| 51. |
- Bergkvist, Max, 1976-
(författare)
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Studies on Polarised Light Spectroscopy
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis project focuses on measurements of dermal microcirculation during vascular provocations with polarised light spectroscopy. This is done with a non-invasive method commercially available as Tissue viability imaging (TiVi) which measures concentration and oxygenation of red blood cells in the papillary dermis. Three studies were done with human subjects and one with an animal model, to validate and compare the TiVi technique with laser Doppler flowmetry, which is an established method of measuring dermal microcirculation.The TiVi consists of a digital camera with polarisation filters in front of the flash and lens, with software for analysis of the picture. When taking a picture with the TiVi, the polarised light that is reflected on the skin surface is absorbed by the second filter over the lens (which is perpendicular to the first filter) but a portion of light penetrates the surface of the skin and is scattered when it is reflected on tissue components. This makes the light depolarised, passes the second filter, and produces a picture for analysis. The red blood cell (RBC) has a distinct absorption pattern that differs between red and green colour compared to melanin and other components of tissue. This difference is used by the software that calculates differences in each picture element and produces a measure of output which is proportional to the concentration of red blood cells. The oxygenation of RBC can also be calculated, as there is a difference in absorption depending on oxygen state.The first paper takes up possible sources of error such as ambient light, and the angle and distance of the camera. The main experiment was to investigate how the local heating reaction is detected with TiVi compared to LDF.In the second paper arterial and venous stasis are examined in healthy subjects with TiVi.The Third paper is an animal study where skin flaps were raised on pigs, and the vascular pedicle is isolated to enable control of inflow and outflow of blood.The measurements were made during partial venous, total venous, and total arterial occlusion. The TiVi recorded changes in the concentration of RBC, oxygenation and heterogeneity and the results were compared with those of laser Doppler flowmetry.In the fourth paper oxygenation and deoxygenation of RBC: s was studied. Studies were made on the forearms of healthy subjects who were exposed to arterial and venous occlusion. Simultaneous measurements were made with TiVi and Enhanced perfusion and oxygen saturation or EPOS, which is a new device that combines laser Doppler flowmetry and diffuse reflectance spectroscopy in one probe.With TiVi, one can measure RBC concentration and oxygenation in the area of an entire picture or in one or multiple user defined regions of interest (ROI). Methods such as laser Doppler flowmetry makes single point measurements, which is a potential source of error both because of the heterogeneity of the microcirculation, and that the circulation be insufficient in the margins of the investigated area. TiVi has been able to measure venous stasis more accurately than laser Doppler flowmetry, and venous stasis is the more common reason for flaps to fail.The TiVi is an accurate way to measure the concentration of RBC and trends in oxygenation of the dermal microcirculation. It has interesting possible applications for microvascular and dermatological research, monitoring of flaps, and diagnosis of peripheral vascular disease. Future clinical studies are needed as well as development of the user interface.
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| 52. |
- Berglund, Björn, 1983-
(författare)
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Deliberations on the impact of antibiotic contamination on dissemination of antibiotic resistance genes in aquatic environments
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The great success of antibiotics in treating bacterial infectious diseases has been hampered by the increasing prevalence of antibiotic resistant bacteria. Not only does antibiotic resistance threaten to increase the difficulty in treating bacterial infectious diseases, but it could also make medical procedures such as routine surgery and organ transplantations very dangerous to perform. Traditionally, antibiotic resistance has been regarded as a strictly clinical problem and studies of the problem have mostly been restricted to a clinical milieu. Recently, non-clinical environments, and in particular aquatic environments, have been recognised as important factors in development and dissemination of antibiotic resistance. Elevated concentrations of antibiotics in an environment are likely to drive a selection pressure which favours resistant bacteria, and are also believed to promote horizontal gene transfer among the indigenous bacteria. Antibiotic resistance genes are often located on mobile genetic elements such as plasmids and integrons, which have the ability to disseminate among taxonomically unrelated species. The environmental bacteria can thus serve as both reservoirs for resistance and hot spots for the development of new antibiotic resistance determinants.There is still a lack of data pertaining to how high antibiotic concentrations are necessary to drive a selection pressure in aquatic environments. The aim of this thesis is to determine the effect of high and low concentrations of antibiotics on environmental bacterial communities from different aquatic environments. In the studies performed, antibiotics were measured using liquid chromatography-mass spectrometry. Bacterial diversity and evenness were assessed using molecular fingerprints obtained with 16S rRNA gene-based denaturing gradient gel electrophoresis, and antibiotic resistance genes and class 1 integrons were quantified using real-time PCR.Water and sediment samples were collected from different rivers and canals in Pakistan. The environments differed in anthropogenic exposure from undisturbed to heavily contaminated. A general trend could be observed of high concentrations of antibiotics correlating to elevated concentrations of antibiotic resistance genes and integrons. Extremely high concentrations of antibiotic resistance genes and integrons were found in the sediments downstream of an industrial drug formulation site, which likely correlated to the high load of antibiotics found in the water. Antibiotic and antibiotic resistance gene concentrations were also shown to increase downstream of Ravi river, which flows through Lahore, a city of more than 10 million inhabitants. Rivers not impacted by anthropogenic contamination were found to contain antibiotics and resistance gene concentrations of similar levels as in Europe and the U.S. Similar measurements were performed in the Swedish river Stångån. The concentrations of antibiotic resistance genes and class 1 integrons were shown to increase in the river after it had passed, and received urban wastewater effluent from the city of Linköping.A series of constructed wetlands were exposed to a mixture of different antibiotics at environmentally relevant concentrations over a few weeks. The antibiotic exposure did not observably affect the bacterial diversity or integron concentrations. Antibiotic resistance genes were found at low background concentrations, but the antibiotic exposure did not observably affect the concentrations. The constructed wetlands were also found to reduce most antibiotics at levels comparable to conventional wastewater treatment schemes, suggesting that constructed wetlands may be useful supplementary alternatives to conventional wastewater treatment.To investigate the effect of antibiotics on an uncontaminated aquatic environment in a more controlled setting, microcosms were constructed from lake water and sediments and subsequently exposed to varying concentrations of antibiotics (ranging from wastewater-like concentrations to 1,000 times higher). The water and sediments were gathered from the lake Nydalasjön, near Umeå, which is not exposed to urban waste. While antibiotic resistance genes and class 1 integrons were found in the lake sediments, no increase in the concentrations of these genes could be observed due to the antibiotic additions.In conclusion, although antibiotic resistance genes and integrons are part of the environmental gene pool, low concentrations of antibiotics do not seem to immediately impact their prevalence. However, aquatic environments exposed to anthropogenic waste do exhibit elevated levels of antibiotic resistance genes and integrons. Aquatic environments heavily polluted with antibiotics also clearly display correspondingly high concentrations of antibiotic resistance genes and integrons. These results clearly indicate the necessity to keep down pollution levels as well as the need to establish the range of antibiotic concentrations which do promote resistance. This must be done in order to enable risk assessments and to establish acceptable levels of antibiotic pollution. It should also be stressed that more research is required to elucidate what effect low levels of antibiotic exposure has on environmental bacterial communities.
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| 53. |
- Bergstrand, Sara, 1978-
(författare)
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Preventing pressure ulcers by assessment of the microcirculation in tissue exposed to pressure
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to combine optical methods into a system with the ability to simultaneously measure blood flow changes at different tissue depths. The goal of such a system was to reveal vascular mechanisms relevant to pressure ulcer etiology under clinically relevant conditions and in relation to the evaluation of pressure-redistribution support surfaces.This thesis consists of four quantitative, cross-sectional studies measuring blood flow responses before, during, and after pressure exposure of the sacral tissue. Two optical methods – photoplethysmography and laser Doppler flowmetry – were combined in a newly developed system that has the ability to discriminate blood flows at different tissue depths. Studies I and II explored blood flow responses at different depths in 17 individuals. In Study I the blood flow was related to tissue thickness and tissue compression during pressure exposure of ≥ 220 mmHg. In Study II, the sacral tissue was loaded with 37.5 mmHg and 50.0 mmHg, and the variation in blood flow was measured. Studies III and IV included 42 healthy individuals < 65 years, 38 healthy individuals ≥ 65 years, and 35 patients ≥ 65 years. Study III included between-subject comparisons of blood flow and pressure between individuals in the three study groups lying in supine positions on a standard hospital mattress. Study IV added within-subject comparisons while the individual was lying on four different types of mattress. The studies explored the vascular phenomena pressure-induced vasodilation (PIV) and reactive hyperemia (RH).The most common blood flow response to tissue exposure in this thesis was PIV, although a decrease in blood flow (a lack of PIV) was observed in some individuals. The patients tended to have higher interface pressure during pressure exposure than the healthy groups but no differences in blood flow responses were seen. Our results showed that pressure levels that are normally considered to be harmless could have a significant effect on the microcirculation in different tissue structures. Differences in individual blood flow responses in terms of PIV and RH were seen, and a larger proportion of individuals lacked these responses in the deeper tissue structures compared to more superficial tissue structures.This thesis identified PIV and RH that are important vascular mechanisms for pressure ulcer development and revealed for the first time that PIV and RH are present at different depths under clinically relevant conditions. The thesis also identified a population of individuals not previously identified who lack both PIV and RH and seem to be particularly vulnerable to pressure exposure. Further, this thesis has added a new perspective to the microcirculation in pressure ulcer etiology in terms of blood flow regulation and endothelial function that are anchored in clinically relevant studies. Finally, the evaluation of pressureredistribution support surfaces in terms of mean blood flow during and after tissue exposure was shown to be unfeasible, but the assessment of PIV and RH could provide a new possibility for measuring individual physiological responses that are known to be related to pressure ulcer development.
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| 54. |
- Bergström, Ida
(författare)
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Pro- and anti-inflammatory actions in coronary artery disease : with focus on CD56+ T cells and Annexin A1
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ¨The atherosclerotic process is considered to be driven by an imbalance between proand anti-inflammatory actions. Still, the inflammatory state in patients with coronary artery disease (CAD) remains to be clarified. Annexin A1 (AnxA1) is a glucocorticoidinduced protein which may have a key role in the anti-inflammatory response as a mediator of glucocorticoid effects.The general aim of this thesis was to deepen the knowledge of pro- and antiinflammatory mechanisms in CAD via phenotypic assessments of immune cell subsets, in particular CD56+ T cells, and exploration of AnxA1. The long-term goal is to reveal basic mechanisms that will lead to the development of biomarkers, which may be used for individualized treatment and monitoring.The AnxA1 protein was constitutively expressed in both neutrophils and peripheral blood mononuclear cells (PBMCs). However, it varied considerably across PBMC subsets, being most abundantly expressed in monocytes. The AnxA1 expression was also higher in CD56+ T cells than in CD56- T cells.The expression of total AnxA1 protein in neutrophils was higher in patients with stable angina (SA) compared with controls. However, this was not accompanied by altered neutrophil activation status. Instead, the neutrophils from patients exhibited an enhanced anti-inflammatory response to exogenous AnxA1, emphasizing the potential of AnxA1 as an inhibitor of neutrophil activity. Only patients with acute coronary syndrome (ACS) showed an increase in cell surface-associated AnxA1.CAD patients, independent of clinical presentation, had increased proportions of CD56+ T cells compared with controls, a phenomenon likely to represent immunological aging. The CD56+ T cells were found to exhibit a distinct proinflammatory phenotype compared with CD56- T cells. In all T cell subsets, the expression of cell surface-associated AnxA1 was significantly increased in ACS patients, while it tended to be increased in post-ACS patients. In addition, dexamethasone clearly inhibited activation of CD56+ T cells in in vitro assays, whereas AnxA1 did not. The findings highlight the need to clarify whether the role of AnxA1 is different in T cells than in innate immune cells.In PBMCs, the mRNA levels of AnxA1 were increased in CAD patients, particularly in ACS patients. Correspondingly, the monocytes in ACS patients exhibited increased AnxA1 protein levels, both totally and on the cell surface. However, only cell surface-associated AnxA1 in monocytes correlated with the glucocorticoid sensitivity of PBMCs ex vivo. We propose the expression of cell surfaceassociated AnxA1 to be a promising candidate marker of glucocorticoid sensitivity, which needs further investigations in larger cohorts and intervention trials. Furthermore, the fact that PBMCs in post-ACS patients exhibited pro-inflammatory activity but no increase in cell surface-associated AnxA1 allow us to speculate that the glucocorticoid action and/or availability might be insufficient in these patients.
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| 55. |
- Berkius, Johan, 1960-
(författare)
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Intensive care in chronic obstructive pulmonary disease : treatment with non-invasive ventilation and long-term outcome
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. When we began this project our knowledge about the outcome of COPD patients admitted to the ICU in Sweden was scarce.Aims: To investigate the characteristics, survival and health-related quality of life (HRQL) of COPD patients admitted to Swedish ICUs. To investigate how ICU personnel decide whether to use invasive or non-invasive ventilatory treatment (NIV) of the newly admitted COPD patient in need of ventilatory support. To investigate outcome according to mode of ventilation.Material and methods: Detailed data, including HRQL during recovery, from COPD patients admitted to ICUs that participated in the Swedish intensive care registry were analysed. A questionnaire was distributed to personnel in 6 of the participating ICUs in order to define factors deemed important in making the choice between invasive and non-invasive ventilation immediately after admission. The answers were analysed.Results: The proportion of COPD patients admitted to Swedish ICUs in need of ventilatory support is 1.3-1.6 % of all admissions. The patients are around 70 years-old and are severely ill on admission, with high respiratory rates and most have life-threatening disturbances in their acid-base balance and blood gases. There are more women than men. The short- and long-term mortality is high despite intensive care treatment. The majority of patients are treated with NIV. The length of stay on the ICU is shorter when NIV is used. The choice between NIV and invasive ventilation in these patients may be irrational. It is guided by current guidelines, but other non-patient-related factors seem to influence this decision. NIV seems to be preferable to invasive ventilation at admission, not only according to short-term benefits but also to long-term survival. Failure of NIV followed by invasive ventilation does not have a poorer prognosis than directly employing invasive ventilation. The health-related quality of life of COPD patients after treatment on Swedish ICUs is lower than in the general population. However it does not decline between 6 and 24 months after ICU discharge. After 24 months the HRQL is quite similar to that of COPD patients not treated on the ICU.Conclusions: COPD patients in need of ventilatory support admitted to Swedish ICUs are severely ill on admission, and their short- and long-term mortality is high despite ICU care and ventilatory treatment. Non-invasive ventilation should be the first line treatment on admission. NIV has short- and long-term benefits compared to invasive ventilation, without increasing mortality risk in case of failure. After discharge from the ICU and recovery, the HRQL of COPD patients is lower than in the general population, but comparable to COPD patients not treated on the ICU.
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| 56. |
- Bernhardsson, Magnus, 1989-
(författare)
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Healing Processes in Cancellous Bone
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most of what is known about the biological response during fracture healing comes from numerous animal studies with shaft fractures in the long bone. However, most patients suffer from fractures closer to the ends of the long bones, in the hip, or in the vertebrae. These types of fractures mainly involve cancellous bone, while shaft fractures concern cortical bone. Compared to cortical bone whose structure is dense and compact, cancellous bone is of spongy and porous structure. A growing number of studies point towards that cortical and cancellous bone heal differently. To even this imbalance in knowledge between these two types of bone tissue, further studies in cancellous bone are justified.In this thesis we delved into the quiet unknown processes behind cancellous bone healing.In the first study we characterized and compared two models for cancellous bone healing in mice and rats: the first model can be used to analyze the morphology and morphometry of the regenerating bone; the second model can measure the mechanical properties of cancellous bone. The two models correspond in their developing patterns during the first week before they diverge. This suggests that these models can be utilized together to evaluate the initial healing in cancellous bone. Furthermore, we saw in the drill hole model that the bone formation is strictly restricted to the traumatized region, with a distinct interface to the adjacent uninjured tissue.The second study characterized the cellular response during the initial healing phase in cancellous bone. The focus was to follow the spatial location of inflammatory and osteogenic cells over time in a cancellous bone injury. In contrast to shaft fractures (cortical bone), where healing is described as sequential events where inflammatory cells are the first to arrive to the trauma before osteogenic cells are recruited and initiate healing, we could see how inflammatory and osteogenic cells appeared early, simultaneously after a cancellous bone injury. This study showed that cancellous bone differs from how fracture healing is normally described.In the third study we explored the role of a subpopulation of lymphocytes (CD8 positive cells), earlier studied in shaft fractures. We wanted to see how their absence would affect the healing in a cancellous bone injury. Without CD8+ cells, cancellous bone healing was impaired as expressed via poorer mechanical properties of the regenerated bone tissue.The fourth and last study issued the influence of uninjured bone marrow on cortical bone healing. We developed a cortical defect model which blocked uninjured marrow from reaching the defect. Without the presence of marrow, the cortical defects ability to regenerate was significantly impaired. This implies that the marrow is important for cortical bone healing.In conclusion, cancellous bone healing is different from its cortical counterpart and the general perception of fracture healing. We have briefly discerned healing mechanisms in cancellous bone that might be of clinical importance: the restricted cancellous bone formation is something to take into consideration when performing arthrodeses; and importance of marrow in skeletal defects (e.g. pseudarthroses). With this thesis, we hope to promote that further investigating on cancellous bone healing is necessary.
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| 57. |
- Bernhardsson, Susanne, 1958-
(författare)
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Advancing evidence-based practice in primary care physiotherapy : Guideline implementation, clinical practice, and patient preferences
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Research on physiotherapy treatment interventions has increased dramatically in the past 25 years and it is a challenge to transfer research findings into clinical practice, so that patients benefit from effective treatment. Development of clinical practice guidelines is a potentially useful strategy to implement research evidence into practice. However, the impact of guideline implementation in Swedish primary care physiotherapy is unknown. To achieve evidence-based practice (EBP), research evidence should be integrated with clinical expertise and patient preferences, but knowledge is limited about these factors in Swedish primary care physiotherapy.The overall aim of this thesis was to increase understanding of factors of importance for the implementation of EBP in Swedish primary care physiotherapy. Specific aims were: to translate and adapt a questionnaire for the measurement of EBP and guidelines; to investigate physiotherapists’ attitudes, knowledge and behaviour related to EBP and guidelines; to examine clinical practice patterns; to evaluate the effects of a tailored guideline implementation strategy; and to explore patients’ preferences for physiotherapy.The thesis comprises four studies (A-D), reported in five papers. In Study A, a questionnaire for the measurement of EBP and guidelines was translated, cross-culturally adapted, and tested for validity (n=10) and reliability (n=42). Study B was a cross-sectional study in which this questionnaire was used to survey primary care physiotherapists in the county council Region Västra Götaland (n=271). In Study C, a strategy for the implementation of guidelines was developed and evaluated, using the same questionnaire (n=271 at baseline, n=256 at follow-up), in a prospective controlled trial. The strategy was based on an implementation model, was tailored to address the determinants of guideline use identified in Study B, and comprised several components including an educational seminar. Study D was an exploratory qualitative study of patients with musculoskeletal disorders (n=20), using qualitative content analysis.The validity and reliability of the questionnaire was found to be satisfactory. Most physiotherapists have a positive regard for EBP and guidelines, although these attitudes are not fully reflected in the reported use of guidelines. The most important determinants of guideline use were considering guidelines important to facilitate practice and knowing how to integrate patient preferences with guidelines. The tailored, multi-component guideline implementation significantly affected awareness of, knowledge of, and access to guidelines. Use of guidelines was significantly affected among those who attended an implementation seminar. Clinical practice for common musculoskeletal conditions included interventions supported by evidence of various strengths as well as interventions with insufficient research evidence. The most frequently reported interventions were advice and exercise therapy. The interviewed patients expressed trust and confidence in the professionalism of physiotherapists and in the therapists’ ability to choose appropriate treatment, rendering treatment preferences subordinate. This trust seemed to foster active engagement in their physiotherapy.In conclusion: The adapted questionnaire can be used to reliably measure EBP in physiotherapy. The positive attitudes found do not necessarily translate to guideline use, due to several perceived barriers. The tailored guideline implementation strategy used can be effective to reduce barriers and contribute to increased use of guidelines. The clinical practice patterns identified suggest that physiotherapists rely both on research evidence and their clinical expertise when choosing treatment methods. Patients’ trust in their physiotherapist’s competence and preference for active engagement in their therapy need to be embraced by the clinician and, together with the therapist’s clinical expertise, integrated with guideline use in the clinical decision making. Further research is needed on how the EBP components and different knowledge sources can be integrated in physiotherapy practice, as well as on implementation effects on patient outcomes.
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| 58. |
- Bivik Stadler, Caroline, 1986-
(författare)
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Genetic pathways controlling CNS development : The role of Notch signaling in regulating daughter cell proliferation in Drosophila
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human central nervous system (CNS) displays the greatest cellular diversity of any organ system, consisting of billions of neurons, of numerous cell sub-types, interconnected in a vast network. Given this enormous complexity, decoding the genetic programs controlling the multistep process of CNS development remains a major challenge. While great progress has been made with respect to understanding sub-type specification, considerably less is known regarding how the generation of the precise number of each sub-type is controlled.The aim of this thesis was to gain deeper knowledge into the regulatory programs controlling cell specification and proliferation. To address these questions I have studied the Drosophila embryonic CNS as a model system, to thereby be able to investigate the genetic mechanisms at high resolution. Despite the different size and morphology between the Drosophila and the mammalian CNS, the lineages of their progenitors share similarity. Importantly for this thesis, both species progenitors show elaborate variations in their proliferation modes, either giving rise to daughters that can directly differentiate into neurons or glia (type 0), divide once (type I), or multiple times (type II).The studies launched off with a comprehensive chemical forward genetic screen, for the very last born cell in the well-studied lineage of progenitor NB5-6T: the Ap4 neuron, which expresses the neuropeptide FMRFa. NB5-6T is a powerful model to use, because it undergoes a programmed type I>0 daughter cell proliferation switch. An FMRF-eGFP transgenic reporter was utilized as readout for successful terminal differentiation of Ap4/FMRFa and thereby proper lineage progression of the ∼20 cells generated. The strongest mutants were mapped to genes with both known and novel essential functions e.g., spatial and temporal patterning, cell cycle control, cell specification and chromatin modification. Subsequently, we focused on some of the genes that showed a loss of function phenotype with an excess of lineage cells. We found that Notch is critical for the type I>0 daughter cell proliferation switch in the NB5-6T lineage and globally as well. When addressing the broader relevance of these findings, and to further decipher the Notch pathway, we discovered that selective groups of E(spl) genes is controlling the switch in a close interplay with four key cell cycle factors: Cyclin E, String, E2F and Dacapo, in most if not all embryonic progenitors. The Notch mediation of the switch is likely to be by direct transcriptional regulation. Furthermore, another gene identified in the screen, sequoia, was investigated. The analysis revealed that sequoia is also controlling the daughter cell switch in the CNS, and this partly through context dependent interactions with the Notch pathway.Taken together, the findings presented in this thesis demonstrate that daughter cell proliferation switches in Drosophila neural lineages are genetically programmed, and that Notch contributes to the triggering of these events. Given that early embryonic processes is frequently shown to be evolutionary conserved, you can speculate that changeable daughter proliferation programs could be applied to mammals, and contribute to a broader understanding of proliferation processes in humans as well.
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| 59. |
- Björck, Hanna, 1979-
(författare)
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Vessel wall integrity : influence of genetics and flow
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow.The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease.Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women.Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca2+ signalling were among the most highly differentially expressed. Up-regulation of Ca2+-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall.Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.
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| 60. |
- Björk Wilhelms, Daniel
(författare)
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Fever : Role of brain endothelial prostaglandins
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.
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