Phenotype-Based Screening of Synthetic Cannabinoids in a Dravet Syndrome Zebrafish Model.

Dravet syndrome is a catastrophic epilepsy of childhood, characterized by cognitive impairment, severe seizures, and increased risk for sudden unexplained death in epilepsy (SUDEP). Although refractory to conventional antiepileptic drugs, emerging preclinical and clinical evidence suggests that modulation of the endocannabinoid system could be therapeutic in these patients. Preclinical research on this topic is limited as cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are designated by United States Drug Enforcement Agency (DEA) as illegal substances. In this study, we used a validated zebrafish model of Dravet syndrome, scn1lab homozygous mutants, to screen for anti-seizure activity in a commercially available library containing 370 synthetic cannabinoid (SC) compounds. SCs are intended for experimental use and not restricted by DEA designations. Primary phenotype-based screening was performed using a locomotion-based assay in 96-well plates, and a secondary local field potential recording assay was then used to confirm suppression of electrographic epileptiform events. Identified SCs with anti-seizure activity, in both assays, included five SCs structurally classified as indole-based cannabinoids JWH 018 N-(5-chloropentyl) analog, JWH 018 N-(2-methylbutyl) isomer, 5-fluoro PB-22 5-hydroxyisoquinoline isomer, 5-fluoro ADBICA, and AB-FUBINACA 3-fluorobenzyl isomer. Our approach demonstrates that two-stage phenotype-based screening in a zebrafish model of Dravet syndrome successfully identifies SCs with anti-seizure activity

Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.

Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing "dark-flash" visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations

Spatial and temporal patterns of deformation at the Tendaho geothermal prospect, Ethiopia

Observations of ground deformation in East Africa have been fundamental for unveiling the tectonics of continental rifting, assessing the seismic and volcanic hazard to development, and identifying geothermal resources. Here we investigate the active natural and anthropogenic processes in the Tendaho Graben, Afar using Interferometric Synthetic Aperture Radar (InSAR) collected by the Envisat satellite in 2004–2010. We used the Poly-Interferometric Rate And time series Estimation (π-RATE) method to calculate displacement in satellite line-of-sight, and a least-square inversion to decompose the line-of-sight displacement into vertical and rift perpendicular components. We observe two zones of deformation: a 20 km wide circular region of subsidence located 10 km northeast of the town of Semera with a maximum displacement rate of ∼5 cm/yr; and elongated zone (50 km) of subsidence in the area of the geothermal prospect, maximum rate of ∼4 cm/yr. The temporal characteristics of subsidence varies between these zones, with an increase in subsidence rate observed in the circular region in August 2008. We used a Bayesian inversion to find the best fitting source models and compared this to locations of seismicity and other geophysical observations. The pattern of deformation is consistent with a combination of magmatic and geothermal processes, but there does not appear to be a direct link to a sequence of dyke intrusions during 2005–2010 at Manda Hararo graben ∼60 km away, but dynamic stress changes or deep crustal flow could account for the observations

Lactate as a Memory-Enhancing Metabolite Across the Lifespan in Male Fischer 344 Rats

Aging is often associated with cognitive decline, including problems with working memory and difficulties forming new memories. These deficits can be directly linked to the hippocampus, an area of the temporal lobe of the brain that is engaged during spatial working memory. Age-related declines may be influenced by changes in important modulatory pathways that impact hippocampal function, including regulation of the metabolite lactate. When astrocytic stores of glycogen are hydrolyzed, lactate is released into the extracellular space where it can be taken up by neurons and used as fuel during moments of activation. We previously found that the extracellular concentration of lactate rises in the hippocampus of young male rats while they performed a spatial working memory task (Newman et al., 2011). Infusions of lactate into the hippocampus of young adult males improved their memory performance on this same task (Newman et al., 2011). Recent data has shown that lactate does not rise as robustly in the hippocampus of old rats during spatial working memory when compared to their young counterparts. To investigate whether age-related memory deficits were a result of reversible shifts in metabolic regulation, young (3 months) and old (24 months) male Fischer 344 rats were given infusions of lactate or a vehicle control directly into the hippocampus immediately before a spatial working memory task. Old rats that received infusions of lactate showed robust improvement on this task compared to saline controls or young rats with the same treatment. These results indicate that age-related shifts in memory may be due to changes in metabolic regulation and may be reversed with the application of specific useful metabolites

Exploring Occupational Therapy’s Role in Childcare Settings

This study focused on exploring the occupational therapist\u27s role in childcare settings. The program development, observations, and hands-on activity allowed for first-hand experience of the role occupational therapists could play in a daycare setting. Incorporating meaningful participation, education, and environmental modifications were a part of this study. The study was conducted in Northeast Nebraska, with a total of 31 participants. Early detection is key to addressing developmental delays in many areas (play, social, leisure, dressing, eating, etc). Developmental screenings can assist caregivers and specialists in knowing and understanding how a child is developing compared to his or her same-aged peers. All participating children completed three screenings, which included a neurodevelopmental checklist, Sensory Profile-2, and a five-reflex screening checklist. A total of 31 children (77% of those attending the daycare) were screened in relation to the three areas discussed. The results of this study did not indicate any significant delays or changes. However, through observation, several children were identified with developmental concerns related to reflexes, sensory processing, and neurodevelopmental skills. Further research is needed on early detection and implementation of best practices within a daycare setting. Childcare providers are in an optimal position to detect and address developmental delays that arise with their respective ages. However, lack of education and inconsistency in training hinder one’s ability to address concerns effectively

Terry Hoage Vineyard Re-Design

This document includes an introduction to the Terry Hoage Vineyard Re-Design project including the problem, the purpose and limitations of the study and a glossary of terms. It also includes an overview of the research found before the design process, a documentation of the design process and a summary with recommendations for students with similar projects. Images are referenced throughout the paper; these images can be found at the end of the paper

Improving the Interprofessional Relationship Between Nurses and Speech-Language Pathologists: A Pilot Study

The research presented in this thesis explores the impact of interprofessional education on undergraduate nursing and speech-language pathology students with an overall goal of improving the interprofessional relationship between the two fields. Utilizing quantitative and qualitative methods in the form of a pre-test, educational materials, live guided observation, and post-tests, the researchers found an increase in the nursing students ’ ability to identify the role of the speech-language pathologist in a medical setting (knowledge). There was also an increase in the speech-language pathology students’ ability to understand how and when to communicate with nurses in a medical setting (knowledge)

Ways of Seeing Early Modern Decorative Textiles

This article reviews and analyses the activities and findings of an AHRC research network, Ways of Seeing the English Domestic Interior, 1500-1700; the case of decorative textiles (2012-13). Critically evaluating the results of four network events, the paper situates them within a broader investigation of the central role of decorative textiles in shaping the experience of domestic interiors in the past and present. In the first publication of its kind, we explore the historiography and current range of approaches to the study, interpretation, and exhibition of historic textiles and analyse the insights offered by bringing together different disciplinary and professional perspectives. We argue for the key significance of these textiles for both historical and modern perceptions of the domestic interior, and contend that it is necessary to pursue innovative, collaborative, cross-disciplinary approaches to researching them in order to understand how they functioned in the early modern period and to inform new directions for their display and presentation in the present

A multidisciplinary study of the final episode of the Manda Hararo dyke sequence, Ethiopia, and implications for trends in volcanism during the rifting cycle

The sequence of dyke intrusions between 2005 and 2010 in the Manda Hararo rift segment, Ethiopia, provided an opportunity to test conceptual models of continental rifting. Based on trends up to dyke 13 in the sequence, it was anticipated that, should magma supply continue, dykes would shorten in length and eruptions would increase in size and decrease in distance from the segment centre as extensional stress was progressively released. In this paper we revisit these predictions by presenting a comprehensive overview of the May 2010 dyke and fissure eruption, the 14th and last in the sequence, from InSAR, seismicity, satellite thermal data, ultra violet SO2 retrievals, and multiple LiDAR surveys. We find the dyke is longer than other eruptive dykes in the sequence, propagating in two directions from the segment centre, but otherwise fairly typical in terms of opening, propagation speed and geodetic and seismic moment. However, though the eruption is located closer to the segment centre, it is much smaller than previous events. We interpret this as indicating that either the Manda Hararo rifting event was magma limited, or that extensional stress varies north and south of the segment centre

Systematic review of the relation between smokeless tobacco and cancer in Europe and North America

<p>Abstract</p> <p>Background</p> <p>Interest is rising in smokeless tobacco as a safer alternative to smoking, but published reviews on smokeless tobacco and cancer are limited. We review North American and European studies and compare effects of smokeless tobacco and smoking.</p> <p>Methods</p> <p>We obtained papers from MEDLINE searches, published reviews and secondary references describing epidemiological cohort and case-control studies relating any form of cancer to smokeless tobacco use. For each study, details were abstracted on design, smokeless tobacco exposure, cancers studied, analysis methods and adjustment for smoking and other factors. For each cancer, relative risks or odds ratios with 95% confidence intervals were tabulated. Overall, and also for USA and Scandinavia separately, meta-analyses were conducted using all available estimates, smoking-adjusted estimates, or estimates for never smokers. For seven cancers, smoking-attributable deaths in US men in 2005 were compared with deaths attributable to introducing smokeless tobacco into a population of never-smoking men.</p> <p>Results</p> <p>Eighty-nine studies were identified; 62 US and 18 Scandinavian. Forty-six (52%) controlled for smoking. Random-effects meta-analysis estimates for most sites showed little association. Smoking-adjusted estimates were only significant for oropharyngeal cancer (1.36, CI 1.04–1.77, <it>n </it>= 19) and prostate cancer (1.29, 1.07–1.55, <it>n </it>= 4). The oropharyngeal association disappeared for estimates published since 1990 (1.00, 0.83–1.20, <it>n </it>= 14), for Scandinavia (0.97, 0.68–1.37, <it>n </it>= 7), and for alcohol-adjusted estimates (1.07, 0.84–1.37, <it>n </it>= 10). Any effect of current US products or Scandinavian snuff seems very limited. The prostate cancer data are inadequate for a clear conclusion.</p> <p>Some meta-analyses suggest a possible effect for oesophagus, pancreas, larynx and kidney cancer, but other cancers show no effect of smokeless tobacco. Any possible effects are not evident in Scandinavia. Of 142,205 smoking-related male US cancer deaths in 2005, 104,737 are smoking-attributable. Smokeless tobacco-attributable deaths would be 1,102 (1.1%) if as many used smokeless tobacco as had smoked, and 2,081 (2.0%) if everyone used smokeless tobacco.</p> <p>Conclusion</p> <p>An increased risk of oropharyngeal cancer is evident most clearly for past smokeless tobacco use in the USA, but not for Scandinavian snuff. Effects of smokeless tobacco use on other cancers are not clearly demonstrated. Risk from modern products is much less than for smoking.</p