Novel Psychoactive Substances 14Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug 19s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ( 1CKratom 1D), synthetic cannabinoids (e.g., 1CSpice 1D), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, ;3-hydroxybutyrate, ;3-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications

Urinary concentrations of GHB and its novel amino acid and carnitine conjugates following controlled GHB administration to humans

Gamma-hydroxybutyrate (GHB) remains a challenging clinical/forensic toxicology drug. Its rapid elimination to endogenous levels mainly causes this. Especially in drug-facilitated sexual assaults, sample collection often occurs later than the detection window for GHB. We aimed to investigate new GHB conjugates with amino acids (AA), fatty acids, and its organic acid metabolites for their suitability as ingestion/application markers in urine following controlled GHB administration to humans. We used LC–MS/MS for validated quantification of human urine samples collected within two randomized, double-blinded, placebo-controlled crossover studies (GHB 50 mg/kg, 79 participants) at approximately 4.5, 8, 11, and 28 h after intake. We found significant differences (placebo vs. GHB) for all but two analytes at 4.5 h. Eleven hours post GHB administration, GHB, GHB-AAs, 3,4-dihydroxybutyric acid, and glycolic acid still showed significantly higher concentrations; at 28 h only GHB-glycine. Three different discrimination strategies were evaluated: (a) GHB-glycine cut-off concentration (1 µg/mL), (b) metabolite ratios of GHB-glycine/GHB (2.5), and (c) elevation threshold between two urine samples (> 5). Sensitivities were 0.1, 0.3, or 0.5, respectively. Only GHB-glycine showed prolonged detection over GHB, mainly when compared to a second time- and subject-matched urine sample (strategy c)

Connecting stellar mass and star-formation rate to dark matter halo mass out to z ~ 2

We have constructed an extended halo model (EHM) which relates the total stellar mass and star-formation rate (SFR) to halo mass (M_h). An empirical relation between the distribution functions of total stellar mass of galaxies and host halo mass, tuned to match the spatial density of galaxies over 0<z<2 and the clustering properties at z~0, is extended to include two different scenarios describing the variation of SFR on M_h. We also present new measurements of the redshift evolution of the average SFR for star-forming galaxies of different stellar mass up to z=2, using data from the Herschel Multi-tiered Extragalactic Survey (HerMES) for infrared-bright galaxies. Combining the EHM with the halo accretion histories from numerical simulations, we trace the stellar mass growth and star-formation history in halos spanning a range of masses. We find that: (1) The intensity of the star-forming activity in halos in the probed mass range has steadily decreased from z~2 to 0; (2) At a given epoch, halos in the mass range between a few times 10^{11} M_Sun and a few times 10^{12} M_Sun are the most efficient at hosting star formation; (3) The peak of SFR density shifts to lower mass halos over time; (4) Galaxies that are forming stars most actively at z~2 evolve into quiescent galaxies in today's group environments, strongly supporting previous claims that the most powerful starbursts at z~2 are progenitors of today's elliptical galaxies.Comment: 15 pages, 12 figures, accepted for publication in MNRA

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Union inclusiveness and temporary agency workers: the role of power resources and union ideology

This article investigates the determinants of union inclusiveness towards agency workers in Western Europe, using an index which combines unionization rates with dimensions of collective agreements covering agency workers. Using fuzzy-set Qualitative Comparative Analysis, we identify two combinations of conditions leading to inclusiveness: the ‘Northern path’ includes high union density, high bargaining coverage and high union authority, and is consistent with the power resources approach. The ‘Southern path’ combines high union authority, high bargaining coverage, statutory regulations of agency work and working-class orientation, showing that ideology rather than institutional incentives shapes union strategies towards the marginal workforce

Gamma-hydroxybutyrate increases brain resting-state functional connectivity of the salience network and dorsal nexus in humans

According to the triple network hypothesis the brain is equipped with three core neurocognitive networks: the default mode (DMN), the salience (SN), and the central executive (CEN) network. Moreover, the so called dorsal nexus, has met growing interest as it is a hub region connecting these three networks. Assessment of resting-state functional connectivity (rsFC) of these networks enables the elucidation of drug-induced brain alterations. Gamma-hydroxybutyrate (GHB) is a GHB/GABA-B receptor agonist that induces a paradoxical state of mixed stimulation and sedation at moderate doses, which makes it a valuable tool to investigate neural signatures of subjective drug effects. Employing a placebo-controlled, double-blind, randomized, cross-over design, we assessed the effects of GHB (35 mg/kg p. o.) in 19 healthy male subjects on DMN-, SN-, CEN-, and dorsal nexus-rsFC measured by functional magnet resonance imaging and applying independent component as well as seed-based analyses, while subjective drug effects were investigated using visual analog scales (VAS). Subjectively, GHB increased VAS ratings of a general drug effect, stimulation, and sedation. Intrinsic DMN-, and CEN-rsFC remained largely unchanged under GHB, but the drug increased SN-DMN-rsFC and SN-dorsal nexus-rsFC, while dorsal nexus-rsFC was reciprocally increased to both the SN (right anterior insula) and to the CEN (right middle frontal gyrus). Increased sedation significantly predicted the observed SN-dorsal nexus-rsFC. In conclusion, GHB generates a unique stimulant/sedative subjective state that is paralleled by a complex pattern of increased functional connectivity encompassing all three core neurocognitive networks of the brain, while increased SN-dorsal nexus-rsFC was demonstrated to be a potential signature of the sedative component of the drug effect

Understanding Dwarf Galaxies in order to Understand Dark Matter

Much progress has been made in recent years by the galaxy simulation community in making realistic galaxies, mostly by more accurately capturing the effects of baryons on the structural evolution of dark matter halos at high resolutions. This progress has altered theoretical expectations for galaxy evolution within a Cold Dark Matter (CDM) model, reconciling many earlier discrepancies between theory and observations. Despite this reconciliation, CDM may not be an accurate model for our Universe. Much more work must be done to understand the predictions for galaxy formation within alternative dark matter models.Comment: Refereed contribution to the Proceedings of the Simons Symposium on Illuminating Dark Matter, to be published by Springe

Where stars form and live at high redshift: clues from the infrared

The relation between dark matter halos and the loci of star formation at high redshift is a pressing question in contemporary cosmology. Matching the abundance of halos to the abundance of infrared (IR) galaxies, we explicit the link between dark matter halo mass (Mh), stellar mass (M*) and star-formation rate (SFR) up to a redshift of 2. Our findings are five-fold. First, we find a strong evolution of the relation between M* and SFR as a function of redshift with an increase of sSFR = SFR/M* by a factor ~30 between z=0 and z= 2.3. Second, we observe a decrease of sSFR with stellar mass. These results reproduce observed trends at redshift z>0.3. Third, we find that the star formation is most efficient in dark matter halos with Mh~5x10^11 Msun, with hints of an increase of this mass with redshift. Fourth, we find that SFR/Mh increases by a factor ~15 between z = 0 and z = 2.3. Finally we find that the SFR density is dominated by halo masses close to ~7x10^11 Msun at all redshift, with a rapid decrease at lower and higher halo masses. Despite its simplicity, our novel use of IR observations unveils some characteristic mass-scales governing star formation at high redshift.Comment: 5 pages, 3 figures, accepted by A&A, y-axis label fixed in Fig 2 and

Guidance for Evidence-Informed Policies about Health Systems: Assessing How Much Confidence to Place in the Research Evidence

In the third paper in a three-part series on health systems guidance, Simon Lewin and colleagues explore the challenge of assessing how much confidence to place in evidence on health systems interventions