Degeneration of the intervertebral disc with new approaches for treating low back pain.

This review paper discusses the process of disc degeneration and the current understanding of cellular degradation in patients who present with low back pain. The role of surgical treatment for low back pain is analysed with emphasis on the proven value of spinal fusion. The interesting and novel developments of stem cell research in the treatment of low back pain are presented with special emphasis on the importance of the cartilaginous end plate and the role of IL-1 in future treatment modalities

Comparing linguistic interpretation schemes for English corpora

Project AMALGAM explored a range of Partof-Speech tagsets and phrase structure parsing schemes used in modern English corpus-based research. The PoS-tagging schemes and parsing schemes include some which have been used for hand annotation of corpora or manual postediting of automatic taggers or parsers; and others which are unedited output of a parsing program. Project deliverables include: a detailed description of each PoS-tagging scheme, and multi-tagged corpus; a “Corpus-neutral ” tokenization scheme; a family of PoS-taggers, for 8 PoS-tagsets; a method for “PoS-tagset conversion”, a sample of texts parsed according to a range of parsing schemes: a MultiTreebank; an Internet service allowing researchers worldwide free access to the above resources, including a simple email-based method for PoS-tagging any English text with any or all PoS-tagset(s). We conclude that the range of tagging and parsing schemes in use is too varied to allow agreement on a standard; and that parserevaluation based on ‘bracket-matching ’ is unfair to more sophisticated parsers

Neural substrates of cue reactivity and craving in Gambling Disorder

Cue reactivity is an established procedure in addictions research for examining the subjective experience and neural basis of craving. This experiment sought to quantify cue-related brain responses in Gambling Disorder using personally tailored cues in conjunction with subjective craving, as well as a comparison with appetitive non-gambling stimuli. Participants with Gambling Disorder (n=19) attending treatment and 19 controls viewed personally tailored blocks of gambling-related cues, as well as neutral cues and highly appetitive (food) images during a functional MRI scan performed ~2-3 hours after a usual meal. fMRI analysis examined cue-related brain activity, cue-related changes in connectivity, and associations with block-by-block craving ratings. Craving ratings in the participants with Gambling Disorder increased following gambling cues compared with non-gambling cues. fMRI analysis revealed group differences in left insula and anterior cingulate cortex, with the Gambling Disorder group showing greater reactivity to the gambling cues, but no differences to the food cues. In participants with Gambling Disorder, craving to gamble correlated positively with gambling cue-related activity in the bilateral insula and ventral striatum, and negatively with functional connectivity between the ventral striatum and the medial PFC. Gambling cues, but not food cues, elicit increased brain responses in reward-related circuitry in individuals with Gambling Disorder (compared to controls), providing support for the incentive sensitisation theory of addiction. Activity in the insula co-varied with craving intensity, and may be a target for interventions.This study was funded by the Medical Research Council—MRC G1002226 (Nutt) and G1100554 (Clark). We wish to thank the study participants and the clinical team at Imanova, Centre for Imaging Sciences. The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. SPS was funded by the Cambridge Home Scholarship Scheme (CHSS)

Sutherlandia frutescens: The meeting of science and traditional knowledge

Sutherlandia frutescens (L.) R.Br. (syn. Lessertia frutescens (L.) Goldblatt and J.C. Manning) is an indigenous medicinal plant extensively used in South Africa to treat a variety of health conditions. It is a fairly widespread, drought-resistant plant that grows in the Western, Eastern, and Northern Cape provinces and some areas of KwaZulu-Natal, varying in its chemical and genetic makeup across these geographic areas.1 Sutherlandia is widely used as a traditional medicine. Extensive scientific studies are being carried out on the safety, quality, and the efficacy of this medicinal plant to validate the traditional claims, elucidate the bioactive constituents, and conduct clinical trials. This has resulted in a unique situation in South Africa’s history, where traditional knowledge and science intersect to provide insight into this popular plant. This photoessay attempts to illustrate the interlinkage of science with the indigenous knowledge of traditional healers, the local knowledge of people who care for the sick, product development, and innovation agenda of the country as it relates to this plant.Web of Scienc

Dynorphin is expressed primarily by GABAergic neurons that contain galanin in the rat dorsal horn

Background The opioid peptide dynorphin is expressed by certain neurons in the superficial dorsal horn of the spinal cord, but little is known about the types of cell that contain dynorphin. In this study, we have used an antibody against the dynorphin precursor preprodynorphin (PPD), to reveal the cell bodies and axons of dynorphin-expressing neurons in the rat spinal cord. The main aims were to estimate the proportion of neurons in each of laminae I-III that express dynorphin and to determine whether they are excitatory or inhibitory neurons. Results PPD-immunoreactive cells were concentrated in lamina I and the outer part of lamina II (IIo), where they constituted 17% and 8%, respectively, of all neurons. Around half of those in lamina I and 80% of those in lamina II were GABA-immunoreactive. We have previously identified four non-overlapping neurochemical populations of inhibitory interneurons in this region, defined by the presence of neuropeptide Y, galanin, parvalbumin and neuronal nitric oxide synthase. PPD co-localised extensively with galanin in both cell bodies and axons, but rarely or not at all with the other three markers. PPD was present in around 4% of GABAergic boutons (identified by the presence of the vesicular GABA transporter) in laminae I-II. Conclusions These results show that most dynorphin-expressing cells in the superficial dorsal horn are inhibitory interneurons, and that they largely correspond to the population that is defined by the presence of galanin. We estimate that dynorphin is present in ~32% of inhibitory interneurons in lamina I and 11% of those in lamina II. Since the proportion of GABAergic boutons that contain PPD in these laminae was considerably lower than this, our findings suggest that these neurons may generate relatively small axonal arborisations

High-statistics modeling of complex pedestrian avoidance scenarios

Quantitatively modeling the trajectories and behavior of pedestrians walking in crowds is an outstanding fundamental challenge deeply connected with the physics of flowing active matter, from a scientific point of view, and having societal applications entailing individual safety and comfort, from an application perspective. In this contribution, we review a pedestrian dynamics modeling approach, previously proposed by the authors, aimed at reproducing some of the statistical features of pedestrian motion. Comparing with high-statistics pedestrian dynamics measurements collected in real-life conditions (from hundreds of thousands to millions of trajectories), we modeled quantitatively the statistical features of the undisturbed motion (i.e. in absence of interactions with other pedestrians) as well as the avoidance dynamics triggered by a pedestrian incoming in the opposite direction. This was accomplished through (coupled) Langevin equations with potentials including multiple preferred velocity states and preferred paths. In this chapter we review this model, discussing some of its limitations, in view of its extension toward a more complex case: the avoidance dynamics of a single pedestrian walking through a crowd that is moving in the opposite direction. We analyze some of the challenges connected to this case and present extensions to the model capable of reproducing some features of the motion

Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn

Background: Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. Results: We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin. Conclusions: These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia

The Dawn of Open Access to Phylogenetic Data

The scientific enterprise depends critically on the preservation of and open access to published data. This basic tenet applies acutely to phylogenies (estimates of evolutionary relationships among species). Increasingly, phylogenies are estimated from increasingly large, genome-scale datasets using increasingly complex statistical methods that require increasing levels of expertise and computational investment. Moreover, the resulting phylogenetic data provide an explicit historical perspective that critically informs research in a vast and growing number of scientific disciplines. One such use is the study of changes in rates of lineage diversification (speciation - extinction) through time. As part of a meta-analysis in this area, we sought to collect phylogenetic data (comprising nucleotide sequence alignment and tree files) from 217 studies published in 46 journals over a 13-year period. We document our attempts to procure those data (from online archives and by direct request to corresponding authors), and report results of analyses (using Bayesian logistic regression) to assess the impact of various factors on the success of our efforts. Overall, complete phylogenetic data for ~60% of these studies are effectively lost to science. Our study indicates that phylogenetic data are more likely to be deposited in online archives and/or shared upon request when: (1) the publishing journal has a strong data-sharing policy; (2) the publishing journal has a higher impact factor, and; (3) the data are requested from faculty rather than students. Although the situation appears dire, our analyses suggest that it is far from hopeless: recent initiatives by the scientific community -- including policy changes by journals and funding agencies -- are improving the state of affairs

Differential Roles of the PKC Novel Isoforms, PKCδ and PKCε, in Mouse and Human Platelets

Background Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation. Methodology/Principal Findings In this study, we focus on the role of two novel PKC isoforms, PKCδ and PKCε, in both mouse and human platelets. PKCδ is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKCδ undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKCε, is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKCε in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcRγ-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor. Conclusions These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms δ and ε in human and mouse platelets and a selective role for PKCε in signalling through GPVI