Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

This Letter was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Scottish Universities Life Sciences Alliance (SULSA) in 2011Peer reviewedPostprin

New nitric oxide donor drugs

Nitric oxide is a recognised dilator of vascular smooth muscle and therefore is central in the control of blood flow. A lack of blood flow in humans can have very important implications in a number of disorders of both cutaneous tissue and internal circulation. In this thesis we look at the synthesis of new nitric oxide donors, their stabilities and their possible medicinal usage. These donors have been based on the S-nitrosothiol group, connected to sugar moieties, simple amino acids or linked glycoaminoacids. The donors prepared have been used to investigate the skin blood flow and localised responses to nitric oxide, proving that NO has an important role in the maintenance of healthy skin. These will be further investigated as possible treatments for disorders involving a lack of cutaneous blood flow, such as connective tissue disorders and the repeated ulceration often seen in diabetic patients. A set of clinical trials have been carried out comparing the responses of healthy patients and sufferers of Raynaud's Phenomenon to exogenous nitric oxide. In this we have highlighted a number of differences and have helped to determine a possible cause of the disorder. We have prepared a number of slow release NO donors which have been shown to produce a sustained vasodilatory response in blood vessels with removed or damaged endothelial cells. These show promise for use in the treatment of patients with circulatory disorders, especially for subjects following treatment for atherosclerosis. Basic studies investigating the stabilities of these compounds have been carried out, in order to aid our understanding of their mode of breakdown

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia

The authors thank the donors, the Research Centre for Women’s and Infants’ Health BioBank program, the Lunenfeld-Tanenbaum Research Institute and the MSH/University Health Network Department of Obstetrics & Gynaecology for the human specimens used in this study.Peer reviewedPublisher PD

Life Science Mini Projects: Taking the Lab Outside the Laboratory

The development of core skills in practical investigation are important for Life Science graduates, however, due to COVID-19 restrictions during this year, Level 3 Human Biology and Physiology students from the University of Glasgow were unable to conduct laboratory-based work. In previous years, students created and undertook small-scale lab-based practical projects at the end of semester 2 to attain course ILOs and graduate attributes. This pandemic year, academic and technical staff proposed that students work in small groups of 5-6 to develop an experimental hypotheses and study design, then collected data in home-based projects over the course of a scheduled experimental week. Whilst students were steered away from projects relying on immobile laboratory equipment in controlled lab environments, they were provided with examples of measurements that could be feasibly performed in isolated ‘real-world’ experiments. Technicians were then able to send wearable measurement devices (e.g. heart rate monitors, continuous glucose monitors) directly to students’ homes to be used during the experimental phase. All data was collected by students at home using laboratory techniques approved by the safety committee. This poster will present the opportunities to staff and students in undertaking ‘real-world’ mini projects and highlight learnings that could be transferred to future academic years. In addition, we will promote the often-overlooked role of laboratory technical staff in teaching provision ; as well as being key to risk assessments and facilitating home-delivery of equipment, laboratory technicians were available for troubleshooting during the data collection phase. Take home messages: 1. Some investigative projects are possible in remote delivery with appropriate planning and safety considerations 2. Remote delivery presented opportunity for creation of experiments with real-world application 3. Technical staff are key members of the teaching team and have valuable expertise to facilitate the learning experience

Enhancement of Medical Interns\u27 Levels of Clinical Skills Competence and Self-Confidence Levels via Video iPods: Pilot Randomized Controlled Trial

Background: Designing and delivering evidence-based medical practice for students requires careful consideration from medical science educators. Social Web (Web 2.0) applications are a part of today’s educational technology milieu; however, empirical research is lacking to support the impact of interactive Web 2.0 mobile applications on medical educational outcomes.Objectives: The aim of our study was to determine whether instructional videos provided by iPod regarding female and male urinary catheter insertion would increase students’ confidence levels and enhance skill competencies.Methods: We conducted a prospective study with medical trainee intern (TI) participants: 10 control participants (no technological intervention) and 11 intervention participants (video iPods). Before taking part in a skills course, they completed a questionnaire regarding previous exposure to male and female urinary catheterization and their level of confidence in performing the skills. Directly following the questionnaire, medical faculty provided a 40-minute skills demonstration in the Advanced Clinical Skills Centre (ACSC) laboratory at the University of Auckland, New Zealand. All participants practiced the skills following the demonstrations and were immediately evaluated by the same faculty using an assessment rubric. Following the clinical skill evaluation, participants completed a postcourse questionnaire regarding skill confidence levels. At the end of the skills course, the intervention group were provided video iPods and viewed a male and a female urinary catheterization video during the next 3 consecutive months. The control group did not receive educational technology interventions during the 3-month period. At the end of 3 months, participants completed a follow-up questionnaire and a clinical assessment of urinary catheterization skills at the ACSC lab.Results: The results indicate a decline in skill competency over time among the control group for both male and female catheterizations, whereas the competency level was stable among the experimental group for both procedures. Interaction results for competency scores indicate a significant level by group and time (P = .03) and procedure and group (P = .02). The experimental group’s confidence level for performing the female catheterization procedure differed significantly over time (P \u3c .001). Furthermore, confidence scores in performing female catheterizations increased for both groups over time. However, the confidence levels for both groups in performing the male catheterization decreased over time.Conclusions: Video iPods offer a novel pedagogical approach to enhance medical students’ medical skill competencies and self-confidence levels. The outcomes illustrate a need for further investigation in order to generalize to the medical school population

Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy

We designed and synthesized perhexiline analogues that have the same therapeutic profile as the parent cardiovascular drug but lacking its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl perhexiline analogues 6a–j were found to be unsuitable for further development, as they retained a pharmacokinetic profile very similar to that shown by the parent compound. Multistep synthesis of perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoroperhexiline analogues. Of these, analogues 50 (4,4-gem-difluoro) and 62 (4,4,4′,4′-tetrafluoro) were highly stable and showed greatly reduced susceptibility to CYP2D6-mediated metabolism. In vitro efficacy studies demonstrated that a number of derivatives retained acceptable potency against CPT-1. Having the best balance of properties, 50 was selected for further evaluation. Like perhexiline, it was shown to be selectively concentrated in the myocardium and, using the Langendorff model, to be effective in improving both cardiac contractility and relaxation when challenged with high fat buffer

Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients

Background  In order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.  Methods  One hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3\%). Cachexia was defined as weight-loss ≥5\%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time–polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581–1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. {\textgreater}1 year post operatively.  Results  Cancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008).  Conclusions  The present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers

CB1 Receptor Negative Allosteric Modulators as a Potential Tool to Reverse Cannabinoid Toxicity

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Antidepressant Activity of Pharmacological and Genetic Deactivation of the Small-Conductance Calcium-Activated Potassium Channel Subtype-3

Funding and Disclosure This research was supported by awards from the Neuroscience Catalyst program (Toronto) (FRB and JNN), the Canadian Institutes of Health Research (FRB and JN) and the National Science and Engineering Research Council of Canada (FRB). M.N. was additionally supported by a CAMH Discovery Fund Post-doctoral Fellowship. Conflict of Interest: None declared. Acknowledgments We thank J. Li, U. Mumtaz, S. Khan, S. Sivaruban, M. Billyard, E. Hauck, D. Oleinichenko, Michael Coombs and Lucas Francis Fowler for technical assistance at different stages of the work.Peer reviewedPostprin