| 1. |
- Abdiu, Avni, 1963-
(författare)
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Growth regulation in sarcomas : studies in vivo and in cell culture
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sarcomas are malignant tumors of mesenchymal origin, and can arise in soft-tissue and in bones. It has been suggested that the abnormal growth regulation in sarcoma cells may be due to an autocrine mechanism, in which the cells are stimulated by an endogenous production of growth factors. Platelet-derived growth factor (PDGF) has been detected in sarcomas, and may be one of the growth factors important for sarcoma growth.PDGF, originally discovered in platelets, is produced by, and binds to, a variety of cells. PDGF plays several roles both in normal conditions and in disease.Suramin is a polyanionic drug with antineoplastic activities, and is known to dissociate growth factors from their receptors. Suramin has been shown to inhibit growth in several tumors and tumor cell lines; however, some tumor cells have been unaffected, or even stimulated, by suramin.The present work was performed in order to a) examine the effects of suramin on sarcoma growth in vivo; b) investigate the kinetics of extravascularly administered PDGF in vivo; c) establish and characterize human sarcoma cells in vitro, including their relation to PDGF; d) evaluate the effects of suramin on sarcoma growth in vitro; e) compare the effects of PDGF on sarcoma growth in vivo and in vitro.Suramin was shown to inhibit growth of two different human osteosarcoma xenografts grown in nude mice. The action is believed to be mainly cytostatic, as the tumors continued to grow, albeit at a lower pace: the tumors of the suramin treated mice had a volume of one-third or less than the untreated ones. The percentage of cells in S and G2-M cell cycle phases was increased by suramin treatment, suggesting a selective effect of the drug in the S and G2 period.Blood and serum levels of 125I, after extravascular administration of 125I-PDGF-AB by intraperitoneal, intramuscular or subcutaneous injection in mice, were found to rise to a maximum 2-4 hours after injection. The levels of radioactivity persisted over several hours. Precipitiation of serum with 10% trichloracetic acid revealed that more than 50% of the radioactivity was in a macromolecular form. Gel chromatography of the serum showed that a major portion of the radioactive material in the circulation had the same molecular size as the original 125I-PDGF-AB.Eight cell lines derived from malignant fibrous histiocytomas (MFH) were established and characterized. A heterogeneity in the morphology of the MFH cell lines was noted. This heterogeneity was also reflected in the expression of mRNA for PDGF, transforming growth factor-alpha (TGF-/alpha/) and their receptors, ability to grow in serumfree media and secretion of PDGF into growth media. Two cell lines, able to grow in serum-free medium, coexpressed MRNA for PDGF, TGF-/aplpha/ and their receptors, suggesting that they may be regulated in an autocrine manner. However, other cell lines, unable to grow in a serum-free medium, also displayed this coexpression of mRNA. The simultaneous expression of a growth factor and its receptor is therefore not generally indicative of an autocrine mechanism.All cell lines, unable to grow in a serum-free medium, were growth inhibited by high-dose suramin (200 ug/ml). The two cell lines, previously noted to grow under serum-free conditions, were not affected by the high-dose suramin treatment. The finding that only serum-dependent human MFH cell lines were inhibited by high doses of suramin indicates that serum dependence in vitro may predict sensitivity of sarcoma cells to suramin.Two human sarcoma xenografts, one osteosarcoma and one malignant fibrous histiocytoma, were treated with human PDGF-AB when grown in nude mice. No effects on tumor growth were noted, although immunohistochemical studies revealed an expression of PDGF receptors. Furthermore, both sarcomas were markedly stimulated by PDGF-AB in vitro. It is concluded that mechanisms or factors other than available PDGF were limiting the growth of the examined tumors in vivo.
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| 2. |
- Abu-Zidan, Fikri M.
(författare)
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Role of platelet-activating factor in sepsis and shock : an experimantal study
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: To study the role of platelet-activating factor (PAF) on cardiovascular and pulmonary dysfunction in sepsis and shock.Design: Experimental study. Setting: Trauma research unit, university department of surgery, Sweden.Material: 76 juvenile domestic pigs. Interventions: The effects of a specific PAF receptor antagonist (BB-882) on haemodynamics and on PAF-induced haemodynamic changes were studied (n = 16). BB-882 was given as pretreatment in non-hypotensive Escherichia coli endotoxaemia (n = 9), during resuscitation after severe haemorrhagic shock (n = 7), hefore post-ischaemic shock which was induced by clamping the aorta above the coliac axis for 45 minutes (n = 8), and as pretreatment in post-haemorrhage septic shock: (n = 6). BB~882 groups were compared with controi groups having the same number of animals which received vehicle instead.Major outcome measures: Heart rate, intravascular pressures, cardiac output, pulmonary and systemic vascular resistance, arteriai blood gas tensions, lung thorax compliance, serum lactic acid and blood sugar concentrations, and packed cell volume.Results: BB-882 effectively counleracted the PAF-induced response on the mean systemic and pulmonary arteriai pressures. lt reduced the rise in pulmonary and systemic vascular resistance and improved the cardiac output in non-hypotensive and post-haemorrhage septic shock when given as pretreatment. lt reduced the hypertension in non-hypotensive sepsis and the hypotension in post-haemorrhage septic shock. BB-8B2 did not infiuence the endotoxin-induced hypoxia or reduced lung thorax compliance in non-hypotensive sepsis and post-haemorrhage septic shock. It did not improve the mean arterial pressure or the cardiac output in haemorrhagic shock alone but it reduced the systemic vascular resistanc'e and was associated with tachycardia and acidosis. It did not affect the post-ischaemic shock after clamping the aorta.Conclusion: PAF is a major mediator of the cardiovascular, but not pulmonary dysfunction in sepsis whether associated with shock or not, while its role on the cardiovascular dysfunction in haemorrhagic and post-ischaemic shock is small.
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| 3. |
- af Klercker, Tom
(författare)
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Method for inductive case-based decision support system over the Internet : exemplified by ear, nose and throat diagnostics in primary care
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is an example of an ear to loaf process:A Preliminary Essential Data Set (PEDS) for Ear, Nose and Throat (ENT) diagnostics in Primary Health Care (PHC) was established by infologic modelling of existing tractates, between the specialist organisations of ENT and PHC, and four contemporary text-books on the subject (I). The PEDS was then compared to the aggregated data from a sample of case-files from a Swedish PHC centre. The quality of the individual medical record was found to be poor and not sufficient for follow-up and Quality Management (QM) purposes (II). The aggregated data from the case-file sample was processed by an inductive "expert" computer program that generated a decision-tree, based on the total number of decisions (diagnoses) in the data-base. This was nearly identical to the PEDS and somewhat less complicated. Infological modelling of the PEDS and the decision-tree resulted in the proposed Essential Data Set (EDS) for ENT diagnostics in PHC. The decision tree was "pruned" to achieve simplicity and ease of use (III). It was converted into a Computer-aided Decision Support System (CDSS) and put on the Internet using World Wide Web (WWW) tools (IV). This system was then implemented in the Skänninge PHC centre where an Electronic Medical Record System (EMRS) was in everyday use. Due to technical difficulties no integration between the two systems was possible. The CDSS was run on a computer outside the centre and this raised the question of secrecy and security (V). Prior to the implementation, and after a study period of four months attitudes towards, and the acceptance of, new Information Technology (IT) was explored by using focus group methodology (VI). It is important that those who are to use the system are intimately involved in its development. The results showed, that participation of the end-users during implementation is crucial for its acceptance. The need for a uniform and agreed terminology was obvious to facilitate co-operation and QM. The importance of nurses and physicians using the same terminology for documentation, was paramount.
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| 4. |
- Alexandersson, Kristina
(författare)
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Sickness absence in a Swedish county : with reference to gender, occupation, pregnancy and parenthood
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The occurrence of sickness absence in relation to gender, occupation, age, pregnancy and parenthood was analysed in a Swedish county. Data on all new sick-leave spells exceeding 7 days in the county of Östergötland (400,000 inhabitants) were recorded in 1985-1987. Information on diagnoses, occupation, age, gender, number of children etc. for each of the 45,000 persons sicklisted/year were included in the database. Incidence measures were obtained using census data as denominator.The largest and most consistent variation in occurrence of sickness absence concerned occupation and gender, When categorising the occupations according to degree of gender-segregation, women in the extremely maledominated group (>90% men) had exceptionally high sick-leave rates, while both men and women in the group of gender-integrated occupations had significantly lower sick-leave rates. These variations with male-and female domination of occupational groups were found for sickness absence in general as well as for sick-leave due to pregnancy-related diagnoses. Men with custody of young children had the lowest sickness absence, young women in the same situation the highest, while there were no gender differences in persons without young children. Sickness absence due to pregnancy-related diagnoses varied to a large degree with occupation, but was still high in occupations with a generally low sickness absence, and increased much more than in any otherdiagnostic group over the three years. About half of the gender differences in sickness absence could be explained by sickness absence among pregnant women.In conclusion, the occurrence of sickness absence was associated with gender, age, occupation, gender segregation of occupation, pregnancy and parenthood. Further research should focus on etiological studies and intervention trials.
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| 5. |
- Almer, Sven, 1953-
(författare)
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Ulcerative colitis : Imaging of inflammation
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ulcerative colitis is a chronic inflannnatory disorder of unknown origin engaging the large bowel. Based on the need for accurate assessment of inflammation, three different non-invasive techniques, two leukocyte scintigraphy techniques and one radiological method, were evaluated in the assessment of active inflammation in altogether 131 patients with ulcerative colitis. Results were compared to those of endoscopy with biopsy, and with histopathological grading of depth of ulceration in colectomy specimens. Nine non-inflamed controls were also includedLeukoeyte scintigraphy using technetium-99m exarnetazime-labelled lenkocytes was found to reliably differ between patients with and without colonic inflammation. A good correlation existed between a simple visual scoring system of lenkocyte scans and colonic inflannnation viewed endoscopically and histologically in ulcerative colitis. In active disease, inflammation was better visualized with technetiurn-99m exametazimelabelled leukocytes than with technetium-99m anti-granulocyte antibody BW 250/183.Air enema radiology was of value in estimating severe mucosal inflammation in acute ulcerative colitis. Presence of faecal residue or a normal air enema film were associated with normal or only mildly inflamed mucosa at colonoscopy, i.e. a friable or ulcerated mucosa can be excluded. The absence of faecal residue or an abnormal finding at air enema X-ray were predictive of endoscopically inflamed mucosa. Air enema radiology underestimated the extent of inflannnation compared to endoscopy or lenkocyte scintigraphy. Air enema radiology was able to demonstrate presence of deep histopathological ulceration in the colectomy specimens from patients with an acute attack of ulcerative colitis.In conclusion, scintigraphy with technetium-99m exarnetazime-labelled lenkocytes can be applied in excluding or confirming bowel inflammation in individual patients, and, in assessing intensity and extent of ulcerative colitis. Air enema radiology should be a first-line investigation in acute colitis to assess the presence of mucosal or deeper ulceration.
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| 6. |
- Ander, Stefan
(författare)
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Preservation of parathyroid function in thyroid and parathyroid surgery
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preservation of normal parathyroid function and calcium homeostasis after operations on the thyroid and parathyroid glands is a difficult assignment in endocrine surgery, and it is crucial to minimise the risks of permanent postoperative hypoparathyroidism. The aim of this thesis was to study the vascular supply of the parathyroid glands and the revascularisation, growth, and function of transplanted parathyroid tissue, in order to add new information about parathyroid preservation.The microcirculation and blood supply of normal, hyperplas~c and adenomatous parathyroid glands were studied with laser Doppler flowmetry in 103 patients during operations on the thyroid and parathyroid glands. In normal parathyroid glands the blood flow was higher compared with that in hyperplastic glands and adenomas. Occlusion of the main trunks of the inferior and superior thyroid arteries reduced the blood flow by 35% and 25%, respectively. The reduction was similar in normal, hyperplastic, and adenomatous parathyroid glands. In 12 patients with single parathyroid adenomas, the increased concentration of parathyroid hormone (PTH) remained mainly unchanged despite appreciable reduction in blood flow. In 16 patients the microcirculation and macroscopic appearance of normal parathyroid glands located anteriorly on the thyroid lobe were analysed before and after dissection for in situ preservation. There was a poor correlation between reduction in blood flow and macroscopic appearance of the glands. Laser Doppler flowmetry (LDF) showed that the disturbed microcirculation often recovered 30-60 minutes after dissection for preservation.Parathyroid tissue obtained from 47 patients operated on for hyperparathyroidism was implanted subcutaneously in athymic mice. The processes of revascularisation, morphology, cell proliferation, and function of normal, hyperplastic, and adenomatous parathyroid tissue were studied at 2 and 4 days and 1, 4, 7 and 12 weeks after transplantation. Vessels were detected by monoclonal antibodies specific for mouse and human endothelial cells. The transplanted tissues were examined by light and electron microscopy and by autoradiography after continuous infusion of tritiated thymidine. The relative amount of viable tissue was assessed with a computer image-analysing program. Graft function was judged by measuring human iPTH in mouse serum.Over 90% of the transplants took and the original structure of the tissue was well preserved. Confluent areas of parathyroid tissue could be seen in 80% of the transplants. The mean loss of viable tissue in all three groups was 45%.Immunohistochemical examination showed ingrowth of vessels from the host into the transplant. The sprouts matured gradually into vessels with thin endothelial linings and capillary fenestrations in adenomatous and hyperplastic transplants but not in transplants of normal tissue.In normal parathyroid tissue the proliferation of parathyroid parenchyma! cells increased only slightly in contrast to the advancing proliferative capacity in adenomatous tissue. In contrast to adenomas, parenchyma! cell proliferative capacity in hyperplastic tissue decreased at 12 week.Concentrations of iPTH were raised at one week in hyperplastic and adenomatous tissue. Twelve weeks after transplantation iPTH concentrations in relation to the amount of transplanted tissue and relative area of viable tissue were comparable in all three groups of transplanted tissue.We conclude that, LDF is a feasible method to study physiological blood flow in human parathyroid glands. Parathyroid blood supply is not as dependent on the inferior thyroid artery as was previously suggested. LDF showed that blood flow recovered in parathyroid glands dissected for in situ preservation and any decision about autografting should be delayed until the end of the operation. Parathyroid transplants re vascularise from host vessels and this is more pronounced and proceeds faster in hyperplastic and adenomatous tissue than in normal transplants. In contrast to nonnal and hyperplastic transplants, adenomatous tissue has a greater and increasing proliferative capacity. The iPTH concentration as an expression of parathyroid function correlates poorly with parenchyma! cell proliferation.
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| 7. |
- Andersson, Kerstin
(författare)
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Inhibition of phagocyte signaling by the Yersinia virulence protein YopH
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Yersinia pseudotuberculosis evades the immediate immune defense of a host organism by inhibiting bactericidal functions of phagocytes, including phagocytosis, cytokine release, and the oxidative burst. Consequently, this pathogen can survive and multiply in lymphatic tissues. An ensemble of proteins called Yops are involved in the virulence of Y. pseudotuberculosis. Through a polarized mechanism, certain Yops are translocated directly into the host cell, where they are assumed to exert their effects. The present studies were performed to gain further knowledge about the role of the tyrosine phosphatase YopH in Yersinia virulence, especially in regard to effects on the immediate functions and signals of phagocytes.Y. pseudotuberculosis was found to resist phagocytic uptake by a mechanism involving translocation of bacterially synthesized YopH into the target cell. The antiphagocytic mechanism had an impact on ingestion of both non-opsonized and IgO-opsonized bacteria. Phagocytosis of a YopH-negative strain was accompanied by induction of tyrosinephosphorylated cellular proteins (among them paxillin), and this involved binding of the bacterial surface protein invasin to ß1 integrins of the eukaryotic cell, which also initiated an immediate Ca2+ signal in the target cell. The phosphotyrosine proteins Cas and FYB were recruited to the focal complex area during phagocytosis of the YopH-negative strain. Furthermore, we found that a phosphatase-inactive YopH eo-localized with focal adhesion to the periphery of a host cell. In phagocytes infected with wild-type bacteria, phosphatase-active YopH dephosphorylated Cas and FYB, which caused disruption of focal complex structures, and inhibition of the Ca2+ signal. The phosphorylation events as well as the Ca2+ signal were rapid responses to bacterial attachment, suggesting that the action of YopH is instantaneous.Genetic studies revealed that the YopH protein contain an inherent sequence important for anchoring at focal complex structures. Specifically, deletion of the amino acids 223-226 disabled YopH to localize to the focal complexes and to inhibit phagocytosis and Ca2+-signaling. This indicates that Y opH must bind to a specific site in focal complexes to focus its activity on the appropriate substrates (i.e. Cas and FYB). Our results show that targeting such complexes is important for Y. pseudotuberculosis, not only as a means of avoiding ingestion by phagocytes, but also for its virulence in mice.
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| 8. |
- Andersson, Roland, 1950-
(författare)
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Appendicitis : Epidemiology and diagnosis
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The study concerns appendicitis, its epidemiology and diagnosis, and the outcome of appendectomy. A population based cohort of 9,274 patients undergoing appendectomy in 1969 to 1990 in Jönköping County was retrospectively studied, and 502 patients admitted for suspected appendicitis to the hospitals in Jönköping and Eksjö between October 1992 and December 1993 were prospectively studied.Appendicitis was found to occur in outbreaks and space-time clusters, indicating an infectious etiology. The incidence of non-perforating appendicitis was strongly age-dependent, with a peak in adolescence, whereas the incidence of perforating appendicitis was stable at all ages. This suggests that perforating and non-perforating appendicitis are separate entities.There was a high rate of negative appendectomies, but during the study period an increasing diagnostic accuracy and decreasing incidence of negative appendectomies was observed, indicating a trend towards a more restrictive attitude to exploration in patients with suspected appendicitis. This was accompanied by a decreasing incidence of non-perforating appendicitis, whereas the incidence of perforating appendicitis was stable. An analysis of population based studies showed a strong relation between surgeons' attitude to exploration and the incidence of non-perforating ap9endicitis, whereas the incidence of perforating appendicitis was unrelated. This is consistent with a high proportion of potentially resolving appendicitis.A conservative management decreases the munber of negative explorations and saves a number of patients with resolving appendicitis from an unnecessary operation. This leads to a high proportion of perforations among the operated patients but the number of perforations is not increased. The perforation rate, therefore, should not be used as a quality measure of the management of patients with suspected appendicitis.The rate of negative explorations is higher in women. This gender difference is found at all ages and is not due to gynecological diseases alone. The explanation is the larger number of women attending for nonsurgical abdominal pain, whereas the rate of diagnostic errors among these patients is similar in men and women.Patients with a negative appendectomy are characterized by high intensity of pain and tenderness without signs of a systemic inflammatory response. Surgeons pay too much attention to pain and tenderness in their decision to operate, and underestimate the importance of temperature, laboratory variables and duration of symptoms.No single clinical or laboratory variable has sufficiently high discriminating power to be used as a true diagnostic test. The inflammatory variables are as important predictors as the clinical findings, and they are especially important in advanced appendicitis. Their diagnostic value is higher at a repeat examination after a few hours of observation.The study show for a need of an improved management of patients with suspected appendicitis, and the potential for improved clinical diagnosis. Inflammatory variables should be given more attention, and pain and tenderness should be interpreted more cautiously. An expectant management, with repeated clinical and laboratory examinations, is advisable once advanced appendicitis has been ruled out.
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| 9. |
- Andersson, Thomas
(författare)
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Cutaneous microdialysis : a technique for human in vivo sampling
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microdialysis enables in vivo sampling of endogenous and exogenous substances in the interstitial fluid. A probe equipped with a tubular semi-permeable dialysis membrane is inserted into the skin, and perfused with a physiological solution. Diffusion of molecules from the extracellular space to the perfusate takes place, and the perfusate is collected for analysis. In this thesis, experimental and clinical applications of human cutaneous microdialysis in the fields of skin inflammation and percutaneous absorption are presented.The in vivo absorption kinetics of the model solvents ethanol and isopropanol, applied in excess to the skin over the dialysis probe, could be demonstrated in all subjects. Ethanol levels increased in a linear fashion to reach a peak at about 100 min, then establishing a plateau level. Isopropanol absorption showed similar kinetics. The absolute levels detected were lower for isopropanol than for ethanol.Laser Doppler perfusion imaging visualized the skin circulatory response to the microdialysis probe insertion. An immediate increase in skin blood perfusion was observed. The response began to subside after 15 min and returned to near normal within 60 min after probe insertion.Histamine, a ubiquitous inflammatory mediator, was studied as a model. Following the skin trauma caused by probe insertion, peak histamine levels were observed in the first 10-min sample, then falling successively to reach baseline within 40-60 min. Multiple regression analysis did not reveal any correlation between probe depth, as measured by ultrasoundtechnique, and obtained histamine levels during the equilibration period following probe insertion. Provocation with compound 48/80 as a positive control for skin histamine release, resulted in increased histamine levels in the perfusate. Histamine release was followed in reactions provoked in the skin of patients with cold urticaria. An up to 80-fold increase of histamine levels was observed, with peak levels 20-30 min after start of ice provocation, returning to baseline within 50-60 min.Human, in vivo, cutaneous microdialysis has the potential to be an important sampling method in studies of skin inflammation and percutaneous absorption of noxious chemicals as well as in dennal and transdermal drug delivery studies.
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| 10. |
- Arbman, Gunnar
(författare)
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Colorectal cancer in Östergötland : risk factors, diagnosis, and quality of treatment
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this investigation colorectal cancer in the county of Östergötland has been studied with emphasis on risk factors, diagnostic efforts, and the results of treatment.In two case-control studies on food and colorectal cancer, a decreased risk was associated with a high intake of cereal fibre, total fibre, and calcium per unit energy consumed as well as a high intake of raw vegetables. Processed meat was associated with an increased lisk for colon cancer and alcohol with an increased risk for rectal cancer. Drug consumption was also found to influence the cancer risk.In a case-control study on occupational factors and the risk for colorectal cancer, some occupations seemed to influence the risk for colon and rectal cancer in different ways. Twenty years of physically active work significantly decreased the risk for left-sided colon cancer but increased the risk for rectal cancer. Accordingly, twenty year of sedentary work significantly decreased the risk for rectal cancer.Known risk factors were found in 12% of colorectal cancer patients, though previous cholecystectomy did not turn out to be a risk factor.The symptoms of colon cancer are vague and unspecific, whereas bleeding is prominent and a dominating symptom in rectal cancer. Conflicting results have been presented regarding the importance of a short delay between onset of symptoms and treatment. In our study, a more favourable stage distribution was found for rectal cancer with a very short delay between start of symptoms and treatment, but not for colon cancer.Results of treatment for colorectal cancer show considerable variation in different series, which can be due to differences in selection and classification as well as in treatment. A computerized system for quality assurance of colorectal cancer was introduced in Östergötland in 1984. All cases diagnosed 1984-1986 were registered in this system, making it possible to study outcome of treatment for an unselected population. The results of treatment in terms of postoperative mortality and five year survival were comparable to the results from specialised international centres, but local recunence rate after operation for rectal cancer was high (20%).To reduce this local recurrence rate, the technique of total mesorectal excision was introduced in three of the surgical departments in the county. Using the system for quality assurance, the local recunence rate during a three year period before the change in technique was compared with a three year period when the new technique was used. The local recunence rate was significantly reduced in the later period without any change in postoperative complications.In conclusion this study shows an environmental influence on cancer-risk that may be different for colon and rectal cancer. The usefulness of a continuous quality assurance system to detect shmtcomings in diagnosis and treatment and to evaluate new techniques is also shown. Finally, total mesorectal excision reduces the local recurrence rate for rectal cancer in an unselected population treated in different kinds of hospital.
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