| 471781. |
- Wangyal, Tashi, et al.
(author)
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Hjärtsvikt
- 2009
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In: Prehospital akutsjukvård, Björn-Ove Suserud och Leif Svensson (red.). - Stockholm : Liber. - 9789147084487 ; , s. 251-256
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Book chapter (other academic/artistic)
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| 471782. |
- Wanhainen, Anders, et al.
(author)
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Misleading study in The Lancet on the outcome of the Swedish AAA screening program : Stor enighet om att screening för bukaortaaneurysm räddar liv.
- 2018
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In: Läkartidningen. - 1652-7518. ; 115
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Journal article (other academic/artistic)abstract
- In a recent publication in The Lancet Johansson and colleagues claim no effect on aneurysm mortality among men participating in the Swedish AAA screening program, and question its justification. The study is, however, limited by a corrupt study design and incorrect data, making the publication misleading. On the contrary, several RCTs and contemporary nationwide data with sufficient follow-up clearly show that AAA screening saves lives and is highly cost-effective. The program has so far identified about 6000 men with an AAA, of whom 1500 have been operated on to prevent rupture. Thus, more than 750 men have experienced a longer life (by a mean of 8 years) as a result of the program. Continuous evaluation of the program is important but requires a scientifically sound methodology.
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| 471783. |
- Waniewski, Jacek
(author)
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Mathematical modeling of fluid and solute transport in peritoneal dialysis
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Optimization of peritoneal dialysis schedule and dialysis fluid composition needs, among others, methods for quantitative assessment of fluid and solute transport. Furthermore, an integrative quantitative description of physiological processes within the tissue, which contribute to the net transfer of fluid and solutes, is necessary for interpretation of the data and for predictions of the outcome of possible intervention into the peritoneal transport system. The current project includes the investigations of 1) the effectiveness of crystalloid osmotic agents in evoking ultrafiltration from blood, 2) the impact of ultrafiltration on protein transport, 3) the evaluation of the role of perfusion in the peritoneal transport, and 4) the integration of the physiological data about transport characteristics of the capillary wall, the tissue, and lymphatic absorption for the description of the net peritoneal transport, using the methods of mathematical modeling. Three different methods were tested for the estimation of fluid transport parameters. All three provided good description of the data, however some differences were found, especially in time dependence of the parameters during a single dwell study. The effectiveness of glucose as an osmotic agent, evaluated as osmotic conductance, were much lower in the patients with permanent ultrafiltration capacity (UFC) loss related to the increased transport of small solutes than in stable patients on continuous ambulatory peritoneal dialysis (CAPD). In contrast, patients with permanent UFC loss related to the increased absorption of fluid from the peritoneal cavity bad similar osmotic conductance as stable patients. A discriminative impact of ultrafiltration on peritoneal transport of albumin, [beta]2-microglobulin, and total protein, was found in stable patients on CAPD: in some patients sieving coefficients for the proteins were high and the initial increase of the protein concentration in dialysate was fast; in another group, with low sieving coefficients for the proteins, and the increase of the protein concentration in dialysate was slow. No difference in the diffusive mass transport coefficients for the proteins and small solutes, neither for fluid transport, between these two groups of patients was found. The perfusion rate of the tissue with blood was included into the distributed model of peritoneal transport. It was shown that changes of perfusion rate during a single dwell study, which might be induced by vasodilatory effect of dialysate, could explain the time-dependence of the diffusive mass transport coefficients (described previously). The model could also explain why the estimations of the effective peritoneal blood flow yielded much different values for gases and then for small solutes. Transport characteristics for the capillary wall, the tissue, and the rate of lymphatic absorption from the tissue, were incorporated into the distributed model, to provide an integrated mathematical description of diffusive and convective transport of solutes of any size. The phenomenological transport parameters, diffusive mass transport parameter and sieving coefficient, the solute penetration depth, and effective peritoneal blood flow, were described as functions of the local, physiological parameters of the peritoneal transport system.
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| 471784. |
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| 471785. |
- Wanngren, Johanna
(author)
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Molecular studies of the γ-secretase complex : focus on genetic and pharmacological modulation
- 2012
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Doctoral thesis (other academic/artistic)abstract
- γ-Secretase is a multi-subunit protease complex, composed of presenilin (PS1 or PS2), Nicastrin, Pen-2 and Aph-1, which generates the Alzheimer disease (AD) related 30-43 amino acid long amyloid β-peptide (Aβ). The complex is also crucial for important cell signaling, such as the Notch receptor pathway. More than 200 different Familial AD (FAD) causing mutations have been identified. They are all restricted to either PS1, PS2 or the amyloid β-precursor protein (APP), from which Aβ is generated, therefore proving how central γ-secretase mediated Aβ production is in AD pathogenesis. A common feature of FAD mutants is an increased Aβ42/Aβ40 ratio production. This results in a more amyloidogenic Aβ product and accelerated oligomerization and plaque formation. A number of γ-secretase inhibitors have been in clinical trials but so far there have been no major progress, due to mechanism-based side effects that is probably caused by impaired Notch signaling. It is therefore very important to develop novel therapeutic strategies targeting Aβ production without interfering with other crucial γ-secretase signaling pathwats. The aim of my thesis was to i) get a better understanding of the molecular basis behind the heterogeneous activity of γ-secretase resulting in different Aβ peptides, ii) to identify novel ways to target γ-secretase mediated Aβ production in a Notch sparing manner, iii) to explore the impact of a novel class of drugs called γ-secretase modulators (GSMs) on different γ-secretase processes. In Paper I, we specifically investigated whether the membrane integration and/or the active site of PS would be affected by different PS1 FAD mutations, which cause an increased Aβ42/Aβ40 production ratio. We found that while some FAD mutations located in hydrophobic domains around the catalytic site (TMD6, H7 and TMD7) changed the membrane integration of PS1, all FAD mutations studied affected the structure of the catalytic site of γ-secretase. In Paper II the large hydrophilic loop of PS1 was examined. Interestingly, by using a deletion mutant strategy, we found that, similar to many FAD mutants, Aβ38, Aβ39 and Aβ40 were dramatically decreased in the absence of the loop, while Aβ42 was affected to a lesser extent, resulting in a net increase in the Aβ42/Aβ40 ratio. Importantly, neither AICD nor NICD formation was impaired, suggesting that the integrity of the loop region is important for proper γ-site cleavage but not for the overall cleavage activity at the ε-site. To further study the mechanism of γ-secretase processing, we reported in Paper III the first study describing single residues in a γ-secretase component besides presenilin, such as Nicastrin, that affects the processing of γ-secretase substrates differently. In the final study, Paper IV, we studied the pharmacology of different GSMs and found that it is possible to generate in vivo potent second-generation γ-secretase-targeting modulatory compounds that are pre-selective for Aβ over Nβ production without affecting NICD formation. These findings may have major implications for the development of GSMs for AD and will be further discussed in the thesis.
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| 471786. |
- Wannheden, Carolina
(author)
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Evidence-based decision support in HIV/TB care : designing treatment, monitoring, and assessment support for care providers
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Introduction: HIV and tuberculosis (TB) coinfection, which is a major challenge for healthcare systems worldwide, requires effective strategies to support care providers in applying best clinical evidence in making treatment decisions about the care of individ- ual patients. Clinical decision support (CDS) systems have the potential to facilitate the implementation of evidence-based guidelines in clinical practice. Aim: The aim of this thesis was to explore how a CDS system could be designed to sup- port the adoption of evidence-based guidelines in the treatment of HIV-related TB. Study design: The HIV outpatient clinic at the Karolinska University Hospital, Huddinge, Stockholm, was the setting for a user-centered design approach structured in three phases: contextual analysis (Studies I and II), design (Study III), and evaluation (Study IV). Study I explores care providers’ challenges and requirements; Study II, which describes socio- demographic and clinical characteristics of patients in this setting, analyzes the factors associated with anti-TB treatment success as well as adverse drug reactions; Study III proposes a CDS framework of drug therapy recommendations that is applied to HIV- related TB treatment guidelines; Study IV formatively evaluates the conceptual design of a CDS prototype that is based on the framework developed in Study III. Methods: In Study I, the contextual analysis is based on observations and interviews. Study II analyses patient treatment outcomes in the research setting between the years 1987 to 2010 (inclusive). Study III presents the design that is based on prototyping and guideline modeling. Study IV uses focus groups of physicians and nurses in the evalua- tion of the design. Results: The contextual analysis revealed challenges related to the complexity of HIV- related TB treatment (Studies I and II). Because the care providers thought they lacked sufficient experience with HIVTB drug therapy, they sought improved support tools and structures (Study I). Combined HIV and TB treatment was related to treatment success, but was also associated with adverse drug reactions (Study II). The design phase ap- plied the eviTMA (evidence-based Treatment, Monitoring, and Assessment) framework to model HIV-related TB treatment guidelines. This resulted in a CDS prototype that models alternative drug therapy options, their expected effects, and recommended mon- itoring routines (Study III). The care providers identified several potential benefits of the eviTMA CDS prototype including support for decision making, collaboration, and qual- ity improvement work (Study IV). Identified concerns that need to be addressed in future include the risk of overdependence on CDS, increased workload, and aspects related to the implementation and maintenance of a CDS system (Study IV). Conclusions: The main contribution of this thesis is the eviTMA CDS framework de- signed to support care providers in the adoption of evidence-based drug therapy rec- ommendations. The framework was evaluated in a CDS prototype for HIV-related TB treatment. Application to other conditions was desired by care providers and should be explored in future.
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| 471787. |
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| 471788. |
- Wanrooij, Paulina Hannele
(author)
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The interface of mitochondrial DNA transcription and replication
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Mitochondria are a dynamic network of subcellular organelles that produce the majority of cellular ATP through the process of oxidative phosphorylation (OXPHOS). The components of the respiratory chain are encoded by two separate genomes, nuclear DNA and mitochondrial DNA (mtDNA), and the proper maintenance of both of these genomic entities is therefore crucial for cellular ATP levels and the survival of the cell. Dysfunction of the respiratory chain leads to cellular energy deficiency and mitochondrial disease, which can manifest in a variety of ways but primarily affects tissues of higher energy demand. Although mtDNA replication and transcription are of vital importance for the cell, the molecular mechanisms behind these processes are not fully understood. In mammalian cells, mtDNA replication initiates from two major sites, the origins of heavy and light strand replication (OriH and OriL, respectively). Activation of both origins requires a short RNA primer that is generated by the mitochondrial transcription machinery. In this way, mtDNA replication and transcription are intricately linked. At OriH, primer 3′ end formation has been suggested to rely on nucleolytic processing of full-length transcripts, but only trace amounts of the nuclease implied in this process are found in mitochondria, making this an unlikely model. In this thesis, we demonstrate that the formation of the primer 3′ end is a sequence-dependent event that is directed by the Conserved Sequence Block II (CSBII) sequence element in mtDNA. During transcription of CSBII, the nascent RNA adopts a G-quadruplex structure that causes premature termination of transcription in vitro. After transcription termination, the primer RNA remains stably associated with the DNA in a persistent RNA-DNA hybrid called an R-loop. We find that this interaction is mediated by hybrid Gquadruplex structures that form between the RNA primer and the DNA non-template strand. When G-quadruplex formation in either the RNA transcript or in the DNA is prevented, the stable association of the primer RNA is lost. The mitochondrial RNA polymerase (POLRMT) is also involved in generating the primer at the origin of light strand replication (OriL). In order to define the essential sequence requirements of mammalian mitochondrial OriL, we employ an in vivo saturation mutagenesis approach combined with biochemical analysis. Our results support an essential role of OriL in the mouse, consistent with the strand-displacement model of mtDNA replication. Furthermore, bioinformatic analysis demonstrates conservation of the OriL structure in vertebrates. POLRMT requires two accessory factors for transcription initiation at mitochondrial promoters. However, the necessity of the mitochondrial transcription factor A (TFAM) in this process has been questioned. We use our defined mitochondrial in vitro transcription system to confirm the important role TFAM in transcription initiation. The requirement for TFAM can be circumvented by conditions that promote DNA breathing, such as low salt concentrations or the use of negatively supercoiled template. We demonstrate that TFAM has the capacity to generate negative supercoils, which we speculate may contribute to melting of the promoter.
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| 471789. |
- Wanselius, Julia, 1990, et al.
(author)
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Fruit and vegetable intake of adolescents living in a Swedish multicultural area
- 2018
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In: EGEA 2018. Nutrition & Health: from science to practice. 7-9 November, Lyon..
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Conference paper (other academic/artistic)abstract
- Dietary related diseases have increased alongside with an increase in body weight in young people during the last decades, and so have also socioeconomic inequalities within youth health. Fruits and vegetables are of great importance for health and contribute with important vitamins, dietary fibre and antioxidants. Thus, people over 10 years of age in Sweden are recommended to eat at least 500 grams of fruits and vegetables per day. Objective: The aim was to compare reported fruit and vegetable intake of adolescents living in a Swedish multicultural area characterized with low socioeconomic status (SES), to the intake of adolescents in a national sample. Methodology: Dietary intake was assessed with food frequency questionnaires among adolescents in 7th grade, mean age 13 years old, (n=118) living in a Swedish multicultural area characterized with low SES, as well as among a national sample of adolescents (n=2292) in the same age. Dietary information was collected in 2014. Results: Adolescents living in the multicultural area had higher frequencies of fruit intake than the national sample (p<0.001). Differences were also seen in number of adolescents who had a daily consumption of fruits (p<0.001), where the multicultural sample had a higher proportion of daily consumers (44 %) than the national sample (25 %). No difference was seen between the groups in frequency of vegetable intake, and neither in daily consumptions of vegetables, where 41 % in the multicultural sample and 38 % in the national sample had a daily consumption respectively. Conclusion: Adolescents living in a Swedish multicultural area characterized with low SES had higher intakes of fruit than adolescents in general. However, intakes of fruits and vegetables need improvement among all groups of Swedish adolescents since not even half of the studied populations had a daily consumption.
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| 471790. |
-
War, Police and Assemblages of Intervention
- 2014
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Editorial collection (other academic/artistic)abstract
- This book reflects on the way in which war and police/policing intersect in contemporary Western-led interventions in the global South. The volume combines empirically oriented work with ground-breaking theoretical insights and aims to collect, for the first time, thoughts on how war and policing converge, amalgamate, diffuse and dissolve in the context both of actual international intervention and in understandings thereof. The book uses the caption WAR:POLICE to highlight the distinctiveness of this volume in presenting a variety of approaches that share a concern for the assemblage of war-police as a whole. The volume thus serves to bring together critical perspectives on liberal interventionism where the logics of war and police/policing blur and bleed into a complex assemblage of WAR:POLICE. Contributions to this volume offer an understanding of police as a technique of ordering and collectively take issue with accounts of the character of contemporary war that argue that war is simply reduced to policing. In contrast, the contributions show how – both historically and conceptually – the two are ‘always already’ connected. Contributions to this volume come from a variety of disciplines including international relations, war studies, geography, anthropology, and law but share a critical/poststructuralist approach to the study of international intervention, war and policing. This volume will be useful to students and scholars who have an interest in social theories on intervention, war, security, and the making of international order.
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