133 research outputs found
The relationship between cyclo-oxygenase isoforms and platelets in the cardiothoracic system
No full textAt present, the cyclo-oxygenase inhibitor aspirin and the P2Y12 receptor blocker clopidogrel are commonly combined to prevent recurrent thrombosis after acute coronary syndrome events. Variable responses to this drug combination have driven the development of prasugrel and ticagrelor, two more potent P2Y12 blockers that constitute a superior therapy when used with aspirin. In parallel, investigations of non-steroidal anti-inflammatory drugs – the drug class that aspirin belongs to – suggest that cyclo-oxygenase inhibition can contribute to thrombosis.
This thesis has investigated the relationship between cyclo-oxygenase inhibition within the cardiothoracic system and pathways of platelet activation.
It has been demonstrated in vitro that the effects of aspirin vary with the level of P2Y12 blockade: at low levels of P2Y12 inhibition aspirin increases the overall anti-platelet effect, although with high levels of P2Y12 blockade aspirin has little to no effect. By giving healthy volunteers prasugrel it was determined that these in vitro observations hold true in man – aspirin added little to the anti-platelet effect of prasugrel and furthermore aspirin reduced urinary metabolites of the anti-thrombotic hormone prostacyclin. These data suggest that concomitant use of aspirin with strong P2Y12 blockers could lessen the overall anti-thrombotic effect.
Whilst initial experiments used 96-well plate assays to model platelet activation, responses in traditional light transmission aggregometry were also investigated. By investigating parameters affecting the pharmacology of P2Y12 blockers and aspirin, it has been possible to ascertain key differences in the way these techniques model platelet aggregation. In addition, immunoblotting and functional studies of tissues from wild type and COX-1 or COX-2 deficient mice suggest that COX-1 is the predominant isoenzyme found within the cardiothoracic system.
Overall, this thesis questions the therapeutic usefulness of aspirin in combination with potent P2Y12 receptor blockers and provides a basis for future work to redefine the role of aspirin in clinical populations
Southern Thailand: from conflict to negotiations?
No full textSummary: In this Analysis, University of Leeds professor Duncan McCargo argues that the recent Malaysian-backed Southern Thai peace initiative has now run into some serious problems. He argues that despite its various shortcomings the initiative is still worthy of support, since it has gained far more traction that any previous attempts to address the decade-long insurgency. Thailand needs to maintain focus on the southern conflict despite its current preoccupation with a national-level political crisis that threatens to topple the government of Yingluck Shinawatra.
Key findings
The conflict in Southern Thailand is one of Asia’s most serious insurgencies, with over 6,000 dead over the last 10 years.
The Malaysian government sponsored negotiations represents the best hope for reaching a political settlement and bringing peace to the region.
However, both sides need to show greater commitment to the negotiations, introducing new structures and procedures
Heat Shock Protein 70 and the relationship to glutamine in the critically ill child
No full textBackground: Specific nutrients such as glutamine have an important role in the management of critically ill patients, modulating the host response to stress, improving outcome. The mechanisms of action of glutamine are thought to be through the release of heat shock protein 70 (HSP70), which helps orchestrate an appropriate inflammatory response to critical illness. HSP70 release stimulates immune activation, maintenance of cell homeostasis, cellular protection, preventing apoptotic cell death and is associated with increased survival following severe trauma. However, much of the work considering the use of glutamine and HSP70 in critical illness has been completed in adults. The focus of the current research was therefore to investigate HSP70 release and its relationship to glutamine and inflammatory markers in healthy adults and paediatric volunteers using a whole blood endotoxin model. In addition to this, describing relationships between glutamine, HSP70 and inflammatory mediators, in a cohort of critically ill children.
Methodology: An in vitro whole blood endotoxin stimulation model using lipopolysaccharide (LPS) was adapted for use in healthy adult (n=18) and paediatric volunteers (n=25) to investigate the effect of glutamine supplementation on the release of HSP70 and inflammatory mediators (IL-6, IL-8, IL-1β, IL-10, TNF-α). Plasma from children with acute meningococcal disease (MD) (n=143) and during convalescence (n=78) was analysed for levels of HSP70, inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α) and glutamine. Following a clinical folder review, transcriptomic analysis of differential gene expression between acute disease and convalescence was carried out in a subset of children.
Results: A whole blood stimulation model was effective in measuring the inflammatory response to endotoxin in vitro over an incubation period of 4 to 24 hours. Glutamine supplementation significantly increased HSP70 expression over time in healthy adult and paediatric volunteers compared to unsupplemented controls (p<0.05). HSP70 levels in vitro rose over time and was correlated with inflammatory mediators (IL-1β, TNF-α, IL-8) in adults, and IL-6, TNF-α in paediatric samples at 4 hours, following glutamine supplementation. There was no relationship between HSP70 and IL-10 in either adults or children. Glutamine supplementation significantly attenuated the release of IL-8 at 24 hours (p<0.05) and in the paediatric in vitro endotoxin model significantly increased TNF-α release at 4 hours (p<0.005). Although there were no other significant differences in the release of inflammatory mediators (IL 6, TNF-α, IL10) between conditions, glutamine supplementation appeared to attenuate the release of inflammatory mediators in adults in contrast to promoting the release of inflammatory mediators in children.
In patients with MD, HSP70 was significantly increased (p=<0.0001) in the acute phase [26.7ng/ml; SD± 79.95 (median 5.7ng/ml; range 0.09 – 600.5ng/ml)] vs. convalescence [mean 3.16ng/ml ±SD; 5.67 (median 1.045ng/ml range 0.001 – 37.31ng/ml)]. Mean glutamine levels during the acute phase were 0.31mmol/l; ±SD 0.13 (median 0.31mmol/l; range 0.50 – 0.64) and for convalescence 0.40mmol/l; ±SD 0.14 (median 0.40mmol/l; range 0.72 – 0.64). During the acute phase of illness, glutamine levels were 52% below the normal range, (using 0.6mmol/l as the lower reference range). In convalescent samples, taken on average 55 days later (35 – 135 days), glutamine levels were found to be 26% below normal range. Results from the transcriptomic analysis show that genes associated with HSP70 and inflammatory signalling pathways, glycolysis and gluconeogenesis are significantly upregulated and those relating to adaptive immunity are downregulated during the acute phase of meningococcal disease compared to convalescence. There were numerous correlations between plasma glutamine and HSP70 with genes associated with p38MAPK signalling pathway during the acute phase of meningococcal disease, suggesting that glutamine and HSP70 could mediate the inflammatory response to infection.
Conclusion: Glutamine supplementation increased the release of HSP70 in an in vitro endotoxin model in children and adults. Children with MD during the acute phase of their illness have significant glutamine depletion, occurring early during the course of the disease, with a concomitant increase in plasma levels of HSP70 and inflammatory mediators. A transcriptomic analysis of differential gene expression showed that genes associated with HSP70 (HSPA1A and HSPA1B) were differentially upregulated during the acute phase of illness. HSP70 genes and plasma levels of HSP70 were correlated, which was suggestive of a role in meningococcal disease. Relationships were found with plasma levels of HSP70 and glutamine and genes associated with p38MAPK signalling pathway during the acute phase of meningococcal disease, suggesting that glutamine and HSP70 could mediate the inflammatory response to infection. Future work would aim to understand the effect of glutamine supplementation on gene expression during critical illness, especially relative to the differential expression of genes associated with HSP70, inflammatory signalling pathways and those relating to the antigen presentation pathway
From-omics to personalized medicine in nephrology: Integration is the key
No full textLarge-scale gene, protein and metabolite measurements ('omics') have driven the resolution of biology to an unprecedented high definition. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these high-throughput technologies unveiling their full potential. Integration is the key to decoding the underlying principles that govern the complex functions of living systems. Extensive computational support and statistical modelling is needed to manage and connect the-omic data sets but this, in turn, is speeding up the hypothesis generation in biology enormously and yielding a deep insight into the pathophysiology. This systems biology approach will transform diagnostic and therapeutic strategies with the discovery of novel biomarkers that will enable a predictive and preventive medicine leading to personalized medicine. © 2013 The Author
Characterisation of a myocardial depressant factor in meningococcal septic shock
No full textEThOS - Electronic Theses Online ServiceGBUnited Kingdo
IL-18 couples innate and adaptive immune cell activation in acute multisystem inflammatory syndrome in children (MIS-C)
No full text<p>This repository contains the scRNA-Seq data (including TCR-Seq and BCR-Seq data) set used in the manuscript titled "IL-18 couples innate and adaptive immune cell activation in acute multisystem inflammatory syndrome in children (MIS-C)". This dataset is generated from 10x cell ranger software. In the study, we have 10 PBMC samples, from 5 MIS-C children at paired time points. T1 stands for admission time and T3 follow-up time, about 1 month post hospital discharge. </p>
Gastric residual volume measurement in British neonatal intensive care units: a survey of practice
No full textObjective: despite little evidence, the practice of routine gastric residual volume (GRV) measurement to guide enteral feeding in neonatal units is widespread. Due to increased interest in this practice, and to examine trial feasibility, we aimed to determine enteral feeding and GRV measurement practices in British neonatal units. Design and setting: an online survey was distributed via email to all neonatal units and networks in England, Scotland and Wales. A clinical nurse, senior doctor and dietitian were invited to collaboratively complete the survey and submit a copy of relevant guidelines. Results: 95/184 (51.6%) approached units completed the survey, 81/95 (85.3%) reported having feeding guidelines and 28 guidelines were submitted for review. The majority of units used intermittent (90/95) gastric feeds as their primary feeding method. 42/95 units reported specific guidance for measuring and interpreting GRV. 20/90 units measured GRV before every feed, 39/90 at regular time intervals (most commonly four to six hourly 35/39) and 26/90 when felt to be clinically indicated. Most units reported uncertainty on the utility of aspirate volume for guiding feeding decisions; 13/90 reported that aspirate volume affected decisions 'very much'. In contrast, aspirate colour was reported to affect decisions 'very much' by 37/90 of responding units. Almost half, 44/90, routinely returned aspirates to the stomach. Conclusions: routine GRV measurement is part of standard practice in British neonatal units, although there was inconsistency in how frequently to measure or how to interpret the aspirate. Volume was considered less important than colour of the aspirate.</p
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