Comprehensive evaluation of the pharmacological and toxicological effects of γ-valerolactone as compared to γ-hydroxybutyric acid: Insights from in vivo and in silico models

Γ-valerolactone (GVL), marketed online as "Tranquilli-G" and "excellent Valium", is used as a legal substitute for γ-hydroxybutyric acid (GHB); however, until now, GVL has only been connected to one Drug-Facilitated Sexual Assault (DFSA) case. Moreover, the pharmaco-toxicological effects of GVL are poorly studied. The aim of this study was to investigate the 1) in vivo effects of gavage administration of GVL (100-3000 mg/kg) on neurological (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, motor activity (bar, drag, and accelerod test) and cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in CD-1 male mice and the 2) in silico ADMET profile of GVL in comparison to GHB and the open active form γ-hydroxyvaleric acid (GHV). The present study demonstrates that GVL inhibits, in a dose-dependent manner, sensorimotor and motor responses and induces cardiorespiratory depression (at a dose of 3000 mg/kg) in mice. The determination of the ED50 in sensorimotor and motor responses revealed that GVL is about 4-5 times less potent than GHB. In silico prediction of ADMET profiles revealed toxicokinetic similarities between GHB and GHV, and differences with GVL. These results suggest that GVL could be used as a substitute for GHB and should be added to forensic toxicology screenings

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Timed written picture naming in 14 European languages

We describe the Multilanguage Written Picture Naming Dataset. This gives trial-level data and time and agreement norms for written naming of the 260 pictures of everyday objects that compose the colorized Snodgrass and Vanderwart picture set (Rossion & Pourtois in Perception, 33, 217-236, 2004). Adult participants gave keyboarded responses in their first language under controlled experimental conditions (N = 1,274, with subsamples responding in Bulgarian, Dutch, English, Finnish, French, German, Greek, Icelandic, Italian, Norwegian, Portuguese, Russian, Spanish, and Swedish). We measured the time to initiate a response (RT) and interkeypress intervals, and calculated measures of name and spelling agreement. There was a tendency across all languages for quicker RTs to pictures with higher familiarity, image agreement, and name frequency, and with higher name agreement. Effects of spelling agreement and effects on output rates after writing onset were present in some, but not all, languages. Written naming therefore shows name retrieval effects that are similar to those found in speech, but our findings suggest the need for cross-language comparisons as we seek to understand the orthographic retrieval and/or assembly processes that are specific to written output

Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: What size of data platforms and which study designs do we need to assess safety issues?

Background: Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.Methods: We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.Results: The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).Conclusions: Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project

OBJECTIVES: To estimate the risk of AMI for individual NSAIDs.METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) match

The influence of first language spelling and response inhibition skills on English-as-an-additional-language spelling

English spelling is widely investigated, but little is known about spelling in English as an additional language (EAL), especially in the context of text production. This study examined the contribution of language-specific Italian and EAL spelling knowledge, and inhibition skills to EAL spelling in Italian adolescents\u2019 essays. Fifty students, attending two language-focused high schools in Italy, completed standardized spelling tests in Italian and English, a Flanker task to assess inhibition skills, and two, persuasive texts in English. Texts were scored for spelling errors, fluency (words/minute), lexical diversity (type token ratio, TTR), and productivity (total words). Spelling errors in EAL writing were 3%. An exploratory factor analysis identified two factors accounting for EAL spelling in writing: a general EAL spelling/writing (including spelling ability, writing fluency, TTR and total words) factor, and a cognitive factor, corresponding to response inhibition skills. Italian spelling skills did not predict EAL-in-text spelling. The only significant predictors of spelling in EAL writing were EAL spelling/writing and inhibition skills. Inhibition skills contributed to explain morphological and code-switch errors, but not phonological and orthographic errors in English texts. These findings align with the contrastive typological framework and phonological and orthographic proximity hypothesis of language transfer

Evaluations of the LODE Temporal Reasoning Tool with Hearing and Deaf Children

LODE is a web tool for children that are novice readers, and is primarily meant for deaf children. It proposes written stories and interactive games for reasoning, globally, on the stories. In this paper, first, we motivate the rationale of LODE, and explain its reasoning games. Then we briefly describe the design of the web client-server architecture of LODE; the server employs a constraint programming system for creating and solving the LODE games in real time. Finally, we concentrate on two evaluations of the latest prototype of LODE: one with hearing novice readers; another one with deaf readers. We conclude by discussing the results of the evaluations, and their implications for LODE

Before, While and After with LODE and Hearing Novice Readers

KRDB Research Centre Technical Report KRDB09-1, Faculty of Computer Science, Free University of Bozen-Bolzano, Ital