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A general procedure to prepare gold nanourchins (GNUs) via a seed-mediated method was followed using dopamine hydrochloride as a reducing agent and silver nitrate salt (AgNO3) as a shape-directing agent. The novelty of this study comes from the successful incorporation of the prepared gold urchins as an aqueous suspension in a nasal pressurized metered dose inhaler (pMDI) formulation and the investigation of their potential for olfactory targeting for direct nose-to-brain drug delivery (NTBDD). The developed pMDI formulation was composed of 0.025% w/w GNUs, 2% w/w Milli-Q water, and 2% w/w EtOH, with the balance of the formulation being HFA134a propellant. Particle integrity and aerosolization performance were examined using an aerosol exposure system, whereas the nasal deposition profile was tested in a sectioned anatomical replica of human nasal airways. The compatibility of the gold dispersion with the nasal epithelial cell line RPMI 2650 was also investigated in this study. Colloidal gold was found to be stable following six-month storage at 4 °C and during the lyophilization process utilizing a pectin matrix for complete re-dispersibility in water. The GNUs were intact and discrete following atomization via a pMDI, and 13% of the delivered particles were detected beyond the nasal valve, the narrowest region in the nasal cavity, out of which 5.6% was recovered from the olfactory region. Moreover, the formulation was found to be compatible with the human nasal epithelium cell line RPMI 2650 and excellent cell viability was observed. The formulated GNU-HFA-based pMDI is a promising approach for intranasal drug delivery, including deposition in the olfactory region, which could be employed for NTBDD applications.

Abstract Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL−1.

New therapeutic options are urgently required for the treatment of Staphylococcus aureus infections. Accordingly, we sought to exploit the vulnerability of S. aureus to naturally occurring polyamines. We have developed and tested the anti-staphylococcal activity of three novel linear polyamines based on spermine and norspermine. Using a panel of genetically distinct and clinically relevant multidrug resistant S. aureus isolates, including the polyamine resistant USA300 strain LAC, compound AHA-1394 showed a greater than 128-fold increase in inhibition against specific S. aureus strains compared to the most active natural polyamine. Furthermore, we show that AHA-1394 has superior biofilm prevention and biofilm dispersal properties compared to natural polyamines while maintaining minimal toxicity toward human HepG2 cells. We examined the potential of S. aureus to gain resistance to AHA-1394 following in vitro serial passage. Whole genome sequencing of two stable resistant mutants identified a gain of function mutation (S337L) in the phosphatidylglycerol lysyltransferase mprF gene. Inactivation of mutant mprF confirmed the importance of this allele to AHA-1394 resistance. Importantly, AHA-1394 resistant mutants showed a marked decrease in relative fitness and increased generation time. Intriguingly, mprF::S337L contributed to altered surface charge only in the USA300 background whereas increased cell wall thickness was observed in both USA300 and SH1000. Lastly, we show that AHA-1394 displays a particular proclivity for antibiotic potentiation, restoring sensitivity of MRSA and VRSA isolates to daptomycin, oxacillin and vancomycin. Together this study shows that polyamine derivatives are impressive drug candidates that warrant further investigation.

The rise of nucleic acid‐based therapeutics continues apace. At the same time, the need for radiolabelled oligonucleotides for determination of spatial distribution is increasing. Complex molecular structures with mostly multiple charges and low solubility in organic solvents increase the challenge of integrating radionuclides. In preclinical research, it is important to understand the fate of new drug candidates in biodistribution studies, target binding or biotransformation studies. Depending on a specific question, the selection of a respective radiolabelling strategy is crucial. Radiometals for molecular imaging with positron emission tomography or single‐photon computed tomography generally require an attached chelating agent for stable complexation of the metal with the oligonucleotide, whereas labelling using carbon‐11/‐14 or tritium allows incorporation of the radioisotope into the native structure without altering it. Moreover, the suitability of direct radiolabelling of the oligonucleotide of interest or indirect radiolabelling, for example, by a two‐step pretargeting approach, for the study design requires consideration. This review focuses on the challenges of radiolabelling nucleic acid‐based molecules with beta‐plus, gamma and beta‐minus emitters and their use for tracking and monitoring. [ABSTRACT FROM AUTHOR]

A general procedure to prepare gold nanourchins (GNUs) via a seed-mediated method was followed using dopamine hydrochloride as a reducing agent and silver nitrate salt (AgNO3) as a shape-directing agent. The novelty of this study comes from the successful incorporation of the prepared gold urchins as an aqueous suspension in a nasal pressurized metered dose inhaler (pMDI) formulation and the investigation of their potential for olfactory targeting for direct nose-to-brain drug delivery (NTBDD). The developed pMDI formulation was composed of 0.025% w/w GNUs, 2% w/w Milli-Q water, and 2% w/w EtOH, with the balance of the formulation being HFA134a propellant. Particle integrity and aerosolization performance were examined using an aerosol exposure system, whereas the nasal deposition profile was tested in a sectioned anatomical replica of human nasal airways. The compatibility of the gold dispersion with the nasal epithelial cell line RPMI 2650 was also investigated in this study. Colloidal gold was found to be stable following six-month storage at 4 °C and during the lyophilization process utilizing a pectin matrix for complete re-dispersibility in water. The GNUs were intact and discrete following atomization via a pMDI, and 13% of the delivered particles were detected beyond the nasal valve, the narrowest region in the nasal cavity, out of which 5.6% was recovered from the olfactory region. Moreover, the formulation was found to be compatible with the human nasal epithelium cell line RPMI 2650 and excellent cell viability was observed. The formulated GNU-HFA-based pMDI is a promising approach for intranasal drug delivery, including deposition in the olfactory region, which could be employed for NTBDD applications. [ABSTRACT FROM AUTHOR]

The nasal cavity is an attractive route for both local and systemic drug delivery and holds great potential for access to the brain via the olfactory region, an area where the blood–brain barrier (BBB) is effectively absent. However, the olfactory region is located at the roof of the nasal cavity and only represents ~5–7% of the epithelial surface area, presenting significant challenges for the deposition of drug molecules for nose to brain drug delivery (NTBDD). Aerosolized particles have the potential to be directed to the olfactory region, but their specific deposition within this area is confounded by a complex combination of factors, which include the properties of the formulation, the delivery device and how it is used, and differences in inter-patient physiology. In this review, an in-depth examination of these different factors is provided in relation to both in vitro and in vivo studies and how advances in the fabrication of nasal cast models and analysis of aerosol deposition can be utilized to predict in vivo outcomes more accurately. The challenges faced in assessing the nasal deposition of aerosolized particles within the paediatric population are specifically considered, representing an unmet need for nasal and NTBDD to treat CNS disorders.

Winds in the Southern Ocean drive exchanges of heat and carbon dioxide between the ocean and atmosphere. Wind dynamics also explain the dominant patterns of both basal and surface melting of glaciers and ice shelves in the Amundsen and Bellingshausen Seas. Long records of past wind strength and atmospheric circulation are needed to assess the significance of these recent changes. Here we present evidence for a novel proxy of past south westerly wind (SWW) strength over the Amundsen and Bellingshausen Seas, based on diatoms preserved in an Antarctic Peninsula ice core. Ecological affinities of the identified diatom taxa indicate an almost exclusively marine assemblage, dominated by open ocean taxa from the Northern Antarctic Zone (NAZ). Back-trajectory analysis shows the routes of air masses reaching the ice core site and reveals that many trajectories involve contact with surface waters in the NAZ of the Amundsen and Bellingshausen Seas. Correlation analyses between ice core diatom abundance and various wind vectors yield positive and robust coefficients for the 1980−2010 period, with average annual SWW speeds exhibiting the strongest match. Collectively, the data presented here provide new evidence that diatoms preserved in an Antarctic Peninsula ice core offer genuine potential as a new proxy for SWW strength.

This article provides a global scene for the scope of child domestic labour and explores the inter-woven relationship between the practice and slavery, as well as the consequences for this uniquely vulnerable group of child workers. In doing so, it seeks to dispel the myths that child domestic work is a safe form of employment for girls (particularly those living with their employers), and that the practice offers any significant benefits for the majority of the children concerned. However, practitioners must avoid demonising employers if they are to assist child domestic workers (CDWs) more effectively, and should facilitate the empowerment of CDWs to protect themselves. Fundamentally, major changes are needed in societal attitudes which promote the continuance of the practice. For the sake of clarity, children and young persons under 18 years who are the subject of this study are referred to as "CDWs" and the work they do as "child domestic labour" (or occasionally as "domestic service"). The word "her" in this study is shorthand for "his and her" and is used because the large majority of CDWs are female.

Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity and rapidly changing landscape of structures make understanding their effects challenging. In particular, the side effects for SCRA use are extremely diverse, but notably include severe outcomes such as cardiac arrest. These side effects appear at odds with the main putative mode of action, as full agonists of cannabinoid receptors. We have hypothesized that SCRAs may act as MAO inhibitors, owing to their structural similarity to known monoamine oxidase inhibitors (MAOI's) as well as matching clinical outcomes (hypertensive crisis) of 'monoaminergic toxicity' for users of MAOIs and some SCRA use. We have studied the potential for SCRA‐mediated inhibition of MAO‐A and MAO‐B via a range of SCRAs used commonly in the UK, as well as structural analogues to prove the atomistic determinants of inhibition. By combining in silico and experimental kinetic studies we demonstrate that SCRAs are MAO‐A‐specific inhibitors and their affinity can vary significantly between SCRAs, most notably affected by the nature of the SCRA 'head' group. Our data allow us to posit a putative mechanism of inhibition. Crucially our data demonstrate that SCRA activity is not limited to just cannabinoid receptor agonism and that alternative interactions might account for some of the diversity of the observed side effects and that these effects can be SCRA‐specific. [ABSTRACT FROM AUTHOR]

Four guanidine derivatives of N4,N9-diacylated spermine have been designed, synthesized, and characterized. These guanidine-containing cationic lipids bound siRNA and formed nanoparticles. Two cationic lipids with C18 unsaturated chains, N1,N12-diamidino-N4,N9-dioleoylspermine and N1,N12-diamidino-N4-linoleoyl-N9-oleoylspermine, were more efficient in terms of GFP expression reduction compared to the other cationic lipids with shorter C12 (12:0) and very long C22 (22:1) chains. N1,N12-Diamidino-N4-linoleoyl-N9-oleoylspermine siRNA lipoplexes resulted in GFP reduction (26%) in the presence of serum, and cell viability (64%). These data are comparable to those obtained with TransIT TKO. Thus, cationic lipid guanidines based on N4,N9-diacylated spermines are good candidates for non-viral delivery of siRNA to HeLa cells using self-assembled lipoplexes.

Gene silencing by siRNA (synthetic dsRNA of 21-25 nucleotides) is a well established biological tool in gene expression studies and has a promising therapeutic potential for difficult-to-treat diseases. Five fatty acids of various chain length and oxidation state (C12:0, C18:0, C18:1, C18:2, C22:1) were conjugated to the naturally occurring polyamine, spermine, and evaluated for siRNA delivery and gene knock-down. siRNA delivery could not be related directly to gene silencing efficiency as N4,N9-dierucoyl spermine resulted in higher siRNA delivery compared to N4,N9-dioleoyl spermine. GFP silencing in HeLa cells showed that the unsaturated fatty acid amides are more efficient than saturated fatty acid amides, with N4,N9-dioleoyl spermine resulting in the most efficient gene silencing in the presence of serum. The alamarBlue cell viability assay showed that fatty acid amides of spermine have good viability (75%–85% compared to control) except N4,N9-dilauroyl spermine which resulted in low cell viability. These results prove that unsaturated fatty acid amides of spermine are efficient, non-toxic, non-viral vectors for siRNA mediated gene silencing.

Discusses the nature of child domestic work (children employed as servants in the households of families other than their own). Suggests a number of practical steps that can be taken to ensure that child domestic workers are afforded a measure of protection which they do not currently receive. (Author)

Child domestic workers, many of whom are female and 'live in', are distinctively characterised by complex and ambiguous relations with employing families, situations which are often motivated and made acceptable by notions of kinship, community obligation and reciprocity. Evidence has tended to emphasise the household conditions of child workers, the causal factors underpinning their situation and the challenges they face in the urban environments where the large majority work. Based on interviews and group discussions conducted with current and former children on both sides of the serving-served relationship in Mwanza (north-western Tanzania), intra-generational household relations from both working and employer child perspectives are examined, offering new data on the interdependence and power-laden nature of peer relationships in this context. For the first time, the research reveals the existence and nature of 'not-quite-friendships' between child domestic workers and children from employing families and how these relationships – bounded by place, space and time – are constituted and manifested. The study of children's relations in the context of child domestic work also offers a new, geographical, dimension to the study of friendship and, more broadly, the role of specific spaces in shaping relationships – an understanding which could usefully be applied to other contexts. [ABSTRACT FROM AUTHOR]

Background and aims: The United Kingdom (UK) Psychoactive Substances Act (PSA), implemented on the 26th May 2016, made the production, supply and sale of all non‐exempted psychoactive substances illegal. The aim of this study was to measure trends in hospital presentations for severe toxicity following analytically confirmed synthetic cannabinoid receptor agonist (SCRA) exposure before and after implementation of the PSA. Design: Observational study. Setting: Thirty‐four hospitals across the UK participating in the Identification of Novel Psychoactive Substances (IONA) study. Participants: A total of 627 (79.9% male) consenting individuals who presented to participating hospitals between July 2015 and December 2019 with severe acute toxicity and suspected novel psychoactive substances exposure. Measurements Toxicological analyses of patient samples were conducted using liquid‐chromatography tandem mass‐spectrometry. Time‐series analysis was conducted on the monthly number of patients with and without analytically confirmed SCRA exposure using Poisson segmented regression. Findings SCRAs were detected in 35.7% (n = 224) of patients. After adjusting for seasonality and the number of active sites, models showed no clear evidence of an upward or downward trend in the number of SCRA exposure cases in the period before (incidence rate ratio [IRR], 1.12; 95% CI, 0.99–1.26; P = 0.068) or after (IRR, 0.97; 95% CI, 0.94–1.01; P = 0.202) the implementation of the PSA. There was also no clear evidence of an upward or downward trend in non‐SCRA exposure cases before (IRR, 1.12; 95% CI, 0.98–1.27; P = 0.105) or after (IRR, 1.01; 95% CI, 0.98–1.04; P = 0.478) implementation of the PSA. Conclusions: There is no clear evidence of an upward or downward trend in the number of patients presenting to UK hospitals with severe acute toxicity following analytically confirmed synthetic cannabinoid receptor agonist exposure since the implementation of the Psychoactive Substances Act. [ABSTRACT FROM AUTHOR]

Summary Sexuality is a fundamental aspect of being human. Guidance states that to support and improve the lives of adults with life-limiting illness, health professionals must address care in the [...]

There are famous examples of simple (e.g., hemlock, Conium maculatum L.) and complex (e.g., opium poppy, Papaver somniferum L., Papaveraceae) piperidine-alkaloid-containing plants. Many of these are highly poisonous, whilst pepper is well-known gastronomically, and several substituted piperidine alkaloids are therapeutically beneficial as a function of dose and mode of action. This review covers the taxonomy of the genera Aconitum, Delphinium, and the controversial Consolida. As part of studying the biodiversity of norditerpenoid alkaloids (NDAS), the majority of which possess an N-ethyl group, we also quantified the fragment occurrence count in the SciFinder database for NDA skeletons. The wide range of NDA biodiversity is also captured in a review of over 100 recently reported isolated alkaloids. Ring A substitution at position 1 is important to determine the NDA skeleton conformation. In this overview of naturally occurring highly oxygenated NDAs from traditional Aconitum and Delphinium plants, consideration is given to functional effect and to real functional evidence. Their high potential biological activity makes them useful candidate molecules for further investigation as lead compounds in the development of selective drugs. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL−1. [ABSTRACT FROM AUTHOR]

New therapeutic options are urgently required for the treatment of Staphylococcus aureus infections. Accordingly, we sought to exploit the vulnerability of S. aureus to naturally occurring polyamines. We have developed and tested the anti-staphylococcal activity of three novel linear polyamines based on spermine and norspermine. Using a panel of genetically distinct and clinically relevant multidrug resistant S. aureus isolates, including the polyamine resistant USA300 strain LAC, compound AHA-1394 showed a greater than 128-fold increase in inhibition against specific S. aureus strains compared to the most active natural polyamine. Furthermore, we show that AHA-1394 has superior biofilm prevention and biofilm dispersal properties compared to natural polyamines while maintaining minimal toxicity toward human HepG2 cells. We examined the potential of S. aureus to gain resistance to AHA-1394 following in vitro serial passage. Whole genome sequencing of two stable resistant mutants identified a gain of function mutation (S337L) in the phosphatidylglycerol lysyltransferase mprF gene. Inactivation of mutant mprF confirmed the importance of this allele to AHA-1394 resistance. Importantly, AHA-1394 resistant mutants showed a marked decrease in relative fitness and increased generation time. Intriguingly, mprF::S337L contributed to altered surface charge only in the USA300 background whereas increased cell wall thickness was observed in both USA300 and SH1000. Lastly, we show that AHA-1394 displays a particular proclivity for antibiotic potentiation, restoring sensitivity of MRSA and VRSA isolates to daptomycin, oxacillin and vancomycin. Together this study shows that polyamine derivatives are impressive drug candidates that warrant further investigation. [ABSTRACT FROM AUTHOR]