Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.

RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans

Improved Detection of Foreign Bodies on Radiographs Using X-ray Dark-Field and Phase-Contrast Imaging

Purpose: The aim of this study was to investigate whether the detection of foreign bodies can be improved using dark-field and phase-contrast radiography compared with conventional (transmission) radiographs. Materials and Methods: Experiments were performed using ex vivo pig paws, which were prepared with differently sized foreign bodies of metal, wood, and glass (n = 10 each). Paws without foreign bodies served as controls (n = 30). All images were acquired using an experimental grating-based large object radiography system. Five blinded readers (second- to fourth-year radiology residents) were asked to assess the presence or absence of any foreign body. Sensitivity and specificity for the detection of metal, wood, glass, and any foreign body were calculated and compared using McNemar test and generalized linear mixed models. Results: Sensitivity for the detection of metal foreign bodies was 100% for all readers and image combinations. The sensitivity for the detection of wooden foreign bodies increased from 2% for transmission images to 78% when dark-field images were added (P < 0.0001). For glass foreign bodies, sensitivity increased from 84% for transmission images to 96% when adding phase-contrast images (P = 0.041). Sensitivity for the detection of any foreign body was 91% when transmission, dark-field, and phase-contrast images were viewed simultaneously, compared with 62% for transmission images alone (P < 0.0001). Specificity was 99% to 100% across all readers and radiography modalities. Conclusions: Adding dark-field images substantially improves the detection of wooden foreign bodies compared with the analysis of conventional (transmission) radiographs alone. Detection of glass foreign bodies was moderately improved when adding phase-contrast images

Do values and political attitudes affect help-seeking? Exploring reported help-seeking for mental health problems in a general population sample using a milieu framework

Abstract Aims Help-seeking for mental health problems is facilitated and hindered by several factors at the individual, interpersonal and community level. The most frequently researched factors contributing to differences in help-seeking behaviour are based on classical socio-demographic variables, such as age, gender and education, but explanations for the observed differences are often absent or remain vague. The present study complements traditional approaches in help-seeking research by introducing a milieu approach, focusing on values and political attitudes as a possible explanation for differences in help-seeking for emotional mental health problems. Methods A representative cross-sectional survey of N = 3,042 respondents in Germany was conducted through face-to-face interviews about past help-seeking for mental health problems, socio-demographic characteristics and values and political attitudes Results Multivariate logistic regression analyses indicated that belonging to a cosmopolitan intellectual milieu group was significantly associated with an increased likelihood of past help-seeking for mental health issues (psychotherapeutic/psychological help-seeking [OR = 2.09, 95% CI: 1.11–3.93, p < 0.05) and primary care (OR = 2.21, 95% CI: 1.15–4.24, p < 0.05]), whereas members of individualist and conservative milieu groups were less likely to report having sought help from a psychotherapist, but not from a general practitioner. Increased odds ratios were also found for a number of socio-demographic variables, such as being aged 26 years and over, a female gender and more than 12 years of formal education. Associations between socio-demographic variables remained significant, and the explained variance of the used models improved considerably when milieu variables were added. Conclusions We discuss how milieu-specific patterns were relevant for explaining differences in mental health service use in addition to socio-demographic factors. It seems promising to consider help-seeking from a milieu perspective to improve disparities in access to and the use of psychotherapy as well as to resource allocation

Particle acceleration at a reconnecting magnetic separator

While the exact acceleration mechanism of energetic particles during solar flares is (as yet) unknown, magnetic reconnection plays a key role both in the release of stored magnetic energy of the solar corona and the magnetic restructuring during a flare. Recent work has shown that special field lines, called separators, are common sites of reconnection in 3D numerical experiments. To date, 3D separator reconnection sites have received little attention as particle accelerators. We investigate the effectiveness of separator reconnection as a particle acceleration mechanism for electrons and protons. We study the particle acceleration using a relativistic guiding-centre particle code in a time-dependent kinematic model of magnetic reconnection at a separator. The effect upon particle behaviour of initial position, pitch angle and initial kinetic energy are examined in detail, both for specific (single) particle examples and for large distributions of initial conditions. The separator reconnection model contains several free parameters and we study the effect of changing these parameters upon particle acceleration, in particular in view of the final particle energy ranges which agree with observed energy spectra.Comment: 17 pages, 12 figures. Accepted for publication in A&

On-line electrochemistry–bioaffinity screening with parallel HR-LC-MS for the generation and characterization of modified p38α kinase inhibitors

In this study, an integrated approach is developed for the formation, identification and biological characterization of electrochemical conversion products of p38α mitogen-activated protein kinase inhibitors. This work demonstrates the hyphenation of an electrochemical reaction cell with a continuous-flow bioaffinity assay and parallel LC-HR-MS. Competition of the formed products with a tracer (SKF-86002) that shows fluorescence enhancement in the orthosteric binding site of the p38α kinase is the readout for bioaffinity. Parallel HR-MSn experiments provided information on the identity of binders and non-binders. Finally, the data produced with this on-line system were compared to electrochemical conversion products generated off-line. The electrochemical conversion of 1-{6-chloro-5-[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl]-3aH-indol-3-yl}-2-morpholinoethane-1,2-dione resulted in eight products, three of which showed bioaffinity in the continuous-flow p38α bioaffinity assay used. Electrochemical conversion of BIRB796 resulted, amongst others, in the formation of the reactive quinoneimine structure and its corresponding hydroquinone. Both products were detected in the p38α bioaffinity assay, which indicates binding to the p38α kinase

Why are flare ribbons associated with the spines of magnetic null points generically elongated?

Coronal magnetic null points exist in abundance as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, that can be analysed using the `squashing factor', $Q$. In this paper we make a detailed analysis of the distribution of $Q$ in the presence of magnetic nulls. While $Q$ is formally infinite on both the spine and fan of the null, the decay of $Q$ away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, $Q$ decays most slowly away from the spine/fan in the direction in which $|{\bf B}|$ increases most slowly. In particular, this demonstrates that the extended, elliptical high-$Q$ halo around the spine footpoints observed by Masson et al. (Astrophys. J., 700, 559, 2009) is a generic feature. This extension of the $Q$ halos around the spine/fan footpoints is important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss how our results can be used to interpret the geometry of observed flare ribbons in `circular ribbon flares', in which typically a coronal null is implicated. We conclude that both the physics in the vicinity of the null and how this is related to the extension of $Q$ away from the spine/fan can be used in tandem to understand observational signatures of reconnection at coronal null points.Comment: Pre-print version of article accepted for publication in Solar Physic

Antimicrobial Natural Products

Although the first antibiotic, penicillin, was discovered in 1928 from a microbial natural source (a mould, Penicillium notatum), there is earlier evidence of using natural materials including moulds and herbs for the treatment of infections. Following the serendipitous discovery of penicillin by Alexander Fleming, there have been hundreds of antibiotics (natural, semisynthetic and synthetic) discovered for clinical uses. However, the pathogenic organisms have developed resistances to existing antibiotics though various mechanisms. Such antibiotic resistance or antimicrobial resistance (AMR) is a critical problem of today’s healthcare system urging the development of new antibiotics. This chapter has primarily focused into antimicrobial compounds developed through natural routes that are currently available as antibiotics for clinical uses and/or are at various developmental stages within the drug development pipeline for potential treatment of minor and life threatening infections. The chapter also provides an overview on the catastrophic problem of antimicrobial resistance, its causes, how it spreads as well as modes of developing antimicrobial resistance (AMR)

Species-Specific Activity of SIV Nef and HIV-1 Vpu in Overcoming Restriction by Tetherin/BST2

Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host–cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIVsmm/mac/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIVmac239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIVsmm, HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts

Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances

New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS