| 41. |
- Akhter, Tansim, 1967-
(författare)
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Carotid Artery Wall Layer Dimensions during and after Pre-eclampsia : An investigation using non-invasive high-frequency ultrasound
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pre-eclampsia is associated with increased risk of cardiovascular disease (CVD) later in life. The ‘gold standard’ for estimating cardiovascular risk - ultrasound assessment of the common carotid artery intima-media thickness (CCA-IMT) - does not convincingly demonstrate this increased risk. The aim of this thesis was to examine whether high-frequency (22 MHz) ultrasound assessment of the individual CCA intima and media layers and calculation of the intima/media (I/M) ratio - can indicate the increased cardiovascular risk after pre-eclampsia. After validation of the method in premenopausal women with systemic lupus erythematosus (SLE) who have a recognized increased risk of CVD, women during and after normal and preeclamptic pregnancies were investigated.Assessment of the individual artery wall layers reliably demonstrated the increased cardiovascular risk in premenopausal women with SLE, while CCA-IMT did not. The artery wall layer dimensions in women with SLE were comparable to those of postmenopausal women without SLE and were 30 years older.Among the women with normal pregnancies negative changes to the artery wall later on in the pregnancy were seen in those with lower serum estradiol, older age, higher body mass index or higher blood pressure early in the pregnancy. About one year postpartum, both the mean intima thickness and the I/M ratio had improved, compared to values during pregnancy. These findings support the theory that normal pregnancy is a stress on the vascular system.Women who developed pre-eclampsia (mean age 31 years) had thicker intima layers, thinner media layers and higher I/M ratios, both at diagnosis and one year postpartum, than women with normal pregnancies, indicating increased cardiovascular risk.Women with a history of severe pre-eclampsia (mean age 44 years; mean 11 years since the last delivery) had thicker intima layers and higher I/M ratios than women with a history of normal pregnancies, indicating long-standing negative vascular effects.Assessment of individual CCA wall layers, but not of CCA-IMT, provided clear evidence of the well-known increased cardiovascular risk in women with SLE or pre-eclampsia. The method has the potential to become an important tool in reducing cardiovascular morbidity and mortality in these women through early diagnosis and intervention.
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| 42. |
- Al-Adhami, Maissa, 1972-
(författare)
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Health of refugee migrants in the early post-migration phase in Sweden : The role of health resources and health promotion
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the early post-migration phase, the health and well-being of newly settled refugee migrants is negatively affected by structural factors such as restrictive immigration policies, hostile political discourse and limited housing and work opportunities. There is a need for a better understanding of how individual health resources and health promotion can mitigate the impact of these ongoing stressors. The thesis aimed to explore, assess, and further the understanding of the role of health promotion and individual health resources for health and well-being of newly settled refugee migrants in Sweden.In Study I, six focus group discussions were conducted with 32 newly settled refugees, exploring their perceptions of a Swedish Civic Orientation (CO) course with added health communication. The results showed that the course inspired them to focus on their health, promoted independence and empowerment, and gave new social contacts. However, the course is needed earlier in the post-migration phase and should be adjusted to better fit refugee migrants’ varying pre-existing knowledge. Study II was a cross-sectional study, exploring how individual resources of newly settled refugee migrants (n=787) were associated with self-rated health and psychological well-being. Logistical regression analysis showed that limited health literacy, lack of emotional support, and low self-efficacy were consistently associated with poor health outcomes. In Study III, interviews with 10 civic communicators were performed to explore their perceptions of an in-depth training course on mental health in relation to observed psychological needs among newly settled refugee migrants. The overall result was that the attainment of new knowledge and new tools enabled them to lead reflective conversations about mental health with participants. Mental health needs were perceived to be related to pre- and post-migration experiences. Barriers included stigma and lack of arenas to address mental health needs of refugee migrants.In Study IV, the effectiveness of a regular and an extended CO course was compared in a quasi-experimental study design among newly settled refugee migrants (n=173 and 143 respectively). Linear mixed models and Chi-square analyses showed that the extended course led to a small, but significant increase in health literacy. No significant differences were observed regarding other outcomes (emotional and practical support, general self-rated health, or psychological well-being).The thesis illustrates the potential of early health promotion initiatives focusing on individual health resources to enhance health. However, overarching structural barriers related to living conditions, work opportunities and inclusion must also be addressed.
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| 43. |
- Al-Amin, Abdullah, PhD student, 1983-
(författare)
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Molecular Approaches to Explore Drug-Target Interactions
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Improved means to assess the clinical potential of drug candidates can critically influence development of new therapeutic entities, a central aim in medical life science. Drug discovery and development relies on construction and selection of small organic compounds or biological agents that bind targets of interest. This thesis includes new methodology to investigate target engagement - that is the tendency for these drugs and drug candidates to bind their intended target molecules versus any off-targets. This is a matter of great importance and current strong interest in the pharmaceutical industry as well as academically and an important aim for precision medicine. Paper I describes the target engagement-mediated amplification (TEMA) technique, an accurate, selective and physiological relevant techniques to monitor target binding by DNA-conjugated low molecular weight drug molecules. The DNA conjugated forms of the drugs are uniquely suited to accurately and sensitively reveal the binding characteristics of drugs directly in relevant tissues. Paper II describes the evaluation of cellular thermal shift assays (CETSA) by multiplex proximity extension assays (PEA), to sensitively measure binding of drugs to their proper targets and off-targets in minimal samples of cells and tissues, and for many targets and samples in parallel. The technique provides valuable advantages during drug development, and potentially also in clinical care. Paper III describes a high-throughput approach to use in situ proximity ligation assays to investigate protein interactions or modifications along with phenotypic responses to drugs or cytokines. The technique allows responses by large numbers of cells to be evaluated by automated microscopy and computer-based analysis. Our approach expands the scope for combined molecular and morphological profiling, offering an information-rich means to profile cellular responses to drugs and other agents at the single cell level.
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| 44. |
- Al-Mashhadi, Ammar Nadhom Farman
(författare)
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High Blood Pressure in Children with Hydronephrosis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The most common cause of secondary hypertension is intrinsic renal disease, but little is known about the influence of hydronephrosis on blood pressure. In this thesis, the risk of development of hypertension in children with hydronephrosis was studied.Experimental and clinical studies were combined in order to investigate the risk of developing elevated blood pressure following conservative treatment of hydronephrosis, and to further explore underlying mechanisms. We started with a clinical study in children (study I), which in agreement with previous experimental studies, showed that blood pressure was lowered by surgical management of hydronephrosis. In parallel, an experimental study was conducted (study II) to investigate the involvement of renal sympathetic nerve activity in development of hypertension following induction of hydronephrosis caused by pelvo-ureteric junction obstruction. Renal denervation of the obstructed kidney attenuated hypertension and restored the renal excretion pattern, effects that were associated with reduced activity of both renal NADPH oxidase derived oxidative stress and components of the renin-angiotensin-aldosterone system.Based on the findings in studies I and II, we continued our studies in children with hydronephrosis, and including two control groups as comparisons with the hydronephrotic group (study III). In the same study, we further investigated potential mechanism(s) of hypertension by analyzing markers of oxidative stress and nitric oxide homeostasis in both urine and blood samples. We demonstrated increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which was restored to normal levels by surgical correction of the obstruction. Finally, in a retrospective cohort study, blood pressure of adult patients undergoing surgical management of hydronephrosis due to pelvo-ureteric junction obstruction was assessed (study IV). Similar to that demonstrated in the pediatric hydronephrotic population, blood pressure was significantly reduced by relief of the obstruction. In addition, blood pressure was increased again if the hydronephrosis recurred, and was reduced again following re-operation.It is concluded that conservative management of hydronephrosis in children is associated with a risk for development of high blood pressure, which can be reduced or even normalized by relief of the obstruction. The mechanism(s), at least in part, is coupled to increased oxidative stress.
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| 45. |
- Al-Saffar, Anas Kh. 1969-
(författare)
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Gastrointestinal Permeability and Motility in Inflammatory Bowel Disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Synchronized motility, permeability and secretory (hormones and enzymes) events are integral to normal physiology. Smooth muscle syncytium operates with enteric nervous system (ENS) and endocrine signalling to accommodate, mix and control passage of ingested materials. The intestinal epithelial cells (IECs) drive digestion and absorption while repelling harmful compounds.This thesis investigated GI barrier function (permeability, mucosal integrity), motility and hormonal patterns in inflammatory bowel disease (IBD) by: 1) assessing GI motility using a wireless motility capsule (WMC, SmartPill®) and video capsule endoscopy (VCE, Pillcam®), 2) investigation of intestinal fatty acid binding protein (I-FABP) as a biomarker of Crohn’s disease (CD) disease activity, 3) evaluation of small intestinal permeability in IBD, 4) investigating meal-related WMC motility and simultaneous hormonal (e.g., Ghrelin, GLP-1, GIP, PYY) patterns in IBD. Reference WMC motility values for transit times for gastric emptying, small bowel, orocecal, small+large bowel, colon and whole gut were established. Software-generated estimates and visually determined values were nearly identical. Compared with VCE estimates (represents fasting conditions), the WMC records longer GET and SBTT. Variations in intra-subject reproducibility must be considered in clinical investigations. This data was then used to investigate IBD patients. I-FABP was primarily expressed in the epithelium of the small bowel and to lesser extent also in the colon and stomach. Circulating I-FABP was elevated in active CD with a magnitude comparable to TNFα. I-FABP lowers and rises again in parallel with TNFα and HBI during infliximab treatment. I-FABP can be used as a jejunum and ileum selective prognostic biomarker for monitoring disease activity. Increased small intestine mucosal barrier permeability to lactulose in both CD and UC was found. Sucralose can serve a dual purpose in quantifying small and large intestinal permeability. Small intestinal hyper-permeability was not revealed as a transporter dependent nutrient (riboflavin) malabsorption. Using the WMC, consistent motility disturbances in IBD were limited, as were differences in pH. However, disturbances within many individuals were found. As part of the investigation, defects in gut peptide and metabolic hormone meal responses were found, typically higher plasma levels. No clear associations between hormones and motility were found. Effects on hunger/satiety signaling in IBD are anticipated.The present thesis shows the utility of the WMC and gut barrier tests in monitoring IBD patients.
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| 46. |
- Alaie, Iman
(författare)
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Adulthood Outcomes of Child and Adolescent Depression : From Mental Health to Social Functioning
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Depression is a common mental disorder affecting people across the lifespan, with first onset frequently occurring in the teenage years. The disorder is costly to society and constitutes one of the leading causes of disability in youths and adults worldwide. Research demonstrates that depression in childhood or adolescence is linked to adverse adult consequences, including mental health problems, physical health issues, various social difficulties, and economic hardships. While the specific factors and mechanisms associated with these long-term adversities are not well understood, previous studies point to the relevance of considering the heterogeneity in early-life depression.The overarching aim of this doctoral thesis was to shed more light on long-term outcomes of childhood and adolescent depression across multiple life domains. This work made use of extensive follow-up data gathered in Sweden and USA, as part of two community-based longitudinal cohort studies of depressed and nondepressed youths prospectively followed into adulthood. In the Uppsala Longitudinal Adolescent Depression Study, participants were interviewed around age 16 (n=631) and age 31 (n=409). Using linkage to nationwide population-based registries, participants were followed up around age 40 (n=576). In the Great Smoky Mountains Study, participants were interviewed at repeated occasions in childhood and adolescence (n=1,420), and at further follow-ups in adulthood extending up to age 30 (n=1,336).Findings from this work suggest that childhood/adolescent depression can have long-lasting associations with a broad spectrum of adverse outcomes. First, the risk of adult depression is known to be elevated among those exposed to depression in early life; however, depressed youths experiencing major conflicts with parents may be at an additionally increased risk of subsequent depression recurrence. Second, early-life depression was found to be associated with higher levels of adult psychiatric disorders, and also with worse health, criminal, and social functioning, even when accounting for a multitude of potential confounders. Third, early-life depression was predictive of poor labor market outcomes, especially for those with persistent depression. This link was partially mediated by the course of depression. Fourth, the welfare burden associated with early depression amounted to considerable public expenditures in adulthood, particularly for those with persistent depression or comorbid psychiatric conditions such as anxiety and disruptive behavior disorders.The adverse long-term consequences in the wake of early-life depression underscore the importance of prevention and treatment approaches that are both efficacious and cost-effective. Such targeted efforts may have the potential to avert later ill-health, impairment, and possibly also economic disadvantage.
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| 47. |
- Alassaad, Anna, 1977-
(författare)
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Improving the Quality and Safety of Drug Use in Hospitalized Elderly : Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization.
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| 48. |
- Albrecht, Lisa M.
(författare)
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Antibiotic Resistance : Selection in the Presence of Metals and Antimicrobials
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The external environment is complex: Antibiotics, metals and antimicrobials do not exist in isolation but in mixtures. Human activities such as animal husbandry, fertilization of agricultural fields and human medicine release high amounts these compounds into the environment. The work in this thesis contributes to our understanding of how the selection of bacterial antibiotic resistance can be facilitated by the pollution by metals and antimicrobials. We show that low levels of antibiotics, metals and combinations thereof can lead to the selection of chromosomally encoded antibiotic resistance genes as well as a multidrug resistance plasmid. The underlying genetic and cellular mechanisms of selection identified relate to mutational changes in a plasmid-encoded metal resistance operon, and metal-associated increases in cellular membrane permeability. We further show that exposure to quaternary ammonium compounds can result in cross-resistance to antibiotics following genetic changes in genes related to efflux, membrane synthesis and transcription/translation. Taken together, the work in this thesis suggests that the stewardship of antibiotics should include prudent use of metals and antimicrobials.
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| 49. |
- Alenkvist, Ida
(författare)
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Epac2 signaling at the β-cell plasma membrane
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Secretion of appropriate amounts of insulin from pancreatic β-cells is crucial for glucose homeostasis. The β-cells release insulin in response to glucose and other nutrients, hormones and neurotransmitters, which trigger intracellular signaling cascades, that result in exocytotic fusion of insulin-containing vesicles with the plasma membrane. Increases of the intracellular concentration of calcium ions ([Ca2+]i) trigger exocytosis, whereas the messenger cyclic adenosine monophosphate (cAMP) amplifies various steps of the secretion process. The protein Epac2 mediates some effects of cAMP, but little is known about its regulation in β-cells. In this study, the spatio-temporal dynamics of Epac2 was investigated in insulin-secreting MIN6-cells and primary β-cells using various cell signaling biosensors and live-cell fluorescence microscopy approaches. Increases in the cAMP concentration triggered translocation of Epac2 from the cytoplasm to the plasma membrane. Oscillations of cAMP induced by glucose and the insulin-releasing hormone GLP-1 were associated with cyclic translocation of Epac2. Analyses of Epac2 mutants showed that the high-affinity cyclic nucleotide-binding domain and Ras-association domains were crucial for the translocation, whereas neither the DEP domain, nor the low-affinity cAMP-binding domain were required for membrane binding. However, the latter domain targeted Epac2 to insulin granules at the plasma membrane, which promoted their priming for exocytosis. Depolarization-induced elevations of [Ca2+]i also stimulated Epac2 translocation, but the effects were complex and in the presence of high cAMP concentrations, [Ca2+]i increases often reduced membrane binding. The stimulatory effect of Ca2+ was mediated by increased Ras activity, while the inhibitory effect reflected reduced concentrations of the membrane phospholipid PtdIns(4,5)P2. Anti-diabetic drugs of the sulfonylurea class, suggested to directly activate Epac2, induced translocation indirectly by depolarizing β-cells to increase [Ca2+]i. Epac2 is an activator of Rap GTPases, and its translocation increased Rap activity at the plasma membrane. It is concluded that the subcellular localization of Epac2 is controlled by a complex interplay between cAMP, Ca2+ and PtdIns(4,5)P2 and that the protein controls insulin release by binding to the exocytosis machinery. These results provide new insights into the regulation of β-cell function and may facilitate the development of new anti-diabetic drugs that amplify insulin secretion.
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| 50. |
- Alfonsson, Sven
(författare)
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Treatment Adherence in Internet-Based CBT : The Effects of Presentation, Support and Motivation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Homework assignments that patient work with between sessions is a key component in both face-to-face and Internet-based Cognitive Behavior Therapy (CBT). However, adherence to assignments is often low and it is largely unclear what factors predict or affect treatment adherence, and in the end, treatment outcomes. The overall aim of this thesis was to investigate if treatment presentation and therapist support can affect adherence and treatment outcome in internet-based CBT, whether adherence can be predicted by motivation variables and to compare differences in face-to-face and online conditions in this regard.A randomized controlled trial with a brief online relaxation program for people with stress and anxiety symptoms was conducted (n = 162). Participants in the enhanced support conditions completed a larger proportion of the online treatment but adherence was not affected by enhanced treatment presentation (Study I). Participants reported reduced symptoms of stress and anxiety after the relaxation program but there were no significant additional effects of enhanced presentation or support (Study II). Participants who adhered to the prescribed assignments reported lower symptom levels at study end, regardless of treatment conditions. Adherence to the online treatment was predicted by subject factors such as treatment credibility prior to the treatment and intrinsic motivation during the treatment (Study III). To further elucidate how motivation may affect adherence, an experiment with a one-session psychotherapy model was subsequently conducted (n = 100). Participants who were randomized to the face-to-face condition reported higher motivation for the assignment and completed significantly more of the homework compared to participants in the online condition (Study IV). Self-reported intrinsic motivation could predict adherence in both conditions while new motivational variables were identified specifically for the online condition.The results from these studies confirm that adherence to assignments in Internet-based CBT is difficult to affect with treatment features but can be predicted early in treatment by subject factors such as treatment credibility and motivation. How such motivational variables can be affected to improve treatments is still unclear.
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