| 1. |
- Nilsson, Kerstin
(författare)
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To work or not to work in an extended working life? Factors in working and retirement decisions
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In most of the industrialised world, the proportion of older and retired people in the population is continuously increasing. This will have budgetary implications for maintaining the welfare state, because the active working section of the population must fund the non-active and old population. Aim: The overall aim of this thesis was to obtain knowledge about older workers’ work and life situation in association with their planning and decision to retire from working life. Method: The thesis includes one qualitative and three quantitative studies conducted in Sweden. Result: Self-rated health was found to be a better measure than diagnosed disease of whether older workers believed they could work until 65 years or beyond. Health seems not to be a general impediment to working in old age if older workers are satisfied with their work situation and have enough time and opportunities to recover from fatigue. In one of Sweden’s most hazardous work environments, older workers were not injured significantly more often than younger workers. Good mental and physical work environment, moderate working pace and working time, and the right competence and possibility for skills development were factors determining whether older workers believed they can extend their working life. Attitude to older workers in the organisation, motivation and work satisfaction were factors determining whether older workers want to extend working life. Health, personal economic incentives, family/leisure pursuits and attitude to pension in society affected both whether people believed they can and wanted to extend their working life. In their final retirement decision, older workers considered: i) their possibility to balance and adapt functional ageing and health to a sustainable work situation; ii) their economic situation; iii) possibilities for social inclusion and coherence; and iv) possibilities for meaningful activities. Whether these requirements were best fulfilled in or outside working life determined the decision to continue working or to retire. Conclusion: If it is desirable for society that people will to extend their working life, both the “can work” and the “want to work” factors need to be met. It is important to provide a good fit inside working life. This requires a focus not only on older workers, but also on organisations and managers in order to provide incentives that keep older workers in the work force.
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| 2. |
- Dardashti, Alain
(författare)
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Importance of renal function in cardiac surgery
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Acute kidney injury (AKI) is a common and serious complication after cardiothoracic surgery and is associated with increased short- and long-term mortality risk. Despite extensive studies in the field, a comprehensive understanding of this syndrome has remained elusive, partly due to divergent definitions of AKI and partly due to the limitations of available routine biomarkers to predict, prevent, and detect AKI. In recent years, much has been done to better define AKI. There is also ongoing work on finding better suited biomarkers for AKI as well as improving treatment of patients at risk or suffering from AKI. In this work we studied different aspects of renal function after cardiac surgery. The first paper shows in a retrsospective study of 5261patients, when preoperative estimated glomerular filtration (eGFR) rate by s-creatinine and preoperative hemoglobin is entered into a Cox analysis together with known traditinoal risk factors for decreased long-term survival, blood transfusion did not affect survival significantly. In the subgroups of patients with normal eGFR and hemoglobin, blood transfusions did not have any effect on longterm survival. In the second paper, incidence of AKI is evaluated in 5746 patients, defined by different measures (i.e creatinine, creatinine clearance and eGFR) and evaluated in relation to long-term mortality. The effect of renal recovery on survival was also described. The Risk, Injury, Failure, Lost and Endstage (RIFLE) system was used to stratify AKI. The study showed that estimated GFR by the modification of diet in renal disease (MDRD) formula had a more robust predictive ability for mortality and that renal recovery in general was associated with better outcome compared with those without renal recovery. The third paper describes a randomized, double-blind, placebo-controlled trial, where the effect of a single high dose erythropoeitin (EPO) preoperatively, as a protective drug against AKI after cardiac surgery, is evaluated. Seventy five patients were enrolled in the study, AKI was evaluated by the changes of s-cystatin C at the third postoperative day from baseline. No protective effect against AKI by EPO could be shown. In the fourth paper the predictive value for mortality of s-creatinine and s-cystatin C and their eGFR were evaluated at different time points in patients undergoing cardiac surgery. The prospective study included 1955 patients. Different creatinine and cystatin C eGFR equations were used in the analysis. S-Cystatin C was shown to have a stronger and earlier predictive value for mortality compred with s-creatinine, and the predictive abliltiy of cystatin C was also shown preoperatievly.
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| 3. |
- Gunnlaugsson, Adalsteinn
(författare)
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Chemoradiation in Gastrointestinal Cancer
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Locally advanced inextirpable gastrointestinal cancer has poor prognosis and is associated with high morbidity. One treatment option is to use radiotherapy, often combined with chemotherapy (chemoradiation), either as preoperative treatment to facilitate surgery or in the palliative setting to relieve symptoms. The aim of this thesis was to investigate efficacy and toxicity of intensive chemoradiation including conformal radiotherapy and newer chemotherapeutic agents. Oxaliplatin and capecitabine together with 50 Gy radiotherapy was used in a national phase I-II study (CORGI), divided in two parts by tumor location. Among 61 patients with locally advanced colorectal cancer, primary tumor or local recurrence, with or without distant metastases, the objective local response rate was 58% and 79% went to surgical resection (paper I) The main side-effect was diarrhea. 39 patients with pancreatic or biliary tract cancer were included (paper II). The maximum tolerated chemotherapy doses were determined. Dose-limiting toxicity was nausea/vomiting. The local response rate was 21 %. In both CORGI studies there was a high frequency of sustained local control at two years. The most important risk factor for diarrhea during chemoradiation was the volume of small bowel that received >15 Gy (paper III). Enteritis is thought to be mediated by eradication of intestinal crypts. In a mouse model we found that adding oxaliplatin and 5-FU to radiation increased the mucosal damage (paper IV). Thus, chemoradiation is effective and feasible in several types of gastrointestinal cancers. Sparing small bowel from radiation is important.
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| 4. |
- Magnusson-Lind, Anna
(författare)
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A peripheral immune response in Huntington's disease and delineation of its importance in disease pathology
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Huntington’s disease (HD) is a fatal, hereditary disease for which there is no cure. It is caused by a mutation in a gene called huntingtin. HD is a so-called neurodegenerative disease, where there is a loss of neurons in areas of the brain that control body movements. This results in uncontrolled dance-like movements (chorea). Traditionally, research on HD has focused round the brain and what is causing the neurodegeneration. There are however other symptoms that cannot be overlooked. Patients are suffering from weight loss despite adequate intake of nutrition. They also suffer from muscle wasting, cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and a subtle increase in inflammatory proteins. These symptoms further affect the quality of life and disease progression for patients with HD. The overall aim of this thesis was to investigate the mechanism behind elevated levels of inflammatory proteins previously detected in HD patients, and how that could affect other aspects of disease pathology, such as muscle wasting. We isolated cells of the immune response, from both HD patients and three different mouse models of HD, and studied their activity as well as function. These studies led us to further investigate intracellular signaling pathways involved in immune cell-function. We also wanted to investigate gene expression in skeletal muscle from a mouse model of HD and to investigate if and how inflammatory proteins could affect muscle cells in culture. Our studies of immune cell-activation showed that immune cells from both HD patients and from three different mouse models of HD produce higher levels of inflammatory proteins when activation is triggered. This seems to be caused by the direct interaction of the mutant huntingtin protein with a signaling pathway called NFκB. We could also see that there are changes in the expression of genes involved in muscle contraction and the immune response in skeletal muscle, and by stimulating muscle cells in culture with inflammatory proteins known to be elevated in HD, we could furthermore see a change in these genes. The results of this thesis warrants for further investigations into the inflammatory response in HD and how it may affect the disease. The findings also support future studies of anti-inflammatory treatment in HD.
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| 5. |
- Åkerberg, Daniel
(författare)
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Differently charged polypeptides and their impact on peritoneal and pleural postoperative adhesion formation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Organization LUND UNIVERSITY Department of Surgery, Clinical Sciences Skånes University Hospital Lund SE-221 85 Lund Sweden Document name DOCTORAL DISSERTATION Date of issue: November 8, 2013 Author(s): Daniel Åkerberg Sponsoring organization Title and subtitle: Differently charged polypeptides and their impact on peritoneal and pleural postoperative adhesion formation Abstract: Abdominal adhesions are formed after previous peritoneal traumas where previous surgery poses the most frequent cause. An increasing number of clinical complications due to adhesions have been detected such as small bowel obstructions, female infertility, and pain. Postoperative adhesions also form in pleura and pericardium after thoracic surgery. Complications include risk of bleeding, organ perforation and prolonged surgery, both in the thorax and abdomen, during reoperations. Previous reports have shown increased healthcare expenditures due to complications of abdominal adhesions. Several prophylactic anti-adhesion devices exist on the market, but none of them are sufficient in every aspect, such as being able to be used during abdominal infections, bleeding and in case of an intestinal anastomosis. The use of two differently charged polypeptides covering the peritoneal wounds during surgery has, in previous studies, shown promising anti-adhesion effects. The aim of this study was to investigate whether the polypeptides in any way affected different important healing aspects of the peritoneum and if the polypeptides may be administered as a spray in an animal study (I). Furthermore, the aim was to elucidate if the administered polypeptides affected important aspects of the healing process during an extended time dynamic pattern (II). It was also investigated whether the polypeptides reduced adhesions after adhesiolysis in the abdomen (III) and pleura (IV), and if there was an impact on peritoneal/pleural healing. In order to investigate the impact of polypeptides, an in vitro cell model was set up (V). A significant decrease in adhesions was seen both in the abdomen and pleura using the polypeptides. A significant decrease in adhesion reformation was seen after adhesiolysis and polypeptide administration. Despite some variation, no significant impact on key parameters of peritoneal and pleural resolving processes were seen after administration of the polypeptides. It was feasible to administer the polypeptides with a spray atomizer. Cell proliferation was decreased when higher concentrations of the polypeptides were administered, indicating a dose response relationship relying on the configuration and amount of charges of the polypeptides. In conclusion, the use of the two differently charged polypeptides to prevent abdominal and pleural adhesions was feasible, reducing adhesions after primary surgery and relaparotomy, without affecting key parameters of the resolving process investigated. Key words: Abdominal adhesions, small bowel obstructions, pain, female infertility, pleural adhesions, peritoneal, pleural, resolving process and key substances. Classification system and/or index terms (if any) Supplementary bibliographical information Language English ISSN and key title 1652-8220 ISBN978-91-87651-18-2 Recipient’s notes Number of pages 150 Price Security classification
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| 6. |
- AbdGawad, Mohamed
(författare)
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Proteinase 3 and Neutrophil Apoptosis in ANCA-Associated Systemic Vasculitis
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis- dying neutrophils surrounding small blood vessels. Previous studies have shown increased plasma PR3 and increased proportion of neutrophils expressing plasma membrane-associated PR3 (mPR3+). Neutrophils were isolated by polymorphprep and membrane expression was measured by FACS. Plasma PR3, pro-PR3 and cytokines were measured by ELISA. Neutrophil apoptosis was measured by FACS after 20h in vitro culture. Expression of pro/anti-apoptotic factors and transcription factors C/EBP-α, C/EBP-β and PU.1 was measured by real-time PCR. Plasma PR3, pro-PR3, and proportion of mPR3+neutrophils were elevated in AASV. mPR3 and CD177 were co-expressed on a subset of neutrophils both in AASV and controls. mPR3 expression was not correlated directly to circulating PR3 or PR3 gene transcription, but was dependent on transcription of the CD177 gene. AASV neutrophils had a significantly lower rate of apoptosis than neutrophils from healthy blood donors (HBD). Lower apoptosis rate did not correlate with clinical data, plasma PR3, cytokine levels, mPR3 expression or level of pro/anti-apoptotic factors. However, C/EBP-α and C/EBP-β were significantly higher in neutrophils from AASV patients than in HBD neutrophils. These results indicate an altered neutrophil phenotype in AASV and suggest that the rate of granulopoiesis is higher, while the rate of neutrophil apoptosis is lower. This may predispose for the presence of dying neutrophils in regions of inflammation in AASV. Additional studies are required to determine why the rate of neutrophil apoptosis is lower in AASV patients and if dysregulation of neutrophil apoptosis contributes directly to the pathogenesis.
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| 7. |
- Abdulla, Aree
(författare)
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Role of platelets and neutrophils in regulating trypsinogen activation and tissue damage in acute pancreatitis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute pancreatitis is an inflammatory disease characterized by a diverse spectrum of clinical presentations ranging from a mild and self-limiting to a severe and systemic disorder. The relationship between inflammation and proteolytic activation in pancreatitis is an elusive issue. The aim of this thesis was to define the influence of platelets and neutrophils as well as their interrelations in relation to trypsinogen activation and tissue damage in pancreatitis. For this purpose, three different experimental models of acute pancreatitis were used in mice. Pancreatitis was induced by retrograde infusion of taurocholate into the pancreatic duct, by intraperitoneal administration of caerulein or L-arginine. Severity of pancreatitis was evaluated by morphological examination of the pancreas as well as serum and pancreatic biochemical markers. Intravital fluorescence microscopy was used to study leukocyte-endothelial interactions in the pancreatic microcirculation. Flowcytometry was used to quantify platelet-neutrophil aggregates and adhesive molecule expression on cells. Induction of pancreatitis provoked a clear cut tissue damage characterized by increased neutrophil infiltration, myeloperoxidase and macrophage inflammatory protein-2 levels, trypsinogen activation peptide, acinar cell necrosis, oedema formation and haemorrhage in the pancreas, as well as elevated serum amylase activity. Depletion of platelets and neutrophils reduced pancreatic tissue damage, neutrophil accumulation and macrophage inflammatory protein-2 formation as well as amylase levels. Also, it was found that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils and mediated by neutrophil-derived matrix metalloproteinase-9 in the pancreas. Platelets were found to regulate neutrophil recruitment in to the pancreas via upregulating P-selectin on pancreatic microvasculature. Depletion of platelets and inhibition of P-selectin not only reduced leukocyte rolling but also tissue damage in acute pancreatitis. Thus, targeting both neutrophil and platelet functions may be a useful strategy in the management of acute pancreatitis.
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| 8. |
- Ahl, Jonas
(författare)
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Respiratory Tract Infections: Aspects of Aetiology, Virulence, and Communicable Disease Control
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The paediatric nasopharyngeal flora is regarded as the largest reservoir for Streptococcus pneumoniae, and the carrier state is always antecedent to infection and a prerequisite for dispersion of these bacteria. Pneumococci are the predominant aetiology of bacterial respiratory tract infections and a major cause of morbidity and mortality, in the most severe cases due to invasive pneumococcal disease (IPD; mainly sepsis and meningitis).The development and spread of resistant pneumococci are facilitated in day care centres (DCCs), which constitute an optimal environment for these processes. In Sweden, penicillin non-susceptible pneumococci (PNSP) have remained relatively uncommon,an important aspect considering that penicillin is the drug of choice for respiratory tract infections. When a tendency towards increasing PNSP was noted in Skåne County in southern Sweden, a DCC intervention program including screening started when an attending child has been found to be PNSP carrier. To restrict dispersion, all carriers were suspended from DCCs until they were declared free from PNSP. Today, there is no scientific proof that such DCC interventions can effectively restrict PNSP dispersion on a community level. Our retrospective study of the DCC interventions showed that 5% of the children were PNSP carriers during an outbreak. Personnel were rarely carriers (0.4%) and, if so, for only a very short time. PNSP was found a long time after the intervention started in a few children cultured late due to absence from the DCC for other reasons, indicating a long-lasting risk for dispersion. Furthermore, PNSP carriage was observed in a substantial number of children at DCC departments other than the department attended by the index case, indicating that the index case is not always at the centre of an outbreak. There was also significant seasonal variation seen as lower carrier rates after major holidays, indicating that these rates decline when children are not at DCCs. Day care group size and young age proved to be risk factors for pneumococcal carriage. Our findings can support development of future guidelines for managing PNSP outbreaks in DCCs. Eradication therapy of children with prolonged PNSP carriage was effective, but none of the treated children harboured any highly resistant or multidrug-resistant strains. Our retrospective study of IPD demonstrated that pneumococcal serotypes differ regarding their capacity to cause septic shock and, together with age and co-morbidities, have an important impact on outcome. The primary endpoint in our investigation was septic shock, a state produced by the immune system and triggered by the invading microorganism. This parameter was chosen instead of the case fatality rate (CFR),which is usually studied as outcome but is biased because serotypes with a low CFR infect healthier and younger individuals and vice versa. Septic shock was significantly more common among patients infected with serotype 3 compared to those with serotype 14, a worrisome finding since the effect of the conjugate vaccine on this serotype seems to be uncertain. Ventilator-associated pneumonia (VAP) is a common infection and complication in intensive care units. We found that the bacterial aetiology in VAP differed depending on whether the patients were receiving antibiotics at the time of the VAP diagnosis. Pseudomonas aeruginosa was a surprisingly widespread cause of early-onset VAP, but most of the patients had been treated with antibiotics. There was a trend towards more resistant bacteria in late-onset VAP.
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| 9. |
- Ahlström-Emanuelsson, Cecilia
(författare)
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Symptoms and aspects on eosinophil activity in allergic rhinitis
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergic rhinitis is a major atopic disease. Even if much is known about the pathophysiology of this condition, and despite the fact that good treatments are available, there is a need for new treatment options, particularly for such aiming at new targets and reduced side effects. Recruitment and activation of eosinophils is a key feature of allergic rhinitis. Eosinophils have different activation modes with subsequent mediator release. Before and during a natural birch pollen season we take nasal biopsies and utilize electron microscopy to assess eosinophil activity. We show that allergen exposure produces a marked increase in piecemeal degranulation and release of mediators (indicated by ECP). Variations in onset, intensity, and duration of natural pollen exposure make it difficult to compare treatments in allergic rhinitis. To overcome this, we demonstrate that repeated individualized allergen challenges can produce symptoms and signs that mimic seasonal disease. We indicate the usefulness of the model by demonstrating dose-dependent symptom-reducing effects of a topical corticosteroid. Preceding observations suggest that ß2-agonists may be treatment candidates for allergic inflammation. Utilizing the above-mentioned allergen challenge model, we examine whether or not a topical ß2-agonist (formoterol) affect eosinophilic inflammation in allergic rhinitis. We demonstrate that the ß2-agonist neither affects symptoms and eosinophilic inflammation in allergic rhinitis nor the efficacy of a topical corticosteroid. Employing the allergen challenge model, and a topical corticosteroid as experimental tool, we demonstrate that production of the eosinophil chemokine CCL5 is particularly corticosteroid sensitive, suggesting that it may be a valid treatment target.
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| 10. |
- Ahmad Kiadaliri, Aliasghar
(författare)
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Towards a Health Economic Simulation Model of Type 2 Diabetes in Sweden
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to provide part of the data required in updating/developing computer simulation models (CSMs) for type 2 diabetes mellitus (T2DM) using data obtained from routine clinical practice in Sweden. In paper I, evolution of five biomarkers (i.e., HbA1c, systolic blood pressure, BMI, LDL and total to HDL cholesterol ratio) over time was estimated using data on 5,043 newly diagnosed T2DM patients from the Swedish National Diabetes Register (NDR) and a dynamic panel data framework. The results indicated that difference between individuals with high and low biomarker values at the baseline was diminishing over time. In paper II, we estimated and validated the risk equations for the first and second major macrovascular events after diagnosis during the five years of follow up using the data on 29,034 T2DM patients from the NDR. We used the Weibull proportional hazard regression to estimate these equations. We found within- and between-event heterogeneities in associations between explanatory variables and the risk of experiencing an event. Validation analysis indicated that all equations had reasonable predictive accuracy in the test sample. In paper III, health utility weights associated with several T2DM-related complications were estimated using survey data on the Swedish version of EuroQol (EQ-5D) instrument among 1,757 T2DM patients collected by the NDR in 2008. The results indicated that history of kidney disorders (–0.114) and stroke (–0.111) had the highest negative effects on the UK EQ-5D index score. Using the UK and Swedish tariffs resulted in discrepant estimates, possibly leading to divergent results from cost–utility analyses. In paper IV, an existing cohort model of T2DM in Sweden was updated using equations from papers II and III, and was used to estimate the lifetime costs and benefits of three second-line treatment alternatives, i.e., GLP-1 agonists, DPP-4 inhibitors, or NPH insulin, as add-on to metformin among T2DM patients in Sweden failing to reach Hba1c ≤ 7% with metformin alone. The results indicated that assuming a willingness to pay of SEK 500,000 per QALY gained in Sweden, treatment strategy with GLP-1 can be considered cost-effective compared to DPP-4 or NPH insulin as second line treatment. The results indicated the importance of developing and refining the equations required in CSMs as new data become available. The data presented in the current thesis are representative of the current clinical practice in Sweden and hence it is suggested that using these data in economic evaluations of T2DM treatment strategies might provide more relevant and accurate results for policy-making in Sweden.
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| 11. |
- Ahnstedt, Hilda
(författare)
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Stroke, Sex and Vascular Receptor Changes in the Brain
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stroke is a severe cerebrovascular disease in which the neuronal tissue and vasculature of the brain undergo ischemia-evoked alterations. We have demonstrated an increased expression of cerebrovascular contractile receptors in the brain. This is hypothesized to mitigate cerebral blood flow and exacerbate tissue damage after stroke. An increased contractile property of these receptors has been demonstrated to occur by MEK/ERK1/2 signaling. The majority of pre-clinical studies on stroke are performed in young healthy male animals, despite the fact there is a difference in male and female stroke incidence. The present thesis therefore aimed to investigate the status of vascular receptor changes after experimental stroke and organ culture, with two focus areas that previously have been missing – studies on human material and female subjects. In human cerebral arteries, we found that increased vasoconstriction of 5-HT1B, AT1 and ETB receptors during organ culture, a model of ischemic-like receptor changes, is mediated by B-Raf/MEK/ERK1/2 signaling. Although, increased mRNA and protein of these receptors were found in arteries from both sexes, the contraction to Ang II and ET-1 was markedly lower in female arteries. Focal cerebral ischemia in female rats induced an enhanced contractile property of cerebrovascular ETB receptors, similar to previous observations in males. Ovariectomy, and thereby loss of progesterone and estrogen, resulted in less ischemia-induced ETB receptor upregulation. Hormone therapy with progesterone, but not estrogen, reversed these changes. The increased ETB receptor expression and vasoconstriction after cerebral ischemia in female rat was demonstrated to be mediated by MEK/ERK1/2 signaling. MEK1/2 inhibition attenuated the ETB receptor upregulation and improved the neurological outcome. The present thesis demonstrates for the first time sex differences in vascular function of human cerebral arteries. The underlying mechanism in decreased responsiveness of female arteries remains to be elucidated. This may involve differences in receptor coupling or signal transduction influenced by female sex steroid hormones, or biological sex. Our experimental studies on stroke suggest the loss of progesterone after ovariectomy suppresses ischemia-induced ETB receptor upregulation. Further, the signal transduction pathway involved in vascular receptor changes after cerebral ischemia is suggested to be similar in both sexes. MEK1/2 inhibition is therefore a promising therapeutic target for stroke therapy in both males and females.
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| 12. |
- Aili, Ulrika
(författare)
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Tumor Selective Antiproliferative Naphthoxylosides
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proteoglycans (PG) are highly anionic macromolecules consisting of a core protein covalently substituted with long unbranched polysaccharide chains called glycosaminoglycans (GAGs). PGs are central components in multicellular organisms, and they may occur in the extracellular matrix (ECM), at the cell surface, or in the secretory pathway. At the tumor cell surface, PGs and GAGs are involved in the pathophysiological steps of tumor progression by regulation of tumor proliferation, invasion, metastasis, angiogenesis, and stem cell differentiation. Xylose is an unusual structural component of mammalian cells and it serves as the linker between the protein and the GAG chain in PG. β-D-xylosides attached to various hydrophobic aglycons can penetrate plasma membranes and act as artificial primers for GAG formation, independently of core protein synthesis. The overall purpose of this project was to investigate the antiproliferative activity of xyloside primed GAG chains and to study different aspects on how xylosides or xyloside primed GAG chains inhibit growth of cancer cells. This thesis demonstrates that the xyloside primed GAG chains produced by tumor cells inhibit growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside pro-drug, while surrounding normal cells do not produce any antiproliferative GAG chains. We have also shown effects on histone acetylation, indicating epigenetic effects.
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| 13. |
- Aits, Sonja
(författare)
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Mechanisms of HAMLET-induced cancer cell death
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HAMLET, a complex of α-lactalbumin and oleic acid, preferentially kills cancer cells and is also effective in vivo. HAMLET causes apoptosis but cells die even if this pathway is inhibited. Thus, the role of autophagy, an alternative cell death pathway, was examined. During autophagy double membrane-enclosed autophagosomes form around cellular material and deliver it to the lysosomes for degradation. After HAMLET treatment, such vesicles were observed and HAMLET also increased granular LC3-GFP staining confirming autophagosome accumulation. In addition, the autophagic form of LC3 increased if lysosomal degradation was inhibited, indicating a true increase in autophagic flux. Several factors that may activate autophagy were identified, including mitochondrial damage, inhibition of the autophagy inhibitor mTOR and increased the expression of autophagy components. Inhibition of autophagy by Atg5 and Beclin-1 siRNAs reduced cell death suggesting that autophagy is an important part of the cell death programme. As autophagy can be initiated by metabolic stress and as metabolism is altered in cancer cells we investigated if HAMLET-induced cell death involves an effect on metabolism. Healthy cells, which were less sensitive to HAMLET, had lower levels of c-Myc, an important regulator of glucose metabolism, and knockdown of c-Myc in cancer cells reduced their sensitivity. In contrast, cancer cell death was enhanced by glycolysis inhibition. HAMLET was also shown to bind the glycolytic enzyme hexokinase 1 (HK1) and to reduce HK activity, ATP levels and lactate release. Also, knockdown of HK1 and the glycolysis-enhancing HIF1A sensitized cancer cells to HAMLET whereas knockdown of the glycolysis-regulating protein PFKFB1 reduced sensitivity. Finally, mass spectrometry-based analysis indicated that HAMLET has a broad impact on metabolism possibly due to binding of HK1. In an additional screen for HAMLET-binding proteins prohibitin-2, a multifunctional protein found at the same cellular sites as HAMLET, was identified. The binding was confirmed in vitro and HAMLET was shown to also bind to the related prohibitin. Co-staining for HAMLET and prohibitins revealed colocalization in the cytoplasm. In addition, nuclear staining for both prohibitins was reduced, as described in camptothecin-induced cancer cell death. Furthermore, prohibitin-2 siRNA reduced cell death after HAMLET treatment suggesting that prohibitins may play a role in HAMLET-induced cell death. Besides cell death, HAMLET also causes cancer cell detachment and α-actinin-4, which crosslinks the actin cytoskeleton and focal adhesions, was identified in a screen as a potential HAMLET target. The binding between HAMLET and α-actinins was confirmed by co-immunoprecipitation and the actin and integrin binding sites on α-actinin were identified as possible sites of HAMLET binding in a peptide binding assay. HAMLET was also shown to colocalize with α-actinin-4 in the cell periphery and to reduce its granular surface staining and intracellular trabecular staining. In addition, HAMLET altered the staining of other focal adhesion components and reduced the level of active focal adhesion kinase and ERK, which can both be regulated via focal adhesions. Healthy cells did not detach after HAMLET treatment but the detachment of cancer cells was even further enhanced by knockdown of α-actinins. In contrast, overexpression of α-actinin-4-GFP delayed blebbing and rounding up further suggesting that α-actinin is involved in HAMLET-induced detachment. In summary, this study indicates that HAMLET activates autophagy and disrupts metabolism at least partly by binding to HK1 and that these events contribute to cell death. The results also suggest that c-Myc and glycolysis are important determinants of HAMLET sensitivity. Furthermore, the study identifies prohibitins as novel HAMLET targets with a potential role in cell death and suggests that HAMLET binding to α-actinins disrupts focal adhesions leading to cell detachment.
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| 14. |
- Akaberi, Shahriar
(författare)
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Persistent hyperparathyroidism in renal transplant patients
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Disorders in mineral metabolism and secondary hyperparathyroidism (sHPT) are well known complications in patients with chronic kidney disease (CKD). Hyperparathyroidism (HPT) persists in a majority of patients after kidney transplantation (KTx). Parathyroidec-tomy (PTX) is indicated in patients who are resistant to medical therapy both before and after KTx. Overall aims of this thesis were to investigate, I, incidence of PTX in patients with therapy resistant sHPT on renal replacement therapy; II, to study the effects of persistent HPT on bone mineral density (BMD) in long-term kidney transplant patients, and III, whether DXA can predict fractures in this patient group. A further aim was, IV, to investigate the role of HPT as a risk factor for new onset diabetes after KTx (NODAT). Results: PTX rate was 8.8 per 1000 person years. This rate varied markedly over time. PTH had a negative impact on cortical bone. Osteoporosis, osteopenia and BMD < 0.9 g/cm2 in the hip region were all independent risk factors for fracture. An elevated PTH level was strongly associated with new onset diabetes after KTx. Conclusion: We believe that the observed variation in PTX rate is due to the results of previous research showing the detrimental effects of mineral disorders and severe sHPT in CKD patients; and to the introduction of novel medications such as cinacalcet. We found that PTH had a negative impact on BMD in KTx patients and that DXA is a useful tool to predict fracture in these patients. In addition, we showed that PTH was strongly associated with NODAT.
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| 15. |
- Akbarshahi, Hamid
(författare)
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Acute pancreatitis, from local defense to remote organ injury
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications such as acute lung injury (ALI). Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults. Heparan sulfate (HS) is a common component of extracellular matrix which lines the ductal cells in the pancreas. During the process of the disease, active enzymes in the pancreas will cause shedding of HS. We have shown that HS is able to start an inflammatory response in the pancreas. This response was mediated via Toll like receptor-4 and involved both MyD88-dependent and –independent pathways. We propose that HS has a role in the monitoring of pancreatic tissue well-being. Acute lung injury is the most common extra-pancreatic complication in the acute pancreatitis. Macrophages are a heterogeneous population based on their anatomical location and their micro-environment. Our data showed an enriched population of CD68+F4/80- macrophages in the lungs of animals with AP. This population had an increased expression of CD206 (a cell marker of alternatively activated macrophages) and CCR2 (the receptor for CCL2, an important chemoattractant for macrophages). Studying lung macrophages for different phenotypic markers, their polarization, activation and recruitment, in the context of acute lung injury, is a novel area to potentially identify interventions which may improve the outcome of acute lung injury. Macrophages are a source of various remodeling cytokines including TGF-β. TGF-β not only participates in the late phase of acute lung injury, but also might be active early in acute lung injury and potentially could contribute to the development of pulmonary edema. Our data showed an increase in the level of TGF-β1 in the lungs of the acute pancreatitis group early on but this was in parallel with an increase in the level of inhibitory Smad7. The level of Smad7 was back to the control level after 24 h when there was an increase in the nuclear translocation of phosphorylated Smad2. Our findings suggest that TGF-β signaling pathway can be activated in the early phase of ALI due to AP and may have a contributing role in the pathogenesis of lung injury. Therefore, TGF-β signaling pathway can represent a potential strategy to be used in the future treatment of ALI.
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| 16. |
- Al-Emrani, Faisal
(författare)
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Socioeconomic patterns of overweight and obesity in Scania, Sweden
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Overweight and obesity are major social and public health concerns globally. The obesity epidemic is caused by a widespread chronic energy imbalance between high-energy intake and low-energy expenditure, but this mechanism appears to be modified by a number of other biological, behavioral, and social factors that interact in a complicated manner. It has become a great challenge to understand the etiology of the global epidemic of obesity and overweight in order to design and implement policies that may counter the rapid growth of this worldwide threat to population health. Socioeconomic inequality and lifestyle factors, together with changes in the global food system and the environment, have been identified as playing a major role. The prevalence of obesity in high-income countries is greater in lower socioeconomic groups, particularly among women, but the mechanisms behind this phenomenon remain unclear, resulting in major negative implications for health equity. The overall objective of this thesis was to assess the association between socioeconomic and lifestyle factors vis-à-vis weight change, overweight, and obesity among Swedish adults in Scania, Sweden. The study population is based on the data from two waves (1999/2000 and 2005) of the Scania Public Health Cohort. It was generated from a large (n = 25,000) random selection of the adult population in the region of Scania, southern Sweden. Participants completed a self-administered postal questionnaire (baseline response rate = 59%). BMI was calculated from self-reported body height and weight. Socioeconomic status was determined by means of job title and description, or by years of education. Mediating mechanisms as well as confounding control was assessed in logistic regression models with special attention to effect-modifying interactions. Study I found that adult and childhood socioeconomic position influence weight gain, but differently by gender and age group. Two waves of socioeconomically determined weight gain patterns appeared in the population studied: one across generations and another contemporary one. Study II concluded that cohort effects play a role in BMI change. However, it was difficult to distinguish between age-period and cohort-period effects because of the linear relationship between age, period, and cohort, and due to the short follow-up. Study III showed a two-fold correlation between social capital and obesity: as a determinant in its own right, and as a modifier of the effect of socioeconomic status on obesity. Study IV demonstrated that women around retirement age with low and mid-level educations were at higher risk of weight gain over a five-year follow-up period, although this association could not be explained by changes in their leisure time physical activity or their social participation. The thesis confirmed a relationship between socioeconomic status and overweight/obesity in the population studied. However, it concluded that these relations are highly complex and dependent on a number of individual and contextual factors that vary over time, between different age groups and birth cohorts, and by gender. The concept of social capital emerged as promising in the developing of general and specific interventions for addressing obesity and overweight on the community level. Such interventions must be created for different age groups. In this regard, the period near retirement appears to play a significant role in weight gain.
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| 17. |
- Alenmyr, Lisa
(författare)
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Sensory mechanisms in the human upper airway - Role of TRP ion channels
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The nasal mucosa is richly innervated with sensory nerves having the ability to detect changes in the environment and mediate symptoms such as secretion and itch. Some TRP ion channels such as TRPV1 and TRPA1 are abundantly expressed in sensory nerves and respond to a wide variety of stimuli, including irritants, inflammatory mediators and temperatures. Another interesting TRP ion channel is TRPV4, which is present in the airway epithelium and capable of sensing warm temperatures and osmotic changes. TRP ion channels may have important roles in airway physiology and pathology. We studied the responses to TRP activation in the upper airway of healthy subjects and patients with allergic rhinitis. Furthermore, we examined the effect of TRPV1 antagonism in allergic rhinitis. We showed that activation of TRPV1 and TRPA1 lead to secretion of MUC5B from submucosal glands, and that TRPV1 activation results in an enhanced rhinorrhea and itch response in patients with allergic rhinitis during pollen season. However, our initial studies were unable to demonstrate any symptomatic relief by a TRPV1 antagonist in allergic rhinitis. Analyses of mRNA of different TRP ion channels indicated TRPV1 expression in nasal epithelium, but we were unable to detect any functional response in ciliated epithelial cells. TRPV4 presented the highest mRNA expression of tested TRP ion channels, and further functional studies implied that TRPV4 may be involved in ciliary beat frequency regulation in primary human epithelial cells. Our studies indicate that TRPV1 expressing sensory neurons and possibly TRPV1 itself are involved in sensory hyperresponsiveness during allergic inflammation, and have a role in itch and mucus secretion. In addition, we suggest that TRPV1 and TRPV4 may contribute to mucociliary defence due to the proposed role of TRPV4 in epithelial ciliary regulation and of TRPV1 in secretion. Further studies are warranted to clarify the roles of TRPV1, TRPA1 and TRPV4 in human airway physiology and in airway disease.
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| 18. |
- Almquist, Per Otto
(författare)
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Measurements of knee rotation in vivo - Development and evaluation of an external device
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this work was to evaluate a newly developed measurement device, the Rottometer, for measuring knee rotation in different flexion angles with different applied torques, in order to establish the normal range of healthy knee rotation reference values and to study possible differences due to age and gender, as well as possible differences between patients with habitual dislocating patella (HDP) and healthy controls. The validity of the Rottometer was evaluated by simultaneous registrations with roentgen stereometric analysis (RSA) (paper I). The two methods showed high correlations concerning the total knee rotation at 90° and 60° of knee flexion angles with 3, 6 and 9 Nm applied torques. The Rottometer was also concluded to be a reliable measurement device concerning the one-week-apart and within day intra-tester as well as the inter-tester reliability at 90°, 60° and 30° with 6 and 9 Nm as well as the examiner’s apprehension of end-feel (paper II). In total, 120 knee healthy subjects (60 females and 60 males) equally distributed in four different age groups (15-30, 31-45, 46-60 and ≥ 61 years) were examined at 90°, 60° and 30° of knee flexion angles with 6 and 9 Nm applied torques as well as the examiner’s apprehension of end-feel (paper III). No differences were found concerning the different flexion angles, between the left and right knee or between the different age groups within the genders. However, the females showed a 10-20 % larger range of knee rotation than the males at all different flexion angles and applied torques. The knee rotation was also examined in 20 patients (15 females and 5 males) with HDP (paper IV). No differences were found between the affected and unaffected knees within the subjects. In accordance with the healthy reference population, the female subjects showed a 10-20 % significantly larger range of rotation than the male subjects in the HDP group, and no differences were found between the patients affected with HDP and age matched healthy controls.
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| 19. |
- Alrashidi, Faleh
(författare)
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New Intraoperative Techniques to Improve Advanced Aortic Root Surgery
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Study I: Thirteen patients underwent a modified Ross operation in which the free-standing pulmonary autograft was supported externally by a Dacron vascular prosthetic jacket (DVPJ). The tailor-made DVPJ prevented dilatation of the neo-aortic root significantly following a median follow-up of 47 months compared to a cohort of l3 matched patients undergoing conventional Ross operation. Study II: Acute intraoperative plateletpheresis (APP) with 25% circulating platelet yield was performed in18 young adult patients undergoing Ross operation. APP in combination with 2 million units of aprotinin reduced the combined need of all blood product transfusions by 47% compared to a matched cohort of 19 patients also undergoing the Ross operation and receiving 2 million units of aprotinin alone (p=.036). Study III: Twenty patients undergoing elective open left heart surgery were de-aired alternately and prospectively either with the conventional technique, (pleural cavities unopened, dead space ventilation during cardiopulmonary bypass) or with a new de-airing technique (pleural cavities open, ventilator disconnected during cardiopulmonary bypass, staged perfusion and ventilation of lungs) The new de-airing technique significantly reduced the de-airing time (10 vs 17 minutes, p<.001) and provided significantly greater freedom from residual air emboli (p= <.001). Study IV: The new de-airing technique was modified by applying active suction in the aortic root before release of the aortic cross clamp (Lund technique). Twenty patients undergoing elective open left heart surgery were prospectively randomized to either the Lund technique or to a standardized CO2 insufflation technique. The magnitude of air emboli as observed on a transesophageal echocardiogram and the number of microembolic signals as recorded by transcranial Doppler were significantly lower with the Lund technique during the de-airing period (P=.00634) and in the first 10 minutes (p =.000377) after weaning from the cardiopulmonary bypass (CPB). The de-airing time was also significantly shorter with the Lund technique (9 vs 15 minutes, p=.001). Arterial pH during CPB was significantly lower in the CO2 group (P=.00351) despite significantly higher gas flows (P=.0398) in the oxygenator.
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| 20. |
- Ameri, Jacqueline
(författare)
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FGF signaling in specification of hESC-derived definitive endoderm
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes affects around 200 million people worldwide. Curing diabetes would require the prevention of autoimmune destruction of beta cells and restoration of the beta cell mass restored either through regeneration or transplantation of the insulin producing cells. Islet transplantation according to the Edmonton protocol have been the most promising therapeutic option for Diabetes type I patients, however, lack of cadaveric donor islets is a major obstacle and new strategies need to be established. Human embryonic stem cells (hESCs) not only offer an excellent source for establishment of strategies for future regenerative cell therapies and drug discovery but also offers en excellent experimental assay for understanding human pancreas development. Pancreas originates from the definitive endoderm (DE), one of the three germ layers. The path from definitive endoderm to pancreatic progenitor cells and finally the insulin producing beta cells involves sequential cell-fate decisions characterized by the expression of multiple transcription factors. Governed by the developmental biological principles that normally control foregut endoderm and pancreas specification, numerous multifactor protocols for directing mature foregut-derived cells from hESCs have been reported. However, to establish less complex and more robust protocols there is a need to further understand the mechanism of action of individual growth and differentiation factors in specification of human pluripotent stem cells towards foregut derived cell lineages. Here, we describe two studies where we have investigated the role of fibroblast growth factor (FGF) signaling, specifically FGF2 and FGF4, and Retinoic acid (RA) in specification of the hESC-derived DE development. Studies in lower vertebrates have demonstrated that FGF2 acts in a restricted manner primarily patterning the ventral foregut endoderm into liver and lung, whereas FGF4 exhibits broad anteriorposterior and left-right patterning activities. Furthermore, whereas FGF2 is not required for ventral pancreas development an inductive role of FGF2 has been shown during dorsal pancreas formation. Whether FGF2 and FGF4 play a similar role during human endoderm development remained however unknown. In contrast, RA has frequently been employed (together with other growth factors) for directed differentiation of hESCs to pancreatic endoderm. In the first study we show that FGF2 in a dosage-dependent manner specifies hESC-derived DE into different foregut lineages such as liver, lung, pancreatic and intestinal cells. Furthermore, by dissecting the FGF receptor intracellular pathway that regulates pancreas specification, we demonstrate for the first time to our knowledge that induction of PDX1+ pancreatic progenitors in part relies on 8 FGF2-mediated activation of the MAPK signaling pathway. In the second study, we show that FGF4 alone is not sufficient for induction of foregut endoderm but that in combination with RA it efficiently induces PDX1+ cells from hESC-derived DE. Specifically, FGF4 promoted cell survival in the differentiating hESCs. Hence, in contrast to studies in lower vertebrates we demonstrate that FGF4 neither patterns hESC-derived DE, nor induces PDX1+ pancreatic progenitors suggesting that FGF4 is not responsible for anterior-posterior patterning of the primitive gut during human development.. Altogether, these observations suggest a broader gut endodermal patterning activity of FGF2 that corresponds to what has previously been advocated for FGF4, implying a functional switch from FGF4 to FGF2 during evolution. Thus, our results provide new knowledge of how cell fate specification of human DE is controlled – facts that will be of great value for future regenerative cell therapies. Finally, we present a method for efficient gene targeting in hESCs, which allows the monitoring of gene expression in living cells.
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| 21. |
- Anderberg, Magnus
(författare)
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Computer-assisted surgery in children
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although positive in terms of patient trauma and recovery time, minimally invasive surgery has several technical drawbacks compared with open surgery. The new da Vinci® Surgical System from Intuitive Surgical® offers technical innovations aiming at overcoming these drawbacks and at improving the surgeon’s operating skills, such as the improved 3-D vision, tremor reduction and flexible instruments with a more natural and intuitive range of motion. In this thesis, the computer-assisted surgical instruments, and their application in paediatric surgery and paediatric urology, were investigated. In a prospective study of the first six fundoplications using the da Vinci® Surgical System, retrospective data from the open surgical procedure and the conventional laparoscopic technique were used as controls. Computer-assisted laparoscopic surgery (CALS) was safe and feasible. The operating time for the computer-assisted procedure was longer than the open one, but comparable to the laparoscopic procedure, and the need for postoperative morphine analgesics and the length of hospital stay were reduced with the two minimally invasive methods. The short-term clinical outcome did not differ, the symptoms of gastroesophageal reflux disease disappeared in all the children. The costs for CALS were compared with the costs for open and laparoscopic surgery in children. The total costs of CAL fundoplication amounted to EUR 9584. The costs for laparoscopic and open fundoplication amounted to EUR 8982 and EUR 10521, respectively. The cost of the CALS instruments per procedure (EUR 2081) accounted for the extra expense compared with laparoscopy. The increased costs for CALS due to longer operating time, were offset by the shorter hospital stay compared with open surgery, 3.8 and 7.9 days, respectively. An experimental study of students with no prior surgical experience and divided by gender was performed to test the hypothesis that maiden users master surgical tasks more quickly with computer-assisted than with standard laparoscopic instruments. Each surgical task was performed four times with one of the techniques before changing to the other. Speed and accuracy were measured. A cross-over technique was used to eliminate gender bias and the experience gained from carrying out the first part of the study. The more advanced task of tying a knot was performed faster with the computer-assisted than with the laparoscopic technique. Shorter time was observed when the change was made from laparoscopy to the computer-assisted technique. Gender did not influence the results. The lack of tactile feedback in computer-assisted laparoscopy seemed to matter. A case-control study of ten consecutive children undergoing computer-assisted retroperitoneoscopic nephrectomy due to a non- or malfunctioning kidney was performed. This prospectively gathered consecutive group of children was compared with a retrospectively collected group of all other children who had undergone open nephrectomy for benign renal disease at our centre between 2005 and 2009. All nephrectomies were performed with the retroperitoneal approach. Endpoints of this study were safety, the operating time, the number of postoperative doses of morphine, the length of hospital stay and the number of complications. Four out of ten patients in the CALS group had a total operating time within the range of the operating time for an open procedure but it was longer for the CALS procedure. The number of postoperative doses of morphine did not differ, but the hospital stay was shorter for the CALS group. The patient benefit from CALS, in the form of low morbidity, improved cosmetics and shorter hospitalisation was associated with the minimally invasive approach. Whether computer-assistance leads to better long-term results and fewer postoperative complications is too early to determine. However, considering all the potential benefits of the CALS instruments, the future will favour its use in paediatric surgery.
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| 22. |
- Andersson, Bodil
(författare)
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Acute pancreatitis - severity classification, complications and outcome
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute pancreatitis, with an annual incidence of approximately 35 per 100 000 inhabitants in Sweden, is in most cases mild and self-limiting. Severe acute pancreatitis, affecting 10-15% of the cases is, however, associated with severe complications and even death. The optimal management of acute pancreatitis includes accurate early prediction of the disease severity. The aims of this thesis were to investigate early severity classification, complications and outcome in acute pancreatitis patients, with special regard to patients developing the severe form of the disease. The results of the studies were: I) Two early risk factors for death were identified: increasing age and hypotension at admission. Deaths were to a high extent related to multiple organ dysfunction. Early recurrence after biliary acute pancreatitis was common. II) A model for early prediction of severity in acute pancreatitis with artificial neural networks was developed, identifying 6 risk factors. The ROC area for the model was 0.92, and it performed significantly better than the APACHE II score. III) Patients with pancreatic pseudocysts were found to be resource demanding in regard to recurrences and repeated hospital visits. Even larger pancreatic pseudocysts could be managed successfully with conservative treatment. IV) In a national Swedish survey, the treatment of patients with pancreatic pseudocysts appeared to be heterogeneous, with different treatment options available and varying local traditions. V) In long-term follow-up after acute pancreatitis, impairment was mainly seen in the endocrine pancreatic function, and especially after severe disease. The time to rehabilitation and return to work and normal life was long, and the costs for the society high. The quality of life years after the disease was, however, as good as in the normal population. VI) A survey of patients dying in acute pancreatitis without reaching the hospital showed that this group represents a substantial part of all deaths from the disease. The dominating aetiology was alcohol. Pulmonary injury was the most common organ manifestation outside the pancreas. To reduce mortality due to acute pancreatitis it is important to target also the patients that never reach hospital.
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| 23. |
- Andersson, Cecilia
(författare)
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New aspects of tissue mast cells in inflammatory airway diseases
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mast cell are found throughout the body, but are especially prominent in tissues that have direct contact with the external milieu such as the skin, gastrointestinal tract and lungs. Mast cells are commonly recognized for their detrimental role in allergic reactions and can, upon activation through the high-affinity receptor for IgE (FcεRI), rapidly produce and secrete many of the mediators responsible for the typical symptoms in urticaria, asthma and rhinitis. However, increasing amount of data show that mast cells have important, even vital, roles in host defence against bacteria, viruses, parasites and venoms. Mast cells exist as two different subtypes, MCT (mucosal mast cells) and MCTC (connective tissue mast cells). These two subtypes differ in their molecular expression and distribution in the body. MCT are for example the dominating subtype in the lungs, while MCTC are most common in the skin and the gastrointestinal tract. Since mast cells (unlike the majority of other immune cells) only mature inside the tissue, their final phenotype is highly dependent on the local tissue milieu. This gives rise to a pronounced heterogeneity within the populations. The mast cell populations differ between human and rodents. In this thesis mast cells were, henceforth, studied in human tissue from patients suffering from allergic and non-allergic inflammatory airway diseases. A variety of histological methods are used to study the balance between MCT and MCTC, mast cell morphology and mediator and receptor expression patterns in different lung compartments. Under healthy baseline conditions, mast cells were abundant at all airway levels with a gradually increasing numbers towards the alveolar parenchyma. The MCT and MCTC populations could be further divided into site-specific subpopulations with regard to expression of mediators and morphology. A main finding was that the alveolar mast cell population had low expression of FcεRI in the healthy human lung. In COPD, CF and IPF, a significant increase in the proportion and density of MCTC with increased expression of CD88, IL-6 and TGF-β were found. Several mast cell alterations correlated to patient lung function and to the degree of remodelling compared to healthy controls. Mast cell numbers did not differ in healthy controls, patients with mild asthma or rhinitis with or without bronchial hyperreactivity. In patients with uncontrolled asthma despite treatment with inhaled corticosteroids, an increase of MCTC was found in the bronchi and alveolar parenchyma. In mild and uncontrolled asthma a significant increase of the expression of FcεRI was found in the alveolar parenchyma In conclusion, the prevailing MCT and MCTC populations could be further divided into site-specific subpopulations dependent on the local microenvironment already at healthy conditions. Mast cell alterations are present in patients with COPD, CF and IPF, diseases characterised by increases in the density of MCTC with increased expression of pro-inflammatory and pro-fibrotic molecules. Uncontrolled atopic asthma patients have expanded MCT and MCTC populations in the alveolar parenchyma. The increase in alveolar mast cell expression of FcεRI might be specific to atopic asthma since we could detect similar changes in mild asthma, but not in patients with allergic rhinitis, CF and COPD.
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| 24. |
- Andersson, Ellen
(författare)
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Crosstalk between Inflammation and Coagulation in Acute Pancreatitis - Experimental and Clinical Studies.
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In various inflammatory conditions a close interplay between inflammation and coagulation is known to exist, where coagulation factor VII (FVII) and tissue factor (TF) are considered to be pivotal players. In this thesis the crosstalk between inflammation and coagulation in acute pancreatitis (AP) has been investigated. The results from the first paper, where active site inactivated FVII (FVIIai) is given as pre-treatment in a rat model of severe AP, show a decreased inflammatory response in the FVIIai pre-treated animals. In the second paper the activation of nuclear factor kappa B (NFκB) is studied in the rat model of severe AP. NFκB is a pivotal transcription factor, involved in the regulation of expression of multiple inflammatory mediators. The results show a decreased activation of NFκB in remote organs in FVIIai pre-treated rats with severe AP. In the third paper the effect of FVIIai administered after the induction of severe AP in the rat model is studied. The results show some anti-inflammatory effects though less evident than in the pre-treatment study. In the fourth paper the incidence, management and outcome of major haemorrhagic complications in AP is studied in a retrospective study. 1356 patients were included. Severe haemorrhagic complications turned out to be very rare. Only 14 patients with severe bleeding were identified. Despite the rareness of this condition, it is a clinical challenge to manage these patients, as severe bleeding complications are associated with a very high mortality. In the fifth paper plasma levels of TF are studied in 49 patients with predicted severe AP. TF at admission was higher in the group of patients that actually developed severe AP, compared to those with a mild form of the disease. The results may indicate a role of tissue factor in the development of severe disease. We conclude that - FVIIai exerts powerful anti-inflammatory effects in experimental severe AP, at least in part by reducing activation of NFκB, - Severe haemorrhagic complications in AP are rare, but associated with a high risk of mortality. - Levels of TF rise early in the course of AP and higher levels of TF early in the course of the disease may be associated with development of severe AP.
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| 25. |
- Andersson, Sabina
(författare)
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Glaucoma Diagnostics
- 2013
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X.
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis addresses several aspects of glaucoma diagnostics from both a clinical and a screening perspective. New instruments for diagnosing glaucoma have been developed over the past years, but little information is available regarding their performance as screening methods and their usefulness in ordinary clinical practice. Purpose of the research underlying this thesis The objectives of the present research were as follows: to compare the accuracy of results of analysis of the optic nerve head (ONH) achieved by computerized imaging using the statistical tools Moorfields Regression Analysis (MRA) and Glaucoma Probability Score (GPS) of the Heidelberg Retina Tomograph (HRT) and by subjective assessment performed by physicians with different degrees of experience of glaucoma (Paper III); to evaluate the effect of a continuous medical education (CME) lecture on subjective assessment of the ONH for diagnosis of glaucoma (Paper II); to investigate subjective assessment of standard automated perimetry (SAP) test results by physicians with varying knowledge of glaucoma with a trained artificial neural network (ANN), and to compare the certainty of the classifications (Paper IV); to compare the diagnostic performance of time-domain Stratus optical coherence tomography (OCT) with that of spectral-domain Cirrus OCT (Paper I), Frequency Doubling Technology (FDT) screening perimetry and scanning laser polarimetry with the GDx VCC in a random population-based sample and in patients with glaucoma of varying disease severity. Methods and results In Paper III, the sensitivity of both MRA (87 - 94%) and GPS (79 - 93%) was higher than that of the average of the 45 physicians (62 - 82%). Furthermore, MRA offered better sensitivity compared to ophthalmologists with subspecialties other than glaucoma (53 - 77%), and was non-significantly higher than that of glaucoma experts (72 - 88%). MRA correctly classified all eyes with advanced glaucomatous visual field defects (Andersson et al. 2011). In Paper II, a one-hour CME lecture on ONH assessment for 96 physicians led to a significant improvement in sensitivity (from 70% to 80%) and a significant decrease in uncertain assessments (from 22% to 13%), whereas specificity remained unchanged (68%) (Andersson et al. 2011). In Paper IV, 30 physicians assessing SAP test results with full Statpac information was compared with a previously trained ANN. ANN reached significantly higher sensitivity (93%) than the average physician (83%), whereas specificity was similar for these two groups (91% and 90% respectively). Diagnostic accuracy was similar among the different groups of physicians and seemingly rather independent of experience. The ANN attained certainty of classification that was in parity with that provided by the glaucoma experts and did not make any completely incorrect classifications of the visual fields (Andersson et al. 2012). In Paper I, 170 subjects from a population-based sample of older subjects (aged ≥ 50 years) and 138 randomized clinical patients with different stages of glaucoma underwent a comprehensive examination that included Stratus OCT, Cirrus OCT, an FDT screening program and the GDx VCC. In the population-based sample, both Stratus and Cirrus OCT showed high diagnostic accuracy with area under the receiver operating curve (AROC) values close to 1.0 (Bengtsson et al. 2012). Both OCT instruments correctly classified all of the clinical glaucoma patients with advanced disease. FDT screening showed high sensitivity (91%) but erroneously gave normal test results for some eyes with advanced disease. GDx VCC had lower sensitivity (73 - 92%) and also led to a large proportion of examinations with an atypical retardation pattern that is known to affect the diagnostic efficiency of this instrument. Conclusions The HRT MRA performed better than most physicians and was consistent with the glaucoma experts. These results suggest that MRA can be a valuable tool for diagnosing glaucoma in ordinary practice, particularly when only a few glaucoma experts are available. CME on ONH analysis had a small, but positive effect on diagnostic accuracy for glaucoma. The ANN trained to classify visual fields performed at least as well as most of the participating physicians, whose performances were remarkably similar regardless of their level of experience. This indicates that available tools for interpreting SAP findings are helpful in assessments of visual field test results. However, SAP is associated with learning effects (Heijl et al. 1989) that may entail low specificity for untrained subjects and hence it is not an ideal screening method for glaucoma. By comparison, the screening test of FDT is rapid and easy, but some eyes with advanced glaucoma were missed. GDx VCC images for a relatively large number of eyes could not be analysed, and is thus not appropriate for screening. The OCT instruments offer both high sensitivity and high specificity, and all eyes with advanced disease were correctly classified as glaucomatous. However, these instruments are still expensive and require special operator skills. Additional development to obtain OCT instrument that is more compact, easier to use and less expensive might render such tomography suitable as a screening tool for glaucoma.
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