| 1. |
- Blom Johansson, Monica, 1965-
(författare)
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Aphasia and Communication in Everyday Life : Experiences of persons with aphasia, significant others, and speech-language pathologists
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this thesis were to describe the experiences of persons with aphasia and their significant others of their conversations and use of communication strategies, examine current practice of family-oriented speech-language pathology (SLP) services, and test a family-oriented intervention in the early phase of rehabilitation.The persons with aphasia valued having conversations despite perceiving their aphasia as a serious social disability. They acknowledged the importance of the communication partners’ knowledge and understanding of aphasia and their use of supporting conversation strategies. Their own use of communication strategies varied considerably. The persons with aphasia longed to regain language ability and to be active participants in society.A majority of the significant others perceived their conversations with the person with aphasia as being less stimulating and enjoyable than conversations before stroke onset. Aphasia was considered a serious problem. The significant others took on increased communicative responsibility, where two thirds had changed their communicative behaviour to facilitate conversations. Type and severity of aphasia were especially related to the communicative experiences of the significant others and their motivation to be involved in SLP services.Thirty percent of the speech-language pathologists worked with people with aphasia and typically met with their families. They considered the involvement of significant others in SLP services as very important, especially in providing information about aphasia and communication partner training (CPT). However, involvement of significant others was restricted because of a time shortage and perceived limited skills and knowledge. In addition, there were national differences regarding aphasia rehabilitation services.The intervention consisted of three sessions directed to significant others (primarily emotional support and information) and three directed to the dyads (a person with aphasia and a significant other) (primarily CPT). All six participants (three dyads) felt that their knowledge and understanding of aphasia had increased and that their conversations had improved. These improvements were also evident to some extent with formal assessments.These results suggest the following: CPT should be an integral part of SLP services, national clinical guidelines are needed, and further education of speech-language pathologists and implementation of new knowledge into clinical practice requires consideration.
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| 2. |
- Grapensparr, Liza
(författare)
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Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes develops through the progressive destruction of the insulin-producing beta-cells. Regeneration or replacement of beta-cells is therefore needed to restore normal glucose homeostasis. Presently, normoglycemia can be achieved by the transplantation of whole pancreas or isolated islets of Langerhans. Islet transplantation can be performed through a simple laparoscopic procedure, but the long-term graft survival is low due to poor revascularization and early cell death.This thesis examined the possibility of using different auxiliary cells (Schwann cells, endothelial progenitor cells, and neural crest stem cells) to improve the engraftment and function of endogenous and transplanted islets.Co-transplantation of Schwann cells with islets improved islet graft function early after transplantation, and caused an increased islet mass at one month posttransplantation. However, the vascular densities of these grafts were decreased, which also related to an impaired graft function.Islet grafts containing endothelial progenitor cells had a superior vascular density, with functional chimeric blood vessels and substantially higher blood perfusion and oxygen tension than control transplants.By culturing and transplanting islets together with neural crest stem cells it was found that islets exposed to these cells had a higher beta-cell proliferation compared with control islets. At one month posttransplantation, the grafts with neural crest stem cells also had a superior vascular- and neural density.The potential of intracardially injected neural crest stem cells to home to the pancreas and ameliorate hyperglycemia in diabetic mice was investigated. During a three-week period after such cell treatment blood glucose concentrations decreased, but were not fully normalized. Neural crest stem cells were present in more than 10% of the pancreatic islets at two days postinjection, at which time the beta-cell proliferation was markedly increased when compared with islets of saline-treated diabetic animals. Three weeks later, a doubled beta-cell mass was observed in animals receiving neural crest stem cells.In summary, islets can easily be transplanted together with different auxiliary cells. Some of these cells provide the possibility of improving vascular- and neural engraftment, as well as beta-cell growth and survival. Systemic administration of neural crest stem cells holds the potential of regenerating the endogenous beta-cells.
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| 3. |
- Moparthi, Satish Babu
(författare)
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Biophysical studies of protein folding upon interaction with molecular chaperones
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proteins are biological macromolecules that serve all functions in cells. Every protein consists of a sequence of amino acids that is folded into a three‐dimensional structure to maintain the unique information it contains and to allow the protein to perform its specific actions. Improper folding caused by mutations in the amino acid sequence or environmental stress can lead to protein aggregation and ultimately to protein conformational disorders such as Parkinson’s disease and other dreadful diseases. Nature has developed special classes of protein guards called foldases and chaperones that can increase folding efficiency in the crowded intracellular milieu by preventing protein aggregation. The present research was aimed to elucidate how chaperones and foldases interact with their target proteins during folding. Special attention was focused on refolding kinetics and dynamic remodulation of site‐specific labeled cysteine variants of the protein human carbonic anhydrase (HCA II) upon interaction with the PPIase cyclophilin18 (Cyp18) and the chaperonin GroEL. Part of the work also compared properties of the group I chaperonin GroEL and the group II chaperonin TRiC, considering how they mediate structural alterations uponinteraction with the cytoskeletal target protein β‐actin. These interactions were studied by various fluorescence techniques, including fluorescence resonance energy transfer (FRET) and fluorescence anisotropy.Refolding of HCA II is an extremely complicated process that involves very fast and slow folding events, and research has shown that Cyp18 enhances the slow rate‐limiting cistrans proline isomerization steps during the refolding process. Furthermore, the active‐site mutant Cyp18R55A has been reported to posses only about 1% catalytic efficiency when acting on short chromogenic peptide substrates. However, we found that Cyp18R55A is as efficient as the wild‐type Cyp18 in accelerating HCA II refolding. We also noted that Cyp18 enhanced the final yield of the severely destabilized HCA IIH107N, and HCA IIH107F mutants by rescuing transient molten globule intermediates from misfolding as a result of condensation of hydrophobic patches at very early stages of the folding process. These findings led to the conclusion that Arg 55, located in the active site of Cyp18, is not required for prolyl cistrans isomerization of protein substrates, and that Cyp18 can function as both a folding catalyst and a chaperone during HCA II folding.Studies have demonstrated that sequestering of protein substrates by the chaperonin GroEL alone results in binding‐induced unfolding of aggregation‐prone molten globule intermediates. It was previously assumed that the co‐chaperonin GroES does not play an independent role in folding. However, based on FRET measurements, we found that GroEL alone stretches the protein substrate as an early event, and also that GroES alone can transiently remodulate the structure of the molten globule intermediate during the refolding process. In addition, GroES acts in i concert with GroEL to exert additive transient stretchng effects on the protein core, and it reverses the unfoldase activity of the GroEL termini, leading to compaction of the structure to attain the more constrained native state.Earlier investigations have shown that partially folded β‐actin binds to both GroEL and the TRiC chaperonin. However, only TRiC guides correct folding of β‐actin, whereas the GroEL–β‐actin interaction is non‐productive. Homo‐FRET measurements on β‐actin mutants labeled with fluorescein during interaction with GroEL and TRiC indicated that interplay with both the chaperonins lead to binding‐induced unfolding and dynamic remodulation of β‐actin. More specifically, the interaction with TRiC resulted in considerable expansion of the entrance of the ATP‐binding cleft of β‐actin by effecting specific modulation of the β‐actin sub‐domains followed by the formation of a compressed state (native‐like) during release from TriC. Conformational rearrangements of β‐actin by GroEL on the other and were ore modest. β‐actin remained rather compact in the complex and consequently did not lead to the native‐like state ven in the encapsulated cis‐cavity when capped by GroES.
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| 4. |
- Arvidsson, Eva
(författare)
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Priority Setting and Rationing in Primary Health Care
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Studies on priority setting in primary health care are rare. Priority setting and rationing in primary health care is important because outcomes from primary health care have significant implications for health care costs and outcomes in the health system as a whole.Aims: The general aim of this thesis has been to study and analyse the prerequisites for priority setting in primary health care in Sweden. This was done by exploring strategies to handle scarce resources in Swedish routine primary health care (Paper I); analysing patients’ attitudes towards priority setting and rationing and patients’ satisfaction with the outcome of their contact with primary health care (Paper II); describing and analysing how general practitioners, nurses, and patients prioritised individual patients in routine primary health care, studying the association between three key priority setting criteria (severity of the health condition, patient benefit, and cost-effectiveness of the medical intervention) and the overall priority assigned by the general practitioners and nurses to individual patients (Paper III); and analysing how the staff, in their clinical practise, perceived the application of the three key priority setting criteria (Paper IV).Methods: Both qualitative (Paper I and IV) and quantitative (Paper II and III) methods were used. Paper I was an interview study with medical staff at 17 primary health care centres. The data for Paper II and Paper III were collected through questionnaires to patients and staff at four purposely selected health care centres during a 2-week period. Paper IV was a focus group study conducted with staff members who practiced priority setting in day-to-day care.Results: The process of coping with scarce resources was categorised as efforts aimed to avoid rationing, ad hoc rationing, or planned rationing. Patients had little understanding of the need for priority setting. Most of them did not experience any kind of rationing and most of those who did were satisfied with the outcome of their contact with primary health care. Patients, compared to medical staff, gave relatively higher priority to acute/minor conditions than to preventive check-ups for chronic conditions when prioritising individual patients in day-today primary health care. When applying the three priority setting criteria in day-to-day primary health care, the criteria largely influenced the overall prioritisation of each patient. General practitioners were most influenced by the expected cost-effectiveness of the intervention and nurses were most influenced by the severity of the condition. Staff perceived the criteria as relevant, but not sufficient. Three additional aspects to consider in priority setting in primary health care were identified, namely viewpoint (medical or patient’s), timeframe (now or later) and evidence level (group or individual).Conclusion: There appears to be a need for, and the potential to, introduce more consistent priority setting in primary health care. The characteristics of primary health care, such as the vast array of health problems, the large number of patients with vague symptoms, early stages of diseases, and combinations of diseases, induce both special possibilities and challenges.
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| 5. |
- Brodtkorb, Thor-Henrik, 1976-
(författare)
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Cost-effectiveness analysis of health technologies when evidence is scarce
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Given the increasing pressures on health care budgets, economic evaluation is used in many countries to assist decision-making regarding the optimal use of competing health care technologies. Although the standard methods of estimating cost-effectiveness underpinning these decisions have gained widespread acceptance, concerns have been raised that many technologies would not be considered for funding, due to scarcity of evidence. However, as long as the amount and quality of evidence used for the analysis are properly characterized, scarce evidence per se should not be seen as a hindrance to perform cost-effectiveness analyses. Characterizing uncertainty appropriately, though, may pose a challenge even when there is a large body of evidence available, and even more so when evidence is scarce. The aims of this thesis are to apply a methodological framework of cost-effectiveness analysis and explore methods for characterising uncertainty when evidence is scarce. Three case studies associated with limited evidence provide economic evaluations on current decision problems, investigate the feasibility of using the framework, and explore methods for characterizing uncertainty when evidence is scarce.The results of the case studies showed that, given current information, providing transfemoral amputees with C-Leg and Airsonett Airshower to patients with perennial allergic asthma could be considered cost-effective whereas screening for hyperthrophic cardiomyopathy among young athletes is unlikely to be cost-effective. In the cases of C-Leg and Airsonett Airshower conducting further research is likely to be cost-effective. The case studies indicate that it is feasible to apply methods of cost-effectiveness in health care for technologies not commonly evaluated due to lack of evidence. The analysis showed that failing to account for individual experts’ might have a substantial effect on the interpretation of the results of cost-effectiveness analysis. Formal expert elicitation is a promising method of characterizing uncertainty when evidence is missing, and thus enable cost-effectiveness and value of further research to be appropriately estimated in such situations.In conclusion, this thesis shows that scarcity of evidence should not preclude the use of cost-effectiveness analysis. On the contrary, in such cases it is probably more important than ever to use a framework that enable us to define key parameters for a decision problem and identify available evidence in order to determine cost-effectiveness given current information and provide guidance on further data collection.
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| 6. |
- Carlsson, Inga-Lill, 1955-
(författare)
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Towards System Supply : Development of Small and Medium-Sized Contract Manufacturers
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One way for a small subcontractor to meet increasing global competition is to develop a system supplying ability, implying a transition in the supply chain toward a larger overall responsibility. As large corporations outsource parts of their manufacturing and services, many small and medium-sized enterprise (SME) suppliers are expected to deepen their capabilities and take on the role of system suppliers. The overall purpose of this thesis is to advance the understanding of how SME contract manufacturers can develop such capabilities, identifying demands and abilities in various steps of this process. The research approach is based on the resource-based view.This longitudinal case study of an SME supplier striving to become a system supplier covers the period from 2006 to 2014. The researcher’s role as business developer and member of the management made it possible to follow the company's development continuously and closely, providing access to relevant internal data complemented with internal and external semi structured interviews and focus discussions. The longitudinal aspect is evident in the overall description of the development of the focal supplier. More specific issues are covered in the separate studies, described in the appended articles.SME suppliers need basic capabilities of qualitative production performance as stepping-stones to develop more system supplier capabilities for added customer value. Development of stable production processes through lean implementation was by the focal supplier seen as a way to reach stable basic performance and to enable continuous development. The study further shows that knowledge integration with customers is an effective means to build system capability and indicates a stepwise and sequential process of developing specific supplier capabilities.The longitudinal case study deepens the knowledge of development of SME system suppliers and specifically point out three prerequisites that need to be in place for the supplier transition: (1) a capability of the supplier to manage internal processes of standardisation and continuous improvements for stable performance without disruptions, (2) a capability to collaborate in development projects with a limited number of customers, and (3) customer commitment to a long-term relationship. A customer demanding improvements is constantly driving its suppliers to better performance and proven supplier capabilities in turn promotes long-term customer commitment. The most essential component in supplier development is a competent and strategically oriented management, capable of identifying the specific system supplier offerings appropriate for the particular company in order to create customer value.This study contributes to better understanding of the conditions of medium-sized contract manufacturing SMEs, from a supplier perspective, and contributes to SCM research in illustrating how shifting responsibilities and subsequent activities in the supply chain may pave new competitive paths for SMEs. One issue here is the importance of knowledge integration for the development of supply chains. This has not often been discussed within SCM and thus provides a contribution to this theory.
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| 7. |
- Drott, Carl Johan, 1984-
(författare)
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Influence of Islet-derived Factors in Islet Microcirculation and Endocrine Function
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes mellitus is a disorder with complex pathology and is frequently associated with vascular complications. In the islet micro milieu locally generated factors may affect both the physiology and the morphology of the tissue. This thesis examines the impact of four different islet-derived factors; thrombospondin-1 (TSP-1), ghrelin, Cocaine and amphetamine regulated transcript (CART) and irisin, and how they influence the endocrine pancreas.TSP-1 is an angiogenesis inhibitor. Islets from TSP-1 deficient mice were hypervascular, but with normal endocrine mass. Beta-cell dysfunction was present in islets of TSP-1 deficient mice, both in vivo and in vitro. When trying to reconstitute TSP-1 in islets of TSP-1 deficient animals through a transplantation model, adult islets failed to recover, showing the importance of TSP-1 for glucose stimulated insulin secretion and thereby glucose homeostasis.Ghrelin inhibited glucose stimulated insulin secretion and decreased the islet blood flow, while the ghrelin receptor antagonist GHRP-6 in fasted, but not fed, rats increased the islet blood flow fourfold and improved the peak insulin response to glucose. The ghrelin receptor GHS-R1α was identified in the alpha cells and the islet arterioles.CART selectively reduced the islet blood flow in the pancreas, and this effect was unaltered by simultaneous administration of an endothelin-A receptor antagonist. CART administration did not affect insulin release, neither in insulin release from isolated islets or in an intravenous glucose tolerance test. Irisin was confirmed located within the pancreatic islets predominately in the alpha-cells. Irisin reduced islet and white adipose tissue blood flow. Irisin was secreted as a response to increased glucose concentrations in vivo. Irisin had no direct effect on insulin secretion.In conclusion, all factors investigated proved to have roles locally in the endocrine pancreas. TSP-1 deficiency caused vascular morphological alterations, and chronic β-cell dysfunction. Ghrelin, CART and irisin all decreased islet blood flow. Ghrelin acted directly through its receptor GHS-R1α in islet arterioles, thereby restricting the insulin response to hyperglycemia, whereas for CART and irisin the specific mechanism continues to be unknown, without identification of a receptor. In order to reach full physiological understanding, the receptors for CART and irisin need to be identified. All four islet-derived factors hold potential for the treatment of type 2 diabetes.
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| 8. |
- Espes, Daniel, 1985-
(författare)
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Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Islet transplantation is a possible curative treatment for type 1 diabetes (T1D). Currently the liver dominates as implantation site, despite the many challenges encountered at this site.Acute hypoxia in islets transplanted to muscle and omentum, two possible alternative sites, was prevailing. However, it was rapidly reversed at both implantation sites, in contrast to when islets were transplanted intraportally. At the intramuscular site hypoxia was further relieved by co-transplantation of an oxygen carrier, polymerized hemoglobin, which also improved the functional outcome. The complement system was activated after islet transplantation to muscle, but did not hamper graft function.Both mouse and human islets transplanted to omentum become well re-vascularized and have a functional blood flow and oxygenation comparable with that of endogenous islets. Animals transplanted with islets to the omentum had a superior graft function compared with animals receiving intraportal islet grafts.Alloxan-diabetic animals were cured with a low number of islets both when the islets were implanted in the omentum and muscle. The islet grafts responded adequately to both glucose and insulin and displayed a favorable mRNA gene expression profile.A challenge in diabetes research and in islet transplantation is that there are no established techniques for quantifying beta-cell mass in vivo. By using radiolabeled Exendin-4, a GLP-1 receptor agonist, beta-cell mass after transplantation to muscle of mice was quantified. The results may well be translated to the clinical setting.By comparing the pancreatic accumulation of [11C]5-hydroxy tryptophan ([11C]5-HTP) as detected by positron emission tomography (PET) in T1D patients with that of healthy controls, a 66% decrease was observed. This may in fact represent the loss of beta-cells, taking into account that other cells within the islets of Langerhans are largely unaffected in T1D. In conclusion, the data presented support the use of alternative implantation sites for islet transplantation. In addition to improving the functional outcome this may enable more transplantations since the number of transplanted islets may be reduced. The techniques investigated for quantifying transplanted and endogenous beta-cell mass may greatly improve our knowledge of the pathophysiology of T1D and become a valuable tool for evaluation of beta-cell mass.
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| 9. |
- Luo, Zhengkang, 1994-
(författare)
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Immunological strategies for counteracting type 1 diabetes focusing on IL-35 producing regulatory immune cells
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is an autoimmune disease where pancreatic β-cells are attacked by immune cells. Regulatory T (Treg) cells play critical roles in suppressing immune responses and their involvement have been intensively studied in T1D. Low dose IL-2 has been proposed to selectively boost Treg cells in T1D, with only limited success. We thus further decreased the IL-2 dosage and treated multiple low dose streptozotocin (MLDSTZ) mice with an ultra-low dose IL-2, but it did not protect STZ mice from hyperglycemia. Similarly, low dose IL-2 only partially prevented diabetes. Treg cells’ phenotype was not protected by either dose. These data suggest that alternative IL-2 therapies might be considered. Regulatory B (Breg) cells suppress pro-inflammatory immune responses by producing anti-inflammatory cytokines IL-10 and IL-35. Decreased IL-35+ and increased IFN-γ+ Breg cell proportions were found in T1D patients, and in diabetic mice. IL-35 treatment prevented increased IFN-γ+ Breg cell proportions in STZ mice. These data illustrate Breg cells’ involvement in T1D, and IL-35 treatment prevents hyperglycemia by maintaining Breg cells’ phenotype.Treg cells’ involvement in diabetic nephropathy (DN) has not been studied. Lower plasma IL-35 was found in DN patients than in T1D patients without DN and healthy controls, and was strongly correlated with kidney function. Decreased IL-35+ and increased IL-17+ Treg cells were found in DN patients. Moreover, Foxp3+ cell infiltration was found in the kidneys of diabetic mice, but it failed to counteract mononuclear cell infiltration. IL-35 treatment prevented DN and Treg cells’ phenotypic shift in STZ mice by maintaining the transcription factor Eos. These results demonstrate that IL-35 may be used to prevent DN. Given the instability of IL-35, we explored the effect of IL-6 signaling blockade. Anti-IL-6R completely protected STZ mice from diabetes. Proteomics indicated enhanced metabolism and down-regulated pro-inflammatory pathways. It maintained Treg cells’ phenotype by increasing IL-35 and decreasing IFN-γ production. It also reduced the number of macrophages and conventional dendritic cells type 2 and their CD80 expression. STZ mice remained normoglycemic despite the discontinuation of anti-IL-6R treatment. Therefore, our results illustrate the outcomes of several potential T1D immunotherapies and highlight the involvement of IL-35 producing immune cells in controlling the disease.
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| 10. |
- Norman, Daniel, 1997-
(författare)
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Physiological Studies of Native and Stem Cell-Derived Islets
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In type 1 and type 2 diabetes, the β-cells of the islets of Langerhans are either destroyed by the immune system or stressed due to peripheral insulin resistance. To improve the life of patients with these diseases, new treatments are needed. This thesis examined the role of irisin and cocaine and amphetamine regulated transcript (CART) in islets of Langerhans and their potential pharmaceutical role in type 2 diabetes. Furthermore, β-cell replacement with stem cell-derived islets of Langerhans (SC-islets) for type 1 diabetes was evaluated for optimal implantation site.In paper I, the physiological role of CART in rat islets was examined. CART was shown to specifically lower islet blood flow, which could be a protective effect in type 2 diabetes. No effect from CART on glucose tolerance or insulin release was seen in rat islets, which highlights species differences.In paper II, the expression of irisin and its effect on hormone secretion and pancreatic blood flow was examined. Irisin was expressed in human islets and was secreted glucose dependently. It also lowered islet blood flow but did not affect glucose-stimulated insulin secretion in isolated human or rat islets. Thus, local secretion of irisin could serve as a protective function by lowering islet blood flow in a high glucose state.In paper III, the expression of irisin in SC-islets and its potential beneficial effects in transplantation was examined. SC-islets were found to express higher levels of irisin than human islets. Irisin treatment had no effects on viability and proliferation in SC-islets, in contrast to previous studies in other species. Thus, irisin signaling likely differs between SC-islets and murine and native human islets.In paper IV, SC-islets were transplanted to multiple sites in mice to find the optimal implantation site in terms of graft maturity, function and composition. The liver proved to be the most favorable site due to its higher expression of islet maturity genes and a higher β-cell function and fraction. This poses a dilemma, as the liver site is the most challenging to biopsy and monitor for safety.In summary, this thesis uncovered new physiological functions of irisin and CART, potentially offering insights relevant to the treatment of type 2 diabetes. Meanwhile, the role of irisin in transplantation of SC-islets seems limited.
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