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31.
  • Gustafsson, Mikael (författare)
  • Motility of human polymorphonuclear leukocytes : An image processing approach
  • 1993
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Cell motility is essential for polymorphonuclear leukocyte (PMN) function in the defense against invading microorganisms and in inflammatory processes. Using digital video microscopy and image processing, individual cells were studied during random locomotion, chemotactic locomotion and phagocytosis. When PMN moved in a specific direction, the lipid membrane was found to flow in the same direction, contradicting the rearward lipid flow model of cell locomotion. This was assessed with video photobleaching of a fluorescent lipid probe, Dii. The motility of PMN could not be blocked by ca2+ depletionand /or inhibition of myosin light chain kinase, suggesting that ea2+ and myosin are not necessary for locomotion. Temporal and spatial characteristics of intracellular free ea2+ and intracellular pH were assessed by loading the cells with esters of Fura-2 and the fluorcscein derivative BCECF, respectively. There was a distinct correlation between the direction of PMN locomotion and the slope of the Ca2+ gradient of the cells. PMN moving randomly on a surface often exhibited a rearward gradient with higher ca2+ concentration in the rear of the cell. Experimental reversal of the gradient, however, did not change the direction of motility. During phagocytosis of yeast particles, Saccharomyces cerevisiae, intracellular free calcium rose within seconds after contact with the prey. Intracellular pH varied between 7.1 and 7.3 and was uniform across the cells. After phagocytosis, phagosomal pH first decreased and then returned to neutraL A role for pH in phagosome-lysosome formation is proposed. PMN loaded with self-quenching concentrations of BCECF exhibited a strict correlation between pseudopod protrusions and increase in fluorescence, indicating water influx and dilution of the probe. This finding may be essential for the understanding of actin cytoskeleton dynamics during cell locomotion.</p>
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32.
  • Gustafsson, Per, 1950- (författare)
  • Oesophageal function, acid reflux and bronchopulmonary disease : A study on children and adolescents with asthma or cystic fibrosis
  • 1991
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>This thesis comprises a literature review of gastro-ocsophageal reflux (GOR) and six studies which aim to determine the prevalence of oesophageal dysfunction (OD) and pathological GOR and their significance concerning the bronchopulmonary disease in children and adolescents with bronchial asthma or cystic fibrosis (CF). Oesophageal function was assessed by manomctry combined with oesophageal provocation tests. 24-hour two-level oesophageal pH monitoring was used to quantify GOR, to study the temporal relationship between acid reflux and asthma symptoms, and to assess the propensity to aspirate. Symptoms of OD and asthma were evaluated by interview and by the use of questionnaires. Severity of bronchopulmonary disease in the CF patients was assessed by radiography and spirometry. A double-blind placebo-controlled trial of ranitidine 150/300 mg per day over four weeks was performed in the asthma group to see if a reduction in acid reflux improved asthma. The relative significance of reflux symptoms and atopic allergy, regarding lung function and bronchial histamine reactivity in asthma, was evaluated. Pathological GOR and OD were significantly more common in asthma and CF patients than in controls. Episodes of acid reflux seemed to provoke asthma symptoms in a few patients. Ranitidine produced a significant but modest reduction in nocturnal/morning asthma symptoms in patients with pathological GOR, when compared to those with normal GOR. Asthma patients with reflux symptoms more frequently experienced asthma attacks initiated by non-specifictrigger factors than patients without such symptoms. The presence of atopic allergy was related to impaired lung function and increased bronchial hyperreactivity. Severity of OD and bronchopulmonarydisease correlated well in CF patients.</p> <p>OD or pathological GOR are found in the majority of children and adolescents with asthma or CF. In CF subjects OD and GOR may be parts of a vicious circle including malnutrition and progressive lung damage. In asthma acid reflux is, on the whole, a mild trigger or a modulatory factor, and appears to influence the airways via oesophago-bronchial reflexes rather than by aspiration. Atopic allergy is still more important than GOR in childhood asthma.</p>
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33.
  • Gustavsson, Åsa (författare)
  • Transthyretin in senile systemic amyloidosis and familial amyloidotic polyneuropathy
  • 1994
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The amyloidoses comprise a heterogeneous group of disorders characterized by the deposition of fibrillar, proteinaceous amyloid deposits in various organs and tissues. To date, 17 different proteins of various sizes have been identified as amyloid proteins. Irrespective of the specific protein comprising the amyloid fibrils, the fibrils are all about 10 nm wide and of indefinite length.</p><p>In the most common familial form of amyloidosis, familial amyloidotic polyneuropathy (FAP), the amyloid fibril protein is the plasma protein transthyretin (TTR). In FAP type I, which is the type found in Sweden, there is a mutation in the TTR gene leading to the substitution of a methionine for valine at position 30. This mutation leads to a form of amyloidosis characterized by polyneuropathy starting in the lower limbs and usually slowly progressing until death occurs. Another TTR-derived form of amyloidosis is senile systemic amyloidosis (SSA). This form of amyloidosis is present in about 25% of people 80 years of age or older. In SSA, amyloid is deposited mainly in the heart but deposits are also found in many other organs.</p><p>In this study it is demonstrated that normal TTR can form fibrils in vitro. Fibril formation studies were also performed in vitro with synthetic peptides corresponding to parts of the TTR amino acid sequence. These results indicate that TTR peptides with 13-strand secondary structure are fibrillogenic in vitro and are likely important in in vivo amyloidogenesis.</p><p>The TTR amino acid and DNA sequences in cases with SSA were determined and found to be normal, thus showing that no mutation is necessary for development of this form of amyloidosis. However, cleavage of TTR may be important in fibrillogenesis since TTR fragments lacking 45-51 N-terminal amino acid residues predominated in the amyloid.</p><p>Antigenic epitopes exposed on normal TTR and TTR derived from amyloid deposits were also examined. The 13-strand H was found to be exposed in amyloid TTR and not in normal TTR, thus suggesting a changed structural conformation of TTR in amyloid fibrils.</p>
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34.
  • Hanberger, Håkan, 1954- (författare)
  • Pharmacodynamic effects of antibiotics : studies on bacterial morphology, initial killing, postantibiotic effect and effecitive regrowth time
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Pharmacodynamics of antibiotics deals with time course of drug activity and mechanisms of action of drugs on bacteria. In this thesis pharmacodynamic parameters have been studied after brief exposure of gram-positive bacteria to daptomycin, imipenem or vancomycin and after short exposure of gram-negative bacteria to amikacin, ampicillin, aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, imipenem, mecillinal,11, or piperacillin.The studies have been focused on morphological alterations, initial killing, postantibiotic effect (PAE) and effective regrowth time (ERT) and a method, based on bioluminescence assay of intracellular A TP has been used. The basic principle behind this technique is that A TP in living cells is present in a relatively constant amount, and hence affords a measure of the number of microbial cells. The PAE describes the delayed regrowth of bacteria after brief exposure to antibiotics. The number of cells measured after this antibiotic exposure describes the initialkilling and is also the start value for calculating the PAE. PAEs of 2-3 h were obtained by bioluminescence for gram-positive bacteria exposed to imipenern or v ancomycin. This is in agreement with results obtained by viable count and is probably due to similiar weak initialdecrease in cell density when assayed by both methods. Long (&gt; 3 h) concentration dependent PAEs and moderate (::;; 1 1ogw) initial decrease in intracellular ATP were in general seen for gram-positive bacteria exposed to daptomycin and for gram-negative bacteria exposed to imipenem or amikacin when assayed by bioluminescence. These very long P AEs and rather weak initial killing have to be compared with the shorter PAEs and stronger initial killing reported by us and others using viable count. Furthermore, this study showed that there was a relatively good concordance between microscopy and bioluminescence, which are direct methods, in determining the initial killing and PAE of imipenem on Escherichia coli. The ERT, defined as the time for bacterial density to increase 1 logw from the pre-exposure inoculum, was independent of the method used for measuring regrowth of E. coli after brief exposure to imipenem. The combination of mecillinam with ampicillin, aztreonam, ceftazidime or piperacillin and the combination of amikacin with ceftazidirne, ceftriaxone or piperacillin induced longer PAEs on gram-negative bacteria than the sum of PAEs of the individual antibiotics. A strong initial killing in combination with a long PAE cause a long ERT and may allow the antibiotic concentration to stay below MIC during long periods of time without any regrowth. This may, in clinical practice, have implications for long dosing intervals .</p>
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35.
  • Holm, Ann-Charlotte (författare)
  • Membrane transport of triiodothyronine : With particular reference to erythrocytes in health and disease
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Cellular T3 uptake was studied in three human cell systems, i.e. cultured lymphocytes, erythrocytes and erythrocyte membrane vesicles.</p><p>The basic experimental procedure included 1) incubation of cells or membranes with T3 tracer and increasing concentrations of unlabelled T3, 2) separation of unbound hormone from hormone bound to cells or membranes, 3) counting of radioactivity, and 4) calculation of saturable uptake and uptake constants. Variations on this basic experimental theme included a) addition of ATP or metabolic inhibitors, b) competition by T4 analogues, c) changes of vesicular volume and permeability, and d) changes of membrane temperature. Finally, the T3 concentration in the erythrocytes was measured.</p><p>The uptake of T3 proved to be carrier-mediated. In lymphocytes it seemed to be energy dependent, but not in erythrocytes, although erythrocyte membrane vesicles had the potential to respond with accelerated uptake to increased energy supply from ATP. The mean Vmax was increased in hyperthyroidism and decreased in hypothyroidism (both p&lt;0.01), and one patient with thyroid hormone resistance had a V max value similar to those of hyperthyroid patients. In patients with low serum free T3 from non-thyroidal causes V max was not altered. The mean Km for T3 uptake in erythrocytes was similar in controls and the patient groups examined.</p><p>Binding of T3 to the membrane sites occurred only in membranes exposed to 25 °C and subsequently to 0 °C. The mean Bmax thus measured was reduced in hypothyroidism (p&lt;0.05).</p><p>The mean erythrocyte T3 concentration was 220 pM in healthy subjects, !50 pM in pregnancy, approximately 190 pM in non-thyroidal illnesses and 60 pM in hypothyroidism (all p&lt;0.01).</p><p>The results show that I) human erythrocytes and lymphocytes take up T3 by carrier-mediated transport, 2) the rate of T3 uptake changes in thyroid diesease but not in pregnancy or nonthyroidal illness, and 3) the erythrocyte T3 concentration is reduced in pregnancy and nonthyroidalillness, as in hypothyroidism.</p>
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36.
  • Holmlund, Ulla, 1946- (författare)
  • Psychogenic needs and masculinity-femininity across adolescence : their relationschips to dysmenorrhea and psychiatric symptoms
  • 1991
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Holmlund, Ulla. 1991. Psychogenic needs and Masculinity-Femininity across adolescence. Their relationships to dysmenorrhea and psychiatric symptoms.</p><p>Personality traits assessed as psychogenic needs, and psychological Masculinity-Femininity defined as interests and attitudes were examined longitudinally from the age of 15 to 25 years in healthy Swedish women.</p><p>Across adolescence, the women became more self-confident and assertive, but also more conforming and socially dependent. Women at 25 were also more conventionally feminine than at 15. Those changes were quite uniform for the individuals of the sample as a whole.</p><p>The relationships between personality variables, psychogenic needs and psychological Masculinity-Femininity, and the occurence of dysmenorrhea were studied. Severe dysmenorrhea was associated to personality variables, mainly high scores in Guilt Feelings and psychological Femininity.</p><p>Possible relationships between dysmenorrhea and the occurence of symptoms of anxiety and depression, and between personality variables and anxiety and depressive symptoms was examined in a subsample, considered to be representative for psychogenic needs. Women with severe dysmenorrhea were slightly more affected by anxiety and depressive symptoms compared to those who never had experienced dysmenorrhea. High scores in the psychogenic needs Defence of Status and Guilt Feelings assessed in early teenage were associated to the presence of anxiety and depressive symptoms in adulthood. The positiverelationships between the reported experience of good relations to siblings and peers, low scores in Defence of Status and Guilt Feelings, and the abscence of psychiatric symptoms, reflect the importance of a favourable early environment for healthy personality development.</p>
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37.
  • Högberg, Thomas, 1947- (författare)
  • Ovarian cancer : Treatment results, prognostic factors, and tumor marker surveillance
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The total population-based material of 426 ovarian malignancies in the Southeast Health Care Region of Sweden during 1984-1987 was surveyed. It seems that with a program of cytoreductive surgery followed by a cisplatinum chemotherapy combination in the metastasizing cases the overall survival figures have improved. A relative overall 5-year survival of 43% was recorded. Age and stage were independent prognostic factors for survival, while histology (epithelial vs, non-epithelial tumors) did not add prognostic information.</p><p>384 patients with ovarian carcinomas were analyzcd separately. An overall relative survival of 40% was recorded. Tite overall corrected 5-yearsurvival for patients prescribed protocol treatment was 49 % compared to 33 % for those treated otlJCrwise. The corrected 5-year survival for patients with FIGO stage Ill -IV tumorswas 35 % if optimal primary cy~oreductive surgery wasperfonned.Patientswith residual tumors greater than 1cm had 13% corrected5-yearsurvival. Patients that underwent intestinal surgery as a part of initial surgical debulking had a very poor survival, even compared with 1l1e group of patients with greater than 3 cm residual tumors left after initial surgery ( 4 vs. 13 %). The secondary laparotomy gave prognostic information only in stages I and ll. Eighteen of 68 patients (26 %) who had macroscopic turn or left at the secondary surgery cmdd be rendered tumor free at the secondary laparotomy. This group had about the same survival as those who were foi.Uld to be in complete response at the secondary laparotomy. It was not possible to ~iatc that this was caused by the ~urgeryper se.</p><p>Geometrical measurements oftumor nuclei on the diagnostic tissue sections generated powerful prognostic factors for survival after secondary laparotomy in 65 patients with advanced ovarian cancer. The existence of very large nuclei seemed to cl1aracterize patients with a bad prognosis.</p><p>The half-life of the turn or marker CA 125 in serum during induction chemothrapy gave equally good prognostic information regarding the survival after secondary laparotomy in 72 patients with advanced ovarian cancer as registering the response to therapy at the secondary laparotomy.</p><p>In 33 ovarian cancer patients monitoring with monthlyscrum CA 125 determinations during follow-up was a reliable method to diagnose a recurrence with very few (0.9%) false positive values.</p><p></p>
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38.
  • Isacsson, Barbro, 1947- (författare)
  • Pharmacokinetics and pharmacodynamics of aminoglycosides
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The pharmacokinetics of amikacin in humans and the pharmacodynamic effects, i.e. initial killing and postantibiotic effect (P AE), of the aminoglycosides were studied in this thesis. For1y-five elderly patients with serious infections were treated in a prospective, comparative and randomized pharmacokinetic study with amikacin given once or twice daily. The administration of a single dose of 15 mg!kg of amikacin yielded a higher peak concentration (55 mg/1) in comparison to the peak concentration (33 mg!l) when the same total dose was given twice daily. The area under the curve (AUC) was the same regardless of the mode of administration. The kinetics of amikacin, 11 mg/kg and 15 mg/kg were studied during a 24 h interval. Using a hiexponential equation the average serum half-lives were quite long, 4.4 - 5.2 h. In practice, a uni-exponential equation is often used, and this may lead to incorrect conclusions about the elimination rate of amikacin. When given to our elderly patients the peak concentration of 11 mg/kg of arnikacin ( 42 mg!l) seems to be sufficiently high in relation to the MICs of important isolated pathogens, i.e. ,2&gt;10 x MIC. Thus this dose may be sufficient for elderly patients when given once daily. The in vitro postantibiotic effects (P AE) of amikacin, gentamicin, netilmicin and tobramycin onGram-negative bacteria and on staphylococci were studied by a bioluminescent assay of bacterial ATP. This method simplified the P AE studies and made such studies possible at high aminoglycoside concentrations. The length of the P AE was concentration-dependent for all the aminoglycosides studied. The mean P AE values of the Gram-negative strains and of the Staphylococcus aureus strains ranged between 3 to 7 h at the aminoglycoside concentrations normally reached in serum during standard dosing. The P AE of arnikacin alone, and in combination with ceftazidime, ceftriaxone or piperacillin, on Gram-negative bacteria and on enterococci was also studied. The combination of 13-lactam antibiotics with amikacin induced longer P AEs than the sum of P AEs of the individual drugs. This synergistic P AE was seen especially when the 13-lactam antibiotics were combined with amikacin concentrations close to MIC. Amikacin alone induced no P AEon the Enterococcus .faecalis strains. APAE of 1.6 h at the most resulted from exposure to piperacillin. In combination, amikacin and piperacillin increased the P AE to 5.5 h. In conclusion, with regard to the pharmacokinetics and the pharmacodynamics there is strong support for the once daily dosing regimens of aminoglycosides. The results of this study could also haveimpact on dosing regimens of antimicrobial combinations and might lead to administration of lower doses of potentially toxic drugs without loss of efficacy.</p>
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39.
  • Ivarsson, Ingemar, 1951- (författare)
  • On treatment of medial gonarthrosis
  • 1991
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>This study, comprising 7 separate papers, is concerned with treatment of medial gonarthrosis.</p> <p>Results after high tibial osteotomy were found to deteriorate 8-9 years after surgery. The best results were seen in knees with preoperative Stage I or II osteoarthrosis and valgus deviation after osteotomy.</p> <p>The rehabilitation period after high tibial osteotomy is long, recovery of the average thigh muscle torque was first seen after 12 months. Stable internal fixation with early mobilization does not seem to be advantageous in this respect.</p> <p>Gait analysis showed signs of insufficient rehabilitation persisting 8-12 months after high tibial osteotomy, with unimproved maximum gait velocity and reduced stride length at constant maximum velocity.</p> <p>Rehabilitation with restitution of muscle torque was faster after unicompartmental arthroplasty and gait parameters did improve.</p> <p>An "anatomical" type of unicompartmental prosthesis seems to be more susceptible to load, with changed strain elicited in external rotationcompared to a meniscus bearing prosthesis.</p> <p>Knees with medial osteoarthrosis showed less rotation clinically duringmotion than healthy knees. The rotation was not significantly affected by a unicompartmental arthroplasty.</p> <p>A radiographic method for detection of prosthetic migration, using tantalum balls implanted in the skeleton, was developed and tested on 20 patients.</p>
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40.
  • Janerot Sjöberg, Birgitta, 1958- (författare)
  • Aortic valvular flow : a clinical and experimental doppler echocardiographic study
  • 1993
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Aortic blood velocity determination by ultrasound Doppler is a safe and valuable tool when evaluating patients with heart disease. The time-course of the velocity signal can be used for detemnining left ventricular function. In a mixed patient material, including patientswith ischaemic and valvular heart disease as well as heart transplants, stroke volume was noninvasively and accurately calculated during rest and exercise (-1 ± 7 m! [diffmean ±I SD]) using suprasternal pulsed Doppler registrations and parasternal 2D aortic anulus dimension imaging. Early during supine exercise (at 40% of upright maximal load) middleaged healthy women increased their cardiac output by 79%, stroke volume by 10%, aortic maximal flow velocity by 27% and maximal acceleration by 43%. This is in contrast to the reaction in women with coronary artery disease and previous infarction where no increase or, in certain patients, a fall in these variables was observed. In this way aortic ultrasound Doppler adds haemodynamic information to the conventional exercise test noninvasively.</p><p>However, whether aortic ultrasound Doppler is used by itself (e.g. in calculations of velocity-changes, integrals and instantaneous pressure drop) or in combination with ultrasound tissue imaging (e.g. in calculations of cardiac output and stenotic valve areas), there are assumptions and simplifications made in the analysis. Theoretical and experimental analysis shows that a three-component Windkessel model is relevant when modelling early proximal aortic flow. Maximal aortic flow velocity and acceleration are not only influenced by the rate of pressure change - and thereby left ventricular con tractility - but also by aortic vessel characteristics. Besides the influence of aortic pressure change, maximal velocity is related to the compliance of aorta and great arteries and maximal acceleration inversely related to the characteristic impedance. This knowledge is of importance when interpreting the spectral Doppler signal. It also gives the future opportunity of assessing aortic compliance and characteristic impedance noninvasively if the aortic pressure change is known. For flow determinations by ultrasound Doppler, knowledge of the 3D flow profile is important. In calculations within the heart this profile is often assumed to be flat. Using 2D colour Doppler it is possible to .reconstruct a true spatial velocity profile using an external time delay device. A nearly flat, but slightly antero-septally skewed, flow profile was found in the subvalvular area in patients with moderate to severe aortic valvular stenosis and in these patients a parasternally measured flow diameter is a good estimate for the mean of two transverse flow axises. Stroke volume determination, using pulsed Doppler ultrasound in this area, may therefore be favourable in patients with aortic stenosis. In contrast to this, flow may be overestimated by more than 40% by using centerline velocity as an estimate of spatial mean velocity in certain patients with aortic regurgitation and in certain normals.</p>
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