Sunitinib mediates mitochondrial ROS production in adult rat cardiac fibroblasts via CaMKII oxidation

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a central mediator of Ca2+-induced signalling in the heart and regulates both normal cardiac physiology and pathology. Sunitinib malate is an oral Type I tyrosine kinase inhibitor (TKI) known to inhibit more than 50 kinases, with anti-angiogenic and anti-proliferative effects affiliated with off-target cardiotoxicity. Previous work has shown that chronic sunitinib treatment significantly increases CaMKII expression and activity and this correlates with significant cardiac dysfunction in vivo.1 Mitochondrial dysfunction, mediated by increased mitochondrial Ca2+ and resultant mitochondrial ROS production, has been proposed as an underlying mechanism for TKI-induced cardiotoxicity in cardiomyocytes.2 However, little is known of how TKIs may affect the non-contractile cells of the heart. Here, we have investigated whether sunitinib treatment increases mitochondrial ROS production in cardiac fibroblasts (CF) and whether CaMKII may play a role in this potential cardiotoxic mechanis

Beyond brain size: Uncovering the neural correlates of behavioral and cognitive specialization

© Comparative Cognition Society. Despite prolonged interest in comparing brain size and behavioral proxies of "intelligence" across taxa, the adaptive and cognitive significance of brain size variation remains elusive. Central to this problem is the continued focus on hominid cognition as a benchmark and the assumption that behavioral complexity has a simple relationship with brain size. Although comparative studies of brain size have been criticized for not reflecting how evolution actually operates, and for producing spurious, inconsistent results, the causes of these limitations have received little discussion. We show how these issues arise from implicit assumptions about what brain size measures and how it correlates with behavioral and cognitive traits. We explore how inconsistencies can arise through heterogeneity in evolutionary trajectories and selection pressures on neuroanatomy or neurophysiology across taxa. We examine how interference from ecological and life history variables complicates interpretations of brain-behavior correlations and point out how this problem is exacerbated by the limitations of brain and cognitive measures. These considerations, and the diversity of brain morphologies and behavioral capacities, suggest that comparative brain-behavior research can make greater progress by focusing on specific neuroanatomical and behavioral traits within relevant ecological and evolutionary contexts. We suggest that a synergistic combination of the "bottom-up" approach of classical neuroethology and the "top-down" approach of comparative biology/psychology within closely related but behaviorally diverse clades can limit the effects of heterogeneity, interference, and noise. We argue that this shift away from broad-scale analyses of superficial phenotypes will provide deeper, more robust insights into brain evolution

Health-economic evaluation of fluocinolone acetonide 190 µg implant in people with diabetic macular edema

Objectives: To assess healthcare resource use and costs of treating people with clinically significant diabetic macular edema (DME) with fluocinolone acetonide (FAc) 190 µg intravitreal implant in routine clinical practice. Methods: The retrospective Iluvien Clinical Evidence (ICE-UK) study collected data on people prescribed the FAc implant in any one of 13 ophthalmology centers between April 1, 2013 and April 15, 2015. Data were collected for 12 months before and after implantation. Standard UK costs were attributed to healthcare resource use. Results: In total, 208 people contributing 233 FAc-treated eyes were selected. Mean age was 68.1 years and 62% were male. The mean (standard deviation, SD) number of anti-vascular endothelial growth factor (anti-VEGF) injections per FAc treated eye in the 12 months prior to implant was 2.8 (2.5), decreasing to 0.6 (1.4) for the same period after implant (p < .001). The corresponding figures for other steroid injections (dexamethasone and triamcinolone) were 0.14 (0.4) before and 0.08 (0.4) after implant (p = .016). There was no statistically significant difference in the number of laser therapies required in the 12 months before and after FAc implant (mean = 0.12 vs 0.11, respectively; p = .626). Overall, mean (SD) healthcare costs were £2,691 (£1,850) before and £1,239 (£1,203) after FAc implant (p < .001). The unit drug and administration cost per FAc implant was £5,680. Conclusions: Excluding the cost of the FAc implant, healthcare costs were significantly reduced in the 12 months post-implant. FAc implant has a duration of 3 years. This needs to be considered when interpreting the cost associated with the FAc implant

Development and exploratory cluster-randomised opportunistic trial of a theory-based intervention to enhance physical activity among adolescents

Peer reviewedPostprin

Ingredients for understanding brain and behavioral evolution: Ecology, phylogeny, and mechanism

This is the final version of the article. Available from The Comparative Cognition Society via the DOI in this record.Uncovering the neural correlates and evolutionary drivers of behavioral and cognitive traits has been held back by traditional perspectives on which correlations to look for-in particular, anthropocentric conceptions of cognition and coarse-grained brain measurements. We welcome our colleagues' comments on our overview of the field and their suggestions for how to move forward. Here, we counter, clarify, and extend some points, focusing on the merits of looking for the "best" predictor of cognitive ability, the sources and meaning of "noise," and the ways in which we can deduce and test meaningful conclusions from comparative analyses of complex traits