| 21. |
- Rutz, Wolfgang
(författare)
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Evaluation of an educational program on depressive disorders given to general practitioners on Gotland : Short and long-term effects
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the years 1983-1984, the Swedish Comittee for the Prevention and Treatment of Depression (PTD) offered an educational program to all general practitioners (GP:s) on the Swedish island of Gotland. 1982 was used as a baseline year. An evaluation of the short-term effects was made continuously until 1985. The long-term effects were followed 1985-1988. According to the immediate evaluation, 80% considered the practical applicability of the program to be high, and the GP:s achieved increasing competence and stringency in handling depressive states.The referrals to the local psychiatric unit decreased to 50% of those at baseline. The total in-patient days due to depressive disorders decreased as well as the average stay. The sick-leave consumption decreased by approximately 50%. In 1982, the prescription of antidepressants was low, 54% of that in the rest of Sweden. In 1985 the corresponding figure was 77%. The prescriptions of lithium remained stable while the prescriptions of sedatives and major tranquilizers decreased as compared to the rest of Sweden. The suicide rate decreased relative to the trends on Gotland and in the rest of Sweden. During the long-term evaluation, the in-patient care for depressive disorders increased again and the suicidal rate returned almost to control values. The prescriptions of antidepressants stabilised. Thus, the effects were strictly time related to the educational program indicating real effects and not only coincidence with local trends on the island.In a cost-benefit analysis the costs for the educational programs, the changes in drug prescriptions and in in-patient care were evaluated as well as indirect costs concerning changes in morbidity and mortality. The results indicate that the PTD educational program on Gotland resulted in savings to the society in the order of about SEK 155 million (USD 26 million). It is concluded that educational programs of this kind should be repeated every second to third year.
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| 22. |
- Saldeen, Katarina
(författare)
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Studies on vasoactivity of fibrin(ogen) derived peptides
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fibrin accumulation is a common fmding in many pathological conditions, such as in inflammatory processes, e.g. in the lungs in pneumonia or pulmonary insufficiency after sepsis. During lysis of the fibrin by plasmin or leukocyte elastase, peptides are released that may contribute to the pathophysiological changes. Peptide 6A, Ala-Arg-Pro-Aia-Lys, released duting plasmin degradation of fibrin( ogen) induced dilation of bovine mesenteric arteries in vitro, increased cAMP in the vessels and released prostacyclin. It also increased coronary and femoral artery blood flow in the dog, probably due to release of prostacyclin and nitric oxide. L-arginine increased femoral blood flow in the dog, but was less potent than peptide 6A, indicating that properties beside the arginine content are important for the vasoactive effect of the peptide. D-arginine had much less effect than Laiginine, indicating that the effect of lrarginine is related to its utilization for synthesis of nitric oxide. Peptide 6A was an effective inhibitor of pulmonary angiotensin converting enzyme (ACE) in vivo in rabbits. It also potentiated the hemodynamic responses to bradykinin, an ACE substrate, and elicited bradykinin responses from normally subeffective circulating bradykinin levels. Peptide 6A showed an endothelium-dependent relaxant effect on rat aorta. Two different ACE inhibitors, one with and one without sulfhydryl groups, both enhanced this effect, indicating that the mechanism underlying the potentiation effect is inhibition of ACE and not related to sulhydryl supplementation.Peptide Bp 30-43, Arg-Pro-Ala-Pro-Pro-Pro-lle-Ser-Gly-Gly-Gly-Tyr-Arg-Ala, caused vasodilation of bovine mesenteric arteries, an increase m both cAMP and cGMP in the vessels and an increased release of prostacyclin. It also induced polymorphonuclear leukocyte emigration in rabbit skin in vivo. A contributory cause of this effect may be release of the vasodilator prostacyctin.In summary, these investigations showed that certain peptides released during degradation of human fibrin(ogen) have vasoactive properties and that the effects are mediated by prostacyclin, nitric oxide and inhibition of ACE. Endogenously released such peptides might contribute to the pathophysiology in inflammation or thrombolysis via the mechanisms described. In addition analogues to these peptides might be of therapeutic interest in the future, e.g. in thrombolysis or critical limb ischemia.
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| 23. |
- Sydsjö, Gunilla, 1956-
(författare)
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Psykosociala riskgraviditeter och deras utfall
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study describes a prospective survey of an index-group of78 pregnant women, who during pregnancy met with certain arbitrarily selected, but well defined criteria associated with drug addiction, moderate mental insufficiency or particular social circumstances of possible relevance to the course of pregnancy and early child development. For comparison, a referencegroup of 78 pregnant women who did not meet the present inclusion criteria, were studied in equal detail. The two groups of women were derived out of a total number of 1575 pregnant women who during the year 1983 registered at the public Antenatal Health Care Service in the community of Linköping. The two groups of women were followed and compared until their children were four years old. By means of repeated personal, semistructured interviews with all the women, together with standardized observations of the women and their children and collection of a range of social, economic, medical,obstetrical and neonatal data, the duration and outcome of pregnancy in relation to the need for medical antenatal care and social wellfare was illustrated in some detail. Furthermore, the psychosocial conditions of the pregnant women, apparent during early pregnancy were related to the development of the interaction and relationship between mother and child as observed during the first 18 months as well as to the somatic and psycho-motor development of the child at four years of age.In summary, at least five per cent of all pregnant women in the community of Linköping were found, already during early pregnancy, to be characterized by drug addiction, suffering from modefate mental insufficiency symptoms or being associated with one or more defined social attributes thought to be of relevance to the course of pregnancy and early child development. These women, when compared to the reference group of pregnant women, were eventually found to require a significantly increased amount of medical attention and social wellfare during pregnancy. However, no significant differences were observed between the groups regarding duration and outcome of pregnancy, thestates of the neonates or the somatic wellbeing of mother and child postnatally.With the beginning soon after delivery, the indexchildren appeared to run a considerably increased risk for an unfavourable somatic as well as psycho-motor development during their ftrst four years of life, as compared to the reference children.It is obvious that present efforts and routines with regard to antenatal medical and social care, at least as presendy practised in Linköping, Sweden, are consistent with regular obstetric courses and outcomes of pregnancies in general in women stigmatized by certain impaired psychosocial conditions. However, if we are to prevent and eventually eliminate the significantly increased risks for an unfavourable somatic and psycho-motor development of the children of these women, we mustprobably introduce complementary elements of an educational and socially reassuring type in the Antenatal Health Care Service.
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| 24. |
- Tarpila, Erkki, 1946-
(författare)
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Factors influencing the inflammatory response and secondary infection in rat pancreatitis
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A rat~model for bile-induced acute pancreatitis is used throughout the experiments. The model, which is well known, mimics the assumed events leading to biliary pancreatitis. The mortality from acute pancreatitis with this model was 23-33% and 73% of all deaths occurred within the first 24 hours.Cholecystokinin (CCK) is the strongest known stimulant of pancreatic enzyme secretion and pancreatic growth. During acute pancreatitis, stimulation with the CCK agonist cerulein augmented the pancreatitis. Blocking of the endogenous CCK by the CCK-receptor antagonist proglumide had no beneficial effect.Resorption of biologically active substances via the peritoneum has been suggested as a pathogenetic mechanism for systemic complications in acute pancreatitis. Peritoneal resorption of fluorescein-isothiocyanate-conjugated dextran 10 000 was studied in rats during acute pancreatitis induced by different means or with bacterial peritonitis. Peritoneal permeability was independent of both induction mode and severity of acute pancreatitis and of whether peritoneal inflammation was induced directly by bacteria or indirectly by pancreatitis. Absorption of toxic substances via the peritoneum seems to be of minor importance for the development of systemic complications in acute pancreatitis.Bacterial peritonitis resulted in hyperamylasemia. Light and electron microscopy in these cases revealed no damage to the exocrine pancreas. The amylase therefore was not of pancreatic origin.Reflux of infected bile or duodenal contents into the pancreatic duct can give rise to infected acute pancreatitis. Rats given infected bile into the pancreatic duct showed incresed consumption of C3, anergy to a recall antigen test and higher mortality than in rats with noninfected pancreatitis. Intraductal injection of infected bile frequently reulted also in infected suppuration of the pancreas after 7 days.Another mechanism for infected acute pancreatitis is translocation of bacteria through the intestinal wall. Acute pancreatitis, induced by sterile bile was associated with translocation of Escherichia coli and systemic contamination two days later. Bacterial overgrowth of both aerobic and anaerobic flora was seen in the intestines, but no damage to the intestinal mucosa. Bacterial translocation was a graded response, depending on the severity of pancreatitis. Pancreatic necrosis, however, was seldom infected 7 days after induction of acute pancreatitis with sterile bile. Bacterial translocation during acute pancreatitis therefore occurs only during the first days. The results of the experiments indicate ascending irfection as the main mechanism for secondary infected pancreatitis in rats with bile-induced acute pancreatitis.
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| 25. |
- Torfgård, Kristina E.
(författare)
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Glyceryl Trinitrate Distribution and the "Remarkable Tolerance"
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To study the distribution of glyceryl trinitrate (GTN), a gas chromatographic method was developed for simultaneous determination of GTN and its dinitrate metabolites in 'plasma and tissues. The distribution of GTN and 1 ,3-g1yceryl dinitrate (1,3-GDN) and 1,2-glyceryl dinitrate (1,2-GDN) was studied in GTN tolerant and nonto1erant rats. An extensive distribution of GTN and GDNs was found, and the highest level of GTN was observed in the adipose tissue of both tolerant aud nontolerant animals. This subcutaneous depot of GTN might affect the pharmacokinetics of the drug. Generally higher concentrations of GTN were found in tissues studied (except for the liver), as compared with blood. Furthermore, high levels of GTN and GDNs were found in the brain, and an increase in cGMP level was also observed there, which might mediate side effects, such as headache, head throbbing and dizziness. The formation of the metabolites 1,3-GDN and 1,2-GDN in plasma werefound to be dependent on the GTN concentration.Long-term administration of GTN was shown to result not only in tolerance, i.e. reduced response to a given dose on repeated administration, but in a decreased elimination rate of GTN, 1,3-GDN, and 1,2-GDN in plasma. Moreover, GTN tolerance was found to reduce both the maximal relaxation and the potency of GTN. An increase in cGMP was found in tolerant vessels, although this was more marked in nontolerant vessels. The cGMP levels noted in vessels do not correlate with tissue GTN levels in rats.Autoradiographic studies show a rapid and homogeneous distribution of radioactivity after iv [14C]-GTN in mice aud rat. Cytochrome P-450 and esterases were found to be involved in the distribution of radioactivity.The present thesis shows that the phosphodiesterase inhibitor dipyridamole can not reverse GTN tolerance in healthy volunteers. Based on this and on previous studies on GTN tolerance, it was concluded that GTN tolerance in humans can only be reversed by applying "nitrate free intervals".
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| 26. |
- Vegfors, Magnus
(författare)
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Pulse oximetry : methodological considerations : experimental, in vitro and human investigations
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pulse oximeters monitor non-invasively the haemoglobin oxygen saturation. Light of two specific wavelengths, red and infrared light, is shined through a tissue, usually the finger, and the intensity of the light transmitted is measured. Oxyhaemoglobin absorbs the light differently when compared to reduced haemoglobin. The light transmission is measured on the pulse beat. It is therefore possible to calculate and display the arterial oxygen saturation.Pulse oximeters are primatily calibrated on healthy humans during transient mild hypoxia. Severe hypoxia is not extensively studied. Furthermore, the influence of alterations in blood flow and haematocrit has not been sufficiently investigated.The aims of this study were therefore to evaluate the accuracy of pulse oximetry during severe hypoxia and assess the influence of haematocrit and blood flow changes on the pulse oximeter readings. An animal- and an in vitro model have been developed, and to be able to assess the influences of blood flow a pulse oximeter probe was attached to the foot of volunteers during limb elevation. In addition, a developed prototype of a fibre optic sensor, measuring heart and respiratory rates using pulse oximeter technique, was compared with visual observation, capnography.impedance plethysmography and an acoustic sensor.Results from the animal model showed a reduced pulse oximeter accuracy when the invasive oxygen saturation was below approximately 85 %, and that the light absorption characteristics for the two wavelengths used in pulse oximetry (660 nm and 940 nm) were similar for rabbit- and human haemoglobin. After haemodilution, an increase in the pulse oximeter readings was found, resulting in an increased accuracy when the invasive oxygen saturation was over 85 %. The results from the in vitro model showed a strong dependency of the pulse oximeter accuracy on the haematocrit value and indicated that the pulse oximeter mainly measures the oxygen saturation in smaller pulsating vessels. During limb elevation in humans, resulting in reduced blood flow, the quotient between red and infrared light was changed resulting in a falsely low pulse oximeter reading. The new fibre optic sensor correlated well with the other methods monitoring respiratory rate. During apnoea the fibre optic sensor detected the event correctly.In conclusion, pulse oximetry correlated well with invasively measured oxygen haemoglobin saturation values when SaO2 > 85 %. Overestimation by the pulse oximeter was found during severe hypoxia. A dependence on the haematocrit value was found in studies using an in vitro- and an animal model. During reduction of blood perfusion in humans, the pulse oximeter readings varied with changes in blood flow. The new fibre optic sensor technique to measure respiratory rate, correlated well with other techniques measuring respiratory rate. The fibre optic technique may have several clinical advantages.
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| 27. |
- Walther, Sten, 1954-
(författare)
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Nebulized corticosteroid in septic lung injury : An experimental study in pigs
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sepsis is occasionally complicated by the adult respiratory distress syndrome (ARDS). Auto injury by immunocompetent cells are given a central role in the pathogenesis, but our understanding of the mechanisms remains fragmentary. Treatment in septic ARDS is mainly supportive, no causal therapy exists. Mortality is high at 50-70%.The main purposes of the prese~t series of experiments in pigs were to study mechanisms involved in Gram positive and Gram negative septic lung injury, and to investigate effects of intrapulmonary delivery of nebulized drug on mediators of injury and on pulmonary integrity and function. Nebulized corticosteroid with a high anti-inflammatory activity, beclomethasone dipropionate 10 and 50 pg/kg given every 6 hours, improved gas exchange, lung mechanics, pulmonary and systemic haemodynamics and outcome for a 44 hour observation period in pigs with staphylococcal sepsis. The pulmonary effects of a corticosteroid with still higher anti-inflammatory activity, fluticasone 100pg/kg, given in endotoxaemia were similar to those seen after beclomethasone dipropionate in staphylococcal sepsis, the main difference was an increase in pulmonary artery pressures followingfluticasone. Angiotensin converting enzyme (ACE) activity in serum was analyzed and related to the stabilized systemic haemodynamics which were found in pigs treated with nebulized corticosteroid. The results indicated an association between systemic vasoregulation and ACE activity in sepsis, but they did not support that blood pressure was preserved by an ACE-dependent mechanism in corticosteroid treated pigs. Sepsis increased pulmonary sequestration of radiolabelled autologous granulocytes. This increase was significantly attenuated by nebulized beclomethasone dipropionate. The endotoxin-induced immediate accumulation of radiolabelled transferrin in the lungs, whichprobably indicated increased transcapillary protein flow, was abolished by fluticasone.In conclusion, nebulized corticosteroid given in moderate doses in sepsis reduced pulmonaty granulocyte sequestration, abolished pulmonary capillary protein leak and attenuated pulmonary dysfunction with resultant increase in survival. These protective effects of nebulized corticosteroid inexperimental septic lung injury indicate a therapeutic role in the treatment of ARDS.
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| 28. |
- Zdolsek, Johann, 1960-
(författare)
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Effects of reactive oxygen species on the cellular vacuolar apparatus
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reactive and potentially harmful oxygen species occur, and are continuously formed, in all cells of a living organism. Increased production of these metabolites are seen in a number of pathological states, for instance in inflammatory foci or during reoxygenation of ischemic tissue. Reactive oxygen species are considered to be associated with aging, the development of cancer and atherosclerosis.The main aim of this study was to investigate the effects of reactive oxygen species on the cellular vacuolar apparatus, in particlar lysosomes.It was found that neither superoxide radicals nor hydrogen peroxide alone had any damaging effect on lysosomes. With the presence of iron and, when hydrogen peroxide is concerned, a reducing agent damage to lysosomes was detected in the form of impaired proton gradient, leakage of lysosomal enzyme and lipid peroxidation, suggesting involvement of hydroxyl radicals.By refining and modifying an existing cytochemical method it was also possible to detect iron at both light- and electron microscopicallevel with preserved ultrastructure. Iron was mainly found in secondary lysosomes.It was also found that hydrogen peroxide-toxicity to cultured cells is iron dependent and could be much reduced by deferoxamine, an iron-chelator. This drug also prevented the hydrogen peroxide-mediated loss of the lysosomal proton gradient, suggesting intralysosomal Fentonreactions with generation of hydroxyl radicals.Acridine orange is an acidotropic photosensitizer which mainly accumulates in lysosomes. By exposing acridine orange-loaded cultured cells to blue light reactive oxygen, found to be singlet oxygen, was generated intralysosomally. This lead to loss of the proton gradient over the lysosomal membrane and a decrease in lysosomal cathepsin activity. Inhibition of lysosomal proteases lead to a reduction in acridine orange-mediated cell death suggesting a role for these enzymes in cell death. Electron microscopy revealed bleb-formation and increased autophagocytosis in photosensitized cells.
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| 29. |
- Öberg, Tommy, 1943-
(författare)
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Trapezius muscle fatigue and electromyographic frequency analysis
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study, comprising 6 separate articles, is concerned with different validity and reliability aspects of the electromyogram mean power frequency (MPF) as an estimator of localized musele fatigue in the trapezius muscle. A series of new, and partly controversial and problematic findings are reported.There was a systematic variation of MPF that was not related to muscle fatigue, but to other factors such as shoulder joint angle, torque and external hand load, which can erroneously be interpreted as muscle fatigue; the largest variation, ±8%, was related to joint angle; movements of the surface electrodes was the most probable explanation of this variation and thus significantly influence the MPF estimates; there was an unacceptably large random variation of single MPF estimates; single estimates should not be used for normalization of MPF; there was no correlation between MPF and subjective muscle fatigue at low load level; MPF did not work as a valid estimator of localized muscle fatigue at low load level; load dose was not a suitable parameter to represent physical stimulus at the evaluation of subjective fatigue; the EMG response to fatigue seemed to be different in healthy muscle compared with diseased muscle in patients with unilateral work-related trapezius myalgia; the changes were more pronounced on the healthy side.All these factors have to be considered if MPF is to be used as an estimator of localized muscle fatigue. Procedures are proposed to overcome some of these difficulties and reduce some of the variations such as a standard procedure for calibration, repeated measurements, regression procedures with calculation of trends insted of evaluation of single MPF estimate etc. There is a need for more research concerning the variation of MPF and procedures to handle this variation.
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| 30. |
- Öllinger, Karin, 1962-
(författare)
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Cellular toxicity of quinones : Redox- and addition chemistry
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Quinoid compounds are widely occurring in nature. They have cytotoxic properties and they are also used as antineoplastic agents. The cytotoxic properties can be explained by the ability of quinones to generate active oxygen species by redox cycling, by addition to cellular nucleophiles, and by inhibition of DNA transcription.This study aims to the characterisation of free radical generating capacity and electrophilicity of 1,4- naphthoquinones as a function of their substitution pattern. Further, the mechanism for adriamycin toxicity to heart myocytes has been investigated.The two-electron reducing enzyme DT-diaphorase reduces 1,4-naphthoquinones bearing methyl-, hydroxy-, methoxy-, and glutathionyl substituents to their corresponding 1 ,4-naphthohydroquinone. The 1 ,4-naphthohydroquinones bearing hydroxy- and glutathionyl substituents are readily oxidized by oxygen, generating superoxide anion radicals and subsequently hydrogen peroxide. All quinones studied can be reduced by the one-electron reducing enzyme NADPH cytochrome P-450 reductase yielding semiquinones that efficiently reduces oxygen to superoxide anion radicals.The nucleophilic addition of glutathione to un- and benzene-ring hydroxy substituted 1,4- naphthoquinones proceeds with glutathione addition at rates decreasing with the number of hydroxy groups, reflecting the decreased electrophilicity of these quinones.The effect of hydroxy-substituent position on 1 ,4-naphthoquinone toxicity in primary rat hepatocyte cultues revealed that substituents in the benzene ring increase the toxicity, compared to 1 Anaphthoquinone, due to an increased efficiency ofredoxcycling. Hydroxy-substituent in the quinoid ring renders a quinone that is much less cytotoxic due to decreased electrophilicity and unfavorable reduction potential.The antineoplastic drug Adriamycin has the broadest spectrum of activity of all chemotherapeutic agents. Its clinical use, however, is diminished by an unique cardiamyopathy. The involvment of oxygen free radicals in adriamycin cardiotoxicity was investigated using primary cultured neonatalrat heart myocytes. The toxicity decreased at low oxygen pressure and was further decreased by addition of the antioxidant N,N' -diphenyl-p-phenylenediamine, indicating that generation of free radicals contribute to the myocardial toxicity.
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