| 41. |
- Bjarnegård, Niclas, 1964-
(författare)
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Aspects on wall properties of the brachial artery in man : with special reference to SLE and insulin-dependent diabetes mellitus
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mechanical properties of the arterial wall are of great importance for blood pressure regulation and cardiac load. With increasing age, large arteries are affected by increased wall stiffness. Furthermore, atherosclerotic manifestations may increase the stiffness even further, both processes acting as independent cardiovascular risk factors affecting the arterial system in a heterogeneous way.The aims of this thesis was to characterize the local mechanical properties of brachial artery (BA) with the aid of ultrasound technique and to evaluate the influence of 1) age, gender, sympathetic stimulation and examination site; 2) type 1 diabetes (DM) and its association to circulatory biomarkers; and 3) to evaluate the general properties of the arterial system with the aid of pulse wave velocity (PWV) as well as pulse wave analysis (PWA) in systemic lupus erythematosus (SLE) and correlate the findings to disease activity and circulatory biomarkers.In the most proximal arterial segment of the upper arm a pronounced age-related decrease in wall distensibility, increase in intima-media thickness (IMT), and a slight increase in diameter were seen. Sympathetic stimulation had no influence on wall mechanics. More distally in BA, no change in diameter, and only minor increase in IMT and decrease in distensibility were seen. No gender differences were found. These findings suggest that the principle transit zone between elastic and muscular artery behaviour is located in the proximal part of the upper arm.Women with uncomplicated insulin-dependent DM had similar diameter, IMT and distensibility in their distal BA as controls, whereas flow-mediated dilatation (FMD) was slightly, and nitrate mediated dilatation (NMD) markedly reduced. NMD was negatively correlated with higher HbA1c levels. Vascular smooth muscle cell function seems to be an early manifestation of vascular disease in women with DM, influenced by long-term hyperglycaemia.Women with SLE had increased aortic PWV compared to controls, a finding positively associated with increased levels of complement factor 3 (C3), but not with disease activity. The increased stiffness of central arteries may be one factor contributing to the increased cardiovascular risk seen in SLE.
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| 42. |
- Bjartmar, Lisa, 1966-
(författare)
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Pharmacological and Developmental Aspects on Neuronal Plasticity
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuronal plasticity means the ability of the brain, its cells and networks to adapt and adjust to new challenges, a process which is ongoing throughout life. The goal of this thesis was to gain better understanding of the molecular events that follow different types of stimulations of brain structures such as the hippocampus, a key region for cognitive functions with overriding control on the corticosteroid system. A better knowledge of the mechanisms involved in neuronal plasticity is fundamental in the development of strategies for improving health in patients suffering from major depression or cognitive disorders such as Alzheimer’s disease.Antidepressant drugs induce the expression of several genes involved in neuronal plasticity, a mechanism which may explain the several weeks time lag between treatment initiation and clinical effect commonly observed in patients. Besides, there are indications that disturbances in the corticosteroid system are involved in the pathogenesis of major depression. Therefore, the mRNA expression of the glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) as well as of the immediate-early genes NGFI-A and NGFI-B was analyzed using in situ hybridization in the hippocampus and cortex after 21 days treatment with various antidepressant drugs having different monoaminergic profiles. The mRNA expression of the transcription factors was selectively increased depending on region and also on the monoaminergic profile of the drug given. Generally, drugs with less specificity for monoamines had an overall more anatomically wide-spread inducible effect.In a follow-up study the message expression of the synaptic protein NP2 was investigated in a similar setting where long-term (21 days) was compared with short-term (3 days) antidepressant treatment. In addition to the hippocampus, the medial habenula, a relay station within the limbic system was analyzed. Overall there was an upregulation of NP2 mRNA expression following long-term treatment irrespective of the monoaminergic profile of the drug. Simultaneously, NP2 mRNA was analyzed in rats exposed to enriched, normal or deprived environments respectively, an experimental setting known to affect neuronal plasticity. However, in contrast to the pharmacological treatment, this environmental stimulation did not lead to alterations in NP2 mRNA expression in any of the regions studied.Finally, the function of NP2 as well as the closely related proteins NP1 and NPR was investigated. The “knock-out mouse” technique was used to eliminate these neuronal pentraxins (NPs), both individually and in various combinations. Since previous data had suggested that the NPs are involved in synaptic development, axonal refinement in the visual system during development was analyzed in these animals. In the NP1/NP2 knock-out mice, synaptic formation, axonal development and refinement occurred at a significantly slower rate than in wild-type mice, indicating that the NPs may be necessary for activity-dependent synaptogenesis.In conclusion, the results of the studies constituting this thesis demonstrate that long-term treatment with antidepressant drugs, possessing different monoaminergic profiles, has selective effects on the expression of NGFI-A, NGFI-B, GR and MR in the mammalian brain. In general, the least selective drugs exhibit the most profound effect suggesting that induction of neuronal plasticity is more effective with multiple neuronal inputs. The results also show that NP2 expression is induced by antidepressant drugs, in contrast to environmental stimulation, supporting the presence of different pathways for inducing neuronal plasticity depending on type of stimuli. Finally, this thesis indicates that the neuronal pentraxins play an important part in synaptic development.
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| 43. |
- Björk, Mathilda, 1977-
(författare)
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Aspects of Disability in Rheumatoid Arthritis : a five-year follow-up in the Swedish TIRA project
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is a progressive disease, often leading to disability. Because the disease course develops rapidly during the first years after diagnosis, more knowledge is needed about the early disease course to minimize later disability. This thesis describes the course of disability in early RA such as hand function, pain intensity, activity limitation and sick leave. In addition, this thesis compares disability between women and men and compares disability between RA patients and referents.This thesis is primarily based on data from the 320 patients that were included in the multi-centre project in Sweden called ‘Early interventions in rheumatoid arthritis’ (TIRA). A wide range of outcome variables was registered between 1996 and 2006 during regular follow-ups from time for diagnosis through the eight-year follow-up. Outcome regarding disease activity and disability of RA patients still remaining in TIRA at the three and five year follow-up respectively are used in this thesis. Data concerning sick leave were obtained for the patients during six years (1993-2001) – three years before and three years after diagnosis. Referents were included in two of the studies. Data regarding disability in referents were obtained according to hand function and activity limitation using the Health Assessment Questionnaire (HAQ). Data for sick leave were obtained for six years in referents, for the same period as the RA patients.For most variables, disability in RA was most pronounced at time of diagnosis but before intervention started. Disability was then reduced already at the 3-month follow-up and thereafter affected but stable during the following five years. The exception was participation, reflected by sick leave, a variable that was stable from inclusion to three years from diagnosis. Activity limitation, pain intensity and sick leave in RA that represents different aspects of disability were explained by other aspects of disability and contextual factors rather than by disease activity. RA affects women and men differently in some aspects. Women had more severe course of activity limitations than men according to HAQ. Men were more affected than women in range of motion, although the differences were small in a clinical perspective. However, pain intensity and frequency of sick leave did not differ between women and men. Patients with RA have pronounced disability in relation to referents although several variables improve soon after diagnosis. This discrepancy refers to hand function as well as activity limitations and sick leave. The frequency of sick leave increased during the year before diagnosis in relation to referents and was thereafter high compared to sick leave in referents.
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| 44. |
- Björkqvist, Maria, 1959-
(författare)
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Coagulase-negative staphylococci septicaemia in newborns : aspects on host-bacterial interactions with special regard to neutrophil and endothelial response
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Newborn infants, especially those born preterm, are immunologically immature and prone to invasive infections. As a result of the increasing survival of very preterm (VPT < 31 weeks gestational age) newborns, nosocomial septicaemia has become a major concern the neonatal intensive care, and coagulase-negative staphylococci (CoNS) are nowadays the most frequently isolated pathogens in neonatal blood cultures. Further insight into host-bacterial interactions is required for the development of preventive strategies against CoNS septicaemia in VPT newborns.Aim of the study: To investigate host-bacterial interactions in neonatal CoNS septicaemia with special regard to the neutrophil and endothelial response and to bacterial virulence factors.Methods and results: Neonatal blood isolates of CoNS collected at Örebro University Hospital, Örebro, Sweden during the years 1983-1997 were characterised clinically and according to species and to phenotypic and genotypic patterns. Biochemial fingerprinting was found useful as a screening tool for selection of phenotypically related strains, but for further discrimination within a phenotypic cluster, genetic fingerprinting by pulsed field gel electrophoresis (PFGE) was required.The isolates of S. epidermidis collected during the later part of the study period (1990-1997, n = 50) were further investigated. A hypervirulent clone of bacteria was identified, representing 7 of the 12 sepsis isolates in that cohort. These 12 isolates of S. epidermidis induced significantly higher endothelial release of neutrophil chemoattractants from human umbilical vein endothelial cell (HUVEC) cultures than did the isolates regarded as skin contaminants (n = 38). There were no differences between the sepsis and contaminant groups in the prevalence of genes for biofilm production, methicillin resistance or fibrinogen-binding protein.The neutrophil oxidative burst occuring after stimulation by different bacterial strains was investigated by a flow cytometric method applied to a whole blood model. The oxidative activity in unstimulated neutrophils was similar in term (n = 10) and preterm (n = 10) newborns. However, the term newborns showed a significantly higher capacity to up-regulate the oxidative burst after bacterial stimulation. Significant differences in oxidative responses to different bacterial strains were observed, but these differences could not be related exclusively to species or invasive capacity.A neutrophil granule protein, human neutrophil lipocalin (HNL), was evaluated as an early marker of neonatal septicaemia in newborns with clinical signs of infection. The serum level of HNL was significantly higher in the infected group of neonates (n = 25) than in the group with non-proven infection (n = 62). In healthy term controls the HNL level was similar at age 3 days to that at birth and close to the level reported in healthy adults.Conclusions: The increased up-regulation of endothelial inflammatory mediators induced by sepsis isolates of S. epidermidis represents an important step in the pathogenesis of neonatal CoNS septicaemia. HNL might be useful as a marker of neutrophil activity also in VPT newborns. The laboratory assays used in the present study can be further developed for future investigations of the pathogenesis and host-bacterial interactions in neonatal CoNS septicaemia.
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| 45. |
- Björnström Karlsson, Karin, 1971-
(författare)
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Cellular mechanisms of anaesthetic agents
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Anaesthesia is given to approximate 5% of the Swedish population annually, with the great advantage of painless surgery, but it also has side effects such as depression of blood pressure that might give a heart infarction. Exactly how anaesthetic agents cause anaesthesia is poorly known. Most anaesthetics have been shown to interact with the GABAA receptor, whose endogenous ligand GABA causes down-regulation of the brain and sleep. To further explore the cellular signal system used by anaesthetics this study was performed.First, two different malignant cell lines, PC-12 and SH-SY5Y, were tested, to evaluate if they could replace animal cells; however, they did not respond with increased intracellular calcium [Ca2+]i upon stimulation with propofol, as the normal rat neurons do. This is probably due to differences in the intracellular signaling systems in these malignant cells. Therefore, the studies in this thesis were performed on rat neurons.Propofol, an intravenous anaesthetic, was shown to cause a bicucullin insensitive increase in [Ca2+]i, where the release from intracellular stores was dependent on a tyrosine kinase. Sevoflurane, a volatile anaesthetic, also caused an ilrunediate increase in [Ca2+]i, but not nitrous oxide. Increased [Ca2+], is supposed to augment the influx of chloride ions through the GABAA receptor, hence hyperpolarising the neuron, and thereby make it anaesthetised.Tyrosine phosphorylation of the GABAA receptor is necessary for its function. Propofol tyrosine phosphorylates another ß2 subunit in the membrane then GABA. Propofol, but not GABA, also caused a tyrosine phosphorylation of actin in both the cytoskeletal and cell membrane fraction. Together these changes might explain the difference between sleep and anaesthesia. Isoflurane, sevoflurane and nitrous oxide all tyrosine phosphmylate a protein, suggested to be the GABAA receptor ß subunit, in different cellular compartments. This might explain their different clinical effects.Propofol and sevoflurane, but not GABA, causes actin rings to be formed in the cell, and for propofol the signal goes via rhoA and rho kinase, that also are involved in the translocation of actin to the cellular membrane. An unl~own 160 kDa protein is tyrosine phosphorylated by propofol, is part of the rho signalling pathway and is regulated by rho, This unknown protein might be involved in the actin reorganisation.
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| 46. |
- Blomgran, Robert, 1975-
(författare)
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Microbe-induced apoptosis in phagocytic cells and its role in innate immunity
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apoptosis, or programmed cell death, is a controlled process by which aged or damages cells are eliminated in multicellular organisms. Neutrophils, short-lived phagocytes of the innate immune system, are highly equipped effectors that can sense, locate, ingest and kill bacterial pathogens. Inflammatory mediators and the presence of bacterial products at the foci of infection regulate the function and life span of these cells. Modulation of neutrophil apoptosis and the subsequent clearance by scavenger cells, such as macrophages, is part of a balanced inflammatory process leading to resolution of inflammation. Many pathogens are capable of modulating host cell apoptosis, and thereby influence the progression of disease. Hence, this thesis was aiming at elucidating mechanisms involved in pathogen- and host-modulated apoptosis and its contribution to the inflammatory process.We found that different routes of bacterial entry, i.e. through invasion or by receptor-mediated phagocytosis, triggered different signaling pathways within phagocytes. Invasion of virulent Salmonella caused apoptosis, a process requiring activation of the Rho GTPases Rac1 and Cdc42. On the other hand, phagocytosis of the non-invasive Salmonella inhibited apoptosis despite similar intracellular survival as the invasive bacteria. Protection against phagocytosis-induced apoptosis was regulated by tyrosine- and PI3-kinase-dependent activation of AKT (also called PKB for protein kinase B). Furthermore, inhibiting the intraphagosomal production of reactive oxygen species (ROS) in neutrophils during phagocytosis of E. coli decreased apoptosis below spontaneous apoptosis, further indicating that both pro- and anti-apoptotic pathways are triggered by receptor-mediated phagocytosis.Type 1 fimbria-expressing E. coli adhering to neutrophils resisted ingestion, and induced a ROS-dependent apoptosis by a cooperative effect of the FimH adhesin and LPS. To explore how compartmentalization of ROS during neutrophil activation was involved in modulating apoptosis, we evaluated the stability of lysosomes. In contrast to phagocytosis of E. coli, the adhesive strain induced intracellular non-phagosomal ROS production which triggered early permeabilization and release of lysosomal enzymes to the cytosol. Cathepsin B and/or L were responsible for targeting of the pro-apoptotic Bcl-2 protein Bid, thereby inducing mitochondrial damage, and apoptosis. These data propose a novel pathway for ROS-induced apoptosis in human neutrophils, where the location of the ROS rather than production per se is important.Moreover, we found that pathogen-induced apoptotic neutrophils, in contrast to uninfected apoptotic neutrophils, activated blood-monocyte derived macrophages to increase their FcγRI surface expression and to produce large quantities of the pro-inflammatory cytokine TNF-α. This demonstrates that during the early phase of infection, pathogen-induced neutrophil apoptosis will help local macrophages to gain control over the microbes. Furthermore, we suggest that heat shock protein 60 and 70 represent a stress signal that enables macrophages to distinguish between, and react differently to, uninfected and inflammatory apoptotic neutrophils.
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| 47. |
- Bolling-Sternevald, Elisabeth, 1955-
(författare)
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Functional Dyspepsia : Symptoms and Response to Omeprazole in the Short Term
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gastrointestinal symptoms have a prevalence of 20-40% in the general adult population in the Western world. These symptoms are generally considered to be poor predictors of organic findings [e.g. peptic ulcer disease (PUD) or malignancy]. Approximately 50% of patients seeking care for such symptoms have no organic explanation for these upon investigation. When other organic or other functional conditions are excluded [e.g. PUD, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)] the remaining patients are labelled as having functional dyspepsia (persistent or recurrent pain and/or discomfort centred in the upper abdomen). Management of functional dyspepsia remains a challenge, reflecting the heterogeneity of the patients and the uncertain role of drug treatment. Also, prognostic factors for treatment success are largely unknown. I have therefore performed a series of studies to shed light on these issues: The first study (Paper I) was performed in a randomly selected adult population (n=1,001) assessing upper and lower gastrointestinal symptoms at two occasions with 1 to 6 month intervals. The results show that gastrointestinal symptoms are common (57%) and fluctuate to some extent in the shorter term. Troublesome dyspeptic symptoms remain in two out of three individuals. This proportion was similar whether or not organic findings were present. In the second study (Paper II) 799 patients with dyspeptic symptoms were evaluated with regard to whether gastrointestinal symptoms, identified by self-administered questionnaires, correlate with endoscopic diagnoses and discriminate organic from non-organic (functional) dyspepsia. The impact of dyspeptic symptoms on health-related well-being was also evaluated. Approximately 50% of these dyspeptic patients were found to have functional dyspepsia at upper endoscopy. A difference was discovered in the symptom profile between patients with organic and functional dyspepsia. Predicting factors for functional dyspepsia were found. This study shows that use of self-administered symptom questionnaires may aid in clinical decision making for patient management, e.g. by reducing the number of endoscopies, although probabilities of risks for organic dyspepsia are difficult to transfer to management of the individual patient. The results also indicate that the health-related well-being in patients with functional and organic dyspepsia is impaired to the same extent, illustrating the need for effective treatment of patients with functional dyspepsia, a group not well served by currently available treatment modalities. The aim of the third study (Paper III) was to develop and evaluate a selfadministered questionnaire focusing on upper abdominal and reflux complaints to allow for identification of patients with heartburn and factors that might predict symptom relief with omeprazole both in GERD and functional dyspepsia patients. The diagnostic validity of the questionnaire was tested against endoscopy and 24-hour pH monitoring. The questionnaire had a sensitivity of 92%, but a low specificity of 19%. Symptom relief by omeprazole was best predicted by the presence of predominant heartburn described as ‘a burning feeling rising from the stomach or lower chest up towards the neck’ and ‘relief from antacids’. These results indicate that this questionnaire which used descriptive language, appeared to be useful in identifying heartburn and predicting responses to omeprazole in patients with upper gastrointestinal symptoms. The fourth study (Paper IV) was a pilot study investigating the symptom response to omeprazole 20 mg twice daily or placebo for a duration of 14 days in 197 patients with functional dyspepsia. We concluded that a subset of patients with functional dyspepsia, with or without heartburn, would respond to therapy with omeprazole. In the final study (Paper V) the aim was to identify prognostic factors for the treatment success to a 4-week course of omeprazole 10 or 20 mg once daily in 826 patients with functional dyspepsia. The most highly discriminating predictor of treatment success was the number of days without dyspeptic symptoms during the first week of treatment. Fewer days with symptoms during the first week indicated higher response rates at four weeks. In addition, positive predictors of treatment response to omeprazole were identified as age >40 years, bothersome heartburn, low scores of bloating and diarrhoea, history of symptoms for <3 months and low impairment of vitality at baseline. The results indicate that early response during the first week to treatment with a proton pump inhibitor seems to predict treatment success after four weeks in patients with functional dyspepsia. Conclusion: These studies have shown that a large proportion of adult individuals in society, both those who seek and those who do not seek medical care, suffer from symptoms located in the upper part of the abdomen regardless of whether an organic cause is present. A subset of patients without organic findings and other functional conditions, i.e. functional dyspepsia, respond to therapy with omeprazole irrespective of the presence or absence of heartburn . An excellent way to predict the response to a full course of omeprazole in functional dyspepsia is to assess the early response (first week) to treatment. These findings allow for better and faster targeting of acid inhibitory therapy in functional dyspepsia, which potentially can result in more effective clinical management of these patients and savings of health care resources.
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| 48. |
- Bolse, Kärstin
(författare)
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Caring for Patients with an Implantable Cardioverter Defibrillator Experiences of Patients and Healthcare Professionals
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: An Implantable Cardioverter Defibrillator (ICD) is a technical device used in the treatment of ventricular arrhythmias. After the implantation of an ICD the entire life situation can be affected with psychological and social consequences for the patient and his/her next of kin. The healthcare professionals play a vital role in providing educational information, support, and technical follow-up of the device. During recent years more and more hospitals have introduced a more team based organisation where the physicians collaborate with specialised ICD nurses. Aim: The overall aim of the thesis was to explore how patients with an ICD experienced their life situation and howhealthcare professionals described their experiences of delivering care to ICD patients. Methods: The design was descriptive, combining both quantitative and qualitative approaches, and the data was collected from Sweden and the USA. The Uncertainty of Illness Scale (MUIS-C) and Quality of life Index (QLI) instruments were used to determine the level of uncertainty and satisfaction with life (I), in-depth interviews with a phenomenographic approach was used to describe how Swedish and US patients living with an ICD conceived their life situation (II, III) and how healthcare professionals’ experienced delivering care to patients with an ICD, (IV). Finally, to explore clinical aspects of ICD care in Sweden, the Delivery of ICD Questionnaire (DOIQ) was used to describe the healthcare professionals’ experiences and a content analysis was used to describe the written educational information material provided to patients (V). Results: There were no differences in uncertainty between pre and post ICD implantation either in Swedish or the US patients. Satisfaction with life was significantly higher among US patients compared to Swedish patients both before and after ICD implantation within the health-functioning, socio-economic and psychological-spiritual domains. The Swedish ICD patients experienced a significantly higher satisfaction with life within the socioeconomic domain after 3 months. (I). The patients felt safe in having an ICD implanted, but the conceptions varied from seeing the device as a life saver to being worried about what could happen. Gratitude at having an ICD varied from happiness at being alive to something that was alien and disturbed the patient. Being more or less dependent included how patient experienced feelings from well-being to grief. Having a network varied from having sufficient support to loneliness. Having a belief in the future ranged from having confidence to look forward to resignation. Gaining awareness described patients’ adaptation to living with an ICD and limitations due to the ICD (II). The patients also underwent a transition from becoming aware of the restriction in the life situation through a process of adaption and having trust in the ICD. This phase was followed by a reorientation phase where they adapted to their life situation and the patient and his/her family regained of their lives (III). The healthcare professionals strove to provide competent and individualised care and infuse confirmation to the patients in form of information, education and support. They gave the patients tools to handle their life situation, through existential support and mediating security (IV). Half of the hospitals had nurse-based clinic and others planned to introduce them. Three hospitals performed follow-up in the form of remote home monitoring. The nurse had specific ICD education from ICD companies and/or various university courses. In the educational information material the biophysical dimensions dominated while the emotional dimension was scarcely described, and the spiritual-existential was not referred to at all (V). Conclusions: This thesis offers a further contribution to the scholarly discussion about the relationship between technology and human existence and how to cope with this transition. Our studies revealed that the embodiment of the ICD reflects a merger of experiences about its presence and potential from both patients’ and healthcare professionals’ perspective. This research hopefully encourages healthcare professionals to carefully reflect on what it is like to live with an ICD and to consider practice improvement for the patients’ and the next of kin.
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| 49. |
- Borg, Karin, 1972-
(författare)
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Sickness Absence with Musculoskeletal Diagnoses : An Eleven-Year Follow-Up of Young Persons
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In Sweden, as well as in most Western countries, sickness absence is a major public health problem that has increased in recent years. This is a complex phenomenon related not only to ill health factors, but also to other factors on the levels of the individual, the family, the workplace, and the society. Most studies of sickness absence are cross sectional, which makes it difficult to investigate aetiological factors. A longitudinal study design is preferable, because sick-leave spells can have a long duration and are often due to chronic or recurrent disorders.Objectives: The aim of the present research was to conduct a pilot study to gain further information about factors associated with sickness absence and disability pension, perceptions of contacts with rehabilitation professionals, and self-rated health over time among younger persons initially on sick leave with low-back, neck, or shoulder diagnoses.Material and methods: An eleven-year prospective cohort study of all individuals who, in 1985, were aged 25–34 years, lived in the municipality of Linköping, Sweden, and had a sick-leave spell ≥ 28 days with low-back, neck, or shoulder diagnoses (n = 213, 61% women). The following information was obtained from registers: number of sick-leave days and spells in 1982–1984; diagnosis and demographical data in 1985 (age, sex, occupation, citizenship, marital status, and income); data on each sick-leave period (date, full/part time), disability pension (date, diagnoses, temporary/permanent, full/part time); emigration (date), and death (date, cause) from 1985 to 1 September 1996. In 1996, a questionnaire was sent to members of the cohort (response rate 73%). Different measures were used to analyse sickness absence and disability pension over the eleven-year period, possible risk factors for disability pension were tested by Cox regression, and possible factors predicting future low levels of sickness absence were tested by logistic regression. Based on the questionnaire perceptions of encounters with rehabilitation professionals were analysed with factor analyses and linear regression, and the so called health-line (a method to collect data on self-rated health over time) was tested, and the results were compared with data on sickness absence and disability ension.Results: The members of the cohort turned out to be a high-risk group for disability pension. After 11 years, 26% of the women and 14% of the men had been granted such benefits, mainly due to musculoskeletal diagnoses, but also with psychiatric diagnoses for half of the men and 17% of the women. Full-time pension was granted more often to men than to women. The women had higher levels of sickness absence. An extended Cox regression model proved suitable for prediction of disability pension. Taking citizenship and long-term sickness absence into consideration, the women had a 1.9 times higher risk of being granted disability pension than the men. Predictors for future low levels of sickness absence were a history of low sickness absence, having a white-collar job, and being married. These associations were not discerned when a pathogenic approach was used, which implies that factors other than the opposite risk factor for disability pension are associated with future low sickness absence. Three dimensions of the individuals’ contacts with professionals were identified: supportive treatment, distant treatment, and empowering treatment.Women perceived both social insurance officers and health care professionals as more supportive than the men did. Contact with social insurance officers was experienced as more supportive and empowering by persons on disability pension than by those not receiving such benefits. Data collected using the health-line (i.e., self-rated health from 1985 to 1995) was correlated with data on annual mean number of sick-leave days and days on disability pension. No tendency to recall bias was noted.Conclusions: Additional research is needed to elucidate the situation of women on sick leave with low-back, neck, and shoulder diagnoses. Further testing and practical application of statistical and epidemiological models for analysing sickness absence and disability pension data should be carried out to ascertain the validity and usefulness of such models.
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| 50. |
- Borutinskaite, Veronika Viktorija, 1977-
(författare)
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Characterization of proteins involved in differentiation and apoptosis of human leukemia and epithelial cancer cells
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today, cancer is understood as an epigenetic as well as a genetic disease. The main epigenetic hallmarks of the cancer cell are DNA methylation and histone modifications. The latter changes may be an optimal target for novel anticancer agents. The main goal of using histone deacetylase inhibitors (HDACIs) would be restoration of gene expression of those tumor-suppressor genes that have been transcriptionally silenced by promoter-associated histone deacetylation. However, HDACIs have pleiotropic effects that we are only just starting to understand. These may also be responsible for the induction of differentiation, cell-cycle arrest and pro-apoptotic effects.There are now so many HDACIs available, with such different chemical structures and biological and biochemical properties, that it is hopeful that at least some of them will succeed, probably in combination with other agents or therapies.In our studies we focussed ourselves on studies some new HDACIs, that can be useful for treating cancers, including leukemia and epithelial cancer. To do that, we used novel HDACIs, like BML-210, and their combination with the differentiation inducer all-trans retinoic acid (ATRA). Cell differentiation and proliferation in general, and specific gene expression require de novo protein synthesis and/or post-translational protein modifications. So, we tried to identify proteins in general and specifically the proteins that could be important for the cell differentiation process, and when and where in the cell the proteins appear.We delineated that HDACIs inhibited leukemia (NB4 and HL-60) cell growth in a time- and dose-dependent way. Moreover, BML-210 blocked HeLa cell growth and promoted apoptosis in a time-dependent way. Combining of BML-210 with ATRA induced a differentiation process in leukemia cell lines that lead to apoptosis. This correlated with cell cycle arrest in G0/G1 stage and changes in expression of cell cycle proteins (p21, p53), transcription factors (NF-κB, Sp1) and their binding activity to consensus or specific promoter sequences. We also assessed histone modifications, i.e. H3 phosphorylation and H4 hyperacetylation due to HDACI, leading to chromatin remodeling and changes in gene transcriptions.We have also studied changes in protein maps caused by HDACIs and differentiation agents, identifying differences for a few proteins due to growth inhibition and induction of differentiation in NB4 cells using BML-210 alone or in combination with ATRA. These proteins are involved in cell proliferation and signal transduction, like Rab, actin and calpain. One of them was alpha-dystrobrevin (α-DB). To further study possible roles of the latter, we determined changes of α-DB protein isoform expression that correlated with induction of differentiation. We thus identified a novel ensemble of α-DB interacting proteins in promyelocytic leukemia cells, including tropomyosin 3, actin, tubulin, RIBA, STAT and others, being important in cytoskeleton reorganization and signal transduction. Using confocal microscopy, we determined that α-DB co-localizes with HSP90 and F-actin in NB4 and HeLa cells. We also revealed that it changes sub-cellular compartment after treatment with ATRA and/or BML-210. α-DB silencing affected F-actin expression in HeLa cells, further supporting the idea that α-DB is involved in cytoskeleton reorganization in cells. Altogether, our results suggest that α−DB may work as a structural protein during proliferation and differentiation processes of human cancer cells.Based on our findings, we suggest that HDACIs, like BML-210, can be promising anticancer agents, especially in leukemia treatment, by inducing apoptosis and regulating proliferation and differentiation through the modulation of histone acetylations and gene expression.
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