Designer drugs on the Internet : a phenomenon out-of-control? : The emergence of hallucinogenic drug Bromo-Dragonfly

Copyright Bentham Science PublishersBased on the material available in both the scientific literature and on the web, the present paper provides an updated pharmacological, chemical, toxicological and behavioural overview of Bromo-Dragonfly (1-(8-bromobenzo[1,2- b;4,5-b']difuran-4-yl)-2-aminopropane; 'B-fly'). B-Fly is a powerful, long lasting, LSD-like, hallucinogenic drug, which has been associated with a number of acute intoxications and fatalities in a number of countries. A critical discussion of the potential of misuse of B-fly but also of the methodological limitations, which are intrinsically associated with the analysis of online, non-peer reviewed, material, is presented. It is concluded that the availability of online information on novel psychoactive drugs, such as B-fly, may constitute a public health challenge. Better international collaboration levels may be needed to tackle this novel and fast growing phenomenonPeer reviewe

Bilastine vs. hydroxyzine : occupation of brain histamine H-receptors evaluated by positron emission tomography in healthy volunteers

A close correlation exists between positron emission tomography (PET)-determined histamine H-receptor occupancy (HRO) and the incidence of sedation. Antihistamines with HRO <20% are classified as non-sedating. The objective was to compare the HRO of bilastine, a second generation antihistamine, with that of hydroxyzine. This randomized, double-blind, crossover study used PET imaging with [ 11 C]-doxepin to evaluate HRO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and HROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall HRO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. A single oral dose of bilastine 20 mg had minimal HRO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine

The Tryptophan System in Cocaine-Induced Depression

Major depression disorder (MDD) is the most prevalent psychiatric comorbid condition in cocaine use disorder (CUD). The comorbid MDD might be primary-MDD (CUD-primary-MDD) or cocaine-induced MDD (CUD-induced-MDD), and their accurate diagnoses and treatment is a challenge for improving prognoses. This study aimed to assess the tryptophan/serotonin (Trp/5-HT) system with the acute tryptophan depletion test (ATD), and the kynurenine pathway in subjects with CUD-primary-MDD, CUD-induced-MDD, MDD and healthy controls. The ATD was performed with a randomized, double-blind, crossover, and placebo-controlled design. Markers of enzymatic activity of indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase, kynurenine aminotransferase (KAT) and kynureninase were also established. Following ATD, we observed a decrease in Trp levels in all groups. Comparison between CUD-induced-MDD and MDD revealed significant differences in 5-HT plasma concentrations (512 + 332 ng/mL vs. 107 + 127 ng/mL, p = 0.039) and the Kyn/5-HT ratio (11 + 15 vs. 112 + 136; p = 0.012), whereas there were no differences between CUD-primary-MDD and MDD. Effect size coefficients show a gradient for all targeted markers (d range 0.72-1.67). Results suggest different pathogenesis for CUD-induced-MDD, with lower participation of the tryptophan system, probably more related to other neurotransmitter pathways and accordingly suggesting the need for a different pharmacological treatment approach

Mephedrone (4-methylmethcathinone; 'meow meow') : chemical, pharmacological and clinical issues

“The original publication is available at www.springerlink.com”. Copyright SpringerRecently, those substances deriving from the active ingredient of the Khat plant, cathinone, have been rising in popularity. Indeed, 4-methylmethcathinone (mephedrone; 'meow meow' and others) has been seen by some as a cheaper alternative to other classified recreational drugs.We aimed here at providing a state-of-the-art review on mephedrone history and prevalence of misuse, chemistry, pharmacology, legal status, product market appearance, clinical/management and related fatalities.Because of the limited evidence, some of the information here presented has been obtained from user reports/drug user-orientated web sites. The most common routes for mephedrone recreational use include insufflation and oral ingestion. It elicits stimulant and empathogenic effects similar to amphetamine, methylamphetamine, cocaine and MDMA. Due to its sympathomimetic actions, mephedrone may be associated with a number of both physical and psychopathological side effects. Recent preliminary analysis of recent UK data carried out in 48 related cases have provided positive results for the presence of mephedrone at postmortem.Within the UK, diffusion of mephedrone may have been associated with an unprecedented combination of a particularly aggressive online marketing policy and a decreasing availability/purity of both ecstasy and cocaine. Mephedrone has been recently classified in both the UK and in a number of other countries as a measure to control its availability. Following this, a few other research psychoactives have recently entered the online market as yet unregulated substances that may substitute for mephedrone. Only international collaborative efforts may be able to tackle the phenomenon of the regular offer of novel psychoactive drugsPeer reviewedFinal Accepted Versio

Étude des opinions des parties prenantes de la filière Porc Noir de Majorque par la méthodologie de World Café Focus Group

A World Café Focus Group (WCFG) was organised with representatives of agents of the Porc Negre Mallorquí (PNM) chain within the framework of the European Union project TREASURE. The WCFG is based on the focus group method, in which interaction between participants is facilitated. Discussions are developed in monothematic tables with a maximum of five people, including the moderator. The WCFG had two main objectives and consisted of two parts. In the first, a SWOT analysis (Strengths, Weaknesses, Opportunities and Threats) was carried out. In the second, marketing strategies of the PNM production system and its products were studied by identifying the four policies that make up the marketing mix: price, product, distribution and communication. Thirteen representatives of the system met, including farmers, producers, processors, administrators, representatives of the Protected Geographical Indication (PGI) and caterers. At the end of each part, a vote was taken in plenary session of the points identified in the monothematic tables that dealt with the SWOT analysis and the marketing mix. The results show production costs as the most important weakness, competition with the “sobrassada” (main product of the PNM) of the Iberian pig as a threat,; the fact of being a differentiated autochthonous race adapted to the territory as a strength and the extension to international markets as an opportunity. Regarding the marketing mix, the strategies valued most were to maintain the premium pricing strategy, enhance the PGI brand, promote the sale of products (other than “sobrassada”) in the hotel and restaurant industry, and increase the presence in sectorial and gastronomic fairs.Postprint (published version

GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (≥50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies

Promoting innovation and excellence to face the rapid diffusion of Novel Psychoactive Substances (NPS) in the EU : the outcomes of the ReDNet project

Objectives: The recent emergence of new psychoactive compounds (NPS) has raised prominent challenges in the fields of drug policy, substance use research, public health and service provision. The Recreational Drugs European Network (ReDNet) project, funded by the European Commission, was implemented to improve the information stream to young people and professionals about effects/risks of NPS identifying online products and disseminating relevant information through technological tools. Methods: Regular multilingual qualitative assessments of websites, drugs fora and other online resources were carried out using the Google search engine in 8 languages from collaborating countries. These included: the UK, Norway, Belgium, Germany, Hungary, Poland, Italy and Spain. Products were tested and prevention messages were developed and disseminated via technological tools such as interactive websites, SMS alert, social networking (Facebook, Twitter), Multimedia (You Tube), Smartphone applications (iPhone), and virtual learning environments (Second Life). Results: The ReDNet project established itself as the first Europe-wide prevention programme designed for NPS based on the efficacy of novel ICT-based forms of intervention. More than 650 NPS products and combinations were identified; relevant information was disseminated to target population and advice was given to both EU/ international agencies and national policy makers. Conclusions: Web monitoring activities are essential for mapping the diffusion of NPS and the use of technological tools can be successfully incorporated in specific prevention programmes. Furthermore, the involvement of multi-disciplinary international partnerships was and continues to be fundamental for responding to such a prominent challenge.Peer reviewedSubmitted Versio

Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma

Background T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. Procedure Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. Results Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. Conclusions In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.We thank the centres of the Sociedad Espanola de Hematologia y Oncologia Pediatricas that submitted cases for consultation, to Noelia Garcia, Silvia Martin and Helena Suarez for their excellent technical assistance and to Nerea Dominguez for updating clinical data. We are indebted to the IDIBAPS Genomics Core Facility and to the HCB-IDIBAPS, the HospitaI Infantil Sant Joan de Deu and the Hospital Universitari Vall d'Hebron Tumour Biobanks, all integrated in the National Network Biobanks of ISCIII for the sample and data procurement. This work was supported by Asociacion Espanola Contra el Cancer (AECC CICPFI6025SALA and 'Ayudas Clinico Formacion AECC 2020' to Jaime Verdu-Amoros), Asociacion de aitas y amas para la humanizacion, socializacion e investigacion del Cancer Infantil y la divulgacion de la donacion de medula osea-La Cuadri del Hospi, Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III (Miguel Servet Program I and II CP13/00159 and MSII18/00015; Itziar Salaverria), Generalitat de Catalunya Suport Grups de Recerca (2017-SGR-1107; Itziar Salaverria), and the European Regional Development Fund 'Una manera de fer Europa'. Joan Enric Ramis-Zaldivar was supported by a fellowship AGAUR FI-DGR 2017 (2017 FI_B01004) from Generalitat de Catalunya. Noelia Garcia has been continuously supported by Accio instrumental d'incorporacio de cientifics i tecnlegs PERIS 2016 (SLT002/16/00336) and PERIS 2020 (SL017/20/000204) from Generalitat de Catalunya. Julia Salmeron-Villalobos was supported by a fellowship from La Caixa (CLLEvolution-HR17-00221). This work was developed partially at the Centro Esther Koplowitz, Barcelona, Spain