnancy Tregs. At the fetalmaternal interface during early pregnancy, Tregs, showing an enhanced suppressive and proliferating phenotype, were enriched as compared with blood. Further, CCR6- TH1 cells, with a presumed moderate TH1 activity were enhanced, whereas pro-inflammatory TH17 and CCR6+ TH1 cells were fewer as compared with blood. This thesis adds to and extends the view of Tregs as key players in immune regulation during pregnancy. In decidua, typical Tregs seem to have an important role in immune suppression whereas systemically, Tregs are under hormonal control and are numerically suppressed during pregnancy. Further, circulating pregnancy Tregs show reduced expression of Foxp3 and an increased degree of cytokine secretion and thereby also possibly plasticity. This would ensure systemic defense against infections with simultaneous tolerance at the fetal-maternal interface during pregnancy.
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| 5. |
- Sandberg, Christer, 1962-
(författare)
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Process intensification in mechanical pulping : Reduced process complexity and improved energy efficiency
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This work shows that, for newsprint quality grades, the production processes for mechanical pulp can be simplified, and the specific electrical energy demand can be reduced with around 600 kWh/ton (30%). The purpose of the work is to demonstrate how the production cost for mechanical pulps can be decreased through increased energy efficiency and reduced number of unit operations. The idea was to improve the main line refining conditions so that no additional fibre development or shive reduction is needed and thereby, the normal screening and rejects treatment system could be omitted.Mechanical pulp is used to produce a variety of products, where the two largest categories are printing papers and paperboard for packaging. The pulp is mainly produced by the breakdown of wood chips between rotating metal discs in machines called refiners with the product and process generally referred to as thermomechanical pulp(ing) (TMP). The refiner process requires high specific electrical energy to separate and develop the fibres to a pulp intended for the production of printing papers. Today, many processes need over 2000 kWh/ton of refining energy plus 200-300 kWh/ton of auxiliary energy (to drive pumps, agitators, screw conveyors, screens, presses, etc.).During the last two decades of the 20th century, the chemical processing industry underwent a transformation. The process development changed from being unit operation focused to function focused. The result is more compact processes with less equipment, higher yield and lower energy demand. When the development is made in an innovative way with such large effects on process performance, it is referred to as process intensification. My work is inspired by the concepts of process intensification, especially the striving for more compact processes with higher efficiency. This work is focused on mechanical pulp, intended for the manufacture of printing paper, produced in refiners with Norway spruce (Picea abies) as raw material. However, this approach could also be applied to mechanical pulp production in integrated paperboard mills and also using other raw materials e.g., pines or hardwoods. The investigated pulps and processes in this work are mainly intended for uncoated paper grades (newsprint, improved newsprint and book paper) printed by the offset printing process. In all studies, the pulps have been produced with full scale mill equipment and evaluated using laboratory measurements. However, in two studies, the produced pulps were evaluated on paper machines and at printing houses.A large number of process concepts have been evaluated in which different approaches have been used to reduce the specific energy and, in some cases, improve pulp quality. The approaches include:1. Impressafiner chip pretreatment 2. Primary high consistency (HC) refiner type (DD, RTS, CD, SD)3. Addition of low doses of sodium sulphite 4. Increased refining temperature (housing pressure)5. Refiner segments and centre plate design6. Increased production rate7. Low consistency (LC) refining in different process positions and in combination with different HC refiner typesThe separate effects of all these techniques have not been evaluated systematically neither have potential synergistic effects of all possible combinations been investigated. Even though a large number of combinations of unit operations have been studied, the emphasis has been on trying to do as much fibre development as possible in a single HC refining stage.The mill trials with spruce as raw material have shown that a low shive content and appropriate fibre development can be attained in a process without separate treatment of long fibres. High intensity primary stage refining (RTS and DD) was necessary to reach a low shive content at a low specific refining energy (SRE), with DD refiners appearing to be the most suitable for simplified processes. DD and RTS refining produced pulps with fibres exhibiting a higher degree of external fibrillation and share of split fibres than SD refining. DD refining produced fibres with lower cell wall thickness and higher light scattering at given fibre length than RTS refining. The lowest specific refining energy was attained for one of the trials using the process, denoted as S:HT:DD-LC-LC, consisting of DD refining at increased production rate, 18 adt/h, increased housing pressure, 6.6 bar(g), and with 5 kg/adt sodium sulphite added to the chips immediately before the refiner. After DD refining the pulp was refined in two LC refining stages. This process required only 1280 kWh/adt SRE to reach a tensile index of 52 Nm/g (Rapid-Köthen). This is 900 kWh/adt lower than the final pulp for newsprint based on SD HC refining, and over 500 kWh/adt lower than Scandinavian BAT processes (2014). Additionally, the auxiliary energy was around 150 kWh/adt lower for the processes without a conventional rejects treatment system. At 52 Nm/g tensile index, the light scattering coefficient was 2-3 m2/kg higher, and the length-weighted average fibre length was around 0.1 mm lower for this process than for SD TMP final pulp. The fibre bonding, indicated by density, tensile index and Z-strength of fibre fraction handsheets, was similar or higher for the S:HT:DD-LC-LC process than the reference SD TMP process with a rejects treatment system. Other interesting process configurations, with somewhat lower efficiencies, included:1. Impressafiner pretreatment of the chips with sodium sulphite before DD refining, with or without subsequent LC refining. Chip pretreatment with the Impressafiner enabled operating the DD refiner at higher intensity (feeding segments and increased production rate) without significant loss of quality and LC refining enabled increased production rate which increased the overall efficiency.2. RTS-SD refining with sodium sulphite added before the second stage SD refiner referred to as RTS-S:SD. The pulp from the RTS-S:SD process had similar fibre length as the S:HT:DD-LC-LC process but lower light scattering coefficient.3. A single-stage DD refiner operating at 15.5 adt/h and 4 bar(g) housing pressure (no sodium sulphite addition), which produced pulp with lower fibre length but higher light scattering coefficient than the S:HT:DD-LC-LC process. Two simplified processes were evaluated on paper machines and in printing houses. The first, denoted DD-LC-F, involved a combination of DD primary refining followed by LC refining and fractionation (screening). The screen rejects were mixed with the main line DD pulp before the LC refiner. The second process was the CPT:S-DD-LC process (№1 above). Good runnability was attained both on the paper machines and in the offset printing presses and the paper quality was similar to the reference paper.For printing paper applications, the proportion of fibre development in LC refining should preferably be relatively low, since it was shown that LC refiners have limited capacity to reduce fibre wall thickness and thereby develop light scattering and fibre fraction Z-strength.Explicit effects on the number of unit operations and production cost have not been evaluated in this work, but clearly both investment and variable costs as well as fixed costs can be reduced with a simplified process.
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| 6. |
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| 7. |
- Berg, Daniel, 1979-
(författare)
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Giftets värde : Apotekares förståelse av opium i Sverige, 1870-1925
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Before the regulation of opium as a “narcotic” in Sweden in 1923, opium was not regulated for its intoxicating properties and was freely available. But not in any kind of shop. Opium was legally available only through the pharmacies. This thesis explores how this free availability of a narcotic was understood by its traders, the pharmacists.The title of this thesis – The Value of Poison – indicates how opium could be conceptualized both as a safe, everyday remedy essential to keep freely available and as a drug of intoxication. As a poison it could be articulated as a matter of primarily pharmacological, not moral or medical, concern. This also gave the pharmacists, with their special knowledge of pharmaka (drugs, poisons), an autonomous space of knowledge free from the ever more intruding “medical gaze”. But, in order to articulate this kind of understanding of opium, another kind of knowledge was needed to be acknowledged: that of the user. In this articulation a “sensus communis” was tied in with a broader cultural knowledge of drugs. Problems with opium were focused on the danger of acute poisoning, not recreational intoxication. Concepts that could have problematized this kind of use were rearticulated as problems either of illegitimate trade, unregulated markets and advertising or of draconian regulation by greedy or sloppy doctors. These rather opposite elements were made equivalent through the articulation of ignorance in both cases, thus further emphasizing the special knowledge of the pharmacist.The thesis locates a process of contradiction that contributes to the eventual diminishing of the discourse of poison towards the end of the period. The pharmaceutical knowledge that guaranteed the discourse was based on a “pharmaceutical gaze” on pharmaka. It pierced through the drug to identify its constituent parts. In this process it was promised that the different effects of opium would be separated. “Narcotic” could be a by-product, to be discarded or controlled, without dispensing of other therapeutic effects. With this ever deeper knowledge of opium, knowledge in the pharmacies was made insufficient for the full understanding or opium, and so too was that of the traditional user. The era of opium as a poison was over.
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| 8. |
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| 9. |
- Nibon, Karin, 1982-
(författare)
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Ge igen med samma mynt : Ekonomiska och sociala relationer i Sundborns socken i Dalarna 1820–1849
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis is to visualize and explain how people’s economic and social relations were connected in the parish of Sundborn, in the south east of Dalarna, in the period 1820-1849. The study is based on records of claims and debts in inventories and parish registers, which enable reconstruction of the private local credit market. The study shows that the majority in the economic network lived in Sundborn, and that while few people had formal loans at the institutional credit market, many had loans by trust at the private local credit market. Also, while few people were lenders, almost everyone was a borrower. The most common credit relationship was between people who lived near one another, and people who lived near one another or were related received a higher average credit. The private local credit market consisted primarily of men. These results have been interpreted with the use of social network theory, it being shown that people depended on their social network to obtain the necessary credit. In creating an economic network graph, I show that households in the parish of Sundborn were interconnected by debt relations. By using this method, it is possible to identify significant persons and potential parish bankers. Through combining the network graph with a landscape map, I show connections between the settlement, the assets, economic relations, centrality and the long valley of Sundborn river. The study opens up possibilities for further development of the same method to visualize historic data and relate it to the landscape, with a view to generating new related questions and spatial analyses.
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