‘Synthetic cannabis’: A dangerous misnomer

The term 'synthetic cannabis' has been widely used in public discourse to refer to a group of cannabinoid receptor agonists. In this paper we detail the characteristics of these drugs, and present the case that the term is a misnomer. We describe the pharmacodynamics of these drugs, their epidemiology, mechanisms of action, physiological effects and how these differ substantially from delta-9-tetrahydrocannabinol (THC). We argue that not only is the term a misnomer, but it is one with negative clinical and public health implications. Rather, the substances referred to as 'synthetic cannabis' in public discourse should instead be referred to consistently as synthetic cannabinoid receptor agonists (SCRAs), a drug class distinct from plant-derived cannabinoids. SCRAs have greater potency and efficacy, and psychostimulant-like properties. While such terminology may be used in the scientific community, it is not widely used amongst the media, general public, people who use these drugs or may potentially do so. A new terminology has the potential to reduce the confusion and harms that result from the misnomer ‘synthetic cannabis’. The constant evolution of this distinct drug class necessitates a range of distinct policy responses relating to terminology, harm reduction, epidemiology, treatment, and legal status

How Furiously Can Colourless Green Ideas Sleep? Sentence Acceptability in Context

We study the influence of context on sentence acceptability. First we compare the acceptability ratings of sentences judged in isolation, with a relevant context, and with an irrelevant context. Our results show that context induces a cognitive load for humans, which compresses the distribution of ratings. Moreover, in relevant contexts we observe a discourse coherence effect which uniformly raises acceptability. Next, we test unidirectional and bidirectional language models in their ability to predict acceptability ratings. The bidirectional models show very promising results, with the best model achieving a new state-of-the-art for unsupervised acceptability prediction. The two sets of experiments provide insights into the cognitive aspects of sentence processing and central issues in the computational modelling of text and discourse

Microdosing and other phase 0 clinical trials: facilitating translation in Drug Development

Increasing costs of drug development and ethical concernsabout the risks of exposing humans and animals to novelchemical entities favor limited exposure clinical trials suchas microdosing and other phase 0 trials. An increasing bodyof research supports the validity of extrapolation from thelimited drug exposure of phase 0 approaches to the full,therapeutic exposure. An increasing number of applicationsand design options demonstrate the versatility and exibilitythese approaches offer to drug developers

Assessing the efficacy and cost of detergents used in a primary care automated washer disinfector

Background: Cleaning of re-usable medical devices is a critical control point in the decontamination cycle, although defined end-points of the process are controversial. Objective: Investigate cleaning efficacy and cost of different detergent classes in an automated washer disinfector (AWD) designed for dental practice. Methods: Loads comprised test soiled dental hand instruments in cassettes and extraction forceps. Residual protein assayed using the International standard method (ISO 15883-5:2005) 1% SDS elution with ortho-phthalaldehyde (OPA) or GBox technology (on instrument OPA analysis). Short (60 minutes) and long (97 minutes) AWD cycles were used with four different classes of detergents, tap water and reverse osmosis water. Results: SDS elution analysis (N = 612 instruments) demonstrated four detergents with both wash cycles achieved equivalent cleanliness levels and below a threshold of 200 μg protein/instrument. GBox methodology (N = 575) using UK Department of Health threshold of 5 μg/instrument side demonstrated that tap water performed with the greatest efficacy for all types of instruments and cycle types. Conclusions: Using International standard methodology, different detergent classes had equivalence in cleaning efficacy. Cheaper detergents used in this study performed with similar efficacy to more expensive solutions. Findings emphasise the importance of validating the detergent (type and concentration) for each AWD

Bite force in the horned frog (Ceratophrys cranwelli) with implications for extinct giant frogs

Of the nearly 6,800 extant frog species, most have weak jaws that play only a minor role in prey capture. South American horned frogs (Ceratophrys) are a notable exception. Aggressive and able to consume vertebrates their own size, these "hopping heads" use a vice-like grip of their jaws to restrain and immobilize prey. Using a longitudinal experimental design, we quantified the ontogenetic profile of bite-force performance in post-metamorphic Ceratophrys cranwelli. Regression slopes indicate positive allometric scaling of bite force with reference to head and body size, results that concur with scaling patterns across a diversity of taxa, including fish and amniotes (lizards, tuatara, turtles, crocodylians, rodents). Our recovered scaling relationship suggests that exceptionally large individuals of a congener (C. aurita) and extinct giant frogs (Beelzebufo ampinga, Late Cretaceous of Madagascar) probably could bite with forces of 500 to 2200 N, comparable to medium to large-sized mammalian carnivores.A. Kristopher Lappin, Sean C. Wilcox, David J. Moriarty, Stephanie A.R. Stoeppler, Susan E. Evans, Marc E.H. Jone

Prevalence and Characteristics Associated with Chronic Noncancer Pain in Suicide Decedents: A National Study

Objective: The aims were to estimate the prevalence of CNCP in suicide decedents, and compare sociodemographic and clinical characteristics of people who die by suicide (i) with and without a history of CNCP and (ii) among decedents with CNCP who are younger (<65 years) and older (65 + years). Method: We examined all closed cases of intentional deaths in Australia in 2014, utilizing the National Coronial Information System. Results: We identified 2,590 closed cases of intentional deaths in Australia in 2014 in decedents over 18 years of age. CNCP was identified in 14.6% of cases. Decedents with CNCP were more likely to be older, have more mental health and physical health problems, and fewer relationship problems, and were more likely to die by poisoning from drugs, compared with decedents without CNCP. Comparisons of older and younger decedents with CNCP found that compared to younger (<65 years) decedents with CNCP, older decedents (65 + years) were less likely to have mental health problems. Conclusions: This is the first national study to examine the characteristics of suicide deaths with a focus on people with CNCP. Primary care physicians should be aware of the increased risk for suicide in people living with CNCP, and it may be useful for clinicians to screen for CNCP among those presenting with suicidal behaviors

A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1α (HIF-1α) does not impair Pro-564 hydroxylation

BACKGROUND: The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the α subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1α in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE). RESULTS: Patients with IE were screened for changes in the HIF-1α coding sequence, and a change in the ODD domain that converts Pro-582 to Ser was identified in several patients. This same change, however, was also detected at a significant frequency, 0.073, in unaffected controls compared to 0.109 in the IE patient group. In vitro hydroxylation assays examining this amino acid change failed to reveal a discernible effect on HIF hydroxylation at Pro-564. CONCLUSION: The Pro582Ser change represents a common polymorphism of HIF-1α that does not impair HIF-1α prolyl hydroxylation. Although the Pro582Ser polymorphism is located in the ODD domain of HIF-1α it does not diminish the association of HIF-1α with VHL. Thus, it is unlikely that this polymorphism accounts for the erythrocytosis in the group of IE patients studied

Development of an in vitro periodontal biofilm model for assessing antimicrobial and host modulatory effects of bioactive molecules

Background: Inflammation within the oral cavity occurs due to dysregulation between microbial biofilms and the host response. Understanding how different oral hygiene products influence inflammatory properties is important for the development of new products. Therefore, creation of a robust host-pathogen biofilm platform capable of evaluating novel oral healthcare compounds is an attractive option. We therefore devised a multi-species biofilm co-culture model to evaluate the naturally derived polyphenol resveratrol (RSV) and gold standard chlorhexidine (CHX) with respect to anti-biofilm and anti-inflammatory properties.&lt;p&gt;&lt;/p&gt; Methods: An in vitro multi-species biofilm containing &lt;i&gt;S. mitis, F. nucleatum, P. Gingivalis&lt;/i&gt; and &lt;i&gt;A. Actinomycetemcomitans&lt;/i&gt; was created to represent a disease-associated biofilm and the oral epithelial cell in OKF6-TERT2. Cytotoxicity studies were performed using RSV and CHX. Multi-species biofilms were either treated with either molecule, or alternatively epithelial cells were treated with these prior to biofilm co-culture. Biofilm composition was evaluated and inflammatory responses quantified at a transcriptional and protein level.&lt;p&gt;&lt;/p&gt; Results: CHX was toxic to epithelial cells and multi-species biofilms at concentrations ranging from 0.01-0.2%. RSV did not effect multi-species biofilm composition, but was toxic to epithelial cells at concentrations greater than 0.01%. In co-culture, CHX-treated biofilms resulted in down regulation of the inflammatory chemokine IL-8 at both mRNA and protein level. RSV-treated epithelial cells in co-culture were down-regulated in the release of IL-8 protein, but not mRNA.&lt;p&gt;&lt;/p&gt; Conclusions: CHX possesses potent bactericidal properties, which may impact downstream inflammatory mediators. RSV does not appear to have bactericidal properties against multi-species biofilms, however it did appear to supress epithelial cells from releasing inflammatory mediators. This study demonstrates the potential to understand the mechanisms by which different oral hygiene products may influence gingival inflammation, thereby validating the use of a biofilm co-culture model.&lt;p&gt;&lt;/p&gt

GATA2 regulates the erythropoietin receptor in t(12;21) ALL.

The t(12;21) (p13;q22) chromosomal translocation resulting in the ETV6/RUNX1 fusion gene is the most frequent structural cytogenetic abnormality in children with acute lymphoblastic leukemia (ALL). The erythropoietin receptor (EPOR), usually associated with erythroid progenitor cells, is highly expressed in ETV6/RUNX1 positive cases compared to other B-lineage ALL subtypes. Gene expression analysis of a microarray database and direct quantitative analysis of patient samples revealed strong correlation between EPOR and GATA2 expression in ALL, and higher expression of GATA2 in t(12;21) patients. The mechanism of EPOR regulation was mainly investigated using two B-ALL cell lines: REH, which harbor and express the ETV6/RUNX1 fusion gene; and NALM-6, which do not. Expression of EPOR was increased in REH cells compared to NALM-6 cells. Moreover, of the six GATA family members only GATA2 was differentially expressed with substantially higher levels present in REH cells. GATA2 was shown to bind to the EPOR 5'-UTR in REH, but did not bind in NALM-6 cells. Overexpression of GATA2 led to an increase in EPOR expression in REH cells only, indicating that GATA2 regulates EPOR but is dependent on the cellular context. Both EPOR and GATA2 are hypomethylated and associated with increased mRNA expression in REH compared to NALM-6 cells. Decitabine treatment effectively reduced methylation of CpG sites in the GATA2 promoter leading to increased GATA2 expression in both cell lines. Although Decitabine also reduced an already low level of methylation of the EPOR in NALM-6 cells there was no increase in EPOR expression. Furthermore, EPOR and GATA2 are regulated post-transcriptionally by miR-362 and miR-650, respectively. Overall our data show that EPOR expression in t(12;21) B-ALL cells, is regulated by GATA2 and is mediated through epigenetic, transcriptional and post-transcriptional mechanisms, contingent upon the genetic subtype of the disease