| 1. |
- Andersson, Anne, 1966-
(författare)
-
Long-term side effects after treatment of Hodgkin's lymphoma
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Long-term side effects associated with the treatment of Hodgkin’s lymphoma (HL) have frequently been reported during the last decades. Studies have shown increased mortality in HL survivors. Following Hodgkin’s lymphoma, second malignancies (SM) and cardiovascular disease (CVD) are the most common causes of death in individuals treated for HL. This study investigates the incidence of side effects such as SM, CVD and infections in a cohort diagnosed with HL in Sweden between 1965 and 1995. In addition, this study identifies covariate risk factors for late side effects in order to develop strategies that prevent morbidity and mortality in HL survivors. Methods Using the Swedish Cancer Registry (SCR) at the National Board of Health and Welfare and the Multi-Generation Registry at Statistics (MGR) Sweden, we identified 6946 individuals diagnosed with HL between the years 1965 and 1995, and their first degree relatives (FDR) (n=17 858). In addition we identified the malignancies and inpatient care for CVD and infections for the HL cohort and their FDR. The standard incidence ratio (SIR) was calculated for the risk of SM, CVD and infections. For SM and CVD the risk also was stratified and calculated for family history of disease. The Swedish Hodgkin Intervention and Prevention study (SHIP), a prospective study, invited 702 individuals treated for HL at the age of 45 years or younger and who were treated in the region of Skåne, Uppsala or Umeå. The participants completed a questionnaire and were invited to an out-patient visit to an oncologist with clinical examination and blood tests. Any pathological findings were referred for further investigation. Results An increased risk for SM in HL long-term survivors was observed and seems to increase with the number of FDRs with cancer. There was also an increased risk for inpatient care due to congestive heart failure (CHF) and coronary artery disease (CAD). A family history of CHF and CAD further increased the risk for these diseases. The risk for inpatient care due to infections was increased and remained increased after 20 years or longer. The risk for infections was associated with splenectomy and hypothyroidism. Radiotherapy was an independent risk factor for cardiovascular disease in the cohort of the prospective study. ConclusionLong-term survivors from HL have an increased risk for developing late side effects such as SM, CVD and infections. Since many HL patients are young and the cure rate from the disease is high, it is of great importance to offer focused surveillance programs to selected individuals who are at high risk, e.g. individuals who received radiotherapy as part of their treatment and who have other known risk factors for cardiovascular disease such as hypertension, hypercholesterolemia, family history and smoking.
|
|
| 2. |
- Andersson, Kennet, 1979-
(författare)
-
Assessment of cerebrospinal fluid system dynamics : novel infusion protocol, mathematical modelling and parameter estimation for hydrocephalus investigations
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with idiopathic normal pressure hydrocephalus (INPH) have a disturbance in the cerebrospinal fluid (CSF) system. The treatment is neurosurgical – a shunt is placed in the CSF system. The infusion test is used to assess CSF system dynamics and to aid in the selection of patients that will benefit from shunt surgery. The infusion test can be divided into three parts: a mathematical model, an infusion protocol and a parameter estimation method. A non-linear differential equation is used to mathematically describe the CSF system, where two important parameters are the outflow conductance (Cout) and the Pressure Volume Index (PVI). These are used both for clinical and research purposes. The analysis methods for the non-linear CSF system have limited the infusion protocols of presently used infusion investigations. They come with disadvantages such as long investigation time, no estimation of PVI and no measure of the reliability of the estimates.The aim of this dissertation was to develop and evaluate novel methods for infusion protocols, mathematical modelling and parameter estimation methods for assessment of CSF system dynamics.The infusion protocols and parameter estimation methods in current use, constant pressure infusion (CPI), constant infusion and bolus infusion, were investigated. The estimates of Cout were compared, both on an experimental set-up and on 20 INPH patients. The results showed that the bolus method produced a significantly higher Cout than the other methods. The study suggested a method with continuous infusion for estimating Cout and emphasized that standardization of Cout measurement is necessary.The non-linear model of the CSF system was further developed. The ability to model physiological variations that affect the CSF system was incorporated into the model and it was transformed into a linear time-invariant system. This enabled the use of methods developed for identification of such systems. The underlying model for CSF absorption was discussed and the effect of baseline resting pressure (Pr) in the analysis on the estimation of Cout was explored using two different analyses, with and without Pr.A novel infusion protocol with an oscillating pressure pattern was introduced. This protocol was theoretically better suited for the CSF system characteristics. Three new parameter estimation methods were developed. The adaptive observer was developed from the original non-linear model of the CSF system and estimated Cout in real time. The prediction error method (PEM) and the robust simulation error (RSE) method were based on the transformed linear system, and they estimated both Cout and PVI with confidence intervals in real time. Both the oscillating pressure pattern and the reference CPI protocol were performed on an experimental set-up of the CSF system and on 47 hydrocephalus patients. The parameter estimation methods were applied to the data, and the RSE method produced estimates of Cout that were in good agreement with the reference method and allowed for an individualized and considerably reduced investigation time.In summary, current methods have been investigated and a novel approach for assessment of CSF system dynamics has been presented. The Oscillating Pressure Infusion method, which includes a new infusion protocol, a further developed mathematical model and new parameter estimation methods has resulted in an improved way to perform infusion investigations and should be used when assessing CSF system dynamics. The advantages of the new approach are the pressure-regulated infusion protocol, simultaneous estimation of Cout and PVI and estimates of reliability that allow for an individualized investigation time.
|
|
| 3. |
- A'roch, Roman, 1959-
(författare)
-
Left ventricular function's relation to load, experimental studies in a porcine model
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Loading conditions are recognized to influence ventricular function according to the Starling relationship for length/stretch and force. Many modern echocardiographic parameters which have been announced as describing ventricular function and contractile status, may be confounded by uncontrolled and unmeasured load. These studies aimed to measure the relation between four different types of assessments of ventricular dysfunction and degrees of load. Study examined the ‘myocardial performance index’ (MPI). Study II examined long axis segmental mechanical dyssynchrony. Study III examined tissue velocities, and Study IV examined ventricular twist. All studies aimed to describe the relation of these parameters both to load and to inotropic changes. Methods: In anesthetized juvenile pigs, left ventricular (LV) pressure and volume were measured continuously and their relationship (LVPVR) was analysed. Preload alterations were brought about by inflation of a balloon tipped catheter in the inferior vena cava (IVCBO). Inotropic interventions were brought about by either an overdose of anesthetic (combine intravenous pentobarbital and inhaled isoflurane, Study I), or beta blocker and calcium channel blocker given in combination (Studies III and IV). In one study (II), global myocardial injury and dysfunction was induced by endotoxin infusion. MPI measurements were derived from LVPVR heart cycle intervals for isovolumic contraction and relaxation as well as ejection time. Long axis segmental dyssynchrony was derived by analyzing for internal flow and time with segmental dyssynchronous segment volume change during systole, hourly before and during 3 hours of endotoxin infusion. Myocardial tissue velocities were measured during IVCBO at control, during positive and then later negative inotropic interventions. The same for apical and base circumferential rotational velocities by speckle tracking. Load markers (including end-diastolic volume) were identified for each beat, and the test parameters were analysed together with load for a relation. The test parameters were also tested during single apneic beats for a relation to inotropic interventions. Results: MPI demonstrated a strong and linear relationship to both preload and after-load, and this was due to changes in ejection time, and not the isovolumic intervals. Long axis segmental dyssynchrony increased during each hour of endotoxin infusion and global myocardial injury. This dysynchrony parameter was independent of load when tested by IVCBO. Peak systolic velocities were strongly load-independent, though not in all the inotropic situations and by all measurement axes. Peak systolic strain was load-dependent, and not strongly related to inotropic conditions. Peak systolic LV twist and untwist were strongly load-dependent. Conclusions: MPI is strongly load-dependent, and can vary widely in value for the same contractile status if the load is varied. Mechanical dyssynchrony measures are load-independen in health and also in early global endotoxin myocardial injury and dysfunction. Peak sytole velocities are a clinically robust parameter of LV regional and global performance under changing load, though peak systolic strain seems to be load-dependent. Left ventricular twist and untwist are load-dependent in this pig model.
|
|
| 4. |
- Barath, Stefan, 1963-
(författare)
-
Respiratory and cardiovascular effects of exposure to oxidative air pollutants
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The negative effects of air pollution on morbidity and mortality have been known since the mid 20th century. The two most well known examples are the Meuse Valley disaster in the 1930’ies and the London black fog in December 1952. Whilst there are numerous epidemiological studies, in which associations between morbidity and mortality and high levels of pollutants have been reported, the underlying mechanisms are not clear. Two of the main air pollutants are particulate matter (PM) mostly emanating from diesel exhaust (DE), and ozone, both of which are highly oxidative. Exposure to DE has resulted in adverse effects both in the respiratory tract and in the cardiovascular system. High ozone levels have also been shown to be associated with increased admissions to hospital for respiratory as well as cardiovascular conditions. The main aim of this thesis was to investigate the respiratory and cardiovascular effects of a combination of exposures to ozone and DE. DE generated during the urban part of the standardized European Transient Cycle (ETC) was compared to DE generated by an idling engine. It was also evaluated whether an acute exposure to ozone would have any effects on the cardiovascular system as assessed by venous occlusion forearm plethysmography and heart rate variability (HRV). In addition, fraction of exhaled nitric oxide (FENO) was evaluated as a potential marker for acute exposure to ozone or DE. Methods: Four double-blind randomized cross-over exposure studies were conducted to investigate the effects of ozone and DE on both the respiratory tract and the vascular function in healthy volunteers. All of the exposures were performed in purposely built “walk-in” chambers with strictly controlled exposures. In the first study, the volunteers were exposed to DE (300µg/m3) generated by an idling engine or to air, for one hour in the morning and to ozone (200 ppb) for two hours in the afternoon. A bronchoscopy with bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed 24 hours after the initial exposure. In study II and III, an assessment of vascular function using venous occlusion forearm plethysmography was performed after an exposure to DE (250 µg/m3) generated under transient running conditions, compared to air exposure (study II) and ozone and air exposure (study III). HRV was assessed under a 24 hour period starting before each exposure (study III). In study IV, FENO measurements were conducted after DE and ozone exposures to investigate whether the previously established airway inflammation would be detectable by this non-invasive method. Results: DE exposure enhanced the established ozone-induced airway inflammation in terms of a pronounced neutrophilia in BW. DE generated under transient running conditions, impaired vascular function in healthy volunteers, whereas exposure to ozone did not. HRV were not altered by exposure to ozone. Exposure to DE caused a significant increase in FENO at the 10 (FENO10) and 50 (FENO50) mL/s flow rates at 6 hours post-exposure, but ozone exposure did not affect FENO at any flow rate or time point. Conclusion: We have tried to mimic real-life exposure to air pollutants. In the first study, an exposure to DE followed by an exposure to ozone in the afternoon resulted in an enhanced airway inflammation, suggesting an additive or synergistic effect, supporting the epidemiological findings of unfavorable effects of the combination of these two air pollutants. DE generated by an engine running at the urban part of the standardized European Transient Cycle impaired two important and complementary aspects of vascular function, the regulation of vascular tone and endogenous fibrinolysis. This has previously been shown with DE generated at idling conditions. This suggests that the mechanisms behind the adverse effects can be found in the properties of the particles and not in the gaseous components. In these studies, exposure to ozone did not impair vascular function in healthy subjects, or cause any alterations in HRV. This suggests that the epidemiological evidence for an increased risk of cardiovascular mortality following acute exposure to ozone might not be totally accurate. Previous controlled exposure studies with ozone have not shown an airway inflammation affecting the endothelium, at least not in the same time-frame as following DE exposure. FENO could possibly be a useful tool for assessing airway inflammation caused by DE, whereas the powerful oxidant ozone did not affect FENO. This suggests that the airway inflammatory effects caused by these two pollutants are regulated via different mechanisms.
|
|
| 5. |
- Bodén, Ida, 1977-
(författare)
-
Near infrared and skin impedance spectroscopic in vivo measurements on human skin : development of a diagnostic tool for skin cancer
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Every year approximately 2800 Swedes are diagnosed with malignant melanoma, the form of cancer that is most rapidly increasing in incidence in the Western world. The earlier we can identify and diagnose a malignant melanoma, the better is the prognosis. In Sweden, 155 000 benign naevi, harmless skin tumours or moles, are surgically excised each year, many of them because melanoma cannot be dismissed by non-invasive methods. The excisions result in substantial medical costs and cause unrest and suffering of the individual patient. For untrained physicians, it is often difficult to make an accurate diagnosis of melanoma, thus a tool that could help to strengthen the diagnosis of suspected melanomas would be highly valuable. This thesis describes the development and assessment of a non-invasive method for early skin cancer detection. Using near infrared (NIR) and skin impedance spectroscopy, healthy and diseased skin of various subjects was examined to develop a new instrument for detecting malignant melanoma. Due to the complex nature of skin and the numerous variables involved, the spectroscopic data were analysed multivariately using Principal Component Analysis (PCA) and partial leas square discriminant analysis (PLS-DA). The reproducibility of the measurements was determined by calculating Scatter Values (SVs), and the significance of separations between overlapping groups in score plots was determined by calculating intra-model distances. The studies indicate that combining skin impedance and NIR spectroscopy measurements adds value, therefore a new probe-head for simultaneous NIR and skin impedance measurements was introduced. Using both spectroscopic techniques it was possible to separate healthy skin at one body location from healthy skin at another location due to the differences in skin characteristics at various body locations. In addition, statistically significant differences between overlapping groups of both age and gender in score plots were detected. However, the differences in skin characteristics at different body locations had stronger effects on the measurements than both age and gender. Intake of coffee and alcohol prior to measurement did not significantly influence the outcome data. Measurements on dysplastic naevi were significantly separated in a score plot and the influence of diseased skin was stronger than that of body location. This was confirmed in a study where measurements were performed on 12 malignant melanomas, 19 dysplastic naevi and 19 benign naevi. The malignant melanomas were significantly separated from both dysplastic naevi and benign naevi. Overall, the presented findings show that the instrument we have developed provides fast, reproducible measurements, capable of distinguishing malignant melanoma from dysplastic naevi and benign naevi non-invasively with 83% sensitivity and 95% specificity. Thus, the results are highly promising and the instrument appears to have high potential diagnostic utility.
|
|
| 6. |
- Brohlin, Maria
(författare)
-
Mesenchymal stem cells for repair of the peripheral and central nervous system
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord. Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons. Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine. After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn. In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.
|
|
| 7. |
- Carlsson, Maine, 1955-
(författare)
-
Nutritional status, body composition and physical activity among older people living in residential care facilities
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of this thesis was to study, whether drinkable yoghurt enriched with probiotic bacteria could have any effect on constipation and body weight (BW) among older people with dementia. Further, it concerns poor nutritional status among older people with physical and cognitive impairments and its relationship with factors commonly occur in older people living in residential care facilities. It also discusses how body composition changes with ageing and the associations between changes in muscle mass and functional balance after a high-intensity weight-bearing exercise program (the HIFE program) and the ingestion of an additional milk-based protein-enriched energy supplement. A six-month feasibility study that included a probiotic drink was performed among 15 old people who were living in special units for people with dementia and who all had constipation. The effects of the probiotic drink on stool habits, and BW were studied. The outcome measures were followed daily for bowel movements and at three and six months for BW. The staff found the study easy to carry out and that the drink was well accepted by the participants. No convincing beneficial effects on stool habits were observed. In addition, a mean BW loss of 0.65 kg/month was registered. A poor nutritional intake, low physical activity level, and an over-night fast of almost 15 hours, 4 hours longer than recommended were also observed. As a part of the FOPANU Study (Frail Older People-Activity and Nutrition Study), a randomized controlled trial was carried out in Umeå - the associations between nutritional status and factors common among old people with physical and cognitive impairments living in residential care facilities was studied. Assessments were made of nutritional status using the Mini Nutritional Assessment (MNA) scale, fat-free mass (FFM) and fat mass (FM) using both bioelectrical impedance spectroscopy (BIS) and skinfold thickness measurements. The effects of a high- intensity functional exercise program with an additional protein-enriched milk drink on ability to build muscle mass were evaluated. Analyses were made to investigate whether nutritional status, assessed using the MNA scale, was associated with medical conditions, drugs, activities of daily living (Barthel ADL index), cognitive impairment (Mini Mental State Examination (MMSE)), and depressive symptoms (Geriatric Depression Scale (GDS)) at baseline. The associations were assessed with multiple linear regression analyses with additional interaction analyses. An independent association was found between poor nutritional status and having had a urinary tract infection (UTI) during the preceding year and being dependent in feeding for both women and men, and having lower MMSE scores for women. A large proportion of the participants, were at risk of malnutrition or were already malnourished. Women, but not men, had significantly lower Fat-Free Mass Index (FFMI) and Fat Mass Index (FMI) with age. Bioelectrical impedance spectroscopy results correlated with skinfold thickness measurements, but on different levels on value for FM%. Despite the high-intensity exercise had long-term effects (at six months, three months after the exercise) on functional balance, walking ability and leg strength. No effects on muscle mass and no additional effects from the protein-enriched drink could be observed after the three months of high intensity exercise. A negative, long-term effect on the amount of muscle mass and BW was revealed at six months (three months after the intervention had ended). The effects from the exercise did not differ for participants who were malnourished. No statistical interactions were observed between sex, depression, dementia disorder, and nutritional status, and the level of functional balance capacity on the outcome at three or six months. In summary, the majority of the included older people with dementia had a low dietary intake, low physical activity level, and lost BW despite receiving a probiotic drink supplement every day for six months. The supplementation had no detectable effect on constipation. Among the participants in the FOPANU Study, UTI during the preceding year was independently associated with poor nutritional status. Being dependent in feeding was associated with poor nutritional status as were lower MMSE scores for women but not for men. Despite the high-intensity exercise program had long-term effects on the fysical function was no effect on the amount of muscle mass at three months observed. The FFM and FM expressed as indexes of body height were inversely related to age for women, but not for men. A high-intensity exercise program did not have any effect on the amount of muscle mass. The ingestion of a protein-enriched drink immediately after exercise produced no additional effect on the outcome and the results did not differ for participants who were malnourished. The negative long-term effect on amount of muscle mass, and BW, indicate that it is necessary to compensate for increased energy demands during a high-intensity exercise program. High age, female sex, depression, mild to moderate dementia syndrome, malnutrition, and severe physical impairment do not seem to have a negative impact on the effect of a high-intensity functional weight-bearing exercise program. Consequently, people with these characteristics in residential care facilities should not be excluded from training and rehabilitation including nutrition. More research is needed in large randomized controlled trials to further explore the association between energy balance and malnutrition among frail old people, with a special focus on UTI and constipation, but also to study how physical exercise affects older people’s nutritional status.
|
|
| 8. |
- Dahlin, Anna, 1979-
(författare)
-
The CpG island methylator phenotype in colorectal cancer : studies on risk and prognosis
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Colorectal cancer (CRC) is the second most common malignancy in developed countries. The mortality is high, with nearly half of patients dying from the disease. The primary treatment of CRC is surgery, and decisions about additional treatment with chemotherapy are based mainly on tumor stage. Novel prognostic markers that identify patients at high risk of recurrence and cancer-related death are needed. The development of CRC has been described in terms of two different pathways; the microsatellite instability (MSI) and chromosomal instability (microsatellite stable, MSS) pathway. More recently, the CpG island methylator phenotype (CIMP), characterized by frequent DNA hypermethylation, has been described as an alternative pathway of tumorigenesis. The event of DNA methylation is dependent on one-carbon metabolism, in which folate and vitamin B12 have essential functions. The purpose of this thesis was to study CIMP in CRC. The specific aims were to investigate the potential role of components of one-carbon metabolism as risk factors for this subgroup of tumors, and the prognostic importance of CIMP status, taking into consideration important confounding factors, such as MSI and tumor-infiltrating T cells. Methods CRC cases and referents included in the Northern Sweden Health and Disease Study (NSHDS, 226 cases and 437 referents) and CRC cases in the Colorectal Cancer in Umeå Study (CRUMS, n=490) were studied. Prediagnostic plasma concentrations of folate and vitamin B12 were analyzed in NSHDS. In both study groups, CIMP status was determined in archival tumor tissue by real-time quantitative PCR using an eight-gene panel (CDKN2A, MLH1, CACNA1G, NEUROG1, RUNX3, SOCS1, IGF2 and CRABP1). MSI screening status and the density of tumor-infiltrating T cells were determined by immunohistochemistry. Results An inverse association was found between plasma concentrations of vitamin B12 and rectal, but not colon, cancer risk. We also found a reduced risk of CIMP-high and CIMP-low CRC in study subjects with the lowest levels of plasma folate. We found that patients with CIMP-low tumors in both NSHDS and CRUMS had a poorer prognosis compared with CIMP-negative, regardless of MSI screening status. We also found that MSS CIMP-high patients had a poorer prognosis compared with MSS CIMP-negative. The density of tumor-infiltrating T cells and CIMP status were both found to be independent predictors of CRC patient prognosis. A particularly poor prognosis was found in patients with CIMP-low tumors poorly infiltrated by T cells. In addition, the density of T cells appeared to be more important than MSI screening status for predicting CRC patient prognosis. Conclusion Rather than being one disease, CRC is a heterogeneous set of diseases with respect to clinico-pathological and molecular characteristics. We found that the association between risk and plasma concentration of vitamin B12 and folate depends on tumor site and CIMP status, respectively. Patient prognosis was found to be different depending on CIMP and MSI screening status, and the density of tumor-infiltrating T cells.
|
|
| 9. |
- Eriksson, Catharina, 1955-
(författare)
-
Immunological mechanisms in systemic autoimmunity : autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that, without powerful treatment, may lead to irreversible joint damage. During the past decade, anti-cytokine therapy has become available, e.g., infliximab, a chimeric antibody targeting the pro-inflammatory cytokine TNF that has a central role in the inflammatory process in RA patients. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that may affect all organs and is characterized by a massive antibody production. Chemokines, chemokine receptors and lipoprotein receptor-related protein 1(CD91) are regulators of inflammation in autoimmune diseases and T-cell migration. Objectives. The aim of this study was to get a deeper understanding how TNF blocking treatment influences inflammatory mechanisms and autoantibody formation in RA with special reference to similarities and differences with SLE. Methods. In patients with RA treated with anti-TNF, and in SLE patients (ACR criteria) clinical evaluation was performed and blood samples analyzed. Autoantibodies were analyzed using indirect immunofluorescence, ELISA and multiplex flow cytometry in samples from anti-TNF treated RA patients (n=59) followed longitudinally for 54 weeks, in pre-diseased samples from SLE patients (n=38) and matched population-based controls (n=152). T-cell expression of chemokine receptors and CD91 was analyzed by flow cytometry, whilst serum levels of chemokines were determined using ELISA in anti-TNF treated RA-patients (n=24) followed longitudinally (30 weeks), and cross-sectionally in SLE-patients (n=23). Expression of mRNA for chemokines was analyzed in T-cells from SLE-patients (n=10) using PCR. Results. After treatment with infliximab, RA patients produced ANA, anti-dsDNA and anti-nucleosome antibodies, but not anti-ENA antibodies. Although these antibodies are considered typical for SLE only one patient developed a transient lupus-syndrome. Antibodies against cell nuclear antigens, including ENA, were detected several years before the first clinical symptom of SLE; anti-SSA was the earliest detectable antibody. In RA-patients before infliximab treatment, the T-cell expression of several chemokine receptors was elevated compared with healthy controls. In contrast, only one soluble chemokine, IP-10 was elevated. After treatment the levels of soluble MIP-1β, MCP-1 and IP-10, and the T-cell expression of CCR2 were decreased. In SLE-patients MIP-1β, MCP-1, SDF-1, IP-10 and RANTES in blood were elevated, whilst expression of CXCR5 and CCR6 on T-cells was lower than in healthy controls. T-cell expression of CXCR2 and CCR1 was elevated in active disease (measured as SLEDAI index), whereas the CXCR5 and CCR2 expression was lower in inactive SLE. In SLE patients with nephritis IP-10 was lower and T-cell expression of CXCR3 and CCR3 elevated compared with patients without nephritis. The expression of CD91 was higher on T-cells from patients not responsive to infliximab treatment compared with responders. Conclusion. These findings indicate that anti-TNF (infliximab) treatment in RA-patients has a major impact on the production of autoantibodies and chemokines. The autoantibody profile in infliximab-treated patients was similar to that predating disease onset in SLE patients with the exception of anti-ENA being detectable in SLE, but the development of lupus-syndromes was rare. The expression of CD91 on T-cells may predict responsiveness to infliximab. The expression of chemokine receptors in SLE- patients seemed to be related to disease activity. Anti-nuclear antibodies were detectable years before clinical disease onset in patients who developed SLE suggesting a gradual pathogenic process.
|
|
| 10. |
- Eriksson, Irene, 1965-
(författare)
-
Urinary tract infection : a serious health problem in old women
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Urinary tract infection (UTI) is a common bacterial infection in women of all ages but the incidence and prevalence increase with age. Despite the high incidence of UTI, little is known about its impact on morale or subjective wellbeing and daily life in old women. UTI in older people can be a complex problem in terms of approach to diagnosis, treatment and prevention because in these patients it frequently presents with a range of atypical symptoms such as delirium, gastrointestinal signs and falls. Even if UTI has been shown to be associated with delirium it has frequently been questioned whether UTI can cause delirium or if it is only accidentally detected when people with delirium are assessed. The main purpose of this thesis was to describe the prevalence of UTI, to identify factors associated with UTI among very old women and to illuminate the impact of a UTI on old women’s health and wellbeing. This thesis is based on two main studies, the GErontological Regional DAtabase (GERDA) a cross-sectional, population-based study carried out in the northern parts of Sweden and Finland during 2005-2007 and a qualitative interview study in western Sweden 2008-2009. Data were collected from structured interviews and assessments made during home visits, from medical records, care givers and relatives. UTI was diagnosed if the person had a documented symptomatic UTI, with either short- or long-term ongoing treatment with antibiotics, or symptoms and laboratory tests judged to indicate the presence of UTI by the responsible physician or the assessor. One hundred and seventeen out of 395 women (29.6%) were diagnosed as having suffered from at least one UTI during the preceding year and 233 of these 395 (60%) had had at least one diagnosed UTI during the preceding 5 years. These old women with UTI were more dependent in their activities of daily living, and had poorer cognition and nutrition. In these women, UTI during the preceding year was associated with vertebral fractures, urinary incontinence, inflammatory rheumatic disease and multi-infarct dementia. Eighty-seven of 504 women (17.3%), were diagnosed as having a UTI with or without ongoing treatment when they were assessed, and almost half (44.8%) were diagnosed as delirious or having had episodes of delirium during the past month. In all, 137 of the 504 women (27.2%) were delirious or had had episodes of delirium during the past month and 39 (28.5%) of them were diagnosed as having a UTI. Delirium was associated with Alzheimer’s disease, multi-infarct dementia, depression, heart failure and UTI. Forty-six out of 319 women (14.4%) were diagnosed as having had a UTI with or without ongoing treatment and these had a significantly lower score on the Philadelphia Geriatric Center Morale Scale (PGCMS), (10.4 vs 11.9, p=0.003) than those without UTI, indicating a significant impact on morale or subjective wellbeing among very old women. The medical diagnoses significantly and independently associated with low morale were depression, UTI and constipation. The experience of suffering from repeated UTI was described in interviews conducted with 20 old women. The interviews were analysed using qualitative content analysis. The participants described living with repeated UTI as being in a state of manageable suffering and being dependent on alleviation. Being in a state of manageable suffering was described in terms of experiencing physical and psychological inconveniences, struggling to deal with the illness and being restricted regarding daily life. Being dependent on alleviation was illustrated in terms of having access to relief but also experiencing receiving inadequate care. In conclusion, UTI is very common among old and very old women and is a serious health problem. UTI seems to be associated with delirium and to have a significant impact on the morale or subjective wellbeing of old women and those affected suffer both physically and psychologically and their social life is limited. UTI was also associated with vertebral fractures, urinary incontinence, inflammatory rheumatic disease and multi-infarct dementia which might raise the suspicion that UTI can have serious medical effects on health in old women.
|
|
