Tribute to the Late Dr. Charles D. Hufford

© 2019 The Authors. Purpose: Δ9-Tetrahydrocannabinol-valine-hemisuccinate, a hydrophilic prodrug of Δ9-tetrahydrocannabinol, synthesized with the aim of improving the ocular bioavailability of the parent molecule, was investigated in a lipid-based nanoparticle dosage form for ocular delivery. Methods: Solid lipid nanoparticles (SLNs) of Δ9-tetrahydrocannabinol-valine-hemisuccinate and Δ9-tetrahydrocannabinol, along with a nanoemulsion of Δ9-tetrahydrocannabinol-valine-hemisuccinate, were tested for glaucoma management in a normotensive rabbit model by using a multiple-dosing protocol. Marketed formulations of timolol maleate and pilocarpine HCl were also tested for their pharmacodynamic profile, post-single dose administration. Results: A peak intraocular pressure (IOP) drop of 30% from baseline was observed in rabbits treated with SLNs loaded with Δ9-tetrahydrocannabinol-valine-hemisuccinate at 90 minutes. Treated eyes of rabbits receiving Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs had significantly lower IOP than untreated eyes until 360 minutes, whereas the group receiving the emulsion formulation showed a drop in IOP until 90 minutes only. In comparison to marketed pilocarpine and timolol maleate ophthalmic solutions, Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs produced a greater effect on IOP in terms of both intensity and duration. In terms of tissue concentrations, significantly higher concentrations of Δ9-tetrahydrocannabinol-valine-hemisuccinate were observed in iris-ciliary bodies and retina-choroid with SLNs. Conclusion: Δ9-Tetrahydrocannabinol-valine-hemisuccinate formulated in a lipid-based nanoparticulate carrier shows promise in glaucoma pharmacotherapy. Translational Relevance: Glaucoma therapies usually focus on decreased aqueous humor production and increased outflow. However, such therapy is not curative, and there lies a need in preclinical research to focus efforts on agents that not only affect the aqueous humor dynamics but also provide neuroprotection. Historically, there have been bench-scale studies looking at retinal ganglion cell death post-axonal injury. However, for a smooth translation of this in vitro activity to the clinic, animal models examining IOP reduction, i.e., connecting the neuroprotective activity to a measurable outcome in glaucoma management (IOP), need to be investigated. This study investigated the IOP reduction efficacy of cannabinoids for glaucoma pharmacotherapy in a normotensive rabbit model, bringing forth a new class of agents with the potential of IOP reduction and improved permeation to the back of the eye, possibly providing neuroprotective benefits in glaucoma management

Research in Higher Education: The Neverending Story

Guest Colum

Handedness and schizotypy in a Japanese sample: an association masked by cultural effects on hand usage

Previous research has shown a robust association between schizotypy and mixed/ambiguous-handedness, but little is known about the universality of this relationship outside Western cultures. The present paper examines this issue in a sample of 413 Japanese students administered (in Japan) the Annett handedness questionnaire and a schizotypy scale (STA). Conventional analyses of current hand preference, using several indices derived from the Annett scale, mostly failed to replicate previous findings. However, there was a significant tendency for greater use of either hand in highly schizotypal males. Furthermore, a significant association between schizotypy and non-right-handedness was found—again only in males—after correcting for the effects of early switching of hand usage, presumed to be due to cultural pressure against left-handedness in Japanese society. These results were found to be highly convergent with findings previously reported for clinical schizophrenia

Heart-beat perception, panic/somatic symptoms and anxiety sensitivity in children

There is considerable evidence implicating heart-beat perception (HBP) accuracy and anxiety sensitivity (AS) in the development of panic in adults. However, to date there have been no studies exploring the association between HBP, AS and childhood panic/somatic symptoms. Seventy-nine children aged 8 to 11 years completed a mental tracking paradigm (Psychophysiology 18 (1981) 483) to assess HBP, the Children’s Anxiety Sensitivity Index (J Clin Chil Psychol 20 (1991) 162) and the Screen for Childhood Anxiety Related Emotional Disorders (J Am Acad Child Adoles Psych 38 (1999) 1230). Those with good HBP (n = 7, 9%) had significantly higher panic/somatic symptoms (t = -1.71, P < 0.05), and AS (t = -2.16, P < 0.02) than those with poor HBP. There were no effects of age, sex or BMI on HBP. Those with high levels of panic/somatic symptoms were seven times more likely to have good HBP and had AS scores 1 S.D. higher than the remainder of the sample. Multivariate analyses revealed that these two phenotypes had independent associations with high panic/somatic symptoms. These results extend the literature on HBP and panic and suggest that in children, as in adults, increased panic/somatic symptoms are associated with enhanced ability to perceive internal physiological cues, and fear of such sensations

What do others think? The why, when and how of using surveys in CBT

Surveys are a powerful technique in cognitive behavioural therapy (CBT). A form of behavioural experiment, surveys can be used to test beliefs, normalise symptoms and experiences, and generate compassionate perspectives. In this article, we discuss why and when to use surveys in CBT interventions for a range of psychological disorders. We also present a step-by-step guide to collaboratively designing surveys with patients, selecting the appropriate recipients, sending out surveys, discussing responses and using key learning as a part of therapy. In doing so, we hope to demonstrate that surveys are a flexible, impactful, time-efficient, individualised technique which can be readily and effectively integrated into CBT interventions

Generalist and Specialist Mite Herbivores Induce Similar Defense Responses in Maize and Barley but Differ in Susceptibility to Benzoxazinoids

While substantial progress has been made in understanding defense responses of cereals to insect herbivores, comparatively little is known about responses to feeding by spider mites. Nevertheless, several spider mite species, including the generalist Tetranychus urticae and the grass specialist Oligonychus pratensis, cause damage on cereals such as maize and wheat, especially during drought stress. To understand defense responses of cereals to spider mites, we characterized the transcriptomic responses of maize and barley to herbivory by both mite species, and included a wounding control against which modulation of defenses could be tested. T. urticae and O. pratensis induced highly correlated changes in gene expression on both maize and barley. Within 2 h, hundreds of genes were upregulated, and thousands of genes were up- or downregulated after 24 h. In general, expression changes were similar to those induced by wounding, including for genes associated with jasmonic acid biosynthesis and signaling. Many genes encoding proteins involved in direct defenses, or those required for herbivore-induced plant volatiles, were strongly upregulated in response to mite herbivory. Further, biosynthesis genes for benzoxazinoids, which are specialized compounds of Poaceae with known roles in deterring insect herbivores, were induced in maize. Compared to chewing insects, spider mites are cell content feeders and cause grossly different patterns of tissue damage. Nonetheless, the gene expression responses of maize to both mite herbivores, including for phytohormone signaling pathways and for the synthesis of the benzoxazinoid 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one glucoside, a known defensive metabolite against caterpillars, resembled those reported for a generalist chewing insect, Spodoptera exigua. On maize plants harboring mutations in several benzoxazinoid biosynthesis genes, T. urticae performance dramatically increased compared to wild-type plants. In contrast, no difference in performance was observed between mutant and wild-type plants for the specialist O. pratensis. Collectively, our data provide little evidence that maize and barley defense responses differentiate herbivory between T. urticae and O. pratensis. Further, our work suggests that the likely route to specialization for O. pratensis involved the evolution of a robust mechanism to cope with the benzoxazinoid defenses of its cereal hosts

R06. Identification of the Cellular Pathways Targeted by Two Antifungal Natural Products Using RNA-Seq Analysis

Corresponding author (NCNPR): Ameeta Agarwal, [email protected]://egrove.olemiss.edu/pharm_annual_posters/1005/thumbnail.jp

Visual Imagery and Self-Questioning: Strategies to Improve Comprehension of Written

This research was published by the KU Center for Research on Learning, formerly known as the University of Kansas Institute for Research in Learning Disabilities.Two learning strategies, visual imagery and-self-questioning, designed to increase reading comprehension were taught to six learning disabled students using a multiple-baseline across strategies design. Results of the study indicate that LD students can learn the two strategies and can apply them in both reading-ability level and grade-level materials. The students' use of the strategies resulted in greater comprehension scores from the pretest in baseline to the posttest after training. Instructional time for each strategy ranged from five to seven hours

Generalist and Specialist Mite Herbivores Induce Similar Defense Responses in Maize and Barley but Differ in Susceptibility to Benzoxazinoids

While substantial progress has been made in understanding defense responses of cereals to insect herbivores, comparatively little is known about responses to feeding by spider mites. Nevertheless, several spider mite species, including the generalist Tetranychus urticae and the grass specialist Oligonychus pratensis, cause damage on cereals such as maize and wheat, especially during drought stress. To understand defense responses of cereals to spider mites, we characterized the transcriptomic responses of maize and barley to herbivory by both mite species, and included a wounding control against which modulation of defenses could be tested. T. urticae and O. pratensis induced highly correlated changes in gene expression on both maize and barley. Within 2 h, hundreds of genes were upregulated, and thousands of genes were up- or downregulated after 24 h. In general, expression changes were similar to those induced by wounding, including for genes associated with jasmonic acid biosynthesis and signaling. Many genes encoding proteins involved in direct defenses, or those required for herbivore-induced plant volatiles, were strongly upregulated in response to mite herbivory. Further, biosynthesis genes for benzoxazinoids, which are specialized compounds of Poaceae with known roles in deterring insect herbivores, were induced in maize. Compared to chewing insects, spider mites are cell content feeders and cause grossly different patterns of tissue damage. Nonetheless, the gene expression responses of maize to both mite herbivores, including for phytohormone signaling pathways and for the synthesis of the benzoxazinoid 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one glucoside, a known defensive metabolite against caterpillars, resembled those reported for a generalist chewing insect, Spodoptera exigua. On maize plants harboring mutations in several benzoxazinoid biosynthesis genes, T. urticae performance dramatically increased compared to wild-type plants. In contrast, no difference in performance was observed between mutant and wild-type plants for the specialist O. pratensis. Collectively, our data provide little evidence that maize and barley defense responses differentiate herbivory between T. urticae and O. pratensis. Further, our work suggests that the likely route to specialization for O. pratensis involved the evolution of a robust mechanism to cope with the benzoxazinoid defenses of its cereal hosts

Physiotherapy for adults with joint hypermobility syndrome: A pilot randomised controlled trial

Background: Joint Hypermobility Syndrome (JHS) is a heritable disorder associated with laxity and pain in multiple joints. Physiotherapy is the mainstay of treatment but there is little research investigating its effectiveness. The aim of this study was therefore to conduct a pilot randomised controlled trial (RCT) to determine the feasibility of conducting a future definitive RCT. Methods: A comprehensive physiotherapy intervention was developed in conjunction with patients and healthcare professionals. It was then piloted and refined on the basis of patient and physiotherapist feedback. A parallel two-arm pilot RCT in two UK secondary care NHS Trusts compared 'Advice' against 'Advice & Physiotherapy'. Inclusion criteria were: >16 years, a diagnosis of JHS, and no other musculoskeletal conditions causing pain. The Advice intervention was a one-off session, supplemented by advice booklets from the Hypermobility Syndromes Association and Arthritis Research UK. All patients could ask questions specific to their circumstances and received tailored advice. Participants were then randomly allocated to 'Advice' (no further advice or physiotherapy) or 'Advice & Physiotherapy' (an additional six 30 minute sessions over 4 months). The Physiotherapy intervention was supported by a patient handbook and delivered on a one-to-one patient-therapist basis. It aimed to increase patients’ physical activity through developing knowledge, understanding and skills to better manage their condition. The primary outcome related to the feasibility of conducting a future definitive RCT. Qualitative interviews with patients and physiotherapists therefore formed a major component of data collection. Secondary outcomes included clinical measures (physical function, pain, global status, self-reported joint count, quality of life, exercise self-efficacy and adverse events); resource use (to estimate cost-effectiveness); and an estimate of the value of information from a future RCT. Outcomes were recorded at baseline, 4 months (at the end of physiotherapy) and 7 months (3 months following physiotherapy). Results: A total of n=29 participants were recruited to the pilot RCT. Recruitment was challenging, primarily due to a perceived lack of equipoise between Advice and Physiotherapy. The qualitative evaluation provided very clear guidance to inform a future RCT, including enhancement of the Advice intervention. Some patients reported that the Advice intervention was useful and the Physiotherapy intervention was evaluated very positively. The rate of return of questionnaires was low within the Advice group but reasonable in the Physiotherapy group. The Physiotherapy intervention showed evidence of promise in terms of primary and secondary clinical outcomes. The Advice arm experienced more adverse events. The value of information estimate indicated the potential for high value from a future RCT. Conclusion: A future definitive RCT of physiotherapy for JHS seems feasible, although the Advice intervention should be made more robust to address perceived equipoise and subsequent attrition