| 91. |
- Kald, Bengt
(författare)
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Platelet-activating factor, intestinal epithelial cells, and Chron's disease : An experimental study
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelet-activating factor (PAF-acethcr, 1-0-alky l-2-acetyl-s n- glycero-3- phosphocholine), is a potent inflammatory mediator that can be formed by a variety of cells and tissues. In the present investigation, the content of PAFacether was determined in mucosal biopsies from the ileum and colon of patients with Crohn's disease and control patients. PAF-acether was found in both groups and was raised in patients with Crohn's disease, both in the ileum and colon.Colonic PAF-accther content was raised irrespective of the presence of colonic inflammation as judged macroscopically. The activity of PAF acetylhydrolase in ileal biopsies was lower in patients with Crohn's disease than in controls, and patients with high disease activity had lower PAF acetylhydrolase activity in plasma than patients in clinical remission or healthy subjects. PAF-acether was also found in small intestinal and colonic mucosa of neonatal rats and was found to decrease as the proportion of epithelial cells decreased during early postnatal development. Cultured intestinal epithelial cells (INT 407 cells) produced PAFaccther when stimulated with calcium ionophorc (A23187) or with phospholipase C from Clostridium perfringens, a naturally occurring bacterial toxin in the intestine. Phospholipase C increased the formation of PAF-acether in INT 407 cells, but did not increase the level of lyso PAF-acethcr. The phospholipase A2 inhibitor 4-bromophcnacyl bromide (BPB) had no significant effect on the PAF- and lysoPAF-acether formation, wheras the calmodulin inhibitor trifluoperazine (TEPA), and the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)- -methyl-piperazine (H-7), decreased the PAF-acether formation, but not the lysoPAF-acether formation. Tumor necrosis factor-alpha (TNA-alpha) potentiated phospholipase A2-mediated release of arachidonic acid (AA), after stimulation with phospholicpase C, withour affecting the formation of PAF-acether.These findings indicate that intestinal epithelial cells are able to produce and metabolize PAF-acether, and that increased PAF-acether formation in INT-407 can be evoked by phospholipase C from Clostridium perfringens , a naturally occuring bacterial toxin. Moreover, the findings add further support to the impirtance of bioactive lipids in inflammatory bowel bowel disease and suggest a possible role for PAF-acether in Croh's disease
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| 92. |
- Karlsson, Margareta, 1942-
(författare)
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DNA ploidy, proliferation markers and prognosis in malignant melanoma
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant melanoma is a serious disease when metastases occur. It is therefore important to investigate possible tools for prediction to the outcome of the disease. In the present investigation 265 patients with cutaneous malignant melanoma and uveal melanoma was investigated with flow cytometry.In 82 patients with stage Ill cutaneous melanoma we found that the DNA ploidy and S-phase fraction on the primacy tumours and the time to the first metastases predicted the post-recurrence survival. Patients with diploid melanoma cells, low S-phase fraction and a long recurrence free interval had a rather favourable prognosis despite presence of regional metastases. In 55 subjects a significantly higher frequency of aneuploidy was found in metastases compared to the primary tumour of the same patients, suggesting a higher growth potential in metastases.A high S-phase fraction measured on the last histologically metastases before chemotherapy treatment was associated with an objective response and a longer survival in 87 patients with disseminated melanoma. The anatomical location of the metastases also predicted objective response, and together with a high S-phase fraction, a large number of metastatic sites and objective response were associated with survival.DNA ploidy together with histopathologic type and tumour size could predict the survival in 96 patients with uveal melanoma. A small, diploid tumour of spindle-cell type gave a significantly longer survival than a large, aneuploid tumour of epithelioid-cell type. In univariate statistical analysis the S-phase fraction predicted survival, but did not remain as a prognostic factor after adjustments for ploidy, histologic type and tumoursize. DNA ploidy and S-phase fraction were correlated with well-known histopathologic features. The proliferation marker Ki-67 was correlated with well-known histopathological features and associated with survival in 79 patients. This was not the case with the proliferation marker PCNA. Patients with uveal melanomas containing a high percentage of Ki-67 positive nuclei had a significant shorter survival than those with a low percentage.
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| 93. |
- Karlsson, Magnus
(författare)
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Ganglionic nerve fibres in ventral roots
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- According to the law of Magendie, the ventral roots channel efferent nerve fibres from the spinal cord to the periphery, while the dorsal roots channel afferent axons from the periphery into the spinal cord. However, as sensory C-fibres have been observed in mammalian ventral roots outside the autonomic outflow, this law has been questioned. On the basis of other observations, though, ganglionic axons have been suggested not to enter the spinal cord via ventral roots. This thesis presents data on the occurrence of C-fibres in simian ventral roots and provides some new aspects on the occurrence, configuration and function of putative ganglionic ventral root axons in the rat.Paper I shows that putative ganglionic C-fibres occur in the primate ventral root L7, which is outside the autonomic outflow. Like in the cat, these axons do not seem to enter the spinal cord via this root. The ventral root SI does also contain C-fibres, but it seems that these fibres are preganglionic autonomic axons. Some putative ganglionic fibres are also present in the lumbosacral spinal pia mater. Hence, these results conform with the law of Magendie. Paper II shows that putative afferent axons in the rat ventral roots L4-S 1 take a longitudinal course, make zig-zag deviations, loop, branch, end blindly or shift to the spinal pia mater. No putative afferent axons enter the spinal cord via ventral roots. These results agree with the law of Magendie. The results of Paper III suggest that sensory and sympathetic ganglionic axons grow into the rat ventral roots L4-L5 and corresponding pia mater during postnatal development. The afferent axons course as decribed in Paper II. The postganglionic sympathetic axons sometimes loop, but most of them enter the pia mater where they usually associate with blood vessels. A few putative sympathetic fibres enter the spinal cord via ventral roots. Some extra postganglionic sympathetic fibres may enter ventral roots during aging. Paper IV shows that putative afferent rat ventral root axons arecapsaicin-resistant and that they fail to evoke plasma protein extravasation in the root and pia mater. In this respect, they differ from similar axons at many other peripheral locations. The results of Paper V show that C-fibres invade the rat ventral root L5 after neonatal, but not adult, sciatic nerve crush. The extra axons do not seem to represent afferents. At least some proportion of these axons seem to represent putative postganglionic sympathetic axons.
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| 94. |
- Kirkegaard Kjølhede, Preben
(författare)
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Burch colposuspension and the pelvic floor
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Burch colposuspension is a surgical method for treatment of stress urinary incontinence, which has become popular due to a high cure-rate. A number of patients, however, develop recurrent urinary incontinence after the colposuspension, or other disabling conditions, such as genital prolapse or voiding difficulties.The study material consists of 243 women with stress urinary incontinence operated on with Burch colposuspension during 1980-88, 57 women with primary stress urinary incontinence assessed during 1991-93, and 16 healthy continent female volunteers.The aims of the study were to investigate the long-term results of the Burch colposuspension, to evaluate the occurrence of genital prolapse and neuropathy in the pelvic floor muscles in relation to the outcome of Burch colposuspension with regard to urinary continence, and to evaluate whether defecography, anorectal manometry and gynecological examination could predict the development of genital prolapse demanding surgery after Burch colposuspension.The study shows that the short-term cure-rate of the Burch colposuspension was high, 95.6%. Median 6 years after the operation 63% were subjectively continent. A further 27% of the women were improved. Prognostic factors for an unsuccessful outcome were immediate and long-tetm voiding difficulties postoperatively, postoperative febrile morbidity, recurrent lower urinary tract infections and previous anti-incontinence operations. After the colposuspension, 15% of the women had been operated on for posterior vaginal wall prolapse.Women, who have recurrent stress urinaty incontinence, seem to have a more pronounced pelvic floor weakness, demonstrated as a higher incidence of rectocele and cystocele, and neurogenic EMG patterns in more muscles in the pelvic floor, than women who are continent after Burch colposuspension.The preoperative gynecological examination, the defecography and the anorectal manometry do not seem to be able to predict the development of genital prolapse demanding surgery after Burch colposuspension.The associations between the occun·ence of genital prolapse and neurogenic EMG patterns, respectively, and the outcome of the Burch colposuspension with respect to continence, demonstrated in the present study, might support the theory that neuromuscular changes in the pelvic floor are contributing factors for the development of recurrent urinary incontinence and genital prolapse after Burch colposuspension. The etiology of recurrent urinary incontinence and urogenital prolapse seems to be multifactorial. Larger prospective studies are however needed to solve the important problems concerning the influence of the neuromuscular function of the pelvic floor on the outcome of anti-incontinence surgery and on the development of genital prolapse.
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| 95. |
- Kjellgren, Karin I.
(författare)
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Antihypertensive medication in clinical practice : Aspects of patient adherence in treatment
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adherence to antihypertensive drug regimens is a well-documented determinant of blood pressure control. A review of the literature shows that little attention has been paid to how antihypertensive medication is managed in clinical practice.The aim of the empirical studies was to document and analyse the prerequisites of patient adherence to antihypertensive medication in routine clinical practice. The studies are based on two complementary sets of data, generated through intensive and extensive studies. In the intensive studies, audio-recordings (n=51) of follow-up appointments with hypertensive patients and their physicians were made in order to explore the nature of interaction ih routine clinical practice. Afterwards, patients (n=33) were interviewed to assess their knowledge of high blood pressure and antihypertensive medication. The extensive studies were population-based and carried out at Swedish primary health care centres (n=55) and clinics of internal medicine (n=ll). The intention of these studies was to assess perceived symptoms among hypertensive patients with (n=l 013) and without (n=l35) antihypertensive medication. Furthermore, concordance between the patients' and physicians' (n=212) views regarding risks of hypertension and benefits from antihypertensive medication was analysed.Most patients had a passive role and initiated few topics during the consultations. Little time was invested in discussing risks related to hypertension. The interviewed hypertensive patients had an unsatisfactory understanding of their condition and of the effects of the medication. The prevalence of perceived symptoms did not differ between patients with and without antihypertensive medication. Patients estimated the effects of medication to be more beneficial than did their physicians. Trade-offs between perceived benefits and side-effects of drug treatment showed that patients were generally unwilling to endure side-effects in return for long-term benefits of treatment. In routine clinical praxis, 14% of the antihypertensive medicated patients had reached a blood pressure o:;l40/90 mm Hg. Target values above 140/90 mm Hg were given for 63% of the patients by their physicians. Among patients who where aware of their target blood pressure, we found close agreement between the values given by patients and physicians. This implies that when the target blood pressure is communicated in clinical practice, the patients remember quite accurately.Better control of hypertension and coexisting risk factors is an essential objective in clinical practice. From the studies, two factors stood out as. important to improve adherence: more knowledge-sharing with the aim of increasing self-care competence and more effort to reduce side-effects of treatment.
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| 96. |
- Kristenson, Margareta, 1950-
(författare)
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The LiVcordia Study : Possible causes for the differences in coronary heart disease mortality between Lithuania and Sweden
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In recent decades coronary heart disease (CHD) mortality has declined in Western Europe and increased in Central and Eastern Europe. A large difference in CHD mortality has developed and the causes are not known. Lithuania and Sweden had similar CHD mortality rates for middle-aged men twenty years ago but in 1994 this mortality was four times higher in Lithuania than in Sweden. Also within countries CHD mortality is higher in low socioeconomic groups.Aim of the study: The LiVicordia (Linköping-Vilnius-coronary-artery-disease-risk-assessment) study aimed at identifying possible explanations for the different CHD mortality rates in the two countries.Method: This cross-sectional study concomitantly compared 150 randomly sampled 50-year-old men in each of the cities Vilnius, Lithuania and Linköping, Sweden from October 1993 nntil March 1995 using identical, standardised methodology. Investigations included a broad range of traditional and psychosocial risk factors for CHD, measures of oxidative stress, a standardised laboratory stress test and ultrasound measures of Peripheral atherosclerosis.Results: The differences found in traditional risk factors for CHD were small. Systolic blood pressure (SBP) was higher in Vilnius men, smoking was similar and plasma LDL cholesterol levels higher in Linköping men. Lower serum levels of the lipid soluble antioxidant vitamins carotene, lycopene and ytocopherol were found in Vilnius men, and also a higher susceptibility of LDL to oxidation in vitro. An unfavourable pattern of psychosocial risk factors for CHD: job strain, social isolation, depression and vital exhaustion characterised Vilnins men, who also showed an attenuated cortisol response to the laboratory stress test. This stress response has earlier been shown in states of chronic stress; loss of dynamic capacity to respond to new demands may be a predisposing factor for disease. Vilnius men had more peripheral atherosclerosis; thicker intima media, more and larger plaques and greater stiffness. Measures of atherosclerosis related to SBP, smoking, LDL cholesterol arrl P-carotene. The same unfavourable profile of risk factors for CHD, which characterised Vilnius men, was also found in underprivileged groups withip the cities. There were few differences in traditional risk factors.Conclusions: Thus, based on our survey on risk factors for CHD, it can be stated that traditional risk factors seem not to explain the different CHD mortality rates between Lithuania and Sweden. Possible alternative explanations are psychosocial strain and oxidative stress. These factors were also found among men in underprivileged groups within the cities. Therfore the influence of the risk factors studied may be relevant also for socioeconomic inequalities in CHD mortality within countries.
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| 97. |
- Kullberg, Carin E.
(författare)
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Long-term glycaemic control and complications in Type 1 diabetes
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The impact of long-term glycaemic control, assessed by HbA1c measurements for five years or more, on diabetic retinopathy, nephropathy, and impaired vibration perception threshold was investigated in adult patients with Type 1 diabetes mellitus. Type 1 diabetes was defined as onset of diabetes before the age of 31, with insulin therapy introduced within 6 months from onset, and with no other known cause of insulin deficiency. A comparison of glycated haemoglobin values, as assessed in different long-term studies of the relationship between glycaemic control and diabetic complications was also made.High long-term mean HbA1c was shown to be strongly associated to development of proliferative retinopathy and nephropathy, and the severity of background retinopathy and impairment of vibration perception threshold in patients with 5-25 yr duration of diabetes. Patients who developed proliferative retinopathy had a long-tenn mean HbA1, of 8.9% (95% Cl 8.1-9.6%, nonnal range 3.5-5.5% HbA1,), and patients who developed nephropathy had a long-term mean HbA1c of &.8% (95% Cl 7 .8-9.9%) prior to the diagnosis of these complications. Patients with HbA1c >8% also had a relative risk of 6.3 (95% Cl 2.9l00% above the normal range, and no patient with HbA1c below 6.5% had> 100% elevated VPT.Low long-term HbA1c was a beneficial factor for avoidance of retinopathy, but was of less importance to prevent microalbuminuria after more than 20 yr of diabetes. No patient with long-term mean HbA1c above 7.3% avoided retinopathy for such a long period, while patients with normoalbuminuria had HbA1c values in the range 4.6-9.9%.Men tended to have more severe lesions than women, without a corresponding gender difference in glycaemic control. Elevated blood pressure was found to be associated with nephropathy, retinopathy, and impaired vibration perception threshold.In the comparison of glycated haemoglobin values from different long-term studies of glycaemic control and complications of diabetes, the differences between the highest and lowest results of the same sample were, on average 2% HbA1c. This difference is of the same magnitude as the reported difference in glycaemic control between intensified and regular treatment in interventional studies.In conclusion, long-term mean HbA,c is a strong predictor of diabetic complications in the individual patient. Standardisation of HbA1c methods, regular monitoring of HbA1c, and intervention aiming at avoidance of poor glycaemic control is therefore essential.
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| 98. |
- Källman, Jan, 1958-
(författare)
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Group B streptococcal infections in neonates : Clinical and pathogenic aspects
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Clinical and pathogenic aspects of Group B streptococci (GBS), as a major pathogen responsible of invasive disease in newborn infants, were investigated.Cases of neonatal septicaemia during 1981-1994 were studied at Orebro Medical Centre Hospital. 132 children ful1filled laboratory and clinical criteria for neonatal septicaemia. The annual incidence increased significantly, from 2.3 cases during the first 7-year period to 3.3 per 1000 live births during the second 7-year period. The increase in incidence between the two 7- year periods was almost entirely due to an increase in Staphylococcus aureus ( from 9 to 32, pTo study the ability of GBS to adhere to the target cell, a cell-culture model with human umbilical vein endothelial cells (HUVEC) was used. Clinical isolates of serotype Ill adhered significantly (p=O.OOOl) better than other serotypes. Isogenic variants of serotype Ill with low amounts of capsule substance adhered significantly (p=O.OOl) better to the HUVEC than variants expressing high amount of capsule substance. The role of GBS capsular substance as a major virulence factor is further underlined by the fact that it impair the phagocytic capacity by polymorphonuclear leukocytes (PMNL). Growth conditions for GBS, simulating different in vivo environments, greatly affect capsule expression.The extent of and the penetration route of GBS over epithelial linings was examined with a model using Madin Darby Canine Kidney cells (MDCK). It was demonstrated that GBS can penetrate intact polarized MDCK cells by transcytosis in a selective apical-to-basolateral direction and the mechanism for this is metabolically dependent.In a chemiluminescence assay (CL), PlviNL function and opsonic capacity were shown to be significantly impaired in neonates and correlate to maturation of the newborn child. This combined defect in cellular and humoral defences may contribute to the increased susceptibility to GBS infection in preterm infants.In a prospective study in newborn having suspected sepsis, IL-6 and C-reactive protein (CRP) were measured early. Early-sampled IL-6 levels were significantly better than early-sampled CRP levels in distinguishing between mild respiratory disorders and septicaemia in the newbom child.
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| 99. |
- Landtblom, Anne-Marie, 1953-
(författare)
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Epidemiological and radiological aspects of multiple sclerosis
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The first aim of this investigation was to analyse possible risk factors for multiple sclerosis (MS) with focus on animal contacts and occupational exposures, especially to organic solvents. Another aim was to search for specific features in solvent-exposed MS patients mainly by the radiological techniques magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ( 1 H MRS) and also by cerebrospinal fluid (CSF) analysis along with a disability scoring. A further aim was to use 1 H MRS to investigate the metabolite status of brain lesions in the three established clinical subtypes of MS and to analyse for possible differences that may explain their different clinical and pathological characteristics. Finally, the national and countywise distribution of MS in Sweden was investigated during a forty year period by mortality and disability statistics. Both a case-control study and a best evidence synthesis with metaanalyses indicated an about doubled risk of MS from exposure to organic solvents, most clearly demonstrated for the male gender. MRI, 1 H MRS, CSF analyses and disability scoring showed no significant difference between the solvent-exposed and non-exposed MS patients, with one exception. Hypointensity in the basal ganglia, known from other studies of solvent-exposed persons, were overrepresented in the exposed MS patients. There were no differences in metabolite status of MS lesions in relapsing remitting, secondary progressive or primary progressive MS. One MRifl H MRS study showed ringlike appearances and lactate in two MS plaques during relapse, interpreted as oedematous transition forms between acute and chronic lesions. Finally, highly significant geographical variations in MS mortality were found, indicating real fluctuations, as well as a possible increase over time. Vämland county had a constantly high mortality and disability pensioning frequency during forty years and was therefore analysed municipalitywise which revealed a small high risk zone in two northern districts.
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| 100. |
- Larsson, Marie
(författare)
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Dendritic cells from human blood : Antigen handling and expression of adhesion molecules
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dendritic cells are a system of professional antigen-presenting cells that initiate the immune responses. Dendritic cells are widely distributed in the body, both in nonlymphoid tissues, lymphoid tissues and fluids of the body. Dendritic cells arise from the bone marrow and can be classified into interstitial dendritic cells in nonlymphoid tissues, interdigitating dendritic cells in secondary lymphoid tissue, dendritic cells in blnod and veiled cells in lymphatics. They can exhibit differences in each of these compartments that relate to maturation state and microenvironment.Dendritic cells process and present antigens efficiently in situ and stimulate responses from naive and memory T cells in the paracortical area of secondary lymphoid organs. Properties contributing to the dendritic cells' specialized function are the efficiency in clustering T cells and giving the right signals needed to activate naive and resting T cells. The present work was focused on elucidating some key properties of DC biology. The results show that mature human blood dendritic cells express sialyl Lewis x (CD15s), sialyl Lewis a, CD44 and CD77. Adhesion of mature blnod dendritic cells to activated endothelium (human umbilical cord endothelial cells) involves Eselectin. Immature blnod (cytokine-driven) dendritic cells use FcyRII for uptake of IgG immune complexes. Annexin V is involved in antigen trafficking in the endocytotic pathway of soluble proteins in mature blood dendritic cells. Immature blood dendritic cells (cytokine-driven) have the capacity to handle uptake of both soluble and microbial antigens, via fluid-phase pinocytosis, receptor-mediatedendocytosis and phagocytosis. No productive infection of influenza virus and no exogenous ll..-2 is demanded when dendritic cells are used as antigen-presenting cells. Dendritic cells induce cytotoxic T cells even with attenuated influenza A virus.
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