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1
McCreesh, Brendan. "Early detection and monitoring of diabetic macular oedema." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399085.
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Ockrim, Z. K. "Diabetic macular oedema : the role of steroids and VEGF." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/16290/.
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Despite advances in controlling diabetes, diabetic macular oedema remains the leading cause of blind registration in the working population in England and Wales. The only proven effective treatment for diabetic macular oedema is laser photocoagulation. However this treatment has limited benefits since it reduces the chance of moderate visual loss by approximately 50% and is unlikely to improve visual acuity. Intravitreal steroids have been used in the treatment for diabetic macular oedema. Initial pilot studies suggest it can decrease retinal thickening and increase visual acuity in the long-term. Vascular endothelial growth factor is thought to play a critical role during the pathogenesis of diabetic macular oedema. The mechanism of action of both steroids and vascular endothelial growth factor on permeability has still to be fully elucidated. The aims of this thesis were to establish a reliable model of retinal microvascular endothelial cells and to characterise cellular changes following exposure to corticosteroids or vascular endothelial growth factor. Separate clinical work was aimed at evaluating the benefits of steroid treatment alone or combined with pars plana vitrectomy as a treatment of diabetic macular oedema. We also aimed to identify any prognostic indicators for treatment by both examining the morphological features of diabetic macular oedema observed on optical coherence tomography and by assaying the vascular endothelial growth factor concentration in the ocular fluids of eyes with diabetic macular oedema. Our results show that our retinal and brain microvascular endothelial cells were morphologically very similar; in particular with respect to the spatial localization of junctional proteins. Vascular endothelial growth factor led to an increase in the permeability and a decrease in the staining of the junctional proteins. By using signal transduction inhibitors, we showed that vascular endothelial growth factor-induced permeability and vascular endothelial growth factor-induced zonula occludens-1 loss occurred via different pathways suggesting that zonula occludens-1 loss was unlikely to be the downstream effector of vascular endothelial growth factor-induced permeability. Hydrocortisone leads to a decrease in permeability and an increase in the junctional expression of a number of tight junctional proteins. Both hydrocortisone and triamcinolone were able to inhibit vascular endothelial growth factor but not lysophosphatidic acid induced permeability suggesting that steroids are able to counteract the effects of certain but all vasoactive compounds. Overall our results suggested that steroids and VEGF lead to opposing effects on microvascular endothelial cells. Our randomized controlled trial showed that intravitreal triamcinolone was no more beneficial than laser photocoagulation for persistent diabetic macular oedema. A retrospective analysis of the morphological characteristics observed on Optical coherence tomography did not provide any characteristic that was prognostic of the outcome of intervention. Additionally, an exploratory case series of pars plana vitrectomy with 4 mg intravitreal triamcinolone was unable to show that combined treatment was of benefit in the long-term. Lastly the intraocular concentration of vascular endothelial growth factor was not predictive of the outcome of treatment.
3
Spooner, Kimberly. "Anti-VEGH Therapy in the Treatment of Macular Oedema." Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21696.
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Macular oedema is one of the most common causes of permanent vision loss in patients with age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion. Anti-Vascular endothelial growth factor agents reduce macular oedema and improve vision in eyes with macular oedema associated with AMD, DR, and RVO. However, not all eyes with resolved macular oedema show satisfactory visual outcomes. Impairment of photoreceptors is primarily responsible for this vision loss. Damage to photoreceptors can be caused by subretinal haemorrhages and exudates. Furthermore, the involvement of the inner retina by impairment of bipolar and ganglion cells due to ischaemia is a significant contributor to vision loss. Despite anti-VEGF therapy, a proportion of patients may have persistent macular oedema. The aim of the work detailed in this thesis is to investigate a number of clinical challenges of anti-VEGF therapy for the treatment of macular oedema, including, burden of treatment on patients, the efficacy of long-term treatment, the development of macular atrophy and treatment resistance. The primary aim of this thesis is to assess the effect of switching therapy to aflibercept for persistent macular oedema, in cases of treatment resistance. Given the spectrum of therapies available to date for the management of macular oedema secondary to RVO, aflibercept was demonstrated to be an effective option in cases of treatment resistance to prior anti-VEGF treatment, and has also shown good long-term outcomes, although with persistent treatment. The present study based on a small cohort of patients indicated that good results on retinal anatomy and function can be accomplished with fewer injections. Large-scale studies are needed to extrapolate these promising results.
4
Patel, Jignesh I. "The pathophysiology of diabetic macular oedema : a clinicopathological assessment." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445927/.
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Diabetic macular oedema (DMO) is a devastating vision-threatening complication of diabetes mellitus. The broad aim of the thesis is to investigate the hypothesis that vitreomacular traction and growth factors are important contributors to the development of DMO. The contribution of vitreomacular traction was evaluated on the macular structural indices (foveal thickness and macular volume by Optical Coherence Tomography) and on functional effects (best corrected visual acuity) after 3-port pars plana vitrectomy (PPV) as part of clinical pilot studies with and without internal limiting membrane peels studies. The evaluation of growth factors in the vitreous, which was obtained at pars plana vitrectomy was performed using ELISA methods,. These vitreous samples from macular oedema patients (clinically graded as nonproliferative diabetic retinopathy NPDR) were compared to patients with full thickness macular holes (FTMH) and proliferative diabetic retinopathy (PDR). Lastly, using an immortalised rat retinal endothelial cell line, the effect of VEGF was explored to determine the molecular change at the junctional level. In the non-randomised pilot series of PPV, there was a significant improvement in the structural and functional indices at 12 months compared to baseline (p=0.037, p=0.01 respectively). However, in the pilot randomised and nonrandomised study including ILM peel, surgery provided little visual improvement despite structural benefit. These clinical studies of pars plana vitrectomy do suggest a role of vitreomacular traction in the development of macular oedema. Vitreal VEGF-A and HGF (angiogenic) concentrations were increased with a corresponding decrease in the angiostatic agents (soluble Flt-1 R antibody and PEDF). There were also changes in the angiopoietin 1 and 2 concentrations with significantly lower concentrations of angiopoietin 1 in macular oedema, suggesting a lower anti-permeability protective effect of angiopoietin 1. Haemodynamic (endothelin-1) and inflammatory (II-1 P) markers in the patients with macular oedema also demonstrated changes compared to control patients especially in endothelin-1 where there was a significant decrease in its concentration in the diabetic macular oedema. The effect of VEGF on cultured immortalised retinal endothelial cells (with primary rat endothelial culture acting as a comparison) did demonstrate that high concentrations of VEGF (100 ng/ml) could disrupt the organisation of tight junctions. These results demonstrate that the development of diabetic macular oedema is multifactorial with a range of physical (vitreomacular) and biochemical (cytokine) forces acting on and within the retina to produce leakage of fluid into the macula.
5
Rocker, Graeme Martin. "Studies on adult respiratory distress syndrome." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235866.
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6
King, Nathalie Ghislaine. "Investigations into the causes and prevention of oedema in coriander." Thesis, University of Birmingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435405.
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7
Al-Kashi, Adam. "An investigation into mechanisms underlying neutrophil-mediated oedema in vivo." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498010.
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Neutrophils play a crucial role in the acute immune response. Inflammatory stimuli recruit neutrophils into the tissues. Post-migratory neutrophils may then engage in pathogen killing and phagocytosis. Oedema-formation is associated with neutrophil transmigration, although evidence indicates that these are mechanistically distinct phenomena. Leukocyte-driven oedema is a feature of many inflammatory diseases including asthma, rheumatoid arthritis, and Crohn's disease, the mechanisms underlying neutrophil-mediated oedema are unclear.
8
Banz, Kelly. "Calming the ocular storm : the effect of corticosteroids in inflammatory oedema." University of Western Australia. Faculty of Life and Physical Sciences, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0093.
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The primary aim of this research is to test the therapeutic potential of certain new generation corticosteroid drugs in order to develop safe and effective treatment for eye diseases that result in oedema, or swelling. The rising incidence of diabetes and the ageing population of developed countries mean that the prevalence of uveitis, diabetic retinopathy and age related macular degeneration will rise. Often, oedema is one of the reasons for vision loss. Corticosteroids are often used to reduce inflammation. Inflammation is one of several sources of oedema. Glucocorticoids, a class of corticosteroids that have anti-inflammatory properties, are thus used to treat ocular oedema. There is an unmet need to support clinical experience of the efficacy of steroids for ocular inflammation and oedema with more substantial scientific evidence. None of the drugs under investigation, with the exceptions of dexamethasone and triamcinolone, have been used for any ocular therapeutic purpose before. This thesis investigates repurposing fludrocortisone to the ophthalmic area. 11-Desoxycorticosterone (11D) and Deoxycorticosterone (DCS), other potentially valuable mineralocorticoids, remain completely untested. Lastly, Kenacort ®, or triamcinolone acetonide (TCA), is only used off-label by ophthalmologists. Methods: In the first study, corticosteroids, and especially mineralocorticoids, were investigated for their treatment efficacy in experimental uveitis, or intraocular inflammation (using a model known as endotoxin induced uveitis). In the second study, endothelial cells from choroidal blood vessels in the back of the eye were used in vitro to study whether corticosteroids reduce paracellular (between cells) permeability. Lastly, since endophthalmitis due to frequent injections is a side effect of corticosteroid use, the pharmacokinetics of different size formulations of corticosteroids were studied in an effort to find a formula that would have a prolonged dwell time within the eye.
9
Kane, Philip John. "Brain oedema : pathophysiological studies in a rodent model of intracerebral haematoma." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308750.
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10
Bahrami, Bobak. "Anti-VEGF Treatment for Diabetic Macular Oedema: Clinical and Laboratory Insights." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18755.
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Diabetic retinopathy (DR) is a leading cause of vision impairment, characterised by vascular damage and neurodegeneration. Anti vascular endothelial growth factor (VEGF) drugs have revolutionised the management of the most common cause of vision impairment in DR, diabetic macular oedema (DMO). These drugs restore vision in DMO and induce regression of vascular changes in DR. Despite anti-VEGF therapy, a proportion of patients may have persistent DMO. The aim of the research presented in this thesis is to investigate the effect of switching therapy between two anti-VEGF drugs for persistent DMO and to assess the potential effects of anti-VEGF drugs in modulating neurodegeneration in DR through production of neurotrophic factors. In a prospective, single-arm, open-label clinical trial of patients with persistent DMO despite prior treatment with bevacizumab, there was a significant improvement in visual and anatomical outcomes when therapy was switched to aflibercept. Artifacts on automated optical coherence tomography calculations were increased in the presence of DMO. Peripheral ischaemia was associated with a poorer baseline vision and greater vision gain. Microperimetry outcomes correlated with objective and subjective vision outcomes. Diabetic conditions were simulated in vitro using ARPE-19 cell-line culture. There was downregulation of pigment epithelium derived factor (PEDF) expression in hypoxic states. In the absence of hypoxia, the addition of anti-VEGF drugs led to a significant downregulation of PEDF. Brain derived neurotrophic factor secretion was downregulated in high glucose states and upregulated in hypoxia. This thesis has addressed a number of key issues relating to persistent DMO, a management challenge with a poor evidence base. Further research is required into the identification of clinical and laboratory biomarkers to individualise pharmacotherapy and identify patients who may be poor and good responders to anti-VEGF therapy.
11
Oh, Soo Y. "Oedema in the hands of people with tetraplegia post spinal cord injury: building the evidence." Thesis, Griffith University, 2021. http://hdl.handle.net/10072/410155.
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Oedema in the hands of people with tetraplegia may occur in the early stages of rehabilitation and if left untreated, can cause joint stiffness, pain and decreased range of motion, subsequently affecting hand function (Boomkamp-Koppen et al., 2005; Faghri, 1997; Guerts, 2000; Howard & Krishnagiri, 2001; Villeco, 2012). Optimal hand and arm function has been considered as one of the most important factors in improving quality of life of people with tetraplegia (Anderson, 2004; Simpson et al., 2012; Snoek et al., 2004; Wagner et al., 2007). It is therefore important that secondary consequences, such as oedema, are managed effectively. However, there is a significant lack of research evidence specific to the management of oedema in the hands of people with tetraplegia. In response, the aim of this thesis was to build the evidence for improved oedema management in the hands of people with tetraplegia. The evidence-based practice (EBP) framework by Hoffmann et al. (2017) guided the development of the research questions within this research program. The first research question sought to explore clinical expertise and asked: What is the current clinical practice for the management of oedema in the hands of people with tetraplegia in Australia? The second research question sought to develop objective research evidence for the management of oedema and asked: What are the effects of two treatment methods (the Boxing Glove [BG] compression bandaging and Coban™ compression bandaging) for the management of oedema in the hands of people with tetraplegia? Finally, the patient’s perspectives were explored with the third research question: What is the experience of the two treatment methods from the perspective of people with tetraplegia? The research program included two studies. Firstly, an online survey of clinicians addressed the first research question and collected data regarding their perception of cause and prevalence of oedema, assessment and treatment methods, and challenges with oedema management and impacts on rehabilitation. The survey findings identified inconsistent practice methods for the management of oedema in the hands of people with tetraplegia and use of common practices that were not supported by evidence. For example, the BG splint, which is unique to the spinal cord injury (SCI) population, was reportedly used by 53% of the participants of the survey, was considered effective by no participants, and is not supported by any evidence. Compression bandaging, which has shown to be effective amongst other clinical areas, was only considered to be effective by 41% of the participants of the survey and again, lacked any evidence specific to people with tetraplegia. These survey findings informed the second study, which addressed the second and third research questions. A convergent mixed methods design focused on exploring the effects and experiences of two treatment methods used in current clinical practice: the BG compression bandaging and Coban™ compression bandaging. An ABA single case design (SCD) study measured changes in circumferential measurements following application of either the BG compression bandaging or Coban™ compression bandaging. Interpretative description (ID) (Thorne, 2016) guided semi-structured interviews that explored the experience of the two treatment methods from the perspective of people with tetraplegia. Five people with tetraplegia with oedema in their hands, participated in the mixed methods study and the converged analysis of the quantitative and qualitative results led to four key findings. Firstly, there was minimal treatment effect measured and described by participants for the BG compression bandaging. Secondly, Coban™ compression bandaging showed a promising treatment effect in reducing oedema in the hands and was the preferred treatment method among people with tetraplegia. Thirdly, oedema returned once Coban™ compression bandaging was removed and some people with tetraplegia were disappointed as they felt that they could do more with their hands when applied. Finally, people with tetraplegia expressed various priorities for rehabilitation, and managing oedema was not always the focus especially for those with other priorities relating to medical issues. The findings from this research program have contributed to an important first step in building the evidence for oedema management of the hands of people with tetraplegia. The findings provide low-level evidence in regards to the application of two commonly used treatment methods to manage oedema in the hands of people with tetraplegia. This research program identified implications to clinical practice, as well as an evidence-to-practice gap, and provide clear directions for future research and knowledge translation.Thesis (Masters)
Master of Philosophy (MPhil)
School of Health Sci & Soc Wrk
Griffith Health
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12
Towler, Pamela Kerr. "Modulation of release and activity of sensory neuropeptides and nitric oxide in the rat." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326080.
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Hammad, Lina Fahmi. "A study of the mechanical and microcirculatory properties in skin subject to venous ulceration." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326616.
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Bothwell, John Henry Fordyce. "Swelling-activated organic osmolyte decrease in brain tissue preparations." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326110.
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Jonge, Jan-Willem de. "Diuretic drug cessation in general practice withdrawing diuretic drugs prescribed for ankle oedema /." [Maastricht : Maastricht : Rijksuniversiteit Limburg] ; University Library, Maastricht University [Host], 1993. http://arno.unimaas.nl/show.cgi?fid=6675.
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Jyothi, Sreedhar. "Current and new concepts in the diagnosis and management of diabetic macular oedema." Thesis, Cranfield University, 2013. http://dspace.lib.cranfield.ac.uk/handle/1826/8600.
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Diabetic macular oedema, which can cause rapid visual deterioration, may not have early warning signs at times. Assessment of diabetic retinal complications is made chiefly by clinical examination combined with optical coherence tomography (OCT) and fundus fluoroscein angiography (FFA). However, assessment usually does not occur until the late stages of diabetic retinopathy (DR), and, as retinal neurologic changes precede clinical changes, as tested in this thesis, by the time clinical assessment is performed, much of the functional visual loss has already occurred. More robust diagnostic modalities are required to detect progression of retinopathy in the early stages, before irreversible damage has already happened, and advances in the treatment of diabetic macular oedema is imperative as the current standard treatment in the form of laser photocoagulation is ineffective in improving the vision as authenticated in the following chapters. In this thesis, both treatment and diagnostic strategies of diabetic macular oedema (DMO) are investigated. Although laser photocoagulation is effective in short term in treating diabetic macular oedema, its mechanism of action is unknown; is associated with considerable collateral damage; and long term visual prognosis is meagre at a mean change in visual acuity at 5 years of -5.23. The 3-year outcome was also inferior to the clinical trial results with more people gaining vision (≥ 15 letter gain) in the diabetic retinopathy clinical research network (DRCRN) group compared to this cohort (26% versus 9%). Furthermore, three times more patients lost vision (> 15 letter loss) in the real-life setting of this cohort compared to the clinical trial results of the DRCRN group (27% versus 8%, respectively). Therefore, improved preventative and treatment modalities are essential to prevent progression in the early stages and to improve functional vision in late stages. In an attempt to look for new treatment strategies, we hypothesized that retinal oxygenation by inhibition of dark adaptation in the rod photoreceptor, could possibly inhibit progression of diabetic maculopathy. Illuminated-mask treatment of individuals with early diabetic maculopathy revealed encouraging results that point to an inexpensive and non-invasive therapy. Whilst 19 out of 34 study eyes with cysts at the beginning of the trial improved, 11 out of 30 fellow eyes with no demonstrable cysts at the onset developed cystic macular changes towards the end of 6 month trial. In the final chapters the correlation of visual functions with anatomic appearance were examined. The results of functional assessments, including visual acuity, colour contrast sensitivity, and microperimetry, had variable relation to structural changes at the macula with OCT. Therefore, an urgent need remains for the development of reliable diagnostic and preventative tools for the early assessment and treatment of visual function defects related to diabetic macular oedema.
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Itobi, Emmanuel Onome. "The impact of post-operative oedema on clinical recovery and its potential causes." Thesis, University of Southampton, 2007. https://eprints.soton.ac.uk/63838/.
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The postoperative period is characterized by massive shifts of fluid between body compartments and accumulation of fluid in the extracellular space, which may manifest clinically as central and or peripheral oedema. The incidence of oedema in patients undergoing routine major abdominal surgery (MAS) is unknown and there are no objective means of quantifying or monitoring its presence. Furthermore, the aetiological factors responsible for post-surgical oedema formation in patients with no overt signs of cardiovascular disturbance are poorly understood and the relationship between the development of oedema and clinical outcomes such as the recovery of gastrointestinal function, postoperative complications and duration of hospital stay is unclear. Observational studies were therefore conducted on patients undergoing MAS. The presence of oedema was related to changes whole-body impedance (Z), obtained at four frequencies (5, 50, 100 and 200 kilohertz (kHz)) using bioelectrical impedance analysis (BIA) and to clinical outcomes. The fluid intake and output and changes in plasma concentration of albumin, total protein, C-reactive protein (CRP) and reduced glutathione in whole blood (GSH) were compared before and after surgery in patients who subsequently developed oedema (OD group) and patients who consistently remained free of oedema (NOD group) Oedema occurred in 40 per cent of the patients observed prospectively and was significantly related to age (odds ratio 1.087 (95 per cent confidence interval (c.i), 1.016 -1.163; P =0.016). The preoperative ratio of Z at 200 kHz to 5 kHz (Z200/Z5) was higher in patients who subsequently developed oedema than those who did not (0.809 v 0.799; P = 0.015), suggesting that it may be possible to identify patients who are prone to abnormal fluid shifts preoperatively. The change in (Z) was greater in the oedematous than non-oedematous groups (at all frequencies (P < 0.001)), and more so at lower frequencies (5kHz) than higher frequencies (100 kHz) (P < 0.001). The impedance quotient (ht2/Z) in the whole group changed in a similar direction at each frequency but to a greater extent in the OD compared to NOD groups. The total volumes of administered fluids in both groups of patients were similar but the average urine output per kg body weight was significantly lower in the OD compared to NOD patients (29.4(2.3) versus 40.5(3.7) mls/kg, P = 0.023). There were no significant differences before and after surgery in the concentrations of albumin, total proteins and GSH in both patient groups. Preoperative CRP concentration in the OD and NOD patients were similar but the mean (s.d) CRP concentration over duration of observation in the OD compared to the NOD patients was significantly greater (148 (54.1) versus 89.6 (43.8) mg/L, P = 0.006). Oedema was associated with a significant delay in the recovery of gut function (median (range) 6(3-17) versus 5(1-13) days, P = 0.020) and prolonged hospital stay (17(8-59) versus 9(4-27) days, P = 0.001) and increased incidence of postoperative complications (65 versus 22%, P = 0.011). This study shows that the incidence of early postoperative oedema is high and preoperative identification and monitoring of surgical patients vulnerable to abnormal fluid shifts may be possible with non-invasive techniques. Age, impaired ability to excrete administered fluid load and an exaggerated inflammatory response to surgical trauma rather than hypoalbuminaemia and hypoproteinaemia were significant factors for oedema formation. Postoperative oedema was associated with a significant increase in postoperative morbidity.
18
Egan, Jonathan Rogers. "The role of myocardial membrane proteins and myocardial oedema in postoperative myocardial dysfunction." Thesis, The University of Sydney, 2009. http://hdl.handle.net/2123/5975.
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The vast majority of children undergoing surgical repair of cardiac lesions do spectacularly well. However a significant proportion, ~ 25%, struggle to progress in the early postoperative period and require additional pharmacological and occasionally mechanical circulatory support. All children typically have some degree of postoperative myocardial dysfunction, with the severe spectrum termed the low cardiac output state (LCOS). LCOS is clinically defined as the requirement for new or escalated inotrope therapy, a widened arteriovenous oxygen difference, cardiac arrest or the need for reinstitution of mechanical circulatory support. LCOS is largely responsible for the morbidity and mortality involved in paediatric cardiac surgery. Despite the predictability of LCOS in the initial postoperative hours, the underlying pathophysiology remains unclear. The period of decline in cardiac function that typifies LCOS is temporally associated with the development of oedema in the tissues of the body, including the heart. This relationship between oedema and dysfunction has increasingly become blurred, with a tendency to elevate the temporal association to a causal link. We sought to explore the causes and contributions to myocardial dysfunction in this setting, including the roles of oedema and ischaemia within the heart. In focusing on oedema and ischaemia we also examined the effects of these insults on relevant myocardial membrane proteins, including those that permit rapid water transport – aquaporins (AQPs), and those involved in membrane mechanics – dystrophin, and membrane repair – dysferlin. Experimental settings which enabled the in vitro dissection of these insults and proteins of interest were combined with a clinically accurate in vivo model. This thesis describes a series of thematically linked experiments that examined LCOS, myocardial oedema and the role of various membrane proteins. We performed isolated cardiomyocyte studies, isolated heart studies as well as a clinically relevant large animal (lamb) cardiopulmonary bypass (CPB) model. Across these models we also explored the role of therapeutically protecting myocardial membranes with Poloxamer 188 (P188) and assessed any influence on myocardial function, oedema and membrane proteins. vi The results from these three models suggest that the clinically accepted dogma of a causative link between myocardial oedema and dysfunction overstates the contribution of myocardial oedema to LCOS. We found that ischaemia/reperfusion was of primary importance in causing myocardial dysfunction. Myocardial oedema without ischaemia had a mild and reversible contribution to myocardial dysfunction, but this was minor in comparison to the gross dysfunction attributable to ischaemia. Isolated cardiomyocytes, with induced oedema, functioned well. Whilst ischaemic cardiomyocytes, with less swelling still had severe contractile dysfunction. Isolated hearts, perfused with an oedema inducing crystalloid perfusate developed myocardial oedema and had minimal reversible systolic and diastolic dysfunction. Isolated hearts which experienced global ischaemia had comparable degrees of myocardial oedema, and significantly greater degrees of myocardial dysfunction that increased in severity with increasing duration of ischaemia. In the lamb CPB model, only those lambs which underwent aortic cross clamping and had a period of ischaemia had poor myocardial function. These lambs also had swollen hearts, raised myocardial AQP1 mRNA and reduced membrane dysferlin protein expression. Membrane dystrophin protein expression was not altered, somewhat unexpectedly with CPB with or without ischaemia. Lambs placed on CPB without ischaemia had good myocardial function, minimal oedema and unchanged membrane protein expression during the survival period. In a blinded lamb CPB trial of P188 there were improved haemodynamics and indicies of myocardial function associated with its use. This was also associated with preservation of dysferlin expression and reduced membrane injury. In parallel isolated heart trials of this therapy, there was a reduction in myocardial oedema associated with its use in non-ischaemic experiments. There was also a suggestion of improved diastolic function in ischaemic experiments, but no change in myocardial water content. In conclusion, we have highlighted the primacy of ischaemia/reperfusion over oedema in contributing to LCOS. We have refuted the accepted dogma that myocardial oedema causes significant dysfunction in itself, with important oedema likely to result from ischaemia. We have shown that AQP1 may be involved in the pathogenesis of the capillary leak syndrome. Finally we have hinted at a role for prophylactic P188 in the vii setting of LCOS, possibly highlighting the role of membrane repair in recovery after surgery. Isolated heart trials of P188 further support a non-rheological mechanism of action and also lend support to the causal separation of myocardial oedema and dysfunction. The integral membrane protein dysferlin, rather than dystrophin, is relevant in the setting of LCOS in the current era.
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Egan, Jonathan Rogers. "The role of myocardial membrane proteins and myocardial oedema in postoperative myocardial dysfunction." Faculty of Medicine, 2009. http://hdl.handle.net/2123/5975.
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Doctor of Philosophy(PhD)The vast majority of children undergoing surgical repair of cardiac lesions do spectacularly well. However a significant proportion, ~ 25%, struggle to progress in the early postoperative period and require additional pharmacological and occasionally mechanical circulatory support. All children typically have some degree of postoperative myocardial dysfunction, with the severe spectrum termed the low cardiac output state (LCOS). LCOS is clinically defined as the requirement for new or escalated inotrope therapy, a widened arteriovenous oxygen difference, cardiac arrest or the need for reinstitution of mechanical circulatory support. LCOS is largely responsible for the morbidity and mortality involved in paediatric cardiac surgery. Despite the predictability of LCOS in the initial postoperative hours, the underlying pathophysiology remains unclear. The period of decline in cardiac function that typifies LCOS is temporally associated with the development of oedema in the tissues of the body, including the heart. This relationship between oedema and dysfunction has increasingly become blurred, with a tendency to elevate the temporal association to a causal link. We sought to explore the causes and contributions to myocardial dysfunction in this setting, including the roles of oedema and ischaemia within the heart. In focusing on oedema and ischaemia we also examined the effects of these insults on relevant myocardial membrane proteins, including those that permit rapid water transport – aquaporins (AQPs), and those involved in membrane mechanics – dystrophin, and membrane repair – dysferlin. Experimental settings which enabled the in vitro dissection of these insults and proteins of interest were combined with a clinically accurate in vivo model. This thesis describes a series of thematically linked experiments that examined LCOS, myocardial oedema and the role of various membrane proteins. We performed isolated cardiomyocyte studies, isolated heart studies as well as a clinically relevant large animal (lamb) cardiopulmonary bypass (CPB) model. Across these models we also explored the role of therapeutically protecting myocardial membranes with Poloxamer 188 (P188) and assessed any influence on myocardial function, oedema and membrane proteins. vi The results from these three models suggest that the clinically accepted dogma of a causative link between myocardial oedema and dysfunction overstates the contribution of myocardial oedema to LCOS. We found that ischaemia/reperfusion was of primary importance in causing myocardial dysfunction. Myocardial oedema without ischaemia had a mild and reversible contribution to myocardial dysfunction, but this was minor in comparison to the gross dysfunction attributable to ischaemia. Isolated cardiomyocytes, with induced oedema, functioned well. Whilst ischaemic cardiomyocytes, with less swelling still had severe contractile dysfunction. Isolated hearts, perfused with an oedema inducing crystalloid perfusate developed myocardial oedema and had minimal reversible systolic and diastolic dysfunction. Isolated hearts which experienced global ischaemia had comparable degrees of myocardial oedema, and significantly greater degrees of myocardial dysfunction that increased in severity with increasing duration of ischaemia. In the lamb CPB model, only those lambs which underwent aortic cross clamping and had a period of ischaemia had poor myocardial function. These lambs also had swollen hearts, raised myocardial AQP1 mRNA and reduced membrane dysferlin protein expression. Membrane dystrophin protein expression was not altered, somewhat unexpectedly with CPB with or without ischaemia. Lambs placed on CPB without ischaemia had good myocardial function, minimal oedema and unchanged membrane protein expression during the survival period. In a blinded lamb CPB trial of P188 there were improved haemodynamics and indicies of myocardial function associated with its use. This was also associated with preservation of dysferlin expression and reduced membrane injury. In parallel isolated heart trials of this therapy, there was a reduction in myocardial oedema associated with its use in non-ischaemic experiments. There was also a suggestion of improved diastolic function in ischaemic experiments, but no change in myocardial water content. In conclusion, we have highlighted the primacy of ischaemia/reperfusion over oedema in contributing to LCOS. We have refuted the accepted dogma that myocardial oedema causes significant dysfunction in itself, with important oedema likely to result from ischaemia. We have shown that AQP1 may be involved in the pathogenesis of the capillary leak syndrome. Finally we have hinted at a role for prophylactic P188 in the vii setting of LCOS, possibly highlighting the role of membrane repair in recovery after surgery. Isolated heart trials of P188 further support a non-rheological mechanism of action and also lend support to the causal separation of myocardial oedema and dysfunction. The integral membrane protein dysferlin, rather than dystrophin, is relevant in the setting of LCOS in the current era.
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Aroney, Christine Margaret. "Patient Reported Outcomes From Clinical Trials in Medical Retina." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16054.
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Purpose: To determine the patient-centred effectiveness of treatment with the slow release dexamethasone intravitreal implant (DEX implant) and intravitreal bevacizumab using the Impact of Vision Impairment Questionnaire (IVI), a vision-related quality of life (VRQoL) measure, in patients with visual impairment secondary to centre-involving diabetic macular edema (DMO). Methods: Patients with DMO were enrolled in a phase 2, prospective, multicenter, randomized, single-masked clinical trial and received either DEX implant 4 monthly or bevacizumab monthly, both pro re nata. VRQoL was measured at baseline and 24 months, using the IVI’s three component scales, namely Reading, Mobility and Emotional Well-being. Rasch analysis was used to generate interval-level estimates of VRQoL, which were then analysed using t-tests to assess changes over time. Results: 48 patients completed the main study; 43 (90%) answered the IVI at the baseline and 24-month (final efficacy) visits. VRQoL improved significantly, with average increases of 1.44, 0.99 and 1.49 logits, for the Reading, Mobility and Emotional well-being scales respectively, from baseline to 24 months, (p<0.001). There was no significant between-group difference in improvement in VRQoL in the DEX implant only compared with the bevacizumab-only group, in any of the three scales listed above (with 1.41, 1.08 and 2.11 logits improvement, in Reading, Mobility and Emotional well-being respectively for DEX implant group, compared to 1.48, 1.06 and 2.11 for bevacizumab; p-values >0.1.) Conclusions: We found that both DEX implant and bevacizumab treatment result in significant and similar improvements in VRQoL in patients with DMO over a 24-month period.
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Moseley, Amanda Louise, and mosedeal@yahoo com au. "The Efficacy of Home Based Exercise Regimes for Limb Oedemas." Flinders University. Medicine, 2007. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20070314.163051.
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Secondary lymphoedema and venous oedema of the limb are the consequence of an imbalance between tissue fluid infiltrate and drainage, which leads to interstitial fluid accumulation, tissue changes, limb discomfort and morbidity. Numerous conservative therapies have been developed to address some of these negative outcomes, with a proportion of these being labour and cost intensive. This makes the investigation of cost effective and easy to implement home based regimes very important. One such therapy is limb exercise, which can be beneficial for limb oedemas through changes in both interstitial pressure and calf muscle activation. Therefore, this thesis explored the benefits of different exercise regimes for limb oedema of both lymphatic and vascular origin. This was achieved through a systematic review of existing conservative therapies for limb oedemas and four clinical trials investigating the benefits of home based exercise regimes. Results demonstrated that various positive and significant outcomes could be gained from the implementation of such regimes, including improvements in both subjective and objective parameters. These results reveal how these chronic and disabling conditions can be maintained by the patient in the home environment in between health care visits. It also demonstrates how self maintenance may alleviate the burden on the health care system.
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Kokai, Orsolya. "Measuring interface pressure applied by garments in secondary upper limb lymphoedema." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23420.
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Lymphoedema, a permanent swelling resulting from deficiencies of the lymphatic system, is a chronic condition, requiring life-long management. The approach to treatment is often multifaceted, and includes a range of modalities such as compression, lymphatic massage, decongestive exercises, and skin care. Compression is considered the cornerstone of lymphoedema management. A wide range of compression options are available, such as bandages, compression garments, intermittent pneumatic pumps and velcro wrapping systems. Compression garments, however, are the most frequently used modality for the ongoing management of lymphoedema. Despite being widely used, uncertainty remains around compression garment prescription, including advice regarding their use. International guidelines, based on expert opinions, make recommendations on the use of compression and advise on the levels of pressure to be applied. However, as the pressure under compression is not routinely measured, it remains unknown if the recommended pressures are being delivered in vivo. In contrast to other chronic conditions requiring a certain dose of pharmacological treatment, the dose of treatment for lymphoedema is therefore unknown. Measuring the pressure under compression would allow quantification of the dose of treatment for lymphoedema. A wide range of devices with varying levels of sophistication of design and way of use are currently available to assess interface pressure, which is the pressure between the skin and the garment. A wide-ranging comparison of device performance has not yet been undertaken; therefore it remains unknow which device/s provide accurate and precise measurements of the applied pressures. To better understand commercially available devices that measure interface pressure, a systematic review was undertaken. The aim of Chapter 2, was therefore, to investigate the performance of devices measuring interface pressure under compression and to assess their accuracy and precision. A systematic searching of the following databases was undertaken: Medline, CINAHL, Web of Science, Scopus, Cochrane Database of Systematic Reviews and PEDro. Search terms included: pressure delivery; compression system; compression therapy; compression bandage; compression garment; short-stretch bandage; measuring system; measuring device; measuring tool; pressure detection; pressure monitoring; interface pressure; pressure sensor and sub-bandage pressure. Only studies that evaluated devices that used commercially available sensors were included. Furthermore, the evaluation of device performance had to occur on a curved surface under static conditions with applied pressures between 20- 60 mmHg, to simulate the in vivo use of compression applied to a limb. Nine studies, assessing 14 devices, were included. These devices were grouped according to the sensors they used. There were fFour groups of sensors were identified: pneumatic, piezoresistive, optical and capacitive. Of all investigated sensors, tThe pneumatic sensor of the Picopress and the FSR 402 piezoresistive sensor showed the overall highest precision, whereas accuracy was highest for the QTC™SP200-10 piezoresistive sensor. Only 50% of the investigated sensors underwent assessment for both accuracy and precision. Of these, the best performing sensor was the Flexiforce piezoresistive sensor in the applied range of 20-60mmHg. Most of the sensors were assessed on either a cylinder or a wooden leg model. For those that were assessed under in vivo conditions, the Pliance X capacitive sensor had the best performance, with an accuracy of 6% maximum difference between applied and measured pressures. Overall, the investigated sensors showed variable accuracy and precision, which were often dependent on the amount of pressure applied, and sensor calibration processes that were performed. These factors should be considered when choosing a device for assessing interface pressure. The actual interface pressures delivered by compression garments used for the treatment of lymphoedema is are not known. Deviations from expected pressures have been found when interface pressure was investigated under compression on leg models, under sports garments or on computerised 3D models using a mathematical formula. It is, therefore, questionable whether compression garments used in the community for the management of lymphoedema deliver the expected pressures. While garment manufacturers provide information about the expected pressures, it is unknown if this level of pressure is being applied by the garment. If garments fail to deliver the expected pressures, factors, such as age of garment, frequency of wash, or severity of the patient’s lymphoedema, could be hypothesised to contribute to the deviation. This requires investigation. It is critical to understand how compression works in real world environments. The aim of Chapter 3, therefore, was to investigate whether measured pressures correspond with expected pressures exerted by compression garments used in the community, and to determine factors related to any discrepancy. A cross sectional study was conducted with 41 participants who used a compression garment for the management of their secondary upper limb lymphoedema. A questionnaire collected information related to each participant, such as body mass index, whether the dominant side was affected, and number of skin infections developed since their garment was prescribed. Lymphoedema status was assessed using the pitting and palpation tests, as well as inter-limb circumference and bioimpedance measurements. Factors related to the garments, such as compression class, type of garment, age, and frequency of wear and wash were also collected. The pressure exerted by the garment was measured using the Pliance X capacitive sensor at two locations: the forearm and the upper arm. Measured pressure was categorised as below, within or above the expected pressure and compared with participant and garment factors using chi-square analysis. Astonishingly, the majority of measured pressure exerted by garments was below the expected pressure (n=30, 75%). Despite guideline recommendations for graduated pressure with the use of compression, only 33% of garments displayed decreasing pressures from distal to proximal. There was no correlation between measured pressures and any of the participant related factors, including lymphoedema status. Likewise, there was no correlation between measured pressures and the age of garments, garment type or frequency of wear and wash. Pressures applied by compression garments for the management of upper limb lymphoedema may not provide the expected level of compression. No participant or garment related factors were found to be related to the discrepancy between measured and applied pressures. Furthermore, whether factors related to garment manufacturing or the clinicians’ measuring skills for garments contribute to the inconsistency, remains unknown. The studies in this thesis, raise important questions around the use of compression garments, such as, much the compression levels provided by garment manufacturers can be relied upon, or whether any other factors can explain why garments in the community are not exerting the expected pressures. They further highlight the necessity of routinely quantifying interface pressure in research into the efficacy of compression. The studies also suggest to consider the value of using interface pressure assessments as an adjunct in clinical practice to guide compression prescription and use.
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Snowden, Christopher Paul. "Pulmonary oedema following elective liver surgery : the role of the systemic response to hepatic ischaemia-reperfusion." Thesis, University of Newcastle upon Tyne, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397351.
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Walsh, Desmond Timothy. "The mechanisms involved in substance P (SP)-induced leucocyte accumulation and oedema formation in #in vivo'." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363062.
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Hui, Chi-hoi, and 許志海. "Nurse-led non-invasive mechanical ventilation guideline for acute pulmonary oedema patients in acute medical wards." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B4658190X.
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Wright, G. A. K. "Hepatic encephalopathy : the role of inflammation, ammonia and aquaporin expression in the pathogenesis of cerebral oedema." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/552050/.
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Current evidence indicates synergy between hyperammonaemia and inflammation in the brain with liver failure. Utilising animal and laboratory experiments, this thesis explored a number of concise questions focused on progression to brain oedema and coma with hepatic encephalopathy (HE). STUDY 1: It is unclear whether the background cirrhotic state or hyperammonaemia predisposes to superimposed inflammation. Question 1: Does lipopolysaccharide (LPS)-induced systemic inflammation worsen brain oedema in cirrhotic bile duct-ligated rats? and is this associated with blood-brain barrier disruption? altered brain ammonia and/or inflammatory pathways? Answer 1: LPSinduced pre-coma/coma and exacerbated cytotoxic oedema, indicating synergy between hyperammonaemia and inflammation associated with brain protein nitrosation. STUDY 2: New ammonia-lowering therapies targeting multiple organs are necessary. Question 2: Does combining L-ornithine and phenylacetate (OP), synergistically improve ammonia reduction? Answer 2: L-ornithine and phenylbutyrate synergistically lead to sustained ammonia-lowering and limited oedema; L-ornithine detoxifying ammonia by providing a substrate for glutamine synthesis and phenylacetate renally excreting the glutamine as phenylacetylglutamine. STUDY 3: Despite apparent synergism, therapies for HE target either hyperammonemia or inflammation, not both. Question 3: Can a reduction in ammonia in cirrhotic rats prevent LPS-induced worsening of brain oedema and progression to pre-coma/coma? Does targeting hyperammonaemia and inflammation together provide therapeutic synergy? Answer 3: Ammonia primes the brain to the deleterious effect of LPS, with the ammonia-lowering effect of OP preventing LPS-induced coma and brain edema. STUDY 4: Aquaporin-4 (AQP4), a bi-directional astrocyte water channel, is thought to provoke brain oedema in neuropathic disorders. Question 4: Is AQP4 causally involved in the brain oedema associated with models of liver failure? Answer 4: AQP4 has no causal role in the brain edema associated with hyperammonemia or inflammation, with or without acute liver dysfunction. However in cirrhosis, AQP4 upregulation, with contemporaneous p38MAPK activation is possibly a compensatory response to inhibit edema formation.
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Ishii, Hisanari. "Effects of propofol on lactate accumulation and oedema formation in focal cerebral ischaemia in hyperglycaemic rats." Kyoto University, 2002. http://hdl.handle.net/2433/149362.
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Yoshitake, Shin. "Anti-fumarase Antibody Promotes the Dropout of Photoreceptor Inner and Outer Segments in Diabetic Macular Oedema." Kyoto University, 2019. http://hdl.handle.net/2433/242905.
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Johansson, Joakim, Emmanuel Bäckryd, Göran Granerus, and Folke Sjöberg. "Urinary excretion of histamine and methylhistamine after burns." Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-85848.
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Background: The increased vascular permeability seen after burn contribute to morbidity and mortality as it interferes with organ function and the healing process. Large efforts have been made to explore underlying pathophysiological mechanisms that generate increased vascular permeability after burns. Many different substances have been proposed as mediators of which histamine, serotonin and oxygen radicals are claimed most important. However, no specific blocker has convincingly been shown to be clinically effective. Early work has claimed increased histamine plasma-concentrations in humans after burn and data from animal models pointed at histamine as an important mediator. Modern human clinical studies investigating the role of histamine as a mediator of the generalized post burn increase in vascular permeability are lacking. less thanbrgreater than less thanbrgreater thanMethod: We examined histamine turnover by measuring the urinary excretion of histamine and methyl histamine for 48 h after burns in 8 patients (mean total burn surface area 24%). less thanbrgreater than less thanbrgreater thanResults: Over time, in this time frame and compared to healthy controls we found a small increase in the excretion of histamine, but no increase of its metabolite methylhistamine. less thanbrgreater than less thanbrgreater thanConclusion: Our findings do not support that histamine is an important mediator of the increased systemic vascular permeability seen after burn.Funding Agencies|Research and Development Unit, Jamtland County Council, Sweden||
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RALSTON, Keira. "THE IMMEDIATE EFFECTS of FUNCTIONAL ELECTRICAL STIMULATION CYCLING on URINE OUTPUT, OEDEMA and SPASTICITY after SPINAL CORD INJURY." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/9986.
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Question: Does functional electrical stimulation (FES) cycling increase urine output and decrease lower limb swelling and spasticity in people with recent spinal cord injury (SCI)? Design: Randomised cross-over trial. Methods: Fourteen participants with a recent motor complete SCI were consecutively recruited from two SCI units in Sydney. Intervention: Participants were randomised to an experimental phase followed by a control phase or vice versa, with a 1-week washout period in between. The experimental phase involved FES cycling four times a week for two weeks and the control phase involved standard rehabilitation for two weeks. Assessments by a blinded assessor occurred at the beginning and end of each phase. Allocation was concealed and an intention-to-treat analysis was performed. Outcome measures: The primary outcome was urine output (mL/hr) and the secondary outcomes were lower limb circumference and spasticity using the Ashworth Scale, and the Patient Reported Impact of Spasticity Measure (PRISM. In addition, participants were asked open-ended questions to explore their perceptions about treatment effectiveness. Results: All participants completed the study. The mean between-group differences (95% CI) for urine output was 82 ml/hr (-35 to 199; p = 0.15). The mean between-group differences (95% CI) for lower limb swelling, spasticity (Ashworth), and PRISM were -0.1 cm (-1.5 to 1.2), -1.9 points (-4.9 to 1.2) and -5 points (-13 to 2), respectively. All point estimates of treatment effects favoured FES cycling. Participants reported many different benefits from FES cycling. Conclusion: There were no clear effects of FES cycling on urine output, swelling and spasticity even though all point estimates favoured FES cycling and participants perceived therapeutic effects.
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Fisher, Damien. "The influence of scleral lens parameters and fitting characteristics on corneal oedema under open and closed eye conditions." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/211357/1/Damien_Fisher_Thesis.pdf.
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Scleral lenses are large rigid contact lenses used to treat diseases that affect the front surface of the eye. This thesis examined how scleral lens fitting characteristics can be optimised to reduce corneal tissue swelling. The results provide clinical guidance for contact lens practitioners and patients worldwide.
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Whittle, Ian Roger. "The contribution of secondary mediators to the etiology and pathophysiology of brain oedema : experimental studies using an infusion model." Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/24421.
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Ubolsakka, Chulee. "Cardiovascular responses to external compression and peripheral oedema during rest and exercise in man : a role for a muscle mechanoreflex?" Thesis, University of Birmingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368382.
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Manakkat, Vijay Godhev Kumar. "The role of Toll-like receptor 9 and ammonia in the development of hepatic encephalopathy, brain oedema and immune dysfunction." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-tolllike-receptor-9-and-ammonia-in-the-development-of-hepatic-encephalopathy-brain-oedema-and-immune-dysfunction(a673d4be-1a02-4d24-ad61-268d83a0822b).html.
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Ammonia plays a central role in the pathogenesis of cerebral oedema in paracetamol-induced acute liver failure (PALF). Infection and inflammation play an important synergistic role in its development. Toll-like receptors (TLRs) sense pathogens and induce inflammation but whether this contributes to the development of cerebral oedema in PALF remains unknown. I postulated that ammonia-induced cerebral oedema and immune dysfunction are mediated by TLR9 and aimed to determine whether this could be prevented in a hyperammonemic TLR9 knockout mouse model. TLR9 expression on circulating neutrophils and their function in PALF was assessed. To examine the influence of PALF plasma and endogenous DNA on TLR9 expression, healthy neutrophils were incubated with PALF plasma with/without DNase. Ammonium acetate (NH4-Ac) was injected intraperitoneally in wild type Black6 (WT-B6), TLR9-/- B6 mice and TLR9fl/fl LysCre B6 mice with TLR9 deleted from neutrophils and macrophages. The TLR9 antagonist ODN2088 was also evaluated. Neutrophil TLR9 correlated with plasma IL-8 and ammonia concentration and increased with severity of hepatic encephalopathy and systemic inflammation. Healthy neutrophil TLR9 expression increased upon stimulation with PALF plasma which was abrogated by pre-incubation with DNase. Following NH4-Ac stimulation, intracellular cytokine (IFN-γ, TNF-α and IL-6) production of lymphocytes and macrophages were increased in WT-B6 mice compared to controls. This was accompanied by increased brain water however in TLR9-/-, cytokine production and brain water content were decreased. This was seen similarly in WT-B6 administered the TLR9 antagonist ODN2088 in conjunction with NH4-Ac. TLR9fl/fl LysCre mice had decreased cytokine production and brain water compared to the TLR9fl/fl group following NH4-Ac injection. Total DNA levels were increased in the circulation after NH4-Ac injection. In summary, ammonia-induced cerebral oedema and immune dysfunction are mediated through TLR9 and DNA dependent. The amelioration of brain oedema and lymphocyte cytokine production by ODN2088 supports exploration of TLR9 antagonism in early PALF to prevent progression to cerebral oedema.
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Heales, Christine Jane. "Anatomical and physiological bases of bone marrow oedema-like structures in magnetic resonance imaging : an in-vitro macro- and microscopic study." Thesis, University of Exeter, 2009. http://hdl.handle.net/10036/72424.
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Bone marrow oedema is a term used to define the appearance of regions of low signal on T1 weighted and high signal on T2 weighted fat-suppressed magnetic resonance images. The potential association between bone marrow oedema and prognosis in pathologies such as osteoarthritis is becoming increasingly recognised through clinical studies. A limited number of clinical studies have linked bone marrow oedema to altered bone density or altered bone marrow perfusion. The principal aims of this study were to investigate these findings in vitro, using the equine forelimb. The presence of bone marrow oedema within the equine forelimb was initially confirmed by undertaking magnetic resonance imaging scans. Bone samples were selected from 10 animals, 5 exhibiting the presence of bone marrow oedema-type abnormalities (BMOA) at the distal metacarpal. Raman microspectroscopy was used to determine the chemical composition of bone and projection radiography to provide a measure of bone density. Micro computed x-ray tomography was undertaken on a subset of three bone samples exhibiting BMOA. A second component of the study utilised contrast enhanced magnetic resonance imaging to enable comparison of perfusion to bone marrow with and without evidence of oedema. A saline flushing agent containing Evan’s blue was used so that subsequent sectioning of the bone would enable visualisation of the distribution of contrast agent as part of a histological examination of the oedematous region. An initial observation was that the majority of bone marrow oedema that was observed in the distal metacarpal appeared in a consistent location, namely the postero-inferior aspect of the bone, corresponding to the point of greatest load thereby suggesting a potential relationship to forces upon the joint. The principal observations were that there appears to be increased bone volume densities in those bone samples with evidence of bone marrow oedema. The Raman microspectroscopy did not demonstrate any statistically significant differences in the chemical composition of bone. Hence the overall impression is that bone marrow oedema is associated with a greater volume of bone, although of similar maturity and composition. There was limited evidence of increased perfusion (suggestive of increased vascularity and / or hyperpermeability) in those samples with bone marrow oedema. This work suggests that these particular bone marrow oedema lesions are associated with bone changes and potentially vascular changes although the aetiology is currently unclear. Further work is needed to determine the clinical significance and prognosis associated with these particular lesions, and whether these findings can be replicated for bone marrow oedema demonstrated at other anatomical locations.
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Strachan, Roger D. "Experimental middle cerebral artery occlusion : a study of the effects of controlled hypotension on infarct size, cerebral oedema, and cerebral blood flow in a rat model of focal cerebral ischaemia, and a preliminary evaluation of the effects of immunosuppression by irradiation on the development of cerebral oedema." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/21555.
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If changes in medical therapy are to be beneficial after the ischaemic insult, they must prevent either systemic complications such as hypotension or hypoxia, or secondary local complications such as cerebral oedema and raised intracranial pressure. This thesis addresses further aspects of these secondary complications. In a rat model of focal cerebral ischaemia (middle cerebral artery occlusion), it looks at the effect that systemic hypotension has on the extent of cerebral infarction, the development of cerebral oedema, and the regional cerebral blood flow. It demonstrates that following middle cerebral artery occlusion, there are changes in autoregulatory phenomena that are not isolated to the ipsilateral hemisphere. Staining and histological techniques have shown differences in anatomical and physiological areas of ischaemic damage that indicate disparities in perfusion deficit and anatomical infarction. New techniques for precise experimental blood pressure control are introduced, with comments on the variability of infarct size despite accurate blood pressure control, yet clear evidence that even a modest reduction in blood pressure after an ischaemic insult causes significant increases in infarct size and cortical oedema formation. It explains why the maintenance of blood pressure and cerebral perfusion is so important if the extent of the ischaemic damage is to be minimised. Finally, it looks at the possible role of peripheral blood components in the generation of cerebral oedema. Using whole body irradiation techniques to suppress peripheral blood cell counts, it demonstrates that oedema formation following middle cerebral artery occlusion is reduced following such treatment. A better understanding of the immune mechanisms involved following an ischaemic insult to the brain may have major therapeutic implications.
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Bėčiūtė, Diana. "Šunų gerklų edemų etiologija, diagnostikos ir gydymo būdai." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2014. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2014~D_20140305_140321-25476.
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Darbo tikslas: įvertinti šunų gerklų edemų etiotropinius faktorius, taikomas diagnostikos priemones bei gydymo ypatumus.
Darbo uždaviniai:
1. Apžvelgti literatūroje pateikiamus duomenis apie gerklų edemų šunims etiologiją.
2. Išanalizuoti patologinio proceso pagrindinius ir pagalbinius diagnozavimo metodus.
3. Išanalizuoti gerklų edemų gydymui taikomas priemones, pateikti patologinio proceso prevencijos būdus.
Buvo renkami duomenys 2005–2012 m. pacientų, kurie sirgo ligomis, sukeliančiomis gerklų edemą. Nuo 2005–2008 m. analizuotos tik pacientų ligos istorijos, kuriems buvo diagnozuota gerklų edema (n=133), o nuo 2008–2012 m. – gyvūnai (n=163) tirti kartu su veterinarijos gydytojais, dalyvauta atliekant diagnostines procedūras bei paskiriant gydymą. Išnagrinėti gerklų edemos etiologiniai veiksniai, jų diagnozavimo ir gydymo būdai.
Tyrimų rezultatai ir išvados: išanalizavus surinktus duomenis apie pacientus, sergančius ligomis, kurios iššaukia gerklų edemą, nustatyta, kad pagrindiniai etiologiniai veiksniai, sukėlę gerklų edemą šunims, buvo laringitas (54 proc. arba 159 atvejai, p>0,05), laringotracheitas (27 proc. arba 78 atvejai, p>0,05), trachėjos kolapsas (11 proc. arba 34 atvejai, p<0,05), brachicefalinis sindromas (6 proc. arba 19 atvejų, p<0,05), navikai gerklų srityje (1 proc. arba 4 atvejai, p>0,05), vabzdžių įgėlimai (0,3 proc. arba 1 atvejis, p>0,05) ir šunidžių kosulys (0,3 proc. arba 1 atvejis, p>0,05). Gerklų edema dažniau diagnozuota patinams (58 proc. arba 17... [toliau žr. visą tekstą]The objective of the research–to understand factors about dogs laryngeal oedema, laryngeal oedema diagnostic and treatment. Task of the research: 1. To analyze information about dogs laryngeal edema in literature. 2. To identify pathological process main and supporting diagnostic procedures. 3. To analyze treatment and ways of prevention of the laryngeal edema in dogs. 2005–2012 years, the information was picked about pacients, who had diseases, which stimulate laryngeal edema, from 2005–2008 information was picked about patients who has diseases which stimulate laryngeal edema, and from 2008–2012, the pacients were researched with vet doctor near abay. Were identifyied 296 pacients and their causes and treatment of laryngeal edema. Results and conclusions: main etiology factors of laryngeal edema in dogs were: laringytis (54 percent or 159 cases, p>0,05), laringotracheitis (27 percent or 78 cases, p>0,05), collapse of trachea (11 percent. or 34 cases, p<0,05), brachicefalic syndrome (6 percent. or 19 cases, p<0,05), tumours (1 percent or 1 case, p>0,05), bite of insect (0,3 % or 1 case, p>0,05) and kennel cough (0,3 % or 1 case, p>0,05). laryngeal edema,was identified more in males (58 percent or 172 cases), than females (42 percent or 124 cases). The patient average age was from 5,2±1,17 years old. Laryngeal edema diagnosed more in pedigreed dogs (72 percent or 214 cases) than in hybrids (28 percent or 82 cases). Major pedigreed dogs had ilnesses, who were from 1 to 5... [to full text]
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Tait, Matthew James. "The role of aquaporin-4 in subarachnoid haemorrhage." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:9b50df6f-9949-4ac2-a920-c1f44872aeb1.
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Introduction. The glial cell water channel aquaporin-4 (AQP4) plays an important ro le in brain oedema, astrocyte migration and neuronal excitability. Current theories of AQP4 function are based largely on experiments using AQP4 -1- mice. These mice have only been partially characterized. I therefore undertook a detailed investigation of baseline brain properties in AQP4 -1- mice. In the second part of my experiments I investigated the role of AQP4 in brain oedema in a mouse model of subarachnoid haemorrhage. Method. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. A mouse model in which 30~1 of autologous blood was injected into the basal cisterns was used to reproduce subarachnoid haemorrhage. Brain water content, intracranial pressure and neurological score were compared in wildtype and AQP4 -/- mice. I also measured blood brain barrier permeability and the osmotic permeability of the glia lim itans, one of the routes of oedema elimination.
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Vella, Sandro. "Pharmacological modulation of insulin resistance : benefits and harms." Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/4428eca5-5018-4816-95d0-30c0a3043409.
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Aims: Thiazolidinediones have been advocated as second or third line insulin sensitizing agents in the management of type 2 diabetes (T2DM). Their widespread use has been hampered by concerns about their cardiovascular safety, including fluid retention. Metformin is established as first-line glucose-lowering pharmacotherapy in T2DM. It has also been suggested that it may have benefits in alleviating insulin resistance in type 1 diabetes (T1DM). This thesis examined: (i) cardiovascular, renal and metabolic differences between individuals with T2DM ‘tolerant’ or ‘intolerant’ of TZDs; (ii) risk factors for TZD-associated oedema in T2DM; and (iii) the potential for metformin as adjunct therapy in T1DM. Methods: (i) A small clinical study characterising TZD tolerant and intolerant individuals with T2DM; (ii) A population-based epidemiological study of TZD induced oedema in individuals with T2DM in Tayside, Scotland (using incident loop diuretic prescription as a surrogate); (iii) A systematic review and meta-analysis of published studies of adjunct metformin in T1DM. Results (i) During a five-day high sodium diet, two known TZD-intolerant individuals with T2DM had reductions in haematocrit, aldosterone, and diastolic BP and increases in ANP and central and peripheral augmentation indices which were outwith reference ranges derived from nine TZD-tolerant individuals; (ii) Predictors of time to loop diuretic prescription included age, body mass index, systolic BP, haematocrit, ALT and macrovascular disease but rates of this outcome did not differ by therapy: 4.3% (TZDs) vs 4.7% (other agents) [unadjusted OR 0.909 (95% CI 0.690, 1.196); p = 0.493]; (iii) In meta-analysis of nine small studies in T1DM (192.8 patient-years of follow-up), metformin was associated with a reduction in total daily insulin dose (6.6 units/day; p < 0.001) but no studies examined cardiovascular surrogates or outcomes. Conclusions: Hypotheses were generated for several potential biomarkers predictive of TZD-induced oedema but the clinical importance of TZDs as a risk factor for oedema in individuals with T2DM was questioned. As there is some evidence for the safety of metformin as an adjunct therapy in T1DM but little evidence of efficacy, larger studies are warranted.
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Bouzat, Pierre. "L'érythropoïétine : un traitement de l'oedème cérébral de l'hypoxie cérébrale post-traumatiques." Phd thesis, Université de Grenoble, 2013. http://tel.archives-ouvertes.fr/tel-00905688.
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L'œdème cérébral et l'hypoxie cérébrale post-traumatiques sont les acteurs principaux de l'apparition des lésions ischémiques secondaires. L'erythropoïétine (Epo) sous sa forme recombinante humaine possède une activité anti-oedémateuse dans un modèle expérimental de TC diffus. Son action sur l'hypoxie cérébrale post-traumatique reste néammoins méconnue. De plus, les effets indésirables hématologiques de l'Epo ont conduit à la synthèse de dérivés de l'Epo ne possèdant pas d'activité hématopoïétique comme l'érythropoïetine carbamylée (CEpo). Dans ce contexte, mon travail de thèse a eu pour but d'évaluer les propriétés de l'Epo et de la CEpo dans le modèle de TC diffus. Un traitement intraveineux par CEpo à la dose de 50 µg/Kg a ainsi permis de diminuer précocemment l'œdème cérébral post-traumatique évalué in vivo par IRM de diffusion et ex vivo par gravimétrie spécifique. Cette propriété a impliqué l'inhibition de la phosphorylation de la voie Erk et s'est accompagnée de l'amélioration des fonctions motrices et cognitives jusqu'à 10 jours après le TC. Après une étude de validation sur des rats sains soumis à différentes conditions d'oxygénation, une méthode de mesure IRM de la saturation locale en oxygène (lSO2) cérébrale combinant l'effet BOLD avec la mesure du volume sanguin cérébral a montré une diminution de l'oxygénation cérébrale post-traumatique. Cette hypoxie cérébrale n'était pas en lien avec une diminution du débit sanguin cérébral attestée par méthode de premier passage d'un agent de constraste. Un collapsus des capillaires cérébraux était par ailleurs retrouvé en microscopie électronique. L'Epo à la dose de 5000 UI/Kg a été capable de restaurer l'oxygénation cérébrale en diminuant l'œdème astrocytaire péricapillaire. L'ensemble de ce travail a permis d'établir les bénéfices d'un traitement par Epo ou par CEpo sur l'œdème cérébral et l'hypoxie cérébrale post-traumatiques.
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Johansson, Daniel, and Robert Lomas. "Ambulanssjuksköterskors upplevelser av Boussignac CPAP inom prehospital vård." Thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-143066.
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Objective: To investigate the experiences of ambulance nurses when using Boussignac CPAPcompared to their previous model, and their suggestions for possible improvements in the use of CPAP in the care of patients with pulmonary oedema. Method: A qualitative study with a descriptive and exploratory approach. Data was collected through ten semi-structured interviews with ambulance nurses, seven men and three women. The analysis was conducted using Lundman and Graneheim’s content analysis. Results: Three categories were identified: Usage, Treatment and Development. Boussignac CPAP is described as easy to use and with fewer elements than the previous model. With this model it is particularly appreciated to have the opportunity to be able to regulate the resistance without fixed settings. Boussignac CPAP is regarded as more convenient in the handover of the patient. The potential for increased use, with the possibility of adjustment without fixed settings of resistance for Boussignac CPAP, is not perceived to be fully realized. Conclusion: Boussignac CPAP is, by the ambulance nurses, perceived to have made the handling of equipment easier and increased quality of care. To make further use of the potential of Boussignac CPAP more training and changes in the guidelines may be needed.Syfte: Att undersöka ambulanssjuksköterskors upplevelser av Boussignac CPAP jämfört med deras föregående modell, samt ambulanssjuksköterskors eventuella förslag till möjliga förbättringar vid användandet av CPAP i vården av patienter med lungödem. Metod: En kvalitativ studie med deskriptiv och utforskande ansats. Data utgörs av tio semistrukturerade intervjuer med ambulanssjuksköterskor, sju män och tre kvinnor. Materialet har analyserats med Lundman och Graneheims innehållsanalys. Resultat: Tre kategorier identifierades: Användning, Behandling samt Utveckling. Boussignac CPAP beskrivs som lättanvänd och med färre moment än föregående modell. Med modellen uppskattas särskilt möjligheten att steglöst reglera motståndet. Boussignac CPAP upplevs som lättare då masken eller dess delar inte behöver plockas av patienten vid överlämnandet från ambulansverksamheten. Förutsättningarna till ökat användningsområde, i och med möjligheten att steglöst ändra motståndet för Boussignac CPAP upplevs inteutnyttjas fullt ut. Slutsats: Boussignac CPAP upplevs av ambulanssjuksköterskorna ha underlättat hanteringen av utrustningen samt ökat vårdkvaliteten för patienten. För att vidare kunna utnyttja potentialen med Boussignac CPAP kan mer utbildning och förändringar i riktlinjer behövas.
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Oliveira, Simone Cristina Buzzo. "Modulação da ação farmacologica de PLA2 botropicas e crotalicas em presença de uma lectina isolada da alga marinha Bryothamnion triquetrum." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314480.
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Orientador: Marcos Hikari ToyamaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Lectinas são proteínas que se ligam de forma específica e reversível a carboidratos. Estão distribuídas pelos mais diversos organismos e apresentam atividades de interesse em pesquisas biológicas e médicas. Neste trabalho, duas isoformas de lectina da alga marinha vermelha Bryothamnion triquetrum foram purificadas por cromatografia de troca iônica seguida por uma de fase reversa. As frações foram nomeadas de BTLD1 e BTLD2 e ambas apresentaram massa molecular aparente em SDSPAGE de aproximadamente 9,0 kDa. A análise dos aminoácidos de ambas as lectinas revelaram moléculas de caráter básico e as regiões Nterminal das lectinas foram seqüenciadas e comparadas entre si e com lectinas de outras algas, apresentando grande similaridade com hypninA1, hypninA2 e BTL. Além disso, o dicroísmo circular revelou que a estrutura secundária das proteínas é predominantemente de arranjo aleatório. A lectina BTLD2, a isoforma mais abundante do extrato da alga, apresentou ação antibacteriana contra a bactéria grampositiva Clavibacter michiganensis subsp. michiganensis (Cmm), mas não foi eficiente contra a bactéria gramnegativa Xanthomonas axonopodis pv. passiflorae (Xap). Também foram utilizados dois modelos de fosfolipases A2, uma isolada do veneno total de Crotalus durissus cascavella que é cataliticamente ativa do tipo Asp 49 (D49), e uma outra PLA2 cataliticamente não ativa do tipo Lys49 (K49), isolada do veneno de Bothrops jararacussu, para ensaios biológicos. A atividade farmacológica e biológica de ambas as PLA2s foi significativamente afetada pela coincubação das mesmas com BTLD2. A formação de heterodímeros de BTLD2 com a PLA2 de Crotalus durissus cascavella ou com a PLA2 de Bothrops jararacussu sugere a formação de um complexo estável em solução com uma massa molecular de aproximadamente 23,0 kDa. A BTLD2 também foi capaz de aumentar significativamente a atividade enzimática da PLA2 de C. d. ascavella em comparação com a PLA2 cataliticamente ativa isolada. As PLA2s de C. d. cascavella e B. jararacussu mostraram forte atividade antibacteriana contra bactérias Cmm e tiveram pouco efeito contra a bactéria Xap. Entretanto, o complexo BTLD2: PLA2 D49 ou K49 mostram um aumento da atividade antibacteriana, principalmente contra a bactéria Xap. As PLA2s induziram atividade edematogênica em pata de ratos e também foram capazes de induzir uma forte agregação plaquetária usando o sistema de plaquetas lavadas. Em ambos os sistemas, o complexo BTLD2: PLA2 mostrou uma atividade menor do que os respectivos controles. Concluindo, os resultados apresentados mostram que esta nova lectina isolada de alga vermelha possui uma evidente capacidade de interação com moléculas de PLA2, tanto cataliticamente ativas quanto inativas, com a formação de heterodímeros. Portanto, esta interação é capaz de modificar significativamente a estrutura terciária da PLA2, uma vez que o complexo mostrou atividade enzimática aumentada além de possivelmente alterar a estrutura de outras regiões moleculares da enzima. É importante verificar que a atividade farmacológica das PLA2s não tem uma correlação direta com a atividade catalítica das mesmas, envolvendo outras regiões que permitem a sua interação com receptores cuja região está distante do sítio catalítico da PLA2
Abstract: Lectins are proteins that bind specifically and reversibly to carbohydrates. They are widely distributed among living organisms and show many activities of biological and medical interest. In this work, two isoforms of lectins isolated from the red marine alga Bryothamnion triquetrum were purified by ion exchange followed by reverse phase chromatographies. The fractions named BTLD1 and BTLD2 showed apparent molecular mass of approximately 9.0 kDa in SDSPAGE. Both lectins probably have a basic character, as indicated the amino acid analyses using the Compute pI/Mw tool at the ExPASy server. The Nterminal sequences were compared between both lectins and also to other lectins, showing similarity with hypninA1, hypninA2 and BTL. The circular dichroism indicated that the secondary structure of the proteins are predominantly random coiled. Additionaly, BTLD2 (the more abundant lectin isoform in the alga extract) showed antibacterial activity against the grampositive bacteria Clavibacter michiganensis subsp. michiganensis (Cmm) but was not effective against the gramnegative bacteria Xanthomonas axonopodis pv. passiflorae (Xap). A possible modulation of phospholipase activity by BTLD2 was also studied using two phospholipases A2, one isolated from Crotalus durissus cascavella venom that is Asp49 (D49) catalytically active, and other PLA2 Lys49 (K49) catalytically non active from Bothrops jararacussu venom. The pharmacological and biological activities of PLA2s were significantly change by incubation with BTLD2. The heterodimer formation of BTLD2 with Crotalus durissus cascavella or Bothrops jararacussu PLA2s appears to be a stable complex in solution with a molecular mass of approximately 23 kDa. BTLD2 significantly increased the enzymatic activity of the PLA2 from C.d. cascavella compared to the PLA2 alone. Both PLA2s (catalytically active and nonactive) showed strong antibacterial activity against Cmm with little effect against Xap. However, the BTLD2: PLA2 D49 or K49 complexes showed increase in antibacterial activity, particularly against Xap. Moreover, both PLA2s induced edematogenic activity in rat paw and strong platelet aggregation in washed platelets system. Interestingly, addition of BTLD2 with consequent formation of the BTLD2: PLA2 complex decreased both PLA2induced edema and platelet aggregation. Taken toghether, these results show that this new lectin isolated from a red alga and named BTLD2 has the capacity to interact with catalytic or noncatalytic PLA2, forming heterodimers. Therefore, this interaction possibly modify the PLA2 tertiary structure; as the complex BTLD2: PLA2 increase the enzymatic activity of PLA2 (i.e., the phospholipase activity) but at the same time decrease pharmacological and biological PLA2 activities not related to catalysis (i.e., platelet aggregation and edema). This suggests that the PLA2 structure is possibly modified in other sites of the enzyme rather than in the catalytic site. It can be concluded that the PLA2s has several binding sites for different molecules comprising the catalytic site responsible for the phospholipase activity and at least one more pharmacological site responsible for the effects observed after interaction with BTLD2. Therefore, the pharmacological activity of PLA2s has no direct correlation with the catalytic activity, involving other binding sites that allow receptor interaction whose position might be far from the catalytic site of PLA2
Mestrado
Bioquimica
Mestre em Biologia Funcional e Molecular
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Chou, Dean. "Computational modelling of brain transport phenomena : application of multicompartmental poroelasticity." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:8ad5cf12-e20c-4944-b27f-b3fd2951faca.
Full textAbstract:
The global population is predicted to increase to around 11 billion by 2100. By 2050, the average age in the most populous age group will be over sixty. The ageing population (over sixty-five) is projected to exceed the number of children by 2047. These demographics imply that as the ageing population section increases, there will be a greater need for long-term care services. In order to adequately prepare against this trend, medical experts and evidence-driven policymakers are realising that personalised healthcare can help alleviate the burden related to the planning and commissioning of services allied to long-term care. Central to this picture is conditions that affect the brain - the most important organ of the human body. Dementia, stroke, and other conditions have a tremendous impact on loss of life, quality of life and healthcare cost. The challenge regarding brain disease is exacerbated further due to the difficulty regarding accessibility of this organ, but also due to the immense complexity regarding its morphology and functionality. In this context, advanced biophysical modelling is considered a promising option for studying brain pathophysiology and becomes a priority investment regarding routes for brain research. Simulations offer the promise of improved, clinically relevant, predictive information, acceleration for the pipeline of drug discovery/design and better planning of long-term care for patients. Within this paradigm, a particular model of water transport in the cerebral environment is essential. Numerous brain disorders arise from water imbalance in the cerebral environment, such as hydrocephalus (HCP), oedema and Chiari malformations to name a few. In this research, a novel multiscale model of fluid regulation and tissue displacement in the cerebral environment is developed, arising from the use of Multiple-network Poroelastic Theory (MPET). Characteristics of a four-network poroelastic model (4MPET) are first explored. Then, this model is extended to a fully dynamic (transient) six-network model (6MPET) via the addition of two new compartments, namely the glial cells compartment and the glymphatic system compartment. The introduction of these two compartments in the MPET paradigm reflects recent seminal findings in cerebral physiology, namely the extent and importance regarding transport/clearance of the perivascular spaces of the brain vasculature. We develop and present a numerical implementation of the 6MPET model, and we utilise this framework to analyse acute HCP and cerebral oedema in a variety of settings, in order to show the enhanced capability of the proposed 6MPET model compared to the classical 4MPET. Investigations of acute hydrocephalus through the fully dynamic 6MPET reveal compensatory trans-ependymal pressure behaviour in the glymphatic compartment. It was also shown that aquaporin-4 (AQP4) deficient expression exaggerates ventriculomegaly, and this too is demonstrated in acute hydrocephalus. Additionally, using the 6MPET model, one is able to witness three mitigating factors for cytotoxic oedema. Specifically, these are: reducing water mobility in the glial cells compartment, increasing the compliance of the glial cells compartment and finally AQP4-deficient expression.
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Harper, Peter Andrew Windsor. "Studies on neurological disorders of neonatal calves associated with spongy changes in the central nervous system : neuroaxial oedema and the inborn errors of amino acid metabolism." Thesis, The University of Sydney, 1987. https://hdl.handle.net/2123/25996.
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Investigations of neurological disease in neonatal calves were conducted over a four and a half year period.
The studies commenced with so called Hereditary Neuraxial Oedema of Poll Hereford calves. It was determined that two distinct disease entities in this breed had led to confusion regarding the diagnosis of this disorder.
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Oliveira, Juliana da Silva Brandi. "Estudo comparativo entre os Enantiômeros da Carvona em Modelos de Inflamação Aguda e de Hipersensibilidade Imediata." Universidade Federal da Paraíba, 2011. http://tede.biblioteca.ufpb.br:8080/handle/tede/6695.
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Previous issue date: 2011-02-28Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Enantiomers are asymmetric compounds that present mirror images of each other, not overlapping and different behaviors in chiral environments, resulting in esterioseletiva discrimination and different biological effects. The carvone is a monoterpene, a constituent of many essential oils found in nature as two enantiomers, (S)-(+)-carvone and (R)-(−)-carvone. The inflammation, a physiological response of the organism, when it occurs exaggerated or inappropriated ways may promote tissue damage and associated pathologies. An example of inflammatory disease is asthma, an immediate hypersensitivity process of the airways and the conventional treatments have significant adverse effects. The aim of this study was to evaluate the carvone enantiomers in experimental models of inflammation and hypersensitivity of the airways. To investigate the effect anti-inflammatory the following parameters were evaluated: NO production by cells J774.A1, paw oedema formation induced by carrageenan, zymosan, compound 48/80 and histamine, cell migration and cytokines production (TNF-α and IL-1β) in the experimental model of peritonitis induced by zymosan in Swiss mice. To evaluate the anti-asthmatic activity of these enantiomers, it was used the experimental model of asthma induced by ovalbumin and the following parameters were analyzed: bronchoalveolar lavage (BAL), mucus production, OVA-specific IgE synthesis, cytokine production (IL-13, IFN-γ and IL-10). The results showed that both enantiomers were able to reduce NO production, inhibit the paw oedema induced by phlogistic agents and inhibit cell migration to the peritoneum, but only the (R)-(−)-carvone was able to reduce levels of TNF-α. In the murine model of asthma, the (R)-(−)-carvone, was able to reduce the cellularity of the BAL, modulate the OVA-specific IgE production, reduce the cell infiltration and mucus in the lungs and further increase the IL-10. However, although the (S)-(+)-carvone has reduced the BAL cellularity and increased IFN-γ levels, it was unable to reduce the cell infiltration in the lung and increase the mucus production. Therefore, both enantiomers of carvone showed anti-inflammatory effect, although only the (R)-(−)-carvone showned potential anti-asthmatic. Additionally, the results presented by (S)-(+)-carvone, revealed a potential adverse effect of this enantiomer in the experimental model of asthma.
Enantiômeros são compostos assimétricos que apresentam a particularidade de serem imagens especulares um do outro, não sobreponíveis e por terem comportamentos diferentes em ambientes quirais, resultando frequentemente na discriminação esterioseletiva e diferentes efeitos biológicos. A carvona é um monoterpeno, constituinte de muitos óleos essenciais e encontrada na natureza na forma de dois enantiômeros: (S)-(+)-carvona e (R)-(-)-carvona. A inflamação uma resposta fisiológica do organismo, quando ocorre de forma exacerbada ou inapropriada pode promover dano tecidual e patologias associadas. Um exemplo de doença inflamatória importante é a asma, um processo hipersensibilidade imediata nas vias aéreas e que tratamentos convencionais apresentam efeitos colaterais importantes. O objetivo desse trabalho foi avaliar os enantiômeros da carvona em modelos de inflamação e de hipersensibilidade das vias aéreas. Para investigar a atividade anti-inflamatória das substâncias os seguintes parâmetros foram avaliados: produção de NO por células J774.A1, formação de edema de pata induzido por carragenina, zimosan, composto 48/80 e histamina, migração de células e produção das citocinas (TNF-α e IL-1β) no modelo de peritonite induzida por zimosan, em camundongos Swiss. Para avaliar a atividade anti-asmática dos enantiômeros, foi utilizado o modelo de asma experimental induzido por ovalbumina e analisado os seguinte parâmetros: celularidade do lavado bronco alveolar (BAL), produção de muco, síntese de IgE OVA-específica, produção de citocinas (IL-13, IFN-γ e IL-10). Os resultados demonstraram que ambos os enantiômeros foram capazes de reduzir a produção de NO, inibir o edema de pata induzido pelos agentes flogísticos utilizados e inibir a migração de células para o peritônio, porém apenas a (R)-( )-carvona foi capaz de reduzir os níveis de TNF-α. No modelo murino de asma alérgica, a (R)-(−)-carvona, foi capaz de reduzir a celularidade do BAL, modular a produção de IgE OVA-específica, reduzir o infiltrado de células e muco no pulmão e ainda, aumentar os níveis de IL-10. Porém, embora a (S)-(+)-carvona, tenha reduzido a celularidade do BAL e aumentado os níveis de IFN-γ, ela não foi capaz de reduzir o infiltrado de células no pulmão e ainda, aumentou a produção de muco. Portanto, ambos enantiômeros da carvona apresentaram efeito anti-inflamatório, embora apenas a (R)-(-)-carvona tenha apresentado potencial anti-asmático e ainda, os resultados apresentados pela (S)-(+)-carvona, revelaram um potencial efeito adverso desse enantiômero em modelo experimental de asma.
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Ritchie, James. "Epidemiology of atherosclerotic renovascular disease : clinical presentations, prognosis and treatment." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/epidemiology-of-atherosclerotic-renovascular-disease-clinical-presentations-prognosis-and-treatment(c86ec7c6-a636-48b7-9f3e-c086b8cc4905).html.
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Atherosclerotic renovascular disease (ARVD) is a significant cause of chronic kidney disease (CKD) and is associated with an increased risk for cardiovascular morbidity and mortality. Randomised controlled trials, representing over 2100 patients, have failed to demonstrate any prognostic benefit of percutaneous renal revascularisation when utilised in addition to standard medical therapy. This negative finding has been interpreted in three ways. Firstly, that ARVD may be an association of CKD and not a specific disease process. Secondly, that published studies have recruited low-risk patients who are least likely to benefit from revascularisation. Thirdly, that the focus of treatment for patients with ARVD should be optimal medical therapy, not renal revascularisation. This research project had a series of linked aims. These were investigated in two large patient cohorts that had been accumulated at this centre over the last decade. These cohorts comprised > 900 patients with ARVD, the Salford Renovascular Database (SRVD), and > 2500 patients with all-cause CKD, the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). The first aim was to consider whether ARVD should be considered as a specific cause of CKD. Here risks for death and progression to renal replacement therapy were compared between patients having ARVD as their primary cause of renal failure and patients with other coded causes of CKD. In this analysis, patients with ARVD had a greater risk for death and a lesser risk for RRT than patients with other forms of CKD.The second aim of this thesis was to consider if specific patient sub-groups of ARVD could be identified. Patients in the SRVD with currently accepted high- risk clinical presentations were selected and outcomes compared to patients without a high-risk presentation. In this analysis, presentation with flash pulmonary oedema (but with not refractory hypertension or rapidly declining renal function) was associated with an increased risk for death and cardiovascular event. When the effects of revascularisation were considered in patients with high-risk presentations, a mortality benefit was observed in patients with flash pulmonary oedema and in patients presenting with rapidly declining renal function and refractory hypertension in combination. A separate analysis was performed in the SRVD to consider if a high-risk sub-group of ARVD patients could be identified using laboratory measurements. Here, a classification tree methodology was employed to identify ARVD patients with the greatest risk for progression to end stage kidney disease. The results of this analysis were converted into a practically applicable clinical scoring system incorporating renal function, proteinuria, medications, smoking history and renal artery occlusion. The final aim of this thesis was to describe how the majority of ARVD patients should be treated. In this analysis of the SRVD effects of treatment with anti- platelet and beta-blocker therapy were considered, and shown to be associated with reduced risks for cardiovascular events and death.
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Vega, Salomón Huancahuire 1981. "Miotoxinas 'PLA 2'D49 e K49 do veneno total de Bothrops brazili : purificação e caracterização estruturação e funcional." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314685.
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Orientadores: Sergio Marangoni, Luis Alberto Ponce SotoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: As enzimas PLA2 provenientes de veneno de serpentes são intensamente estudadas devido a que os envenenamentos constituem um dos principais problemas de saúde em muitos paises. Por outro lado, estas toxinas ajudam a revelar aspectos desconhecidos da fisiologia celular e tisular. Neste trabalho, apresentamos a purificação e a caracterização bioquímica e farmacológica de duas miotoxinas fosfolipases A2: BbTX-II e BbTX-III, a partir de veneno de Bothrops brazili. As duas proteínas foram isoladas e purificadas usando um procedimento simples e rápido envolvendo duas etapas cromatográficas, exclusão molecular em Sephadex G-75 e HPLC de fase reversa (C18). A eletroforese de ambas miotoxinas mostrou massas relativas em torno de 13 e 27 kDa (para monômeros e dímeros respectivamente). Espectrometria de massa por MALDI-TOf confirmou a pureza das proteínas e mostrou que possuem massas moleculares em torno de 13,8 kDa. A análise de aminoácidos mostrou alto conteúdo de aminoácidos básicos e hidrofóbicos, assim como 14 resíduos de Cys. BbTX-III apresentou atividade PLA2 na presença de um substrato cromogênico, mostrando comportamento sigmoidal, principalmente à baixas concentrações. Atividade máxima foi alcançada em pH 8 e entre 35-45 oC. BbTX-III mostrou-se completamente dependente de Ca2+ e, na presença dos íons Mg2+, Mn2+, Cd2+ e Zn2+, a atividade enzimática foi reduzida a níveis similares aos observados na ausência de Ca2+. A análise de composição de aminoácidos mostrou alta presença de Lys, His e Arg (pI 8,46). A presença de 14 resíduos de cisteína sugere a formação de 7 pontes dissulfeto. O estudo de homologia da seqüência da PLA2 BbTX-III mostrou que existem posições extremamente conservadas nas PLA2. S(1), L(2), E(4) 7 a 10 (QMIL), Y(21). Os resíduos conservados Y(28), G(30), G(32), D(49), H(48) e Y(52) estão direta ou indiretamente ligados com a catálise. Além disso, BbTX-III apresentou algumas mutações: K(35) -> G(35), R(51) -> Y(51) e D(118) -> A(118) que estão estrategicamente posicionadas para a expressão da atividade catalítica. Apesar destas substituições, as atividades farmacológicas e a atividade catalítica são mantidas. O efeito neurotóxico de BbTX-III foi analisado in vitro na preparação neuromuscular biventer cervicis de pintainhos. O resultado mostrou que a toxina é menos potente quando comparada com venenos crotálicos. BbTX-III demonstrou efeito miotóxico local in vivo através da liberação de creatina quinase (CK) e, efeito inflamatório, através de edema de pata. Como a BbTX-III produziu forte efeito inflamatório, a hidrólise de fosfolipídios poderia ser relevante neste fenômeno. BbTX-II foi caracterizada como uma PLA2 K49 (cataliticamente inativa) em função das características físico-químicas evidenciadas: massa de 13,68 kDa, 121 resíduos de aminoácidos, caráter básico (pI 8.73) e alto grau de homologia seqüencial na sua estrutura primária, quando comparada com outras PLA2B K49 procedentes de veneno de serpentes botrópicas. O alinhamento com outras seqüências completas de PLA2 BK49 mostrou a presença de algumas mutações importantes. Assim, as substituições Y?N(27), N?P(58) e L?F(114) não modificaram os efeitos biológicos aqui estudados, revelando que poderiam estar relacionados com outras atividades. Os resíduos N(28), K(111), L(32) poderiam contribuir com a interrupção da catálise. Esta nova PLA2 K49 BbTX-II mostrou miotoxicidade local in vivo, atividade inflamatória e letalidade, corroborando que se enquadra dentro da família de proteínas PLAB2B K49. Os estudos de neurotoxicidade revelaram um efeito neurotóxico in vitro na preparação biventer cervicis de pintainho (20 µg/ml). BbTX-II e BbTX-III mostraram ser miotoxinas com atividade edematogênica e neurotóxica, independentemente de apresentarem atividade catalítica (BbTX-III) ou não (BbTX-II) Apoiando a existência de regiões moleculares distintas à catalítica responsáveis pelos efeitos farmacológicos. Os efeitos farmacológicos da toxina BbTX-III (PLA2B D49) provavelmente tenham uma estrita relação entre a atividade enzimática e a ligação da toxina com micro-domínios na membrana plasmática onde sua atividade seja maximizada e cause danos relevantes na organização da membrana. No caso da BbTX-II (PLAB2 K49) possivelmente a combinação de aminoácidos aromáticos/hidrofóbicos e positivamente carregados da região C-terminal seja a responsável de alterar a integridade da membrana plasmática.
Abstract: The enzymes PLA2 coming of venom snake are studied intensely due to that the poisonings constitute one of the main problems of health in many countries. On the other hand, these toxins help to reveal unknown aspects of the cellular and tissue physiology. In this work, we presented the purification and biochemical and pharmacological characterization of two myotoxic phospholipases A2: BbTX-II and BbTX-III from Bothrops brazili venom. The two proteins were isolated and purified using a simple and fast procedure involving two chromatographic steps, molecular exclusion in Sephadex G-75 and reverse-phase HPLC (C-18 column). Both myotoxins showed around 13 and 27 kDa (for monomers and dimers, respectively) relative mass. MALDI-TOf mass spectrometry confirmed the purity of the proteins showing molecular masses around 13,8 kDa. Amino acid analysis showed a high content of hydrophobic and basic amino acids as well as 14 cysteine residues. BbTX-III presented PLA2 activity in the presence of a chromogenic substrate, showing sigmoidal behavior, mainly at low concentrations. Maximum PLA2 activity was reached at pH 8 and 35-45 oC. Maximum activity required Ca2+ and, in the presence of Mg2+, Mn2+, Cd2+ and Zn2+, was reduced at similar levels as observed in the absence of Ca2+. Amino acids analysis of composition showed high presence of Lys, His and Arg (pI 8,46). The presence of 14 cystein residues suggested the formation of 7 disulfide bridges. Sequence homology of the PLA2 BbTX-III revealed positions extremely conserved in PLA2 S(1), L(2), E(4) 7 to 10 (QMIL), Y(21). The conserved residues Y(28), G(30), G(32), D(49), H(48) and Y(52) are direct or indirectly linked to the catalysis. Besides, BbTX-III presented some mutations: K(35) -> G(35), R(51) -> Y(51) and D(118) -> A(118) that are strategically positioned for the expression of catalytic activity. Despite these substitutions, the pharmacological and catalytic activities are maintained. The neurotoxic effect of BbTX-III was analyzed in vitro at chick biventer cervicis muscle preparation. Our results showed that the blockage of the muscle contraction was lower when compared with crotalic venoms. BbTX-III demonstrated in vivo myotoxic local effect through the liberation of creatine kinase (CK) and inflammatory effect through paw edema. As BbTX-III produced strong inflammatory effect, the phospholipids hydrolysis could be relevant in this phenomenon. BbTX-II was characterized as PLA2 homologous K49 (catalytically inactive), because its chemical and physical evidenced characteristics: mass of 13,68 kDa, 121 amino acids residues, basic character (pI 8.73) and high sequential homology in its primary structure, when compared with other PLA2 K49 from venom of Botrhops serpents. The alignment with other complete sequences of PLA2 homologous K49 showed the presence of some important mutations. Substitutions Y->N(27), N->P(58), and L->F(114) did not modify the biological activities here studied, revealing that it could be related to other activities. The residues N(28), K(111), L(32) could contribute with the interruption of the catalysis. This new PLA2 K49 BbTX-II showed in vivo myotoxic local effect, inflammatory and lethality activities, evidencing it was fitted to the family of proteins PLA2 K49 homologous. Beside BbTX-II revealed in vitro neurotoxyc effect at chick biventer cervicis muscle preparation (20 µg/mL). BbTX-II and BbTX-III showed to be myotoxins to activity edematogenic and neurotoxyc independently of present catalytic activity (BbTX-III) or no (BbTX-II) Supporting the existence of molecular areas different to the catalytic responsible for the pharmacological effects. The pharmacological effects of the toxin BbTX-III (PLA2 D49) they probably have a strict relationship between the enzymatic activity and binding of the toxin with micro-domains in the plasmatic membrane where the activity is maximized and cause relevant damages in the organization of the membrane. In the case of the BbTX-II (PLA2 K49) possibly the combination of amino acids aromatics/hidrophobics and positively loaded of the area C-terminal it is the responsible of altering the integrity of the plasmatic membrane.
Mestrado
Bioquimica
Mestre em Biologia Funcional e Molecular
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Evans, Kevin Andrew. "Hypoxia and vascular nitric oxide bioavailability : implications for the pathophysiology of high-altitude illness." Thesis, University of South Wales, 2009. https://pure.southwales.ac.uk/en/studentthesis/hypoxia-and-vascular-nitric-oxide-bioavailability(3cd64bcd-5fb9-4209-a6f3-ab219e906a17).html.
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Introduction: Nitric oxide (NO) is an integral molecule implicated in the control of vascular function. It has been suggested that vascular dysfunction may lead to the development of acute mountain sickness (AMS), high-altitude cerebral oedema (HACE) and high-altitude pulmonary oedema (HAPE), though data to date remains scarce. Therefore, there is a clear need for further work to address the role of NO in the pathogenesis of high-altitude illness. Aims: There were two primary aims of the current work: (1) To examine whether hypoxia mediated changes in systemic NO metabolism are related to the development of AMS and sub-clinical pulmonary oedema and (2) to examine whether hypoxia mediated changes in the trans-cerebral exchange kinetics of NO metabolites are related to the development of AMS and headache. Hypothesis: We hypothesise that hypoxia will be associated with an increase in reactive oxygen species (ROS) formation, resulting in a decrease in vascular NO bioavailability (O2•- + NO → ONOO•-, k = 109 M.s-1). The reduction in NO will lead to vascular dysfunction and impaired oxygen (O2) delivery. Subsequent hypoxaemia will result in pulmonary vascular vasoconstriction and the development of sub-clinical pulmonary oedema within and mild brain swelling. Symptoms and reductions in NO bioavailability will be more pronounced in those who develop AMS since they are typically more hypoxaemic. Alternatively, a hypoxia mediated increase in NO, during vasodilatation, specifically across the cerebral circulation, may activate the trigminovascular system resulting in headache and by consequence, AMS. Methods: Study 1 – AMS symptoms, systemic venous NO concentration and nasal potential difference (NPD), used as a surrogate biomarker of extravascular lung oedema, were quantified in normoxia, after a 6hr passive exposure to 12% oxygen (O2) and immediately following a hypoxic maximal exercise challenge (≈6.5 hrs). Final measurements were 2 obtained two hours into (hypoxic) recovery. Study 2 – AMS, radial arterial and internal jugular venous NO metabolite concentrations and global cerebral blood flow (CBF), using the Kety-Schmidt technique, were assessed in normoxia and after a 9hr passive exposure to 12.9% O2. AMS was diagnosed if subjects presented with a combined Lake Louise score of ≥5 points and an Environmental Symptoms Questionnaire – Cerebral score of ≥0.7 points. Results: Hypoxia was associated with a reduction in total plasma NO, primarily due to a reduction in nitrate (NO3•) and a compensatory increase in red blood cell (RBC)-bound NO(P < 0.05 vs. normoxia) in both studies. Study 1 – Exercise reduced plasma nitrite (NO2•) (P< 0.05 vs. normoxia) whereas RBC-bound NO did not change. NO was not different in those who developed AMS (AMS+) compared to those who remained comparatively more healthy (AMS-) (P < 0.05). NPD was not affected by hypoxia or exercise and was not different between AMS+ and AMS- (P > 0.05). Study 2 – Hypoxia decreased arterial concentration of total plasma NO due primarily to a reduction in NO2•- and nitrate (NO3•-). Hypoxia did not alter the cerebral metabolism of RSNO, whereas the formation of RBC-bound NO increased. Discussion: These findings suggest that alterations in systemic or trans-cerebral NO metabolism are not implicated in the pathophysiology of AMS or sub-clinical pulmonary oedema. However, hypoxia was associated with an overall reduction in the total NO pool (NOx), whereas, selected alterations in more vasoactive NO metabolites were observed. Reductions in the partial pressure of O2 (pO2) were thought to be a key regulator in these changes. Overall net increases in RBC NO and corresponding reductions in plasma NO2• in the face of no alterations in NOx indicates that rather than being simply consumed, NO is reapportioned to other NO metabolites and this may be implicated in the pathophysiology of AMS.
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Julien, Christophe. "Oedème angioneurotique et déficit en inhibiteur de la C1-esterase : à propos d'un cas." Montpellier 1, 1990. http://www.theses.fr/1990MON11265.
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Cazeaux, Thierry. "Rôle de protection des barbituriques vis à vis de l'oedème cérébral." Paris 5, 1989. http://www.theses.fr/1989PA05P038.
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