| 1. |
- Schmidt, Manuela
(författare)
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Persons who frequently use psychiatric emergency services : perspectives on who they are, what their needs are and howthey are encountered by healthcare professionals
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall objective of the thesis was to describe who persons that frequently use psychiatric emergency services (PES) in Sweden are, to explore what needs they experience as well as how healthcare professionals working at PES view the needs of those persons and experience encounters with them.This thesis includes both quantitative (I, II) and qualitative (II, III, IV) research designs and applies a broad range of data collection methods, such as use of register data (I), use of survey data (II), individual interviews and focus group interviews (III, IV). Data were analysed with statistical tests (I, II) and with qualitative content analysis (II, III, IV).Study I is based on visits to PES during 2013–2015. A total of 27,282 persons made 67,031 visits. Of those 27,282 persons, 8.1% could be identified as frequent PES users, accounting for nearly two fifths of all visits. In Study II, 81 persons who frequently visited PES participated. The participants in Studies III and IV were healthcare professionals working at PES, such as assistant nurses, nurses with specialised education in psychiatry, and physicians. Nineteen healthcare professionals participated in individual interviews in both Study III and Study IV, and each of the studies was complemented with a focus group interview involving five and six professionals respectively.The findings of this thesis were as follows: persons who frequently use PES in Sweden are a small, yet highly heterogeneous group who make a disproportionately high number of visits and differ significantly from other PES visitors; persons who frequently use PES and healthcare professionals at PES are in agreement about the complex and intertwined need patterns of the patients that originate from problems in everyday living, acute psychiatric suffering, and insufficient care possibilities, and thus were found to suffer from illness, unfavourable life circumstances and inadequate care; healthcare professionals at PES experienced the encounter as consisting of caring, professional, and humane processes where persons who frequently use PES were seen as fellow human beings and as unique, and were treated with as much respect, kindness, humility, confirmation, and empowerment as possible; and that in order to have caring encounters with persons who frequently use PES, the healthcare professionals also needed to nurture the relationship with oneself and with colleagues. Those results were interpreted by means of person-centredness and in light of a recovery-oriented care approach. Even though the latter has received more acknowledgement and acceptance within psychiatric care in the last decade, it needs to be developed and implemented further in the Swedish psychiatric care context.
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| 2. |
- Bruce, Barbro
(författare)
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Problems of language and communication in children; Identification and intervention
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis addresses identification and intervention of language and communication problems in children. The issue of identification is addressed in study I by investigating communicative ability in 18-month-old children, and in study II by exploring the prevalence of language and communication problems in children with complex problems, such as attention deficit hyperactivity disorder (ADHD). The issue of intervention is addressed in studies III and IV by analysing verbal interaction in conversations, in which one of the participants is a child with specific language impairment (SLI). Study III explores how dialogues between children with SLI and typically developing peers (TLD) representing the same age (age peers), and the same language level (language peers) respectively, differ with respect to responsiveness, assertiveness and reciprocity. Study IV investigates interactional style and elicitation strategies of speech/language pathologists (SLP) during intervention, and how these factors influence the child with SLI. The results from study I show that receptive skills and symbolic play at 18 months of age are significantly associated with language ability three years later. Study II, in which language skills in children with ADHD were explored, indicates that language ability plays an important role for all other aspects of children's development and behaviour, with the exception of motor skills. Use of language and language comprehension caused these children many more problems than structural aspects of language production. Furthermore, reading and writing problems were found to be very frequent. Study III shows that dialogues between children with SLI and TLD age peers are characterized by more responsiveness and topic coherence than dialogues between children with SLI and TLD language peers. However, the children with SLI were more assertive, i.e., introduced more topics, in dialogues with language peers. Study IV indicates that the children with SLI talked more and had a higher mean length of utterance (MLU) in the free conversational context, whereas the individually selected grammatical targets occurred more often in the training context. In the conversational context the SLPs linked, i.e., attended, more to the child's focus and gave more feedback, while in the training context the individually selected grammatical targets occurred more often and the children were more frequently asked to follow instructions. The results have important clinical implications. First; screening procedures at Child Health Care (CHC) centres should be recommended to focus on receptive language skills and play behaviour, and not only on size of vocabulary at 18 months of age. Second; language skills, in particular language comprehension, language use and literacy skills were found to cause children with ADHD problems, and should therefore be assessed. Third; it is of great value for children with SLI to be in mixed groups with peers representing different ages and language levels, and to avoid the risk of not being selected as playmates. Fourth; increased awareness of how interactional style and elicitation strategies influence the developing language skills in children with SLI can be used in intervention planning, depending on the goals of the specific intervention procedures for the individual child.
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| 3. |
- Deyhle Jr, Richard
(författare)
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Cross-modal Imaging in Lung Research: From µCT dosimetry to synchrotron phase contrast microtomography biomechanical insights in preclinical lung injury models
- 2024
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung diseases continue to present a large burden to public health, especially in industrialized countries. For abetter understanding of the underlying patho-mechanisms in lung related diseases as well as for testing theefficacy of novel therapies, preclinical studies in animal models are indispensable. The significance of preclinical X-ray based micro-computed tomography (µCT) research lies in its ability to provide high-resolution, non-invasive lung imaging of small animals as the air inside the lung acts as a natural contrast and to image the lung parenchyma longitudinally to assess functional and morphological alterations and test efficacy of therapeutic interventions. This often requires requires imaging protocols that balance between sufficient image quality and clinically relevant radiation absorbed doses. A reproducible method for evaluation of absorbed radiation absorbed doses is desirable. Absorbed radiation absorbed doses were measured in a polymethyl methacrylate (PMMA) phantom using standard TLD and a novel type of OSLD made form household salt. Four imaging protocols from MILabs “xUHR-µCT” scanner were tested. A large discrepancy was observed from results compared to vendor-provided values. The results indicate a need for thorough empirical dose measurements prior to performing longitudinal studies. Four-dimensional imaging, allows for investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. It is of significant interest to have direct visualization and quantification of interstitial lung diseases at spatial resolutions beyond the capabilities of clinical and conventional absorption-based only CT. Thus far, the high intensity of synchrotron X-ray light sources offer a tool to investigate dynamic morphological and mechanistic features, enabling dynamic in-vivo microscopy. This investigation elucidates the direct effects of interventions targeting the pathophysiology of Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury (VILI) on the terminal airways and alveolar microstructure within intact lungs. In such conditions, the relationship between microscopic strain within the mechanics of the alveolar structure and the broader mechanical characteristics and viscoelastic properties of the lungs remains poorly understood. A time-resolved synchrotron phase-contrast micro-computed tomography imaging acquisition protocol based on the synchronization between the mechanical ventilation and the cardiac activity was used to resolve the lung parenchyma motion with an effective isotropic voxel size of 6 µm. Quantitative maps of microscopic local lung tissue strain within aerated lung alveolar tissue under protective mechanical ventilation in anesthetized rats were obtained. This approach was used to assess the effect of alterations in lung tissue biomechanics induced by lung injury at 7 days after single-dose, intratracheal bleomycin instillation in combination with short-term high-tidal volume (VT) mechanical ventilation. Overall, this work address the aspects of radiation exposure to in experimental imaging of small animals and lays a foundation for a more nuanced understanding of lung injury and mechanical ventilation. In the future, it may result in a more effective and less injurious respiratory support for patients with acute lung injury or chronic lung diseases.
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| 4. |
- Skog, Malin
(författare)
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Experiences of Screening for Postpartum Depression in Non-Native-Speaking Immigrant Mothers in the Swedish Child Health Services. Nurses’ and Mothers’ Perspectives.
- 2018
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Postpartum depression (PPD) är ett globalt folkhälsoproblem. Mödrar som migrerar till ett annat land har en ökad risk att drabbas av PPD. Före-komsten av PPD bland utlandsfödda mödrar beräknas vara så hög som 20 procent, vilket nästan är dubbelt så hög som bland inhemsk västerländsk befolkning. Asylsökande och flyktingar är särskilt sårbara grupper som löper en ännu högre risk att drabbas, speciellt de som migrerat inom 10 år. Likaså de mödrar som inte talar språket i sitt nya hemland. PPD uppstår vanligtvis fyra till sex veckor efter förlossningen och kan ha långvariga traumatiska effekter inte bara på moderns egen hälsa utan även på hennes partners och framförallt på barnets hälsa och utveckling. Mot bakgrund av detta rekommenderar Socialstyrelsen att screening av nyblivna mödrar för PPD regelmässigt genomförs av sjuksköterskan i barnhälsovården (BHV) sex till åtta veckor efter förlossningen. Screeningen genomförs med hjälp av Edinburgh Postnatal Depression Scale (EPDS), som är en skala översatt och validerad till många olika språk. Skalan består av tio olika påståenden speciellt utvecklade för screening för PPD. Skalan används i kombination med ett samtal för att bedöma moderns psykiska mående. Vid screening av icke-svenskspråkiga mödrar instrueras sjuksköterskorna att använda ett översatt validerat formulär, ta hänsyn till moderns läs- och skrivkunnighet, tolkens arbete samt hur olika kulturella tolkningar av påståendena i skalan kan påverka resultatet. Screening av utlandsfödda mödrar har visat sig vara en utmanande arbetsuppgift för sjuksköterskorna. Tidigare forskning pekar på att dessa mödrar inte erbjuds delta i screening i samma omfattning som den inhemska befolkningen. Statistik visar också att invandrarmödrar i större utsträckning väljer att tacka nej till att delta i screening och likaså att bland de som deltar är det inte så många som förväntat som screenas ut i förhållande till den höga förekomsten av PPD i gruppen. Det övergripande syftet med studierna var att öka kunskapen om screening för PPD av icke-svenskspråkiga invandrarmödrar genom att belysa deras och BHV-sjuksköterskors erfarenheter. Ett ändamålsenligt urval användes vilket innebar att deltagare med erfaren¬¬heter av ämnet erbjöds delta i individuella intervjuer. Det insamlade text¬materialet analyserades med latent innehållsanalys med induktiv ansats. Det är en deskriptiv kvalitativ metod som syftar till att förutsättningslöst skapa kategorier och teman i avsikt att beskriva fenomenet för att öka förståelsen och kunskapen. Vid latent innehållsanalys tolkas även det underliggande budskapet i texten. Med syftet att belysa hur BHV-sjuksköterskor identifierar tecken på PPD hos icke-svenskspråkiga invandrarmödrar genomfördes 13 individuella inter-vjuer. Resultatet visade att en förutsättning för att kunna tolka den moderns sinnesstämning var etablerandet av en trans-kulturell vårdrelation som fördjupades. Sjuksköterskorna använde sig av kulturell kunskap för att uppfatta och tolka tecken på PPD i interaktionen med modern och i observationer av samspelet mellan mamma och barn, med tolken och anhöriga. Samtidigt orsakade bristande kulturell kompetens frustration hos sjuksköterskorna när de försökte anpassa screeningen efter de givna förutsättningarna och även när de försökte få mamman att öppna sig eller ta emot extern hjälp. Sjuksköterskorna förlitade sig även på sin intuition när de tolkade mammans sinnesstämning. För att få kunskap om hur icke-svenskspråkiga invandrarmödrar upplever att delta i screening för PPD i BHV intervjuades 13 med albanska, arabiska eller badinani som modersmål. Andra tolkar än de som användes i intervjusituationen lyssnade på ljudinspelningarna och validerade det utskrivna materialet. Resultatet visade att deltagandet i screeningen påminde mödrarna om deras brist på stöd i sin nuvarande livssituation, men sågs även som en möjlighet att erfara andra sätt att tänka kring psykisk ohälsa och nya källor till stöd. Kvalitén på relationen med sjuksköterskan var av betydelse för om modern valde att delta i screening och uppleva den som meningsfull. Innebörden av PPD var i allmänhet oklar, men möjligheten att delta i screening och därigenom bli behandlad som alla andra mödrar uppskattades. Kulturella föreställningar om psykisk ohälsa, negativa förväntningar kopplade till sitt upplevda värde som kvinna, skam över att inte vara tillräckligt tacksam för sitt nya liv och negativa upplevelser av interaktionen i samband med screeningen gjorde det utmanade för dem att tala om sitt mående. Studierna visar att screening för PPD av icke-svenskspråkiga invandrarmödrar kan underlättas av upprepad information om PPD både muntligt med hjälp av tolk, men även genom översatt material, ett förtroendefullt samtal med assistans av kvinnlig auktoriserad kontakttolk samt kunskap hos BHV-sjuksköterskor om olika utmaningar hos dessa mödrar för att kunna tala om psykiskt mående. Den förtrogenhetskunskap som erfarna BHV-sjuksköterskor besitter och använder sig av för att tolka icke-svenskspråkiga mödrars mående behöver ytterligare studeras. Det är också av intresse att undersöka om utbildning av BHV-sjuksköterskorna i kulturkänslig screening kan göra att screeningen av denna sårbara grupp av mödrar mer effektiv.
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| 5. |
- Lamei, Sepideh
(författare)
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The effect of honeybee-specific lactic acid bacteria on american foulbrood disease of honeybees
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The honeybee, Apis mellifera, is one of the most economically important pollinators and highly valued for its honey and wax production. Managed honeybees occupy an increasingly critical role in agricultural productivity and food security. American foulbrood (AFB) is a highly contagious and destructive bacterial honeybee brood disease caused by Paenibacillus larvae that affects beekeeping worldwide. However, only a minority of bacteria associated with honeybees are harmful. Honeybee-specific Lactic Acid Bacteria (hbs-LAB), a defined group of beneficial bacteria inhabiting the honey crop, have strong antimicrobial properties important for honey production and honeybee health that could be exploited for combating diseases such as AFB. The aim of this thesis was to investigate the effect of hbs-LAB on P. larvae and AFB, both in culture, in individual larval bioassays, and at colony level. First we showed that the laboratory cultivation of the 13 distinct hbs-LAB was significantly improved by the addition of L-cysteine and fructose to the medium and optimized a culture-independent molecular technique for the detection and identification of the individual hbs-LAB species. Secondly the effect of the cell free supernatant, the secretome, from a culture mix of the 13 hbs-LAB species was investigated on P. larvae growth and associated larval mortality. The results showed that this secretome strongly inhibited the multiplication of P. larvae vegetative cells but that spore germination appeared to be unaffected, and that it decreased the mortality of P. larvae infected larvae. Finally it was shown that oral administration of hbs-LAB supplement to honeybee colonies had no influence on colony-level P. larvae spore levels or colony strength. Furthermore, the results showed that although the antibiotic tylosin decreased AFB symptoms in colonies, it had no effect on P. larvae spore levels. In conclusion, the colony-level results do not contradict the antagonistic effects observed in individual larvae in laboratory studies, but rather suggest that supplementary administration of live bacteria may not be the most effective way to harness such effects in a useful application.
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| 6. |
- Nilsson, Kerstin
(författare)
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To work or not to work in an extended working life? Factors in working and retirement decisions
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In most of the industrialised world, the proportion of older and retired people in the population is continuously increasing. This will have budgetary implications for maintaining the welfare state, because the active working section of the population must fund the non-active and old population. Aim: The overall aim of this thesis was to obtain knowledge about older workers’ work and life situation in association with their planning and decision to retire from working life. Method: The thesis includes one qualitative and three quantitative studies conducted in Sweden. Result: Self-rated health was found to be a better measure than diagnosed disease of whether older workers believed they could work until 65 years or beyond. Health seems not to be a general impediment to working in old age if older workers are satisfied with their work situation and have enough time and opportunities to recover from fatigue. In one of Sweden’s most hazardous work environments, older workers were not injured significantly more often than younger workers. Good mental and physical work environment, moderate working pace and working time, and the right competence and possibility for skills development were factors determining whether older workers believed they can extend their working life. Attitude to older workers in the organisation, motivation and work satisfaction were factors determining whether older workers want to extend working life. Health, personal economic incentives, family/leisure pursuits and attitude to pension in society affected both whether people believed they can and wanted to extend their working life. In their final retirement decision, older workers considered: i) their possibility to balance and adapt functional ageing and health to a sustainable work situation; ii) their economic situation; iii) possibilities for social inclusion and coherence; and iv) possibilities for meaningful activities. Whether these requirements were best fulfilled in or outside working life determined the decision to continue working or to retire. Conclusion: If it is desirable for society that people will to extend their working life, both the “can work” and the “want to work” factors need to be met. It is important to provide a good fit inside working life. This requires a focus not only on older workers, but also on organisations and managers in order to provide incentives that keep older workers in the work force.
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| 7. |
- Hosseini Maaf, Bahram
(författare)
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Genetic Characterisation of Human ABO Blood Group Variants with a Focus on Subgroups and Hybrid Alleles
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABO is the most important blood group system in transfusion medicine and transplantation immunology. The ABO blood groups differ by the presence or absence of antigens on RBCs and antibodies in plasma. Accurate determination of ABO status is critical. Genomic typing can increase the precision of blood group determination in complicated cases, e.g. when variant expression of A or B antigen is encountered. The overall aim of this study was to compare the molecular diversity of ABO alleles with various phenotypes, and to contribute to our knowledge of the ABO gene and encoded glycosyltransferases. Novel alleles (six Aweak, eleven Bweak, seven O) were identified containing single-point mutations. Structure/function studies explained the weakening of some B subgroup glycosyltransferases. Two new hybrid Ax alleles were characterised. Analysis of introns 2-5 revealed 44 previously unknown, allele-related polymorphisms that proved valuable allelic markers. These findings enabled localisation of cross-over regions in two other new hybrids: 1) an O1v allele fused with an A2 allele, 2) the novel O1bantu-A2 combination that explained the Abantu phenotype. Phylogenetic and population analyses indicated that O1bantu is a unique and distinct evolutionary lineage so far only found among individuals of African descent. Of clinical importance, a new approach to ABO genotyping was developed that identifies all common alleles, most null and weak A/B subgroups as well as hybrid alleles resulting from recombinational crossing-over events. In summary, 30 novel alleles were identified and characterized, representing 30% of all alleles reported since the start of this study in 2001.
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| 8. |
- Qian, Hong
(författare)
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Regulation of Hematopoietic Stem and Progenitor Cells by Bone Marrow Niche Components
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Throughout the lifespan of an individual, enormous numbers of mature blood cells are generated by hematopoietic stem cells (HSCs) in the bone marrow (BM). The HSC is a cell that can self-renew to maintain the HSC pool and differentiate into all types of mature blood cells. HSCs can also be mobilized out of the BM into blood and can be isolated from different sources including mobilized blood, umbilical cord blood, BM and fetal liver for clinical and experimental purposes. HSCs are widely used as an effective therapy for treatment of hematopoietic and some non-hematopoietic diseases. HSCs reside and develop in the BM in specialized microenvironments, termed niches. However, specific niche components and the molecular mechanisms underlying the regulation of HSC self-renewal, differentiation and migration by the niche remain poorly defined. In the present thesis, we have analysed the interactions of hematopoietic stem and progenitor cells (HSPCs) with niche components and their role in the regulation of HSC migration, self-renewal and differentiation. Specifically, the functional role of integrin receptors in HSPC migration and the role of the blood cell growth factor thrombopoietin (THPO) in HSC maintenance during hematopoietic cell development and after transplantation have been studied. By using both function-blocking antibodies and integrin alpha6 gene-deleted embryos in a mouse transplantation model, we have found that integrin alpha6 receptor, highly expressed on HSPCs, is important for homing of adult HSCs and HPCs to BM in vivo. Furthermore, we have shown that integrin alpha6 receptor is not involved in fetal liver HSC homing and engraftment, whereas it plays a role in fetal liver HPC homing. Importantly, alpha4 was found to be essential for both adult BM and fetal liver HSC and HPC homing. By using functional assays and phenotypic HSC analysis of Thpo-/- mice, we demonstrated that THPO is critically involved in postnatal and post-transplantation HSC maintenance. The distinct role of THPO in postnatal HSC maintenance was accompanied by accelerated HSC cell cycle kinetics in Thpo-/- mice and reduced expression of cyclin-dependent kinases p57Kip2 and p19INK4D. Taken together, we have for the first time provided the evidence that integrin alpha6 functions as a homing receptor for BM HSPCs and fetal liver HPCs, and that THPO regulates the maintenance of postnatal quiescent HSCs, of critical importance to avoid postnatal HSC exhaustion. Notably, our studies on functions of integrin alpha6 and THPO in HSCs emphasize ontogeny related differences in HSC regulation.
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| 9. |
- Borg, Christel
(författare)
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LIVSTILLFREDSSTÄLLELSE HOS ÄLDRE, SÄRSKILT MED NEDSATT FUNKTIONSFÖRMÅGA SAMT INFORMELLA VÅRDARE I relation till hälsa, självkänsla, sociala och ekonomiska resurser i ett svenskt och europeiskt perspektiv
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- I relation till hälsa, självkänsla, sociala och ekonomiska resurser i ett svenskt och europeiskt perspektiv. Knowledge of factors contributing to life satisfaction among older people is needed, both in the context of those with reduced self-care capacity and among healthy older people and those providing help to others. Such knowledge may be helpful in developing primary and secondary interventions. The overall aim of this thesis was to investigate life satisfaction and its relation to factors such as physical and mental health and social and financial resources among people (60?89 years old) with and without reduced self-care capacity in six European countries, and among informal caregivers (50?89 years old) in Sweden. The aim was further to investigate the extent, need and type of support provided or desired among informal caregivers. This is part of the cross-national European Study of Adults? Wellbeing (ESAW) including six European countries N=12 478 (the Netherlands, Luxemburg, Italy, Austria, UK and Sweden). The Older Americans? Resources Schedule (OARS), Life Satisfaction Index Z (LSIZ) and Rosenberg self-esteem scale were used. Study I comprised 522 people (65?89 years old) with reduced self-care capacity, study II comprised 151 informal caregivers with a high caregiving extent, 392 with a low caregiving extent and 1258 non-caregivers from the Swedish sample. In study III 2195 people with reduced self-care countries. The data were analysed by descriptive and inferential statistics using non-parametric statistics, logistic and linear regression. Low life satisfaction (LSIZ) was related to higher age, being a woman, high degree of reduced self-care capacity, living in special accommodations, feeling lonely and poor financial resources. Feeling lonely, reduced self-care capacity, feeling worried, poor health and poor financial resources in relation to needs predicted low life satisfaction (Paper I). Frequent caregivers with a high extent of caregiving had lower LSIZ than those with less frequent caregiving and noncaregivers, while no differences were found between less frequent caregivers and non-care caregivers in LSIZ. Lower LSIZ was associated with not being employed, low social resources, not refreshed after a night's sleep, poor health, and frequent caregiving (Paper II). In paper III it was found that there were differences as well as similarities in factors predicting LSIZ in that self-esteem and overall health were important in all countries among older people with reduced self-care capacity and reduced self care capacity in three of six countries, whilst in paper IV four factors were found to be common in all ESAW countries. The factors were social resources, financial resources, feeling greatly hindered by health problems and low self-esteem. Factors of importance for life satisfaction thus seem to differ depending on the personal situation and social and political system. These differences should be taken into account when outlining and providing preventive, rehabilitative and support for these groups.
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| 10. |
- Buza-Vidas, Natalija
(författare)
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Cytokine Regulation of Hematopoietic Stem Cells and Lymphopoiesis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Large numbers of blood cells need to be continuously replaced in order to sustain the crucial functions of the immune system, oxygen transport and blood clotting. The large diversity of cell types required to maintain the integrity of the blood system are all produced from blood forming or hematopoietic stem cells (HSCs). HSCs have the unique property of self renewal, ensuring life-long replenishment of all the blood cell types. Hematopoietic growth factors, so called cytokines, have previously been demonstrated to be important for the survival and proliferation of committed progenitor cells and development of different blood cell lineages. However, their potential role in regulating HSCs remains to a large degree unresolved. Herein, we provide data that establish the adaptor protein LNK as an important negative regulator of postnatal HSC expansion, acting as an inhibitor of the cytokine Thrombopoietin, known to be important for HSC maintenance and/or expansion. Furthermore, whereas previous studies demonstrated that another cytokine, fms-like tyrosine kinase receptor 3 (FLT3) ligand (FL), is an important regulator of B cell progenitors but has a redundant role in steady state maintenance of mature B cells, we here demonstrate that FL plays a crucial role in the regeneration of not only B cell progenitors but also mature B cells after bone marrow (BM) transplantation and chemotherapy. In addition, through studies of FL-deficient mice we show that FL plays an important role in maintaining conventional B cells with age, but is redundant in maintaining a normal compartment of fetally/postnatally derived B1 and marginal zone B cells. It has been disputed whether FL also is important in HSC regulation. Our present findings establish that FL is not important for regulating HSC maintenance or expansion neither during fetal development or in adult steady state hematopoiesis, nor following BM transplantation or chemotherapy-induced BM ablation. Finally, through identification of a multipotent progenitor in adult BM, with sustained granulocyte-monocyte and lymphocyte potential, but little or no megakaryocyte and erythroid potential, we provide evidence for a strict separation of myelopoiesis and lymphopoiesis, not being the first lineage commitment step of HSCs.
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| 11. |
- Fernebro, Josefin
(författare)
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Soft Tissue Sarcoma Patterns multiplicity, heterogeneity and growth characteristics
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Soft tissue sarcomas (STS) represent a group of rare and heterogenous tumors that optimally should be diagnosed and treated within multidisciplinary teams. This thesis has studied various aspects ? pathological, genetical, and clinical ? of STS. In study I, we demonstrated that 20% of the patients in a population-based series of 818 STS developed second primary malignancies. An increased risk of developing a second malignancy was identified (SMR 1.3; 95% CI=1.0-1.5), with a particularly high risk of developing a second STS (SMR 17.6; 95% CI=8.1-33.5). Study II included 13 patients who had developed at least two primary STS and we applied array-based comparative genomic hybridization to study the genetic profiles of these tumors. Cluster anaysis and comparison between the genetic profiles suggested that 8 cases represented second primary STS, whereas 5 cases likely represented soft tissue metastases. In study III cDNA microarray was applied to 26 synovial sarcomas and identified differentially expressed genes in relation to gene fusion type. Among the discriminators were several genes that have previously been found to be up-regulated in SS, including AXL, ZIC2, SPAG7, AGRN, FOXC1, NCAM1. In study IV we assessed the impact of targeting peripheral versus central tumor areas using tissue microarray-based staining for Ki-67 in leiomyosarcomas and demonstrated that the Ki-67 expression was higher in the tumor periphery in 18/25 tumors. These observations suggest that Ki-67 evaluation for prognostic purposes should be standardized regarding the part of the tumor investigated. In study V, peripheral tumor growth pattern was evaluated on preoperative MRI with correlations to microscopical growth pattern and prognosis. All tumors with diffuse infiltration on MRI also showed microscopical infiltration, whereas MRI failed to identify infiltration in one-third of the microscopically infiltrative tumors. Diffusely infiltrative growth on MRI correlated with prognosis with a 2.5 times increased risk of metastases (p=0.01) and a 3.7 times higher risk of local recurrence (p=0.02). In summary, we have demonstrated that patients with STS are at increased risk of developing second primary tumors, including STS, with genetic profiles supporting independent tumor origin. We have also demonstrated that the underlying gene fusion type in synovial sarcoma influence the gene expression profile. Finally, the tumor periphery seems to provide the best information; our studies suggest that evaluation of Ki-67 staining should be standardized, perhaps to the periphery, and that MRI-based classification of the peripheral tumor growth pattern may provide prognostic information
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| 12. |
- Francis, Princy
(författare)
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Genetic Profiling in Soft Tissue Sarcoma
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Soft tissue sarcomas (STS) are a heterogeneous group of highly malignant mesenchymal tumors that account for ~1% of all malignancies. Frequent heterogeneity and pleomorphism along with suboptimal diagnostic reproducibility and insufficient prognostic markers make clinical management of these tumors difficult. This thesis has applied microarray-based gene expression and copy-number profiling to STS. The studies provide clues to the genetic pathways involved in STS development and identify profiles linked to diagnosis and prognosis. The results from Study I that concerns intratumor versus intertumor heterogeneity of gene expression profiles in malignant fibrous histiocytoma (MFH) and leiomyosarcoma (LMS), suggest that intratumor heterogeneity may be particularly relevant in small tumor series and thus serve as a reminder to run larger sample sets for increased reliability. Study II established expression patterns related to the SS18-SSX fusion variants and metastatic potential in synovial sarcoma (SS). The differential expression of various developmental genes, transcription factors, histones, and metallothioneins suggests that the gene fusion variants have distinct downstream effects. In Study III, 177 STS of mixed histopathological subtypes were profiled using cDNA microarrays. Distinct gene expression patterns were identified in subtypes with specific translocations or mutations. Herein, frequent upregulation of developmental genes, from e.g. the Wingless and Hedgehog signaling pathways, was demonstrated. The more pleomorphic STS showed overexpression of genes involved in proliferation, adhesion, motility and protein degradation. Moreover, a prognostic signature partly characterized by hypoxia-related genes was identified within the pleomorphic STS. Study IV applied array-based comparative genomic hybridization in MFH and LMS, and demonstrated extensive genetic complexity with multiple recurrent gains and losses, novel amplifications and homozygous deletions. Losses in chromosomal regions 6q14 and 7q36 provided prognostic information independent of previously established risk factors. In summary, these studies demonstrate the potential of genetic profiling in STS and herein, define intratumor heterogeneity, demonstrate that gene fusion variants in SS yield different downstream effects, identify diagnostic and prognostic subsets within STS, and in the pleomorphic tumors, discern prognostically important alterations within the plethora of genetic aberrations that characterize many STS.
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| 13. |
- Halvarsson, Britta
(författare)
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Morphological Features and Mismatch Repair in Colorectal Tumors
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein. The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V). In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to >95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas. Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.
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| 14. |
- Holmberg, Anna H
(författare)
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Risk faktors for fracture in middle-aged men and women
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The number of fractures is increasing worldwide, and fractures frequently cause long-term disability, impaired quality of life and sometimes death. The Malmö Preventive Project, a population-based, prospective study, consisting of 22 444 men, mean age 44 and 10 902 women, mean age 50 years, provides data for evaluation of common public health conditions, such as fracture and diabetes. The follow-up was 19 and 15 years for men and women, respectively. Multiple risk factors for fracture were identified. In women, the most important risk factors were advancing age (relative risk RR 1.56, Confidence Interval 95% 1.45-1.68), previous fracture (RR 2.00, CI 95% 1.56-2.58) and diabetes (RR 1.87, CI 95% 1.26-2,79). In men, advancing age (RR 1.19, CI 95% 1.12-1.26), mental health problems (RR 1.92, CI 95% 1.47-2.51), increased levels of ? glutamyl transferase (RR 1.24, CI 95% 1.18-1.31) and diabetes (RR 2.38, CI 95% 1.65-3.42) were major risk contributors. Impaired glucose tolerance, evaluated through an oral glucose tolerance test, was in both genders associated with a substantially decreased risk of fractures, independent of age, BMI and smoking. This thesis has identified multiple risk factors for low-energy fracture, in both men and women, highlighting diabetes and mental health problems as major contributors in this age group. Current management strategies and therapeutic guidelines are not addressing a number of the identified risk factors. Subsequently, risk assessment can be substantially improved by adding these risk factors to intervention algorithms for middle-aged individuals.
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| 15. |
- Jones, Helena
(författare)
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THE ROLE OF PHOSPHODIESTERASE 3B IN CAMP-MEDIATED REGULATION OF INSULIN SECRETION
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes mellitus (T2DM) is characterized by various combinations of ?-cell failure and insulin resistance leading to hyperglycemia and glucose intolerance. In order to maintain glucose tolerance in the insulin resistance state, increased insulin secretion is a requirement and it is because of inadequate islet adaptation that glucose intolerance develops in T2DM. The pathophysiology of T2DM is not fully understood and more knowledge is needed concerning both insulin action and ?-cell physiology and adaptation. The general aim of this thesis was to investigate the role of ?-cell cAMP-degrading phosphodiesterase 3B (PDE3B) in the regulation of insulin secretion and whole body energy homeostasis. The specific aims were (i) to study the physiological importance of well-regulated ?-cell-cAMP levels for insulin release and whole body energy homeostasis during a long-term metabolic challenge, (ii) to evaluate the role of PDE3B in biphasic insulin secretion and its intracellular localization, and (iii) to investigate the mechanisms for regulation of PDE3B activity in ?-cells. It was previously shown that PDE3B attenuates glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) potentiated-insulin secretion. It is shown here that accurate regulation of ?-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance. This finding is coupled to the novel discovery that PDE3B, shown to localize to the exocytotic machinery, functions as a specific attenuator of cAMP-mediated potentiation of depolarization-induced insulin secretion. Further, we have begun to elucidate the details concerning the regulation of PDE3B activity in ?-cells. Data are presented suggesting that PDE3B activity in ?-cells is intricately regulated by phosphorylation and dephosphorylation, probably by the action of several differentially regulated kinases and phosphatases. In conclusion, this thesis contributes to the knowledge regarding the importance and function of cAMP-mediated regulation of stimulus-secretion coupling in pancreatic ?-cells and demonstrates that dysfunction of cAMP-PDE3B signalling results in a substantially increased sensitivity to the adverse effects of a high-fat diet.
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| 16. |
- Jönsson, Göran
(författare)
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Studies on hereditary C2 deficiency: Frequent occurrence of severe infections, atherosclerosis and rheumatological manifestations
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The complement system is a part of the innate immunity and is essential in the defence against microorganisms. Hereditary C2 deficiency (C2D) is one of the most common complement deficiency states with an estimated prevalence of 1:20,000 in persons of Western descent. In the present investigation, the identification of more than 40 C2D persons at a single centre combined with long observation periods provided a unique basis for assessment of C2D-associated manifestations and diseases. The predominant clinical manifestation was severe bacterial infections. The infections were mainly caused by Streptococcus pneumoniae. Repeated infections occurred primarily during infancy and childhood. On the other hand, about 25-30 % of the C2D persons remained healthy during the observation period. Immunological factors as IgG subclass levels, GM allotypes, complement proteins, and Fc receptors were assessed to explain this difference. Homozygosity for the G2M*n allele was strongly associated with protection against severe infections (p<0.001). This indicated that an efficient antibody response to polysaccharide antigens is of great importance in C2D. Mannan-binding lectin deficiency also contributed to the susceptibility to infection. The association between C2D and systemic lupus erythematosus (SLE) was confirmed, but notably the severity of SLE in patients with C2D was similar to that of other SLE patients. Another novel finding was a high occurrence of anti-cardiolipin antibodies (aCL) and antibodies to the collagen-like region of C1q. Both autoantibodies have a pro-atherosclerotic effect that might explain the high occurrence of cardiovascular disease found in the cohort. Interestingly, anti-phospholipid syndrome was not observed despite the high occurrence of aCL. Vaccination in 25 C2D persons resulted in antibody responses which show that C2D persons benefit from vaccination against infections caused by encapsulated bacteria such as pneumococci.
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| 17. |
- Kronblad, Åsa
(författare)
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Role of cyclin D1 as an estrogen receptor cofactor and the influence of hypoxia on estrogen receptor regulation, with focus on prognositic and treatment predictive features in breast cancer
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Estrogen receptor (ER) status can define breast cancer patients who would benefit from adjuvant tamoxifen therapy. However, resistance to tamoxifen is often observed and possible mechanisms may be loss or reduction of ER, dysfunctional ER- signaling and ligand independent activation of the receptor. Hypoxia and hypoxia inducible factor-1? (HIF-1) expression has been correlated to loss of ER in breast tumors. Cyclin D1, initially described as a cell cycle regulator, might also function as a cofactor to ER inducing ligand independent activation of the receptor. We therefore determined the relation between ER, cyclin D1 and HIF-1 expression in primary breast tumors and cell lines. Further, the prognostic and treatment predictive value of cyclin D1 and HIF-1 was analyzed in breast cancer patients receiving two years of tamoxifen versus no adjuvant treatment. The results indicated that ER heterogeneity in primary breast tumors was associated with cyclin D1 and HIF-1 expression. Further, breast cancer patients with cyclin D1 high tumors did not benefit from tamoxifen treatment. The survival for untreated patients with cyclin D1 high tumors was nevertheless slightly better than for patients with cyclin D1 low tumors. Hypoxia was also strongly linked to ER downregulation in DCIS and invasive breast cancer and caused ER downregulation in breast cancer cell lines. Interestingly, hypoxic cells were less differentiated, showing changes in morphology, proliferation and cytokeratin 19 expression. The hypoxia induced ER reduction was due to both proteasomal degradation and decreased transcription and active extracellular regulated kinase (ERK1/2)was involved in the transcriptional regulation of ER. Consequently, tamoxifen treatment did not affect proliferation as efficiently in hypoxia as in normoxia, but ERK1/2 inhibitors efficiently increased the tamoxifen effect in hypoxia. Unexpectedly, tumor specific HIF-1 expression was not a predictive marker for tamoxifen response in premenopausal breast cancer patients but associated with a worse recurrence free survival. These results suggest that cyclin D1 is a predictive marker for tamoxifen resistance and HIF 1 a marker of poor prognosis in breast cancer. Targeting cyclin D1 and/or ERK1/2 in conjunction with tamoxifen represent new treatment strategies for improving the tamoxifen response.
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| 18. |
- Link, Katarina
(författare)
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Childhood malignant disease and consequences for growth hormone secretion, intellectual function and cardiovascular risk
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In childhood onset growth hormone deficiency (GHD) a reduction in cardiac left ventricular mass (LVMi) and impairment of cardiac systolic function, as well as in glomerular filtration rate (GFR) has been shown. In study I, we showed that a low dose of GH treatment for 10 months resulted in increased LVMi and kidney size. No significant improvement in cardiac systolic function or GFR, except for a normalisation in GFR in 3 patients, was recorded. Hypopituitary patients receiving conventional hormone treatment, but without GH replacement, have an increased mortality from cardiovascular disease and a reduced insulin sensitivity. Hypothalamic-pituitary hormone insufficiencies are well known consequences of cranial radiotherapy (CRT) and CRT has previously been part of treatment regimens in childhood acute lymphoblastic leukemia (ALL) to prevent central nervous system relapses. A decline in intellectual function has been shown 4-8.5 years after treatment with18-24 Gy of CRT in childhood ALL patients, but information on longer follow-up is missing. In study II, we aimed to investigate cardiovascular risk factors in former ALL patients, and in study III to evaluated insulin sensitivity before and after 12 months of GH treatment. In study IV, we evaluated neuropsychological performance and self-rated mental well-being. All comparisons were made with matched population controls. Further, the impact of 12 months of GH treatment on neuropsychological test scores was evaluated. We have shown that, at a median 17 years after treatment with CRT and chemotherapy, the former ALL had an increase in cardiovascular risk factors, including dyslipidemia, increased fibrinogen levels, insulin resistance, increase in fat mass and decrease in lean mass, and a marked reduction in cardiac dimensions and performance. We suggested that GH deficiency (GHD), induced by CRT is a primary cause, because 91% of the former ALL patients were GHD, and strong correlations between stimulated GH secretion and several of the cardiovascular risk factors were recorded. GH treatment for 12 months had positive effects on body composition, but no significant improvement on insulin sensitivity was recorded. There was no difference in the self reported quality of life, but significantly lower scores in neuropsychological performance was recorded in former ALL patients, where early age at treatment had a strong negative impact on test scores. GH treatment for one year, in a subset on former ALL patients, did not improve neuropsychological performance. In study V, we showed that the GHRH-arginine test can not be used to rule out GHD due to its low negative predictive value (27%), but a failed GH response accurately reflects the presence of radiation induced GHD, illustrated by a high positive predictive value (91%).
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| 19. |
- Magnusson, Mattias
(författare)
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The Role of Hox Transcription Factors in the Regulation of Hematopoiesis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hematopoiesis is a lifelong, dynamic process, originating from a low number of hematopoietic stem cells (HSCs) residing in the adult bone marrow with the ability to self-renew and generate all blood lineages throughout life. Recent findings have demonstrated that the Homeobox (Hox) transcription factors are important regulators of both normal and malignant hematopoiesis, controlling proliferation, differentiation and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. This thesis focuses on the role of HOXA10 and Hoxb4, and its interaction with Hoxb3, Hoxa9 and the cell cycle regulator p21 in hematopoiesis. These Hox-genes are all expressed in the HSC compartment, and are then downregulated upon differentiation. In support of this, overexpression of HOXB4 is known to strongly increase HSCs self-renewal in vivo and in vitro. To investigate the physiological role of Hoxb4 we generated a Hoxb4 and a Hoxb3/Hoxb4 knockout mouse model and found that HSCs lacking Hoxb4 exhibit a reduction in their proliferative response to hematopoietic stress. This phenotype was slightly enhanced by the additional deletion of the neighboring gene Hoxb3, demonstrating redundancy of function between these genes. We further explored the complex interactions within the Hox clusters by generating a triple knockout lacking Hoxa9/b3/b4. However, the reconstitution ability of Hoxa9/b3/b4 knockout HSCs did not decline beyond the repopulating defect seen in Hoxa9 knockout HSCs. Using retroviral gene transfer we found that overexpression of HOXB4 in p21 deficient HSC further enhanced the HSCs self-renewal effect in vitro, demonstrating that temporary overexpression of HOXB4 and suppression of p21 could be useful for future HSC expansion protocols. The expression level of HOXB4 is crucial for the HSC fate decisions and to delineate the role of HOXA10 in hematopoiesis, we generated an inducible mouse model for HOXA10. Our findings from this study demonstrate that HOXA10 acts as a master regulator of hematopoiesis governing both proliferation and differentiation of hematopoietic progenitor and stem cells, through direct regulation of the genes Gfi-1, Dkk-1, HLF and Gata-1, where distinct fate outcomes depend on the HOXA10 concentration. In summary, our findings unravel new interactions and molecular pathways acting within, or downstream of Hox genes to regulate hematopoietic progenitor and stem cells.
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| 20. |
- Mark, Linda
(författare)
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Structural and functional studies of novel viral complement inhibitors
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Viruses have developed several strategies to evade the complement system, a part of the immune system. The fourth open reading frame of the human virus Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a type 1 transmembrane protein. This contains four complement control protein domains (CCP domains), and is thus structurally similar to human complement inhibitors. We named it KSHV complement control protein (KCP). Using recombinant KCP, we showed that it can inhibit the complement system by disrupting a key enzymatic complex, the C3 convertase. We predicted the 3D structure of KCP by homology modeling. Functionally important sites in KCP were mapped using mutants where either one to three amino acids, or entire CCP domains, were altered. We also found that a patch of positively charged amino acids in CCP 1-2 of KCP can bind to heparin and weakly to heparin like proteoglycans at the surface of cells, which seems to aid the virus in the attachment step prior to cell entry. In order to study the biological role of complement inhibition for this type of virus, we want to use the KSHV homologue rhesus rhadinovirus (RRV), since this virus is both technically easier to work with than KCP and also permits in vivo studies, by naturally infecting Rhesus Macaques. RRV complement control protein (RCP) is the KCP homologue in RRV. We have characterized its gene, confirmed that RCP is expressed and present on the surface of virus and performed experiments indicating that it is a functional complement inhibitor.
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| 21. |
- Rydengård, Victoria
(författare)
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ANTIMICROBIAL ACTIVITIES OF HISTIDINE-RICH GLYCOPROTEIN AND CATIONIC PEPTIDES
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In an environment full of potential pathogens it is of importance for organisms to mount a fast and effective defence. Antimicrobial peptides are ancient and integral effector molecules of the innate immune system. They are found in all kinds of species from bacteria to plants and animals, indicating their importance during evolution. They possess a broad-spectrum antimicrobial activity and some peptides can also participate in wound healing and connect the innate and adaptive immune systems. Results presented in this thesis show that structural motifs connected with heparin-binding may confer antimicrobial activity to a given peptide. Peptides from various heparin-binding endogenous proteins exerted antimicrobial activity against Gram-positive and Gram-negative bacteria and similar results were obtained with consensus sequences for heparin-binding. Furthermore, we demonstrated that replacement of lysine and arginine by histidine in the consensus motifs abrogated the antibacterial effects of these peptides. Antibacterial effects of the histidine-rich consensus peptides were restored by the addition of Zn2+ or low pH. Similar results were obtained with histidine-rich peptides derived from domain 5 of kininogen and histidine-rich glycoprotein (HRGP). HRGP, an abundant heparin-binding plasma protein, exerted antimicrobial effects against Gram-positive and Gram-negative bacteria and fungi. The antibacterial activity of HRGP was dependent on Zn2+-ions or low pH, and the antifungal activity was increased under low pH conditions. Electron microscopy demonstrated that HRGP induced lysis of bacteria and fungi. Truncated HRGP, devoid of the heparin-binding and histidine-rich domain, was not antimicrobial. In addition, HRGP was found to have antifungal effects ex vivo when bound to fibrin clots.
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| 22. |
- Werntoft, Elisabet
(författare)
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Older people's views of prioritisation and resource allocation in health care
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate older people's views and experience of prioritisation and resource allocation in health care, which is important because older people are the group that use public health care and service most. The aim was also to investigate differences in the view of prioritisation and resource allocation in relation to age, gender, housing, health-related quality of life, financial situation and degree of dependency between the participants receiving and those not receiving care and service. A further aim was to describe older people's reasoning about prioritisation in health care. The sample was identified in a longitudinal cohort study in southern Sweden called Good Ageing in Skane (GAS), 902 participants not receiving care and service, aged 60?93 years, and 146 participants receiving care and service, aged 66?100 years. Data were collected in personal interviews based on a questionnaire. The total sample was divided into the age groups young-old (60?75 years), old-old (76?84 years) and oldest old (85?100 years). Quantitative descriptive statistics, comparative statistics and multinomial and multiple logistic regression analyses as well as qualitative analyses were used when analysing the data. Eighty-one percent of the participants not receiving care and service and 85 % of the participants receiving care and service did not want age to be a criterion for prioritisation (Papers I and III) but their reasoning revealed that they experienced that being old meant low priority (Paper IV). In their reasoning the participants saw prioritisation as a necessity but also emphasised that all people are of equal value and that everyone should have the same rights to health care regardless of age (Paper IV). It was clearly stated that the participants wanted physicians to decide who should be prioritised (Papers I and III). The findings also showed that the oldest-old and men prioritised younger people to a higher extent than the other two age groups, while women prioritised older patients to a higher extent (Paper I). The participants not receiving care and service were furthermore reluctant to give priority to treatment for lifestyle-related diseases than participants receiving care and service (Framework). The participants? reasoning in relation to the willingness to pay for treatment revealed that they experienced that buying treatment requires wealth (Paper IV). Most of the participants not receiving care and service (63 %) but only 48 % of participants receiving care and service wanted to pay ?1100 to get cataract surgery at once instead of being on a waiting list for 18 months, but significantly fewer participants receiving care and service actually had access to ?1500 (p<0.001) (Framework). Women were also less willing to pay for treatment than men, which also seemed to be associated with a worse economic situation (Paper II). The results showed that older people did not emphasise age as a criterion for prioritisation, which is in contrast to earlier studies including younger people. This thesis further showed that age, gender, financial situation and receiving care and service or not, influenced the way the respondents viewed prioritisation and resource allocation, while housing, grade of dependency and HRQoL seemed to have limited influence.
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| 23. |
- Flansbjer, Ulla-Britt
(författare)
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STRENGTH TRAINING AFTER STROKE: EFFECTS ON MUSCLE FUNCTION, GAIT PERFORMANCE AND PERCEIVED PARTICIPATION
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to evaluate the effects of strength training on muscle function, gait performance and perceived participation in subjects with chronic mild to moderate post-stroke hemiparesis. A main impairment after stroke is reduced muscle strength. This post-stroke weakness is a major contributor to mobility limitations, which can prevent the resumption of activities of daily living and have an adverse effect on perceived participation: persons? lived experiences of involvement in their life situation. Improving muscle function is important in stroke rehabilitation, but strengthening exercises have been controversial due to the hypothesized risk of increasing muscle tone. To be able to evaluate changes following strength training, we need equipment and methods that provide reliable measurements of muscle strength and gait performance and also an increased knowledge about the relationships between muscle strength, gait performance and perceived participation in chronic post-stroke subjects. In the first two studies the reliability of different tests, assessing isokinetic knee muscle strength and gait performance, was evaluated. In the third study the relationships between isokinetic knee muscle strength, gait performance and perceived participation were analysed. The 50 subjects participating in these studies (mean age 58 ±6.4 years, 6-46 months post-stroke) were able to walk independently, and could understand both verbal and written information. The results showed that all measurements for isokinetic knee muscle strength and gait performance were reliable and for each measurement, limits were set to detect real improvements following an intervention. The relationship between knee muscle strength in the paretic knee muscles and gait performance was significant, and gait performance was in turn related to perceived participation. This indicates that improvements in knee muscle strength could have a potential effect on gait performance and perceived participation. To evaluate changes following an intervention, both isokinetic knee muscle strength measurements and gait performance tests are reliable and sensitive enough to detect real (clinical) improvements. In the fourth study the effects of progressive resistance training (PRT) on knee muscle function, gait performance and perceived participation were evaluated. Twenty-four subjects (mean age 61 ±4.9 years) participated in this single-blinded randomised controlled study (ratio 2:1 training/control). All subjects were more than 6 months post stroke, could understand both verbal and written information, had muscle weakness greater than 15% in the paretic knee muscles (mean isokinetic peak torque at 60°/s) and were able to walk independently. The intervention consisted of PRT for the knee extensor and flexor muscles twice weekly, for ten weeks, at a load about 80% of maximum strength (6-8 reps, in 2 sets). Measurements of knee muscle strength, muscle tone, gait performance and perceived participation were performed before and after the intervention. The results showed that ten weeks of PRT significantly improved knee muscle strength, without any increase in muscle tone. Gait performance improved, with slow walkers at baseline having the best gains. Improvements in gait performance were, furthermore, related to improvements in perceived participation. For the control group there were some improvements in gait performance, but low or no increase in knee muscle strength and perceived participation. In conclusion, PRT improves knee muscles strength and gait performance, without any negative effects on muscle tone and improvements in gait performance, in turn, positively affects perceived participation. Thus, PRT is an effective form of training in chronic stroke patients that can be used both as physiotherapy treatment for those with residual hemiparesis and as fitness training for those with a minor disability.
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| 24. |
- Nilsson, Lisbeth
(författare)
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Driving to Learn. The process of growing consciousness of tool use - a grounded theory of de-plateauing.
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Driving to Learn project explored possible achievements of training people with cognitive disabilities in a joystick-operated powered wheelchair utilizing the grounded theory approach. Theoretical sampling led the concomitant collection and analysis of data. During a period of 12 years, 45 participants with profound cognitive disabilities, aged 12 months to 52 years, were engaged in the project. Typically developed infants and participants with less degree of cognitive disabilities formed two reference groups. Data sources were video-recordings, field notes, interviews and information from medical records. Constant comparative analyses led the emergence of an eight-phase process of growing consciousness of tool-use, training strategies, a tool for assessment of joystick-use and identification of factors influencing the outcome of the training. The tool was tested for inter-rater reliability and used to evaluate the outcome of the 45 participants. Growing consciousness was by amplification conceptualised to a grounded theory of de-plateauing. Attainment of de-plateauing was reliant on the interdependent properties motivation, endurance, responsiveness, adaptability and access to resources with high predictability and usability. De-plateauing was defined as a positional change exceeding preconceived expectations. I argue that the grounded theory of de-plateauing might be useful in many more fields, where the phenomenon of plateauing attitudes is present either explicitly or implicitly.
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| 25. |
- Roybon, Laurent
(författare)
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Stem Cell Plasticity Controlling Neuronal Differentiation Prior to Cell Transplantation
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson's disease (PD) is the second most common neurodegenerative disease and affects 2% of the population over 65 years of age. The disease is characterized by the progressive loss of dopaminergic neurons. Over time, symptoms increase and, in particular, lead to a dramatic slowness of movements. Unfortunately, when the fi rst symptoms are discovered, more than 50% of the dopaminergic neurons are already dead. Until now, endogenous neural precursors, derived from the patients? own brains, have not been found proliferate and differentiate into to dopamine neurons that can reverse the symptoms of the disease. Therefore it is necessary to transplant neurons in order to replace those lost due to the disease. The fi rst benefi cial effect of cell therapy in PD patients grafted with fetal nigral tissue was reported in 1990. To date, around 400 patients have been transplanted worldwide. However, due to post-surgery complications, lack of donor tissue and unpredictable variability in the outcome of the surgery, clinical trials were stopped in the late 90ies (Bjorklund et al., 2003). In the early 90?s, the concept of neural stem cells as source of cells for cell replacement therapies emerged. The culture of single neural stem cells, in vitro, could lead to the formation of an entire neural lineage (Reynolds and Weiss, 1992; Reynolds and Weiss, 1996). Rapidly, researchers investigated the potential of such cells to be used as cell replacement therapy for neurological disorders. Thus, all types of stem cells, including neural stem cells, embryonic stem cells and later bone marrow stem cells were subjected to extensive experimental work aiming to generate specifi ed neuronal subtypes for transplantation purposes. Most of the work was dedicated to the generation of dopaminergic neurons. The studies we have performed for this thesis aimed at improving and understanding differentiation of these different types of stem cells into neurons, especially dopaminergic neurons. Using different protocols we assessed the potential of the hematopoietic stem cells, which are non-neuronal committed stem cells, to cross lineage boundaries and transdifferentiate into neural cells. We investigated whether gene overexpression could override the intrinsic programs of regionalized and specifi ed neural stem cells and redirect their differentiation toward a dopaminergic fate. The studies we performed indicate that lineage commitment and regional identity are barriers to stem cell plasticity. We fi nally assessed the differentiation potential of human pluripotent embryonic stem cells and found that time-dependant predifferentiation is required for safe transplantation of human embryonic stem cells-derived cells into the brain. In general, we concluded that the current methods for generating midbrain dopaminergic neurons from hematopoietic, neural and embryonic stem cells are diffi cult and need further improvements to make these stem cells good candidates of cells to be successfully used in restorative therapy for neurodegenerative diseases. However, we present promising results for the future use of embryonic stem cells (ESC) for transplantation in neurodegenerative diseases. We speculate that ESC may become the most promising stem cells to be used in the future for neural replacement due to their unlimited capacity of differentiation.
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