| 41. |
- Edoff, Karin, 1973-
(författare)
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Sensory nerve fibres, neuropeptides and cartilage : Experimental studies in the rat
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During development, maintenance and repair after injury, reciprocal interactions occur between the peripheral nervous system and the target tissues. In the Papers presented in this thesis, different aspects of such netvetarget influences between peripheral nerve fibres and skeletal tissues dtuing development and repair have been investigated in the rat. Developing rat cartilaginous bone primordia have a richly innervated and vascularised perichondriwn. In addition, larger bones exhibit cartilage canals containing blood vessels and putative sensory nerve fibres. Tills evoked the question if there is a nervous regulation of skeletal development. Denervation of the hind paws of young rats resulted in a deficient length growth but had no influence on the progress of secondary ossification. Since growth is mainly due to events in cartilage, cartilage projecting sensory neurones were identified and examined. Sensory neurones projecting to the rat cartilaginous distal femoral epiphyses were located mainly in the dorsal root ganglia (DRG) L3 and L4 and exhibited small or medium-sized diameters. A large proportion of these neurones contained the neuropeptides CGRP and/or SP. However, application of CGRP to cartilage explants in vitro did not stimulate the chondrocytes in terms of an elevation of the level of cyclic AMP. Another possibility would be that the neuropeptides affect the developmental growth of bone and chondrocytes indirectly via effects on the blood vessels. Experiments .involving tracing as above and eo-culture of labelled DRG neurones and perichondrial cells in combination with immunohistochenllstty or electrophysiology showed that the traced cultured neurones contained CGRP and/or SPin in vivo-like proportions and that most of the cartilage-projecting neurones were proton sensitive, This prompted the suggestion that the nerve fibres in the perichondrium and in cartilage canals might release CGRP and SP in response to local tissue acidosis, thereby promoting tissue homeostasis by monitoring the balance between vascular supply and metabolic load and by influencing angiogenesis and blood flow. Subsequently, possible target influences on the local presence of perichondrial sensory nerve fibres were investigated. Application of inflammation related cytokines (IL-1ß, IL-6 and LIF) affected sensory neurones eo-cultured with perichondrium- or skin-derived fibroblast-like cells in terms of survival and neurite growth. These effects were strongly influenced by the origin of the target cells. Finally, experiments using the adult rat patella showed that osteochondral defects heal spontaneously but incompletely and that healing is not accompanied by an increase of local nerve fibres at the times examined. In conclusion, the present results indicate that cartilagerelated sensory nerve fibres influence skeletal growth, that a high proportion of these neurones contain CGRP and SP, that CGRP does not activate chondrocytes in cartilage slices, that many cartilage related sensory nerve fibres are proton-sensitive· and likely have a vasoregulatory role, that inflammatory mediators have distinct effects on sensory neurones eo-cultivated with perichondrial cells and that healing of an osteochondral defect in the rat patella does not involve a local increase of cartilage-related nerve fibres.
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| 42. |
- Ekbäck, Gustav
(författare)
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Perioperative blood saving techniques with coagulative evaluation in orthopedic surgery
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allogeneic blood transfusion, although often needed in major surgery with large per-and postoperative bleeding, is fraught with dangers such as clerical mishandling, immunosuppression and blood-borne infections. It is therefore important to find ways to avoid allogeneic blood transfusion by means of less bleeding, better tolerance of the bleeding or alternatives to allogeneic blood.Aim of the study: To evaluate different methods of blood saving in total hip replacement (THR) surgery, their efficacy, and the possible risks, especially hyper- and hypocoagulation.Patients and methods: A total of 179 patients and eight volunteers were included in five studies. All patients were operated by primary TI-IR. Blood loss, allogeneic transfusions, coagulation parameters (platelets, bleeding time, fibrinogen, APTT, PT, soluble fibrin, TAT), fibrinolysis parameters (D-dimer, tPA, PAT, PAP), functional coagulation analysis (Sonoclot, TEG) and frequency of deep vein thrombosis (ultrasonography) were investigated according to the different study regimes. Thitiy patients undergoing predonation of autologous blood (PAD) with or without autotransfusion were compared with a control group of 15 patients without blood saving treatment. Fatty patients undergoing immediate prcopcrative platelet rich plasma (PRP) harvest and autotransfusion were compared with 40 patients undergoing PAD and autotransfusion. The spontaneous and induced activation of the platelets in the blood of20 patients undergoing THR with or without additive PRP harvest were also studied with flow cytometry. The efficacy of tranexamic acid (TA) as a blood saving method was examined in a study including 40 patients. As Sonoclot coagulation analysis was the single most important coagulation analysis during the studies, a methodological examination including eight volunteers was done for the instrument.Results and discussion: If no blood saving method is used there is a very strong possibility of allogeneic blood transfusion (100% of the patients studied needed blood). Autotransfusion is not sutlicient as a single transfusion reducing method (53% patients studied still needed blood). PAD+ autotransfusion gives sufficient reduction in allogeneic blood transfusion (5-27% of patients in tlte different studies needed blood) but needs prcopcrativc planning, and PAD is not accepted by Jehovah's Witnesses. PRP reduces allogeneic blood transfusion as effectively as predonation of two units of blood (15% of studied patients needed blood) and can replace PAD in unplanned operations and for Jehovah's Witnesses. The majority of platelets are in a resting state during THR and PRP harvest. PRP harvest did not affect the degree of platelet activation, but there were great individual differences between patients (spontaneous activated platelets, i.e. presenting P-Selektin during the operation, between 1 %-23%). Most of the platelets in the c-PRP were not activated at the time ofretransfusion but were easily activated upon stimulation with the physiological activator ADP. TA therapy started prcoperatively is easily performed and reduces bleeding by 35%, probably by significantly reducing induced fibrinolysis perioperatively. During primary THR surgety there was an early postoperative hypocoagulation during the first postoperative day, with a hypercoagulation later postoperativcly, and an observed maximal value about 7 to 10 days postopcrativcly that was still evident three weeks postopcratively. Per- and early postoperatively there was also a marked fibrinolysis that was normalized on day 1 postoperatively. Six of the 120 patients examined with ultrasonography had DVTs, all after the first week postoperatively. There were no differences in the frequency of detected DVTs, irrespective oftrcahnent with PAD, PRP or TA. Sonoclot coagulation analysis was found to be a valuable tool in detecting hypercoagulability but was restricted by a high variability. This variability can be lowered by a dual machine setting, repetitive analysis and directly analyzed arterial samples.Conclusion: The combination ofperioperative autotransfusion and PAD is effective in preventing allogeneic blood transfusions during primary THR. PRP harvest is as effective as PAD and is useful for patients who cannot donate blood. A minor propotiion of the patient's platelets are activated during the surgery irrespective of whether or not there is PRP harvest. TA therapy started preoperatively reduces fibrinolysis during the day of surgery and reduces per-and postoperative bleeding by 35%. Primmy THR surgery gives rise to an initial hypocoagulation followed by a hypercoagulation with an observed maximal value about 7 to 10 days postoperatively which is still evident three weeks postoperatively. However, the observed frequency of thrombosis was low (5%) in the 120 patients examined with utrasonography. Sonoclot analysis is an efficient tool for following this hypercoagulation. The high variability of the method can be reduced with a dual machine setting, repetitive analysis and directly analyzed arterial samples.
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| 43. |
- Eklund, Lena, 1969-
(författare)
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Molecular alterations in squamous cell carcinomas of the skin : emphasis on genes on chromosome 9q
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Skin cancer is the most common type of cancer in the western world. The incidence of melanoma and non-melanoma skin cancer is continuously increasing and, in Sweden, 2300 new cases per year are diagnosed of squamous cell carcinoma (SCC) alone. In this thesis, we have investigated genes and proteins from signal transduction pathways important for tumor development. Special emphasis has been put on chromosomal region 9q22-q31 where frequent loss of heterozygosity has been observed in non-melanoma skin cancers.Mutation analysis of the PTCH1 and XPA genes, connected to the familial cancer syndromes nevoid basal cell carcinoma syndrome and xeroderma pigmentosum, respectively, was performed. Based on lack of mutation or altered mRNA expression, we conclude that these two genes are not likely to be involved in development of sporadic SCCs. Next, we studied the correlation of the two phenotypes, anchorage independence and tumorigenicity, to the loss of chromosome 9 material in a panel of somatic cell hybrids. By microsatellite analysis, we show that the anchorage independence gene is located distal to the marker D9S155. The mapping of the gene for tumor suppression revealed three commonly deleted regions on chromosome regions 9p23-p22, 9p21-p12 and 9q31-q33. Another two candidates from the 9q22-q31 region, CORO2A and TßR-I, were investigated both at the gene and the protein level. We did not detect any alterations in the TßR-I gene or protein, but CORO2A protein was over-expressed in 4 of 40 (10%) tumors, indicating an involvement in sec carcinogenesis in a subset of tumors. In one healthy individual from the control population, we found a heterozygous germline mutation in CORO2A creating a stop codon, which results in a truncated protein. Thus, one functional allele might be sufficient to sustain a normal cellular function. When investigating occurrence of aberrant protein expression in the interconnected Wnt and Notch pathways, Notch1 was found to be expressed in only 5 of 40 (14%) of the normal epidermal cells, while strong staining was displayed in all the tumors. No altered expression of the most central protein of the Wnt pathway, ß-catenin, was observed, but the up-stream Dvl-1 protein was found to be up-regulated in 8 of 38 (21%) tumors. Dvl-1 was also detected in the nucleus in the majority of normal and tumor cases and a potential nuclear localization signal was identified in the Dvl-1 A isoform.None of the genes from the chromosomal region 9q22-q31 displayed alterations consistent with those of a tumor suppressor gene. Most likely, this gene remains to be identified.
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| 44. |
- Ekman, Bertil
(författare)
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IGF-I in growth hormone deficiency and in type 1 diabetes
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Both GH-deficiency and type 1 diabetes are associated with low IGF-I levels. The aim with our studies was to develop a dose titration model to obtain physiological IGF-I levels in growth hormone deficiency and to evaluate the relationship between glycaemic control and IGF-I in diabetes. First we established reference values for insulin like growth factor-I (IGF-I) and insulin like growth factor bindingprotein-1 (IGFBP-1) from 101 women and 101 men randomly selected from the population registry. No gender differences in IGF-I levels were fmmd. IGF-1 decreases with advancing age in both sexes, whereas IGFBP-1 increases with age.Titrating the GH dose according to population based reference values of IGF-I might be a way to obtain a fairly physiological substitution dose of GH. We hypothesised that a safe and probably effective maintenance dose of GH should increase IGF-I to the mean or slightly below the mean according to age adjusted reference levels. Eighteen adult hypopituitary patients with severe GH deficiency were titrated in steps, according to age adjusted IGF-I levels, to an individual dose of recombinant GH. For comparison 17 untreated healthy control subjects were evaluated. Similar IGF-1 levels armmd the mean for corresponding age were obtained in both sexes, but the maintenance median GH dose was more than twice in the women compared to men. The :individual dose differed markedly and elderly patients needed lower GH doses due to unchanged GH-sensitivity. Six months on the maintenance GH dose induced changes in blood-glucose, lipids, and insulin sensitivity index, indicating increased insulin resistance, which compared with the controls, were a normalisation. No major changes were seen in the variables of the renin-angiotensin-system. A significant increase in atrial natriuretic peptide seems also to be a normalisation if compared with the controls. The patients had less muscle strength and endmance at baseline compared with the controls and increased the muscle strength and endmance about 10 % after GH-substitution, an effect associated with the increase in IGF-I.Paradoxically circulating IGF-I is decreased in type 1 diabetes despite increased GH levels. We studied 134 adult patients with type I diabetes (aged 20-60 years), without endogenous insulin secretion, and found that circulating IGF-I were decreased to about 70 % of the values in the reference population. No con·elation between glycaemic control and IGF-I levels was found.To conclude the GH dose obtained when normalising circulating IGF-I according to population-based IGF-I levels, depends on GH-sensitivity (gender) and the IGF-1 level aimed for (age). In comparison with matched controls several OR-dependent variables are improved. In type 1 diabetes, our results suggests that the low IGF-I levels are independent of glycaemic control, and can not be corrected with subcutaneous insulin substitution.
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| 45. |
- Emilsson, Kent, 1963-
(författare)
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Mitral annulus motion in left ventricular pumping
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focus on the role of the mitral annulus motion (MAM) versus outer contour changes in the short axis, in left ventricular (LV) pumping. The influence of atrial contraction on LV dimensions and volumes and the relation between MAM and ejection fraction (EF) in sinus rhythm and in atrial fibrillation was also studied.Echocardiography was used in all studies and in the study about circumflex artery motion angiography was also used.In a study including 20 healthy adults the role of MAM, i.e. the systolic shortening of the left ventricle in the long axis, as the main mechanism of LV pumping was confirmed. There was also, however, a significant contribution to the stroke volume from an outer contour decrease in the short axis during systole. At the chordae tendineae level a cross sectional area decrease of 24% was measured. From calculations based on measures of the long axis shortening of the LV, the outer short axis diameter of the LV and calculated stroke volume, a mean systolic cross sectional area decrease of about 6% was found along the whole length of the ventricle. The higher cross-sectional area decrease at the chordae level is thougth to be caused by regional differences.In previous studies the relation between EF and MAM has been assumed to be linear, but in a meta-analysis of 434 patients it was shown that the relation is non-linear and that a linear regression model overestimates EF in the low range of MAM. It was shown that the relation between EF and MAM in adults is influenced by age but only in the normal range of EF or MAM and not in patients with decreased EF (EF <0.5 or MAM < 10mm). The relation was also shown to be influenced by the LV wall thickness.In 20 patients with atrial fibrillation the ratio EF/MAM was shown to be higher than in 20 age- and gender matched patients with sinus rhythm, due to a decrease in MAM, caused by the loss of atrial contraction.The relation between EF and MAM is thus complex and it therefore seems logical not to "translate" MAM to EF. MAM should be used as such related to reference values in the assessment of LV systolic function.In 13 patients who had atrial fibrillation the stroke volume was shown to increase after successful direct-current cardioversion due to an increase in long axis diastolic elongation of the LV and thereby increased diastolic volume, when atrial contraction was regained.In 28 patients the angiographic measure of circumflex artery motion amplitude tended to be higher than MAM in the higher range of amplitudes while the opposite was found in the lower range of amplitudes.In 13 patients with normal EF it was shown that the motion amplitude of a site epicardially at the most basal lateral part of the LV wall was significantly (P < 0.001) higher than endocardially, but in 13 patients with decreased EF (< 0.5) there was no significant difference between the two sites. The motion amplitude epicardially corresponds to the motion amplitude of the circumflex artery.In the 13 patients with normal EF the motion amplitude of the closed mitral valves was significantly lower than the motion amplitude epi- and endocardially during systole, with a rather conic shape of the atrioventricular plane at the onset of systole. In end-systole the different parts of the left atrioventricular plane, the epicardial part, the endocardial part (mitral annulus) and the valves were almost on the same level.
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| 46. |
- Engblom, David, 1975-
(författare)
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Prostaglandin E2 in immune-to-brain signaling
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Upon immune-challenge, signaling from the immune system to the brain triggers an array of central nervous responses that include fever, anorexia, hyperalgesia and activation of the hypothalamus-pituitary adrenal axis. These symptoms are dependent on cytokines produced at the site of inflammation. However, because cytokines cannot penetrate the blood-brain barrier, the mechanism by which cytokines activate the central nervous system has remained elusive. Among several hypotheses, it has been suggested that prostaglandin E2 (PGE2) synthesized at the blood-brain interface and subsequently binding to PGE2 receptors expressed on deep neural structures may be responsible for the immune-to-brain signaling.During inflammatory conditions PGE2 is produced from prostaglandin H2 by the inducible isomerase microsomal prostaglandin E synthase-1 (mPGES-1). By using in situ hybridization, we investigated the expression of this enzyme in the brain of rats subjected to immune challenge induced by intravenous injection of interleukin-1ß. We found that mPGES-1 mRNA had a very restricted and low expression in the brain of naive rats. However, in response to inunune challenge it was rapidly and heavily induced in cells of the cerebral vasculature. Further, we found that the cells expressing mPGES-1 co-expressed cyclooxygenase-2 mRNA and interleukin-1 receptor type 1 mRNA. Thus, circulating interleukin-1 may bind to brain vascular cells and induce the expression of cyclooxygenase-2 and mPGES-1, leading to the production of PGE2 that can diffuse into the brain and trigger central nervous responses. We also showed that the same mechanism may be operating in a model for autoimmune disease. Thus, rats with adjuvant-induced arthritis, a model of rheumatoid arthritis, displayed a similar mPGES-1 and cyclooxygenase-2 induction in interleukin-1 receptor bearing brain endothelial cells.To examine the functional role of the central induction of mPGES-1, we studied the febrile response in mice deficient in the gene encoding mPGES-1. These mice showed no fever and no central PGE2 production in response to immune challenge induced by intraperitoneal injection of the bacterial fragment lipopolysaccharide, demonstrating that PGE2 synthesized by mPGES-1 is critical for immune-induced fever.We also studied the expression of receptors for PGE2 in the parabrachial nucleus, an autonomic brain stem structure involved in the regulation of food intake, blood pressure and nociceptive processing. We found that neurons in the para brachial nucleus express PGE2 receptors of type EP3 and EP4 and that many of the EP3 and some of the EP4 expressing neurons in this nucleus are activated by immune challenge. The PGE2 receptor expressing neurons also expressed mRNAs for various neuropeptides, such as dynorphin, enkephalin, calcitonin gene related peptide and substance P. Taken together with previous observations, these findings indicate that the PGE2 receptor expressing cells in the parabrachial nucleus are involved in alterations in food intake and in nociceptive processing during immune challenge.In summary, these data show the presence of a mechanism, involving cerebrovascular induction of mPGES-1, that conveys an inflammatory message from the blood-stream through the blood-brain barrier to relevant deep neural structures. Further, the findings show that this mechanism is critical for the febrile response and is activated during both acute and prolonged inflammatory conditions. This identifies mPGES-1 as a potential drug target for the alleviation of central nervous symptoms of inflammatory disease, such as fever, pain and anorexia.
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| 47. |
- Engström, Sven, 1949-
(författare)
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Quality, costs and the role of primary health care
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of this thesis is to describe and analyse the role of primary care in health care systems in terms of health, health care utilisation and costs, and to study the feasibility of retrieval of data from computerised medical records to monitor medical quality.The thesis includes five studies, a systematic literature review, a register study of utilisation of hospital and primary care, a study based on data from computerised medical records of individual patients cost for primary care, and two studies of management of respiratory infections in primary care based on data from computerised medical records of twelve health centres.The general findings of the literature review were that an expansion of the primary care component of the health care system would most likely result in better health, lower hospital care consumption and lower expenses for care. The personal physician and continuity of care were core elements to achieve this, and the significance of the way primary care is organised and funded was evident.In the register study fifty health centres were compared. Age and rates of outpatient hospital visits were the most important factors explaining the variation of rates of hospitalisations between the health centres’ areas. Hospital district also influenced hospitalisation rates in the different health centres’ areas, indicating that the health care structure in the district per se was an important factor. The rates of visits to general practitioners correlated negatively with rates of hospitalisations.The study of costs in primary care showed that the variation in the costs of the individual patients was substantial, also within age groups and within the diagnosis-related Adjusted Clinical Groups (ACG). Age and gender explained a smaller part of the variation in costs per patient in primary care. Adding the ACG weight had a major influence on improving the ability to explain the variation in costs at patient level. The ACG system might be of value in the calculation of weighted capitation in Swedish primary care, but appears to be sensitive to the thoroughness with which physicians register diagnoses.The retrieval of data from computerised medical records comprised a total number of 19 965 encounters for respiratory tract infections i.e. 199 per 1000 inhabitants during the year 2001. Most frequent diagnoses were common cold, acute tonsillitis, and acute bronchitis. The number of antibioticprescriptions was 7 961, accounting for 47% of the episodes. The most commonly prescribed antibiotics were phenoxymethylpenicillin (61%), tetracyclines (18%) and macrolides (8%).A rapid test was performed in 43% of the encounters: for C-reactive protein (CRP) in 31%; for Group A beta-haemolytic streptococci (StrepA) in 22%; and both tests were performed in 10% of the encounters. The findings in the study indicate that StrepA and CRP tests were used too frequently and often with minor contributions to patient management. The frequencies of tests and of antibiotic prescriptions varied greatly between health centres in a way that hardly could be explained by differences in morbidity.Computerised medical records provided a source of clinical information, which might be a feasible and pragmatic method for studying daily practice, and for follow-up of adherence to guidelines in general practice.
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| 48. |
- Eriksson, Mats, 1959-
(författare)
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Aspects of prevention and assessment of neonatal pain
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Improvements in neonatal care have led to improved mortality and morbidity rates. An increased number of infants that are born more prematurely are being treated for prolonged time periods in the neonatal care units. The care includes many procedures that might inflict pain on the newborn infants. Pain is a protective mechanism, but it can have negative short- and long-term consequences on vulnerable infants. In order to prevent and treat pain, reliable pain assessment is needed. The aim of this research was to improve pain relief at blood sampling in the neonatal period, by non-pharmacological methods, and to investigate skin conductance as a pain assessment tool in newborn infants.Study I was a randomised trial with 120 infants divided into four groups, who received 1 ml 10% glucose, 30% glucose, breast milk or no solution, orally, two minutes prior to the heel-stick. In the group given 30% glucose the crying time was significantly shorter than in the control group. Significantly fewer infants in the 30% glucose group did not cry at all, and the heart rate increased less in that group than in the control group.Study II was a randomised trial with 120 infants divided into four groups, undergoing blood sampling with either heel-stick or veneplmcture and receiving 1 ml 30% glucose orally, or no fluid, prior to the painful event. The crying time was significantly shorter and PIPP pain score lower in the venepuncture group than in the heel-stick group when no glucose was given. When glucose was given, PIPP score was lower in both glucose groups than in the groups without glucose, but no difference was seen between the two glucose groups. Crying time in the glucose group was shorter than ill the group without glucose when heel-stick was performed.In study III we used a randomised controlled double-blind design. Two hundred and one infants were randomly allocated to one of two groups receiving either 0.5 g EMLA® on the dorsum ofthehandfor 60 minutes followed by a recovery period of 15 min, and 1 ml sterile water in the mouth 2 min prior to venepuncture, or 0.5 ml placebo cream on the hand and 1 ml 30% glucose orally. PIPP scores were lower in the glucose group and fewer infants were scored as having pain (PIPP > 6). Crying time during the first 3 ruin was shorter in the glucose group.Study IV was designed in a randomised, controlled double-blind way, where 57 infants were divided into two groups, receiving either 1 ml sterile water or 30% glucose three times daily for 3-5 days. Before undergoing routine blood sampling all infants had 1 ml 30% glucose instilled in the mouth. There was no difference in PIPP score, crying time or heart rate increase between the groups.In study V galvanic skin response and other pain assessment methods were investigated in 32 infants during three procedures performed in a randomised order: 1) gently touching an ann or a leg (no stress or pain), 2) putting a alcohol-soaked cloth on the tnmk skin (stress) and 3) performing heel-stick for routine blood sampling (pain). GSR conductance level increased more in the painful than in the stressing situation. Number of waves and amplitude of the waves increased more during pain than during touching. Crying time was higher dming the painful situation than during the stressful intervention and PIPP was higher during pain than during touching and stress.In conclusion, we found that 1 ml 30% glucose reduces pain signs from heel-stick and from venepuncture in neonates. Glucose does this better than EMLA ® cream and the effect is better than that of changing from heel-stick to venepuncture. Repeated administration of 1 ml 30% glucose for 3-5 days does not decrease the pain relieving effect.GSR can contribute to differentiate pain from stress but more research is needed to achieve a clinically useful application.
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| 49. |
- Esamai, Fabian
(författare)
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Cerebral malaria in children in the highlands of Kenya : Aspects of pathogenesis and clinical presentation
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Malaria affects over 300 million persons in the world each year with a mortality of close to 2 million. In developing countries malaria has been endemic in the lowlands for centuries with no occurrence in the highlands above 2000 metres above sea level. This pattern has changed over the last decade whereby malaria is occurs in epidemics with a high morbidity and mortality among the inhabitants of the highlands especially children and pregnant women. Eldoret and its environs in Kenya is a highland area with an altitude of 2300 metres above sea level where malaria was rare up to the late 1980s. Since 1988 malaria occurs in epidemics in this region with a high prevalence of severe malaria especially cerebral malaria(CM). This led to the conduct of stndies that fonn the basis of this thesis with the aim of delineating aspects of pathogenesis and the clinical presentation of CM in the Western highlands of Kenya.Materials and Methods: Cross sectional, retrospective and prospective studies were conducted to study the prevalence of malaria among inpatients at the Moi Teaching and Referral Hospital (MTRH); to describe the clinical presentation of CM in the highlands; to compare temperatures in CM and uncomplicated malaria(UM) cases and to assay the serum tumour necrosis factor alpha (TNFa) and transforming growth factor beta (TGF-13)1 levels in these patients.A total of 4 720 children were retrospectively and prospectively studied over an 18 month period (1991-1993) to establish the top 20 diseases at the MTRH. This was followed by a prospective study of 23 CM and 12 UM cases in 1997. All the presenting features of the cases with CM were tabulated on admission and analysed so as to establish the clinical presentation of CM in this region and compare this to the standard as described by the World Health Organisation (WHO). A comparison was made between the brain, core and skin temperatures of the CM and UM cases with normal children acting as controls.This was a follow up of a similar stndy in 1993 that compared core and skin temperatures between measles, CM and UM with normal children as controls. Serum TNF-a and TGF-131 levels were assayed and compared among the CM and UM patients in the 1997 study and included the assay of cerebrospinal (CSF) TNF-α and TGF-β1 in CM.Results and conclusions: Malaria accounted for 3 3% of all admissions over the study period with a case fatality rate of 2.2% and a mortality rate of 10.7%. Most children with CM were aged 3-10 years and were of good nutritional status. They presented in coma, with fever, headache, convulsions and hyperparasitaemia and with a short duration of illness of less than 3 days. Severe anaemia and hypoglycaemia were not common features. Malaria is the leading cause of morbidity in the children stndied. CM in the highlands presents as that seen among non-immunes. There were no differences in brain, core and skin temperatures between the CM and UM patients. The brain temperature was however always lower than core temperature even in normal controls with brain temperature having a positive correlation with core temperature as the body temperature rises. Thus, the role of fever in the pathogenesis of CM is still unclear The serum TNF-α and TGF-β1 levels were the same in UM and CM cases with TNF-α and TGF-β1 having an inverse relationship to each other. Patients with deeper levels of coma had higher levels of TNF-α and lower levels of TGF-β1.
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| 50. |
- Escobar Kvitting, John-Peder, 1976-
(författare)
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Quantification of cardiovascular flow and motion : aspects of regional myocardial function and flow patterns in the aortic root and the aorta
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Quantification of cardiovascular flow and motion is essential in the diagnosis, treatment and follow-up of cardiovascular disease. The accuracy and quantification of many imaging methods used in this field have important shortfalls, however, that result from limitations in spatial and temporal dimensions. Improvement in application of these methods requires an in-depth understanding of the technical and perceptual aspects that contribute to errors in their use.Visual assessment of echocardiographic images for asynchrony in regional myocardial motion during systolic contraction is an example of the need for better definition of limitations. The discernible delay in wall motion improved from 89 ms to 71 ms by allowing side-by-side comparison to normal motion. Clinically important delays are almost certainly missed with current "eyeballing" methods. Different and more quantitative approaches to this problem have been developed. Anatomic M-mode (AMM) assesses motion along an arbitrary line within a two-dimensional (2D) image, and was demonstrably robust in the clinical setting when used with second harmonic imaging at a depth less than 20 cm and with angle correction ofless than 60°. Doppler myocardial (DMI) imaging and strain rate imaging (SRI) were also shown to reliably demonstrate the effects of inotropic stimulation, total and severe ischemia on asynchrony in a closed chest pig model. Quantification of the changes induced by inotropy and total ischemia was possible with both methods, but the effects of stunning were not. Regional myocardial function and cardiovascular flow can also be assessed with time-resolved, three-directional, three-dimensional (3D) velocity data acquired using phase contrast magnetic resonance imaging (PC-MRI). This multidimensional data demonstrated longitudinal velocity gradients along all four walls of the left ventricle, with miuirnal apical longitudinal motion. The 3D velocity vector from single points in the ventricular wall shows that the motion over the cardiac cycle is complex in all dimensions. The flow patterns in the aortic root were also studied using time-resolved 3D PC-MRI in normal volunteers and patients who had undergone aortic-valve sparing surgery using straight Dacron grafts. In normals, vortices appeared in the sinuses of Valsalva in late systole, increased in size with the deceleration of aortic outflow and moved together as the valve closed in early diastole. These normal flow structures have never before been demonstrated in three dimensions in man. In the postoperative patients, lacking both sinuses and sinotubular junction, vortices were not observed.Many imaging methods can be improved by a critical definition of the limits oftheir reliability. This can prompt the modifications and new methods which allow us to move beyond the original shortcomings and contribute new knowledge regarding the pathophysiology of cardiovascular disease.
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