| 51. |
- Grenegård, Magnus, 1963-
(författare)
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Platelets : intracellular signalling and cellular interaction
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Activation of platelets is essential to prevent excessive blood loss at the site of vascular injury. These highly reactive cell fragments are also involved in several pathological conditions, in particular arterial thrombosis, which, in the coronary vessels, can lead to reduced blood flow, vessel occlusion and myocardial infarction.The present research was focused on the anti-platelet properties, mechanisms of actions, and interactions of GEA 3175 and adenosine. The former a novel nitric oxidecontaining and cyclic GMP-elevating compound, the latter a cyclic AMP-elevating · purine nucleoside. Separately, the two substances significantly reduced the cytosolic , Ca2+ responses, but only marginally suppressed subsequent functional responses in thrombin-stimulated human platelets. However, coadministration of the compounds synergistically inhibited platelet aggregation and abolished dense granule secretion 1 and exposure of P-selectin, and also markedly reduced binding of fibrinogen to the i surface of platelets. The results imply that the stronger inhibition of platelet functions was due to potent blocking of the initial Ca2+ transient and abrogation of mechanisms involved in the influx of extracellular Ca2+. Together, the findings clearly manifest the importance of an interaction between different inhibitory intracellular pathways in order to completely suppress the activity of tbrombin activated platelets.Cell- and drug-comparative studies revealed that GEA 3175 provoked aremarkable long-acting inhibition of contractile responses and a concomitant i sustained increase in cyclic GMP levels in airway smooth muscle tissue. The mechanisms of relaxation involved iberiotoxin-sensitive K + channels and okadaic ' acid-sensitive phosphatases. Separately, GEA 3175 and adenosine markedly inhibited the respiratory burst in chemoattractant-activated neutrophil granulocytes. Opposite to the situation in platelets, the two compounds did not interact synergistically and coadministration had only a negligible effect on cytosolic Ca2+ signals in neutrophils. These data clearly demonstrate cell type-specific responses to cyclic GMP- and cyclic AMP-elevating agents.This thesis also delineates the regulatory effects of platelets on neutrophil cellular and intracellular responses. Simple mixture of suspensions of human platelets and neutrophils caused prominent changes in the neutrophil in regard to cytoskeletal arrangement, cytosolic Ca2+ responsiveness, and capacity to generate reactive oxygen species. Platelet-derived factor(s) induced a marked suppression of the respiratory burst in activated neutrophils, an effect attributed to peripheral accumulation of ! filamentous actin and enhanced release of endogenous adenosine from the neutrophil. The chemotactic-peptide-induced rise in cytosolic Ca2+ in neutrophils was dramatically amplified in the presence of platelets, and ATP released from the platelets may play a role in this priming phenomenon, However, additional experiments showed that the amplified Ca2+ response was virtually independent of the state of activation of the platelet, required extracellular Ca2+ ions, and was completely insensitive to the NO-donor GEA 3175. Further analysis strongly indicated that platelets affected the cyclic AMP-sensitive phase of the Ca2+ response in neutrophils. In conclusion, multiple mediators and mechanisms participate in the platelet-mediated modulation of neutrophil responses, and greater understanding of the complex mechanisms and consequences of the interactions between these blood cells may provide useful information for the design of pharmacological tools and methods to control the inflammatory reaction.
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| 52. |
- Grönroos, Eva
(författare)
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Leukotriene D4-induced signal transduction in human epithelial cells
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although the structures of the cysteinyl-leukotrienes have been known for almost twenty years, and their biological effects for almost sixty years, very little is known about the signaling propenies of these compounds. The aim of the present research was to further elucidate the components that are involved in the signaling mechanisms of leukotriene D4 (L TD4) in a human epithelial cell line. Stimulation with LTD4 was found to induce the mobilization of intracellular calcium as well as the influx of calcium through the plasma membrane. Although the LTD4 receptor probably belongs to the seven-transmembrane-spanning G-protein-coupled receptors, phospholipase Cyt is tyrosine phosphorylated and translocated to the plasma membrane upon stimulation with L1D4. The unknown, genistein-insensitive kinase responsible for this effect is directly or indirectly activated by a monomericG-protein that probably belongs to the Rho fantily. We were unable to see any direct association between a Rho protein and phospholipase Cy1, instead we found that the monomeric G-protein Rapl associates with phospholipase Cyt in unstimulated cells. After stimulation the content of Rapl increases in the plasma membrane,simultaneously as it dissociates from phospholipase Cy1 in a manner dependent on protein kinase A. The L1D4-induced calcium influx is mediated through a pertussistoxin- sensitive 0-protein. Engagement of the L TD4 receptor also induces a rapid increase in cAMP and the activation of a genistein-sensitive tyrosine kinase. Both of these events are necessary for the LTD4-induced calcium influx. The increase in cAMP probably precedes the activation of the tyrosine kinase, since preincubation with Rp-cAMPS, which inhibits protein kinase A, interferes with the L 1D4-induced tyrosine phosphorylation. The identities of the kinases involved in the calcium mobilization and influx are still unresolved. Taken together, our findings show that L TD4 stimulation of the intestinal epithelial cell line INT 407 results in the activation of at least three different G-proteins and two kinases of importance for the regulation of cytosolic calcium levels in these cells.
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| 53. |
- Gullberg, Mats, 1953-
(författare)
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Health care professionals' self description
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the present thesis was to survey and analyse professional self of health care professionals, focusing on perceptions of self, and on their attitudes towards aspects of sense of responsibility.Studies were accomplished with quantitative techniques using questionnaires and/or instruments. A total of 803 respondents was included, and the first study (I) presented the development of the PSDF and comprised 30 registered nurses. The next study (II) examined results from 332 medical laboratory technologists who answered the PSDF. In the third study (III) 68 occupational therapists responded to the PSDF. The fourth study (IV) was a six-year follow-up of 43 registered nurses from the beginning of their training to three years after graduation, and they responded to the PSDF, the SRF and to the Form for ranked sources of encouragement. The fifth study (V) comprised four professional groups from a university hospital in Sweden (physicians, physiotherapists, registered nurses and enrolled nurses), and 312 responded to the set of forms (the PSDF, the SRF, and the Form for ranked sources of encouragement).The main theoretical approach was based on symbolic interactionism, where the self is a significant notion. Concepts on attitude, sense of responsibility and encouragement were important.The results showed that there are components of self description that is 'specific to one professional group, but also components that uncover similarities. Three important components of professional self were outlined; professional conduct, work ability and empathy. Important issues were also encouragement for work done, which influences the professional self, and that the positive attitudes to sense of responsibility showed similarities with characteristics of professional self.In conclusion, two propositions were addressed: that professionals' self description is composed of three meaningful dimensions; professional conduct, work ability and empathy, and that the professional self can be improved throughdevelopment of intrinsic attitudes and behaviours.
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| 54. |
- Gupta, Anil
(författare)
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Aspects of recovery following day care anaesthesia : A clinical and experimental study
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A new test for the assessment of psychomotor recovery - the perceptive accuracy test - was designed and tested in a group of volunteers. It was found to be reproducible and not associated with any significant learning. Two hundred patients (ASA I-ll) undergoing day care arlhroscopic surgery were then studied in order to determine which anaesthetic technique is associated with the best recovery profile. No pharmacological premedication was given to any of the patients. The methodology was standardized in all studies so that the anaesthetic technique was similar between the groups, except for the study dmgs. Postural stability was measured following the injection of midazolam intravenously, using computerized dynamic posturography, Recovery was assessed using a combination of tests including a recovery scale, psychomotor tests and assessment of mood. Discharge times and post-operative complications were also recorded. Results showed that induction of anaesthesia with propofol followed by maintenance with isoflurane in oxygen and air, and alfentanil as analgesic, were associated with a good recovery profile. Maintenance of anaesthesia with propofol instead of isoflurane proved to be a satisfactory alternative. Early recovery was more rapid in patients anaesthetized with desflurane, but this group had a worse overall mood score, and a higher incidence of minor postoperative complications compared to the group in which anaesthesia was based on isoflurane. Postural stability was affected at 45 min after midazolam administration. The perceptive accuracy test was found to be sensitive in the detection of residual effects of anaesthetics, it was not associated with significant 'learning', it was easy to use, and the results obtained were 'on-line' and did not require tedious calculations.In summary, induction of anaesthesia with propofol followed by maintenance with isoflurane in oxygen and air, and alfentanil for analgesia is associated with rapid recovery, minimal post-operative complications and good overall mood scores. total intravenous anaesthesia based on propofol is a suitable alternative. Computerized dynamic posturography is a new method for studying balance disturbances. Perceptive accuracy test is sensitive in the detection of residual effects of anaesthetics but more studies are needed to describe its exact place amongst the battery of psychomotor tests.
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| 55. |
- Gustafsson, Urban
(författare)
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Microcirculation in skeletal muscle during hypoperfusion : An experimental study regarding some psysiological and pharmacological factors influencing blood flow and oxygen pressure distributions
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The vascular bed in skeletal muscle plays an important role in the regulation of the systemic circulation. The present study was undertaken to investigate how capillary blood flow and oxygenation in skeletal muscle are affected by: a) a reduction in the levels of respiratory gases in blood, hypocapnia or hypoxia, and b) the interaction of anesthetics (pentobarbital, propofol, ketamine) during hemorrhage, and c) hypotension induced pharmacologically by adenosine, sodium nitroprusside or acetylcholine.The experiments were performed on the vastus medialis muscle in mechanically ventilated anesthetized rabbits. Skeletal muscle microvascular perfusion was investigated with a local hydrogen clearance technique (LHC) (using a multi wire microelectrode) and laser-Doppler flowmetry (LDF). Skeletal muscle oxygen pressures (Pt02) and pH wereassessed using a multiwire Clark-type oxygen or an antimony (pH) microelectrode.Hypocapnia (arterial PC02 2.3 kPa) decreased LDF flow and Pt02, whereasmuscle tissue pH remained unchanged. This was interpreted as being due to a reduction in microvascular perfllsion induced by vasoconstriction. This led to a decline in both tissue oxygenation and in the removal of acid metabolites, which counteracted a developing tissue alkalosis. Apart form the vasoregulatory role of carbon dioxide, it appears that muscle tissue pH is an important factor in the control of skeletal muscle perfusion. Hypoxia (arterial P02 4.0 kPa) reduced LHC flow and Pt02. This was reversed by the administration of ritanserin (serotonin antagonist), despite a further reduction in blood pressure. This supports the concept that the decline in capillary perfusion during systemic hypoxia is at least partly mediated by serotonin.Hemorrhage was induced by withdrawal of blood to a mean arterial blood pressure of 40 mmHg, and measurements (LHC, LDF) were carried out during the spontaneous recovery period. When ketarnine wa<> used as anesthetic a higher capillary perfusion was found as compared to pentobarbital or propofol. These differences may be mediated, as suggested by the results from other studies, by the cardiovascular stimulating properties of ketamine, the effects on the renin-angiotensin system by pentobarbital and venomotor tone by propofol.Hypotension, 20-25% reduction in mean arterial blood pressure, induced by adenosine, was associated with a decrease in skeletal muscle capillary blood flow and an increase in PtOz. This may be explained by a redistribution of capillary flow and/or a reduction in local oxygen demand. Hypotension induced by sodiuin nitroprusside to a similar level, on the other hand, increased capillary blood flow, mostly in the high flow range, whereas the oxygen pressure distributions were reduced. This may be caused by an increased local oxygen demand. Acetylcholine-induced hypotension decreased capillary blood flow which was most pronounced in the high flow range, while oxygen pressure distributions decreased homogeneously in a manner similar to that seen during hemorrhage.The findings presented rnay be of importance in clinical situations with compromised skeletal muscle circulation.
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| 56. |
- Gustavsson, Johanna, 1956-
(författare)
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Insulin control of glucose transport in caveolae microdomains of the plasma membrane
- 1997
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Caveolae are invaginated, dynamic microdomains in the plasma membrane and believed to be involved in receptor-mediated uptake of small molecules (potocytosis) and in signal transduction. A phosphatidylinositol glycan, a precursor of potential insulin second messengers, has been found to be enriched in the caveolae-fraction of adipocyte plasma membranes (Parpal et al., 1995, J Cell Biol 131:125-135). We now demonstrate that the insulin receptor is localized to caveolae microdomains. This was investigated in i) 3T3-Ll adipocyte plasma membranes by a morphological method (double immunofluorescence labeling and contbcal microscopy) and in ii) caveolae isolated by a biochemical, detergent-free method. The insulin receptor was enriched in caveolae and, in response to insulin, phosphorylated on tyrosine which indicated that the insulin receptor was active.Insulin stimulates the translocation of glUcose transporter protcins from intracellular stores to the plasma membrane which leads to an increased glucose uptake. Long-chain 1 ,2-diacylgiycerol, one of two potential second messengers for insulin, has been found to stimulate glucose uptake in rat adipocytes (Stn\1fors, 1988, Nature, 335:554-556). Here, we report that long-chain 1,2-diacylglycerol, emulsified in taurodeoxycholate, stimulates the translocation of GLUT4 to the plasma membrane. Moreover, physiological long-chain 1,2~diacylglycerols are taken up by different cell types in amounts sufficient to have biological eftects, equally well in the absence or presence of taurodeoxycholate.We also report that a rapid translocation of GLUT4 to the plasma membrane was followed by a slower transition of GLUT4 into caveolae. Accumulation of GLUT4 in caveolae coincided with the insulin-stimulated increase in glucose uptake. This offers a mechanistic explanation for the observed discrepancy between the appearance of GLUT4 in the plasma membrane and the delayed increase in glucose uptake.Non-hydrolyzable GTP-analogs stimulate the translocation of GLUT4 and increase glucose uptake in permeabilized cells. The small GTP·binding protein RaM is suggested to be involved in these processes since Rab4 has been localized to GLUT4-containing vesicles and is redistributed in response to insulin. We found that Rab4 is enriched in caveolae and that the amount of Rab4 increased in caveolae, in the same extent a<> GLUT4 did, in re!.J)Onse to insulin.Caveolae are characterized by high levels of sphingolipids and cholesterol. Depletion of cholesterol, which disrupts the integrity of caveolae, abolished insulin-stimulated glucose uptake reversibly. Insulin's control of protein pho.<:phorylation was also abolished while j3-adrenergic signaling was unaffected.The results suggest that caveolae are crucial Jor insulin-signuling in adipocytes and a disruption of these structures may have consequences for the development of insulin re.~istance and diabetes mellitus.
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| 57. |
- Haglund, Lena, 1953-
(författare)
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Occupational therapy assessment in general psychiatric care
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to develop an Instrument to Investigate psychiatric patients' occupational performance In order to identify their need of occupational therapy service. A literature review and analysis of different concepts used to describe the patient's activity resulted In the construction of new concepts which subdivide the activity Into elementary parts; operations, single actions, generated actions, action sequences and simultaneous actions.Occupational therapists (n = 38) In general psychiatric care collaborated In a study of the agreement level when deciding whether patients (n = 10) should be Included In, or excluded from, occupational therapy service. The results Indicate the imJ?Orlance of studying In more detail the screening process and the development of screening mstruments.One instrument, the Occupational Case Analysis Interview and Rating Scale (OCAIRS), was identified. The instrument, which gives Information about patients' adar.tive occupational functioning, was translated Into Swedish and tested for interrater reliability In two different studies. The result showed that the second version of the instrument had good lnterrater agreement.In order to investigate whether a patient's adaptive occupational functioning is related to diagnoses of schizophrenia or mood disorders, a study was made on three groups of inpatients: patients with schizophrenia (n = 18), major depression (n = 20) and bipolar disorders (n = 22). To examine the patient's occupational functioning OCAIRS was used. The result Indicated that the patient's adaptive occupational functioning was related to psychiatric diagnoses. Patients with schizophrenia and with bipolar disorders had great difficulties In adapting to everyday occupation and were In need of intervention from the occupational therapist. Patients with maJor depression, however, do not seem to have the same need of intervention.By Interviewing 145 patients, the predictive values of OCAIRS was calculated. OCAIRS seems to predict Inclusion and exclusion Into occupational therapy, seems to select which patients are In immediate need of treatment, and seems to identify those who need a new assessment later on. However, the results Indicate a need to Investigate how the rating of the different components In OCAIRS influence the occupational therapist when judging the patient's need of occupational therapy.
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| 58. |
- Hallböök, Olof, 1954-
(författare)
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Colonic pouch anastomosis after rectal excision for cancer
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Anastomoses at the level of the pelvic floor will become increasingly more common in rectal cancer surgery when total mesorectal excision is used as a standard procedure to obtain local mdicality. A consequence of such low anastomoses is increased risk of healing disturbances and poor distal bowel function, The aim of this thesis was to focus on reconstruction after total mesorectal excision. A randomized trial comparing the conventional straight anastomosis (n=52) and the colonic pouch anastomosis (n=45) showed that the pouch patients had fewer bowel movements per 24 hours, less nocturnal evacuations, urgency and incontinence at one year after surgery. The superiority of colonic pouches could not, however, be verified by a general quality of life instrument, the Nottingham Health Profile. One disadvantage with the pouch reconstruction was that some patients experienced difficult evacuation. The trial also showed less anastomotic leakage in the pouches. This may partly be attributable to the concept of side-to-end reconstruction, which had a better preserved blood flow at the site of anastomosis than the straight (end-to-end) alternative, as shown by intraoperative laser Doppler flowmetry. In the search for specific mediators of the functional adaption after a restorative rectal excision two gut peptides, peptide YY and enteroglucagon, were sequentially measured in both plasma and neorectal mucosa after surgery. No major changes occurred. Manovolumetric investigation of the rectal substitute showed that construction of colonic pouches restores volume, improves compliance and sensory function compared with straight anastomoses. Compared with healthy rectum, pouches exhibit sensory deficits and decreased compliance despite adequate volume, factors which may partly explain why some pouch patients experience impaired evacuation. Maximum volume of the pouches was positively correlated with degree of evacuation difficulty. This association was verified by logistic regression with adjustment for confounding factors. Obviously colonic pouches cannot have the unique reservoir function of the healthy rectum. However, in-spite of physiological changes regarding sensory function, compliance, motility and reflex inhibition, patients having a colonic pouch anastomosis will usually experience satisfactory clinical bowel function.
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| 59. |
- Halldorsdottir, Sigiridur
(författare)
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Caring and uncaring encounters in nursing and health care : Developing a theory
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of the present thesis was to develop a theory on caring and uncaring encounters within nursing and health care from the patient's perspective.Results of an analysis of two phenomenological studies (paper I), as well as research findings from five other phenomenological studies (papers II-VI), were used to develop the theory.Caring and uncaring can be conceptualized on a continuum symbolizing five basic modes of being with another, which, for example, involves a neutral mode of being with another, where the individual is perceived as neither caring nor uncanng.There are two major metaphors in the theory, that of the bridge, symbolizing the openness in communication and the connectedness experienced by the recipient of care in an encounter perceived as caring. The other metaphor is the wall, which symbolizes negative or no communication, detachment and lack of a caring connection, experienced by the recipient in an encounter perceived as uncaring.In the theory the importance of professional caring within nursing and health care is proposed, essentially involving competence, caring, and connection. The above-mentioned 'bridge' is developed through mutual trust and the development of a connection between the professional and the recipient. This connection is a combination of professional intimacy and a comfortable distance of respect and compassion -- professional distance. On the other hand, uncaring involves perceived indifference and incompetence, creating distrust, disconnection and the above-mentioned 'wall' of negative or no communication.The recipient of professional caring is influenced positively. Theconsequences, which are an increased sense of well-being and health, can be summarized as empowerment. Uncaring, however, has the negative consequences of decreased sense of well-being and health, which can be summarized as discouragement. Empowerment and discouragement in this context are defined as subjective experiences of the recipients of care.The importance of seeing the recipient in his or her inner and outer contexts is emphasized in the theory. The inner context involves perceived needs, expectations, previous experiences and sense of self, which in the perspective of the recipient of nursing can be summarized as both a sense of vulnerability and the need for professional caring. The perceived hospital environment comprises the recipient's outer context.It is concluded that nurses and other health professionals can, by theirprofessional caring or lack of it, be powerful sources of empowerment ordiscouragement to those whom they are pledged to serve.
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| 60. |
- Hellberg, Carina
(författare)
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β2 integrin-induced signal transduction in granulocytic cells
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neutrophil granulocytcs are highly mobile, phagocytic white blood cells whose motile functions are critically dependent on adhesion receptors belonging to the B2 integrin subfamily. These integrins are vital for neutrophil functions due to their ability to generate intracellular signals. The B2 integrin~rnediated phagocytosis of complement-opsonised particles is believed to be regulated by PKC. Particle engulfment has previously been found to be accompanied by accumulation of DG, a lipid known to activate PKC. In the present experiments, this DO originated mainly from PLD-mediated hydrolysis of phosphatidylcholinc. The subsequent activation of PKC was demonstrated by the ability of this kinase to phosphorylate the PKC~ specific substrate MARCKS. Moreover, PKC regulated the activity ofPLD in a positive way and thereby maintained its own activity. PKC has also been shown to phosphorylate the B2 subunit of the integrin. Although this phosphorylation does not regulate the avidity of the integrins, it may be needed for the induction of intracellular signals. However, antibody-induced ligation of B2 integrins did not alter the phosphorylation status of these integrins, indicating that this phosphorylation is not involved in the generation of second messengers. In contrast, pretreatment of cells with phorbol esters inhibited the tyrosine kinase activation and the subsequent rise in cytosolic free Ca2+ in a way that correlated with its ability to induce a phosphorylation of the B2 subunit of the integrin. Therefore, a PKC-mediated phosphorylation of this subunit may represent a mechanism for other receptors to regulate the signalling capacity of B2 integrins.The B2 integrin-induced ca2+ signal was shown to be due to both a release of ca2+ from intracellular stores and an influx across the plasma membrane, Moreover, integrin ligation induced a tyrosine phosphoryialion of PLCy2 accompanied by a small formation of Ins(1,4,5)P3, indicating that PLCy2 is responsible for the intracellular release of ca2+. Further evidence was provided by the findings that an activation tyrosine kinase(s) precedes, and is a prerequisite for, the rise in cytosolic free ca2+ concentration. The Src family tyrosine kinase Fgr is activated by B2 integrin-dependent neutrophil adhesion, and this occurs through mechanisms that are yet unidentified. The present results show that ligation of B2 integrins elicited a rapid and transient association of Fgr with B2 integrins. The tyrosine kinase inhibitor genistein did not affect this association, but it did prevent the subsequent dissociation. The interaction between these two proteins could represent an initial step in the B2 integrin-induced activation of Fgr, whereas the dissociation of Fgr from B2 integrins appears to be dependent on the activation of a tyrosinekinase, probably Fgr itself.
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