The design and synthesis of compounds that moderate nitric oxide levels

Nitric oxide (NO) is a potent biological messenger known to play key roles in many biological processes. Medical conditions such as angina, cancer and some neurodegenerative diseases have been shown to benefit from nitric oxide related therapy. The moderation of in vivo levels of nitric oxide is important when considering any lead compounds that exploit NO pathways. It has been theorised that conditions such as Alzheimer’s and Parkinson’s disease may benefit from a reduction in the levels of NO present in the brain. By inhibiting the nNOS enzyme in brain tissue it is possible to reduce the levels of NO and produce an effective way of treating a number of different neurodegenerative diseases. A series of novel, and chemically simple NOS inhibitors were sought out, building upon evidence alluded from three-dimensional structural docking studies performed using pymol and a 3D virtual environment facility. In conditions that could benefit from a higher concentration of NO, such as angina and arteriosclerosis, the use of NO-donors is an attractive option. The synthesis of a series of novel NO-donors, based on a furoxan scaffold, of sufficient stability was achieved allowing NO release and vasodilatory studies to be conducted. Compound 94 induced 100% reversal of contraction in rat aortic, renal and pulmonary vessels and was able to release NO under both photochemical and oxidative conditions with an IC50 0.25μM. The vasodilatory effect of compound 94 and other compounds in the series was found to be reproducible and reversible. When compared to the BNF listed NO donor, sodium nitroprusside (SNP, 9), compound 94 produced a more sustainable relaxation with no fluctuations in vascular tone. Mechanistically NO release was confirmed using mass spectroscopy and a nitric oxide analyser (NOA) through the application of ozone based chemiluminescence and provided interesting evidence towards the decomposition of this novel furoxan. In addition, a second series of novel NO donors based on the diazeniumdiolates was successfully synthesised alongside X-ray crystallography data, which is pertinent to the debate surrounding the reactivity of both the internal and terminal oxygens in the NONO moiety. These diazeniumdiolate based donors were also investigated using the NOA to identify the bet conditions for NO release, which were found to be light at 254nm

Plasticity of boldness in rainbow trout, Oncorhynchus mykiss: do hunger and predation influence risk-taking behaviour?

Boldness, a measure of an individual's propensity for taking risks, is an important determinant of fitness but is not necessarily a fixed trait. Dependent upon an individual's state, and given certain contexts or challenges, individuals may be able to alter their inclination to be bold or shy in response. Furthermore, the degree to which individuals can modulate their behaviour has been linked with physiological responses to stress. Here we attempted to determine whether bold and shy rainbow trout, Oncorhynchus mykiss, can exhibit behavioural plasticity in response to changes in state (nutritional availability) and context (predation threat). Individual trout were initially assessed for boldness using a standard novel object paradigm; subsequently, each day for one week fish experienced either predictable, unpredictable, or no simulated predator threat in combination with a high (2% body weight) or low (0.15%) food ration, before being reassessed for boldness. Bold trout were generally more plastic, altering levels of neophobia and activity relevant to the challenge, whereas shy trout were more fixed and remained shy. Increased predation risk generally resulted in an increase in the expression of three candidate genes linked to boldness, appetite regulation and physiological stress responses – ependymin, corticotrophin releasing factor and GABAA – but did not produce a significant increase in plasma cortisol. The results suggest a divergence in the ability of bold and shy trout to alter their behavioural profiles in response to internal and exogenous factors, and have important implications for our understanding of the maintenance of different behavioural phenotypes in natural populations

Assessing what is needed to resolve a molecular phylogeny: simulations and empirical data from emydid turtles

<p>Abstract</p> <p>Background</p> <p>Phylogenies often contain both well-supported and poorly supported nodes. Determining how much additional data might be required to eventually recover most or all nodes with high support is an important pragmatic goal, and simulations have been used to examine this question. Most simulations have been based on few empirical loci, and suggest that well supported phylogenies can be determined with a very modest amount of data. Here we report the results of an empirical phylogenetic analysis of all 10 genera and 25 of 48 species of the new world pond turtles (family Emydidae) based on one mitochondrial (1070 base pairs) and seven nuclear loci (5961 base pairs), and a more biologically realistic simulation analysis incorporating variation among gene trees, aimed at determining how much more data might be necessary to recover weakly-supported nodes with strong support.</p> <p>Results</p> <p>Our mitochondrial-based phylogeny was well resolved, and congruent with some previous mitochondrial results. For example, all genera, and all species except <it>Pseudemys concinna</it>, <it>P. peninsularis</it>, and <it>Terrapene carolina </it>were monophyletic with strong support from at least one analytical method. The Emydinae was recovered as monophyletic, but the Deirochelyinae was not. Based on nuclear data, all genera were monophyletic with strong support except <it>Trachemys</it>, and all species except <it>Graptemys pseudogeographica</it>, <it>P. concinna</it>, <it>T. carolina</it>, and <it>T. coahuila </it>were monophyletic, generally with strong support. However, the branches subtending most genera were relatively short, and intergeneric relationships within subfamilies were mostly unsupported.</p> <p>Our simulations showed that relatively high bootstrap support values (i.e. ≥ 70) for all nodes were reached in all datasets, but an increase in data did not necessarily equate to an increase in support values. However, simulations based on a single empirical locus reached higher overall levels of support with less data than did the simulations that were based on all seven empirical nuclear loci, and symmetric tree distances were much lower for single versus multiple gene simulation analyses.</p> <p>Conclusion</p> <p>Our empirical results provide new insights into the phylogenetics of the Emydidae, but the short branches recovered deep in the tree also indicate the need for additional work on this clade to recover all intergeneric relationships with confidence and to delimit species for some problematic groups. Our simulation results suggest that moderate (in the few-to-tens of kb range) amounts of data are necessary to recover most emydid relationships with high support values. They also suggest that previous simulations that do not incorporate among-gene tree topological variance probably underestimate the amount of data needed to recover well supported phylogenies.</p

What are the common areas of risk and their characteristics found in intermediate care from an occupational therapy perspective? A scoping review

Engaging with risk is a certain and unavoidable part of occupational therapy. Intermediate care services are mostly accessed by older people with complex needs, yet little is known in the literature about the extent, type and nature of risk involved in these services. Method: A scoping review was systematically conducted to map the common areas of risk (risk domains) from an occupational therapy perspective. Thematic analysis was conducted in order to identify the risk characteristics related to the literature reviewed. Results: Twenty-five journal articles were identified and arranged into ten risk domains: falls, discharge, practice errors, activities of daily living, pressure care, frailty management, patient handling, loneliness, nutritional care, and language barriers. Three risk characteristics were identified 1) Risk awareness and identifying risk, 2) Decision-making under risk 3) Improving safety. Conclusion: Occupational therapists play a diverse role in mitigating risk for older people which is not fully explored beyond addressing deficits in functional ability and hazardous environments. The process of how risk is controlled, reconciled with occupation and how positive risk-taking is facilitated are implicit and not directly addressed within the literature reviewed. The findings reveal gaps in knowledge and provide a foundation for further research

Investigating the effect strength of positive risk-taking barriers on discharge decisions in occupational therapy intermediate care: A factorial survey

Positive risk-taking in occupational therapy intermediate care is a requirement yet little is known about how positive risk-taking barriers influence discharge decisions at different experience levels. Method. A factorial survey was used to investigate positive risk-taking barriers (i.e. Limited Capacity, Risk Averse Family, Blame Culture and No Support). Participants self-categorised their experience level into Novice or Semi-expert or Expert before analysing four vignettes relating to recommending a home discharge for an older adult. Data were analysed using Multiple Regression and One-Way Analysis of Variance. Results. 74 participants responded to 281 vignettes. The barriers that reduced the likelihood to recommend a home discharge for an older adult were ‘No Support’, Novices (β = -.315, p=0.002), Semi-experts (β = -.313, p=0.001) Experts (β = -.254, p=0.009); ‘Limited Capacity’, Novices (β = -.305, p<0.003), Semi-experts (β = -.254, p=0.006) Experts (β = -.376, p=0.001) and ‘Blame Culture’ Semi-experts (β = -.240, p=0.010). Novices were found to be less likely to recommend a home discharge by comparison. Conclusion. The ‘Limited Capacity’, ‘No Support’ and ‘Blame Culture’ barriers had the strongest effect and Novices were less likely to recommend a home discharge overall. These findings could inform future research and pre-registration Occupational Therapy education

Is it time to stop being crude? Elderly mortality rates in a refugee camp in Maban County, South Sudan

Background: Mortality is a key indicator in defining and monitoring the scale and severity of a complex humanitarian emergency. While collection of age-disaggregated data is advised in guidelines such as the Sphere handbook, in practice data are rarely disaggregated beyond the under-5s. Despite widespread use of prospective mortality surveillance systems in complex emergencies, there are few guidelines on their implementation and limited evidence of their value. In 2012, 68,000 refugees from Sudan settled in Maban County, South Sudan. MSF introduced a community based surveillance system in Jamam camp to monitor mortality and reported causes of death. Observation of a high proportion of deaths in older refugees led to the adaptation of the surveillance system to collect age-specific mortality data. Here we describe the implementation, outcomes and lessons learnt

HPI reactivity does not reflect changes in personality among trout introduced to bold or shy social groups

Physiological stress responses often correlate with personalities (e.g. boldness). However, this relationship can become decoupled, although the mechanisms underlying changes in this relationship are poorly understood. Here we quantify (1) how an individual’s boldness (response to novel objects) in rainbow trout, Oncorhynchus mykiss, changes in response to interactions with a population of either bold or shy conspecifics and we (2) measured associated post-stress cortisol levels. Initially-bold trout became shyer regardless of group composition, whereas shy trout remained shy demonstrating that bold individuals are more plastic. Stress-induced plasma cortisol reflected the original personality of fish but not the personality induced by the treatment, irrespective of population personality. Change in boldness of bold trout may indicate preference towards initially subordinate behaviour when joining a new population. However, here we provide further evidence that behavioural and physiological parameters of coping styles may become uncoupled whereby behavioural changes are not correlated with stress responsiveness

Burn wounds: Infection and healing

Early wound closure is the ultimate goal of burn care. While excisional therapy is necessary in the treatment of both large, full-thickness and deep, partial skin-thickness burns, the majority of burns are superficial partial skin-thickness injuries requiring a different clinical approach. In superficial wounds, cosmetic and functional restoration in conjunction with relief from pain and prevention of infection is as important as rapid wound closure. The moist wound healing associated with hydrocolloid dressings may provide an alternative treatment modality for certain partial-thickness injuries. In comparable wounds, these dressings produce good functional and cosmetic results, rapid reepithelialization, and improved patient comfort.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31957/1/0000910.pd

Donor site repair

Delayed healing of skin donor sites may be costly and life threatening, especially in patients with large body-surface area burns. A donor site dressing should maximize the ability of the wound to heal without increasing the risk of local infection, systemic infection, or both. Specifically, the possibility of a secondary infection may either slow the healing process or ultimately convert the donor site to a full-thickness wound. A number of materials, ranging from gauze to biological agents, have been investigated for use as donor site dressings. The use of hydrocolloids for donor sites has been studied extensively, and, compared with conventional dressings, improved healing rates are reported. Our recent study using a hydrocolloid dressing confirmed earlier research showing fewer infections and more rapid donor site healing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31958/1/0000911.pd

Radially dependent stray field signature of chiral magnetic skyrmions

Magnetic skyrmions are topological spin structures that arise in chiral magnetic systems which exhibit broken inversion symmetry and high spin-orbit coupling resulting in a sizable Dzyaloshinskii-Moriya interaction. Understanding the local spin texture of skyrmions is a vital metrological step in the development of skyrmionic technologies required for novel logic or storage devices in addition to providing fundamental insight into the nanoscale chiral interactions inherent to these systems. Here, we propose that there exists a radially dependent stray field signature that emanates from magnetic skyrmions. We employ quantitative magnetic force microscopy to experimentally explore this stray field signature. To corroborate the experimental observations a semianalytical model is developed which is validated against micromagnetic simulations. This unique approach provides a route to understand the unique radially dependent field signature from skyrmions, which allows an understanding of the underlying local magnetization profile to be obtained. From a practical standpoint, our results provide a rapid approach to validate outputs from numerical or micromagnetic simulations. This approach could be employed to optimize the complex matrix of magnetic parameters required for fabricating and modeling skyrmionic systems, in turn accelerating the technology readiness level of skyrmionic based devices