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  • Filbey, Derek (författare)
  • Alloimmunization during pregnancy with special emphasis on anti-D : Laboratory and clinical management
  • 1995
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The laboratory and clinical management of alloimmunized in pregnancy has been investigated according to a protocol currently in use in Örebro region. A 12 year epidemiological study showed the prevalence of alloimmunization to be 0.57% in this Swedish populationwith a 0.24% incidence of clinically significant antibodies that can induce haemolytic disease of the newborn (HDN). Rh antibodies, predominantly anti-D, are still the causes of most cases of severe HDN in which 45/47 babies required exchange transfusion. During the studyperiod, 14 mothers were successfully treated with plasma exchange during pregnancy owing to high anti-D antibody concentrations. Only two other blood group syswms, Kell and Duffy, besides Rh affected newborns to alloimmunized mothers to such a grade that exchange transfusion of the newborns was necessary. All generally accepted for the fetus clinically nonsignificant antibodies were also followed and shown not to cause HDN. In 3 instances, anti-D was detected in partial RhO-positive mothers who were carrying normal RhO-positive fetuses,a study to identify these partial RhD individuals and to group them into D-categories was performed. The ability of the indirect antiglobulin titre (IAT), AutoAnalyzer (AA) quantitation and chemiluminescence l£st (CLT) performed on maternal anti-D serum during pregnancy to discriminal£ babies affected or unaffected by HDN has been studied. It was found that all methods had their weaknesses, but AA-quantitation and CLT improved speeifieity when compared to the IAT-titration method. However, a great improvement was achieved when the results of IAT-titration and AA-quantitation, as determined by the cut-offlimits applied to discriminate unaffected from affected newborns, were combined; specificity was then found to increase from 60-78% to 93% and was further increased with the addition of the CLT test to 95%. Finally, the detection of HLA class II monocyte-reactive antibodies and their potential protective role in ameliorating HDN has been viewed.</p>
  • Foldevi, Mats, 1952- (författare)
  • Implementation and evaluation of problem-based learning in general practice.
  • 1995
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The Faculty of Health Sciences, Linköping, Sweden, started the reformedmedical curriculum in 1986. Problem-based Learning as an educational method was introduced into the entire curriculum. It was a response to requests for community-orientation by increasing the involvement of general practice. A new extensive communication skills training - the 'Strand', a new form of examination- 'phase examination', and recurrent clerkships in general practice in the clinical phase were also introduced. The medical cuniculum, with its focus on general practice, together with these innovations are presented in a case report of its implementation and development.</p><p>The similarities between quality assurance and problem-based learning, as processes and methods, are also identified, described and discussed.</p><p>Two of the innovations where general practice is a main contributor, namely, the clerkships in general practice and the phase examination 1 and 2 have been evaluated. Of the 115 students, in semester six to nine in the autumn of 1992, 74% filled in the clerkship evaluation questionnaire. The overall rating was very positive. Regression analysis of the rated variables showed that the quality of the tutoring was the strongest determinator of the overall rating. No decline in the students' ratings in the latter semesters was found.</p><p>A qualitative study was made on all free comments made by the same study group in the same questionnaires. This study identified an area not covered in the quantitative evaluation, the important elements of the student-tutor relationship.</p><p>The 'phase examinations' have been found to be a valid assessment ofcommunication skills, integrative knowledge and the search for scientificinformation. The use of general practitioners as assessors has strengthened the role of general practice in the curriculum.</p>
  • Forslund, Tony, 1956- (författare)
  • Nitric oxide modulates neutrophil function
  • 1997
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>An important role of the neutrophils is to attack and destroy microbial intruders. In order to do so, these leukocytes must adhere to the blood vessel wall, pass through the endothelial cell layer, move through the tissues to the point of infection, ingest the intruder and destroy it.</p><p>The aim of this thesis was to study the effects of nitric oxide (NO) on the different steps in the inflammatory response of the neutrophil.</p><p>Adhesion to a collagen surface was decreased by pretreatment with a NO-releasing substance, and this was mimicked by pretreatment with a functional cGMP-analogue, indicating a role of the NO/cGMP pathway. Homotypic adhesion, aggregation, was not affected by external NO, but when the precursor of endogenous NO-production CLarginine) was added, the aggregation increased. Measurements of total F-actin content in cells showed that a NO-releasing substance decreased the total amount of F-actin, while cGMP increased it. Treatment with L-arginine had no effect.</p><p>Phagocytosis was neither affected by endogenous NO, nor by a NO-releasing substance. However, if the prey itself released NO, both the adhesion to and phagocytosis of the target was decreased. This NO-particle also inhibited the production of oxygen metabolites, as measured using Luminal-dependent chemiluminescence. The inhibition was almost exclusively affecting the intracellular production of oxygen metabolites, as could be seen when neutrophils were stimulated with FMLP or PMA after an incubation with the NO-releasing particles.</p><p>Treatment of neutrophils with the NO-releasing substance nitroprusside resulted in a decrease of the respiratory burst. It was primarily the extracellular release that was diminished. This effect can be explained by an inhibition of the enzyme producing oxygen metabolites. Endogenous NO-production increased the chemiluminescence whereas an inhibitor of the NO-synthase decreased it. A possible explanation for these effects is an NO-inhibition of the protection against hydrogen peroxide, i.e. catalase activity, resulting in an increased amount of oxygen metabolites.</p><p>In conclusion, these results shows that NO has different effects depending on where it is produced and in what quantities. It modulates the different steps of the inflammatory response of neutrophils. Control of NO-formation could therefore be a way to control inflammation.</p>
  • Fredriksson, Mats (författare)
  • Epidemiological studies on colorectal cancer : Some design issues and analytical considerations
  • 1997
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Determinants of colon and rectal cancer have been studied in two case-control data sets, one from the north of Sweden, i.e., Norrland, and the other from the county of Östergötland. In the studies carried out, the main interest was focused on occupational aspects, but diet, medication and earlier diseases were also considered, including a detailed interview regarding diet for a sample of the subjects in Östergötland.</p><p>A main finding was an association between sedentary work and an increased risk of colon cancer whereas a decreased risk was seen for rectal cancer. Forestry and agricultural work was associated with a reduced risk. Railway employees had an increased risk in Norrland and a tendency to increased risk in Östergötland. Among specific exposures, asbestos was associated with an increased risk. Rectal cancer did not share any of these factors except for a decreased risk for forestry work. The main finding regarding rectal cancer was an increased risk for painters who sanded walls before painting. It seems as occupational exposures influence the risk of colon and rectal cancer in different ways.</p><p>Regarding diet, reduced risks was seen for daily intake of cheese and to some extent for fiber rich diet. In Östergötland, a protective effect was seen for calcium and cereal fiber on colon cancer. Tea was associated with a reduced risk, whereas coffee or alcohol did not show any association. Increased risk was found for smoked food. Fiber had a protective effect on rectal cancer, whereas alcohol appeared as a strong risk factor.</p><p>The Norrland study was also analyzed regarding drug intake and other diseases than cancer. In particular, increased risks was associated with iron and verapamil medication. No effect was seen regarding acetylsalicylic drugs. Ulcerative colitis appeared as a strong risk factor and other determinants of risk were cholecystectomy and hyperplasia oftl1e prostate. Appendectomy was associated with a decreased risk.</p><p>Information regarding inactivation of the tumor suppressor gene p53 was available for some cases in the Östergötland study, providing for a new approach by means of a case-control analysis. High intake of alcohol andthe use of hydralazine-containing drugs were associated with an inactivated gene, whereas iron medication and familial colorectal cancer were not. The results indicate that dividing the cases in subgroups based on molecular biology may reveal more specific associations between exposure and subgroups of colorectal cancer.</p><p>Some variables were further analyzed in order to check if there would be any gain in using time or intensity as an effect variable as compared to a crude exposure variable. Considering design issues and data analysis, it was found that if a crude determinant indicates that there is an association, then a more in-depth analysis by using time or intensity variables might be worthwhile. A simple method for categorizing continuous variables was also demonstrated. Furthermore, a more thorough analysis of the association between dietary fat and physical activity indicated an interaction between low physical activity and high intake of fat.</p><p>Validity aspects were critically discussed in relation to the studies. Selection and information bias were found unlikely to have occurred in the kind of data at hand and neither differential nor non-differential misclassification should be a serious problem. Confounding, including combinations wiih misclassification, was considered, in relation to the studies, but with the methods used such a phenomena is less likely to have influenced the results.</p>
  • Frennesson, Christina, 1949- (författare)
  • Age-related maculopathy and macular degeneration : New diagnostic and therapeutic procedures
  • 1996
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Age-related maculopathy (ARM) may progress into age-related macular degeneration (AMD), which is often disastrous to near vision and reading. Currently used treatment is generally not successful in a long-term perspective. Therefore, searching for an early detection of functional disturbances as well as for prophylactic treatment appears important.</p> <p>Colour contrast sensitivity was measured in patients with soft drusen maculopathy (early ARM). No deterioration in visual function was observed with conventional tests. A highly significant elevation (p&lt;0.001-0.0001) of thresholds for all three colour axes was found, indicating an impairment of retinal function. A tendency towards a bimodal distribution was seen, suggesting a subgroup with a more prominent decrease in foveal sensitivity and possibly at higher risk of progression into the exudative form of the disease. Colour contrast sensitivity appears to be a more sensitive measure of early functional disturbances of the retina than provided by the currently used tests.</p> <p>Contrast sensitivity was measured peripheral to an absolute central scotoma in patients with AMD and was found to be significantly lower (p&lt;0.001) than In normals at the same degree of eccentricity. This finding may explain the variations in the need for magnification in low vision patients with identical visual acuity for achieving the same visual performance.</p> <p>A new system for evaluating paramacular function and establishing the most suitable area for eccentric viewing was designed. The method facilitates the procedure of teaching and training the patient to use the eccentric viewing technique successfully. Reading speed increased significantly (p&lt;O.OOl) with significantly fewer one-hour training sessions (p&lt;O.OOl) than needed with the current training method.</p> <p>In a prospective, randomised study, patients with early ARM were treated with green argon laser photocoagulation perifoveally over the drusen area. Parameters such as visual acuity, colour contrast sensitivity and central visual field were unchanged at the 12-month follow-up. The total drusen area decreased significantly (p&lt;0.0001) after laser photocoagulation over a period of 12 mOnths. No complications were noticed. In a matched control group, the area of drusen tended to increase, and there was a significant difference {p&lt;O.OOl) in drusen area between the two groups after 12 months. In the control group, mean visual acuity (p=0.008) and colour contrast sensitivity along the tritan axis {p=0.044) decreased, and three patients advanced to the exudative stage of AMD during follow-up. The results seem to indicate a promising prophylactic potential of the treatment.</p>
  • Gao, Jizong (författare)
  • The Entheses of the Medial Meniscns and Ligaments of the Knee Joint : Descriptive and Experimental Studies
  • 1997
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Meniscal injuries are common in sports. Surgical removal of the meniscus to relieve symptoms is associated with a high risk for late knee joint osteoarthrosis and pain. Meniscal repair or replacement has therefore been advocated. In meniscal replacement procedures proper fixation of the substitute to bone is decisive to guarantee normal meniscal load transmitting function and prevention of osteoarthrosis. Secure fixation of the graft is also essential for the success of ligament reconstruction. Thus, this thesis concentrates on exploration of normal morphology of the insertions of the medial meniscus and other knee ligaments, their ultimate strength and failure mode, and finally the capacity of the meniscal insertion for repair and reconstruction in a rabbit animal model.</p><p>Extreme mechanical demands are posed on the insertion which connects highly loaded and mobile ligamentous tissue to bone. The abrupt change in tissue stiffness in the insertion is made more gradual by interposition of uncalcified and calcified fibrocartilage tissues of intermediate stiffness between the soft ligament and the hard bone. The thickness of calcified fibrocartilage in an insertion seems to be related to the amount of bending at this site. The interface between calcified fibrocartilage and bone is irregular thereby increasing the contact area between these 2 mechanically different tissues and their resistance to separation; its configuration is individual in each ligament and seems adapted to the loads to which the insertion is subjected. During mechanical testing failures through insertional structures were rare, which confirmed the effectiveness of this tissue configuration. Presence of nerve fibres in meniscal insertional structures suggests sensory function beside the mechanical ones. Hence, all of these specific features need to be reestablished after a reconstructive procedure to ensure adequate insertional function.</p><p>Transection of meniscal insertions without refixation resulted in repair which after 12 weeks showed tissue differentiation and maturation according to local loading conditions. The repair tissue in the anterior insertion which is mainly loaded in tension acquired ligament-like appearance; in the posterior insertion, which is subjected to compressive, shear and tensile loading, fibrocartilage-like tissue had formed. Calcified and uncalcified fibrocartilages mimicing insertional tissue formed after refixation of the insertion into a bone channel, but a nonnal collagen matrix, interface to bone and mechanical strength did not reestablish.</p><p>A meniscal insertion healed in prolongated position after transection, and in a case with refixation, it was found partially pulled out. This resulted in both instances in a displacement of the meniscus to the joint periphery and signs for osteoarthrosis similar to what has been found after removal of the meniscus. Thus, despite some capacity of the repair tissue to differenciate and mature to insertionspecific tissue after transection or reconstruction a normal load transmission function of the meniscus probably did not reestablish, and osteoarthrosis was common. Further studies are necessary to improve the fixation of meniscal or ligament substitutes to bone.</p>
  • Garpenholt, Örjan (författare)
  • Vaccination against Haemophilus influenzae type b in Sweden : Aspects of epidemiology, economy and the process of introduction
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Since 1992-1993 vaccination against Haemophilus influenzae type b (Hib) with conjugated vaccines is included in the general Swedish childhood vaccination programme. In this thesis the introduction of Hib vaccination has been evaluated.</p><p>The epidemiology and clinical spectrum of invasive H. influenzae disease was prospectively studied during the pre-vaccination period in a well-defined population of Sweden 1987-1992. The incidence (cases/100 000/personyear) was 5.9 for all ages and 55 in children 0 to 4 years of age. Serotype b was the dominating type, especially in children. Three patients died in connecting with illness and six developed permanent sequelae.</p><p>In national studies, the incidence before and after introduction of the Hib vaccination programme was compared. The source for the studies was the report system from the clinical microbiology laboratories to the Swedish Institute of Infectious Disease Control. Already within one year after introduction a decreased incidence was observed. In the prevaccination period the incidence was 34 in 0 to 4 years old children. In 1998 the incidence had decreased to 1.6 in the same age group. Thirteen children were identified with invasive Hib disease in spite of vaccination. Effectiveness, which take in account both direct and indirect effects of vaccination in 0 to 4 years old children was calculated to 96.0% (95 %Cl, 94.2-97.4). To study the impact of Hib vaccination in the on the diagnosis epiglottitis a national register of all patients treated at Swedish hospitals was used. In the age group 0-4 year the incidence decreased with 95 % after introduction of Hib vaccination. Even in older ages a decrease was observed but this trend did not reach statistically significance.</p><p>An evaluation of the economic consequences of a general childhood vaccination programme against Hib in Sweden was conducted. A retrospective prevaccination annual cohort of 0-4 year old children was compared with an annual cohort of the same age group after a completely implemented vaccination programme against Hib. The cost analysis shows that vaccination against Hib is cost saving when indirect costs are included in the analysis. In the cost-benefit analysis it is shown that society will gain -88 million Swedish Crowns annually when Hib vaccination is totally implemented.</p><p>The process of introducing general childhood Hib vaccination was studied. The critical factors for implementation of the immunisation programme were found to be the vaccine product, conception of the disease, government economy and public decision-making. Five activity systems were found to be involved in the implementation process, the systems of vaccine production, government administration, news distribution, science, and disease prevention. To structure the results a theoretical framework was used, Culture Historical Activity Theory. The study shows that a broad range of aspects must be considered before an intervention such as a general vaccination programme can be implemented in society.</p>
  • Ghassemifar, M. Reza (författare)
  • Connective tissue contraction in wound healing : An experimental study in vivo and in vitro
  • 1996
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Contraction of connective tissue is an important part of tissue repair that reduces the wound space and helps to decrease the formation of scar tissue, both of which are needed to restore tissue integrity. In the present study, certain cellular mechanisms that are active during connective tissue contraction were assessed and the influence of transforming growth factor-.131 on these mechanisms was evaluated in normal rat and protracted mouse contraction. A new double-embedding technique for sectioning of thin tissue membranes was developed and a multisequence template was constructed that allowed quantification of a number of target mRNAs [:rGF -.131, TGF -.13 type li receptor, alpha-SM actin and .13-actin) from 0.5-2 11g of total RNA. The fibroblast-populated collagen lattice model (FPCL) was used for studies of contraction in vitro, and, in vivo, the perforated mesentery models of rat and mouse were employed. Fourier transformation image analysis was used to assess the orientation of actin in mesenteric wound fibroblasts.</p> <p>Studies in vitro showed that rat, but not mouse, macrophage conditioned medium stimulated contraction of FPCL in serum free medium and that supplementation with serum impaired FPCL contraction. In vivo, rat wound fibroblasts expressed alpha-SM actin during closure of perforations, as shown by in situ hybridization. Using quantitative RT-PCR, it was shown that the expression of alphaSM actin was increased lOO-fold in wounded as compared to unwounded tissue, and that TGF -.131, while stimulating closure of perforations, also increased alpha-SM actin mRNA 4-5 fold inwounded tissue of both rat and mouse. However, the expression of alpha-SM actin was considerably higher in the wounded mesenteriesof rats than in those of mice. TGF -.131 was expressed by normal, unstimulated peritoneal macrophages and, for the first time, shown tobe downregulated in activated, wound macrophages in both rat and mouse. The orientation of actin bundles in wound fibroblasts wasderanged in impaired healing in zinc deficiency but unaffected by TGF -.131 in stimulated contrition.</p> <p>In conclusion, the results have shed further light on various cellular activities during connective tissue contraction. A number of differences were found between rats and mice that help to clarify the mechanism of protracted healing in the mouse. The complex interaction of these mechanisms await to be further elucidated.</p>
  • Gottvall, Eva (författare)
  • The direct current electroretinogram and the standing potential of the rabbit under different stimulus and adapting conditions
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The electroretinograrn (ERG) reflects the summation of electrical responses generated by neurons and non-neuronal cells in the retina and pigment epithelium in response to light. The major ERG components are the fast, negative a-wave, the fast, positive b-wave and the slow, positive c-wave. The ERG is superimposed on the standing potential of the eye (SP).</p><p>Experiments were performed on albino and pigmented rabbits under general anesthesia. The aim was to study the development of the ERG with time in response to repeated light stimuli of different intensities (Paper I) or different interstimulus intervals (Paper II). The effects of a prolonged uniocular dark adaptation period (Paper III) and the influence of possible diurnal rhythms (Paper IV) were investigated, as was the long-term development and reproducibility of the ERG in experiments performed on consecutive days (Paper V). The influence of intravitreally injected dopamine at different concentrations on the development of the ERG was also studied (Paper VI).</p><p>When using light stimuli of high intensity and short interstimulus interval (Papers I and II) the c-wave amplitude was immediately reduced after the first stimulus, but recovered to a large extent. The parallel behavior of the c-wave and SP suggested the presence of a pigment epithelial mechanism behind the recovery of the c-wave. The a- and b-wave amplitudes were immediately reduced, but recovered only to a limited extent. The final amplitudes of the b-and c-waves and to a large extent also of the a-wave seemed to be fairly independent of stimulus intensity.</p><p>When one eye was dark adapted and the other eye simultaneously exposed to repeated widely spaced light stimuli of moderate intensity (Paper III) the b- and c-wave amplitudes of the unoccluded eye slowly increased during the course of several hours, but the a-wave amplitude was more stable. When the cover was removed from the previously occluded eye the a- and b-wave amplitudes immediately attained the level of those recorded from the contralateral eye, which had been light adapted by the stimuli. The phenomenon may suggest a mechanism for transfer of information between the eyes.</p><p>The development of the ERG amplitudes and the SP was studied during the course of the day by repeating identical series of light stimuli every hour, and by commencing the experiments at different points of time (Paper IV). The amplitude of the b-wave did not reach relative stability until 2.5 to 3.5 hours after the beginning of dark adaptation, and that of the cwave continued to rise throughout the experiments. Since the pattern was similar in experiments starting in the morning and in the afternoon, it seems less probable that diurnal rhythms caused the findings.</p><p>The long-tenn development of the ERG during several hours of stimulation with light of high intensity was studied in identical experiments performed on consecutive days (Paper V). In addition to the findings described in Papers I and II, a peak in the b-wave amplitude was observed 20-21 min after the start of light stimulation. There were no significant differences between experiments performed on consecutive days.</p><p>The effects of intravitreally injected dopamine of different concentrations on the development of the ERG was studied in Paper VI. During exposure to repeated light stimuli of moderate intensity the b- and c-wave amplitudes were reduced with a decreased or even abolished amplitude increment with time in the eye injected with dopamine, and the responses were related to the concentration of the drug. The peaks in the b-and c-wave amplitude seen in the control eye when frequent stimuli of high intensity were used were abolished in the eye injected with dopamine at higher concentrations of the drug. Thus, dopamine may affect the adaptive process of the retina.</p>
  • Gottvall, Tomas (författare)
  • Red cell alloimmunization during pregnancy
  • 1996
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>We have evaluated a new screening program to detect red cell alloimmunization during pregnancy that was introduced in the south-east region of Sweden in 1981. The screening program is based on two antibody tests at 25 and 35 gestational weeks for all pregnant  women regardless of maternal Rh(D) status. During the period 1983-89, all pregnant women in the region were tested (78,300) and 0.37% were found to exhibit red cell alloimmunization. Antibodies with anti-D specificity were the most common (34%), followed hy anti-E (24%), anti-Kell (17%) and anti-c (11%). These immunizations also caused the most severe cases of hemolytic disease of the newborns. The screening program was efficient since no newborn subjected to exchange transfusion was overlooked. Most of the new immunizations occurred among the Rh(D) positive women (63%). However, the cost of detecting a few severely affected fetuses among the Rh(D) positive women is high. In this group of pregnancies, it seems sufficient with only one antibody screening test, if done at 25 gestational weeks.</p><p>The standard variables commonly used to predict fetal hemolytic disease (FHD) were studied. A low antibody titer level in maternal sernm (≤32) accurately predicted unaffected fetuses. When moderately elevated antibody titer levels (≥64) were present, complementary test variables were needed for a relaihle prediction of FHD. In Rh(D) alloimmunizations, the anti-D concentration in maternal serum, with a cut-off level of 0.7 µg/mL, was the best complementary variable. We could accurately distinguish a low-risk group from a high-risk group of pregnancies. Measurement of the bilirubin content in aruniotic fluid (ΔOD<sub>450</sub>) did not give any further information of relevance in predicting PHD.</p><p>High-dose intravenous immunoglobulin (IVIG) treatment appeared to prevent a further deterioration of PHD when a moderate to severe FHD was present (B-hemoglobin concentration between 70-100 g/L). This was observed as a stabilized fetal hemoglobin concentration and an increased fetal anti-D concentration, both interpreted as an effect of a decreased erythrophagocytosis in the fetal reticuloendothelial system.</p><p>We propose a flowchart with guidelines for the management of pregnancies complicated by red cell alloimmunization.</p>
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