| 1. |
- Edvardsson, Maria, 1972-
(författare)
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Circulating levels and assessment of clinical laboratory analytes, in >80-year-old, apparently healthy, moderately healthy, and frail individuals
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood samples are often used to investigate the possible presence of disease and to make treatment decisions. In the interpretation of the results, comparison either with previous values from the same individual or with a set of appropriate group-based reference intervals are used. Current reference intervals for common laboratory analytes are often based on measurements from apparently healthy persons aged 18–65 years. Age is accompanied by a general decline in organ functions and it is difficult to determine whether a change in levels of laboratory analytes in an elderly individual can be attributed to age alone, independent of environmental or disease processes. Frailty can be seen as a consequence of age-related multifactorial deterioration – physical, cognitive and sensory – resulting in vulnerability and lack of adaptability to internal stressors such as infection or new medication and/or external stressors such as fall at home. Consensus about the definition of “frail” and “frailty” is missing, both nationally and internationally, the question arises whether different definitions of “frailty” affect the interpretation of analytes when comparing different groups of elderly.The overarching aim of the thesis was to interpret and assess circulating levels of some clinical laboratory analytes in relation to conventional reference values in ≥80-year-old, “apparently healthy”, “moderately healthy”, and “frail” individuals. Data originated from other studies, in which blood samples were collected from individuals ≥80-year-old. Comparisons in Paper I of levels of some laboratory analytes, from 138 nursing home residents (NHRs), was made with blood from reference populations, both blood donor and the NORIP study. The results indicated differences for some immunological (complement factor 3 and 4, immunoglobulin G and M) and chemical analytes (alanine aminotransferase (ALT), phosphate, albumin, sodium, creatinine and urea), but no differences in levels occurred for aspartate aminotransferase (AST), gamma-glutamyltransferase (γ-GT) or lactate dehydrogenase (LDH). It was unclear whether the differences were due to differences in age between the elderly and the reference populations or whether the elderly individuals had chronic diseases and were on medication. In Paper II, 569 individuals elderly individuals ≥80 years old were classified as “healthy”, “moderately healthy”, and “frail”, based on diseases, medications and physical and cognitive abilities. Statistical differences between the groups were found for the investigated analytes; albumin, ALT, AST, creatinine and γ-GT. In Paper IV, individuals from Paper II (n=569) were divided into two groups and thereafter divided into “apparently healthy”, “moderately healthy”, and “frail”. One group was subdivided into “apparently healthy”, “moderately healthy” and “frail” based on physical and cognitive abilities and the other group was divided based on the frailty index (FI). There was no statistical difference found between “apparently healthy” and “moderately healthy" groups, regardless of classification model used. Among “frail” individuals, differences in levels occurred for three out of the five investigated analytes: ALT, creatinine and g-GT, with lower levels occurring when the FI classification model was used. No differences in levels occurred for albumin or AST in “frail” individuals, regardless of classification model used. The aim of Paper III was to study whether 1-year changes in complete blood count (CBC) (including haemoglobin (Hb), red blood cell (RBC), erythrocyte volume fraction (EVF), mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), white blood cell (WBC) and platelet count (PLT)), C-reactive protein (CRP) and interleukin (IL)-1β, IL-1RA, IL-6, IL-8 and IL-10 are associated with survival in elderly NHRs aged >80 years. Elevated levels of CRP and IL-8 during 1-year follow-up were associated with reduced length of survival in elderly NHRs. Based on the present thesis it is clear that there is need for reference intervals that consider both age and health status in elderly individuals. A reasonable conclusion when interpreting levels of analytes in elderly individuals with disease or frailty is that individual evaluation based on the individual’s previous levels, is recommended.
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| 2. |
- Grodzinsky, Ewa, 1958-
(författare)
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Serological markers in subclinical and clinical gluten enteropathy
- 1994
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An enzyme-linked immunosorbent assay (ELISA) has been developed for the measurement of anti-gliadin antibodies (AGA), thereby providing a practical and cheap assay for use in the diagnosis of coeliac disease (CD). Since gliadin is a common food antigen for most people, a large group of apparently healthy blood donors (n=l866) was analysed, as well as children and adults with symptoms more or less suggesting CD. The effects of various cut-offvalues on the sensitivity, specificity and predictive value (PV) of the test were calculated, both alone and together with anti-endomysium antibodies (EMA). A high prevalence value, of at least 1/256 (7!1866), for gluten enteropathy (GE) was found in the blood donor population. Moreover, a high frequency of CD among fanners with diffuse symptoms, conceivably due to a high exposure to gluten by inhalation, was also observed. It was impossible to combine high sensitivity with high specificity for both IgA- and IgG AGA, and vice versa, in adults. A significant increase in the mean lgA AGA level with age was seen when the blood donors were divided into age groups. A positive PV of 18-25% was found for IgA-AGA, depending on how-the cut-off value was defined. For IgG-AGA the positive PV was 0% (0/35) among asymptomatic subjects. IgA-EMA yielded both high specificity and a high positive PV, but a lower sensitivity than IgA-AGA, especially in children younger than 2 years, with signs of CD. When screening for GE in a population with expected low prevalence, measurement of IgA-AGA is suggested as a primary test because of fairly good sensitivity, technical simplicity, and low cost. Sera found to be positive are then re tested with IgA-EMA, which gives a positive PV close to 100%. For populations with a moderate or high expected prevalence for CD, our results indicate that different tests should be used depending on the age of the population studied. In younger children ( < 2 years old) lgA-AGA yielded a high sensitivity (lOO%) and a high specificity (86%). fu older children (> 2 years old) and adults the use of IgA-EMA seems more suitable, because of the high specificity (99-100%) and positive PV (95-100% ). Since, however, the negative PV was not 100%, a negative test result does not exclude CD.
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| 3. |
- Gustafsson Bragde, Hanna, 1979-
(författare)
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Biomarkers of Inflammation and Intestinal Mucosa Pathology in Celiac Disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by gluten. The only currently available treatment is complying with a lifelong gluten-free diet, which should not be commenced before a CD diagnosis has been established by diagnostic test results (including histopathologic assessment of small intestinal biopsies and CD-specific antibody levels). This makes diagnostic swiftness and accuracy important. In cases with low CD-specific antibody levels and/or low-grade intestinal injuries the diagnosis can be difficult to establish. The main objective of this thesis was to complement and improve CD diagnostics by identifying and implementing new biomarkers, mainly based on gene expression, in small intestinal biopsies and blood. In paper I, genes were selected to reflect villous height, crypt elongation, immune response, and epithelial integrity. The results showed that a subset of those genes could discriminate active CD mucosa from mucosa without CD-related changes and grade the intestinal injury. In paper III, an unbiased investigation of gene expression in CD mucosa was performed using transcriptome analysis. Active CD and non-CD mucosa showed differential expression in a subset of genes, and some were differentially expressed in CD mucosa before histopathologic assessment could confirm intestinal alterations compatible with a CD diagnosis. Gene set analysis revealed that there are many biological processes affected in CD mucosa, including those associated with immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation.In parallel, gene expression was investigated in stabilised whole blood. Blood is a more accessible sampling material than intestinal biopsies, and stabilised blood is suitable for routine diagnostics since transcript levels are preserved at sampling. In paper II, expressions from a selection of genes were quantified in stabilised whole blood (RNA) and/or plasma (protein). Three genes with differential expression in CD were identified. Compared to the CD-specific autoantibodies against tissue transglutaminase (anti-TG2) alone, the addition of the information from the new potential markers resulted in a nonsignificant contribution to the diagnostic capacity of anti-TG2. An unbiased investigation using transcriptome analysis (paper IV) showed that gene level expression differences in stabilised whole blood were small between CD and non-CD. However, expression differences on a gene set level could potentially be used in CD diagnostics. CD-associated biological processes suggested by the results included a pro-inflammatory response, negative regulation of viral replication, proliferation, differentiation, cell migration, cell survival, translation, and haemostasis.Expression analysis using real-time polymerase chain reaction (PCR) is easy to perform, with instrumentation available at most clinical laboratories. Although select solitary biomarkers could be very useful in the diagnosis of CD, basing gene expression profiles on pathway information instead of single genes might also disclose disease heterogeneity between patients and add stability to a diagnostic method based on gene expressions. In conclusion, the results of this work demonstrate that analysing the expression of a few small intestinal genes can complement CD diagnostics. The application of gene expression analysis in cases with minor small intestine histopathological changes shows promising results, but needs further investigations. Additionally, gene expressions in other inflammatory diseases of the small intestine need to be investigated and compared with CD to complete the picture. Moreover, the findings from this work give clues about the biological contexts in which CD resides, and the potential of gene expression in blood at a gene set level is of interest for further investigations.
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| 4. |
- Olsen Faresjö, Åshild
(författare)
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Irritable bowel syndrome diagnosed in primary care : Occurrence, treatment and impact on everyday life
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: IBS is the most common functional gastrointestinal disorders and affects approximately 10-20 % of the general population and is widespread in all societies and socio-economic groups. Although the disorder does not have a life-threatening course, it still seriously affects the patients in their everyday life.Aim: The general aims of this thesis were to estimate the occurrence of irritable bowel syndrome in the general population and to achieve a better understanding of present treatment of this disorder and impact on every-day life in those suffering from IBS.Material and methods: The LIPS study comprises two parts. Part I was a retrospective register study where the data collection was based on computerised medical records at three selected Primary Health Care centres in a defined region. Part II was a population based case-control study. The identified IBS cases from part I constitute the cases, while their control groups were randomly selected from the population census register in the same area as the cases. Data in part II were collected by means of a postal questionnaire to cases and controls. The study was conducted in Linköping, a city located in the south-east of Sweden with 135 000 inhabitants.Results: The female IBS patients reported lower influence on planning their work and working hours as well as fewer opportunities to learn new things at their work compared to their controls, even after adjustments in multiple logistic regressions for potential confounders like; mood, sleeping problems and perceived health. The female IBS patients had considerably lower HRQOL in all dimensions compared to their controls, even when compared to male patients. Younger female IBS cases (18-44 years) reported lower mental health on the SF-36 scale than the older IBS female cases (p=0.015). In the multivariate analysis these variables, lack of influence on planning the work, family history of IBS, anxiety and sleeping disturbance displayed an association with being diagnosed with IBS in women. In men, lack of influence on working pace, family history of IBS was associated with an IBS diagnosis.The consultation incidence of IBS in part I was 3.4 (95% CI 3.20-3.70) per 1000 person-years for all IBS cases, among females; the incidence rate was 4.6 per 1000 person-years (95% CI 4.16-4.97) and males; 2.3 per 1000 person-years (95% CI 2.01-2.59). The dominating pharmacological treatment prescribed for abdominal complaints were fibre and bulking laxatives agents as well as acid suppressive drugs. These variables had an independent impact on the probability of a follow-up consultation; diagnosed co-morbidity besides the IBS diagnosis, rectoscopy ordered and laboratory tests ordered.Conclusions: IBS patients identified in primary care are significantly affected in their working-life compared to individuals in the general population. Especially female IBS-patients report lower decision latitude at work and they also appear to have a particularly impaired psychosocial functioning in their every day life and impaired HRQOL. Factors associated with IBS diagnosis among females are anxiety as well as family history of IBS and lack of co-determination at work.The incidence rate of IBS was 3.4 per 1000 person-years which increased with age and with an overrepresentation of females. IBS patients did not appear to be heavy utilisers of primary care and those who attended were treated by their GP without further consultation. The strongest predictors for having a follow-up consultation were diagnosed co-morbidity, rectoscopy and laboratory tests ordered
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| 5. |
- Rendek, Zlatica, 1983-
(författare)
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Faecal Calprotectin Diagnostics : Focus on Primary Care and Suspected Sources of Error
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with gastrointestinal symptoms often present a diagnostic challenge for general practitioners. Faecal calprotectin (FC) is commonly used as a marker of intestinal inflammation and is useful for differentiating between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), as well as for the follow-up of patients with IBD and monitoring treatment response. However, several other causes of increased FC levels have been acknowledged, including intake of non-steroidal anti-inflammatory drugs or proton pump inhibitors and respiratory infections. Currently, there is insufficient knowledge about how these factors affect FC levels. It is crucial that physicians who use calprotectin as a diagnostic tool have the ability to conduct a sound evaluation of the test result to ensure accurate clinical decisions, and potentially avoid unnecessary referrals and invasive investigations.The aim of this thesis was to investigate the contribution of FC in the diagnostics of gastrointestinal disease in primary care, its diagnostic value and accuracy as a predictor of gastrointestinal disease and the influence of different sources of error on calprotectin levels. In particular, the effects of oral diclofenac (a non-steroidal anti-inflammatory drug [NSAID]), omeprazole (a proton pump inhibitor [PPI]) and respiratory tract infection on FC levels are investigated. The normalization interval after cessation of diclofenac and omeprazole is assessed.The first study is a retrospective analysis of data on all FC tests on adults conducted in primary care in Östergötland County in 2010. A higher proportion of patients with a positive FC result were diagnosed with IBD and organic gastrointestinal disease compared with those with a negative FC result. Predictors of IBD were positive FC, diarrhoea, rectal bleeding and male sex. Predictors of organic gastrointestinal disease were found to be positive FC, age >35 years, abnormal clinical findings and duration <3 months. FC had the highest sensitivity and negative predictive value compared with demographic factors, symptoms and duration. Intake of NSAIDs, PPIs and acetyl salicylic acid showed marginal effects on the diagnostic accuracy of FC for IBD and organic gastrointestinal disease. Among patients with a negative FC test, on whom no further investigations were performed, no missed diagnoses of IBD or organic gastrointestinal disease were detected at a 5-year follow-up.The second study investigates the effect of diclofenac intake on FC levels. We found that shortterm intake of oral diclofenac was associated with increased FC levels and that FC returned to normal within 2 weeks of cessation.The third study reports on a randomized open-label clinical trial and investigates the effect of omeprazole, diclofenac and co-administration of these drugs on FC levels. The findings regarding diclofenac were consistent with those of the second study. Short-term intake of omeprazole alone or when co-administered with diclofenac was associated with increased FC levels. The normalization interval was 3 weeks after cessation.The fourth study, a prospective cohort study, examines the effect of an acute respiratory tract infection on the FC level. Faecal and salivary calprotectin levels were not found to be increased during respiratory tract infections. This study did not confirm any correlation between calprotectin levels in saliva and faeces during infection.In conclusion, FC reliably rules out IBD and contradicts the presence of other organic gastrointestinal diseases in patients with gastrointestinal symptoms attending primary care. Patients with a positive FC test together with other symptoms, such as diarrhoea, rectal bleeding, short duration or age >35 years should be prioritized for further investigations. Short-term intake of diclofenac, omeprazole, or their co-administration in healthy individuals is associated with increased FC levels. In patients with an increased FC level on diclofenac, it is sufficient to repeat the FC test 2 weeks after cessation. In patients on omeprazole alone or when co-administered with diclofenac, the FC test should be repeated 3 weeks after cessation. Acute respiratory tract infections were not found to be associated with increased faecal or salivary calprotectin levels.
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| 6. |
- Sund-Levander, Märtha, 1954-
(författare)
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Measurement and evaluation of body temperature : Implications for clinical practice
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim was to explore factors influencing the normal variation and measurement of body temperature. Additional aims were to study morbidity, mortality and the clinical presentation of pneumonia and predictors for survival in elderly nursing-home residents. Two hundred and thirty seven non-febrile nursing home residents (aged 66-99 years) and 87 healthy adults (aged 19-59 years) were included. In elderly individuals, the morning ear and rectal body temperature was measured at baseline and pneumonia and survival was observed at one- two and three-year. In healthy adults the rectal, ear, oral and axillary temperature were measured simultaneously on one morning and repeated measurements were performed in three subjects.Overall, the range of normal body temperature was wider then traditionally stated. In elderly nursinghome residents, functional and cognitive impairment and BMI < 20 were related to a lower body temperature and medication with analgesics to a higher. Compared to adults < 60 years elderly persons had a higher average ear and a lower rectal temperature. Men and postmenopausal women < 60 years had lower body temperature than premenopausal women. The repeated measurements showed a wide individual variability irrespective of the site of measurement, and that replicated measurements do not improve accuracy. When comparing the rectal temperature with oral, ear and axillary readings the average difference was > 0.5°C with a wide individual variation.The yearly incidence of nursing-home acquired pneumonia varied between 6.9% and 13.7%. Functional impairment, chronic obstructive pulmonary disease (COPD) and male sex were related to a higher risk of acquiring pneumonia and presenting non-specific symptoms were common. Age and functional impairment predicted mortality, irrespective of gender, while cerebral vascular insult, a lower body mass index and malnutrition in women and heart disease, COPD, medication with sedatives and mortality rate index in men were gender specific predictors. Surviving women had a higher baseline body temperature than non-surviving, while no such difference was found in men.When assessing body temperature, it is important to consider the site of measurement, technical design, operator technique, age and gender and, in elderly nursing-home residents, physical and cognitive impairment, body constitution and medication with analgesics. The best approach is to use an unadjusted mode, without adjusting to another site. To prevent a delayed diagnosis of pneumonia, one should be aware of a low baseline body temperature and lack of specific clinical symptoms in elderly nursing-home residents. Preserving and/or improving functional, cognitive, nutritional status and preventing agitation and confusion would improve survival in nursing-home residents.
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