Analytical characterization of N,N-diallyltryptamine (DALT) and 16 ring-substituted derivatives

Many N,N-dialkylated tryptamines show psychoactive properties in humans and the number of derivatives involved in multidisciplinary areas of research has grown over the last few decades. Whereas some derivatives form the basis of a range of medicinal products, others are predominantly encountered as recreational drugs, and in some cases, the areas of therapeutic and recreational use can overlap. In recent years, 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) has appeared as a new psychoactive substance (NPS) and ‘research chemical’ whereas 4-acetoxy-DALT and the ring-unsubstituted DALT have only been detected very recently. Strategies pursued in the authors’ laboratories included the preparation and biological evaluation of previously unreported N,N-diallyltryptamines (DALTs). This report describes the analytical characterization of seventeen DALTs. Fifteen DALTs were prepared by a microwave-accelerated Speeter and Anthony procedure following established procedures developed previously in the authors’ laboratories. In addition to DALT, the substances included in this study were 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 4,5-ethylenedioxy-, 5-methyl-, 5-methoxy-, 5-methoxy-2-methyl-, 5-ethoxy-, 5-fluoro-, 5-fluoro-2-methyl-, 5-chloro-, 5-bromo-, 5,6-methylenedioxy-, 6-fluoro-, 7-methyl, and 7-ethyl-DALT, respectively. The DALTs were characterized by nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) quadrupole and ion trap (EI/CI) mass spectrometry (MS), low and high mass accuracy MS/MS, ultraviolet diode array detection and GC solid-state infrared analysis, respectively. A comprehensive collection of spectral data was obtained that are provided to research communities who face the challenge of encountering newly emerging substances where analytical data are not available. These data are also relevant to researchers who might wish to explore the clinical and non-clinical uses of these substances

Decision-making and referral processes for patients with motor neurone disease: a qualitative study of GP experiences and evaluation of a new decision-support tool

Background The diagnosis of motor neurone disease (MND) is known to be challenging and there may be delay in patients receiving a correct diagnosis. This study investigated the referral process for patients who had been diagnosed with MND, and whether a newly-developed tool (The Red Flags checklist) might help General Practitioners (GPs) in making referral decisions. Methods We carried out interviews with GPs who had recently referred a patient diagnosed with MND, and interviews/surveys with GPs who had not recently referred a patient with suspected MND. We collected data before the Red Flags checklist was introduced; and again one year later. We analysed the data to identify key recurring themes. Results Forty two GPs took part in the study. The presence of fasciculation was the clinical feature that most commonly led to consideration of a potential MND diagnosis. GPs perceived that their role was to make onward referrals rather than attempting to make a diagnosis, and delays in correct diagnosis tended to occur at the specialist level. A quarter of participants had some awareness of the newly-developed tool; most considered it useful, if incorporated into existing systems. Conclusions While fasciculation is the most common symptom associated with MND, other bulbar, limb or respiratory features, together with progression should be considered. There is a need for further research into how decision-support tools should be designed and provided, in order to best assist GPs with referral decisions. There is also a need for further work at the level of secondary care, in order that referrals made are re-directed appropriately

SHOP-Net: Moving from Paper to Mobile

Stock-ordering is one of the challenges that microenterprises face, because shop owners often need to leave their shops to travel to suppliers of goods. Triple Trust Organization (TTO) is a non-profit organization (NGO) that works with microenterprises around Cape Town and addresses this problem. They act as a supplier and fetch stock orders from shops they work with. Their ordering system relied on paper order forms and had a number of inefficiencies. To address these inefficiencies, a mobile-based stock-ordering system was designed with TTO. This system allows orders to be recorded and sent to a server at the TTO office using a mobile phone application where the orders are then processed. This system successfully increased TTO’s efficiency in three ways, namely, improved data processing ability, increased order accuracy and increased access to information. The evaluation was done according to their success criteria and the system has been in use for seven months. We argue that evaluations with NGOs should go further than just the management but include all of those affected by the system

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline

Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA

SHOP-Net: Moving from Paper to Mobile

This paper describes the SHOP-Net system, a mobile handset-based stock ordering system. SHOP-Net replaces a paper-based system with a digital screen- based system. We present how it was developed and evaluated using a user-centered design methodology with associated Human Computer Interaction (HCI) methods, in conjunction with a Non-Governmental Organization (NGO) that works with micro-enterprises. The importance of engaging both users and managers in design and evaluation is highlighted. A short pilot study has been conducted. Despite early teething challenges regarding the management of information made available to the server, the system seems promising and easy to learn. Furthermore, the various stakeholders at the NGO are enthusiastic for it to be put into full use

Does Non-Moral Ignorance Exculpate? Situational Awareness and Attributions of Blame and Forgiveness

In this paper, we set out to test empirically an idea that many philosophers find intuitive, namely that non-moral ignorance can exculpate. Many philosophers find it intuitive that moral agents are responsible only if they know the particular facts surrounding their action. Our results show that whether moral agents are aware of the facts surrounding their action does have an effect on people’s attributions of blame, regardless of the consequences or side effects of the agent’s actions. In general, it was more likely that a situationally aware agent will be blamed for failing to perform the obligatory action than a situationally unaware agent. We also tested attributions of forgiveness in addition to attributions of blame. In general, it was less likely that a situationally aware agent will be forgiven for failing to perform the obligatory action than a situationally unaware agent. When the agent is situationally unaware, it is more likely that the agent will be forgiven than blamed. We argue that these results provide some empirical support for the hypothesis that there is something intuitive about the idea that non-moral ignorance can exculpate

Climatic and cultural changes in the west Congo Basin forests over the past 5000 years

Central Africa includes the world's second largest rainforest block. The ecology of the region remains poorly understood, as does its vegetation and archaeological history. However, over the past 20 years, multidisciplinary scientific programmes have enhanced knowledge of old human presence and palaeoenvironments in the forestry block of Central Africa. This first regional synthesis documents significant cultural changes over the past five millennia and describes how they are linked to climate. It is now well documented that climatic conditions in the African tropics underwent significant changes throughout this period and here we demonstrate that corresponding shifts in human demography have had a strong influence on the forests. The most influential event was the decline of the strong African monsoon in the Late Holocene, resulting in serious disturbance of the forest block around 3500 BP. During the same period, populations from the north settled in the forest zone; they mastered new technologies such as pottery and fabrication of polished stone tools, and seem to have practised agriculture. The opening up of forests from 2500 BP favoured the arrival of metallurgist populations that impacted the forest. During this long period (2500–1400 BP), a remarkable increase of archaeological sites is an indication of a demographic explosion of metallurgist populations. Paradoxically, we have found evidence of pearl millet (Pennisetum glaucum) cultivation in the forest around 2200 BP, implying a more arid context. While Early Iron Age sites (prior to 1400 BP) and recent pre-colonial sites (two to eight centuries BP) are abundant, the period between 1600 and 1000 BP is characterized by a sharp decrease in human settlements, with a population crash between 1300 and 1000 BP over a large part of Central Africa. It is only in the eleventh century that new populations of metallurgists settled into the forest block. In this paper, we analyse the spatial and temporal distribution of 328 archaeological sites that have been reliably radiocarbon dated. The results allow us to piece together changes in the relationships between human populations and the environments in which they lived. On this basis, we discuss interactions between humans, climate and vegetation during the past five millennia and the implications of the absence of people from the landscape over three centuries. We go on to discuss modern vegetation patterns and African forest conservation in the light of these events.Peer reviewe

Response of littoral chironomid community and organic matter to late glacial lake level and environmental changes at Lago dell'Accesa (Tuscany, Italy).

International audienceThis study focuses on the response of lacustrine littoral chironomid communities to late glacial changes in limnological, environmental and climate conditions in the Mediterranean context. Late glacial chironomid (Diptera: Chironomidae) assemblages, organic petrography and geochemistry were analysed in a sediment core from the littoral zone of Lago dell'Accesa (Tuscany, Italy), where the lake-level fluctuations and the vegetation history have been previously reconstructed. Comparison of the chironomid stratigraphy to other proxies (pollen assemblages, organic petrography and geochemistry, lake-level) and regional climate reconstruction suggested the predominant influence of lake-level changes on the littoral chironomid fauna. The main lowering events that occurred during the Oldest and the Younger Dryas were followed by higher proportions of taxa typical of littoral habitats. A complementary study of organic matter suggested the indirect impact of lake-level on the chironomids through changes in humic status and habitat characteristics, such as the type of substrate and aquatic macrophyte development. Several chironomid taxa, such as Glyptotendipes, Microtendipes and Cricotopus type patens, were identified as possible indicators of low lake-level in the late glacial records. Nevertheless, this study suggested that parallel analyses of organic matter and chironomid assemblages may be needed to circumvent misinterpretation of littoral chironomid assemblage stratigraphy. There was a weak response of the chironomid assemblages to small lake-level lowerings that corresponded to the Older Dryas and Preboreal oscillations. A higher level of determination, e.g. to the species group level, may be necessary to increase the sensibility of the indicators to lake-level changes

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces