| 1. |
- Svantesson, Cecilia
(författare)
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Respiratory mechanics during mechanical ventilation in health and in disease
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The elastic pressure-volume (Pel-V) curve of the respiratory system can be used as a guide for improved ventilator management. It may indicate risks of lung damage associated with collapse or overdistension of lung units. The work described in this thesis was aimed at developing methods for the determination and characterisation of the Pel-V curve under static and dynamic conditions and at a better understanding of the Pel-V relationship in health and disease. A Servo Ventilator 900C, controlled by a computer, allowed standardised and accurate recording of extended Pel-V curves. The flow interruption technique was used to determine static Pel-V (Pel,st-V) curves and viscoelastic pressure-volume loops. A method for the determination of the dynamic Pel-V curve during a single prolonged insufflation, which can be used in clinical routines, was developed. An iterative technique was applied for the estimation of parameters characterising the elastic and viscoelastic behaviour of the respiratory system according to linear and non-linear models. During ventilation with small tidal volumes, the Pel,st-V curve was essentially linear in health and disease. At larger tidal volumes it was non-linear. Hysteresis in the Pel,st-V curve was very small in healthy humans and rabbits and in patients with critical lung disease of various kinds. The viscoelastic behaviour was best described by a non-linear model. The high viscoelastic recoil pressure observed at high volumes may contribute to lung damage. The influence of collapse and recruitment on the Pel-V curve in healthy subjects is not limited to the lower part of the curve, but extends up to high volumes and pressures. The conceptual and technical development, as described in this thesis, will hopefully pave the way for a better general understanding of the physiology behind the features of the Pel-V curve and for its use in ventilator management in clinical routines.
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| 2. |
- Wallin, Lena
(författare)
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99mTc-DMSA renal scintigraphy in the diagnosis and follow-up of acute pyelonephritis in children.
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the present thesis was to define and evaluate a strategy for identification of children who are at risk of developing progressive renal lesions after acute pyelonephritis. Tc-DMSA renal scintigraphy is widely accepted as the most sensitive method for detecting parenchymal lesions and diagnosing acute pyelonephritis. Qualitative and quantitative evaluation standards were elaborated to improve the interpretation of DMSA scintigraphy. The normal DMSA distribution pattern, the average background uptake, and scintigraphic kidney length according to age were assessed in 95 presumably healthy kidneys. Furthermore, typical DMSA distribution patterns in acute pyelonephritis were assessed on 65 kidneys in 38 children, and typical DMSA distribution patterns of 152 kidneys with vesicoureteric reflux in 101 children with and without previous pyelonephritis. Measurement of scintigraphic kidney length, width and volume was validated in piglets and on a kidney phantom. The scintigraphic kidney length was found to be an accurate measure of renal size, whereas kidney width and volume were less reliable, at least on small kidneys. Criteria of kidney swelling in acute pyelonephritis were defined, and found to be beneficial for identifying reinfections in the absence of clinical symptoms. In 34 children with acute pyelonephritis quantitative and qualitative DMSA scintigraphic findings were correlated to clinical symptoms and laboratory data, in the acute stage and at follow-up. We found that a quantitative DMSA scintigraphy in the acute stage of pyelonephritis and again after one year will identify children who are at risk of developing progressive renal lesions. Qualitative assessment of DMSA distribution pattern is not reliable enough in this respect.
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| 3. |
- Melin, Tor
(författare)
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Early steps of Eicosanoid precursor absorption and tissue distribution.
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Eicosanoids are important for a wide range of physiological and pathophysiological processes.How their essential fatty acid precursors are absorbed and tissue distributed is not well charactherized. When given orally to rats, arachidonic acid (20:4) was retained in the small intestine to a larger extent than linoleic acid (18:2).More 20:4 than 18:2 was incorporated in phospholipids (PL) of the small intestine, with the strongest preference for phosphatidyl ethanolamine and phosphatidyl inositol. More of the 20:4 than of 18:2 was directed to the liver. Essential fatty acid deficient (EFAD) rats had an increased incorporation of 18:2 in all tissues, and an increased PL incorporation of both 20:4 and 18:2 compared to controls. EFAD human HepG2 cells had an increased delta-6- and delta-5-desaturase activity. Both enzymes had a rate limiting function.Chylomicron 20:4- and 20:5-diacylglycerol esters were resistant to in vitro incubations with lipoprotein lipase (LPL) but not to hepatic lipase.18:2 and other shorterchain fatty acid esters were not LPL resistant. When 20:4 was injected intravenously to rats, 8% of the dose was secreted in the bile during 24h. Diverting the bile with a drain decreased the recovery of small intestinal 20:4 by 75%, but did not decrease the recovery in stomach and colon. The pools of 20:4 injected i.v. in albumin bound form and injected esterified in chylomicrons did not equilibrate even after 96 h. The selective chanelling of 20:4 to the liver via chylomicrons, and biliary secretion, points to an enterohepatic circulation of 20:4.
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| 4. |
- Verbaan, Hans
(författare)
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Chronic hepatitis C infection. With special reference to prevalence, aggravating factors and longterm outcome
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the discovery of hepatitis C virus (HCV) in 1989, it has proved to be a formidable health problem with a major impact on morbidity and mortality throughout the world. In this investigation, patients with chronic hepatitis C infection have been studied with special reference to prevalence, aggravating factors and longterm outcome. The prevalence of HCV infection was high (approximately 10 %) among patients assessed because of chronic liver disease. Although most patients were asymptomatic at entry, the majority of liver biopsied patients with HCV infection manifested histological changes such as CPH, CAH and cirrhosis. A parenteral route of HCV transmission was established in the majority of antiHCV positive patients, and the frequency of community acquired chronic hepatitis C was low. Non-invasive assessment to predict histological grade and stage appears to be of limited value. Individual test results were characterized by considerable overlap between the histological groups, and PIIIP, CLIV and IgG seem to be nonspecific correlates of histological activity. The rate of development of severe liver disease among HCV positive patients appears to be dependent both on endogenous and exogenous factors. Alcohol abuse and ACT deficiency were both independent risk factors for the development of cirrhosis. A high proportion of HCV infected individuals are at serious longterm risk of severe or fatal illness. During a median followup time of 10 years, more than 60 % of the deceased HCV positive patients developed cirrhosis, and approximately 30 % had concomitant HCC.
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| 5. |
- Endre, Tomas
(författare)
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The hypertension-prone man: A study on the pathogenesis of hypertension with regard to insulin sensitivity
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypertensive individuals, even non-obese, have been shown to be resistant to the insulin-mediated glucose uptake in peripheral tissues {mainly skeletal muscle}. The aim of this study was to investigate hypothetical pathophysiological mechanisms for the development of hypertension with regard to insulin sensitivity in normotensive men with a family history of hypertension (RELs) as compared to men with no such family history (CONs). RELs were resistant to the insulin-mediated glucose uptake and had a lower maximal oxygen uptake. There was a positive correlation between insulin sensitivity and maximal oxygen uptake in both groups. When compensating for differences in maximal oxygen uptake the differences in insulin sensitivity disappeared. RELs had retained insulin-mediated forearm vasodilation. Thus, skeletal muscle blood flow did not seem to be the major determinant of glucose disposal. On the other hand, the positive correlation between glucose disposal and the decrease in forearm vascular resistance found in RELs suggests that insulin-induced vasodilation may be a limiting factor for glucose uptake in insulin-resistant individuals. REL had less capillaries per FTb muscle fiber and marginally greater diffusion distance from the capillary to the muscle cell, which may be a contributory factor to low insulin sensitivity in RELs. There was no difference in glycogen synthase activity between the groups so this can not explain the lower glucose disposal rate in RELs. Insulin sensitivity may also partly be influenced by the effect of testosterone on glycogen synthase activity. REL had lower concentrations of SHBG and total testosterone, but similar free testosterone levels. The most likely explanation for this is that the SHBG level is primarily influenced by the relative hyperinsulinemia induced by the lower insulin sensitivity. Serum triglycerides and LDL/HDL ratio were elevated in RELs RELs had retained insulin-stimulated tubular sodium reabsorption, which in a hyperinsulinemic state may cause sodium retention. The lack of suppresion of aldosterone secretion during insulin infusion in RELs may also add to the enhancement of sodium retention and contribute to the development of hypertension. RELs had decreased fibrinolysis but also higher levels of several anti-coagulant proteins. The clinical implication for these disturbances for future development of cardiovascular disease warrants additional studies. In conclusion, men with a family history of hypertension are insulin resistant, have a lower physical capacity, and fibrinolytic capacity, as well as elevated blood lipids as compared to controls, a constellation that may make them more prone to develop cardiovascular disease. The lower capillarisation of skeletal muscle and a more insulin-resistant muscle fibre profile may partly explain the lower insulin sensitivity. The retained antinatriuretic effect of insulin and decreased aldosterone suppression during insulin infusion may enhance sodium retention and initiate blood pressure elevation.
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| 6. |
- Persson, Jerker
(författare)
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Ultrasound and atherosclerosis. Evaluation of methods, risk factors and intervention.
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The importance of studying cardiovascular disease before the process leads to hard end-points has been recognised, and methods to quantify early atherosclerosis have been taken in use in many research centres around the world. An ultrasound method with a computer assisted image analysing system was developed in co-operation with the Wallenberg Laboratory for Cardiovascular Research and Chalmers University of Technology in Gothenburg, Sweden. The objectives of the studies were to determine the validity and reproducibility of the method, to describe the associations between known cardiovascular risk factors and as well ultrasound-determined degree of atherosclerosis cross-sectionally as progression of these parameters, and to elucidate the effects of multifactorial intervention on cardiovascular risk factors. The method proved valid and reproducible when evaluating early atherosclerosis, reflected by intima-media thickness (IMT) in the Carotid artery. Measurements of IMT in the Femoral artery and plaque size were less reproducible. In multiple regression models, ultrasound-determined degree of atherosclerosis cross-sectionally, as well as change in the degree, correlated to known cardiovascular risk factors with small differences between men and women. However, in general, the degrees of explanation were low in the multiple regression models, and the strongest determinator of progression in IMT, plaque occurrence and degree of stenosis were the baseline values, reflecting regression towards the mean. In a small pilot study, multifactorial intervention on cardiovascular risk factors resulted in no measurable effect on ultrasound-determined progression of atherosclerosis. Using the experience gained from our studies, the ultrasound method is well-suited for application in research on atherosclerosis progression and regression. In prospective studies, to avoid regression towards the mean, duplicate investigations at baseline and follow-up are recommended. In intervention studies, a more aggressive pharmacological treatment than what was the case in our study, should be applied after proper sample size calculations.
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| 7. |
- Östraat, Öyvind
(författare)
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Experimental modulation and suppression of anti-allograft immune response
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract The objective of this investigation was to characterise the immunomodulatory or immunosuppressive effects of single drug treatment and the potential synergistic or additive effects of combined treatment with the focus on ciprofloxacin, thalidomide, mycophenolate mofetil, azathioprine, cyclophosphamide or leflunomide added to cyclosporin A (CyA). A rat cardiac transplant model was used to study graft survival and the influence on lymphocytes was evaluated by in vitro tests. Ciprofloxacin stimulated rat lymphocyte proliferation and IL-2 production in vitro and reduced the inhibitory effect of CyA at low concentrations. In the transplant model, however, graft survival was enhanced and further prolonged by combined treatment with ciprofloxacin and CyA. Addition of thalidomide to cultures of human or rat lymphocytes was not associated with any inhibitory effects. On the contrary, after incubation with metabolised thalidomide, the IL-2 production was significantly increased. However, thalidomide reduced the rat CD4 /CD8 T cell ratio and was demonstrated to prolong graft survival. The immunomodulatory drug linomide may induce rejection in the transplant model despite CyA treatment and this was used to test additive or synergistic effects of combined therapy with CyA and another drug. Thalidomide and CyA, as dual treatment, overcame the challenge of linomide. Mycophenolate mofetil and cyclophosphamide prolonged graft survival as sole treatment but azathioprine did not. However, all three drugs were demonstrated to enhance the immunosuppressive effect of CyA when studied in the linomide model. Leflunomide was found to induce graft unresponsiveness as sole treatment in a low responder rat strain combination. The criteria for the linomide model were fulfilled only in a high responder rat strain combination and now the effect of leflunomide was reduced only when given in a low dose regimen. An additive effect was demonstrated after combined leflunomide and CyA treatment in this model.
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| 8. |
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| 9. |
- Ahlm, Clas, 1956-
(författare)
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Distribution of puumala virus in Sweden
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Puumala virus, belonging to the genus hantavirus, is the causative agent of nephropathia epidemica (NE), a relatively mild form of hemorrhagic fever with renal syndrome. Puumala virus occurs endemically in Central and Northern Europe and Western Russia. In Sweden, NE is reported from the northern and central parts but virtually not at all from the southern part of the country. The bank vole (Clethrionomys glareolus) is the main reservoir of Puumala virus and humans are infected by inhalation of aerosolized animal secreta. In northern Sweden, the density of the bank vole population varies cyclically in intervals of 3-4 years and the incidence of NE shows a covariation.The prevalence of serum antibodies to hantaviruses in northern Sweden was studied in a stratified and randomly selected adult population sample comprising 1538 subjects. As expected, the prevalence increased with age. There was no difference between men and women, which was unexpected based on a male:female ratio of > 2:1 in clinical reports. By use of an immunofiuorescent assay, a seroprevalence of 5.4% and by a newly developed enzyme-linked immunosorbent assay (ELISA) with recombinant Puumala virus nucleocapsid protein as antigen, a prevalence of 8.9% was recorded. This is about or more than ten times higher than what would be calculated from clinical reports.By use of the ELISA, an occupational risk of acquisition of Puumala virus infection was demonstrated. Serum samples from 910 farmers and 663 referent subjects living in various rural parts of Sweden were tested. Among farmers from the Puumala virus-endemic northern and central parts of the country, the seroprevalence (12.9%) was higher (p=0.01) than in referents (6.8%). In the southern part of Sweden, only 2/459 persons had antibodies. Only a limited number of children with NE had been previously reported. In a separate study, 32 children with Puumala virus infection were identified and the clinical picture of NE in children was found to be similar to that of adult cases.Variations in the prevalence of Puumala virus in the bank vole population within an endemic region are not well known. Here, a higher mean rodent density and a higher prevalence of Puumala virus-specific serum antibodies were recorded in the vicinity of households afflicted with NE than in rural control areas. The data indicated that the risk of exposure locally within an endemic region may vary widely and tentatively suggested that a threshold density of bank voles might be necessary to achieve before effective spread of Puumala virus within the rodent population may occur.There is no firm evidence of the occurrence of Puumala virus among wild living animals other than rodents. A study of Swedish moose, an animal which is ecologically well characterized, was performed. Convincing evidence of past Puumala virus infection was found in 5/260 moose originating from Puumala virus-endemic areas but in none of 167 animals from nonendemic areas. Based on the low seroprevalence recorded, moose seemed to serve as endstage hosts rather than being active parts of the enzootic circle of transmission.In conclusion, the present investigations confirmed that the exposure to Puumala virus is geographically well restricted in Sweden. Seroprevalence studies indicated that only a minor proportion of individuals infected with Puumala virus are clinically reported, with a bias in favour of men. NE was confirmed to occur in children, with a clinical picture similar to that of adults. An occupational risk was defined for acquisition of Puumala virus infection. Studies in rodents suggested that there may be wide local variations within a limited area in the risk of exposure to Puumala virus. The studies validated the usefulness of a newly developed ELISA based on recombinant nucleocapsid peptides of hantaviruses and finally, methodological progress was reached when Puumala virus was, for the first time, successfully isolated from a Scandinavian patient.
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| 10. |
- Benoni, Göran
(författare)
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Fibrinolysis and blood loss in major arthroplasty. The effect of tranexamic acid
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood loss in major arthroplasty may be abundant and often necessitates blood transfusions. These may transmit disease and entail an immunological burden to the recipient. After trauma and surgery, the fibrinolytic system reacts with a short period of increased activity, followed by a fibrinolytic shut-down. In this thesis we investigated the impact of the early fibrinolytic activation on blood loss in total hip (THR) and knee arthroplasty (TKA), and the effect of a fibrinolytic inhibitor, tranexamic acid (TA), on postoperative blood loss and blood transfusions in these operations. A retrospective analysis of 179 TKA indicated that the use of TA decreased blood loss by a mean of 340 ml. The effect was confirmed in a double-blind randomised study of 86 TKA. Tranexamic acid (10 mg/kg) was given shortly before the release of the tourniquet and three hours postoperatively. The blood loss (mean + SD) in patients receiving TA was 730 + 280 ml versus 1410 + 480 ml in the placebo group (p<0.001). The number of blood transfusions were reduced by 2/3. In a randomised, double-blind study of 39 THR, TA was given after the cementing of the femoral component in order to avoid fibrinolytic inhibition during the pulmonary embolisation that often occurs during this procedure. The administration was repeated after three hours. There was no significant effect of TA on blood loss in THR, possibly because the drug was administered too late. Analyses of blood specimens from the wounds and peripheral veins during the operations showed an activation of coagulation and fibrinolysis, most pronounced in the wounds. TA significantly decreased D-dimers in the wounds in TKA, but not in peripheral blood. We found no significant effect of TA on oxygen saturation, measured by pulse oxymetry. In a separate study we investigated the pharmacokinetics of TA in THR and found that 10 mg/kg body weight i.v. resulted in therapeutic plasma concentrations during surgery. In conclusion we have thus found a profound local activation of fibrinolysis in TKA and THR. The prophylactic administration of TA significantly reduced blood loss and the need of blood transfusions in TKA. We found, however, no such effect when TA was given at the end of the operation in THR.
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