An exploration of the experiences and utility of functional electrical stimulation for foot drop in people with multiple sclerosis

Purpose: Functional electrical stimulation (FES) is effective in improving walking in people with multiple sclerosis (MS) with foot drop. There is limited research exploring people’s experiences of using this device. This study aims to explore the utility, efficacy, acceptability, and impact on daily life of the device in people with MS. Methods: An interpretative phenomenological approach was employed. Ten participants who had used FES for 12 months were interviewed. Transcripts were analysed, and emergent themes identified. Results: Nine participants continued to use the device. Three relevant super-ordinate themes were identified; impact of functional electrical stimulation, sticking with functional electrical stimulation, and autonomy and control. Participants reported challenges using the device; however, all reported positive physical and psychological benefits. Intrinsic and external influences such as; access to professional help, the influence of others, an individual’s ability to adapt, and experiences using the device, influenced their decisions to continue with the device. A thematic model of these factors was developed. Conclusions: This study has contributed to our understanding of people with MS experiences of using the device and will help inform prescribing decisions and support the continued, appropriate use of FES over the longer term

3D quantitative imaging of unprocessed live tissue reveals epithelial defense against bacterial adhesion and subsequent traversal requires MyD88.

While a plethora of in vivo models exist for studying infectious disease and its resolution, few enable factors involved in the maintenance of health to be studied in situ. This is due in part to a paucity of tools for studying subtleties of bacterial-host interactions at a cellular level within live organs or tissues, requiring investigators to rely on overt outcomes (e.g. pathology) in their research. Here, a suite of imaging technologies were combined to enable 3D and temporal subcellular localization and quantification of bacterial distribution within the murine cornea without the need for tissue processing or dissection. These methods were then used to demonstrate the importance of MyD88, a central adaptor protein for Toll-Like Receptor (TLR) mediated signaling, in protecting a multilayered epithelium against both adhesion and traversal by the opportunistic bacterial pathogen Pseudomonas aeruginosa ex vivo and in vivo

Neuroanatomy of the crocodylian Tomistoma dowsoni from the Miocene of North Africa provides insights into the evolutionary history of gavialoids

The interrelationships of the extant crocodylians Gavialis gangeticus and Tomistoma schlegelii have been historically disputed. Whereas molecular analyses indicate a sister taxon relationship between these two gavialoid species, morphological datasets typically place Gavialis as the outgroup to all other extant crocodylians. Recent morphological-based phylogenetic analyses have begun to resolve this discrepancy, recovering Gavialis as the closest living relative of Tomistoma; however, several stratigraphically early fossil taxa are recovered as closer to Gavialis than Tomistoma, resulting in anomalously early divergence timings. As such, additional morphological data might be required to resolve these remaining discrepancies. ‘Tomistoma’ dowsoni is an extinct species of gavialoid from the Miocene of North Africa. Utilising CT scans of a near-complete, referred skull, we reconstruct the neuroanatomy and neurosensory apparatus of ‘Tomistoma’ dowsoni. Based on qualitative and quantitative morphometric comparisons with other crocodyliforms, the neuroanatomy of ‘Tomistoma’ dowsoni is characterised by an intermediate morphology between the two extant gavialoids, more closely resembling Gavialis. This mirrors the results of recent studies based on the external anatomy of these three species and other fossil gavialoids. Several neuroanatomical features of these species appear to reflect ecological and/or phylogenetic signals. For example, the ‘simple’ morphology of their neurosensory apparatus is broadly similar to that of other long and narrow-snouted (longirostrine), aquatic crocodyliforms. A dorsoventrally short, anteroposteriorly long endosseous labyrinth is also associated with longirostry. These features indicate that snout and skull morphology, which are themselves partly constrained by ecology, exert an influence on neuroanatomical morphology, as has also been recognised in birds and turtles. Conversely, the presence of a pterygoid bulla in Gavialis and several extinct gavialoids, and its absence in Tomistoma schlegelii, could be interpreted as a phylogenetic signal of crocodylians more closely related to Gavialis than to Tomistoma. Evaluation of additional fossil gavialoids will be needed to further test whether these and other neuroanatomical features primarily reflect a phylogenetic or ecological signal. By incorporating such previously inaccessible information of extinct and extant gavialoids into phylogenetic and macroecological studies, we can potentially further constrain the clade's interrelationships, as well as evaluate the timing and ecological association of the evolution of these neuroanatomical features. Finally, our study supports recent phylogenetic analyses that place ‘Tomistoma’ dowsoni as being phylogenetically closer to Gavialis gangeticus than to Tomistoma schlegelii, indicating the necessity of a taxonomic revision of this fossil species

Targeted next-generation sequencing for routine clinical screening of mutations

In many fields it is now desirable to sequence large panels of genes for mutation, to aid management of patients. The need for extensive sample preparation means that current approaches for assessing mutation status in the clinical setting are limited. A recent publication demonstrates a single-step, targeted, true single-molecule sequencing approach to assessing the mutational status of BRCA1. Fragmented DNA samples are loaded directly onto a flow cell and sequenced, thus detecting both small- and large-scale mutations with minimal sample preparation and high accuracy

The effect of intervertebral cartilage on neutral posture and range of motion in the necks of sauropod dinosaurs

The necks of sauropod dinosaurs were a key factor in their evolution. The habitual posture and range of motion of these necks has been controversial, and computer-aided studies have argued for an obligatory sub-horizontal pose. However, such studies are compromised by their failure to take into account the important role of intervertebral cartilage. This cartilage takes very different forms in different animals. Mammals and crocodilians have intervertebral discs, while birds have synovial joints in their necks. The form and thickness of cartilage varies significantly even among closely related taxa. We cannot yet tell whether the neck joints of sauropods more closely resembled those of birds or mammals. Inspection of CT scans showed cartilage:bone ratios of 4.5% for Sauroposeidon and about 20% and 15% for two juvenile Apatosaurus individuals. In extant animals, this ratio varied from 2.59% for the rhea to 24% for a juvenile giraffe. It is not yet possible to disentangle ontogenetic and taxonomic signals, but mammal cartilage is generally three times as thick as that of birds. Our most detailed work, on a turkey, yielded a cartilage:bone ratio of 4.56%. Articular cartilage also added 11% to the length of the turkey's zygapophyseal facets. Simple image manipulation suggests that incorporating 4.56% of neck cartilage into an intervertebral joint of a turkey raises neutral posture by 15°. If this were also true of sauropods, the true neutral pose of the neck would be much higher than has been depicted. An additional 11% of zygapophyseal facet length translates to 11% more range of motion at each joint. More precise quantitative results must await detailed modelling. In summary, including cartilage in our models of sauropod necks shows that they were longer, more elevated and more flexible than previously recognised

Site-targeted mutagenesis for stabilization of recombinant monoclonal antibody expressed in tobacco (Nicotiana tabacum) plants.

This study examined the degradation pattern of a murine IgG1κ monoclonal antibody expressed in and extracted from transformed Nicotiana tabacum. Gel electrophoresis of leaf extracts revealed a consistent pattern of recombinant immunoglobulin bands, including intact and full-length antibody, as well as smaller antibody fragments. N-terminal sequencing revealed these smaller fragments to be proteolytic cleavage products and identified a limited number of protease-sensitive sites in the antibody light and heavy chain sequences. No strictly conserved target sequence was evident, although the peptide bonds that were susceptible to proteolysis were predominantly and consistently located within or near to the interdomain or solvent-exposed regions in the antibody structure. Amino acids surrounding identified cleavage sites were mutated in an attempt to increase resistance. Different Guy's 13 antibody heavy and light chain mutant combinations were expressed transiently in N. tabacum and demonstrated intensity shifts in the fragmentation pattern, resulting in alterations to the full-length antibody-to-fragment ratio. The work strengthens the understanding of proteolytic cleavage of antibodies expressed in plants and presents a novel approach to stabilize full-length antibody by site-directed mutagenesis.-Hehle, V. K., Paul, M. J., Roberts, V. A., van Dolleweerd, C. J., Ma, J. K.-C. Site-targeted mutagenesis for stabilization of recombinant monoclonal antibody expressed in tobacco (Nicotiana tabacum) plants

Design of Polymeric Nanocapsules for Intranasal Vaccination against Mycobacterium Tuberculosis: Influence of the Polymeric Shell and Antigen Positioning.

Tuberculosis (TB) is the leading cause of death from a single infectious microorganism and Bacillus Calmette Guerin (BCG), the only authorized vaccine, does not confer protection against pulmonary TB. Based on the hypothesis that mucosal protection could help to prevent the infection at the site of entrance, the objective of this work was to develop an intranasal vaccine against Mycobacterium tuberculosis (Mtb), the microorganism that causes TB. Our approach consisted of the use of polymeric nanocapsules (NCs) with an oily core and a polymer shell made of chitosan (CS) or inulin/polyarginine (INU/pArg). The immunostimulant Imiquimod, a Toll-like receptor-7 (TLR-7) agonist, was encapsulated in the oily core and a fusion protein, formed by two antigens of Mtb, was absorbed either onto the NC surface (CS:Ag and INU:pArg:Ag) or between two polymer layers (INU:Ag:pArg) in order to assess the influence of the antigen positioning on the immune response. Although CS NCs were more immunostimulant than the INU/pArg NCs in vitro, the in vivo experiments showed that INU:pArg:Ag NCs were the only prototype inducing an adequate immunoglobulin A (IgA) response. Moreover, a previous immunization with BCG increased the immune response for CS NCs but, conversely, decreased for INU/pArg NCs. Further optimization of the antigen and the vaccination regime could provide an efficacious vaccine, using the INU:pArg:Ag NC prototype as nanocarrier

Biodegradation of the Alkaline Cellulose Degradation Products Generated during Radioactive Waste Disposal.

The anoxic, alkaline hydrolysis of cellulosic materials generates a range of cellulose degradation products (CDP) including α and β forms of isosaccharinic acid (ISA) and is expected to occur in radioactive waste disposal sites receiving intermediate level radioactive wastes. The generation of ISA's is of particular relevance to the disposal of these wastes since they are able to form complexes with radioelements such as Pu enhancing their migration. This study demonstrates that microbial communities present in near-surface anoxic sediments are able to degrade CDP including both forms of ISA via iron reduction, sulphate reduction and methanogenesis, without any prior exposure to these substrates. No significant difference (n = 6, p = 0.118) in α and β ISA degradation rates were seen under either iron reducing, sulphate reducing or methanogenic conditions, giving an overall mean degradation rate of 4.7×10−2 hr−1 (SE±2.9×10−3). These results suggest that a radioactive waste disposal site is likely to be colonised by organisms able to degrade CDP and associated ISA's during the construction and operational phase of the facility

Adaptive Prediction Error Coding in the Human Midbrain and Striatum Facilitates Behavioral Adaptation and Learning Efficiency.

Effective error-driven learning benefits from scaling of prediction errors to reward variability. Such behavioral adaptation may be facilitated by neurons coding prediction errors relative to the standard deviation (SD) of reward distributions. To investigate this hypothesis, we required participants to predict the magnitude of upcoming reward drawn from distributions with different SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. In line with the notion of adaptive coding, BOLD response slopes in the Substantia Nigra/Ventral Tegmental Area (SN/VTA) and ventral striatum were steeper for prediction errors occurring in distributions with smaller SDs. SN/VTA adaptation was not instantaneous but developed across trials. Adaptive prediction error coding was paralleled by behavioral adaptation, as reflected by SD-dependent changes in learning rate. Crucially, increased SN/VTA and ventral striatal adaptation was related to improved task performance. These results suggest that adaptive coding facilitates behavioral adaptation and supports efficient learning.This study was supported by the Wellcome Trust (W.S., P.C.F.), Bernard Wolfe Health Neuroscience Fund (P.C.F.) and the Niels Stensen Foundation (K.M.J.D.). We thank William Stauffer, Armin Lak and Joost Haarsma for useful discussions.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.neuron.2016.04.01

Sexually dimorphic role for vasopressin in the development of social play

Despite the well-established role of vasopressin (AVP) in adult social behavior, its role in social development is relatively unexplored. In this paper, we focus on the most prominent social behavior of juvenile rats, social play. Previous pharmacological experiments in our laboratory suggested that AVP regulates play in a sex- and brain region-specific manner in juvenile rats. Here we investigate the role of specific AVP systems in the emergence of social play. We first characterize the development of play in male and female Wistar rats and then ask whether the development of AVP mRNA expression correlates with the emergence of play. Unexpectedly, play emerged more rapidly in weanling-aged females than in males, resulting in a sex difference opposite of that typically reported for older, juvenile rats. AVP mRNA and play were correlated in males only, with a negative correlation in the bed nucleus of the stria terminalis and a positive correlation in the paraventricular nucleus of the hypothalamus. These findings support the hypothesis that AVP acts differentially on multiple systems in a sex-specific manner to regulate social play and suggest a role for PVN and BNST AVP systems in the development of play. Differential neuropeptide regulation of male and female social development may underlie well-documented sex differences in incidence, progression, and symptom severity of behavioral disorders during development