Researching the lives of disabled children and young people

Why a Special Issue of Children & Society dedicated to disabled children and young people? The simple answer to that question is ‘because disabled children are children first and foremost’. The vast majority of disabled children and young people in the western world live at home with their families, most attending mainstream schools, and disabled children and young people worldwide have rights to inclusion and equal treatment enshrined in national legislation and international conventions. Yet they often remain left out – from generic children’s research, from policy-making about children’s services and, in their everyday lives, from inclusion in friendship groups and social and sporting activities

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

Return of the lysergamides. Part V: Analytical and behavioural characterization of 1-butanoyl-d-lysergic acid diethylamide (1B-LSD)

The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One of the most recent additions to this series of LSD analogs is 1-butanoyl-LSD (1B-LSD), a constitutional isomer of 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B-LSD employing nuclear magnetic resonance spectroscopy (NMR), low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B-LSD from 1P-ETH-LAD was straightforward. LSD and other serotonergic hallucinogens induce the head-twitch response (HTR) in rats and mice, which is mediated by 5-HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B-LSD has LSD-like behavioral effects. 1B-LSD produced a dose-dependent increase in HTR counts, acting with ~14% (ED50 = 976.7 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B-LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B-LSD serves as a pro-drug for LSD. Further investigations are warranted to confirm whether 1B-LSD produces LSD-like psychoactive effects in humans

Nicotinic Acetylcholine Receptor Agonists Attenuate Septic Acute Kidney Injury in Mice by Suppressing Inflammation and Proteasome Activity

Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI. Based on their anti-inflammatory properties, we examined the effects of nicotinic acetylcholine receptor agonists on renal damage using a mouse model of lipopolysaccharide (LPS)-induced AKI where localized LPS promotes inflammation-mediated kidney damage. Administration of nicotine (1 mg/kg) or GTS-21 (4 mg/kg) significantly abrogated renal leukocyte infiltration (by 40%) and attenuated kidney injury. These renoprotective effects were accompanied by reduced systemic and localized kidney inflammation during LPS-induced AKI. Consistent with these observations, nicotinic agonist treatment significantly decreased renal IκBα degradation and NFκB activation during LPS-induced AKI. Treatment of human kidney cells with nicotinic agonists, an NFκB inhibitor (Bay11), or a proteasome inhibitor (MG132) effectively inhibited their inflammatory responses following stimulation with LPS or TNFα. Renal proteasome activity, a major regulator of NFκB-mediated inflammation, was enhanced by approximately 50% during LPS-induced AKI and elevated proteasome activity was significantly blunted by nicotinic agonist administration in vivo. Taken together, our results identify enhanced renal proteasome activity during LPS-induced AKI and the suppression of both proteasome activity and inflammation by nicotinic agonists to attenuate LPS-induced kidney injury

Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems

Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes

Myoelectric Signal Transmission from Implanted Epimysial Electrodes Using a Bone-Anchor as a Conduit

Introduction Current Upper-limb myoelectric prostheses rely on only 2 control signals from surface electrodes, placed over antagonistic muscles in the amputation stump, for limb control. While this has benefits over the traditional body-powered control, there are disadvantages; electrode lift-off, impedance variation, cross-talk, reliability, and limitations in intuitive control. To address these problems, electrodes can be implanted directly on individual muscles responsible for specific actions. Not only does this address skin-related issues, it reduces cross-talk and greatly increases the number of control channels for multi degrees of freedom intuitive control. Bone-anchored devices can be used to overcome problems with prosthetic attachment and additionally used to transfer control signals from these implantable electrodes to the prosthesis. [1] In above-elbow amputees, targeted muscle reinnervation (TMR) enables more signal generation by redirecting nerves previously controlling the amputated muscles in the forearm, to surrogate muscles in the torso (e.g. pectoralis major). [2] We describe in vivo model using implantable electrodes to record myoelectric signals (MES) in normal muscles and following TMR, utilizing a bone-anchor as a conduit to carry signals across the skin barrier. Materials and Methods An in vivo n=6 ovine model was used. A bone-anchor was placed trans-tibially and bipolar electrodes sutured to M. Peroneus Tertius (PT). In a further n=1, motor nerve to PT was divided and coapted with a motor branch from peroneal nerve. MES were recorded over a 12-week period. Functional recovery in the TMR model was assessed by MES and force-plate analysis (FPA). Results In the n=6 group, there was a positive correlation between signal to noise ratio (SNR) and time since implantation (p < 0.005), with a mean SNR of 7 by week 12. In the TMR model, functional recovery was observed after 6 weeks. Difference between legs returned to normal (pre-op: left 4.7 N/kg, right 4.8 N/kg; 80 days post-op: left 4.1 N/kg, right 4.3 N/kg). Recorded MES from TMR muscle compared favourably with healthy muscle. Conclusions We have demonstrated that a bone-anchor is a reliable and robust conduit for transmitting MES over a period of 12 weeks. The combination of implanted electrodes & direct skeletal fixation offers clear advantages over current systems for prosthetic attachment & control. This system forms the basis of a complete solution for prosthetic rehabilitation, which can also be used in the context of TMR. References 1. Al Ajam et. al., 2013. PMID: 23358938 2. Kuiken et. al., 2004. PMID: 1565863

Summarising the retinal vascular calibres in healthy, diabetic and diabetic retinopathy eyes

Retinal vessel calibre has been found to be an important biomarker of several retinal diseases, including diabetic retinopathy (DR). Quantifying the retinal vessel calibres is an important step for estimating the central retinal artery and vein equivalents. In this study, an alternative method to the already estab- lished branching coefficient(BC) is proposed for summarising the vessel calibres in retinal junctions. This new method combines the mean diameter ratio with an alternative to Murray’s cube law exponent, derived by the fractal dimen- sion,experimentally, and the branch exponent of cerebral vessels, as has been suggested in previous studies with blood flow modelling. For the above calcu- lations, retinal images from healthy, diabetic and DR subjects were used. In addition, the above method was compared with the BC and was also applied to the evaluation of arteriovenous ratio as a biomarker of progression from diabetes to DR in four consecutive years, i.e. three/two/one years before the onset of DR and the first year of DR. Moreover, the retinal arteries and veins around the optic nerve head were also evaluated. The new approach quantifies the vessels more accurately. The decrease in terms of the mean absolute percentage error was between 0.24% and 0.49%, extending at the same time the quantification beyond healthy subjects

'Hidden' expatriates: international mobility in the United Arab Emirates as a challenge to current understanding of expatriation

Expatriates are often assumed to have enhanced terms and conditions and, because that makes them expensive, to be in key managerial or technical specialist roles. Employees who come from abroad and are in more manual or even menial roles are usually referred to as ‘migrants’. However, there are millions of people around the world who are not migrants, their intended sojourn in a foreign country is seen by them and their employers as temporary, but their employment contracts are far from advantageous compared with those of locals. These ‘hidden’ expatriates are brought into focus in the emerging Arab Gulf States. In some of these countries, the population consists mainly of expatriates, with the local population a small minority: These expatriates include many in lower-management or manual or menial jobs. We demarcate these expatriates from organisationally assigned expatriates, self-initiated expatriates and migrants. We use qualitative data from such expatriates in the United Arab Emirates to explore the issues this raises for governments, employers and the expatriates – and for our understanding of the phenomenon of expatriation

The use of a bone-anchored device as a hard-wired conduit for transmitting EMG signals from implanted muscle electrodes.

The use of a bone-anchored device to transmit electrical signals from internalized muscle electrodes was studied in a sheep model. The bone-anchored device was used as a conduit for the passage of a wire connecting an internal epimysial electrode to an external signal-recording device. The bone-anchored device was inserted into an intact tibia and the electrode attached to the adjacent M. peroneus tertius. "Physiological" signals with low signal-to-noise ratios were successfully obtained over a 12-week period by walking the sheep on a treadmill. Reliable transmission of multiple muscle signals across the skin barrier is essential for providing intuitive, biomimetic upper limb prostheses. This technology has the potential to provide a better functional and reliable solution for upper limb amputee rehabilitation: attachment and control