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Effects and mechanisms of actions of cyclosporin, FK506 and 15-deoxyspergualin
No full textImmunosuppressive drugs can be used to deal with unwanted or inappropriate immune reactions, such as the rejection of a transplanted organ. However, treatment with these drugs are often associated with serious adverse effects, and therefore less toxic immunosuppressants are desired. The aims of the present study were to evaluate the immunologic effects of cyclosporin-sulphate, FK506 and 15-deoxy-spergualin (DSG). CsA-sulphate, a previously unidentified CsA metabolite, is present in high concentration in the bile and plasma of transplanted patients. In vitro and in vivo studies showed that this metabolite has limited immunosuppressive effects. It is likely that the mother compound is responsible for both the immunosuppressive and adverse effects associated with treatment. FK506 is structurally completely distinct from CsA, but was found to have identical immunosuppressive effects in vitro, although at l0-l00 times lower concentrations.Based on studies of combinations of the two drugs, the effects CsA and FK506 are stipulated to be additive. The similar and additive effects of the drugs indicate that they share a common mechanism of action. The prevailing theory is that the drugs first bind to their respective immunophilin. The drug-immunophilin complexes inhibit the calcineurin-mediated dephosphorylation and thus the translocation to the nucleus of the cytoplasmic component of the transcription factor NF-AT. DSG have immunosuppressive properties that are distinct from CsA and FK506, but its mechanism of action remains elusive. In a safety-study, where DSG was given in combination with methyl-prednisolone as treatment of acute graft rejection in kidney transplant recipients, the effects of DSG on blood mononuclear cells were studied. DSG decreased the number of leukocytes, and results indicated that DSG may affect B-cells and perhaps also CD4+ cells.Our in vitro studies confirmed an effect of DSG on the development of cytotoxic T cells. DSG also suppressed the proliterative responses to S. aureus and PHA, if added within 24 hours after stimulation. These effects could be explained by a DSG-dependent reduced Il-6 production. However, addition of recombinant Il-6 only partly restored the development of cytotoxic T-cells, and thus, additional Il-6 independent steps should be DSG-sensitive in the differentiation of CTL. In the transplantation of fetal porcine islet cells, reactivity against the graft is likely to have been induced via the indirect activation pathway of immune recognition. CsA was found to be less efficient in inhibiting the cytotoxicity induced by xenogeneic porcine Iymphocytes via the indirect as compared to the direct pathway. In contrast, DSG inhibited the induction of cytotoxicity equally, irrespective of activation pathway. Although DSG did not suppress antibody production to pig PBL in mice completely, it was more efficient than CsA. DSG may act by modulating the activities of the heat shock proteins Hsc70 and Hsp90. This thesis adds to the knowledge of the effects and mechanisms of action of cyclosporin, FK506 and DSG, knowledge that may be valuable for the optimal treatment of transplant recipients, and in the further development of immuno-suppressive drugs.</p
Beat-to-beat variability of QRS amplitude and heart rate in ischemic heart disease : diagnostic potentials
No full textThe diagnostic potential of beat-to-beat QRS amplitude variability in patients with coronary artery disease (CAD) was evaluated with variance ECG and compared to exercise stress test and myocardial scintigraphy (SPECT). Two high prevalence populations of 199 and 166 patients each were investigated. The discriminative accuracy of the different methods was assessed employing receiver operating curves constructed by successive consideration of several variance ECG generated CAD index cut point values and various threshold criteria based on ST segment depression with or without exertional chest pain.The CAD index provided a significant discrimination which was matched by exerse stress test only when chest pain variable was added to ST segment depression as a discriminating criterion. Overall pathological findings at SPECT was better identified by the CAD index than by symptom limited exercise stress test. While the index was strongly diagnostic for persistent perfusion defects or combined defects, exer se stress test was diagnostic for transient defects only. Relative to pathology at coronary angiography, the CAD index had a diagnostic capa ty at least as good as that of SPECT and better than that of exer se stress test. Beat-to-beat QRS amplitude variability during dobutamine provoked myocardial ischemia was investigated in 15 patients with angiographically verified CAD. Compared to healthy controls, dobutamine infusion induced a significant increase in variability in the patients, as a sign of electrical instability of the myocardium.Variance ECG was evaluated six months after myocardial infarction (AMI)(n=73) and after coronary by pass grafting (CABG) (n=56). Patients with AMIand initially low index values increased their index. In patients subjected to CABG, the CAD index increased significantly during the six months which was prominent and reversible in character in patients with initial low index.The changes in CAD index following ischemic cardiac events may provide new insights into the dynamics of ischemic heart disease. Beat-to-beat variability of heart rate (750 beats) was recorded in healthy individuals and in patients with recent AMI, in the basal state and afterautonomic blockade. The variability was analysed in time- and frequency domain (linear methods) together with quantitative measurements of Lyapunov exponent, correlation and fractal dimension and qualitative assessment by the evolution in phase space (nonlinear methods). Heart rate variability was found to exhibit characteristics of low dimensional chaos. Patients with AMI showed significantly less complex behaviour than healthy controls but the difference was eliminated by atropine, suggestive of vagal toneas a major cause. Heart rate variability and its modulation can be described equally by linear and nonlinear methods. Nonlinear methods are deterministic thus possessing a potential to predict and control electrical instability.</p
Non-urgent and heavy use of the emergency department : intervention and follow-up studies
No full textThe "inappropriate" use of emergency departments (EDs) - for non urgent or minor ailments and high-frequency use, "heavy use" - is causing great concern to several Western countries, irrespective of differing health care systems.Through a trial at Huddinge Hospital, about a quarter of the patients who sought care at the ED during day-time were classified by the reception staff as non-urgent cases in the sense of not needing the special resources of an emergency department.Of these non-urgent cases, 55% patients could be referred by a registered nurse to more appropriate care providers. Seven per cent were found to need the resources of the ED after all, 11% did not agree to be referred and 27% could not be referred due to organizational hindrance, mostly insufficient capacity at the primary health care centres.The referred patients were found to have a more positive attitude to the ED than had patients who had been treated in the usual way at the ED (66% versus 48%). However, the attitudes to primary care were not more favourable in referred patients (45% versus 41%).The proportion of patients in the referred group who used the ED the year following the trial was significantly reduced. The users, however, continued to turn to the ED with non-urgent health problems. Heavy ED users were found also to consume considerable amounts of primary care at the health care centres.Long-term follow-up of a population sample showed that without any intervention, heavy ED users continue to have a high utilization of hospital care. Mortality among heavy ED users was significantly elevated: the Standardized Mortality Ratio was 2.0 (95% confidence interval: 1.9 to 2.1) and the risk of dying prematurely (before reaching age 65) was more than four-fold compared with non-users. Violent death, especially suicide and intoxication were six times that of the non-users.List of scientific papersI. Hansagi H, Carlsson B, Olsson M, Edhag O. Trial of a method of reducing inappropriate demands on a hospital emergency department. Public Health. 1987 Mar;101(2):99-105. https://doi.org/10.1016/S0033-3506(87)80046-X II. Hansagi H. Referral of non-urgent cases from an emergency department: patient compliance, satisfaction and attitudes. [Submitted] https://pubmed.ncbi.nlm.nih.gov/2291099 III. Hansagi H, Allebeck P, Edhag O. Health care utilization after referral from a hospital emergency department. Scandinavian Journal of Social Medicine. [Accepted] https://pubmed.ncbi.nlm.nih.gov/2602922 IV. Hansagi H, Norell SE, Magnusson G. Hospital care utilization in a 17,000 population sample: 5-year follow-up. Soc Sci Med. 1985;20(5):487-92. https://doi.org/10.1016/0277-9536(85)90364-8 V. Hansagi H, Allebeck P, Edhag O, Magnusson G. Frequency of emergency department attendances as a predictor of mortality: nine-year follow-up of a population-based cohort. [Submitted] https://pubmed.ncbi.nlm.nih.gov/2390308 </p
Social network, perceived ill health and use of an emergency department : a descriptive and experimental study
No full textThe contents of this thesis are focused on relationships between social integration, social network and social support, on the one hand, and perceived ill health and care utilization on the other.The aims of the thesis were to: investigate the relationship between social network, perceived ill health and utilization of an emergency department (ED); relate the frequency of ED use to socio-demographic risk indicators for social disintegration; describe the psycho-social and medical situation of a group of heavy users of ED services In comparison to the general population; relate changes in social network in a group of heavy users to utilization of ED; evaluate the effects of hospital social worker intervention for heavy users of ED.The hypothesis was that if the informal network fails or becomes insufficient or if the work sector is deleteriously affected, the individuals may choose to turn to public agencies such as health care and social welfare for help. This hypothesis was tested in one such agency, the somatic ED of a general hospital.The main findings were that social network variables such as perceived loneliness, lack of close friend, less contact with extended family, living alone, being outside the labour force and having economic problems were related to a higher utilization of ED resources. It was demonstrated that subjects living in areas characterized by high geographical mobility, high proportions of unemployed and of immigrants used ED services to a higher extent than those who lived in areas which did not show these socio-demographic risk indicators for social disintegration. Heavy users of ED were medically and psycho-socially more burdened than the general population of the catchment area. Individuals who originally recurrently visited the ED but whose access to support giving networks improved, reduced their number of ED visits in the course of time. Hospital social worker intervention for a group of heavy ED users reduced the effect of age, health problems and living alone on ED use, but did not affect total utilization rate.In conclusion, use of emergency care is a complex product of many, sometimes concomitant factors; medical, social, psychological and structural. Some of these factors lay within the reach of individual or professional actions and interventions, but some, such as employment opportunities, geographical mobility and organization of care, are only amenable on societal level.List of scientific papersI. Heavy users of an emergency department : psycho-social and medical characteristics, other health care contacts and the effect of a hospital social worker intervention. Genell Andrén, К. and Rosenqvist, U. Soc Sci Med. 1985;21(7):761-70. https://doi.org/10.1016/0277-9536(85)90124-8 II. Heavy users of an emergency department - a two year follow-up study. Genell Andrén, К, Rosenqvist, U. Soc Sci Med. [Accepted] https://doi.org/10.1016/0277-9536(87)90040-2 III. An ecological study of the relationship between risk in dictators for social disintegration and use of a somatic emergency department. Genell Andrén, К and Rosenqvist, U. Soc Sci Med. [Accepted] https://doi.org/10.1177/140349488801600205 </p
Antigens and antibodies involved in humoral immunity to plasmodium falciparum
No full textMalaria plasmodiidae cause more death and disease than any other known human pathogen. The parasite still threatens half of the world population {2.5 billion) and 300 million people are considered to become infected every year. More than 1 million African children annually die from malaria and there are an estimated 80 million clinical cases/year in the world. How protection or immunity to the parasites is mounted in humans is still partially unknown, although both cellular and antibody mediated immunity has been implied.This thesis describes several aspects of the humoral immune response to Plasmodium falciparurn in humans. Sera from individuals with different degrees of exposure to the parasite or with clinical immunity were used to study antibodies to P. falciparum antigens by means of ELISA, indirect immunofluorescence, immunoprecipiation and immunoblotting. Antibodies of IgM and all four IgG isotypes were detected both in sera from immune donors and in those with their first infection. However, whereas high titered sera contained antibodies of IgM and IgG1-4 isotypes, IgG2 and IgG4 antibodies were frequently missing in low titered sera. This could indicate that the isotype expression, on the average, follows the downstreams order of the Igh-C genes and is correlated with the intensity of immunization as occurring in infection. Using the same methods for a detailed investigation of sera from children and adults living in a holoendemic area of Liberia, no (or weak) correlations between age-dependent acquisition of P.falciparum immunity and overall antibody activities or isotype expression were seen.List of scientific papersI. Wahlgren M, Berzins K, Perlmann P, Björkman A. Characterization of the humoral immune response in Plasmodium falciparum malaria. Estimation of antibodies to P. falciparum or human erythrocytes by means of microELISA. Clin Exp Immunol. 1983 Oct;54(1):127-34. https://pubmed.ncbi.nlm.nih.gov/6352102 II. Wahlgren M, Berzins K, Perlmann P, Persson M. Characterization of the humoral immune response in Plasmodium falciparum malaria. II. IgG subclass levels of anti-P. falciparum antibodies in different sera. Clin Exp Immunol. 1983 Oct;54(1):135-42. https://pubmed.ncbi.nlm.nih.gov/6352103 III. Perlmann H, Berzins K, Wahlgren M, Carlsson J, Björkman A, Patarroyo ME, Perlmann P. Antibodies in malarial sera to parasite antigens in the membrane of erythrocytes infected with early asexual stages of Plasmodium falciparum. J Exp Med. 1984 Jun 1;159(6):1686-704. https://doi.org/10.1084/jem.159.6.1686 IV. Wahlgren M, Perlmann H, Berzins K, Björkman A, Larsson A, Ljungström I, Patarroy ME, Perlmann P. Characterization of the humoral immune response in Plasmodium falciparum malaria. III. Factors influencing the coexpression of antibody isotypes (IgM and IgG-1 to 4). Clin Exp Immunol. 1986 Feb;63(2):343-53. https://pubmed.ncbi.nlm.nih.gov/3516466 V. Wåhlin B, Wahlgren M, Perlmann H, Berzins K, Björkman A, Patarroyo ME, Perlmann P. Human antibodies to a Mr 155,000 Plasmodium falciparum antigen efficiently inhibit merozoite invasion. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7912-6. https://doi.org/10.1073/pnas.81.24.7912 VI. Wahlgren M, Björkman A, Perlmann H, Berzins K, Perlmann P. Anti-Plasmodium falciparum antibodies acquired by residents in a holoendemic area of Liberia during development of clinical immunity. Am J Trop Med Hyg. 1986 Jan;35(1):22-9. https://doi.org/10.4269/ajtmh.1986.35.22 VII. Wahlgren M, Aslund L, Franzén L, Sundvall M, Wåhlin B, Berzins K, McNicol LA, Björkman A, Wigzell H, Perlmann P, et al. A Plasmodium falciparum antigen containing clusters of asparagine residues. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2677-81. https://doi.org/10.1073/pnas.83.8.2677 VIII. Wahlgren, M, Lundgren-Sjöberg, K, Wåhlin, B, Perlmann, H, Udomsangpetch, R, Berzins, K & Perlmann, P. Malaria infected erythrocytes from spontaneous rosettes with uninfected cells coated with antigens released by the parasite. [Submitted]</p
On sperm nuclear zinc and chromatin decondensation : an in vitro study on the physiology of the ejaculated human spermatozoon
No full textEjaculated human spermatozoa were studied in vitro with respect to their capacity to decondense the chromatin in sodium dodecyl sulfate (SDS). The content of zinc in sperm heads was studied in epididymal, vasal, and ejaculated human spermatozoa. These were the main results:(1) Soon after ejaculation most spermatozoa decondensed the chromatin in SDS with zinc-chelating EDTA. Only few spermatozoa decondensed in SDS alone.(2) During storage, many spermatozoa lost the capacity to decondense in SDS-EDTA. Half of all spermatozoa lost this capacity within the first hour after ejaculation whether they were washed and stored in a buffered salt solution (BSS) within 20 minutes after ejaculation, or simply stored in the original seminal plasma. During prolonged storage (24 hours) the capacity was better retained among spermatozoa stored in BSS, than in those stored in seminal plasma. Furthermore, among spermatozoa treated with EDTA before storage, the loss of capacity for decondensation during storage was enhanced. In contrast, the initial capacity for decondensation was completely prevented in spermatozoa supplemented with zinc during 24 h storage in BSS.(3) The ejaculated human sperm head contained significant amounts of zinc bound within the nuclear matrix. With EDTA-treatment, 90% of sperm head zinc could be removed soon after ejaculation. After 24 h storage in seminal plasma significantly less zinc could be released by exposure to EDTA.(4) Epididymal and vasal sperm heads had significantly lower contents of zinc than ejaculated sperm heads.(5) The zinc content of ejaculated sperm heads from various portions of split ejaculates was neither correlated to the total seminal plasma zinc concentration, nor to the concentrations of measured subfractions of zinc bound to various groups of zinc-ligands. However, most of the variations in sperm head zinc could be explained by variations in total sperm number and concentration of fructose secreted by the seminal vesicles.The results seem to justify the conclusion that the human spermatozoon takes up zinc at ejaculation from the concomitantly expelled prostatic fluid, and that zinc subsequently acts as a reversible stabilizer of the sperm chromatin. The results also imply that inappropriate stabilization by zinc of the sperm chromatin is likely to occur in spermatozoa from men with prostatic dysfunction, men expelling the spermatozoa mainly in vesicular fluid, and men expelling high total numbers of spermatozoa. The possibility is discussed that zinc stabilizes the quarternary structure of the sperm chromatin by chelating between e.g. amino- and thiol-groups of adjacent nucleoprotein fibers. Concomitantly, zinc would protect these thiol-groups from being comitted into superstabilizing disulfide-bridge crosslinks. Thereby would zinc preserve a potential of the chromatin for rapid decondensation in the ooplasm.List of scientific papersI. Björndahl L & Kvist U. Loss of an intrinsic capacity for human sperm chromatin decondensation. Acta Physiol Scand. 1985 Jun;124(2):189-94. https://doi.org/10.1111/j.1748-1716.1985.tb07651.x II. Kvist U & Björndahl L. Zinc preserves an inherent capacity for human sperm chromatin decondensation. Acta Physiol Scand. 1985 Jun;124(2):195-200. https://doi.org/10.1111/j.1748-1716.1985.tb07652.x III. Roomans GM, Lundevall E, Björndahl L & Kvist U. Removal of zinc from subcellular regions of human spermatozoa by EDTA treatment studied by X-ray microanalysis. Int J Androl. 1982 Oct;5(5):478-86. https://doi.org/10.1111/j.1365-2605.1982.tb00279.x IV. Kvist U, Björndahl L, Roomans GM & Lindholmer C. Nuclear zinc in human epididymal and ejaculated spermatozoa. Acta Physiol Scand. 1985 Oct;125(2):297-303. https://doi.org/10.1111/j.1748-1716.1985.tb07719.x V. Björndahl L, Kjellberg S, Roomans GM & Kvist U. The human sperm nucleus takes up zinc at ejaculation. Int J Androl. 1986 Feb;9(1):77-80. https://doi.org/10.1111/j.1365-2605.1986.tb00869.x VI. Björndahl L & Kvist U. Sperm number and vesicular fluid limit sperm nuclear zinc uptake in split ejaculates. [Submitted]</p
Selection of the principal cause of death : studies on the basis of mortality statistics for rheumatoid arthritis
No full textThe official statistics of Sweden for 1971-75 show a 2.7-fold increase in mortality for men and a 3.0-fold increase for women attributed to rheumatoid arthritis (RA) as the underlying cause of death. In order to investigate the basis of this observed increase, all death certificates for 1971 and 1975 with a diagnosis of RA (N=1224) were studied. All information was re-coded according to the original entry on the death certificates.The aims of the study were to seek an explanation of the observed increase by investigating the National Central Bureau of Statistics' (NCBS) registration procedure, and to identify inadequacies in the completion of death certificates and major interpretation problems facing the certifiers and coders in the reporting and registration of the causes of death.The investigation showed that the observed increase was due to changes in the NCBS' registration procedure: An increased tendency by the NCBS to favour RA in the registration of the underlying cause of death even when RA was not reported as the underlying cause on the death certificates. Physicians had reported a slight decrease for men and practically no change at all for women between the years when RA was considered the underlying cause of death.The major inadequacies identified on the certificates were (1) an inadequate causal sequence, (2) diagnoses making the conditions difficult or impossible to code, (3) more than one diagnosis for each link in the causal sequence leading to death, and (4) an underlying condition not stated in accordance with other provisions of the official WHO instructions. The NCBS was found to have registered RA as the underlying cause instead of physicians' stated underlying condition (i) when RA was likely to have caused the stated underlying condition, (ii) when the non-RA diagnosis was the only entry in part I of the certificate and rendered an incomplete description of the fatal course of events, (iii) when the non-RA condition could only be classified by a rest-category code of the International Classification of Diseases (ICD), and (iv) when the non-RA condition was considered 'trivial'.The NCBS' increased registration of RA as the underlying cause of death in the period examined could not be explained by inadequately made out death certificates, nor by a strict application of the rules for coders on selection of the underlying cause of death issued in the ICD.Several interpretation problems were identified of significance to cause-of-death statistics in general and different interpretations were discussed. Some of these problems were caused by inadequacies on the certificates. Others concerned incompleteness, ambiguities, and manifold meanings of the basic concepts and rules governing the reporting and registration of causes of death.List of scientific papersI. Lindahl, B.I.B. On the Selection of Causes of Death: An Analysis of Who’s Rules for Selection of the Underlying Cause of Death. In: Nordenfelt, L., Lindahl, B.I.B. (eds). Health, Disease, and Causal Explanations in Medicine. Philosophy and Medicine. vol 16, 1984. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-6283-5_16II. Lindahl, B.I.B. The reliability of Swedish mortality statistics for rheumatoid arthritis. Scandinavian Journal of Rheumatology. 13:289-296, 1984. https://doi.org/10.3109/03009748409111298 III. Lindahl, B.I.B. and Allander, E. Problems in the classification of cause of death diagnoses affecting the reliability of mortality statistics for rheumatoid arthritis. Journal of Chronic Diseases. [Accepted] https://doi.org/10.1016/0021-9681(85)90136-5 IV. Lindahl, B.I.B. The causal sequence on death certificates: Errors affecting the reliability of mortality statistics for rheumatoid arthritis. Journal of Chronic Diseases. [Accepted] https://doi.org/10.1016/0021-9681(85)90007-4 V. Lindahl, B.I.B. In what sense is rheumatoid arthritis the principal cause of death? A study of the national statistics office's way of reasoning based on 1224 death certificates. [Submitted] https://doi.org/10.1016/0021-9681(85)90094-3 </p
Excessive use of medical care or rational patient behaviour? A study of a large hospital emergency department
No full textThe role of hospital emergency departments has over the years been gradually extended, especially in large urban areas. In Stockholm, visits to hospital emergency departments increased by 30 per cent between 1973 and 1977. The southwestern district, one of Stockholm's five health care districts, has had the highest visiting rates - since 1975 40 per cent above average. A large university hospital, the Huddinge Hospital, was opened in this district in 1972. The study is an inquiry into the use of the Huddinge Hospital emergency department by the population in its catchment area. The study encompassed not only those who used the emergency department but an approximately 10 per cent sample (17 004 people) of the population. Data was collected from the hospital emergency department, medical records, by interviews with users and non-users and from registers. During the 15 months' observation (January 1976 to March 1977) 29 per cent of the population visited the hospital emergency department (range for different subareas 22 to 46 per cent). The total number of visits was 566 per 1000 population. Compared with Swedish citizens, immigrants more often visited the emergency department (19 per cent more visits) but less often used the outpatient clinics. Marked differences between Swedes and immigrants were found in the illness behaviour. The role of proximity in the use of the hospital emergency department was anlysed by dividing the catchment area into 20 subareas. The subareas closer to the hospital had up to four times higher visiting rates compared with areas further away. The travelling distance to the hospital and the proportion of immigrants together explained 81 per cent of the differences in visiting rates between the subareas. In one geographically defined subarea, 15 per cent of the population visited district GPs while 30 per cent visited the hospital emergency department. An estimated 39 to 64 per cent of the visits to the hospital emergency department were general practitioner-type cases. In a representative sample of users and non-users of the emergency department, strong association was found between health status, social factors and the level of use of the emergency department. The hospital emergency department is a major source of medical care for the population in the catchment area. A considerable part of its diversified role is to compensate for the low capacity of the primary care services in the area.List of scientific papersI. Magnusson, G. Utilization of a hospital emergency department in Stockholm. The effects of age, sex and marital status. Scandinavian Journal of Social Medicine. [Accepted] https://doi.org/10.1177/140349488000800310 II. Magnusson, G. and Aurelius, G. Illness behaviour and nationality: A study of hospital care utilization by immigrants and natives in a Stockholm district. Social Science & Medicine. [Accepted] https://pubmed.ncbi.nlm.nih.gov/7394578 III. Magnusson, G. The role of proximity in the use of hospital emergency department. Sociology of Health and Illness. [Accepted] https://doi.org/10.1111/1467-9566.ep10487794 IV. Magnusson, G. The hospital emergency department as the primary source of medical care. Scandinavian Journal of Social Medicine. [Accepted] https://doi.org/10.1177/140349488000800311 V. Magnusson, G. Association between health status, social factors and level of emergency department use. Medical Care. [Submitted]</p