| 1. |
- Adolfsson, Lars, 1955-
(författare)
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Arthroscopy in the upper extremity
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This stndy comprising six separate papers, is concerned with the techniques of, and bevaluation of arthroscopy as a diagnostic and therapeutic tool in different pathologic conditions in the upper extremity.Arthroscopy proved to increase diagnostic accuracy in 177 examined patients with anterior shoulder instability or shoulder pain. Previously not well described patterns of pathological morphology in the ventral joint capsule after anterior shoulder dislocations were disclosed. A new classification system of rotator cuff pathology to be used for arthroscopy in the subacromial impingement syndrome is suggested. Different stages of rotator cuff pathology were found to influence the clinical results after arthroscopic acromioplasty in 79 patients.An anatomical stndy on 16 cadaver elbows revealed the close proximity between commonly used arthroscopic portals and important neurovascular structures. The usefulness and potential risks of each portal were demonstrated and a preferred procedure for diagnostic elbow arthroscopy was suggested.Wrist arthroscopy was performed in 30 patients with long-standing post-traumatic pain and resulted in increased diagnostic accuracy. In patients where clinical examination and radiography had shown no abnormality, arthroscopy demonstrated serious carpal ligament injuries and related instability.A technique for arthroscopic wrist synovectomy was described in patients with rheumatoid arthritis. In 18 wrists of 16 patients, a reasonably radical synovectomy could be achieved with this atraumatic method. Primary results showed decreased pain and increased grip-strength in all patients and an increased range of motion in some.
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| 2. |
- Bengtsson, Bengt-O
(författare)
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On the hypersensitivity syndrome induced by the selective serotonin reuptake inhibiting antidepressant Zimeldine : A clinical and experimental study
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Zimeldine, the first selective neuronal serotonin (5-H1) reuptake inhibitor to be registered as an antidepressant was withdrawn from common use due to an acute flu-like adverse syndrome comprising fever, myalgia and/or arthralgia and signs of disturbed liver function. A few of these patients also developed a peripheral neuropathy, in the most serious form a Guillain-Barré syndrome (GBS). The reaction was tentatively termed a hypersensitivity syndrome (HSS).Patients who had developed a HSS during zimeldine therapy (HSS-patients) were compared to control patients who tolerated the drug.No predictor to the HSS emerged concerning demographic data, psychiatric illness, previous medical history, medications with zimeldine or other drugs, other diseases, professional or nutritional circumstances. Nor was there any sign that HSS-patients who also developed neurological symptoms had a different profile of the HSS than other HSS-patients. Earlier zin1eldine treatment per se was not seen to predispose for development of a HSS or any other kind of adverse experience during subsequent therapy. The spectrum of adverse reactions was in agreement with those reported in previous studies and no new case of the GBS was revealed. The estimated frequency of HSS ranged from 0.63 to 3.4 % in spontaneous reports to the regnlatory authority and 1.4- 13% in a written inquiry. Among closely monitored inpatients 31 %developed a HSS. The mechanism for the HSS does not seem to be related primarily to the 5-HT reuptake inhibition as such. No HLA-associated disposition for the HSS was found. Nor was there any support for a HLA-associated disposition for depressive disorders. The pathogenetic mechanism for the HSS seems to involve an inlmunological response to antigens related to zimeldine.Zimeldine and its main primary metabolite norzimeldine both suppressed clinical signs of experimental allergic neuritis (EAN) in Lewis rats. Imrnunomodulatory effects in vitro of zimeldine, its metabolites norzimeldine and CPP 200 as well as of other monoamine reuptake inhibiting antidepressants were identified in the same EAN model.These observations call for further research on immunological mechanisms in the pathogenesis of mental disorders as well as on the potential role of drugs acting on the monoamine systems in the treatment of autoimmune diseases. The findings also justify a discussion on the application of immunological methods in the testing of new psychopharmacological drugs.Based on the presented results the tentatively used term for the adverse reactions to zimeldine, the hypersensitivity syndrome, seems justified.
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| 3. |
- Comba, Pietro
(författare)
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Epidemiologic studies of nasal cancer and occupational exposures
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The object of the present research has been to elucidate the associations between malignant epithelial neoplasms of the nasal cavities and paranasal sinuses and workplace exposures to ascertained as well as suspected cancer causing agents and processes.The research includes six independent case-control studies, located in various Italian regions. These regions are characterized by different patterns of industrialization, resulting in an involvement of various occupations of interest. Furthermore, the main findings of a national programme of surveillance of nasal cancer are presented.The regions selected for the studies were the district ofBiella in Piedmont (high proportion of the active population employed in textile industry), the province of Brescia in Lombardy (high proportion of the activepopulation employed in metal industry), the provinces of Verona and Vicenza in Venetia (an area characterized by textile and leather industry and by farming), the province of Siena (a mainly rural area, with a well-established wood industry) and the province of Pisa (characterized by the presence of wood and leather industry); the two latter provinces are both located in Tuscany. The national surveillance program was based on the collaborative effort of 61 ear, nose and throat departments operating all over Italy. Finally, a case-control study involving subjects from the National Cancer Institute in Milan provided information at a national level, since patients from all over the country attend this centre.The present research confrrmed the well established risk of nasal cancer associated with the occupations of woodworker and leatherworker. The combined estimates of the odds ratios were 6.0 (90% CI: 3.8-9.3) and 5. 7 (90 % Cl: 2.8-12), respectively, which are lower and somewhat less dramatic effects than seen in some of the earlier studies.A significant association between nasal cancer and some other occupations was detected, namely metal industry, the combined estimate of the odds ratio being 2.3 (90 % Cl: 1.2-4.3), textile and gannent industry (OR: 2.2; 90% Cl: 1.2-4.1), mining and construction industry (OR: 2.8; 90% Cl: 1.6·5.0), fanning (OR: 2.3; 90% Cl: 1.4-3.8) and other occupations entailing exposures to dusts and fumes (OR: 2.0; 90% Cl: 1.1-3.6).The etiologic fraction associated with all hazardous occupational exposures was about 60 %, indicating that a considerable preventive effect could be achievable by improving the quality of the work environment. With regard to the high fatality of this disease, and the serious impairments of quality of life among the survivors, the importance of prevention is not only obvious but also ethically imperative.
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| 4. |
- Fällman, Maria
(författare)
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Complement receptor-mediated signal transduction in human neutrophils : A role for protein kinase C in the phagocytic process
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The neutrophil granulocyte comprises the first line of human defense against invading microorganisms. A versatile motile machinery enables the cell to migrate to the inflammatory site and there engulf and destroy the pathogens by phagocytosis. Engulfment is facilitated by opsonization of the microbes with C3b or C3bi complement fragments or with immunoglobulins, proteins which respectively bind to complement receptors (CRs) and Fe receptors on the neutrophil surface. The aim of the present thesis was to investigate the transmembrane signaling events involved in receptor-mediated engulfment. Experimentially induced inhibition of the phagocytic capacity of human neutrophils could be reversed by pretrcating the cells with protein kinase C (PKC)-activating agents such as PMA and a synthetic diglyceride. This indirectly suggests an important role for PKC in the process of engulfment. Presentation of opsonized yeast particles to neutrophils stimulated the phosphoinositide signaling pathway, resulting in an accumulation of Ins(1,4,5)P3 (IP3) and diglyceride (DG; the endogenous activator of PKC) with a time kinetic correlating that of the cellular uptake of the particles. However, in calcium-depleted neutrophils, formation of IP3 was totally abolished during phagocytosis of complement-opsonized yeast particles, thereby excluding this signal as a regulator of the engulfment process. DG, on the other hand, was still produced in these cells, suggesting a source other than phosphatidylinositols for the generation of this second messenger. Further studies revealed that a major part of CR-mediated DG formation originated from phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine (PC). The presence of DG suggested a subsequent activation of PKC, which was confirmed by the demonstration of CR-mediated phosphorylation of a well-known PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS). Moreover, the activity of PLD was shown to be regulated by PKC, which stimulated the production of its own activator by enhancing the activity of the lipase: PKC should thereby be able to maintain its own activity.Furthermore, we could also show that both CRI and CR3 can mediate PLO activation and that the degree of this activation is potentiated by PMA pretreatment and dependent on the fonn of ligand presentation. In conclusion, CR-mediated phagocytosis is associated with PLDmediated hydrolysis of PC and stimulation of PKC, the activity of the latter enzyme appears to be an important regulatory event in the engulfment process.
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| 5. |
- Grönberg, Anders
(författare)
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Reactive arthritis : The human antibody responce elicited by Yersinia enterocolitica and Clamydia trachomatis
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A central issue in the pathogenesis of reactive arthritis (ReA) is whether or not individuals developing arthritis have an aberrant immune response to individual antigens of potential triggering microorganisms. Although evidence exists that Yersinia and Chlamydia are two agents that precipitate ReA it has not been shown that these pathogens share common antigens. To address this hypothesis, the antibody responses in individuals with ReA associated with Yersinia or Chlamydia have been analysed.Results reveal that 60% of patients with ReA following urogenital infectionhave antibodies to C. trachomatis, compared to 33% of patients withankylosing spondylitis and 19% of healthy blood donors.All patients infected with Y. enterocolitica developed IgG and IgA immuneresponses against a limited number of antigens, which can be detected within weeks of the onset of symptoms. The immune response to most of these antigens persisted throughout the follow-up period (the longest being 993 days). The IgG response was partly directed against different antigens not involved in the IgA response. There were substantial differencies between patient sera as regards anti genic specificity patterns. Individual variations were more pronounced than any putative similarities among patients with ReA or uncomplicated enterocolitis (UEC).Sera from patients with Y. enterocolitica-triggered ReA with or withoutantibodies to Chlamydia and sera from patients with UEC caused by Y. enterocolitica were analysed for cross-reactions with Salmonella typhimurium and C. trachomatis, representing two arthritis-associated bacteria. It was found that three antigens were restricted to arthritis associated organisms. Affinity purification suggested that one antigen of 74 kDa was recognized in Yersinia-, Salmonella-, and Chlamydia antigen preparations.A standardized method for quantitative Western blot analysis, using ascanning and image-processing system, was developed. Using this system it was found that the degree of antibody response could vary significantly between different runs. The amount of antigen transferred was found to be the key factor affecting the interpretation of the antibody response.
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| 6. |
- Gunnarsson, Lars-Gunnar
(författare)
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On the occurrence and possible causes of motor neuron disease in Sweden
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A series of investigations have been performed to study secular trends of motor neuron disease (MND) morbidity and mortality in Sweden, to identify time and/or space clusters, if any, and to uncover risk factors. The occurrence of the disease was estimated from incidence, prevalence and mortality rates, and the strength of various determinants was evaluated by means of the case-control approach, using population controls. The studies comprised different periods of time between 1961 and 1990.The mortality rate from MND in Sweden, for both genders taken together, doubled from 1961 to 1985, reaching 2.5 per 100,000 person-years, and the incidence rates were of a similar magnitude. The age-specific mortality rates peaked at 70 to 75 years of age. Regarding separate birth cohorts the peak was less clear, however, and the mortality rates tended to increase continuously with advancing age. An epidemic of MND was identified in the county of Skaraborg during the period 1973-1984, when three times as many males as expected had onset of MND, especially involving the farm-working population. In the community surveys involving the counties of Viirmland and Skaraborg the 50% survival rate was slightly more than two years.Among males high adjusted odds ratios were obtained for electricity work (0R=6.7, 95% Cl 1.0-32.1), welding (0R=3.7, 95% Cl 1.1-13.0) and exposure to impregnating agents (0R=3.5, 95% Cl 0.9-13.1). Heredity with regard to a neurodegenerative disease and/or thyroid disease yielded OR=2.1, 95% Cl 1.0-4.3. The highest odds ratio was found for the combination of such heredity, exposure to solvents and male gender (0R=l5.6, 95% Cl 2.8-87.0).In sum, an increase in MND seems to have taken place during the last few decades. The regional epidemic especially among males in agricultural work, the high risk estimates regarding some occupational exposures of mainly chemical nature, and the interaction with heredity, indicate that environmental factors might play a role in the pathogenesis of MND, and that a subpopulation might be particularly susceptible.
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| 7. |
- Hanberger, Håkan, 1954-
(författare)
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Pharmacodynamic effects of antibiotics : studies on bacterial morphology, initial killing, postantibiotic effect and effecitive regrowth time
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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 (> 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 .
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| 8. |
- Holm, Ann-Charlotte
(författare)
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Membrane transport of triiodothyronine : With particular reference to erythrocytes in health and disease
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cellular T3 uptake was studied in three human cell systems, i.e. cultured lymphocytes, erythrocytes and erythrocyte membrane vesicles.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.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<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.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<0.05).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<0.01).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.
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| 9. |
- Högberg, Thomas, 1947-
(författare)
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Ovarian cancer : Treatment results, prognostic factors, and tumor marker surveillance
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.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.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.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.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.
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| 10. |
- Isacsson, Barbro, 1947-
(författare)
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Pharmacokinetics and pharmacodynamics of aminoglycosides
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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>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.
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