Increasing Tetrahydrobiopterin in Cardiomyocytes Adversely Affects Cardiac Redox State and Mitochondrial Function Independently of Changes in NO Production

Tetrahydrobiopterin (BH4) represents a potential strategy for the treatment of cardiac remodeling, fibrosis and/or diastolic dysfunction. The effects of oral treatment with BH4 (Sapropterin™ or Kuvan™) are however dose-limiting with high dose negating functional improvements. Cardiomyocyte-specific overexpression of GTP cyclohydrolase I (mGCH) increases BH4 several-fold in the heart. Using this model, we aimed to establish the cardiomyocyte-specific responses to high levels of BH4. Quantification of BH4 and BH2 in mGCH transgenic hearts showed age-based variations in BH4:BH2 ratios. Hearts of mice (\u3c6 \u3emonths) have lower BH4:BH2 ratios than hearts of older mice while both GTPCH activity and tissue ascorbate levels were higher in hearts of young than older mice. No evident changes in nitric oxide (NO) production assessed by nitrite and endogenous iron–nitrosyl complexes were detected in any of the age groups. Increased BH4 production in cardiomyocytes resulted in a significant loss of mitochondrial function. Diminished oxygen consumption and reserve capacity was verified in mitochondria isolated from hearts of 12-month old compared to 3-month old mice, even though at 12 months an improved BH4:BH2 ratio is established. Accumulation of 4-hydroxynonenal (4-HNE) and decreased glutathione levels were found in the mGCH hearts and isolated mitochondria. Taken together, our results indicate that the ratio of BH4:BH2 does not predict changes in neither NO levels nor cellular redox state in the heart. The BH4 oxidation essentially limits the capacity of cardiomyocytes to reduce oxidant stress. Cardiomyocyte with chronically high levels of BH4 show a significant decline in redox state and mitochondrial function

Water Safety Education Programs in Culturally and Linguistically Diverse Seattle Communities: Program Design and Pilot Evaluation

Drowning is a public health concern that disproportionally affects children and minorities in Washington State. Community health educators from Seattle Children’s Hospital designed a Water Safety Education and Lifejacket Giveaway Program for low-income parents of preschool-aged children from culturally and linguistically diverse backgrounds. The program was interpreted into multiple languages and parents and children in attendance received free lifejackets. The mixed-methods pilot evaluation of this program found statistically significant relationships between language and self-reported parent swim skill level (English-speaker OR 4.6; 95%CI: 1.84 – 11.54); and confidence of keeping one’s child safe (English-speaker OR 3.34; 95%CI: 1.10 – 10.4). Additionally, parents who self-reported that they could swim had four times the odds of feeling confident in keeping their children safe around the water (95% CI: 1.21 - 13.28). Qualitative data from follow-up interviews identified that the program boosted parent knowledge and confidence in safe water practices. Multi-lingual delivery and the role of partner preschools was critical to this program’s success. Specific programmatic focus on adult parent/caregiver skills and knowledge that reduce risk around the water should be a priority for future efforts to reduce drowning

Intellectual Property Management in Health and Agricultural Innovation: Executive Guide

Prepared by and for policy-makers, leaders of public sector research establishments, technology transfer professionals, licensing executives, and scientists, this online resource offers up-to-date information and strategies for utilizing the power of both intellectual property and the public domain. Emphasis is placed on advancing innovation in health and agriculture, though many of the principles outlined here are broadly applicable across technology fields. Eschewing ideological debates and general proclamations, the authors always keep their eye on the practical side of IP management. The site is based on a comprehensive Handbook and Executive Guide that provide substantive discussions and analysis of the opportunities awaiting anyone in the field who wants to put intellectual property to work. This multi-volume work contains 153 chapters on a full range of IP topics and over 50 case studies, composed by over 200 authors from North, South, East, and West. If you are a policymaker, a senior administrator, a technology transfer manager, or a scientist, we invite you to use the companion site guide available at http://www.iphandbook.org/index.html The site guide distills the key points of each IP topic covered by the Handbook into simple language and places it in the context of evolving best practices specific to your professional role within the overall picture of IP management

Intellectual Property Management in Health and Agricultural Innovation: A Handbook of Best Practices, Vol. 1

Prepared by and for policy-makers, leaders of public sector research establishments, technology transfer professionals, licensing executives, and scientists, this online resource offers up-to-date information and strategies for utilizing the power of both intellectual property and the public domain. Emphasis is placed on advancing innovation in health and agriculture, though many of the principles outlined here are broadly applicable across technology fields. Eschewing ideological debates and general proclamations, the authors always keep their eye on the practical side of IP management. The site is based on a comprehensive Handbook and Executive Guide that provide substantive discussions and analysis of the opportunities awaiting anyone in the field who wants to put intellectual property to work. This multi-volume work contains 153 chapters on a full range of IP topics and over 50 case studies, composed by over 200 authors from North, South, East, and West. If you are a policymaker, a senior administrator, a technology transfer manager, or a scientist, we invite you to use the companion site guide available at http://www.iphandbook.org/index.html The site guide distills the key points of each IP topic covered by the Handbook into simple language and places it in the context of evolving best practices specific to your professional role within the overall picture of IP management

Reducing Disparities in the Burden of Cancer: The Role of Patient Navigators

Many racial and ethnic minority patients with cancer face barriers related to access to health care and information. Patient navigators, say the authors, could help to overcome these barriers

Neuropsychological deficits in disordered screen use behaviours : A systematic review and meta-analysis

Over the last few decades, excessive and disordered screen use has become more prevalent, prompting investigations into its associated consequences. The extent to which disordered screen use behaviours impact neuropsychological functioning has been reportedly mixed and at times inconsistent. This review sought to synthesise the literature and estimate the magnitude of overall cognitive impairment across a wide range of disordered screen use behaviours. We also sought to determine the cognitive domains most impacted, and whether the observed impairments were moderated by the classification of screen-related behaviours (i.e., Internet or gaming) or the format of cognitive test administration (i.e., paper-and-pencil or computerised). A systematic search of databases (Embase, PsycINFO, MEDLINE) identified 43 cross-sectional articles that assessed neuropsychological performance in disordered screen use populations, 34 of which were included in the meta-analysis. A random-effects meta-analysis revealed significant small/medium (g = .38) cognitive deficits for individuals with disordered screen use behaviours relative to controls. The most affected cognitive domain with a significant medium effect size (g = .50) was attention and focus followed by a significant reduction in executive functioning (g = .31). The classification of disordered screen use behaviours into Internet or gaming categories or the format of cognitive testing did not moderate these deficits. Additionally, excluding disordered social media use in an exploratory analysis had little effect on the observed outcomes. This study highlights a number of methodological considerations that may have contributed to disparate findings and shows that disordered screen use can significantly impact cognitive performance. Recommendations for future research are also discussed. Data for this study can be found at https://osf.io/upeha/

Ketamine as the anaesthetic for electroconvulsive therapy:the KANECT randomised controlled trial

C.AS. reports grants from Vifor Pharma, outside the submitted work. I.C.R. (deceased) declared personal fees from AstraZeneca, Sanofi Aventis and Sunovion, and non-financial support from Lundbeck, between 2009 and 2014 and all outside the submitted work. Volume 212, Issue 5 May 2018 , p. 323 Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial – CORRIGENDUM Gordon Fernie, James Currie, Jennifer S. Perrin, Caroline A. Stewart... https://doi.org/10.1192/bjp.2018.76 Published online: 06 April 2018 Summary: This notice describes a correction to the above mentioned paper.Peer reviewedPublisher PD

Estimation of self-sustained activity produced by persistent inward currents using firing rate profiles of multiple motor units in humans

Persistent inward calcium and sodium currents (IP) activated during motoneuron recruitment help synaptic inputs maintain self-sustained firing until de-recruitment. Here, we estimate the contribution of the IP to self-sustained firing in human motoneurons of varying recruitment threshold by measuring the difference in synaptic input needed to maintain minimal firing once the IP is fully activated compared with the larger synaptic input required to initiate firing prior to full IP activation. Synaptic input to ≈20 dorsiflexor motoneurons simultaneously recorded during ramp contractions was estimated from firing profiles of motor units decomposed from high-density surface-EMG. To avoid errors introduced when using high-threshold units firing in their nonlinear range, we developed methods where the lowest-threshold units firing linearly with force were used to construct a composite (control) firing rate profile to estimate synaptic input to the higher-threshold (test) units. The difference in the composite firing rate (synaptic input) at the time of test unit recruitment and de-recruitment (ΔF=Frecruit-Fde-recruit) was used to measure IP amplitude that sustained firing. Test units with recruitment thresholds 1-30% of maximum had similar ΔFs, which likely included both slow and fast motor units activated by small and large motoneurons, respectively. This suggests that the portion of the IP that sustains firing is similar across a wide range of motoneuron sizes. Higher-threshold units had more prolonged accelerations in firing rate at the onset of recruitment compared to lower-threshold units, likely reflecting IP activation closer to firing onset in the higher-threshold units, but well before firing onset in the lower-threshold units

Early Mississippian sandy siltstones preserve rare vertebrate fossils in seasonal flooding episodes

Flood-generated sandy siltstones are under-recognised deposits that preserve key vertebrate (actinopterygians, rhizodonts, and rarer lungfish, chondrichthyans and tetrapods), invertebrate and plant fossils. Recorded for the first time from the lower Mississippian Ballagan Formation of Scotland, more than 140 beds occur throughout a 490 m thick core succession charac-terised by fluvial sandstones, palaeosols, siltstones, dolostone ‘cementstones’ and gypsum from a coastal–alluvial plain setting. Sandy siltstones are described as a unique taphofacies of the Ballagan Formation (Scotland, UK);they are matrix-supported siltstones with millimetre-sized siltstone and very fine sandstone lithic clasts. Common bioclasts include plants and mega-spores, fish, ostracods, eurypterids and bivalves. Fossils have a high degree of articulation compared with those found in other fossil-bearing deposits, such as conglomerate lags at the base of fluvial channel sandstones. Bed thickness and distribution varies throughout the formation, with no stratigraphic trend. The matrix sediment and clasts are sourced from the reworking of floodplain sediments including desiccated surfaces and palaeosols. Secondary pedogenic modification affects 30% of the sandy siltstone beds and most (71%) overlie palaeosols or desiccation cracks. Sandy siltstones are interpreted as cohesive debris flow deposits that originated by the over-bank flooding of rivers and due to localised floodplain sediment transport at times of high rainfall; their association with palaeosols and desiccation cracks indicates seasonally wet to dry cycles throughout the Tournaisian. Tetrapod and fish fossils derived from floodplain lakes and land surfaces are concentrated by local erosion and reworking, and are preserved by deposition into temporary lakes on the floodplain; their distribution indicates a local origin, with sediment transported across the floodplain in seasonal rainfall episodes. These deposits are significant new sites that can be explored for the preservation of rare non-marine fossil material and provide unique insights into the evolution of early terrestrial ecosystems