Metabolites of Arachidonic Acid and Their Role in Inflammatory Disease

Arachidonic acid (AA), after it is released from cell membrane phospholipids, may be metabolized by the cyclo-oxygenase (CO) enzyme leading to formation of the prostaglandins (PG's) and thromboxanes (TX's) or by the 5-lipoxygenase (5-LO) leading to formation of the leukotrienes (LT's). These metabolites are collectively known as eicosanoids. The PG's,especially PGE2 and PGI2 (prostacyclin) have important roles in the development of the cardinal signs of inflammation including erythema, oedema and pain. However, PGE2 and PGI2 can also have anti-inflammatory actions. Thromboxane A2 (TXA2) is a vasoconstrictor and a potent inducer of platelet aggregation while PGI2 is a vasodilator and a potent inhibitor of platelet aggregation. The balance between TXA2 synthesis by platelets and PGI2 synthesis by vascular endothelium is thought to be an important mechanism in haemostasis while an imbalance is thought to play a role in the development of some disease states. Leukotriene B4 (LTB4) is thought to mediate leukocyte behaviour during the inflammatory response since it is a potent chemokinetic and chemotactic agent for polymorphonuclear leukocytes (PMN's) and also induces adhesion, aggregation and degranulation of PMN's. Although the individual properties of PGI2, TXA2 and LTB4 are well recognized, their precise role in specific inflammatory diseases is often not known, although such information may facilitate the development of effective treatments. The remit of this thesis was to use available methodology (although not uncritically), to measure levels of these mediators in several inflammatory disease states and to examine some other aspects of their participation, with a view to assessing their role in these conditions. The effect of various therapies on production of these mediators, both in vitro and ex vivo was also examined. The studies reported in Chapter 5 looked at the role of eicosanoids in some inflammatory vascular diseases. Theories regarding the pathogenesis of Raynaud's phenomenon (RP) and approaches to it's treatment have been numerous. This work has shown that in RP secondary to progressive systemic sclerosis (PSS), plasma levels of PGl2-metabolites were unexpectedly elevated. Furthermore, the platelet sensitivity to iloprost (a stable analogue of PGI2) in these patients was shown to be decreased, but was normalized after PG therapy. The beneficial effect of PGl2/iloprost infusion in PSS may therefore be considered as overcoming platelet resistance to PGI2 rather than supplementing an inadequate production of PGI2. The production of LTB4 from stimulated PMN's of patients with RP secondary to PSS and vibration-induced white finger (VWF) was also shown to be increased. The relevance of this observation to the development of vasospasm and vascular occlusion is discussed. The observation of increased levels in VWF supports the growing opinion that this condition is a true secondary Raynaud's syndrome. The finding of increased LTB4 production in PSS suggests that cellular resistance to the inhibitory effects of PGI2 may be a generalized phenomenon in this condition. A recent advent in the treatment of RP has been the use of iloprost. The effect of transdermal iloprost on LTB4 production from PMN's of normal volunteers and Raynaud's patients was investigated. It was concluded that iloprost had some inhibitory effect on LTB4 production, but that it's anti-platelet and vasodilatory effects may be more important in RP. The possibility that some of the beneficial effects of ketanserin (a serotonin antagonist) and stanozalol (an enhancer of fibrinolysis) in RP could be due to an effect on PMN LTB4 production was also examined. Henoch-Schonlein purpura (HSP) is a type of childhood vasculitis. Results are presented which show that plasma from these patients has a diminished or absent ability to support vascular PGI2 generation. Further experiments were undertaken to determine whether this was due to reduced stimulation of PGI2 synthesis or active inhibition. Chapter 6 examined LTB4 production in rheumatoid arthritis (RA) and psoriatic arthritis (PA). It was found that isolated PMN's from RA patients had an increased capacity to produce LTB4 and that this was not secondary to non-steroidal antiinflammatory drug (NSAID) therapy. Weak but significant correlations were found between LTB4 and markers for joint disease activity. Likewise, an increased capacity for LTB4 production was observed in PMN's from PA patients. The relevance of this to both the skin and joint manifestations of the disease is discussed

Fibrotic interstitial lung disease - palliative care needs:a World-Café qualitative study

Objectives: The importance of palliative care in those with advanced fibrotic interstitial lung diseases (F-ILD) is recognised, but the palliative care requirements of patients and caregivers affected by F-ILD regardless of disease course are not established. We set out to explore this and identify optimal solutions in meeting the needs of a F-ILD population in Ireland. Methods: Implementing a World-Café qualitative research approach, we captured insights evolving, iteratively in interactive small group discussions in response to six predefined topics on palliative care and planning for the future. Thirty-nine stakeholders participated in the World-Café including 12 patients, 13 caregivers, 9 healthcare professionals, 4 industry representatives and 1 representative of the clergy. Results: Palliative care emerged as fundamental to the care and treatment of F-ILDs, regardless of disease progression. Unmet palliative care needs were identified as psychological and social support, disease education, inclusion of caregivers and practical/legal advice for disease progression and end-of-life planning. Participants identified diagnosis as a particularly distressing time for patients and families. They called for the introduction of palliative care discussions at this early-stage alongside improvements in integrated care, specifically increasing the involvement of primary care practitioners in referrals to palliative services. Conclusion: Patients and caregivers need discussions on palliative care associated with F-ILD to be included at the point of diagnosis. This approach may address persisting inadequacies in service provision previously identified over the course of the last decade in the UK, Ireland and European F-ILD patient charters.</p

Chemical characterization of ambient aerosol collected during the northeast monsoon season over the Arabian Sea: Anions and cations

Ambient aerosol samples were collected over the Arabian Sea during the month of March 1997, aboard the German R/V Sonne, as part of the German JGOFS project (Joint Global Ocean Flux Study). This is the third study in a series of analogous measurements taken over the Arabian Sea during different seasons of the monsoon. Dichotomous high volume collector samples were analyzed for anions and cations upon return to the laboratory. Anthropogenic pollutant concentrations were larger during the first part of the cruise, when air masses originated over the Indian subcontinent. Total NSS‐SO42− concentrations amounted to 2.94 ± 1.06 μg m−3 of which 92.1 ± 4.5% was present in the fine fraction. NSS‐SO42− source apportionment analysis with multivariate linear regression models revealed that in the coarse fraction half is biogenically and half anthropogenically derived, while in the fine fraction only 6% seemed of biogenic origin and 84% anthropogenic and 10% crustal in nature. Chloride deficits up to 99.1% in the fine fraction were observed. The average Cl− deficit in the fine fraction was 89.0 ± 9.4%, potentially related to NSS‐SO42− acid displacement and Cl reactive species formation, while in the coarse fraction it was 25.6 ± 21.3%, with NO3− being the preferred species for acid displacement

Data Descriptor : Collocated observations of cloud condensation nuclei, particle size distributions, and chemical composition

Cloud condensation nuclei (CCN) number concentrations alongside with submicrometer particle number size distributions and particle chemical composition have been measured at atmospheric observatories of the Aerosols, Clouds, and Trace gases Research InfraStructure (ACTRIS) as well as other international sites over multiple years. Here, harmonized data records from 11 observatories are summarized, spanning 98,677 instrument hours for CCN data, 157,880 for particle number size distributions, and 70,817 for chemical composition data. The observatories represent nine different environments, e.g., Arctic, Atlantic, Pacific and Mediterranean maritime, boreal forest, or high alpine atmospheric conditions. This is a unique collection of aerosol particle properties most relevant for studying aerosol-cloud interactions which constitute the largest uncertainty in anthropogenic radiative forcing of the climate. The dataset is appropriate for comprehensive aerosol characterization (e.g., closure studies of CCN), model-measurement intercomparison and satellite retrieval method evaluation, among others. Data have been acquired and processed following international recommendations for quality assurance and have undergone multiple stages of quality assessment.Peer reviewe

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Development of a Revalidation Programme for Facilitators to Improve the Student Experience of Problem-Based Learning

No abstract available

Development of a Revalidation Programme for Facilitators to Improve the Student Experience of Problem-Based Learning

No abstract available

Implementation of a Peer Observation Programme for Problem Based Learning (PBL) Facilitators

No abstract available