| 1. |
- Abbo, Catherine
(författare)
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Profiles and outcome of traditional healing practices for severe mental illnesses in two districts of Eastern Uganda
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The WHO estimates that more than 80% of African populations attend traditional healers for health reasons. However, little is known about the profiles and outcome of this traditional approach to treatment of mental illnesses. Main Objective: The purpose of this study was to describe the profiles and outcome of traditional healing practices for severe mental illnesses in Jinja and Iganga districts in the Busoga region of Eastern Uganda. Methods: Four studies were conducted (I-IV). Study I used Focus Group Discussions with Case Vignettes with local community members and traditional healers to explore the lay concepts of psychosis. Studies II and III concerned a cross-sectional survey of patients above 18 years at the traditional healer s shrines and study IV was made on a prospective cohort of patients diagnosed with psychosis in study III. Manual content analysis was used in study I; quantitative data in studies II, III and IV were analyzed at Univariate, Bivariate and Multivariate levels to determine the association between psychological distress and socio-demographic factors; for study IV, factors associated with outcome were analyzed. One-way ANOVA for independent samples was the analysis used in Study IV. Results: The participants differentiated schizophrenia (eddalu, ilalu) from mania (kazoole) and psychotic depression (described as illness from too much thinking), describing the symptomatology and natural course. Clan/family/cultural issues were mentioned as causing schizophrenia and psychotic depression, while physical causes and a failed relationship with God were mentioned for mania. Other causes were witchcraft, genetics and substance misuse. Choice of care depended on what was believed to be the cause of the psychotic symptoms (I).The prevalence of psychological distress was 65.1%. Significant associated factors were having a co-wife, more than four children; debts and lack of food. The distressed group was more likely to need explanations for ill health. Those who visited both the healer and a health unit were less likely to be distressed (II). Of the 387 respondents, 60.2% had diagnosable current mental illness and 16.3% had had one disorder in their lifetime. Of those with diagnosable current mental illnesses, 29.7% had psychosis; 5.4% a major depressive episode; 5.6% anxiety disorders; 3.6% mixed anxiety-depression; and 3.9% suicidality. Symptoms were severe in 37.7%, moderate in 35.1%, and mild in 13.2%. Patients with moderate to severe symptoms were more likely to use both biomedical services and traditional healers (III). All the symptom scales showed a percentage reduction of more than 20% at the three- and six-month follow-ups. The differences between the mean scores of the scales were all significant (P<0.0001). The Turkey HSD test was also consistently significant at P<0.01 except for psychotic depression. Over 80% of the participants used biomedical services for the same symptoms in the study period. Patients who combined treatment were less likely to be cases at the three-month follow-up (P=0.002; OR 0.26[0.15-0.58]), but more likely at the six-month follow-up (P=0.020; OR 2.05 [1.10-3.18]). Being in debt was associated with caseness at both three and six months. Conclusion: The community gave indigenous names to psychoses (Mania, Schizophrenia and Psychotic depression) and had multiple explanatory models for them. Thus multiple solutions for these problems are sought (I). Traditional healers shoulder a large burden of care of patients with mental health problems (II and III). An overwhelming majority of Ugandans with psychosis use both biomedical and traditional healing systems. The combined use of these two systems seems to confer some benefits (IV). Implications: For policy makers, for mental health professionals, for traditional healers, for researchers indeed for all those who share the goal of improving the mental health of individuals there can be no alternative to engaging with traditional healers.
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| 2. |
- Abd, Hadi
(författare)
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Interaction between waterborne pathogenic bacteria and Acanthamoeba catellanii
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Waterborne bacteria cause global public health problems. Francisella tularensis causes tularemia, which is a fatal disease in humans. Pseudomonas aeruginosa is an opportunistic and nosocomial pathogen of humans. Vibrio cholerae O1 and V. cholerae O139 infect only humans and cause epidemic and pandemic cholera. The principal natural reservoirs of these pathogens are largely unknown. To find their aquatic reservoirs is an important factor in the epidemiology of the infections. Acanthamoebais a genus of free-living amoebae, which are found in the aquatic system and include several species and seem to have an increased role as reservoirs to many pathogenic bacteria. Acanthamoeba castellanii was co-cultured with each of the above mentioned bacteria for more than 2 weeks in order to study the interaction. Growth of the microorganisms, localisation and survival of intracellular bacteria was estimated by cell count, viable count, flow cytometry, PCR, fluorescence as well as electron microscopy. The results showed that F. tularensis localised in A. castellanii, multiplied within vacuoles and survived in intact trophozoites, excreted vesicles and cysts. Co-cultivation enhanced growth of F. tularensis, which grew and survived intracellularly for more than 3 weeks. In contrast, growth of singly cultured bacteria decreased significantly to non-detectable level within 2 weeks confirming the intracellular behaviour of the bacterium. The co-cultivation decreased growth of the amoebae in comparison to growth of singly cultured amoebae. Co-cultivation of A. castellanii with different strains of P. aeruginosa PA103 producing different effector proteins secreted by type III secretion system (TTSS) resulted in the death of the amoeba populations. Different analysis disclosed that the number of co-cultured amoebae decreased over time in comparison to the number of singly cultured cells. The TTSS effector proteins ExoU and ExoS induced necrotic cell death to the most of A. castellanii. The interaction between V. cholerae and A. castellanii resulted in growth and survival of V. cholerae O1 as well as O139 in the cytoplasm of trophozoites and in the cysts of A. castellanii. Co-cultivation enhanced growth of V. cholerae, which grew and survived intracellularly for more than 2 weeks, whereas, singly cultured bacteria decreased significantly to non-detectable level within few days disclosing an intracellular behaviour of V. cholerae. In conclusion, methods used in this project showed predation between A. castellanii and the extracellular P. aeruginosa, symbiosis between A. castellanii and each of the facultative intracellular bacterium F. tularensis as well as V. cholerae.
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| 3. |
- Abdalla, Amir Osman
(författare)
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Immunological and clinical long-term effects of idiotype vaccination in multiple myeloma patients
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In spite of the promising results shown by new anti-myeloma agents, multiple myeloma (MM) remains incurable and additional therapy to overcome the inevitable disease recurrence is greatly needed. Immunotherapy is currently under evaluation as a novel alternative or complementary therapy in many cancer types. The idiotype (Id) protein is a unique myeloma specific antigen that may be targeted in therapeutic vaccination. This thesis presents and discusses results of ld vaccination in early stage MM patients and underscores the immunological and clinical effects of the vaccine. In the first study we analyzed the time kinetics of cytokine genes expression (IL-2, IL-5, IFNgamma, GM-CSF and TNF-alpha) and granzyme B in healthy donors to be used as supplementary markers for antigen-specific I lymphocytes in subsequent studies. For most cytokines, the time for maximum accumulation seemed to be obtained after 4 to 8 h of activation. However, a sustained high level could be noticed for up to 24 h. Granzyme B gene expression showed a continuous gradual increase and late maximal accumulation (48-72 h). We concluded that cytokine genes expression would better be measured after 4-8 h of specific stimulation, but also up to 24 h of stimulation is acceptable. Granzyme B may preferentially be measured after 48 h of activation. In the second study, Id-specific T cell responses were evaluated by multiple read-out systems in 18 patients vaccinated with the ld together with either interleukin (IL)- 12 alone or a combination of IL- 12 and granulocyte macrophage colony stimulating factor (GM-CSF). IL12 alone was noted to induce a Th1 polarized immune response, while the combination of IL12 and GM-CSF induced a significantly higher frequency of responding patients but with a Th2 profile. In the third study Id-specific T cell responses were monitored simultaneously in peripheral blood and bone marrow of 10 patients. Id-specific responses we found to occur at a similar frequency of patients in both compartments. Comparison of the responses during active immunization with those at the late follow-up showed that the responses decreased significantly by time and shifted from a Th1 to a Th2 profile. In the fourth study, 28 patients were immunized as indicated earlier over 110 weeks. Id-specific T cell responses were noted in 33% of patients in the IL- 12 group and 85% in the GM-CSF/IL 12 group (p - 0.003). Two third of the responsive patients subsequently lost their specific immunity while developing progressive disease. Median time to disease progression (TTP) was found to be significantly longer in immune responders compared to non-responders. Immune non-response was associated with an increase in the numbers of CD4+/CD25+ cells (Treg cells). Two patients in the IL-12 group had a clinical response (> 50% and > 25% reduction of their respective M-component concentrations). In the last study patients were monitored for an Id-specific T cell response, and the presence of circulating myeloma B cells (CMC) by real time ASO-PCR during a median time of 46 weeks of maintained ld vaccination. Reduction and/or stable levels of CMC were observed in 6/11 patients. Three patients showed progressive increase in the number of CMC and in 2 patients CMC could not be detected. Patients (n=6) who showed a reduction and/or a stable CMC level mounted an Id-specific T cell response, while those with increasing numbers of CMC (n=3) failed to mount tumor specific T cell immunity (p<0.02). Taken together, these results indicate that ld immunization in early stage MM patients can induce tumor-specific immune responses that may correlate with reduction of CMC as well as TTP, and clinical responses may also occur. Immune non-response may be associated with increased numbers of Treg cells and progressive disease. Adjuvant cytokines can be a versatile tool for manipulating and directing the anti-tumor immune response.
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| 4. |
- Abdelwahab, Mahmoud Taie
(författare)
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Studies of the device perfect capsule in an animal model to reduce lens epithelial cell proliferation
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The sealed-capsule irrigation device, the Perfect Capsule, is a surgical device designed to target lens epithelial cells (LECs) during cataract surgery and prevent posterior capsule opacification (PCO). This is especially important in cases in which the posterior capsule must stay intact after cataract surgery, such as when implanting accommodative lenses. It also can be used when PCO is expected to be extensive, such as in pediatric cataract surgery. This thesis was created to evaluate the use of the Perfect Capsule in small young eyes with very proliferative lens epithelial cells in an animal model with young rabbits. In the first study, 30 4-week-old rabbits had bilateral clear lens extraction. The Perfect Capsule was implanted in one eye and sealed-capsule irrigation was performed with either balanced salt solution (BSS), distilled deionized water (DDW), or 5-fluorouracil (5-FU) 50 mg/ml for 5 minutes. The capsule then was flushed with BSS to wash out the residual substance. The contralateral eye did not undergo sealed-capsule irrigation. The after-cataract was evaluated clinically and in images taken at 5.5 weeks after surgery and histologically after the endpoint 6 weeks postoperatively. Only 5-FU effectively prevented the development of after-cataract. The second study evaluated the safety of irrigation with 5-FU in 30 8-week-old rabbits. Clear lens extraction was performed in one eye and the Perfect Capsule was implanted in three of the four groups. In one group, the capsule was irrigated for 5 minutes with BSS, in the second group with 5-FU 50 mg/ml, and in the third group with 5-FU 50 mg/ml and then BSS to wash out the residual substance. In the fourth group, the Perfect Capsule was not used; to mimic leakage in the device 0.2 ml of 5-FU 50 mg/ml was instilled in the capsule, left for 30 seconds, and washed out with I/A. Safety was evaluated by comparing pachymetry, endothelial cell count, and histologic findings after the endpoint of 24 or 48 hours postoperatively (half of each group at each time point). There was no difference in pachymetry or endothelial cell count among the groups. Histology showed no damage in the central or peripheral retina or the trabecular meshwork due to the substance used. We concluded that it is safe to use the Perfect Capsule with 5-FU even if leakage occurs. The third study evaluated the possibility of lowering the 5-FU concentration and maintaining a sufficient preventive effect on LEC proliferation. We also evaluated irrigation with thapsigargin, which was reported to be effective in in vitro human studies. Thirty 4-week-old rabbits had clear lens extraction in one eye. The Perfect Capsule was implanted and the capsule was irrigated for 2 minutes with either BSS, 5-FU 50 mg/ml, 5-FU 25 mg/ml, or thapsigargin and then BSS for 10 seconds. The after-cataract was evaluated clinically and in images taken 5 weeks postoperatively and histologically at 6 weeks postoperatively. The 50 mg/ml concentration of 5-FU successfully prevented after-cataract formation. Thapsigargin was ineffective in this animal model. In the fourth study, we used transmission electron microscopy (TEM) to determine if the posterior capsule is damaged by 5-FU or thapsigargin or just by the use of the Perfect Capsule. Clear lens extraction was performed in 4-week-old rabbits. We studied two eyes that were irrigated for 2 minutes with BSS, two eyes with 5-FU 50 mg/ml, two eyes with 5-FU 25 mg/ml, and two eyes with thapsigargin. The substances were washed out with BSS for 10 seconds. We also included two control eyes that had not had surgery. At 6 weeks postoperatively, the capsules were extracted and fixed for TEM. The analyses showed no ultrastructural damage to the posterior capsules in any group.
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| 5. |
- Abdi, Saber
(författare)
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Asthenopia in schoolchildren
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Asthenopia is a term used to describe different symptoms associated with the use of the eyes, such as pain, blurred vision, diplopia, headaches. Asthenopia is most often reported in association with near vision. Children with asthenopia complain of such symptoms particularly when reading and writing. Asthenopia is often divided into two main categories: refractive including refractive errors and anisometropia, and muscular, comprising strabismus and convergence insufficiency. Asthenopia due to accommodative problems has in the present studies been regarded as muscular asthenopia. In paper I the prevalence of asthenopia, refractive errors and binocular disorders was determined in a representative population of 216 Swedish schoolchildren aged 6 - 15 years. The prevalence of asthenopia was 23.1 %. The prevalence of hypermetropia and myopia changed with age, while astigmatism, convergence ability and strabismus did not. Accommodative insufficiency was more common in the older schoolchildren. Asthenopia was related to uncorrected visual acuity and refractive errors, and to accommodative insufficiency. Paper II described the orthoptic and ophthalmological findings in a group of 120 schoolchildren with asthenopia. The effect of asthenopia treatment was also evaluated. The most frequently occurring findings related to asthenopia were refractive errors, heterophoria and accommodative insufficiency. With appropriate treatment with glasses, prism or orthoptic exercises for 3 - 6 months, 112 out of the 120 children (93%) became asymptomatic. In paper III 49 schoolchildren with asthenopia due to accommodative insufficiency were assessed with the Visual Analogue Scale (VAS) and the grade of asthenopia was correlated with the degree of accommodative deficiency. The aim was to investigate if VAS grading of the asthenopic symptoms could be used as an instrument to indicate the level of improvement of accommodative insufficiency after treatment. A statistically significant reduction of asthenopic symptoms as graded with the VAS scale was observed, and the improvement in accommodation was also significant. However, there was no correlation between VAS values and the accommodation before and after treatment, and VAS values can only give a general impression of the level of accommodative ability in asthenopia (p < 0.001). Paper IV described how accommodative insufficiency influenced reading performance. Twelve children with asthenopia due to accommodative insufficiency were examined. Reading eye movements were recorded before and after treatment of asthenopia, using the IR corneal reflection technique, Orbit Eye trace System. Large variations in reading patterns were found. Despite successful accommodative treatment (p < 0.001), no correlation was found to the different eye movement parameters that could suggest that reading velocity was improved.
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| 6. |
- Abdurahman, Samir
(författare)
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Studies on HIV-1 core assembly
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main objective of this thesis was to define the roles of Gag (p55), in particular, the capsid (CA, p24) protein in human immunodeficiency virus type 1 (HIV-1) particle assembly. More specifically, i) to determine the relative contribution of some specific residues and/or sequences in HIV-1 CA core assembly and virus release, ii) to characterize the importance of two conserved residues with quite opposing intra-molecular contacts with other CA residues in capsid assembly, iii) to define the role and significance of a specific amino acid involved in formation of a conserved β-hairpin structure in HIV-1 capsid assembly, and iv) to define the active antiviral metabolite of an antiviral tripeptide amide previously found to affect HIV-1 capsid assembly and infectivity. The HIV-1 CA plays a crucial role in both assembly and maturation of the virion. Two highly conserved sequences located in the C-terminal domain (CTD) of HIV-1 CA were investigated with site directed mutagenesis, a valuable technique used widely to study the structure and function of CA in HIV-1 capsid assembly. We showed that mutations of specific residues within the two conserved sequences in the C-terminal domain could affect viral protein expression, virus assembly, release and infectivity. In addition, we showed that these residues are essential for proper proteolytic processing of the Gag/Gag-Pol precursors in a cell-type dependent manner, as well as, for proper morphogenesis of HIV-1 particles. The importance of two particular amino acid residues, Glu98 and Glu187, located within each of the two CA domains were investigated. In contrast to Glu98 which has no intra-molecular contacts, Glu187 has extensive intra-molecular contacts with eight other CA residues. Furthermore, Glu187 has been shown to be important for a salt-bridge formation in a head-to-tail dimer of HIV-1 CA. We performed detailed analysis to assess the potential effects of mutating these two Glu residues for Ala and Gly, respectively, on Gag processing, virus infectivity, viral cDNA production and virus morphology. In spite of the lack of contact with the other residues of CA as revealed by the structural data, Glu98 was shown herein as a critical element in the action of CA to correctly form mature cores. Our data also showed that the two residues in the study displayed deviated biological properties than the ones being predicted from crystallography and/or analysis of inter-atomic contacts. Thus, Glu187 was found to be dispensable although the residue was predicted to be important for the N-C CA-dimer formation. As the CA CTD dimer formation is one of the fundamental interactions driving CA multimerization, which also involves hexamerization of the CA N-terminal domains (NTD), we investigated the role and significance of aspartate 51 (D51) which previously has been shown to play a key role in virus assembly and maturation by forming a β-hairpin structure that is highly conserved among retroviruses. In addition to the D51A substitution reported elsewhere, we showed that substitutions of aspartate with glutamate, glutamine, or asparagine, three amino acid residues that are structurally close and have similar properties in protein as aspartate, could not rescue the structural integrity of the protein. It has previously been shown that addition of the tripeptide GPG-amide, corresponding to a motif found in both conserved sequences described above, could induce non-infectious HIV-1 particles with aberrant core structures. We identified and demonstrated that it is a metabolite of GPG-amide that affects HIV-1 infectivity. This metabolite was purified and its structure determined by NMR to be alpha-hydroxy-glycineamide (alpha-HGA). alpha-HGA binds to the HIV-1 CA and affects its ability to assemble into tubular or core structures in vitro and in vivo. As an antiviral, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity and a novel mechanism of antiviral action. In conclusion, our findings suggest that mutations in CA are lethal when affecting proper CA core assembly and that the semi-stable non-covalent protein interactions in HIV-1 CA can be specifically disrupted by small molecules, such as alpha-HGA.
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| 7. |
- Abelin Törnblom, Susanne
(författare)
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Mediators of cervical ripening in preterm birth : experimental and clinical investigations
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Preterm birth (PTB) is by far the leading worldwide cause of infant mortality and morbidity. Despite decades of research, the frequency of PTB has not decreased and the basic mechanisms initiating the onset of labour are still poorly understood. Vaginal preterm birth cannot take place without cervical softening and remodelling. Cervical ripening at term is an inflammatory-like process, in which complex interactions between cytokines, prostaglandins and nitric oxide (NO) are believed to play key roles, with NO acting as the final mediator. An understanding of the mediators regulating this process in connection with spontaneous preterm labour is of equally great importance, e.g., when, due to maternal/foetal complications, induction of premature cervical ripening and onset of labour is desired. Aim: Compare preterm cervical ripening to the analogous process occurring at term. Methods: Transvaginal cervical biopsy specimens were obtained and serum samples taken. Women, exhibiting no clinical signs of infection and undergoing preterm labour with a ripe cervix or preterm birth without labour (unripe cervix) were compared to un-infected women delivering at term, with or without labour. Peripheral white blood cell counts (WBC) and serum levels of C-reactive protein (CRP) were determined by routine procedures in the clinical laboratory. The other parameters monitored and procedures employed were as follows: prostaglandin dehydrogenase, (PGDH), and cyclooxygenase, (COX) proteins (immunohistochemistry (IHC) and dual immunofluorescence) and mRNA Ls (Northern blot). NO synthase; bNOS, eNOS and iNOS proteins (IHC) and mRNA Ls (Real-time RT-PCR) IL-6, IL-8, MCP-1, RANTES and TNF- ¿ proteins (ELISA/ Immulite) and IL-8, MCP-1 and RANTES mRNA (RT-PCR). Induction of cervical ripening and labour was performed using local administration of PgE2 and/or intravenous infusion of oxytocin. Results: The only significant differences between women undergoing preterm and term labour were in the levels of expression of bNOS, eNOS, and iNOS mRNA Ls, which where all higher in the preterm group. Other significant changes were only seen upon comparisons of women undergoing and not undergoing labour, irrespective of the gestational age of the foetus. Thus, cervical levels of IL-8 and MCP-1 mRNA Ls and proteins, and of IL-6 protein and serum WBC counts and levels of CRP were all higher in connection with labour. An indication of increased prostaglandin activity, i.e., reduced cervical expression of PGDH mRNA, was also observed in women in labour. In the clinical investigation induction of cervical ripening and labour with PgE2 applied locally, preterm, term or at postterm was not associated with any differences, in the mode of delivery or neonatal outcome. The fact that postterm pregnancy is a high risk obstetric situation, was emphasized by the four-fold higher frequency of extensive postpartum bleeding, >1000 ml, in this situation compared to labour at term. Conclusions: This study supports the hypothesis that preterm cervical ripening involves an inflammatory process, which may constitute a normal physiological adaptation to the onset of labour. The elevations in WBC count and serum level of CRP are striking indicators of active labour. NO appears to play a crucial role in preterm cervical ripening, consistent with its presumed acting as the final mediator. Local application of PgE2 to induce preterm cervical ripening and labour is effective and safe, for both mother and child.
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| 8. |
- Abhiman, Saraswathi
(författare)
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Prediction of function shift in protein families
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- With the availability of a large number of complete genome sequences, it has become essential to annotate the protein sequences derived from them as precisely as possible. Even though presently available computational methods can predict broad functionality for most protein sequences, there is room for improvement in order to get more precise functional annotation. Analysis of functional conservation and divergence in protein families can improve the quality of annotation for available genome sequences. Such an analysis adds an extra level of usefulness to protein families as it would predict which subgroups in a family share identical functions and which groups are likely to have diverged in function. Many genes of pharmacological interest occur in large families for which understanding the specific function is important. This thesis describes large-scale analysis of functional shifts in protein families. Initially, we created a large dataset of protein families and subfamilies with known functional differences and assessed how well function shifts can be predicted by using existing methods for identifying subfamily specific functional residues. We showed that these methods can discriminate between same function and different function subfamilies and achieved a prediction accuracy of 71%. This approach predicted many previously unknown cases of function divergence (Paper I). A new measure was introduced for predicting function shift, which is representative of all positions in the alignment and by combining it with previously proposed measures, we achieved further improvement of function shift prediction (Paper II). A web resource was developed, available freely to the public for disseminating subfamily classification and function shift analysis of protein families (Paper Ill). We analyzed multi-species ortholog groups for functional shifts using the methods proposed and predicted many new cases of functional shifts between ortholog and paralog subfamilies (Paper IV). This work demonstrates the power of classifying protein families into subfamilies along with function shift analysis for better annotation of protein sequences emerging from genome sequencing efforts. The methods and resources developed as part of this thesis represent a valuable resource for scientists elucidating detailed functional aspects of proteins, thus helping in evolutionary studies, comparative genomics and better drug designs for Human diseases.
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| 9. |
- Abraham Nordling, Mirna
(författare)
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Hyperthyroidism : incidence and long term quality-of-life
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyperthyroidism is a common disorder which in general affects approximately 2 % of women and 0.2 % of men. There are three main types of hyperthyroidism, caused by increased thyroid hormone production: Graves disease, toxic multinodular goitre and solitary toxic adenoma. Three main treatment modalities are common for Graves hyperthyroidism: surgery, radioiodine, or antithyroid drugs. The aim of this thesis was to investigate the incidence of hyperthyroidism and the possible influence of the choice of treatment for Graves hyperthyroidism on health-related aspects of quality of life after 14-21 years, furthermore, to study whether patients with a history of hyperthyroidism, especially Graves disease, have an increased risk of committing suicide later in life. In the first study, the total, age-specific incidence and the incidence of subgroups of hyperthyroidism in the county of Stockholm were determined during the years 2003-2005. They were identified by the clinical status, the thyroid hormone and antibody levels and in some cases by thyroid scintigraphy. Eight specialised units/hospitals in the county of Stockholm participated in the registration. During this period 1431 new well defined cases of hyperthyroidism on adults, >= 18 years of age were diagnosed. The total annual incidence was found to be 32.7/100 000. The annual incidence of Graves disease was 24.5/100 000, of toxic nodular goitre 3.3/100 000 and of solitary toxic adenoma 4.9/100 000. In the second and third, studies we focused on long-term differences in health-related aspects of quality of life of patients who had been randomised in 1983-1990 to treatment with antithyroid drugs, surgery, or radioiodine for Graves hyperthyroidism. The treatment groups were compared with an age-and sex-matched Swedish reference population and with one another. We also addressed the question whether the quality of life was influenced by the current thyroidal hormonal status or the level of thyroxine (T4) substitution. Two quality of life questionnaires (36-item Short Form Health Status Survey (SF-36) and Quality of Life 2004 (QoL2004)) were answered by the patients and hormonal status was recorded. The results showed a lower SF-36 score on mental aspects of quality of life (p< 0.05) and vitality (p< 0.05) compared with a reference Swedish population. There were no differences in quality of life score between the three modes of treatment for Graves hyperthyroidism. We also found that the results obtained with SF-36 were not related to the current serum levels of thyroid hormones, as subjects with suppressed S-TSH reported QoL scores above as well as below the average score for the general reference population in both physical component summary and mental component summary. In the fourth study, the risk of suicide among patients with a history of hyperthyroidism was investigated, since a pilot study had indicated an elevated suicide rate among patients previously treated for Graves hyperthyroidism. A comprehensive retrospective cohort study was therefore performed. The cohort included 43 633 patients who had been treated with radioiodine or surgically for hyperthyroidism in the years 1950-2005. The number of observed deaths in the cohort was compared with the expected, based on the suicide death rate in the age-, gender- and calendar period-matched general Swedish population, yielding standardised mortality ratios (SMR). The total SMR was 1.24 (95% CI, 1.04-1.47). The overall SMR among men and women with a history of Graves disease was 1.35 (95% CI, 1.07 - 1.66). A likely increase in risk of suicide among patients with a history of hyperthyroidism was observed.
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| 10. |
- Abrahamsson, Anna
(författare)
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Studies on the mechanism of regulation of bile acid synthesis in humans with some aspects on genetic factors
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the present investigation we studied human bile acid synthesis and its regulation both in vivo and in vitro and also evaluated a possible influence of polymorphisms in the CYP7A1 and CYP8B1 genes on bile acid synthesis in vivo. The following observations were made: · Primary human hepatocytes cultured on matrigel under serum-free conditions produced bile acids consistent with the pattern in vivo, i.e. predominately CA (70%) and CDCA (25%), both conjugated with glycine or taurine. · Both glycine-conjugated and free bile acids suppressed bile acid synthesis and mRNA levels of CYP7A1 in cultures of human primary hepatocytes in the order CDCA>DCA>CA>UDCA. Also mRNA levels of CYP8B1 and CYP27A1 were suppressed but to a much lesser extent. Addition of GCDCA as well as GDCA resulted in higher levels of mRNA for SHP supporting a mechanism by which FXR suppresses CYP7A1 through induction of SHP. · Upregulation of bile acid synthesis in humans by cholestyramine treatment resulted in higher levels of mRNA of not only CYP7A1, but also of HNF-4alpha. This is consistent with a mechanism in which HNF-4alpha is an important stimulating nuclear factor involved in bile acid synthesis. · Earlier described polymorphisms in the promoter region of the CYP7A1 gene could not be associated with variation in CYP7A I enzyme activity in liver biopsies or rate of bile acid synthesis evaluated by serum levels of 7alpha-hydroxy-4-cholesten-3 -one or by isotope dilution kinetics. The genotypes did not differ in experiments with a reporter system for transcriptional activity or in EMSA analysis measuring binding of nuclear extracts. · Differences in ratio of CA and CDCA in gallbladder bile observed in a number of human subjects could not be explained by polymorphisms in the CYP8Bl gene. The results obtained emphasize marked species differences in the mechanisms for regulation of bile acid synthesis. Genetic polymorphism in the key enzymes does not appear to be of major importance for this regulation.
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