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- Bladh, Marie
(författare)
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Birth Characteristics’ Impacton Future Reproduction and Morbidity Among Twins an dSingletons
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Globally, in both developed and developing countries, the twinning rates have increased since the early 70’s. A large proportion of twins are born preterm and/or small-for-gestational-age (SGA) and/or with a low birth weight. Several studies have been performed on the long-term effect of these non-optimal birth characteristics on future reproductive performance and morbidity. Yet, most studies exclude twins or higher order pregnancies and thus the findings are based on singleton pregnancies only.The aim of the present thesis was therefore to investigate the impact of non-optimal birth characteristics in terms of preterm birth, small-for-gestational age, and low birth weight, on the reproductive pattern and morbidity among twins and singletons Furthermore, the present thesis attempted to establish whether twins and singletons were affected in the same manner.The studies included in this thesis are prospective population-based register studies, including all men and women, alive and living in Sweden at age 13, who were born between 1973 and 1983 (1,000,037 singletons and 16,561 twins) for the first three studies with follow-up till the end of 2006 and 2009. The last study included all men and women, alive and living in Sweden at age 13, who were born between 1973 and 1993 (2,051,479 singletons and 39,726 twins) with follow-up till the end of 2012.In general, twins were found less likely to reproduce between 13 and 33 years of age compared with singletons. Stratifying data by different birth characteristics, it was found that twins had a lower likelihood of reproducing on several different birth characteristics (appropriate-for-gestational-age, normal birth weight, low birth weight, term birth, preterm birth). However, twins born very preterm had an increased likelihood of reproducing compared with singletons born very preterm.Not taking birth characteristics into account, twinning was associated with a higher degree of hospitalization. However, accounting for the diverging birth characteristics this difference diminished and for some diagnoses the relationship was reversed such that twins were actually less likely to be hospitalized compared with singletons.In terms of the heritability of non-optimal birth characteristics singleton mothers born preterm were more predisposed to give birth to a child that was preterm while singleton mothers born SGA more often gave birth to a child either born preterm or SGA. Among twins this heritability was not as evident. The only difference observed was among twin mothers born SGA who were more likely to give birth to a child born SGA.In the extended cohort comprising those born between 1973 and 1993, male and female twins were found to be less likely to become parents compared with singletons. No difference was found among women in terms of having a second child, while male twins were more likely to have a second child compared with male singletons. It was also found that the likelihood of becoming a first-time parent and second-time parent was positively associated with the number of siblings.
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| 2. |
- Garvin, Peter, 1976-
(författare)
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Plasma levels of matrix metalloproteinase‐9 in a normal population : a psychoneuroendocrinological approach
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several large‐scale epidemiological studies have demonstrated the prognostic significance of psychosocial factors and stress for coronary artery disease (CAD). Observations of sudden changes in CAD incidence have led to the proposal of mechanisms regarding atherosclerotic plaque vulnerability. The collagen‐degrading enzyme matrix metalloproteinase-9 (MMP-9) is increased in rupture‐prone plaques with high inflammatory activity, and circulating levels of MMP-9 are raised in patients with acute coronary syndrome. However, the distribution of MMP‐9 levels and its relations to psychosocial factors and the stress hormone cortisol have not been previously explored in a normal population.The aim of this dissertation was to examine in a normal population the association of circulating levels of MMP-9 with traditional cardiovascular risk factors including levels of C-reactive protein (CRP), with psychosocial factors, and with saliva levels of cortisol. In addition, the reliability of a new method of ambulatory saliva sampling for assessment of cortisol levels was evaluated. A sub‐sample of the Life conditions, Stress, and Health (LSH)-study, a population based study exploring psychoneuroendocrinological pathways mediating the differences in CAD incidence over socioeconomic status, was used. Plasma levels of MMP-9 were examined in a sample randomly drawn from the LSH‐study (n=400), aged 45 to 69 years at enrollment.The main findings were: 1) there was a positive association between plasma MMP-9 levels and total risk load of cardiovascular risk factors. The findings were persistent after adjusting for CRP and could not be attributed to a single risk factor. 2) After adjusting for traditional cardiovascular risk factors and CRP, MMP-9 levels were positively associated with psychosocial risk factors and negatively associated with psychosocial resources. 3) Pooling saliva samples prior to laboratory analysis were as reliable as arithmetic means for assessment of diurnal cortisol variation in a field research setting. 4) There was a positive association between circulating levels of MMP‐9 and saliva levels of cortisol, both diurnal peak level and evening level of cortisol. The observed associations between MMP‐9 and traditional cardiovascular risk factors, psychosocial factors, and saliva cortisol levels suggest a psychoneuroendocrinological pathway linking stress to plaque vulnerability and provide increased understanding of the association between psychosocial factors and CAD.
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| 3. |
- Gnosa, Sebastian, 1984-
(författare)
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Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The incidence and death rate for colorectal cancer (CRC) decreased during the last decades as a result of improved diagnosis and treatment. However, CRC is still the third most common cancer in the world, and is responsible for about 700 000 deaths per year worldwide. Therefore, it is important to understand the mechanisms of the disease, and to find molecular markers in order to further improve prognosis, and to develop new treatment strategies. Astrocyte elevated gene-1 (AEG-1), encoded by the MTDH gene, is upregulated in a variety of cancers. AEG-1 is involved in cell survival, proliferation, migration, invasion, metastasis, angiogenesis, and apoptosis.The aim of this thesis was to investigate the role of AEG-1 in CRC development and the impact of AEG-1 on the response of radiation treatment. The AEG-1 expression, analysed in different CRC patient cohorts in paper I and III, was increased in the tumour tissue compared with the normal mucosa, and higher in the lymph node and liver metastases. Expression analyses in normal and cancer cell lines confirmed these results. In paper II, sequencing of the complete coding sequence of the MTDH gene in 356 patients revealed 50 single nucleotide variants of which 29 were novel. Eight exonic variants were detected, including three frameshift variants which were probably pathogenic, and two missense variants located in functional protein regions. There was no correlation of the MTDH variants or AEG-1 expression with the patient survival. In paper III, we also investigated the impact of AEG-1 on the response to radiation treatment. AEG-1 knockdown decreased the cellular survival upon radiation in several colon cancer cell lines. The AEG-1 expression was furthermore analysed in patients, which were randomised to either surgery alone or preoperative radiotherapy (RT), followed by surgery. The rectal cancer patients with high AEG-1 expression treated with RT had a significantly higher risk of developing distant recurrence and had a worse disease free survival, likely due to the metastasis promoting properties of AEG-1. In paper IV, the impact of AEG-1 knockdown and radiation on migration and invasion was analysed in colon cancer cell lines in vitro and in a novel zebrafish model in vivo. AEG-1 knockdown decreased migration and invasion, and radiation-enhanced migration and invasion in the cell lines tested.In conclusion, our data suggest that AEG-1 is involved in CRC development, while MTDH gene variants probably not have a high clinical importance in CRC. Furthermore, AEG-1 is a promising radiosensitising target and a valuable prognostic marker in CRC. We further showed that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced cell migration and invasion.
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| 4. |
- Lyth, Johan, 1980-
(författare)
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Clinical-epidemiological studies on cutaneous malignant melanoma : A register approach
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The incidence of cutaneous malignant melanoma (CMM) is steadily increasing. Most of the patients have thin CMM with a good prognosis and a 5-year survival of about 90%. The prognosis is highly related to tumour thickness and clinical stage at diagnosis. Effective systemic treatment for patients with metastatic disease has only recently been available. This thesis aims to increase knowledge of trends in tumour thickness, prognostic factors, socioeconomic differences and medical costs in patients with CMM.The population-based Swedish melanoma register is the main source of data in all papers in the thesis. Papers I-III include patients from all of Sweden while paper IV is delimited to the County of Östergötland. Cox regression and logistic regression are the main multivariable methods used. Paper IV is focused on stage-specific costs of CMM by comparing direct healthcare costs to a general population.For men, there has been a shift over time towards thinner tumours at diagnosis accompanied by an improved survival. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men. Tumour ulceration, tumour thickness and Clark’s level of invasion all showed significant independent long-term prognostic information in T1 CMMs. By combining these factors, three distinct prognostic subgroups were identified. Lower level of education was associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. The direct healthcare costs for CMM patients were significantly higher than for the general population, independent of clinical stage. CMM patients diagnosed in clinical stage III-IV were associated with particularly high costs.Even though the survival among Swedish patients with CMM is among the highest in the world and still seems to improve, the results of this thesis emphasise the need of improved early detection strategies. This may be of particular concern in men, older women, and groups with a low level of education. The results also imply that the costs for the management of CMM patients may be reduced if early detection efforts are successful and lead to a more favourable stage distribution. The finding of a better risk stratification of thin CMMs may help to improve the management of this large patient group.
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| 5. |
- Nygren, Maria, 1981-
(författare)
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Stress in childhood and the risk of type 1 diabetes
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: It is still unknown why children develop type 1 diabetes (T1D), although both genetic predisposition and environmental factors seems to be involved. Stress has been suggested as one environmental factor contributing to the development of T1D since the stress hormones may increase the need for insulin or increase insulin resistance. The family is important for the child’s emotional security, development, and regulation of emotions, hence stress among the parent’s may influence the child’s experiences of stress and coping with stressors.Aim: The aim of the current thesis was to evaluate self--‐assessment measurements of psychological stress in the family and to investigate if psychological stress in the family is involved in the development of childhood T1D.Methods: The All Babies in Southeast Sweden (ABIS) study is a prospective cohort study following children born in southeast Sweden between 1997 and 1999. All parents of children born in the region, approximately 21600 were asked to participate. In total, questionnaire data has been obtained from n=16142 (response rate approximately 75%) in some of the six data--‐collections and between 15845 (73%) and 4022 (19%) at each data collection. Psychological stress in the family was measured by questionnaires assessing: Serious life events experienced by the child and the parent, parenting stress, parental dissatisfaction, parental worries, the parent’s adult attachment, and the parents’ social support. Identification of cases with T1D was done through the national register SweDiabKids. At Dec the 31st 2012 had in total 104 (0,64%) children been diagnosed with T1D. Diabetes--‐cases included in the study samples was n=42 and n=58.Results: Parenting stress, parental worries, and size of social support were judged as reliable measurements assessing different aspects of psychological stress in the family, as well as they were all associated to children’s mental health in early adolescence. A serious life event experienced in childhood (measured by checklist at age 5--‐6, 8 and 10--‐ 14 years) was associated with an increase in risk for manifest T1D up to 13--‐15 years of age. None of the variables measuring psychological stress among parents were found to associate with risk of T1D.Conclusions: In addition to a checklist assessing serious life events experienced by the child is self--‐assessment measurements of parenting stress, parental worries and the parent’s social support be useful in large--‐scale studies as proxies for psychological stress of the child. The current study is the first unbiased prospective study that can confirm an association between the experience of a serious life event and increased risk of T1D. The result was independent of the child’s BMI and the parents’ educational level. Our results gives us strong reason to believe that psychological stress caused by serious life events can play a part in the immunological process leading to the onset of T1D.
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| 6. |
- Rosell, Johan
(författare)
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Long-term effects of adjuvant tamoxifen treatment on cardiovascular disease and cancer
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this thesis were to investigate the long-term effects of adjuvant tamoxifen treatment on breast cancer recurrence and mortality, cardiovascular disease, and the incidence of secondary cancer.Between 1982 and 1992, postmenopausal patients with early stage breast cancer were included in a randomized clinical study of 2 or 5 years of postoperative tamoxifen therapy. The trial was planned by the Swedish Breast Cancer Group, and it included 4610 patients. Follow-up on causes of death, hospitalizations and secondary cancers were obtained from national population-based registries. All-cause mortality, breast cancer-specific mortality and mortality from coronary heart disease were decreased in the 5-year group, but the incidence of endometrial cancer was increased (Paper I). The incidence and mortality of cerebrovascular diseases were increased during the active treatment phase, and reduced after the active treatment (Paper II). Similar results were seen for subgroups of cerebrovascular diseases such as stroke and ischemic stroke. In the 5-year group, the morbidity from coronary heart disease was reduced during treatment but not after treatment was stopped (Paper III). This was the case also for heart failure and for atrial fibrillation/flutter. For secondary cancers the lung cancer risk was reduced, as well as the lung cancer mortality (Paper IV). An increased risk was observed for endometrial cancer, but appeared to decrease over time. The risk of contralateral breast cancer was reduced, with most of the reduction after treatment was stopped. For distance recurrences the risk was reduced both during treatment and a few years after treatment was stopped. The breast cancer mortality was also reduced, especially during the post-treatment phase.
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