| 51. |
- Fagerås-Böttcher, Malin, 1969-
(författare)
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Immunological factors in breast milk in relation to allergy in mother and child
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The allergy preventive effect of breast-feeding against the development of allergy is controversial and some of this controversy may be due to differences in the composition of breast milk between different mothers.Aim: To analyse IgA, cytokine and chemokines levels in human milk and relate the findings to matemal allergy and to development of atopic disease and IgA production in the infants, and furthermore, to assess the effects of breast milk on CBMC cytokine production. To approach these aims, several assays and methods had to be developed.Material and Methods: The levels of total IgA, secretory IgA and ß-lactoglobulin, ovalbumin and Fel d 1 specific IgA antibodies in breast milk and saliva, as well as IL- 4, -5, -6, -8, -10, -13, -16, IFN-γ, TGF-ß, eotaxin, MIP-1α and RANTES in breast milk were analysed by ELISA. Cytokine responses from phytohaemagglutinin, cat dander or ovalbumin stimulated cord blood mononuclear cells were studied in the absence or presence of colostrum.Results: The composition of immunological factors in breast milk varied widely between different mothers. The levels of secretory IgA and ß-lactoglobulin and ovalbumin specific IgA were higher in breast milk from non-allergic than allergic mothers. On the other hand, allergic mothers had higher levels of IL-4, IL-8 and RANTES in their breast milk. There were no relation between the levels of secretory IgA, cytokines and chemokines in breast milk and the development of atopic disease and salivary IgA production in the infants, however. Colostrum inhibited phytohaemagglutinin induced IFN-γ and IL-4 production and cat dander induced IFN-γ production. In contrast, allergen induced IL-5, IL-10 and IL-13 production was enhanced by colostrum. The effects of breast milk on cytokine production were independent of the atopic status of the mothers. The inhibiting effect of colostrum on phytohaemagglutinin induced IFN-γ production correlated with breast milk TGF-β levels, and was partly blocked by the addition of an anti-TGF-ß antibody.Conclusion: There were great individual variations regarding the levels of total and allergen specific IgA, cytokines and chemokines in human milk. Furthermore, breast milk from allergic and non-allergic mothers differed in several aspects. These differences seemed to be of minor importance for the development of atopic disease and IgA production in the breast-fed infant up to two years of age, however. The composition of human milk and the observed effects of breast milk on allergen and mitogen induced cytokine production confirms the anti-inflammatmy properties of human milk, and also suggest possible mechanisms whereby breast-feeding may protect against development of atopic disease. Our results do not support that the effects of breast-feeding are dependent on differences in the immunological composition of the milk, however.
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| 52. |
- Fahlgren, Anna, 1972-
(författare)
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Early knee osteoarthrosis after meniscectomy : studies in rabbits
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Post-traumatic osteoarthrosis develops after intraarticular injuries. It is a disease, which affects both articular cartilage and subchondral bone, and progresses over 10-20 years. Irreversible damage has often occurred by the time clinical diagnosis is possible. More knowledge about the early phase of the disease might yield measures to detect and delay or even prevent progression. This thesis evaluates changes in articular cartilage and subchondral bone at an early stage of post-traumatic osteoarthrosis.Simultaneous changes in articular cartilage and subchondral bone were evaluated 3 to 40 weeks post-operatively in a rabbit meniscectomy model for post-traumatic osteoarthrosis. Rabbits were meniscectomized in the right knee and sham-operated in the left knee. Osteoarthrotic cartilage changes were evaluated by histology. Changes in the subchondral bone were evaluated by histology, scintimetry and dual-energy X-ray absorptiometry (DEXA). Joint space narrowing, and its utility as diagnostic tool at early stages of osteoarthrosis, was assessed with weight-bearing radiographs. The prognostic value of transforming growth factor-ßI (TGF-ß1) and proteoglycan fragment concentrations in the joint fluid at an early stage was also assessed.We found slight cartilage changes and an increased metabolic activity in the subchondral bone as early as 3 weeks after meniscectomy. However, sham-operated knees displayed similar changes, although to a lesser degree. Cartilage fibrillation progressed at areas of high load within the meniscectomized knee joint. The subchondral bone showed a general response such as high scintimetric activity 3 weeks after surgery, and a decreased bone mineral density at later time points. Local adaptation in areas of high load within the subchondral bone was also seen. There was an increased osteoid content at the border between the cancellous bone and the marrow cavity already 3 weeks after meniscectomy, and at 13 weeks the subchondral bone plate was thickened. This thickening of the bone plate persisted up to 40 weeks. Joint space narrowing occurred after removal of the meniscus, but weight-bearing radiographs were not sensitive enough to measure early cartilage changes. Increased concentration of TGF-ß1 in the joint fluid at 3 weeks after surgery was associated with a higher degree of histological osteoarthrotic changes at a later time point.Simultaneous changes in both cartilage and bone were apparent already 3 weeks after surgery, indicating that both tissues are involved from a very early stage. The localisation of cartilage changes illustrates that mechanical consequences of meniscectomy play a crucial role in progression of the disease. Surgical trauma resulted in increased release of TGF-ß1 at 3 weeks after surgery. This was found to be indicative for the severity of later osteoarthrosis. Thus, factors solely associated with the surgical trauma may also be important for the progression of osteoarthrosis.
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| 53. |
- Falk, Lars, 1954-
(författare)
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Urethritis and cervicitis with special reference to Chlamydia trachomatis and Mycoplasma genitalium : diagnostic and epidemiological aspects
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to elucidate urethritis and cervicitis and the possible causes with special reference to Chlamydia trachomatis and Mycoplasma genitalium. Despite mandatory partner notification legislated in 1988, the incidence of C trachomatis infection in Sweden has undergone a 10% annual increase since 1997, following a decline in the early 1990s. Nonchlamydial-non-gonococcal urethritis (and cervicitis) (NCNGU) is more common than chlamydial infection and gonorrhoea at Sexually transmitted disease (SID) clinics. Mycoplasma genitalium, originally isolated in 1980, is one probably important cause of NCNGU.Specimens from men and women infected with C trachomatis who attended the Örebro STD-clinic (1999-2000) were genotyped by sequencing of the omp 1, which encodes the major outer membrane protein (MOMP) (I, II). Both invasive and first void urine (FVU) specimens (n=237) were successfully sequenced from 231 C trachomatis-positive individuals (96 women and 135 men). Genotype E was the most common strain (47%) followed by F (17%) and K (9%). The prevalence of Ba, D, D/B-120, D/B-185, G, H, Ia and J genotypes was 0.4 to 6%. There were few gap mutations compared with reference strains. 161 sexual networks comprising 688 individuals were compiled. Specimens were sequenced from at least two patients in 47 of 161 networks. In seven of these 47 networks (15%) there were discrepant genotypes. At the follow-up visit five of 204 individuals (2%) were still C trachomatis-positive. Two harboured a new genotype and thus had contracted a new C trachomatis infection. Partner notification was successful in only 30 of 161 networks (19%), meaning that all elicited partners were tested and transmission of infection ceased. The main reason for non-success was insufficient information for partner identification from the index patients and, if the partner attended another clinic, the results of the C trachomatis test were prohibited by Swedish law from being revealed to the tracer.Microscopic signs, symptoms of infection and prevalence of C trachomatis and M genitalium were compared among men and women attending the Örebro STD-clinic in 2000 (III, IV). In a study performed in 2002, 59 young women invited to the national cervical cancer-screening program were tested for C trachomatis and M genitalium (IV). There was no statistically significant difference in microscopic signs in men or women infected with either of the bacteria. Women infected with C trachomatis or M genitalium more often had microscopic signs of infection than those women in the cancer screening group without infection, and the difference was statistically significant (IV). Symptomatic urethritis was more prevalent in M genitalium than in C trachomatis infected men (III). The prevalence of C trachomatis and M genitalium in male STD-attendees was 12% and 7%, respectively. In female STD-attendees the corresponding figures were 10% and 6%, respectively, whereas only one woman in the screening group was C trachomatis-positive and none was infected with M genitalium (IV). Both C trachomatis and M genitalium were found significantly more often in partners of men and partners of women with the corresponding infection, than in partners of men with a non specific urethritis (NSU) or women with a non-specific urethritis/cervicitis. These studies show that M genitalium is a common infection among STD-clinic attendees and that it is not a widespread commensal bacterium in society.In an open treatment pilot study (V) in men and women infected with M genitalium, the standard treatment for urethritis and cervicitis, i.e. tetracycline, was compared with azithromycin 500 mg the first day and 250 mg the following four days. Tetracyclines did not eradicate M genitalium in 71% of the women and in 63% of the men, whereas all who were treated with azithromycin were M genitalium negative at the follow-up visit. Randomised controlled trials (RCT) are needed to study azithromycin in different dosages.
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| 54. |
- Falkmer, Torbjörn, 1958-
(författare)
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Transport mobility for children and adolescents with cerebral palsy (CP)
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The transport mobility of children and adolescents with cerebral palsy (CP) is of vital interest for the individual, as well as for society. Enhanced transport mobility can be related to improved functional health status and a higher degree of autonomy, which in turn may reduce the demand for societal support. UN Resolution 48/96, together with Swedish legislation and "Vision Zero" have in different ways established that the transport system must be designed to meet also the needs of children and adolescents with disabilities. Hence, it is necessary to identify and eliminate obstacles hindering children and adolescents with CP from using public transport and other means of transport, such as their own cars, at the same level as other members of society. However, in the case of children and adolescents with CP, the transport situation and the learner driver's educational situation have so far been largely unknown.Aim: The general aim of the thesis was to describe and analyse, from a legislative and a public health perspective, the transport mobility situation for children and adolescents with CP. Furthermore, the general aim was to identify obstacles for the target group to use public transport and other means of transportation, at the same level as other members of the society, and to suggest improvements that will remove the identified obstacles.Material and methods: Several different data collection methods were used. Data, concerning travel habits and parents' perceived risks regarding transportation, were taken from a postal questionnaire addressed to parents of children and adolescents with CP. In order to estimate the numbers of potential learner drivers with CP in each age group in Sweden, a literature review was conducted, based on Swedish material. Furthermore, logbooks for learner drivers with CP were analysed retrospectively, in order to identify procedures, problems and key tasks in their driver education. Visual search strategies for learner drivers with CP were analysed, utilizing an eye tracker, and an attempt was made to introduce a screening tool for predicting the outcome of driver education.Results: Children and adolescents with CP were found to be transported under unsafe conditions, causing worry among their parents. When transporting children in the family vehicle, the parents were exposed to a very heavy burden, which increased their worry. The prevalence of potential learner drivers with CP who were in need of highly specialised driver education, including individually adapted driver training vehicles, was estimated to be 0.15 per 1,000 of a population-based age group of learner drivers in Sweden. Complex procedures, structural problems and financial obstacles made it difficult for adolescents with CP to obtain a driving licence and an adapted vehicle. The total duration of the driving tuition given by a driving instructor was found to be almost nine times higher for learner drivers with CP than for non-disabled learner drivers. Visual search strategies among learner drivers with CP were found to be less flexible than among other learner drivers. This fact indicated a need for better methods of teaching such strategies to this group as an integral component of their driver education. The validity of the motor-free visual perceptual test, TVPS-UL, for predicting the outcome of driver education for learner drivers, was found to be low. In order to find a reliable and valid screening tool for this purpose, future studies should focus on cross-validation of visual perceptual and dual task performance tests for different types of independent variables, such as obtaining a driving licence or not, accident involvement and driving ability.Conclusion: The transport system was found, from a legislative and public health perspective, to be unsuitable to meet the needs of children and adolescents with CP. Suggestions for improving transport mobility for children and adolescents with CP are provided. Several of these suggestions are practical, concrete and contextual for Swedish conditions, and some of them necessitate future research. However, a number of these suggestions are also applicable in an international context.
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| 55. |
- Farnebäck, Malin, 1972-
(författare)
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Quantitative analysis of melanoma transcripts : with emphasis on methodological and biological variation
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The introduction of RT-PCR made it possible to detect circulating tumor cells in melanoma patients by analysis of melanoma-associated transcripts, especially tyrosinase. Since the development of the first PCR method for tyrosinase mRNA, several studies have presented varying results. In the present thesis I have developed and used quantitative PCR methods in order to evaluate methodological and biological factors which may explain the disparity in the literature.Two methods were developed for tyrosinase, one competitive PCR and one real-time PCR method. With the real-time PCR technique, quantitative methods were also developed for tyrosinase related protein (TRP)-1, TRP-2, MART-1/Melan-A, S-100, GD2 synthase, MAGE-A3 and MAGE-A12. Methodological studies on the RNA extraction showed that the silica based RNA extraction method QIAamp gave considerably higher yields compared with the phenol-chloroform based extraction methods Ultraspec and FastRNA. Further studies showed that yields comparable with the QIAamp method could be obtained with the mRNA extraction method GenoPrep. Optimization of the cDNA synthesis procedure revealed that the reverse transcriptase and factors in the RNA sample inhibited the following PCR. This was avoided by diluting the cDNA sample before PCR.The stability of the tumor cell RNA in the samples is of great concern when it comes to transporting samples from distant hospitals to the laboratory. It was found that blood collected in ACD was best, although insufficiently, stabilized when stored at +4 °C compared with room temperature. Similar stability was also obtained for PAXgene tubes stored at room temperature, however the stability of RNA was much improved when the PAXgene tubes were frozen.Studies on the biological variation in cultured melanoma cell lines and tissue sections from melanoma metastases showed that the expression of melanoma associated transcripts varied widely. In melanoma cell lines the expression of the transcripts tyrosinase, TRP-1, TRP-2 and MART-1/Melan-A was related to the pigmentation of the cell lines. The pigment-related transcripts and S-100 were expressed at higher levels than GD2 synthase, MAGE-A3 and MAGE-A12 in the melanoma metastases. The expressions of TRP-2 and GD2 synthase appeared to be influenced by therapy. In metastases from patients treated with a combination of cisplatinum, DTIC and interferon-α2b, TRP-2 was expressed at higher levels and GD2 synthase at lower levels compared with untreated patients.
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| 56. |
- Ferdousi, Hosne Ara, 1957-
(författare)
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Pollinosis in children with special reference to the development of asthma
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Children with rhinoconjunctivitis and increased bronchial hyperreactivity (BHR) are prone to develop asthma later in life. Eosinophil granule proteins in serum are indirect measures of eosinophil activity and regarded as markers of inflammation. Measurement of eosinophil cationic protein (ECP) has also been evaluated for prediction, diagnosis and monitoring of treatment in children with asthma. In 1992, a multicenter preventive allergy treatment study (PAT-study) was started in order to prevent the development of asthma in children with pollinosis using specific immunotherapy treatment (SIT). Sensitization to cat allergen is common in asthma and up to 50% of children with asthma are sensitized. Exposure to cat allergen can not be avoided because exposure occurs in schools and even in homes without a cat and is a major cause of persisting airway inflammation and asthma in cat sensitized schoolchildren. Data are needed to know the level of allergen maintaining BHR or asthma.The aims of the thesis were: 1) To assess the relationship between seasonal symptoms of allergy, BHR, PEP-variability and release of markers of inflammation. 2) To investigate the level of markers of inflammation, and PEF variability, in healthy school children. 3) To investigate the diagnostic value of the tests e.g. BHR and mediators of allergic inflammation for diagnosis of asthma in pollinosis. 4) To investigate the efficacy of SIT regarding prevention of asthma, BHR, and polysensitization. 5) To assess, the levels of cat allergens inhaled daily by asthmatic schoolchildren sensitized to cat and relate the levels of allergen to symptoms of asthma and BHR.The PAT study population comprised 205 birch and/or grass pollen allergic children with pollinosis, from 7 centres in 5 countries in Northern and Central Europe, 28 were enrolled in the Linköping. We recruited 56 healthy school children to study the normal level of inflammatory markers and PEFR variability and 10 asthmatic schoolchildren sensitized to cat to assess the allergen levels in their daily environment.In the pollinosis children, sensitization status was determined by skin and conjunctival provocation test and RAST. Mediators of allergic inflammation like ECP, EPX, and neutrophil mediators like MPO were measured by RIA methods, non-specific BHR by Methacholine and/or cold air challenge tests and bronchial lability by PEF variability using Mini Wrights Peak-Flow meters. The level of cat allergens in dust samples were measured by ELISA, and in air by amplified ELISA methods. SIT was given by birch and/or grass pollen allergen extracts (Alutard), during a period of 3 years.In pollinosis children in Linköping, there was no correlation between mediators of allergic inflammation in serum and symptoms and signs of clinical asthma. BHR and PEFR-variability persisted in the autumn, though s-ECP and s-EPX did not, indicating that mediators of inflammation do not reflect asthma. Positive MBPT and IHCA tests were more often found in the children with clinical asthma. The other investigated tests were not useful for screening of asthma in this group of children with pollinosis. In healthy schoolchildren, the mean daily PEF variations were 7.35 and 6.74%, and the 9Sth percentiles were 18 and 14% during the spring and autumn respectively. The 95th percentils for s-ECP were 41 and 38 µg/L, for s-EPX 74 and 62µg/L, for s-MPO 987 and 569 µg/L and for u-EPX tucreatinine 165 and 104 µg/mmol, during spring and autumn, respectively. Our findings for mediator levels in schoolchildren were higher than reported in adults. There was a significant decrease in the levels of the eosinophil and neutrophil mediators from May to November (p ≤ 0.001) and so did the PEF variability (p=0.037) in our healthy children. As normal reference values post seasonal data would be more appropriate. In the environment of cat sensitive children, exposure levels of cat allergen varied from 0.5 µg/g to 751 µg/g dust in homes (median, 36 µg/g) and from 17 µg/g to 378 µg/g in schools (median, 137 µg/g). Airborne allergen levels varied from 13 to 2184 pg/m3 (median, 43 pg/m3 ) in the homes and 68 to 7718 pg/m3 (median 352 pg/m3) in the schools. The inhaled dose was 8 pg to 2336 pg/min. A relation between BHR and exposure level was found. In the PAT-study, children actively treated with SIT had significantly fewer asthma symptoms after 3 years (odds ratio 2.52; p<0.05) and MBPT was improved (p<0.05) compare to the control group. Thus, SIT reduced the development of asthma in our children with pollinosis.We followed the pollinosis children in Linköping in our centre for 11 years. Our findings were: I) there was a trend of diminishing in sensitivity to MBPT and in PEF variation with age. 2) Pollen counts in different years influenced MBPT results in that particular year. 3) MBPT in 1992 could predict the development of asthma in 1994.
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| 57. |
- Fjellstedt, Erik
(författare)
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Clinical and genetic studies on patients with cystinuria
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cystinuria is a genetic disorder with autosomal recessive inheritance. It is caused by a defective proximal tubular reabsorbtion of cystine and the dibasic amino acids. The low urinary solubility of cystine causes a life-long stone disease, contributing to about 1% of all urinary stones in adults. Treatment is based on high fluid intake and the use of sulfhydryl compounds such as tiopronin and D-penicillamine to decrease the urinary concentration of cystine, and alkalinization of the urine to increase the urinary solubility of cystine. Reduction of sodium intake is also a favoured regimen because of eo-transportation of sodium and cystine in the proximal tubules. Advancements in molecular genetics have led to the identification of two genes associated with cystinuria (SLC3A1 and SLC7A9). These genes cannot, however, explain all cases of cystinuria.Investigation of SLC3A1 in 53 Swedish patients with cystinuria revealed 12 novel mutations, and the allelic frequency of the most common mutation (M467T) was shown to be 0.5% in a normal population. (Paper I). Studies of SLC7A9 revealed three novel and one previously known mutation. One patient had novel mutations in both alleles, one patient showed a novel mutation in one of the alleles and one patient showed a previously known mutation in SLC7A9 and two in SLC3A1, leaving 14 patients in whom cystinuria was not explained by genetic observations (Paper m. In order to relate these genetic findings to excretion of cystine in the urine, 33 patients treated with sulfhydryl compounds were studied (Paper III). Ten of these patients showed either mutation in one of the SLC3A1 alleles (8) or a complete lack of mutations in both genes (2). These 10 patients showed a significantly higher urinary excretion of total cystine compared to 23 patients in whom both SLC3A1 alleles were mutated (p < 0.01). The same was true for the 8 patients with only one SLC3A1 allele mutated (p < 0.05). These findings support the existence of yet unknown genes involved in the regulation of urinary cystine excretion, the basis of cystine stone formation. Treatment is primarily aimed at the prevention of such stones and should be guided by the urinary cystine concentration, trying to avoid supersaturation. In order to improve patient surveillance in terms of urinary supersaturation with cystine a procedure was introduced comprising one daytime and one night urine sample during the 24-hour period (Paper IV). Twenty-six patients were followed over a 3.5 year period using this strategy. It was found that 47% of cystine supersaturation episodes (> 1200 µmol/L) would have evaded detection by analysis carried out in 24-hour urine collections. Furthermore, a significant decrease in the frequency of renal stone episodes (p < 0.05) and active stone removals (p < 0.01) was found when compared to a previous, equivalent period during which 24-hour urine collections were used. The period guided by divided urine samples was also characterized by a significant decrease in free cystine concentrations (p < 0.01) and a significant increase in urinary volumes (p < 0.05). In the tiopronin-treated patients, there was a significant increase in the tiopronin dose and a subsequent decrease in urinary cystine excretion (p < 0.05). The use of cystine analysis in divided urine samples thus made a higher degree of individual treatment possible. The effects of sodium bicarbonate and potassium citrate were compared in 14 cystinuric patients (Paper V). Potassium citrate has been the favoured agent, as it does not contain sodium, but there have been no reports in which potassium citrate has been compared to sodium bicarbonate in the treatment of patients with cystinuria. Sodium bicarbonate was effective in alkalizing the urine, but caused a significantly increased urinary sodium excretion (p < 0.01). A significant correlation was found between urinary sodium and cystine excretion in tiopronin treated patients (p < 0.001). Potassium citrate was shown to produce a significant increase in urinary pH. Potassium citrate was associated with a significant increase in plasma potassium (p < 0.05), but no case of severe hyperkalemia was found. Potassium citrate could thus be recommended for urinary alkalinization in cystinuric patients without severe renal impairment.
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| 58. |
- Foldemo, Anniqa, 1953-
(författare)
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Living with schizophrenia from the perspective of outpatients and their parents
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate how outpatients with schizophrenia experienced their situation in terms of need and quality of life. A further aim was to investigate how their parents experienced the need of their daughter or son and how it influenced their own life. In order to investigate need and quality of life of outpatients with schizophrenia according to DSM-III-R, (n=19) at baseline and five-year follow-up (n=17) the outpatients completed the following questionnaires: Camberwell Assessment of Need (CAN-R), the Quality of Life Scale (QLS-100), the Global Assessment of function (1) and the Clinical Global Impression (CGI) at follow-up the Insight Scale (2). In study II, outpatients with schizophrenia according to DSM-IV (n=32) and their parents (n=44) and staff (n=31) were included. To investigate the outpatients' need both the patients, their parents and staff completed the CAN-R questionnaire. In study III, the quality of life of the parents (n=38) was investigated with the help of the questionnaire Quality of Life Index (QLI), which was completed by the parents and a reference group (n=689). In addition, the questionnaire Burden Assessment Scale (BAS) was used in order to describe the parents' burden. In order to better understand how living with outpatients with schizophrenia (n=8) influenced parents, the parents were interviewed and data were analysed according to the Empirical Phenomenological Psychological (EPP) method. The total number of needs in study I, according to CAN, was 7.1 ± 3.2 at the baseline and 6.3 ± 2.8 at the follow-up. Using our cut-off point, 5 patients at the baseline and 1 at the follow-up had greater problems. The outpatients were more satisfied with their quality of life after five years than baseline (p< 0.05). The need ranking of key workers and patients showed a correlation rho=0.68 (p<0.05) at the baseline and rho=0.74 (p<0.05) at the follow-up. The difference in number of needs was that the key workers identified more topics where the patients had needs than the patients did themselves. The outpatients in study II, rated the total score of the severity of needs at a mean of 7 ± 4, while the mean score for both parents and the staff was 9 ± 5. The unmet needs in mean values for the patients were 2 ± 2 and 4 ± 5 for both parents and the staff. The needs ranking between patients and parents and patients and staff both showed a correlation of rho=0.65 (p<0.01). The correlation between parents and staff was rho=0.95 (p<0.01). Parents and staff rated needs in different areas. There was a correlation between the total number of needs and how the patients functioned rho=0.53 (p <0.01) and the severity of illness rho=0.64 (p<0.01), respectively, assessed by GAF and CGI. The parents were significantly less satisfied with their overall quality of life with a mean value of 19.5 ± 4.0 compared with the reference group, which had a mean value of 21.2 ± 4.1 (p<0.05); however, when divided into age groups, there was no significant difference in quality of life in the oldest age group 71-80. There were significant correlations between lower overall quality of life and higher burden r=0.58 (p<0.01) as well as between lower psychological/spiritual values and higher burden r=0.42 (p<0.05). The experience of living with a mentally ill daughter or son includes both emotions and changed reality that parents must adapt to. Four points relating to the general structure of themes were identified; emotions in parenthood, changes in the families, interaction with others and adaptation to the illness. All the themes included also five subthemes: confusion following the first appearance of the illness, interpreting the illness and loss in terms of grief, the importance of support, adaptation to the loss and feelings about the future in terms of worry and hope. In order to support the outpatients and their parents, it is important to assess need, listen more on their experiences and increase our knowledge about their situation.
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| 59. |
- Forsberg, Maria, 1973-
(författare)
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Signal transduction in human phagocytic cells during phagocytosis, oxidative activation and apoptosis
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neutrophils and macrophages are professional phagocytic cells that play a crucial role in host defense against invading microorganisms. They bind to, internalize, and subsequently kill microbes with an arsenal of reactive oxygen metabolites and microbicidal agents. The microbes are recognized by cell surface receptors, mainly by the phagocytic receptors FcγR and complement receptor 3 (CR3) that recognize IgG and complement fragments C3b/C3bi, respectively. Microbial pathogens such as Salmonella typhimurium have developed sophisticated mechanisms to avoid the host defense system and enter the cells by invasion, mediated by a type III secretion system.The objective of this thesis was to investigate the signaling pathways during receptor-mediated phagocytosis by FcγRIIa, FcγRIIIb and complement receptor 3 (CR3), or during invasion by Salmonella typhimurium in human phagocytic cells. We have focused on the intracellular signaling pathways controlling phagocytosis, production of reactive oxygen metabolites, and apoptosis. Paper I-III focus on signal transduction events triggered after ligation of CR3, FcγRIIa, and FcγRIIIb in human neutrophils. Both activation of CR3 and FcγR induced production of reactive oxygen metabolites (ROM), where CR3 induced the most prominent response. The ROM production was dependent on intracellular Ca2+, tyrosine kinase activation, and phospholipase D (PLD) activity. FcγRIIa induced a strong phosphorylation Syk, which was less pronounced following FcγRIIIb ligation, and absent after CR3 activation. Our data indicate that CR3 and FcγR activate different signaling pathways. By exposing neutrophils to TNF-α prior to ligation of CR3, the oxidative response was strongly enhanced, whereas the response to FcγR-ligation was unaffected. This increase was in part due to a p38 MAPK-dependent upregulation of CR3 on the cell surface, but also due to modulation of intracellular signaling pathways since Syk was activated by CR3 as well as FcγR in TNF-α treated cells. In contrast to macrophages where only FcγR activates Rac, Cdc42, and the subsequent ROM production, we show that CR3 as well as FcγR activate the GTPases Rac2 and Cdc42 in human neutrophils. Their downstream target p21 activated kinase was also activated, and Rac2 translocated to the membrane fraction. Correct function of these small GTP-binding proteins was necessary for generating a proper signal for ROM production in these cells.One survival strategy exploited by microbial pathogens might be to induce apoptosis of tbe host. Invasive Salmonella typhimurium efficiently entered U937 cells and induced a pronounced degree of apoptosis in contrast to its opsonized mutants, which were internalized by receptor-mediated phagocytosis but failed to induce apoptosis. Invasion by Salmonella typhimurium activated Rac1 and Cdc42 independently of PI3 K and tyrosine kinase activation. Inhibition of Racl and Cdc42 inhibited both invasion and the induction of apoptosis. Receptor-mediated phagocytosis activated the survival signals Akt/PKB which protected the cells from apoptosis. Thus, control of apoptosis is a fine tuned balance between pro- and anti-apoptotic signaling proteins.
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| 60. |
- Franzén, Thomas, 1955-
(författare)
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Success and failure of conventional and laparoscopic fundoplication in gastro-oesophageal reflux disease
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The outcome of antireflux surgery in a single institution during two decades is presented.101 consecutive patients operated with open partial2 70° fundoplication and crural repair during 1982-1989 were prospectively analysed. All stages ofpreoperative oesophagitis were represented. Reflux competence, symptomatology, and postoperative side-effects were evaluated six months and ten years postoperatively. Recurrence (8%) was more common in patients who had severe oesophagitis before operation. The operative method is effective for long-term reflux control, it does not cause dysphagia, and it has few side-effect. Some months prior to the introduction oflaparoscopic fundoplication our unit had changed from partial to total fundoplication as a standard operation for gastro-oesophageal reflux disease (GORD). It was then convenient to perform the total Nissen fundoplication laparoscopically. All 50 patients operated with laparoscopic technique during a 30-months period 1992-1994 were prospectively compared with 21 patients operated with open technique. Nine patients were converted and then analysed in the open group. We tried to select patients with uncomplicated disease for laparoscopy but 7 patients in this group had severe disease diagnosed at preoperative endoscopy or/and at operation. In the open group 9 patients had severe disease. The patients were investigated six months, two years, and five years postoperatively. Early postoperative manometry was prognostic for recurrence. At long term follow-up the reflux control was similar, 10% of the patients operated with laparoscopy had recurrence and 8% of the patients operated with open technique.Summer 1994 to spring 1998 we included 93 patients with uncomplicated GORD in a randomised clinical trial between laparoscopic and open 360° floppy Nissen fundoplication with crural repair. 45 patients were operated on laparoscopically and 48 patients underwent laparotomy. Only one patient was converted and then analysed in the laparotomy group. The patients were investigated before operation, half a year after and at long-term follow-up (33-79 months postoperatively). Long-term follow up also included endoscopy. Operation time was significantly longer for laparoscopy compared to laparotomy, 155.6 (±36.5) minutes and 104.3 (±30.7) minutes respectively (p<0.05). Laparoscopy patients had significantly shorter hospital stay, 3.6 (±1.9) days, compared to 5.8 (±1. 7) days for laparotomy patients. Sick leaves were 20.7 (±9.9) days for laparoscopy patients and 28.3 (14.7) for laparotomy patients. The difference was significant (p<0.05). Early postoperative reflux control was similar for laparoscopic and conventional fundoplication. Early side-effects were more frequent after laparoscopy. Significantly less laparoscopy patients were satisfied at long-term follow-up; only 62% of the laparoscopy patients were satisfied compared to 91% of the laparotomy patients.We have investigated the mechanisms and anatomical failures in twenty-one patients reoperated after laparoscopic total fundoplication. Recurrent heartburn occurs when wrong part of the stomach is used for the fundoplication. Dysphagia after failed laparoscopic total fundoplication is caused by hiatal fibrosis or other mechanical causes rather than a normal and tight fundoplication.Also the reproducibility of an important diagnostic tool for GORD, the 24-hour pH monitoring, was evaluated. Twenty-two adult patients admitted to The Oesophageal Laboratory for 24-hour pH monitoring were investigated twice, six weeks apart, under identical conditions. The test was strictly standardised with the use of an antimony pH- probe and the patients hospitalised during 24 hours. We found that a normal 24-hour pH test should be assessed with caution because the biological variability of gastro-oesophageal reflux is not negligible from time to time.
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