Eye as a window to the brain: investigating the clinical utility of retinal imaging derived biomarkers in the phenotyping of neurodegenerative disease.

Background Neurodegenerative diseases, like multiple sclerosis, dementia and motor neurone disease, represent one of the major public health threats of our time. There is a clear persistent need for novel, affordable, and patient‐acceptable biomarkers of these diseases, to assist with diagnosis, prognosis and impact of interventions. And these biomarkers need to be sensitive, specific and precise. The retina is an attractive site for exploring this potential, as it is easily accessible to non‐invasive imaging. Remarkable technology revolutions in retinal imaging are enabling us to see the retina in microscopic level detail, and measure neuronal and vascular integrity. Aims and objectives I therefore propose that retinal imaging could provide reliable and accurate markers of these neurological diseases. In this project, I aimed to explore the clinical utility of retinal imaging derived measures of retinal neuronal and vessel size and morphology, and determine their candidacy for being reliable biomarkers in these diseases. I also aimed to detail the methods of retinal imaging acquisition, and processing, and the principles underlying all these stages, in relation to understanding of retinal structure and function. This provides an essential foundation to the application of retinal imaging analysis, highlighting both the strengths and potential weaknesses of retinal biomarkers and how they are interpreted. Methods After performing detailed systematic reviews and meta‐analyses of the existing work on retinal biomarkers of neurodegenerative disease, I carried out a prospective, controlled, cross‐sectional study of retinal image analysis, in patients with MS, dementia, and ALS. This involved developing new software for vessel analysis, to add value and maximise the data available from patient imaging episodes. Results From the systematic reviews, I identified key unanswered questions relating to the detailed analysis and utility of neuroretinal markers, and diseases with no studies yet performed of retinal biomarkers, such as non‐AD dementias. I recruited and imaged 961 participants over a two‐year period, and found clear patterns of significance in the phenotyping of MS, dementia and ALS. Detailed analysis has provided new insights into how the retina may yield important disease information for the individual patient, and also generate new hypotheses with relation to the disease pathophysiology itself. Conclusions Overall, the results show that retinal imaging derived biomarkers have an important and specific role in the phenotyping of neurodegenerative diseases, and support the hypothesis that the eye is an important window to neurological brain disease

Western Australian readings

When Churchlands College of Advanced Education opened in February, 1972 the first students undertook a short course in West Australian history, with particular emphasis on discovery, settlement and the gold boom of the 1890\u27s. The course has gradually expanded and Western Australian Readings is an attempt to compile a limited collection of source material to which students can refer

Inflammation and resolution in exercise-induced skeletal muscle injury: The effect of NSAID treatment on pro-inflammatory and anti-inflammatory/pro-resolving lipid mediators.

Current approaches in the treatment of exercise-induced muscle injury rely on the inhibition of pro-inflammatory pathways to alleviate cardinal signs of inflammation; redness, swelling, heat and pain. However, recent research suggests that the cellular events which occur early in acute inflammation engage an active and coordinated inflammatory resolution program characterised by a switch from pro-inflammatory mediators to production of active pro-resolution factors that govern the withdrawal of inflammation whilst facilitating tissue healing. This led to the identification of novel classes of anti-inflammatory/pro-resolving lipid mediators, including the lipoxins (LX), resolvins (Rv), and protectins (P), which may provide new targets in the treatment of inflammation. METHODS: Sixteen untrained male subjects (age 23±0.7yr, mass 88±3.1kg) were assigned to a placebo (PLA) (n=8) or ibuprofen (IBU) (n=8) group. Subjects completed a single bout of resistance exercise consisting of 3 sets of 8-12 repetitions of a squat, leg press and leg extensions at 80% 1RM. Intravenous blood samples were obtained at rest, at 30 min intervals between 0 and 3 h and again at 24 h post exercise. The IBU group orally consumed 400mg of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen pre-exercise, and again at 5 and 10 h post exercise (1200 mg/day). Serum lipid mediator profiles were analysed via LC-MS targeted lipidomics. RESULTS: Acute exercise increased serum levels of pro-inflammatory eicosanoid species derived from both the COX-1 and 2 (prostaglandins: e.g. PGF2α, PGE2, PGD2, TXB2) and 5-LOX (leukotrienes: e.g. LTB4, LTB5) pathways. Additionally, heightened circulating levels of novel pro-resolving lipid mediators derived from arachidonic acid (LXA4 and LXB4), EPA (RvE1) and DHA (RvD1 andPD1 isomer) were detected post-exercise. Both the pro-inflammatory COX-1 & 2/5-LOX responses, as well as pro-resolving lipid mediator biosynthesis were blunted by the administration of the COX-1 and 2 inhibiting NSAID ibuprofen. CONCLUSION: Pro-inflammatory eicosanoids as well as novel pro-resolving bioactive lipid mediators are acutely up regulated following unaccustomed resistance exercise; a response which is diminished by IBU treatment. We hypothesize that the active resolution of exercise-induced inflammation may be important in effective post-exercise recovery and that a shift from anti-inflammatory interventions towards those which promote active resolution may hasten natural withdrawal of inflammation whilst facilitating the successful repair and regeneration of damaged muscle tissue

Professional guideline versus product label selection for treatment with IV thrombolysis: an analysis from SITS registry

Introduction: Thrombolysis usage in ischaemic stroke varies across sites. Divergent advice from professional guidelines and product labels may contribute. Patients and methods: We analysed SITS-International registry patients enrolled January 2010 through June 2016. We grouped sites into organisational tertiles by number of patients arriving ≤2.5 h and treated ≤3 h, percentage arriving ≤2.5 h and treated ≤3 h, and numbers treated ≤3 h. We assigned scores of 1–3 (lower/middle/upper) per variable and 2 for onsite thrombectomy. We classified sites as lower efficiency (summed scores 3–5), medium efficiency (6–8) or higher efficiency (9–11). Sites were also grouped by adherence with European product label and ESO guideline: ‘label adherent’ (>95% on-label), ‘guideline adherent’ (≥5% off-label, ≥95% on-guideline) or ‘guideline non-adherent’ (>5% off-guideline). We cross-tabulated site-efficiency and adherence. We estimated the potential benefit of universally selecting by ESO guidance, using onset-to-treatment time-specific numbers needed to treat for day 90 mRS 0–1. Results: A total of 56,689 patients at 597 sites were included: 163 sites were higher efficiency, 204 medium efficiency and 230 lower efficiency. Fifty-six sites were ‘label adherent’, 204 ‘guideline adherent’ and 337 ‘guideline non-adherent’. There were strong associations between site-efficiency and adherence (P < 0.001). Almost all ‘label adherent’ sites (55, 98%) were lower efficiency. If all patients were treated by ESO guidelines, an additional 17,031 would receive alteplase, which translates into 1922 more patients with favourable three-month outcomes. Discussion: Adherence with product labels is highest in lower efficiency sites. Closer alignment with professional guidelines would increase patients treated and favourable outcomes. Conclusion: Product labels should be revised to allow treatment of patients ≤4.5 h from onset and aged ≥80 years

Redistribution of Calving Caribou in Response to Oil Field Development on the Arctic Slope of Alaska

Aerial surveys were conducted annually in June 1978-87 near Prudhoe Bay, Alaska, to determine changes in the distribution of calving caribou (Rangifer tarandus granti) that accompanied petroleum-related development. With construction of an oil field access road through a calving concentration area, mean caribou density (no./sq. km) decreased from 1.41 to 0.31 (P=0.05) with 1 km and increased from 1.41 to 4.53 (P=0.04) 5-6 km from the road. Concurrently, relative caribou use of the adjacent area declined (P<0.02), apparently in response to increasing surface development. We suggest that perturbed distribution associated with roads reduced the capacity of the nearby area to sustain parturient females and that insufficient spacing of roads may have depressed overall calving activity. Use of traditional calving grounds and of certain areas therein appears to favor calf survival, principally through lower predation risk and improved foraging conditions. Given the possible loss of those habitats through displacement and the crucial importance of the reproductive process, a cautious approach to petroleum development on the Arctic Slope is warranted.Key words: Alaska, calving, caribou, disturbance, oil fieldRÉSUMÉ. Des photographies aériennes ont été prises au mois de juin chaque année de 1978 à 1987 près de la baie Prudhoe en Alaska, en vue de déterminer les changements dans la distribution des caribous (Rangifer tarandus granti) qui mettaient bas, changements accompagnant les projets de mise en valeur reliés au pétrole. Avec la construction d’une route d’accès à un champ pétrolifère à travers une zone importante de mise bas, la densité moyenne du caribou (nombre d’individus/km2) diminuait de 1,41 à 0,31 (P = 0,OS) à moins d’1 km de la route et augmentait de 1,41 à 4,53 (P = 0,04) à une distance de 516 km de la route. En même temps, l’utilisation relative de la zone adjacente par le caribou diminuait (P < 0,02), apparemment enréponse à l’augmentation de la mise en valeur de surface. On suggère que la perturbation de la distribution associée à la construction de routes diminuait la capacité de la zone environnante à supporter des femelles parturientes et qu’un espacement insuffisant des routes aurait pu faire chuter l’activité générale de mise bas. L’utilisation de terrains traditionnels de mise bas ainsi que de certaines zones à l’intérieur de ces terrains semble favoriser la survie des veaux, en particulier grâce à une baisse de la prédation et à de meilleures conditions de pâturage. Étant donné que le caribou pourrait être évincé de cet habitat et vu l’importance cruciale du processus de reproduction, on recommande une approche prudente à l’exploitation du pétrole sur le versant arctique.Mots clés: Alaska, mise bas, caribou, perturbation, champ pétrolifèr