| 1. |
- Backman, Helena, 1979-
(author)
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Lung function and prevalence trends in asthma and COPD
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Background: Asthma and chronic obstructive pulmonary disease (COPD) are common obstructive airway diseases with a substantial burden in terms of morbidity, mortality and costs. Smoking is the single most important risk factor for COPD, and is associated with incident asthma. It is important to know if the prevalence of asthma and COPD is increasing or decreasing in the population in order to effectively allocate health care resources. The definitions of these diseases have varied over time which makes it difficult to measure changes in prevalence. The preferred method is to estimate the prevalence with the same procedures and definitions based on cross-sectional population samples with identical age distributions in the same geographical area at different time points. Measurements of lung function (spirometry) are required to diagnose COPD, and spirometry is used to evaluate disease severity and progress of both asthma and COPD, where observed values are compared to reference values. The most commonly used reference values in Sweden are published during the mid 1980s, and there are few evaluations of how appropriate they are today based on Swedish population samples. The aim of the thesis was to estimate trends in the prevalence of asthma and COPD in relation to smoking habits, and to evaluate and estimate reference values for spirometry.Methods: The project was based on population-based samples of adults from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Postal questionnaires were sent to large cohorts, recruited in 1992 (n=4851, 20-69 years), 1996 (n=7420, 20-74 years) and 2006 (n=6165, 20-69 years), respectively. The questionnaire included questions on respiratory symptoms and diseases, their comorbidities and several possible risk factors including smoking habits. Structured interviews and spirometry were performed in random samples of the responders to the 1992 and 2006 surveys, of which n=660 (in 1994) and n=623 (in 2009) were within identical age-spans (23-72 years). The trend in asthma prevalence was estimated by comparing the postal questionnaire surveys in 1996 and 2006, and the trend in COPD prevalence was estimated by comparing the samples participating in dynamic spirometry in 1994 and 2009, respectively. The prevalence of COPD was estimated based on two different definitions of COPD. Commonly used reference values for spirometry were evaluated based on randomly sampled healthy non-smokers defined in clinical examinations of participants in the 2006 postal questionnaire (n=501). The main focus of the evaluation was the global lung function initiative (GLI) reference values published in 2012, for which Z-scores and percent of predicted values were analysed. New sex-specific reference values for spirometry were estimated by linear regression, with age and height as predictors. These new OLIN reference values were also evaluated on a sample of healthy non-smokers identified in the population-based West Sweden Asthma Study.Results: Although the prevalence of smoking decreased from 27.4% to 19.1%, p<0.001, between 1996 and 2006, the prevalence of physician-diagnosed asthma increased from 9.4% to 11.6%, p<0.001. The prevalence of symptoms common in asthma such as recurrent wheeze did not change significantly between the surveys or tended to decrease, while bronchitis symptoms such as cough and sputum production decreased significantly. The evaluation of the GLI reference values showed that the predicted values were significantly lower compared to the observed values in Norrbotten, which makes the percent of predicted too high. This was especially true for FVC percent predicted with a mean of 106%. In general, the deviations were more pronounced among women. New OLIN reference values valid for the Norrbotten sample were modelled and showed a high external validity when applied on the sample from western Sweden. The prevalence of moderate to severe COPD decreased substantially over the 15-year period between 1994 and 2009, regardless of definition.Conclusions: In parallel with substantially decreased smoking habits in the population between 1996 and 2006, the prevalence of several airway symptoms decreased while the prevalence of physician-diagnosed asthma increased. These results suggest increased diagnostic activity for asthma, but may also suggest that the asthma prevalence has continued to increase. In contrast to asthma, the prevalence of COPD tended to decrease and moderate to severe COPD decreased substantially. The continuous decrease in smoking in Sweden during several decades prior to the study period is most likely contributing to these results. The evaluation of reference values showed that the GLI reference values were lower than the observed spirometric values in the population, especially for women, why the new up-to date reference values may be of importance for disease evaluation in epidemiology and in the health care as well.
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| 2. |
- Haider, Zahra, 1988-
(author)
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DNA methylation signatures in precursor lymphoid neoplasms : with focus on clinical implications & the biology behind
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Precursor lymphoid neoplasms, namely acute lymphoblastic leukemias (ALL) and lymphoblastic lymphomas (LBL), are characterized by an aggressive proliferation of malignant progenitor B- or T-cells. To improve risk classification at diagnosis, better prognostic and treatment stratifying biomarkers are needed. Altered DNA methylation pattern is a hallmark of neoplastic transformation, and has been employed as a molecular prognostic and predictive marker in various cancers, including hematological malignancies. Our research group previously identified a CpG island methylator phenotype (CIMP) panel that classified pediatric T-ALL patients into prognostic subgroups.The aim of this thesis was to evaluate distinct DNA methylation signatures in precursor lymphoid neoplasms, and to validate the prognostic value of CIMP classification in separate patient cohorts. Additionally, the biological mechanisms underlying the distinct CIMP methylation signatures in these malignancies were investigated.The prognostic relevance of CIMP classification was validated in an independent Nordic cohort of pediatric T-ALL patients. Combination of CIMP status with minimal residual disease (MRD) status, could further dissect the high-risk MRD positive T-ALL patients into two CIMP subgroups with significantly distinct outcomes. Furthermore, CIMP classification at diagnosis was shown to predict overall survival in relapsed BCP-ALL patients. CIMP methylation signatures were also identified in T-LBL patients, indicating a broader relevance of CIMP based classification in lymphoid malignancies. Investigating the biology behind CIMP methylation signatures showed the association of CIMP status with the proliferative history of the leukemic cells. A differential transcriptomic analysis revealed a correlation of CIMP subgroups with known T-ALL drivers, as well as with novel genes in T-ALL biology. Finally, we identified distinct DNA methylation patterns and genetic aberrations in T-ALL and T-LBL that might contribute to the different clinical presentation of these two diseases. In conclusion, we validated the prognostic significance of CIMP methylation signature in precursor lymphoid malignancies and identified transcriptomic profiles that associated with the subgroups. DNA methylation is a strong candidate for further risk classification in lymphoid neoplasms and our findings can contribute to the identification of new potential targets for treatment.
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| 3. |
- Semasaka Sengoma, Jean Paul, 1976-
(author)
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Pregnancy and delivery-related complications in Rwanda : prevalence, associated risk factors, health economic impact, and maternal experiences
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Background: Every year more than 1.5 million women suffer from pregnancy and delivery-related complications (PDCs) during pregnancy and childbirth worldwide, and these women are a vulnerable population for lifelong consequences, somatically, psychologically and financially. Following the establishment of Millennium Development Goal no 5, which targeted a reduction of 75% of the maternal mortality ratio from 1990 to 2015, many efforts were made to reduce maternal mortality worldwide. In low-income countries saving a pregnant woman’s life requires a focused medical intervention so that near-miss cases of death are considered as obstetric success and thus postpartum follow-up may be neglected. In Rwanda, maternal mortality is estimated to 210 per 100,000 live births and main obstetric complications are hypertensive disorders during pregnancy, obstructive/prolonged labour, post-partum haemorrhage (PPH) and sepsis/infections. However, the specific prevalence of PDCs as well as their consequences to the woman and her family is currently relatively unknown.Aims: The overall aim of this thesis was to determine the prevalence of PDCs and their associated risk factors and to investigate delivered women’s experiences of PDCs, the consequences of these complications on postpartum health and family situation, and to estimate the societal economic costs of pregnancy, delivery and postpartum-related problems.Subjects and methods: A population-based cross-sectional study including 921 women who gave birth within the past 13 months prior to time of data collection (Paper I) and a health facility-based study including 817 women that were at discharge time (Paper II) were conducted in the Northern Province of Rwanda and Kigali City. Fifteen women who experienced PDCs were interviewed through individual in-depth qualitative interviews (Paper III). A micro costing approach to collect health facility data and household costs including opportunity cost, transport and food cost was conducted to estimate the societal economic cost of PDCs (Paper I-V). Descriptive statistics, Chi-Square, bi- and multivariable logistic regression, Cox regression, and health economic analysis were applied for quantitative data analyses (Papers I, II and IV). Qualitative manifest and latent content analysis was used for qualitative data analyses (Paper III).Results: Prevalence of anaemia, hypertension, diabetes mellitus during pregnancy, and severe bleeding during pregnancy and labour were estimated to 15.0%, 4.9%, 2.4%, and 3.7%, respectively (Paper I). In total, 56.4% of the participants were transferred and the majority were transferred from health centres to district hospitals, with caesarean section (CS) as the main reason for transfer. Almost three-quarters of the women started labour spontaneously; 5% had induced labour and 28.4% of all pregnant women were delivered by CS (Paper II). Pre-eclampsia/eclampsia, PPH, and caesarean section (CS) due to prolonged labour/dystocia represented 1%, 2.7% and 5.4% of all participants, respectively (Paper II). Risk factors for CS due to prolonged labour or dystocia were poverty, nulliparity, and residence far from health facility (Paper II). The prevalence of poor-self rated health (poor-SRH) for participants who gave birth within the past 14 months prior to time of data collection was 32.2% at one day postpartum, 7.8% at one month, and 11.7% at time of the interview (Paper I). Most participants who had experienced PDCs reported that they were previously unaware of the complications they had developed, and they claimed that at discharge they should have been better informed about the potential consequences of these complications (Paper III). Most participants blamed the health care system as the cause of their problems due to the provision of inadequate care. Participants elaborated different strategies for coping with persistent health problems (Paper III). PDCs negatively affected participants’ economic situation due to increased health care expenses and lowered income because of impaired working capacity (Paper III). The estimated total societal cost of a normal uncomplicated vaginal delivery was 107 United States dollars (USD). The incremental cost of a vaginal delivery followed by PPH was 55 USD. The incremental cost of prolonged, dystocic or obstructed labour resulting in a CS was 146 USD. The incremental cost of pre-eclampsia with vaginal delivery and pre-eclampsia with CS were 289 and 339 USD, respectively. The major cost categories of the estimated costs for each mode of delivery were staff, the hospitalisation rooms, and household expenditures (Paper IV).Conclusions: A high prevalence of poor self-rated health status was reported in the early postpartum period. Identified factors associated with poor-SRH were severe bleeding, hypertension, infection, and anaemia during pregnancy and postpartum haemorrhage. The estimated prevalences of specific pregnancy and delivery-related complications were relatively low, probably in part due to underestimation. Rwandan women experiencing PDCs are facing many challenges and problems during pregnancy, delivery and postpartum period. The costs of PDCs were calculated to be very high in comparison to the net median monthly wage in Rwanda. In addition, the Rwandan health system presents weaknesses in relation to the prevention of PDCs. Above all, there is an insufficient postpartum health care provision and community support to women experiencing PDCs. The results from this thesis call for interventions, to improve the postpartum health care services and call for the community sensitisation for the increased support to women who face difficult living circumstances because they have experienced severe pregnancy and delivery-related complications.
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| 4. |
- Spang, Christoph, 1984-
(author)
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The plantaris tendon in relation to the Achilles tendon in midportion Achilles tendinopathy : studies on morphology, innervation and signalling substances
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Midportion Achilles tendinopathy (tendinosis) is a troublesome painful condition, often characterised by pain, local swelling, tenderness and functional disability. Despite extensive research, the pathogenesis is poorly understood and treatment remains challenging. Features related to the peritendinous connective tissue can be of importance. Recently it has been suggested that the plantaris tendon might be involved in this condition. Furthermore, it has been hypothesised that tendon pain and the tendinosis-related tissue changes in tendinopathy might be mediated by signalling substances such as glutamate and acetylcholine. A clinical observation, not scientifically evaluated, has been that unilateral treatment for bilateral Achilles tendinosis can lead to an effect on the contralateral side. The aim of this work was to examine the morphology and innervation patterns in the plantaris tendon and the peritendinous connective tissue in between the Achillles and plantaris tendons in midportion Achilles tendinopathy, and to evaluate if plantaris tendon removal has an effect on Achilles tendon structure. Another aim was to determine if unilateral treatment for Achilles tendinopathy targeting the peritendinous connective tissue can result in bilateral recovery. Furthermore the presence of non-neuronal cholinergic and glutamate systems was examined. Sections of plantaris tendons with adjacent peritendinous connective tissue from patients with midportion Achilles tendinopathy were stained for morphology (H&E), and innervation patterns were evaluated using antibodies against general nerve marker (PGP9.5), sensory (CGRP) and sympathetic (TH) nerve fibres and Schwann cells (S-100β). Furthermore immunostainings against non-neuronal aceylcholine (ChAT) and glutamate signalling components (glutamate, VGluT2, NMDAR1) were performed. Plantaris tendon cells were cultured and also stained for glutamate signalling components, and were stimulated with glutamate and glutamate receptor agonist NMDA. Furthermore, Ultrasound Tissue Characterisation (UTC) was used to monitor the integrity of the Achilles tendon collagen structure after plantaris tendon removal. Plantaris tendons exhibited tendinosis-like tissue patterns such as hypercellularity, collagen disorganisation and large numbers of blood vessels. The peritendinous connective tissue between the plantaris and Achilles tendons contained large numbers of fibroblasts and blood vessels and to some extent macrophages and mast cells. A marked innervation was found in the peritendinous connective tissue and there were also nerve fibres in the loose connective tissue spaces within the tendon tissue proper. Most nerve fibres were identified as sensory fibres. Some nerve fascicles in the peritendinous connective tissue showed absence of axons but homogenous reactions for Schwann cell marker. Tenocytes and cells in the peritendinous connective tissue expressed ChAT, glutamate, VGluT2 and NMDAR1. Tendon cells in vitro expressed VGluT2, NMDAR1 and glutamate. UTC showed significant improvement of Achilles tendon integrity 6 months after surgical plantaris tendon removal and scraping procedure. Eleven out of thirteen patients reported of a bilateral recovery after unilateral surgical treatment. The results of this work show that plantaris tendons exhibit tendinosis-like tissue changes, internal innervation and features that suggest occurrence of glutamate and acetylcholine production and signalling. Plantaris removal improves Achilles tendon structure suggesting possible compressive/shearing interference between the Achilles and plantaris tendons in tendinopathy. The peritendinous connective tissue shows marked innervation, which thus might transmit pain when being compressed. The partial absence of axons indicates a possible nerve degeneration. On the whole, the study gives new evidence favouring that the plantaris tendon and the peritendinous connective tissue might be of importance for pain and the tendinopathy process in midportion Achilles tendinopathy.
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| 5. |
- Wagner, Ryan G, 1984-
(author)
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The Burden of Epilepsy : using population-based data to define the burden and model a cost-effective intervention for the treatment of epilepsy in rural South Africa
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Rationale Epilepsy is a common, chronic, neurological condition that disproportionately affects individuals living in low- and middle- income countries, including much of sub-Saharan Africa. Epilepsy is treatable, with the majority of individuals who take anti-epileptic drugs experiencing a reduction, or elimination, of seizures. Yet the number of individuals taking and adhering to medication in Africa is low and interventions aimed at improving treatment are lacking.Aims To define the epidemiology of convulsive epilepsy in rural South Africa in terms of incidence, mortality and disability-adjusted life years; to determine outpatient, out-of-pocket costs resulting from epilepsy treatment; to establish the level of adherence to anti-epileptic drugs amongst people with epilepsy; and, to determine whether the introduction of routine visits to people with epilepsy by community health workers is a cost-effective intervention for improving adherence to anti-epileptic drugs.Methods Nested within the Agincourt Health and Demographic Surveillance System, this work utilized a cohort of individuals diagnosed with convulsive epilepsy in 2008 to determine health care utilization and out-of-pocket costs due to care sought for epilepsy. Additionally, using blood samples from the cohort, anti-epileptic drug adherence was measured and, following the cohort, mortality rates were determined. Using these collected epidemiological parameters, disability-adjusted life years due to convulsive epilepsy were determined. Finally, combining the epidemiological and cost parameters, a community health worker intervention was modeled to determine its incremental cost-effectiveness ratio.Key Findings The burden of convulsive epilepsy is lower in rural South Africa than other parts of Africa, likely due to lower levels of known risk factors. Yet the burden, especially in terms of mortality, remains high, as does the treatment gap and health care utilization. Findings from the economic evaluation found the introduction of a community health worker to be highly cost-effective and would likely lower the burden of epilepsy in rural South Africa.Implications Epilepsy contributes to the burden of disease in rural South Africa, with high levels of mortality and a substantial treatment gap. The introduction of a community-health worker is likely to be one cost-effective, community based intervention that would lower the burden of epilepsy by improving adherence to anti-epileptic drugs. Implementing this intervention, based on these findings, is a justified and important next step.
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| 6. |
- Bergman, Frida, 1984-
(author)
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Active workstations : a NEAT way to prevent and treat overweight and obesity?
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Background: Modern society is triggering sedentary behaviours in different domains. Different strategies can be used to reduce the time spent sitting and increase physical activity in the office environment, which is one domain where sedentary time is often high. One such strategy could be to install treadmill workstations. With these, the office workers can walk on a treadmill while performing their usual work tasks at the computer. However, the long-term effects of these workstations are not known. Aim: The overall aim of this thesis was to investigate the long-term effects on sedentary behaviour, physical activity and associated health factors of installing treadmill workstations in offices compared to regular office work.Method: In this randomized controlled trial, 80 sedentary, middle-aged, healthy office workers with overweight or obesity were individually randomized into either an intervention or a control group. Those in the intervention group had a treadmill workstation installed at their sit-stand desk, to use for at least one hour per day for 13 months. They further received boosting e-mails at four time-points during the study. Participants in the control group continued to work as normal at their sit-stand office desk. All participants also received a health consultation at the beginning of the study, where they got to discuss physical activity and diet recommendations. Measurements reported include physical activity and sedentary behaviour, anthropometric measurements, body composition, metabolic outcomes, stress, depression and anxiety, cognitive function, structural brain images and interview data. Linear mixed models were used for the main statistical analyses of the quantitative data. An exploratory approach was also undertaken, using orthogonal partial least squares regression on the baseline data. Finally, interview data from participants in the intervention group were analysed using a modified Grounded Theory approach.Results: The intervention group increased their daily walking time and their number of steps at all follow-ups compared to the control group. Concomitantly, a decrease in moderate-to-vigorous intensity physical activity (MVPA) was observed within both groups, mainly during weekends. No intervention effects were observed on any of the body, cognitive or brain volume measurements. Our exploratory analyses revealed a significant association between smaller hippocampal volume and percentage sitting time among participants over 51 years of age. From the interview data, we discovered a core category, “The Capacity to Benefit”. The categories were described as the ideal types the Convinced, the Competitive, the Responsible and the Vacillating, based on the principal characteristics of the participants representing their different motivational status and strategies to reach the goal of benefitting from the intervention. Conclusion: It is possible to increase daily physical activity in office environments by introducing treadmill workstations. Future interventions should adapt strategies for the individuals based on their motivational level, but should also workwith the social and physical environment and with factors within the organization to gain the best effects of these interventions.
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| 7. |
- Bobinski, Lukas, 1977-
(author)
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On evolution of intracranial changes after severe traumatic brain injury and its impact on clinical outcome
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Severe traumatic brain injury (sTBI) is a cause of death and disability worldwide and requires treatment at specialized neuro-intensive care units (NICU) with a multimodal monitoring approach. The CT scan imaging supports the monitoring and diagnostics. The level of S100B and neuron specific enolase (NSE) reflects the severity of the injury. The therapy resistant intracranial hypertension requires decompressive craniectomy (DC). After DC, the cranium must be reconstructed to recreate the normal intracranial physiology as well as to address cosmetic issues. The evolution of the pathological intracranial changes was analyzed in accordance with the three CT classifications: Marshall, Rotterdam and Morris-Marshall. The Rotterdam scale was best in describing the dynamics of the pathological evolution. Both the Rotterdam score and Morris- Marshall classification showed strong correlation with the clinical outcome, a finding that suggests that they could be used for prognostication. We demonstrated a clear correlation between the CT classifications and concentrations of S100B and NSE. The results revealed a concomitant correlation between NSE and S100B and clinical outcome. We found that the interaction between the ICP, Rotterdam CT classification, and concentrations of biochemical biomarkers are all associated with DC. We found a high percentage of complications following cranioplasty. Our results call into question whether custom-made allograft should be considered the best material for cranioplasty. It is concluded that both the Rotterdam and Morris-Marshall classification contribute to clinical evaluation of intracranial dynamics after sTBI, and might be used in combination with biochemical biomarkers for better assessment. The decision to perform DC should include a re-assesment of ICP evolution, CT scan images and concentration of the biochemical biomarkers. Furthermore, when determining whether DC treatment should be used, surgeon should also consider the risks of the following cranioplasty.
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| 8. |
- Brunström, Mattias, 1988-
(author)
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Effect of antihypertensive treatment at different blood pressure levels
- 2017
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Doctoral thesis (other academic/artistic)abstract
- BackgroundHigh blood pressure is associated with an increased risk of cardiovascular disease and premature death. The shape of association between blood pressure and the risk of cardiovascular events is debated. Some researchers suggest that the association is linear or log-linear, whereas others suggest it is J-shaped. Randomized controlled trials of antihypertensive treatment have been successful in hypertension, but ambiguous in the high normal blood pressure range. Previous systematic reviews have not found any interaction between baseline systolic blood pressure and treatment effect, with beneficial effects at systolic blood pressure levels well below what is currently recommended. These reviews, however, use a method to standardize treatment effects and study weights according to within-trial blood pressure differences that may introduce bias.MethodsWe performed two systematic reviews to assess the effect of antihypertensive treatment on cardiovascular disease and mortality at different blood pressure levels. The first review was limited to people with diabetes mellitus. The second review included all patient categories except those with heart failure and acute myocardial infarction. Both reviews were designed with guidance from Cochrane Collaborations Handbook for Systematic Reviews of Interventions, and are reported according to PRISMA guidelines. We included randomized controlled trials assessing any antihypertensive agent against placebo or any blood pressure targets against each other. Results were combined in random-effects meta-analyses, stratified by baseline systolic blood pressure. Non-stratified analyses were performed for coronary heart disease trials and post-stroke trials. Interaction between blood pressure level and treatment effect was assessed with Cochran’s Q in the first review, and multivariable-adjusted metaregression in the second review.The third paper builds on data from the second paper, and assesses the effect of standardization according to within-trial blood pressure differences on the results of meta-analyses. We performed non-standardized analyses, analyses with standardized treatment effects, and analyses with standardized treatment effects and standard errors. We compared treatment effect measures and heterogeneity across different methods of standardization. We also compared treatment effect estimates between fixed-effects and random-effects meta-analyses within each method of standardization. Lastly, we assessed the association between number of events and study weights, using linear regression.ResultsForty-nine trials assessed the effect of antihypertensive treatment in people with diabetes mellitus. Treatment effect on cardiovascular mortality and myocardial infarction decreased with lower baseline systolic blood pressure. Treatment reduced the risk of death and cardiovascular disease if baseline systolic blood pressure was 140 mm Hg or higher. If baseline systolic blood pressure was below 140 mm Hg, however, treatment increased the risk of cardiovascular death by 15 % (0-32 %).Fifty-one trials assessed the effect of antihypertensive treatment in primary prevention. Treatment effect on cardiovascular mortality, major cardiovascular events, and heart failure decreased with lower baseline systolic blood pressure. If baseline systolic blood pressure was 160 mm Hg or higher treatment reduced the risk of major cardiovascular events by 22 % (95 % confidence interval 13-30 %). If systolic blood pressure was 140-159 mm Hg treatment reduced the risk by 12 % (4-20 %), whereas if systolic blood pressure was below 140 mm Hg, treatment effect was neutral (4 % increase to 10 % reduction). All-cause mortality was reduced if systolic blood pressure was 140 mm Hg or higher, with neutral effect at lower levels.Twelve trials compared antihypertensive treatment against placebo in people with coronary heart disease. Mean baseline systolic blood pressure was 138 mm Hg. Treatment reduced the risk of major cardiovascular events by 10 % (3-16 %), whereas the effect on mortality was neutral (7 % increase to 11 % reduction).Standardization of treatment effects resulted in more extreme effect estimates for individual trials. This caused increased between-study heterogeneity, and different results with fixed- and random-effects model. Standardization of standard errors shifted weights from trials with many events to trials with large blood pressure differences. This caused biased overall effect estimates. Standardization of standard errors also resulted in wider confidence intervals, masking the previously increased heterogeneity. This reduced the possibility to find different treatment effects at different blood pressure levels.Conclusion The effect of antihypertensive treatment depends on blood pressure level before treatment. Treatment reduces the risk of death and cardiovascular disease if baseline systolic blood pressure is 140 mm Hg or higher. Below this level, treatment is potentially harmful in people with diabetes, has neutral effect in primary prevention, but might offer additional protection in people with coronary heart disease. Standardization should generally be avoided in meta-analyses of antihypertensive treatment. Previous meta-analyses using standardized methods should be interpreted with caution.
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| 9. |
- Lehmann, Manuela, 1986-
(author)
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SOD1 misfolding and aggregation in ALS : in the light of conformation-specific antibodies
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Mutations in the superoxide dismutase 1 (SOD1) gene are linked to the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). ALS-associated mutations affect the stability of the SOD1 protein and promote its unfolding. As a consequence, disordered SOD1 species can misfold and accumulate into insoluble aggregates. Cytoplasmic inclusions containing misfolded SOD1 are a hallmark of ALS pathology in patients as well as transgenic mouse models. However, it remains unclear, which SOD1 species are pathogenic and how they arise and contribute to the disease.The aim of this thesis was to use antibodies as tools to study the role of disordered and aggregated SOD1 species in ALS. These antibodies recognize epitopes exposed in disordered SOD1 species and hence, discriminate between natively folded SOD1 and the disordered or misfolded protein.SOD1 is expressed in all cell types, but aggregates of misfolded SOD1 are predominantly found in motor neurons and associated glial cells in the spinal cord of ALS patients. To understand why misfolded SOD1 targets the motor system, we used ELISA and immunocapture methods to quantify soluble SOD1 species in patient-derived cell models of ALS. The highest levels of soluble disordered SOD1 were detected in induced pluripotent stem cell (iPSC)-derived motor neuron and astrocytes cultures (MNACs) compared to fibroblasts, iPSCs and sensory neuron cultures. These results suggest that the selective vulnerability of motor areas to SOD1-ALS could derive from an enhanced burden of disordered SOD1.To understand factors that might promote SOD1 unfolding, we focussed on the disulfide bond that is required for the stability of natively folded SOD1. Formation of the bond is oxygen-dependent and reduction of the bond promotes SOD1 unfolding. We studied the stability of SOD1 in patient-derived cells exposed to lowered oxygen tensions. This induced increases in disulfide-reduced, disordered mutant and wild-type SOD1. The response was time- and concentration-dependent and more pronounced in MNACs, where even increased aggregation of mutant SOD1 was observed. These results are consistent with the enhanced vulnerability of the motor system in ALS and suggest that conditions causing impaired oxygen perfusion could contribute to the initiation and progression of the disease.Inclusions containing aggregated misfolded wild-type SOD1 have been found in sporadic ALS (sALS) patients without SOD1 mutations and those carrying mutations in genes other than SOD1. However, other groups have reported contrasting results and the contribution of misfolded wild-type SOD1 to ALS pathology is controversial. Guidelines for preservation, storage, and analysis of tissues under standardized conditions would facilitate the comparison of results between different laboratories. We established an optimized immunohistochemistry protocol to detect misfolded wild-type SOD1 in paraffin-embedded spinal cord samples from sALS patients. We also developed a method to immunocapture disordered SOD1 from frozen post-mortem tissue. High, but variable, levels of disordered SOD1 were detected in spinal cords from sALS patients. Our data support a possible pathological role of misfolded wild-type SOD1 in sALS.Recent evidence suggests that SOD1 aggregates can induce templated aggregation of disordered SOD1 and spread from cell-to-cell via a prion-like mechanism. To test if antibodies could block this process in vivo, we conducted an immunotherapy study in a model of prion-like spread, where SOD1 aggregate seeds are inoculated into the lumbar spinal cord of SOD1G85R transgenic mice and lead to accelerated disease onset and progression. Novel monoclonal antibodies (mAb) against disordered domains of SOD1 aggregates were developed and validated for their reactivity to disordered and aggregated SOD1 species in vitro and in vivo. Immunotherapy using a mAb against the C-terminal end of SOD1 attenuated the onset and progression of prion-like SOD1 spread. However, no effect was seen on onset, duration or progression of the underlying disease. This suggests that, under the conditions tested, immunotherapy against disordered domains of SOD1 does not affect intracellular aggregation and additional strategies might be needed to reduce intracellular accumulation of misfolded SOD1 aggregation.In conclusion, we show that conformation-specific antibodies are powerful tools to investigate disordered and potentially pathogenic species of SOD1 in various biochemical, cellular and in vivo contexts. The development of the novel immunocapture strategy could facilitate future research on characterizing SOD1 aggregates from mouse tissues, patient-derived cells or post-mortem tissues with the goal of determining their role in ALS disease pathogenesis.
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| 10. |
- Randell, Eva, 1960-
(author)
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Adolescent boys’ health : managing emotions, masculinities and subjective social status
- 2016
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Doctoral thesis (other academic/artistic)abstract
- The health of adolescent boys is complex and surprisingly little is known about how adolescent boys perceive, conceptualise and experience their health. Thus, the overall aim of this thesis was to explore adolescent boys’ perceptions and experiences of health, emotions, masculinity and subjective social status (SSS).This thesis consists of a qualitative, a quantitative and a mixed methods study. The qualitative study aimed to explore how adolescent boys understand the concept of health and what they find important for its achievement. Furthermore, the adolescent boys’ views of masculinity, emotion management and their potential effects on wellbeing were explored. For this purpose, individual interviews were conducted with 33 adolescent boys aged 16-17 years. The quantitative study aimed to investigate the associations between pride, shame and health in adolescence. Data were collected through a cross-sectional postal survey with 705 adolescents. The purpose of the mixed methods study was to investigate associations between SSS in school, socioeconomic status (SES) and self-rated health (SRH), and to explore the concept of SSS in school. Cross-sectional data were combined with interview data in which the meaning of SSS was further explored. Individual interviews with 35 adolescents aged 17-18 years were conducted.In the qualitative study, data were analysed using Grounded Theory. In the quantitative study, statistical analyses (e.g., chi-square test and uni- and multivariable logistic regression analyses) were performed. In the mixed method study, a combination of statistical analyses and thematic network analysis was applied.The results showed that there was a complexity in how the adolescent boys viewed, experienced, dealt with and valued health. On a conceptual level, they perceived health as holistic but when dealing with difficult emotions, they were prone to separate the body from the mind. Thus, the adolescent boys experienced a difference between health as a concept and health as an experience (paper I). Concerning emotional orientation in masculinity, two main categories of masculine conceptions were identified: a gender-normative masculinity and a non-gender-normative masculinity (paper II). Gender-normative masculinity comprised two seemingly opposite emotional masculinity orientations, one towards toughness and the other towards sensitivity, both of which were highly influenced by contextual and situational group norms and demands, despite that their expressions are in contrast to each other. Non-gender-normative masculinity included an orientation towards sincerity, emphasising the personal values of the boys. Emotions were expressed more independently of peer group norms. The findings suggest that different masculinities and the expression of emotions are intricately intertwined and that managing emotions is vital for wellbeing. The present findings also showed that both shame and pride were significantly associated with SRH, and furthermore, that there seems to be a protective effect of experiencing pride for health (paper III). The results also demonstrated that SSS is strongly related to SRH, and high SRH is related to high SSS, and further that the positioning was done in a gendered space (paper IV).Results from all studies suggest that the emotional and relational aspects, as well as perceived SSS, were strongly related to SRH. Positive emotions, trustful relationships and having a sense of belonging were important factors for health and pride was an important emotion protecting health. Physical health, on the other hand, had a more subordinated value, but the body was experienced as an important tool to achieve health. Even though health was mainly perceived in a holistic manner by the boys, there were boys who were prone to dichotomise the health experience into a mind-body dualism when having to deal with difficult emotions.In conclusion, this thesis demonstrates that young, masculine health is largely experienced through emotions and relationships between individuals and their contexts affected by gendered practices. Health is to feel and function well in mind and body and to have trusting relationships. The results support theories on health as a social construction of interconnected processes. Having confidence in self-esteem, access to trustful relationships and the courage to resist traditional masculine norms while still reinforcing and maintaining social status are all conducive to good health. Researchers as well as professionals need to consider the complexity of adolescent boys’ health in which norms, values, relationships and gender form its social determinants. Those working with young boys should encourage them to integrate physical, social and emotional aspects of health into an interconnected and holistic experience.
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