Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Impact of source data on the interpretation of contrast-enhanced magnetic resonance angiography of the lower limbs

Background The primary purpose of this study is to examine whether use of source data is effective in increasing the number of arterial segments that can be interpreted from maximum intensity projections of lower limb MR angiograms. Correlation between sites of arterial disease and venous contamination was also measured. Interpretation of source data is performed routinely by radiologists, but the value of this has not been well studied with randomized studies. Results The proportion of segments visible above the knee was 87% using maximal intensity projection alone (MIP) and 88% when the MIP was combined with source data. The proportions were 67% for MIP and 72% for MIP plus source data below the knee. There was substantial agreement between presence of arterial disease and venous contamination in the calf and thigh. Conclusion The use of source data increases the number of assessable segments, but not individuals, by a statistically significant but small amount (1.2%, p <0.05). This study supports the association between arterial disease and venous contamination

The fire toxicity of polyurethane foams [Review]

Polyurethane is widely used, with its two major applications, soft furnishings and insulation, having low thermal inertia, and hence enhanced flammability. In addition to their flammability, polyurethanes form carbon monoxide, hydrogen cyanide and other toxic products on decomposition and combustion. The chemistry of polyurethane foams and their thermal decomposition are discussed in order to assess the relationship between the chemical and physical composition of the foam and the toxic products generated during their decomposition. The toxic product generation during flaming combustion of polyurethane foams is reviewed, in order to relate the yields of toxic products and the overall fire toxicity to the fire conditions. The methods of assessment of fire toxicity are outlined in order to understand how the fire toxicity of polyurethane foams may be quantified. In particular, the ventilation condition has a critical effect on the yield of the two major asphyxiants, carbon monoxide and hydrogen cyanid

The “ebb and flow” of student learning on placement

There is a rise in interest in work based learning as part of student choice at subject level in the UK (DOE 2017) but there remains an absence of specific guidance on how to best support higher education students learning on placement. An alternative HE experience in England, the degree apprenticeship, underlies the continued focus by policy in securing placement experiences for students without stipulating the type of support that is required at the ‘coal face’ of work based learning. Policy documents (UUK 2016), that urge universities to enter into partnership agreements with both employers and FE colleges to plug skills shortages, are noticeably lacking in their appreciation of the unique qualities of work based learning and how best to support students in this setting (Morley 2017a). Unfortunately, this is not unusual as placements have predominantly been an enriching ‘add on’ to the real business of academic learning in more traditional university programmes. Support initiatives, such as that described in chapter 9, are a rare appreciation of the importance of this role. Undergraduate nursing programmes currently support a 50:50 split between practice learning in clinical placements and the theory delivered at universities. Vocational degrees, such as this, provide an interesting case study as to how students can be supported in the practice environment by an appreciation of how students really learn on placement and how hidden resources can be utilised more explicitly for practice learning. During 2013 – 2015 a professional doctorate research study (Morley 2015) conducted a grounded theory study of 21 first year student nurses on their first placement to discover how they learnt ‘at work’ and the strategies they enlisted to be successful work based learners

Energy Reallocation to Breeding Performance through Improved Nest Building in Laboratory Mice.

Mice are housed at temperatures (20-26°C) that increase their basal metabolic rates and impose high energy demands to maintain core temperatures. Therefore, energy must be reallocated from other biological processes to increase heat production to offset heat loss. Supplying laboratory mice with nesting material may provide sufficient insulation to reduce heat loss and improve both feed conversion and breeding performance. Naïve C57BL/6, BALB/c, and CD-1breeding pairs were provided with bedding alone, or bedding supplemented with either 8g of Enviro-Dri, 8g of Nestlets, for 6 months. Mice provided with either nesting material built more dome-like nests than controls. Nesting material improved feed efficiency per pup weaned as well as pup weaning weight. The breeding index (pups weaned/dam/week) was higher when either nesting material was provided. Thus, the sparing of energy for thermoregulation of mice given additional nesting material may have been responsible for the improved breeding and growth of offspring

The Impact of Moving from EQ-5D-3L to -5L in NICE Technology Appraisals

Background: The EuroQol-5 Dimension (EQ-5D) instrument is the National Institute for Health and Care Excellence (NICE)’s preferred measure of health-related quality of life (QoL) in adults. The three-level (3L) value set is currently recommended for use, but the five-level (5L) set is increasingly being used in practice. Objective: We aimed to explore the impact of moving from 3L to 5L in NICE appraisals. Methods: We adapted our existing mapping for use with health state utility values derived from a population where the original distribution of utilities was unknown. We used this mapping to estimate 5L utilities for 21 comparisons of interventions from models used in NICE technology appraisal decision making, covering a range of disease areas. Results: All utilities increased using 5L, and the differences between highest and lowest utilities decreased. In ten oncology comparisons, using 5L generally increased the incremental quality-adjusted life-years (QALYs) as the benefit from improving survival increased. In four non-oncology comparisons where the intervention improved QoL only, the incremental QALYs decreased as the benefit of improving QoL was reduced. In seven non-oncology comparisons where interventions improved survival and QoL, there was a trade-off between increasing the benefit from survival and decreasing the benefit from improving QoL. Conclusion: 3L and 5L lead to substantially different estimates of incremental QALYs and cost effectiveness. The direction and magnitude of the change is not consistent across case studies. Using 5L instead of 3L may lead to different reimbursement decisions. NICE will face inconsistencies in decision making if it uses 3L and 5L concurrently