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  • af Bjerkén, Sara, 1979- (författare)
  • On dopamine neurons nerve fiber outgrowth and L-DOPA effects
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Parkinson’s disease is a disorder mainly characterized by progressive degeneration of dopamine producing neurons in the substantia nigra of the midbrain. The most commonly used treatment strategy is to pharmacologically restore the lost function by the administration of the dopaminergic precursor L-DOPA. Another treatment strategy is to replace the degenerated neurons with immature fetal ventral mesencephalic tissue, or ultimately stem cell-derived tissue. Grafting trials have, however, revealed poor reinnervation capacity of the grafts, leaving much of the striata dopamine-denervated. An additional drawback is the upcoming of dyskinesia (involuntary movements), a phenomenon also observed during L-DOPA treatment of Parkinson’s disease patients. Attempts to characterize nerve fiber formation from dopamine neurons have demonstrated that the nerve fibers are formed in two morphologically diverse outgrowth patterns, one early outgrowth seen in the absence of astrocytes and one later appearing outgrowth seen in co-existence with astrocytes.</p> <p>The overall objective of this thesis has been to study the dopaminergic outgrowth including guidance of nerve fiber formation, and to look into the mechanisms of L-DOPA-induced dyskinesia. The first paper in this thesis characterizes the different outgrowth patterns described above and their relation to different glial cells. The study demonstrated the two different outgrowth patterns to be a general phenomenon, applying not only to dopamine neurons. Attempts of characterization revealed no difference of origin in terms of dopaminergic subpopulations, i.e. A9 or A10, between the outgrowth patterns. Furthermore, the “roller-drum” technique was found optimal for studying the dual outgrowth sequences.</p> <p>The second and the third paper also utilized the “roller-drum” technique in order to promote both patterns of neuronal fiber formation. The effects of glial cell line-derived neurotrophic factor (GDNF) on the formation of dopamine nerve fibers, was investigated. Cultures prepared from gdnf knockout mice revealed that dopaminergic neurons survive and form nerve fiber outgrowth in the absence of GDNF. The dopaminergic nerve fibers exhibited an outgrowth pattern consistent with that previous observed in rat. GDNF was found to exert effect on the glial-associated outgrowth whereas the non-glial-associated was not affected. Astrocytic proliferation was inhibited using cytosine β-D-arabinofuranoside, resulting in reduced glial-associated outgrowth. The non-glial-associated dopaminergic outgrowth was on the other hand promoted, and was retained over longer time in culture. Furthermore, the non-glial-associated nerve fibers were found to target the fetal frontal cortex. Different developmental stages were shown to promote and affect the outgrowths differently. Taken together, these data indicate and state the importance of astrocytes and growth factors for neuronal nerve fiber formation and guidance. It also stresses the importance of fetal donor age at the time for transplantation.</p> <p>The fourth and fifth studies focus on L-DOPA dynamics and utilize in vivo chronoamperometry. In study four, 6-OHDA dopamine-depleted rats were exposed to chronic L-DOPA treatment and then rated as dyskinetic or non-dyskinetic. The electrochemical recordings demonstrated reduced KCl-evoked release in the intact striatum after chronic L-DOPA treatment. Time for maximal dopamine concentration after L-DOPA administration was found to be shorter in dyskinetic animals than in non-dyskinetic animals. The serotonergic nerve fiber content in the striatum was evaluated and brains from dyskinetic animals were found to exhibit significantly higher nerve fiber density compared to non-dyskinetic animals. Furthermore, the mechanisms behind the conversion of L-DOPA to dopamine in 6-OHDA dopamine-depleted rats were studied. Local administration of L-DOPA in the striatum increased the KCl-evoked dopamine release in the intact striatum. Acute application of L-DOPA resulted sometimes in a rapid conversion to dopamine, probably without vesicle packaging. This type of direct conversion is presumably occurring in non-neuronal tissue. Furthermore, KCl-evoked dopamine releases were present upon local application of L-DOPA in the dopamine-depleted striatum, suggesting that the conversion to dopamine took place elsewhere, than in dopaminergic nerve fibers. In conclusion, these studies state the importance of astrocytes for neuronal nerve fiber formation and elucidate the complexity of L-DOPA conversion in the brain.</p>
  • Ahlm, Clas, 1956- (författare)
  • Distribution of puumala virus in Sweden
  • 1997
  • Ingår i: digitalisering@umu. - Umeå : Umeå universitet. - 91-7191-404-8
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Puumala virus, belonging to the genus hantavirus, is the causative agent of nephropathia epidemica (NE), a relatively mild form of hemorrhagic fever with renal syndrome. Puumala virus occurs endemically in Central and Northern Europe and Western Russia. In Sweden, NE is reported from the northern and central parts but virtually not at all from the southern part of the country. The bank vole (<em>Clethrionomys glareolus</em>) is the main reservoir of Puumala virus and humans are infected by inhalation of aerosolized animal secreta. In northern Sweden, the density of the bank vole population varies cyclically in intervals of 3-4 years and the incidence of NE shows a covariation.</p><p>The prevalence of serum antibodies to hantaviruses in northern Sweden was studied in a stratified and randomly selected adult population sample comprising 1538 subjects. As expected, the prevalence increased with age. There was no difference between men and women, which was unexpected based on a male:female ratio of &gt; 2:1 in clinical reports. By use of an immunofiuorescent assay, a seroprevalence of 5.4% and by a newly developed enzyme-linked immunosorbent assay (ELISA) with recombinant Puumala virus nucleocapsid protein as antigen, a prevalence of 8.9% was recorded. This is about or more than ten times higher than what would be calculated from clinical reports.</p><p>By use of the ELISA, an occupational risk of acquisition of Puumala virus infection was demonstrated. Serum samples from 910 farmers and 663 referent subjects living in various rural parts of Sweden were tested. Among farmers from the Puumala virus-endemic northern and central parts of the country, the seroprevalence (12.9%) was higher (p=0.01) than in referents (6.8%). In the southern part of Sweden, only 2/459 persons had antibodies. Only a limited number of children with NE had been previously reported. In a separate study, 32 children with Puumala virus infection were identified and the clinical picture of NE in children was found to be similar to that of adult cases.</p><p>Variations in the prevalence of Puumala virus in the bank vole population within an endemic region are not well known. Here, a higher mean rodent density and a higher prevalence of Puumala virus-specific serum antibodies were recorded in the vicinity of households afflicted with NE than in rural control areas. The data indicated that the risk of exposure locally within an endemic region may vary widely and tentatively suggested that a threshold density of bank voles might be necessary to achieve before effective spread of Puumala virus within the rodent population may occur.</p><p>There is no firm evidence of the occurrence of Puumala virus among wild living animals other than rodents. A study of Swedish moose, an animal which is ecologically well characterized, was performed. Convincing evidence of past Puumala virus infection was found in 5/260 moose originating from Puumala virus-endemic areas but in none of 167 animals from nonendemic areas. Based on the low seroprevalence recorded, moose seemed to serve as endstage hosts rather than being active parts of the enzootic circle of transmission.</p><p>In conclusion, the present investigations confirmed that the exposure to Puumala virus is geographically well restricted in Sweden. Seroprevalence studies indicated that only a minor proportion of individuals infected with Puumala virus are clinically reported, with a bias in favour of men. NE was confirmed to occur in children, with a clinical picture similar to that of adults. An occupational risk was defined for acquisition of Puumala virus infection. Studies in rodents suggested that there may be wide local variations within a limited area in the risk of exposure to Puumala virus. The studies validated the usefulness of a newly developed ELISA based on recombinant nucleocapsid peptides of hantaviruses and finally, methodological progress was reached when Puumala virus was, for the first time, successfully isolated from a Scandinavian patient.</p>
  • Ahlm, Kristin, 1956- (författare)
  • Traffic and drowning incidents with emphasis on the presence of alcohol and drugs
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Worldwide, fatal traffic injuries and drowning deaths are important problems. The aim of this thesis was to investigate the cirumstances of fatal and non-fatal traffic injuries and drowning deaths in Sweden including analysis of the presence of alcohol and drugs, which are considered to be major risk factors for these events. Data where obtained from the database of National Board of Forensic Medicine.</p><p>In the first study, we investigated 420 passenger deaths from 372 crashes during 1993-1996. There were 594 drivers involved. In total, 21% of the drivers at fault were alcohol positive compared to 2% of drivers not at fault (p&lt;0.001) (Paper I). During 2004-2007, crashes involving 56 fatally and 144 non-fatally injured drivers were investigated in a prospective study from Northern Sweden (Paper II). The drivers were alcohol positive in 38% and 21%, respectively. Psychoactive drugs were found in 7% and 13%, respectively. Benzodiazepines, opiates and antidepressants were the most frequent drugs found in drivers. Illict drugs were found 9% and 4% respectively, with tetrahydrocannabinol being the most frequent of these drugs (Paper II).</p><p>We investigated 5,125 drowning deaths in Sweden during 1992-2009 (Paper III). The incidence decreased on average by about 2% each year (p&lt;0.001). Unintentional drowning was most common (50%). Alcohol was found in 44% of unintentional, 24% of intentional, and 45% of undetermined drowning deaths. Psychoactive substances were detected in 40% and benzodiazepines were the most common substance. Illicit drugs were detected in 10%. Of all drowning deaths, a significantly higher proportion females commited suicide compared with males (55% vs. 21%, p&lt;0.001). Suicidal drowning deaths (n=129) in Northern Sweden were studied further in detail (Paper IV). of these, 53% had been hospitalized due to a psychiatric diagnosis within five years prior to the suicide. Affective and psychotic disorders were the most common psychiatric diagnoses. Almost one third had performed a previous suicide attempt. One fourth had committed suicide after less than one week of discharge from hospital. Alochol was found in 16% and psychoactive drugs in 62% of these cases, respectively. </p><p>In conclusion, alcohol and psychoactive drugs are commonly detected among injured drivers and drowning victims, and probably play a role in these events. Most of the individuals that tested positive for alcohol and high blood concentrations, indicating alochol dependence or abuse. This association warrants futher attention when planning future prevention. </p>
  • Ahmed Hassan Ahmed, Osama, 1972- (författare)
  • Rift Valley fever challenges and new insights for prevention and control using the “One Health” approach
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Rift Valley fever (RVF) is an emerging viral zoonosis that causes frequent outbreaks in east Africa and on the Arabian Peninsula. The likelihood of RVF global expansion due to climate change and human anthropogenic factors is an important issue. The causative agent, RVF virus, is an arbovirus that is transmitted by several mosquito species and is able to infect a wide range of livestock as well as people. The infection leads to mass abortions and death in livestock and a potentially deadly hemorrhagic fever in humans. RVF has severe socio-economic consequences such as animal trade bans between countries, disruption of food security, and economic disaster for farmers and pastoralists as well as for countries. Human behavior such as direct contact with infected animals or their fluids and exposure to mosquito bites increases the risk for contracting the disease.</p><p>To better understand the challenges associated with RVF outbreaks and to explore prevention and control strategies, we used the One Health approach. The local community had to be involved to understand the interaction between the environment, animals, and humans. We focused on Sudan, Saudi Arabia, and Kenya. First, we systematically reviewed the literature and then we performed cross sectional community-based studies using a special One Health questionnaire. Climatic and remote sensing data were used in combination with statistics to develop a sub-region predictive model for RVF.</p><p>For both Saudi Arabia and Sudan, the ecology and environment of the affected areas were similar. These areas included irrigation canals and excessive rains that provide an attractive habitat for mosquito vectors to multiply. The surveillance systems were unable to detect the virus in livestock before it spread to humans. Ideally, livestock should serve as sentinels to prevent loss of human lives, but the situation here was reversed. Differences between countries regarding further spread of RVF was mainly determined by better economic and infrastructure resources.</p><p>In Sudan, there was a lack of knowledge and appropriate practices at the studied community regarding RVF disease symptoms and risk factors for both animals and humans. The community was hesitant in notifying the authorities about RVF suspicion in livestock due to the lack of a compensation system. The perceived role of the community in controlling RVF was fragmented, increasing the probability of RVF transmission and disease.</p><p>In Kenya, our study found that better knowledge about RVF does not always translate to more appropriate practices that avoid exposure to the disease. However, the combination of good knowledge, attitudes, and practices may explain why certain communities were less affected. Strategies to combat RVF should consider socio-cultural and behavioral differences among communities. We also noticed that RVF outbreaks in Kenya occurred in regions with high livestock density exposed to heavy rains and wet soil fluxes, which could be measured by evapotranspiration and vegetation seasonality variables. We developed a RVF risk map on a sub-regional scale. Future outbreaks could be better managed if such relevant RVF variables are integrated into early warning systems.</p><p>To confront RVF outbreaks, a policy is needed that better incorporates ecological factors and human interactions with livestock and environment that help the RVF pathogen spread. Early detection and notification of RVF is essential because a delay will threaten the core of International Health Regulations (IHR), which emphasizes the share of information during a transboundary disease outbreak to avoid unnecessary geographical expansion.</p>
  • Al-Alawi, Kamila, 1974- (författare)
  • Team-based approach in the management of diabetes at primary health care level in Muscat, Oman challenges and opportunities
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Introduction: The growth of type 2 diabetes is considered an alarming epidemic in Oman. The efficient team-based approach to diabetes management in primary health care is an essential component for providing ideal diabetic care. This thesis aimed to explore the current situation related to team-based management of type 2 diabetes in public Primary Health Care Centres (PHCCs) under the Ministry of Health (MOH) in Oman, including the various challenges associated with diabetes management and the most preferable Human Resources for Health (HRH) management mechanism, and to examine how this could be optimized from provider and patient perspectives.</p><p>Materials and methods: The entire project was conducted in Muscat Governorate and was based on one quantitative and three qualitative studies. In the quantitative study, 26 public PHCCs were approached through cross-sectional study. The core diabetes management team recommended by the MOH for PHCCs in Oman was explored in terms of their competencies, values, skills, and resources related to the team-based approach to diabetes management. For the qualitative studies, five public purposely-selected PHCCs were approached. The diabetes consultations conducted by the core members and other supportive members involved in diabetes management were observed and later the Primary Health Care Providers (PHCPs) were interviewed. The different approaches explored challenges related to diabetes management and the most preferable HRH mechanism by PHCPs. Seven type 2 diabetes patients with different gender, employment status, and education were consequently interviewed to explore their perceptions towards the current diabetes management service and their opinions towards nurse-led clinics.</p><p>Results: The survey provided significant and diverse perceptions of PHCPs towards their competencies, values, skills, and resources related to diabetes management. Physicians considered themselves to have better competencies than nurses and dieticians. Physicians also scored higher on team-related skills and values compared with health educators. In terms of team-related skills, the difference between physicians and nurses was statistically significant and showed that physicians perceived themselves to have better skills than nurses. Confusion about the leadership concept among PHCPs with a lack of pharmacological, technical, and human resources was also reported. The observations and interviews with PHCPs disclosed three different models of service delivery at diabetes management clinics. The challenges explored involved PHCCs’ infrastructure, nurses’ knowledge, skills, and non-availability of technical and pharmaceutical support. Other challenges that evolved into the community were cultural beliefs, traditions, health awareness, and public transportation. Complete implementation of task-sharing mechanisms within the team-based approach was selected by all PHCPs as the most preferable HRH mechanism. The selection was discussed in the context of positive outcomes, worries, and future requirements. The physicians stated that nurses’ weak contribution to the team within the selected mechanism could be the most significant aspect. Other members supported the task-sharing mechanism between physicians and nurses. However, type 2 diabetes patients’ non-acceptance of a service provided by the nurses created worries for the nurses. The interviews with type 2 diabetes patients disclosed positive perceptions towards the current diabetes management visits; however, opinions towards nurse-led clinics varied among the patients.</p><p>Conclusions and recommendations: The team-based approach at diabetes management clinics in public PHCCs in Oman requires thoughtful attention. Diverse presence of the team members can form challenges during service delivery. Clear roles for team members must be outlined through a solid HRH management mechanism in the context of a sharp leadership concept. Nurse-led clinics are an important concept within the team; however, their implementation requires further investigation. The concept must involve clear understandings of independence and interdependence by the team members, who must be educated to provide a strong gain for team-based service delivery.</p>
  • Al-Amiry, Bariq, 1976- (författare)
  • Radiological measurements in total hip arthroplasty
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Varje år opereras ungefär 1 miljon patienter runt om i världen och 20,000 patienter i Sverige med en total höftledsprotes (THA). Höftledsprotesoperation anses vara en av de mest framgångsrika, säkra och kostnadseffektiva kirurgiska åtgärderna med ett syfte att smärtlindra, återställa rörligheten och förbättra livskvaliteten. Höftleden drabbas av artros, åldersrelaterad sjukdom som orsakar destruktion av leden. Vid operation med THA är det viktigt att återställa de biomekaniska krafterna runt höftleden med en adekvat så kallad femoral offset (FO), avståndet mellan höftens rörelsecentrum och mitten av bäckenet, postoperativ benlängdsskillnad (BLS) och ett tillfredsställande komponentläge. Den preoperativa planeringen och den postoperativa röntgenbedömningen av dessa parametrar kräver god tillförlitlighet, det vill säga validitet och reproducerbarhet både mellan olika bedömare och vid upprepade mätningar av samma bedömare. Således är radiologiska mätningar före och efter THA oerhört viktiga för att få bästa resultat efter THA. Det finns inte tillräckligt med information i litteraturen om effekten av den preoperativa radiologiska artrosgraden och symptomduration av artrosen på utfallet av THA. Dessutom behövs ytterligare forskning för att studera effekten av obesitas på de radiologiska mätningarna efter THA.</p>
  • Alafuzoff, Irina, 1952- (författare)
  • Histopathological and immunocytochemical studies in age-associated dementias the importance of rigorous histopathological criteria for classification of progressive dementia disorders
  • 1985
  • Ingår i: digitalisering@umu. - Umeå : Umeå universitet.
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Dementia is an age-associated organic brain disorder, recogniz­able by the essential features of psychological or behavioral abnormality associated with permanent dysfunction of the brain interfering with social and occupational functioning.</p><p>There are two clinical and three histopathological forms of dementia 1) primary degenerative dementia, (PDD), or Alzhei­mer's dementia/Senile dementia of Alzheimers type (AD/SDAT) which is associated with clinical features of uniform progres­sion and insidious onset of symptoms and histopathologically i- dentified by the occurrence of neurofibrillary tangles (NFT) and senile/neuritic plaques (SP/NP) in various cortical and subcor- tical regions; 2) vascular dementia, or multi-infarct dementia (MID), which is associated with clinical features of stepwise progress and patchy distribution of deficits, and histopatholo­gically identified by the occurrence of multiple large and/or small haemorrhagic and/or ischaemic infarcts in various cortical and subcortical regions and 3) intermediate form of dementia or "mixed” ("combined") dementia (AD-MID), which is histopatho- logically associated with the coexistance of symptoms and le­sions observed in AD/SDAT and MID, and clinically referred to the MID group. The DSM-III criteria separate the demented into two groups, AD/SDAT and MID, while there are no unique clinical criteria for the AD-MID patients. The clinical diagnosis of dementia according to the DSM-III criteria was shown to be in­sufficient . Histopathological diagnostic criteria were postu­lated by us for 1) pathological changes developing in mentallyunimpaired ageing, 2) AD/ SPAT, 3) MID and 4) AD-MID.</p><p>These histopathological classes could be separated, by means of multivariate data analysis. The pathology in AD-MID was shown not to be merely a linear combination of the AD/SDATand MID pathology.</p><p>Intrathecal synthesis of Ig, oligoclonal bands or other abnormal proteins in the CSF could not be demonstrated in aged non-demen- ted and demented patients.</p><p>The blood-cerebrospinal barrier (B-CSF-B) or blood-brain barrier (BBB) function alters with age and this alteration was shown to be more pronounced in MID and AD-MID patients. In MID and AD-MID patients the BBB alteration involves primarily the grey matter while in AD/SDAT patients the alteration would appear to involve only the white matter. The BBB dysfunction and a possible complement activation, either through antibody-anti- gen activation or other complement activators, was visualized in MID and AD-MID patients as perivascular serum protein depo­sits in the grey matter, always with a capillary in the center. The occurrence of some serum proteins in plaques, and the previously descibed localization of plaques in close relation­ship to the capillaries, suggest that altered BBB function and serum factors may be involved in the etiology and maturation of plaques while the etiology and maturation of tangles may not be directly dependent on these factors, as they were never labelled with any of the antisera studied.</p>
  • Alanentalo, Tomas, 1978- (författare)
  • Optical projection tomography based 3D-spatial and quantitative assessments of the diabetic pancreas
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The gastrointestinal tract comprises a number of digestive organs including the stomach and pancreas. The stomach is involved in the digestion and short term storage of food while the pancreas is a mixed endocrine and exocrine gland which provides the body with hormones and enzymes essential for nutritional utilisation. The pancreas consists of three different cell lineages, acinar, ductal and endocrine cells. The endocrine cells, organised in the islets of Langerhans, are scattered throughout the exocrine parenchyma and regulate blood glucose levels by production of hormones such as glucagon and insulin.</p> <p>The Nkx family of homeodomain proteins controls numerous processes during development. Previous studies have identified two members belonging to the Nkx6 subfamily of Nkx proteins, Nkx6.1 and Nkx6.2. We have described the cloning and embryonic expression pattern of Nkx6.3. All three members of the Nkx6 gene family were shown to be expressed in partially overlapping domains during the development of the gastrointestinal tract and the central nervous system. Nkx6.2 was also identified as a transient marker for pancreatic exocrine cells.</p> <p>Analysing gene expression patterns and morphological features in tissues and organs is often performed by stereologic sampling which is a labour-intensive two dimensional approach that rely on certain assumptions when calculating e.g. β-cell mass and islet number in the pancreas. By combined improvements in immunohistochemical protocols, computational processing and tomographic scanning, we have developed a methodology based on optical projection tomography (OPT) allowing for 3D visualisation and quantification of specifically labelled objects within intact adult mouse organs. In the pancreas, this technique allows for spatial and quantitative measurements of total islet number and β-cell mass. We have further developed a protocol allowing for high resolution regional analyses based on global OPT assessments of the pancreatic constitution. This methodology is likely to facilitate detailed cellular and molecular analysis of user defined regions of interest in the pancreas, at the same time providing information on the overall disease state of the gland.</p> <p>Type 1 diabetes mellitus (T1D) can occur at any age and is characterized by the marked inability of the pancreas to secrete insulin due to an autoimmune destruction of the insulin producing β-cells. Information on the key cellular and molecular events underlying the recruitment of lymphocytes, their infiltration of the islets of Langerhans and consequent β-cell destruction is essential for understanding the pathogenesis of T1D. Using the developed methodology we have recorded the spatial and quantitative distribution of islet β-cells and infiltrating lymphocytes in the non obese diabetic (NOD) mouse model for T1D. This study shows that the smaller islets, which are predominantly organised in the periphery of the organ, are the first to disappear during the progression of T1D. The larger islets appear more resistant and our data suggest that a compensatory proliferative process is going on side by side with the autoimmune-induced β-cell destruction. Further, the formation of structures resembling tertiary lymphoid organs (TLOs) in areas apparently unaffected by insulitis suggests that local factors may provide cues for the homing of these lymphocytes back to the pancreas.</p>
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