Effect of biodiesel on PAH, OPAH, and NPAH emissions from a direct injection diesel engine

Abstract

Polycyclic aromatic hydrocarbon (PAH), oxy- and nitro-derivate PAH (OPAH and NPAH) emissions from a direct injection diesel engine fueled with conventional fossil diesel (D), waste cooking oil biodiesel (B100), and their two blends (B20 and B50) were compared. The results show that B100 can reduce low molecular weight PAHs such as naphthalene, acenaphthylene, and fluorene as much as 90% compared with diesel. However, the emissions of high molecular weight PAHs including benzo[b]fluoranthene, benzo[k]fluoranthene, and benzo[a]pyrene decrease slightly when using B100. The emission levels for PAHs and OPAHs present comparable, while NPAH emission levels are five to ten times lower than those of PAHs and OPAHs. Compared with diesel, PAH and NPAH emissions significantly decrease. On the contrary, an increase trend of OPAH emission has been observed with adding biodiesel. For the specific parent PAHs and its oxygenated and nitrated derivatives, the fractions of parent PAHs gradually decrease with increasing biodiesel content in the blends, while the corresponding oxygenated and nitrated derivative fractions observably increase, especially for the high molecular weight compounds. Considering the increase of OPAH and NPAH fractions in total particle-phase PAHs when using biodiesel, in-depth biodiesel cytotoxicity assessment should be conducted.

The content of the potentially toxic elements, iron and manganese, in the grapevine cv Tamjanika growing near the biggest copper mining/metallurgical complex on the Balkan peninsula: phytoremediation, biomonitoring, and some toxicological aspects

Abstract

Plants growing in areas polluted by heavy metals represent excellent models for the investigations related to their potentials for hazardous metals accumulation which further may help in the estimation of plant practical biomonitoring and phytoremediation potentials. In this study, the potentials of the grapevine cultivar Tamjanika from a highly polluted region in Eastern Serbia, with intensive copper mining and metallurgical activities, were estimated in regard to the potentially toxic elements such as iron and manganese; the potential danger from these metals through fruit consummation is also considered. Used methods were the following: ICP-OES analysis, calculation of biological coefficients, the Pearson correlation study, one-way ANOVA, and hierarchical cluster analysis. The results revealed that a great majority of the recorded concentrations in different plant organs were in the range of normal concentrations, as well as that the calculated accumulation rates for both metals were very low. The data also pointed to generally minimal to moderate enrichment by these metals which represents totally dissimilar situation in comparison with other heavy metals detected in the very same plant samples. The results of this study suggested that the investigated plants of the grapevine cv Tamjanika assimilated iron and manganese predominately according to their individual needs, and confirmed that the utilization of this plant species can be very effective in different biomonitoring procedures and also in the phytoremediation procedure known as phytostabilization. At the same time, it was obvious that even in aggressive circumstances its fruit was protected from some serious contamination and kept pretty safe for consummation.

Effects of Vitamin D levels and supplementation on atopic dermatitis: A systematic review

Pediatric Dermatology, EarlyView.

Correction to: Adsorption and removal of chromium (VI) contained in aqueous solutions using a chitosan-based hydrogel

The original publication of this paper contains an error. The correct 4th heading in Table 1 should be "Non-linear sips isotherm". The original article has been corrected.

The use of rituximab in treatment of epidermolysis bullosa acquisita: Three new cases and a review of the literature

Dermatologic Therapy, EarlyView.

Anterior, frontal congenital triangular alopecia, redundancy in therapy without improvement

Dermatologic Therapy, EarlyView.

Reviewers’ list December 2018

Overexpression of Desmoglein 2 in a mouse model of Gorlin syndrome enhances spontaneous basal cell carcinoma formation through STAT3-mediated Gli1 expression

Activation of the Hedgehog (Hh) pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCC), with loss of function of Patched1 (Ptc1) being the most common genomic lesion. Sporadic BCCs also overexpress desmoglein-2 (Dsg2), a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively.

Frontiers in pigment cell and melanoma research

Pigment Cell &Melanoma Research, EarlyView.

Imatinib inhibits CSF1R that stimulates proliferation of rheumatoid arthritis fibroblast‐like synoviocytes

Clinical &Experimental Immunology, Volume 0, Issue ja, -Not available-.

Patterns of Superficial Midfacial Fat Volume Distribution Differ by Age and Body Mass Index

Abstract

Background

The changes that occur to midfacial fat with increasing age and BMI are poorly understood. The aim of this study was to determine how superficial cheek fat volume and distribution are differentially predicted by changes in BMI versus age.

Methods

We conducted a retrospective observational study of patients with facial computed tomography scans. Superficial cheek fat volumes were measured, and multiple linear regression analysis was performed to model the relationships between cheek fat and corresponding sex, age, and BMI data.

Results

A total of 109 patients were included in our analysis (51 male, 58 female). The subjects' ages ranged from 21.7 to 91.1 years with a mean (SD) age of 59.7 (15.0) years. The mean (SD) superficial cheek volume of the subjects was 10.46 (2.57) cc. Female subjects had a significantly greater mean total superficial cheek fat volume compared to male subjects (11.18 cc vs. 9.64 cc; P < 0.001). The results of multiple linear regression analysis indicated that together, age, sex, and BMI explained 50.8% of the variance in cheek fat volumes (R² = 0.51, P < 0.001). BMI significantly predicted total cheek fat volume (β = 0.239, P < 0.001), in addition to age (β = 0.029, P < 0.017) and sex (β = − 1.183, P = 0.001; female = 0, male = 1). Age predicted the greatest gain of fat in the caudal subdivision of cheek (β = 0.015, P < 0.001), whereas BMI predicted the greatest gain in the cephalad subdivision (β = 0.106, P < 0.001).

Conclusions

Age, sex, and BMI are important predictors of midfacial fat volume. This study shows that increases in age and BMI differentially predict the distribution of superficial cheek fat.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

FDA Clears Omadacycline (Nuzyra) for Two Infections

Omadacycline is a modernized tetracycline with broad-spectrum activity that is designed to overcome tetracycline resistance.
FDA Approvals

Eye-Movement Intervention Enhances Extinction via Amygdala Deactivation

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n = 24), we found that goal-directed eye movements activate a dorsal frontoparietal network and transiently deactivate the amygdala (_p² = 0.17). Connectivity analyses revealed that this downregulation potentially engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, it reduced spontaneous fear recovery 24 h later (_p² = 0.21). Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement (r = 0.39). In conclusion, we show that extinction learning can be improved with a noninvasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working-memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits (e.g., amygdala deactivation) similar to those that support cognitive control of emotion.

SIGNIFICANCE STATEMENT Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via noninvasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working-memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation potentially engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppressing amygdala activity can alter retention of emotional memories.

Having More Choices Changes How Human Observers Weight Stable Sensory Evidence

Decision-making becomes slower when more choices are available. Existing models attribute this slowing to poor sensory processing, to attenuated rates of sensory evidence accumulation, or to increases in the amount of evidence required before committing to a decision (a higher decision threshold). However, studies have not isolated the effects of having more choices on sensory and decision-related processes from changes in task difficulty and divided attention. Here, we controlled task difficulty while independently manipulating the distribution of attention and the number of choices available to male and female human observers. We used EEG to measure steady-state visually evoked potentials (SSVEPs) and a frontal late positive deflection (LPD), EEG markers of sensory and postsensory decision-related processes, respectively. We found that dividing attention decreased SSVEP and LPD amplitudes, consistent with dampened sensory responses and slower rates of evidence accumulation, respectively. In contrast, having more choices did not alter SSVEP amplitude and led to a larger LPD. These results suggest that having more options largely spares early sensory processing and slows down decision-making via a selective increase in decision thresholds.

SIGNIFICANCE STATEMENT When more choices are available, decision-making becomes slower. We tested whether this phenomenon is due to poor sensory processing, to reduced rates of evidence accumulation, or to increases in the amount of evidence required before committing to a decision (a higher decision threshold). We measured choice modulations of sensory and decision-related neural responses using EEG. We also minimized potential confounds from changes in the distribution of attention and task difficulty, which often covary with having more choices. Dividing attention reduced the activity levels of both sensory and decision-related responses. However, having more choices did not change sensory processing and led to larger decision-related responses. These results suggest that having more choices spares sensory processing and selectively increases decision thresholds.

Cholecystokinin Switches the Plasticity of GABA Synapses in the Dorsomedial Hypothalamus via Astrocytic ATP Release

Whether synapses in appetite-regulatory brain regions undergo long-term changes in strength in response to satiety peptides is poorly understood. Here we show that following bursts of afferent activity, the neuromodulator and satiety peptide cholecystokinin (CCK) shifts the plasticity of GABA synapses in the dorsomedial nucleus of the hypothalamus of male Sprague Dawley rats from long-term depression to long-term potentiation (LTP). This LTP requires the activation of both type 2 CCK receptors and group 5 metabotropic glutamate receptors, resulting in a rise in astrocytic intracellular calcium and subsequent ATP release. ATP then acts on presynaptic P2X receptors to trigger a prolonged increase in GABA release. Our observations demonstrate a novel form of CCK-mediated plasticity that requires astrocytic ATP release, and could serve as a mechanism for appetite regulation.

SIGNIFICANCE STATEMENT Satiety peptides, like cholecystokinin, play an important role in the central regulation of appetite, but their effect on synaptic plasticity is not well understood. The current data provide novel evidence that cholecystokinin shifts the plasticity from long-term depression to long-term potentiation at GABA synapses in the rat dorsomedial nucleus of the hypothalamus. We also demonstrate that this plasticity requires the concerted action of cholecystokinin and glutamate on astrocytes, triggering the release of the gliotransmitter ATP, which subsequently increases GABA release from neighboring inhibitory terminals. This research reveals a novel neuropeptide-induced switch in the direction of synaptic plasticity that requires astrocytes, and could represent a new mechanism by which cholecystokinin regulates appetite.

A Critical Role for Sorting Nexin 1 in the Trafficking of Metabotropic Glutamate Receptors

Group I metabotropic glutamate receptors (mGluRs) function as modulators of neuronal physiology and they have also been implicated in various neuropsychiatric disorders. Trafficking of mGluRs plays important roles in controlling the precise localization of these receptors at specific region of the cell, as well as it regulates the activity of these receptors. Despite this obvious significance, we know very little about the cellular machineries that control the trafficking of these receptors in the CNS. Sorting nexin 1 (SNX1) has been shown to regulate the endosomal sorting of few cell surface receptors either to lysosomes where they are downregulated or back to the cell surface. Using "molecular replacement" approach in hippocampal neurons derived from mice of both sexes, we show here that SNX1 plays critical role in the trafficking of mGluR1, a member of the group I mGluR family. Overexpression of dominant-negative SNX1 or knockdown of endogenous SNX1 resulted in the rapid recycling of the receptor. Importantly, recycling via the rapid recycling route, did not allow the resensitization of the receptors. Our data suggest that both, N-terminal and C-terminal region of SNX1 play critical role in the normal trafficking of the receptor. In addition, we also show here that SNX1 regulates the trafficking of mGluR1 through the interaction with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), a protein that has been implicated in both signaling and vesicular trafficking. Thus, these studies reveal a mechanistic role of SNX1 in the trafficking of group I mGluRs and its physiological implications.

SIGNIFICANCE STATEMENT Group I mGluRs are activated by the neurotransmitter glutamate in the CNS, and play various important roles in the brain. Similar to many other receptors, trafficking plays crucial roles in controlling the precise localization as well as activity of these receptors. Despite this obvious significance very little is known about the cellular machineries that control the trafficking of these receptors. We demonstrate here, that SNX1 plays a critical role in the trafficking of mGluR1, a member of the group I mGluR family. SNX1-mediated trafficking is critical for the resensitization of the receptor. SNX1 controls the trafficking of the receptor through the interaction with another protein, Hrs. The results suggest a role for SNX1 in the regulation of group I mGluRs.

General Transformations of Object Representations in Human Visual Cortex

The brain actively represents incoming information, but these representations are only useful to the extent that they flexibly reflect changes in the environment. How does the brain transform representations across changes, such as in size or viewing angle? We conducted a fMRI experiment and a magnetoencephalography experiment in humans (both sexes) in which participants viewed objects before and after affine viewpoint changes (rotation, translation, enlargement). We used a novel approach, representational transformation analysis, to derive transformation functions that linked the distributed patterns of brain activity evoked by an object before and after an affine change. Crucially, transformations derived from one object could predict a postchange representation for novel objects. These results provide evidence of general operations in the brain that are distinct from neural representations evoked by particular objects and scenes.

SIGNIFICANCE STATEMENT The dominant focus in cognitive neuroscience has been on how the brain represents information, but these representations are only useful to the extent that they flexibly reflect changes in the environment. How does the brain transform representations, such as linking two states of an object, for example, before and after an object undergoes a physical change? We used a novel method to derive transformations between the brain activity evoked by an object before and after an affine viewpoint change. We show that transformations derived from one object undergoing a change generalized to a novel object undergoing the same change. This result shows that there are general perceptual operations that transform object representations from one state to another.

The Lifespan Trajectory of the Encoding-Retrieval Flip: A Multimodal Examination of Medial Parietal Cortex Contributions to Episodic Memory

The formation of episodic memories is associated with deactivation during encoding and activation during retrieval in the posteromedial cortex (PMC). We hypothesized that the encoding/retrieval (E/R) flip is a critical component of episodic memory across the lifespan because structural and metabolic changes in the PMC coincide with the fine tuning of the episodic memory system in development and the reductions of memory performance in aging. The aims of the present study were, first, to describe lifespan trajectories of PMC encoding and retrieval activity in 270 human participants (167 females) from 6 to 80 years of age. Our second goal was to construct a model for episodic memory development in which contributions from brain activity, cortical thickness (CT), and structural connectivity are accounted for. We found that modulation of neural activity in response to memory encoding and retrieval demands was not fully developed until adolescence and decreased from adulthood through old age. The magnitude of the E/R flip was related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence could be accounted for by the E/R flip, CT, and mean diffusivity together. However, only CT and the E/R flip provided unique contributions with which to explain memory performance. The results suggest that neural dynamics in the PMC is related to the development of episodic memory during childhood and adolescence. The similar trajectories of the E/R flip and episodic memory emergence and decline through development and aging further suggests that a lifelong relationship exists.

SIGNIFICANCE STATEMENT Modulation of neural activity in the posteromedial cortex (PMC) in response to memory encoding/retrieval (E/R) demands (E/R flip) does not reach its peak until adolescence and decreases from adulthood through old age. The magnitude of the E/R flip is related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence can be accounted for by the E/R flip and brain structure together. The results suggest that neural dynamics in the PMC is related to the development of episodic memory function during childhood and adolescence and the similar trajectories of the E/R flip and episodic memory performance through development and aging suggests that a lifelong relationship exists.

Retrospective Cues Mitigate Information Loss in Human Cortex during Working Memory Storage

Working memory (WM) enables the flexible representation of information over short intervals. It is well established that WM performance can be enhanced by a retrospective cue presented during storage, yet the neural mechanisms responsible for this benefit are unclear. Here, we tested several explanations for retrospective cue benefits by quantifying changes in spatial WM representations reconstructed from alpha-band (8–12 Hz) EEG activity recorded from human participants (both sexes) before and after the presentation of a retrospective cue. This allowed us to track cue-related changes in WM representations with high temporal resolution (tens of milliseconds). Participants encoded the locations of two colored discs for subsequent report. During neutral trials, an uninformative cue instructed participants to remember the locations of both discs across a blank delay, and we observed a monotonic decrease in the fidelity of reconstructed spatial WM representations with time. During valid trials, a 100% reliable cue indicated that the color of the disc participants would be probed to report. Critically, valid cues were presented immediately after the termination of the encoding display ["valid early" (VE) trials] or midway through the delay period ["valid late" (VL) trials]. During VE trials, the gradual loss of location-specific information observed during neutral trials was eliminated, while during VL trials it was partially reversed. Our findings suggest that retrospective cues engage several different mechanisms that together serve to mitigate information loss during WM storage.

SIGNIFICANCE STATEMENT Working memory (WM) performance can be improved by a cue presented during storage. This effect, termed a retrospective cue benefit, has been used to explore the limitations of attentional prioritization in WM. However, the mechanisms responsible for retrospective cue benefits are unclear. Here we tested several explanations for retrospective cue benefits by examining how they influence WM representations reconstructed from human EEG activity. This approach allowed us to visualize, quantify, and track the effects of retrospective cues with high temporal resolution (on the order of tens of milliseconds). We show that under different circumstances retrospective cues can both eliminate and even partially reverse information loss during WM storage, suggesting that retrospective cue benefits have manifold origins.

This Week in The Journal

Distinct Co-Modulation Rules of Synapses and Voltage-Gated Currents Coordinate Interactions of Multiple Neuromodulators

Multiple neuromodulators act in concert to shape the properties of neural circuits. Different neuromodulators usually activate distinct receptors but can have overlapping targets. Therefore, circuit output depends on neuromodulator interactions at shared targets, a poorly understood process. We explored quantitative rules of co-modulation of two principal targets of neuromodulation: synapses and voltage-gated ionic currents. In the stomatogastric ganglion of the male crab Cancer borealis, the neuropeptides proctolin (Proc) and the crustacean cardioactive peptide (CCAP) modulate synapses of the pyloric circuit and activate a voltage-gated current (I_MI) in multiple neurons. We examined the validity of a simple dose-dependent quantitative rule, that co-modulation by Proc and CCAP is predicted by the linear sum of the individual effects of each modulator up to saturation. We found that this rule is valid for co-modulation of synapses, but not for the activation of I_MI, in which co-modulation was sublinear. The predictions for the co-modulation of I_MI activation were greatly improved if we assumed that the intracellular pathways activated by two peptide receptors inhibit one another. These findings suggest that the pathways activated by two neuromodulators could have distinct interactions, leading to distinct co-modulation rules for different targets even in the same neuron. Given the evolutionary conservation of neuromodulator receptors and signaling pathways, such distinct rules for co-modulation of different targets are likely to be common across neuronal circuits.

SIGNIFICANCE STATEMENT We examine the quantitative rules of co-modulation at multiple shared targets, the first such characterization to our knowledge. Our results show that dose-dependent co-modulation of distinct targets in the same cells by the same two neuromodulators follows different rules: co-modulation of synaptic currents is linearly additive up to saturation, whereas co-modulation of the voltage-gated ionic current targeted in a single neuron is nonlinear, a mechanism that is likely generalizable. Given that all neural systems are multiply modulated and neuromodulators often act on shared targets, these findings and the methodology could guide studies to examine dynamic actions of neuromodulators at the biophysical and systems level in sensory and motor functions, sleep/wake regulation, and cognition.

Rhythm and Synchrony in a Cortical Network Model

We studied mechanisms for cortical gamma-band activity in the cerebral cortex and identified neurobiological factors that affect such activity. This was done by analyzing the behavior of a previously developed, data-driven, large-scale network model that simulated many visual functions of monkey V1 cortex (Chariker et al., 2016). Gamma activity was an emergent property of the model. The model's gamma activity, like that of the real cortex, was (1) episodic, (2) variable in frequency and phase, and (3) graded in power with stimulus variables like orientation. The spike firing of the model's neuronal population was only partially synchronous during multiple firing events (MFEs) that occurred at gamma rates. Detailed analysis of the model's MFEs showed that gamma-band activity was multidimensional in its sources. Most spikes were evoked by excitatory inputs. A large fraction of these inputs came from recurrent excitation within the local circuit, but feedforward and feedback excitation also contributed, either through direct pulsing or by raising the overall baseline. Inhibition was responsible for ending MFEs, but disinhibition led directly to only a small minority of the synchronized spikes. As a potential explanation for the wide range of gamma characteristics observed in different parts of cortex, we found that the relative rise times of AMPA and GABA synaptic conductances have a strong effect on the degree of synchrony in gamma.

SIGNIFICANCE STATEMENT Canonical computations used throughout the cerebral cortex are performed in primary visual cortex (V1). Providing theoretical mechanisms for these computations will advance understanding of computation throughout cortex. We studied one dynamical feature, gamma-band rhythms, in a large-scale, data-driven, computational model of monkey V1. Our most significant conclusion is that the sources of gamma band activity are multidimensional. A second major finding is that the relative rise times of excitatory and inhibitory synaptic potentials have strong effects on spike synchrony and peak gamma band power. Insight gained from studying our V1 model can shed light on the functions of other cortical regions.

Across Species "Natural Ablation" Reveals the Brainstem Source of a Noninvasive Biomarker of Binaural Hearing

The binaural interaction component (BIC) of the auditory brainstem response is a noninvasive electroencephalographic signature of neural processing of binaural sounds. Despite its potential as a clinical biomarker, the neural structures and mechanism that generate the BIC are not known. We explore here the hypothesis that the BIC emerges from excitatory–inhibitory interactions in auditory brainstem neurons. We measured the BIC in response to click stimuli while varying interaural time differences (ITDs) in subjects of either sex from five animal species. Species had head sizes spanning a 3.5-fold range and correspondingly large variations in the sizes of the auditory brainstem nuclei known to process binaural sounds [the medial superior olive (MSO) and the lateral superior olive (LSO)]. The BIC was reliably elicited in all species, including those that have small or inexistent MSOs. In addition, the range of ITDs where BIC was elicited was independent of animal species, suggesting that the BIC is not a reflection of the processing of ITDs per se. Finally, we provide a model of the amplitude and latency of the BIC peak, which is based on excitatory–inhibitory synaptic interactions, without assuming any specific arrangement of delay lines. Our results show that the BIC is preserved across species ranging from mice to humans. We argue that this is the result of generic excitatory–inhibitory synaptic interactions at the level of the LSO, and thus best seen as reflecting the integration of binaural inputs as opposed to their spatial properties.

SIGNIFICANCE STATEMENT Noninvasive electrophysiological measures of sensory system activity are critical for the objective clinical diagnosis of human sensory processing deficits. The binaural component of sound-evoked auditory brainstem responses is one such measure of binaural auditory coding fidelity in the early stages of the auditory system. Yet, the precise neurons that lead to this evoked potential are not fully understood. This paper provides a comparative study of this potential in different mammals and shows that it is preserved across species, from mice to men, despite large variations in morphology and neuroanatomy. Our results confirm its relevance to the assessment of binaural hearing integrity in humans and demonstrates how it can be used to bridge the gap between rodent models and humans.

Postnatal Restriction of Activity-Induced Ca2+ Responses to Schwann Cells at the Neuromuscular Junction Are Caused by the Proximo-Distal Loss of Axonal Synaptic Vesicles during Development

Terminal or perisynaptic Schwann cells (TPSCs) are nonmyelinating, perisynaptic glial cells at the neuromuscular junction (NMJ) that respond to neural activity by increasing intracellular calcium (Ca²⁺) and regulate synaptic function. The onset of activity-induced TPSC Ca²⁺ responses, as well as whether axonal Schwann cells (ASCs) along the nerve respond to nerve stimulation during development, is unknown. Here, we show that phrenic nerve stimulation in developing male and female mice elicited Ca²⁺ responses in both ASCs and TPSCs at embryonic day 14. ASC responses were lost in a proximo-distal gradient over time, but could continue to be elicited by bath application of neurotransmitter, suggesting that a loss of release rather than a change in ASC competence accounted for this response gradient. Similar to those of early postnatal TPSCs, developing ASC/TPSC responses were mediated by purinergic P2Y₁ receptors. The loss of ASC Ca²⁺ responses was correlated to the proximo-distal disappearance of synaptophysin immunoreactivity and synaptic vesicles in phrenic axons. Accordingly, developing ASC Ca²⁺ responses were blocked by botulinum toxin. Interestingly, the loss of ASC Ca²⁺ responses was also correlated to the proximo-distal development of myelination. Finally, compared with postnatal TPSCs, neonatal TPSCs and ASCs displayed Ca²⁺ signals in response to lower frequencies and shorter durations of nerve stimulation. Together, these results with GCaMP3-expressing Schwann cells provide ex vivo evidence that both axons and presynaptic terminals initially exhibit activity-induced vesicular release of neurotransmitter, but that the subsequent loss of axonal synaptic vesicles accounts for the postnatal restriction of vesicular release to the NMJ.

SIGNIFICANCE STATEMENT Neural activity regulates multiple aspects of development, including myelination. Whether the excitation of developing neurons in vivo results in the release of neurotransmitter from both axons and presynaptic terminals is unclear. Here, using mice expressing the genetically encoded calcium indicator GCaMP3 in Schwann cells, we show that both terminal/perisynaptic Schwann cells at the diaphragm neuromuscular junction and axonal Schwann cells along the phrenic nerve exhibit activity-induced calcium responses early in development, mediated by the vesicular release of ATP from the axons of motor neurons acting on P2Y₁ receptors. These ex vivo findings corroborate classic in vitro studies demonstrating transmitter release by developing axons, and thus represent a tool to study the mechanisms and significance of this process during embryonic development.

Active Sound Localization Sharpens Spatial Tuning in Human Primary Auditory Cortex

Spatial hearing sensitivity in humans is dynamic and task-dependent, but the mechanisms in human auditory cortex that enable dynamic sound location encoding remain unclear. Using functional magnetic resonance imaging (fMRI), we assessed how active behavior affects encoding of sound location (azimuth) in primary auditory cortical areas and planum temporale (PT). According to the hierarchical model of auditory processing and cortical functional specialization, PT is implicated in sound location ("where") processing. Yet, our results show that spatial tuning profiles in primary auditory cortical areas (left primary core and right caudo-medial belt) sharpened during a sound localization ("where") task compared with a sound identification ("what") task. In contrast, spatial tuning in PT was sharp but did not vary with task performance. We further applied a population pattern decoder to the measured fMRI activity patterns, which confirmed the task-dependent effects in the left core: sound location estimates from fMRI patterns measured during active sound localization were most accurate. In PT, decoding accuracy was not modulated by task performance. These results indicate that changes of population activity in human primary auditory areas reflect dynamic and task-dependent processing of sound location. As such, our findings suggest that the hierarchical model of auditory processing may need to be revised to include an interaction between primary and functionally specialized areas depending on behavioral requirements.

SIGNIFICANCE STATEMENT According to a purely hierarchical view, cortical auditory processing consists of a series of analysis stages from sensory (acoustic) processing in primary auditory cortex to specialized processing in higher-order areas. Posterior-dorsal cortical auditory areas, planum temporale (PT) in humans, are considered to be functionally specialized for spatial processing. However, this model is based mostly on passive listening studies. Our results provide compelling evidence that active behavior (sound localization) sharpens spatial selectivity in primary auditory cortex, whereas spatial tuning in functionally specialized areas (PT) is narrow but task-invariant. These findings suggest that the hierarchical view of cortical functional specialization needs to be extended: our data indicate that active behavior involves feedback projections from higher-order regions to primary auditory cortex.

Not All Predictions Are Equal: "What" and "When" Predictions Modulate Activity in Auditory Cortex through Different Mechanisms

Using predictions based on environmental regularities is fundamental for adaptive behavior. While it is widely accepted that predictions across different stimulus attributes (e.g., time and content) facilitate sensory processing, it is unknown whether predictions across these attributes rely on the same neural mechanism. Here, to elucidate the neural mechanisms of predictions, we combine invasive electrophysiological recordings (human electrocorticography in 4 females and 2 males) with computational modeling while manipulating predictions about content ("what") and time ("when"). We found that "when" predictions increased evoked activity over motor and prefrontal regions both at early (~180 ms) and late (430–450 ms) latencies. "What" predictability, however, increased evoked activity only over prefrontal areas late in time (420–460 ms). Beyond these dissociable influences, we found that "what" and "when" predictability interactively modulated the amplitude of early (165 ms) evoked responses in the superior temporal gyrus. We modeled the observed neural responses using biophysically realistic neural mass models, to better understand whether "what" and "when" predictions tap into similar or different neurophysiological mechanisms. Our modeling results suggest that "what" and "when" predictability rely on complementary neural processes: "what" predictions increased short-term plasticity in auditory areas, whereas "when" predictability increased synaptic gain in motor areas. Thus, content and temporal predictions engage complementary neural mechanisms in different regions, suggesting domain-specific prediction signaling along the cortical hierarchy. Encoding predictions through different mechanisms may endow the brain with the flexibility to efficiently signal different sources of predictions, weight them by their reliability, and allow for their encoding without mutual interference.

SIGNIFICANCE STATEMENT Predictions of different stimulus features facilitate sensory processing. However, it is unclear whether predictions of different attributes rely on similar or different neural mechanisms. By combining invasive electrophysiological recordings of cortical activity with experimental manipulations of participants' predictions about content and time of acoustic events, we found that the two types of predictions had dissociable influences on cortical activity, both in terms of the regions involved and the timing of the observed effects. Further, our biophysical modeling analysis suggests that predictability of content and time rely on complementary neural processes: short-term plasticity in auditory areas and synaptic gain in motor areas, respectively. This suggests that predictions of different features are encoded with complementary neural mechanisms in different brain regions.

Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders

Sensory processing, and auditory processing in particular, is altered in individuals with neurodevelopmental disorders such as autism spectrum disorders (ASDs). The typical maturation of the auditory system is perturbed in these individuals during early development, which may underlie altered auditory reactivity that persists in later life. Of the many genes that regulate the auditory system development, loss-of-function mutations in the CNTNAP2 gene are strongly associated with language processing deficits and ASD. Therefore, using a novel Cntnap2 knock-out rat model, we tested the impact of Cntnap2 loss on auditory processing, filtering, and reactivity throughout development and young adulthood in male and female animals. Although hearing thresholds were not altered in Cntnap2 knock-out animals, we found a reduction in response amplitudes and a delay in response latency of the auditory brainstem response (ABR) in juvenile Cntnap2 knock-out rats compared with age-matched controls. Amplitudes and latency of the ABR largely normalized by adulthood, indicating a delayed maturation of auditory processing pathways in Cntnap2 knock-out rats. Despite the reduced ABR amplitudes, adolescent Cntnap2 knock-out animals displayed increased startle reactivity accompanied by disruptions in sensory filtering and sensorimotor gating across various conditions, most of which persisted in adulthood. All of these observations show striking parallels to disruptions reported in ASD. Our results also imply that developmental disruptions of sensory signal processing are associated with persistent changes in neural circuitries responsible for implicit auditory evoked behavior, emphasizing the need for interventions that target sensory processing disruptions early during development in ASD.

SIGNIFICANCE STATEMENT This is the first study of brainstem auditory processing in a novel knock-out rat model with very high construct and face validity for autism spectrum disorders. Electrophysiological and behavioral measures of implicit auditory-evoked responses were systematically taken across developmental stages. Auditory processing, filtering, and reactivity disruptions show striking similarities to observations in autism. We also show for the first time that, whereas auditory brainstem responses normalize by adulthood, disruptions in brainstem-mediated auditory-evoked behavior persist. This indicates that early developmental perturbations in sensory processing can cause permanent maladaptive changes in circuitries responsible for auditory reactivity, underlining the importance for interventions early during development aiming at normalizing sensory processing.

Suppressing Interferon-{gamma} Stimulates Microglial Responses and Repair of Microbleeds in the Diabetic Brain

Microcirculatory damage is a common complication for those with vascular risk factors, such as diabetes. To resolve vascular insults, the brain's immune cells (microglia) must rapidly envelop the site of injury. Currently, it is unknown whether Type 1 diabetes, a condition associated with chronic immune system dysfunction, alters microglial responses to damage and what mechanisms are responsible. Using in vivo two-photon microscopy in adult male mice, we show that microglial envelopment of laser-induced cerebral microbleeds is diminished in a hyperglycemic mouse model of Type 1 diabetes, which could not be fully rescued with chronic insulin treatment. Microglia were important for vessel repair because reduced microglial accumulation in diabetic mice or near-complete depletion in healthy controls was associated with greater secondary leakage of the damaged vessel. Broadly suppressing inflammation with dexamethasone in diabetic mice but not healthy controls, significantly enhanced microglial responses to microbleeds and attenuated secondary vessel leakage. These enhancements were associated with changes in IFN- signaling because dexamethasone suppressed abnormally high levels of IFN- protein levels in brain and blood serum of diabetic mice. Further, blocking IFN- in diabetic mice with neutralizing antibodies restored normal microglial chemotaxic responses and purinoceptor P2ry12 gene expression, as well as mitigated secondary leakage. These results suggest that abnormal IFN- signaling disrupts microglial function in the diabetic brain, and that immunotherapies targeting IFN- can stimulate microglial repair of damaged vessels.

SIGNIFICANCE STATEMENT Although Type 1 diabetes is an established risk factor for vascular complications, such as microbleeds, and is known to hinder wound healing in the body, no study has examined how diabetes impacts the brain's innate immune reparative response (involving cells called microglia) to vascular injury. Here we show that microglial responses to brain microbleeds were diminished in diabetic animals, which also exacerbated secondary leakage from damaged vessels. These impairments were related to abnormally high levels of the proinflammatory cytokine IFN- because reducing IFN- with immunosuppressant drugs or blocking antibodies helped restore normal microglial responses and repair of damaged vessels. These data highlight the use of IFN- modulating therapeutics to enhance vascular repair in at-risk populations.

Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis

This network meta-analyses of 19 randomized clinical trials conducted in the United States and Europe examines antibiotic agents and treatment modalities to assess treatment effectiveness and drug-related adverse outcomes in early cutaneous Lyme borreliosis.

Exercise for Leg Ulcers

In this issue of JAMA Dermatology, Jull et al use meta-analysis to suggest an additional healing benefit of exercise in patients with venous leg ulcers (VLUs). Combining and analyzing data from 5 relatively small studies (the largest with 63 participants), the authors found that 61% of participants (57 of 94) who exercised and received compression healed at 12 weeks compared with 46% (44 of 96) of participants who received compression alone. Although the type of exercise administered varied among the trials, the results were driven by 2 studies that used progressive resistance exercises involving calf muscle strengthening coupled with physical activity (walking). In addition to providing rationale for an adjunctive therapeutic modality for patients with VLUs, this article also highlights the power of properly performed meta-analysis to provide clarity where previously none existed.

Alopecia Universalis and Chronic Graft-vs-Host Disease Treated With Ruxolitinib

This case report describes alopecia universalis and chronic graft-vs-host disease occurring after allogenic hematopoietic stem-cell transplantation and treated with ruxolitinib.

Introducing “Images in Dermatology”

It is often said that dermatology is a "visual specialty." While it is more than that, there is no escaping the central importance of the clinical examination to dermatologic diagnosis. The appearance, the morphology, the shape and distribution of lesions—these features are the illustration of illness, the manifestation of cutaneous or even systemic disease. The critical role of the physical examination, imparting the ability to make a diagnosis visually, is part of the art of dermatology and is shared by few other medical specialties.

Enhanced photocatalytic activity of BiVO 4 powders synthesized in presence of EDTA for the decolorization of rhodamine B from aqueous solution

Abstract

Bismuth vanadate (BiVO₄) powders were successfully synthesized in presence of EDTA via microwave irradiation and used as photocatalysts in the oxidation reaction of rhodamine B (rhB) under visible light. Different concentrations of EDTA (0.5 to 10%) to chelate Bi³⁺ ions were employed on the BiVO₄ synthesis. Under the presence of EDTA, a monoclinic crystalline structure was obtained, whereas a mixture of monoclinic and tetragonal phases was observed in the absence of EDTA. In addition, the use of different EDTA concentrations promoted the formation the different shapes of particles. The BiVO₄ sample synthesized with low concentration of EDTA (0.5%) exhibited about 85% of rhB decolorization in 300 min at pH 7.5. Therefore, this high efficiency can be attributed to a combination of intrinsic properties such as the morphology type and monoclinic structure of BiVO₄ particles.

Effective industrial regeneration of arsenic poisoning waste selective catalytic reduction catalyst: contaminants removal and activity recovery

Abstract

In this work, an environmental friendly industrial regeneration approach has been proposed to remove the surface poisoning and recover the catalytic activity of waste V₂O₅-WO₃/TiO₂ catalyst. Alkaline treatment and acid wash are combined for the waste catalyst regeneration process, which is applied for the arsenic and alkali metal removal, respectively. The crystal structure was well maintained as anatase phase and the surface area was increased during the regeneration, which is favorable for the following active component addition step and regenerated process. The XPS results illustrated that the surface contaminants (arsenic and sodium) were removed and V(IV) was loaded on the regenerated catalyst. Based on the deNO_x evaluations, the catalytic activity of the regenerated sample is increased to the level of commercial fresh catalyst. The present industrial regeneration process provides a promising method for the comprehensive recovery of waste catalyst and further understanding in the field of secondary resource recycle.

Antimicrobial and antifouling properties of versatile PPSU/carboxylated GO nanocomposite membrane against Gram-positive and Gram-negative bacteria and protein

Abstract

Biofouling is a serious issue in membrane-based water and wastewater treatment as it critically compromises the efficacy of the water treatment processes. This investigation demonstrates the antimicrobial and antifouling properties of a nanocomposite membrane system composed of carboxyl-functionalized graphene oxide (COOH-GO) and polyphenylsulfone (PPSU). The PPSU/COOH-GO nanocomposite membrane exhibited excellent antimicrobial properties, achieving maximum bacteriostasis rates of 74.2% and 81.1% against the representative Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa, respectively) and 41.9% against the representative Gram-positive bacterium (Staphylococcus aureus). The PPSU/COOH-GO nanocomposite membrane inhibited the attachment, colonization, and the biofilm formation of three species. Antifouling was assessed through filtration experiments using a model foulant bovine serum albumin (BSA). The fouling mechanisms were investigated by Hermia's models (complete blocking, intermediate blocking, standard blocking, and cake formation), and the analysis involved fitting the volumetric flux decline experimental data to models. The fouling study revealed a less irreversible fouling and increased flux recovery ratio for the PPSU/COOH-GO nanocomposite membrane. Complete blocking of pores and cake formation were the major fouling mechanisms for the membrane.

N-acetylmannosamine (ManNAc) supports the growth of Borrelia burgdorferi in the absence of N-acetylglucosamine (GlcNAc)

Abstract

Borrelia burgdorferi, the causative agent of Lyme disease, lacks the ability to biosynthesize many essential nutrients de novo, including N-acetylglucosamine (GlcNAc). This amino sugar is required for cell wall synthesis, and is a component of the complex growth medium used for in vitro propagation. When cultured without free GlcNAc B. burgdorferi cells exhibit a unique biphasic growth pattern. We hypothesized that genes involved in the GlcNAc starvation response would be differentially expressed when compared to cells cultured in complete medium, and investigated this using transcriptomics. Twenty-one genes were differentially regulated in wild-type and starvation-adapted cells cultured without GlcNAc compared to wild-type cells cultured with GlcNAc. Of those, three genes involved in carbohydrate utilization were upregulated: bbb04 (chbC) encoding a subunit of the chitobiose transporter, bb0629 (fruA-2) encoding a putative carbohydrate transporter, and bb0644 (nanE) encoding a putative GlcNAc-6-phosphate-2-epimerase predicted to catalyze the conversion of N-acetylmannosamine-6-phosphate (ManNAc-6-P) to GlcNAc-6-P. Quantitative RT-PCR was used to confirm differential expression of select genes, and substitution of free GlcNAc with free ManNAc resulted in growth to high cell density suggesting B. burgdorferi cells can utilize free ManNAc for cell wall synthesis and energy production.

Catfish Mucus Alters the Flavobacterium columnare Transcriptome

Abstract

Columnaris disease, caused by Flavobacterium columnare, severely impacts the production of freshwater finfish species. Therefore, efforts to better understand the biological processes of F. columnare, including the formation of biofilms and their contribution to disease, are ongoing. In this study, we incubated F. columnare cultures with channel catfish mucus and used high-throughput RNA sequencing to evaluate global changes in gene expression. Our data shows that mucus activates in vitro biofilm formation. The analysis of F. columnare transcriptomes after the addition of mucus revealed significant differentially expressed genes (DEGs) between the planktonic and biofilm states. DEGs common among all biofilms were enriched for gene ontology groups including signal transduction, ligand binding and cellular homeostasis and are likely necessary for biofilm formation. Iron acquisition systems included TonB dependent receptor and ferroxidase genes were expressed among all biofilms, while siderophore synthesis genes were only expressed in mucus-stimulated biofilms. The current analysis of F. columnare transcriptomes adds valuable information about the basic biological processes that occur during the planktonic and biofilm states. This work serves as a basis for future studies on understanding how biofilms are established and how they contribute to disease progression

Dr David Pothier 1973‐2018

Clinical Otolaryngology, EarlyView.

SF! Haraway’s Situated Feminisms and Speculative Fabulations in English Class

Abstract

This article draws on Donna Haraway's call for feminist speculative fabulation as an approach to qualitative research methodologies and writing praxis in schools. The first section of the article outlines how I conceptualize speculative thought, through different philosophers and theorists, and provides a brief literature review of speculative fiction used in secondary English curricula. The article then focuses on an in school creative writing project with grade 9 English students. In the student examples that I attend to, speculative fabulations and situated feminisms (race, gender, sexuality) are entangled, rendered complex, and in tension. In the final section, I discuss the Whiteness of mainstream speculative fiction and argue that speculative fabulation must be accountable to situated feminisms in how we read, write, and conduct research.

Tongue psoriasis: Clinical aspects and analysis of epidemiological associations in 313 children, with a systematic literature review

Publication date: October 2018

Source: Annales de Dermatologie et de Vénéréologie, Volume 145, Issue 10

Author(s): D. Pourchot, C. Chiaverini, E. Bourrat, S. Barbarot, P. Vabres, T. Hubiche, C. Droicourt, M. Piram, I. Kupfer-Bessaguet, M. Ferneiny, E. Puzenat, X. Balguérie, A. Beauchet, A.-C. Bursztejn, E. Mahé, Groupe de recherche de la Société française de dermatologie pédiatrique

Summary

Background

Little information is available on the prevalence and clinical aspects of tongue involvement in children with psoriasis. The aim was to evaluate the prevalence, clinical aspects and risk factors concerning tongue involvement in children with psoriasis.

Patients and methods

This study was carried out in two stages. We performed a multicentre, cross-sectional study in 23 French dermatology centers. All children seen for psoriasis during the one-year study were systematically included. The clinical features of the tongue and of psoriasis were recorded. Association with clinical aspects of psoriasis and comorbidities was evaluated. We then carried out a literature review to evaluate the prevalence of tongue involvement in children with psoriasis and its positive predictive value for psoriasis. A search was conducted in the PUBMED database using the following keywords: "child" and "psoriasis" and ("tongue" or "glossitis" or "migratory glossitis" or "benign migratory glossitis" or "geographic tongue" or "fissured tongue").

Results

7.7% of the 313 children with psoriasis had tongue involvement. The clinical aspects were geographic tongue (4.2%), fissured tongue (2.8%) and both (0.64%). There was no association between tongue involvement and the clinical characteristics of the children. Two hundred and ninety-five articles were referenced and 3 were analysed. Psoriasis is very rare in cases of tongue abnormalities.

Conclusion

The prevalence of tongue involvement was 7.7% in children with psoriasis. No clinical or epidemiological association was shown. Tongue involvement does not modify the management of psoriasis. In the literature review it was not possible to evaluate either the prevalence of tongue involvement in psoriasis or the positive predictive value thereof.

Résumé

Introduction

Il y a peu d'informations dans la littérature sur les atteintes de la langue au cours du psoriasis de l'enfant. L'objectif était d'évaluer la fréquence, les aspects cliniques et les facteurs de risque d'atteinte linguale chez les enfants psoriasiques.

Patients et méthodes

Ce travail a été effectué en deux étapes : (1) une étude transversale a été menée dans 23 centres dermatologiques français, notant les aspects cliniques de la langue et du psoriasis chez les enfants atteints de psoriasis, ainsi que les associations et les comorbidités ; (2) une revue systématique de la littérature a ensuite été effectuée afin d'évaluer la prévalence l'atteinte linguale chez l'enfant et sa valeur prédictive du psoriasis. Une recherche a été réalisée en interrogeant la base de données PUBMED. Les mots clés saisis étaient : « child » et « psoriasis » et (« tongue » ou « glossitis » ou « migratory glossitis » ou « benign migratory glossitis » ou « geographic tongue » ou « fissured tongue »).

Résultats

(1) Parmi 313 enfants atteints de psoriasis 7,7 % présentaient une atteinte linguale sous forme de langue géographique (4,2 %), langue fissurée (2,8 %) ou les deux (0,6 %). L'atteinte linguale n'était associée à aucune particularité démographique ou clinique, ni aucune comorbidité. (2) Parmi 295 articles référencés, 3 ont finalement été retenus. Le psoriasis reste très rare en cas d'anomalie linguale.

Conclusion

La prévalence de l'atteinte linguale chez les enfants psoriasiques était de 7,7 %. Aucune association clinique ou épidémiologique n'a été montrée. L'atteinte linguale ne modifie pas la prise en charge du psoriasis. La revue systématique de la littérature ne permettait pas d'évaluer une prévalence de l'atteinte linguale dans le psoriasis ni la valeur prédictive positive de cette atteinte.

Editorial board

Publication date: October 2018

Source: Annales de Dermatologie et de Vénéréologie, Volume 145, Issue 10

Author(s):

Investigating the role of TAM family receptors in Merlin deficient tumours

Abstract

BACKGROUND

TAM (TYRO3, Axl and MER) family of receptor tyrosine kinase has been recognised to be upregulated in tumours of diverse origin. Moreover, they are shown to be under negative control of protein merlin, encoded by Neurofibromatosis type II (NF2) gene. Mutation of NF2 gene is responsible for the development of multiple nervous system tumours such as schwannomas, meningiomas and ependymomas. Conventional chemotherapy is ineffective for this group of tumours due to their benign nature, and surgery/radiosurgery carry significant risk due to the multiplicity and location of tumours, thus effective drug therapy is urgently needed.

METHODS

In this study, we are using schwannomas and meningiomas tumour lysates and primary cells to examine the functional and direct correlation of TAM family receptors using confocal microscopy, co-immunoprecipitation and lentivirus based knockdown experiments followed by western blot.

RESULTS AND CONCLUSIONS

Confocal microscopy revealed close association of all three receptors however, co-immunoprecipitation experiments showed direct interaction only between AXL and TYRO3 in schwannomas. Moreover, expression of AXL found to be dependent on TYRO3 and MER. Besides interaction with own members, TAM family receptors also interact with other receptor groups such as integrin β1. Moreover, meningiomas also showed overexpression of all three TAM members in grade-I tumours. Overexpression and activation of TYRO3, AXL and MER found in NF2-/- meningiomas primary cells and which could be reversed on Merlin reintroduction. Investigating the role of TAM family receptors in pathobiology of schwannoma and meningioma will help to determine the best molecule to target therapeutically for NF2 tumours.

BRIDGING THE GAP – BENEFITS OF NEUROSURGICAL TISSUE FOR PRE-CLINICAL RESEARCH

Abstract

The use of primary human neural tissue for research provides an invaluable insight into human neural function that cannot be achieved in any other way. Despite this it is successfully collected and used in only a small minority of units. We have established a collaboration between the Wessex Neurological Centre and the University of Southampton that allows us to study using human tissue resected during neurosurgery, and have used this tissue for over a decade. Tissue is most commonly collected from oncological, epilepsy and vascular operations. Here we share our experiences of the practicalities of working with live human glioma tissue and try to provide some insights for practicing neuro-oncology surgeons. We discuss the ethical considerations and practical difficulties of the co-ordination of the clinical and academic teams, and challenge of optimization of the tissue for the research. We will present the mechanisms in place to optimize the study of human neural tissue. We will review the progression from resection of tissue from glioma surgery to epilepsy surgery to any neurosurgical procedure in which the normal brain is resected and tissue discarded. We discuss the different models that can be used and the application locally to glioma stem cells, pathways activated in TBI, tissue damage from haemoglobin, the electrophysiology of the normal brain and with age and the inflammatory response of microglia. We will present examples of the value of human tissue studies. Firstly we will show the importance of primary glioma tissue compared to established glioma cell lines. Secondly, we will demonstrate some electrophysiological differences between humans and rodent that could only be investigated through the use of live human tissue obtained at operation. We will also demonstrate how we have moved to streamline tissue collection and propose a move to establish a national framework for such experiments.

Children’s Brain Tumour Drug Delivery Consortium

Abstract

INTRODUCTION

There is an urgent need to expedite the development of new or repurposed drugs for children's cancer. An additional challenge in the developing brain is to ensure the drug is delivered to the tumour at therapeutic and non-toxic concentrations for sufficient duration to achieve the biological effect. Children's brain tumours account for over 20% of childhood cancers and differ significantly in their biological characteristics from their adult counterparts.

METHODS

The authors participated in an international CNS drug delivery workshop funded by the charity Children with Cancer UK in February 2016, where different experimental techniques aimed at optimising CNS drug delivery in children's brain tumours were discussed.

RESULTS

The workshop was reported by e-cancer (http://ecancer.org/journal/10/full/630-highlights-of-children-with-cancer-uk-s-workshop-on-drug-delivery-in-paediatric-brain-tumours.php; http://ecancer.org/conference/831-drug-delivery-in-paediatric-brain-tumours.php). We were encouraged to develop a proposal to establish an international research consortium to raise awareness and promote collaboration in the field. This is now funded for two years by Children with Cancer UK. The Children's Brain Tumour Drug Delivery Consortium seeks to strengthen collaborative developments by working closely with the international children's brain tumour community, encouraging and facilitating discussions between a multi-disciplinary network of clinicians and researchers within pharma and academia as well as a range of funders and stakeholders. As of March 2018, we have 94 individuals from 11 nations registered as members, with diverse stakeholders represented by academics, clinical academics, charities, public/patient groups, industry and regulatory bodies.

CONCLUSION

We present this abstract to the BNOS conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event, and to extend our invitation for collaborators to join the consortium.

NEUROIMAGING CLASSIFICATION OF PROGRESSION PATTERNS IN GLIOBLASTOMA: A SYSTEMATIC REVIEW

Abstract

BACKGROUND

Our objective was to report current neuroimaging classification systems of spatial patterns of progression in glioblastoma, report the terminology used to describe 'progression' and to assess the compliance of these studies with the Response Assessment in Neuro-Oncology (RANO) Criteria.

METHODS

We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry.

RESULTS

From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were not (Group 1) and 50 studies that used labels that were based on radiation volumes. In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to 'progression', of which the most frequent were 'recurrence' (99%) and 'progression' (92%). We identified 37% (n=33/90) of studies published following the release of the RANO classification were adherent compliant with the RANO criteria.

CONCLUSIONS

Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardisation of terminology and classification systems used in studying progression with neuroimaging would increase the efficiency of our research in our attempts to more successfully treat glioblastoma.

NEUROPSYCHOLOGY CONTRIBUTIONS TO THE NEURO-ONCOLOGY MDT

Abstract

Cognitive impairment is detectable in the majority of patients presenting with primary brain tumour and is a major cause of disability, often being cited as the single greatest cause of burden to affected individuals and their carers (Locke et al. 2008). In addition, psychological reactions to diagnosis and treatment can include acute distress, anxiety and depression. Collectively, these symptoms may complicate treatment and influence quality of life (QoL). This presentation provides a rationale for the inclusion of neuropsychologists in neuro-oncology multidisciplinary teams. It summarises relevant outcomes of brain tumours and associated treatments and highlights evidence-based neuropsychological practice. This includes not only psychometric assessment but also cognitive rehabilitation and psychologically-based interventions (such as Problem Solving and Cognitive Behaviour Therapies). Learning outcomes include exposure to a specific assessment approach using the Neuropsychological Assessment Battery (NAB), components of cognitive rehabilitation, and the psychological impact of brain tumours. Reference: Locke et al (2008). Cognitive rehabilitation and problem-solving to improve quality of life of patients with primary brain tumours: A pilot study. J Support Oncol, 6, 383–391.

USING QUALITATIVE RESEARCH METHODS TO OPTIMISE RECRUITMENT: THE ROAM (RADIATION VERSUS OBSERVATION FOLLOWING SURGICAL RESECTION OF ATYPICAL MENINGIOMA) INFORMATION STUDY

Abstract

AIM

ROAM is a randomised controlled trial comparing radiation to observation following complete surgical resection of atypical meningioma. We embedded a qualitative sub-study within ROAM with the aim of optimising patient recruitment.

METHODS

Audio-recorded recruitment consultation (N=25), and semi-structured interviews with clinicians (N=14) and patients (N=22), including decliners and consenters. Analysis of transcribed audio-recordings was informed by content and thematic analysis.

RESULTS

Analysis identified areas where communication was problematic. Giving patients their pathology results immediately before discussing ROAM left them overwhelmed and unable to absorb trial information. Interviewed clinicians were keen to participate in ROAM but some indicated concerns regarding the eligibility of patients at either ends of the age spectrum, believing such patients may not tolerate radiotherapy well. Clinicians' presentation of the trial arms in consultations often lacked balance (emphasising the process and side effects of radiotherapy but providing limited information regarding active monitoring) and their terminology inadvertently led to misinterpretations among some patients. When interviewed, several patients struggled to see the logic of radiotherapy after hearing in previous consultations that further treatment was unnecessary. Patients who declined ROAM were concerned about the side effects of radiotherapy and viewed it as burdensome; many struggled to interpret key details of ROAM due to problematic communication.

CONCLUSIONS

Embedded qualitative studies can identify barriers to recruitment in neuro-oncology trials and suggest ways to address these. We have amended the patient information leaflet, provided workshops and a webinar for oncologists and surgeons to enhance communication about ROAM, with the aim of optimising patient recruitment. Surgeons can aid recruitment by explaining to patients before surgery that they may be eligible for ROAM, if following surgery, they are diagnosed with atypical meningioma.

Development of nanoparticles with ‘improved drug loading’ for local delivery to the brain in the treatment of medulloblastoma

Abstract

Poor CNS penetration by cancer drugs limits their application in sensitive brain tumours such as medulloblastoma. An alternative approach, delivering drugs directly to residual tumour using nano particulate delivery systems (NPDS) could reduce some of these problems. The main challenges hindering the clinical translation of the use of NPDS for local delivery of drugs to the residual tumour are inadequate drug loading and erratic release. This study focusses on understanding the conditions required for the development of a NPDS with sufficient drug loading for post-surgical delivery to the residual tumour. This was done by selecting known effective drugs; Etoposide, etoposidephosphate and teniposide and matching them with modified poly (glycerol) adipate based polymers based on the interactions observed between them. Fourier transform infra-red spectroscopy (FTIR), contact angle measurements and drug release experiments have been used to screen the drugs and substituted PGA based polymers. Based on the interactions observed, polymers were matched with the specific drugs. Two types of drug nanoparticles were prepared from these combinations. Drug loaded matrix polymer nanoparticles (NP) were prepared by an interfacial deposition method and a novel process of applying a polymer coating to drug nanoparticles, polymer coated drug nanoparticles (PCDNP) was also developed. The following drug loading results were obtained for etoposide (NP:5%, PCDNP: 77%) and teniposide (NP: 23%, PCDNP: 32%). This systematic approach to monitor drug and polymer interactions to match polymers to drugs resulted in the formulation of nanoparticles with higher drug loading. Keywords: Medulloblastoma, Nanoparticles, Etoposide, Etoposide phosphate, Teniposide, Poly(glycerol)-adipate

ASSOCIATION BETWEEN METABOLIC PARAMETERS FROM DYNAMIC 18F-FLUOROMETHYLCHOLINE PET, PHARMACOKINETIC PARAMETERS FROM DCE-MRI, CHOLINE TO CREATINE RATIOS FROM MRS AND TISSUE IMMUNOHISTOCHEMISTRY FOR CHOLINE KINASE ALPHA EXPRESSION IN HUMAN BRAIN GLIOMA

Abstract

INTRODUCTION

Proton MR spectroscopy and Choline-PET probe different aspects of choline metabolism, and quantitative dynamic MRI yields information on vascular permeability and perfusion. The relationship between these features in different grades of glioma is, however, unclear.

METHOD

14 patients with suspected primary supratentorial glioma were recruited to this study. The mean values over the whole tumour (T2-FLAIR hyperintense regions) of DCE-derived pharmacokinetic parameters were correlated with tumour to background ratio (

TBR

ratio of SUV_max in tumour to SUV_mean in contralateral white matter for the 7-17-minute static PET images). Dynamic PET macroparameters were quantified with spectral analysis (SA) in six patients for whom metabolite data were available. Choline to creatine ratios (Cho/Cr) were extracted from 2D-CSI data over 257 MRS voxels and correlated with TBR. Tissue immunohistochemistry for choline kinase alpha expression in targeted biopsies was carried out in regions of tumour with high and low uptake on PET and Cho/Cr on MRS.

RESULTS

We observed a positive significant correlation between DCE-MRI derived parameters and parameters obtained through SA of the dynamic choline-PET data as well as TBR. We also observed a positive significant correlation between MRS Cho/Cr and TBR, although this was weak when excluding WHO Grade IV tumours. We did not observe a strong correlation between choline markers on imaging and choline kinase alpha expression.

CONCLUSION

The correlation between both DCE and MRS parameters with TBR indicates that a number of biological features affect the uptake of the PET tracer. DCE-MRI provides complimentary information to blood volume and permeability that may augment interpretation of PET data; and help address questions such as the degree to which tracer uptake is dominated by blood brain barrier permeability rather than metabolic activity. Choline imaging with PET and MRS may reflect metabolic processes that are not simply related to choline kinase alpha expression.

Pineal region glioblastoma: report of two long term survivors

Abstract

BACKGROUND

Pineal region glioblastoma (GBM) is an rare entity and is considered to have a poor prognosis similar to cerebral GBM. The current literature describes approximately 28 cases of pineal region GBM reported worldwide with no case series of more than 3 patients. Even with radical treatment the median survival is reported as 6 months (range 6–24 months) with occasional reports describing survival in the range of 24–38 months.

METHODOLOGY

Retrospective audit of all cases of GBM treated in our unit between 2008 and 2018. Data were collected from pathology reports, case notes, clinic letters and MDT outcomes.

RESULTS

We identified only two cases of pineal region GBM in male patients, aged 21 years and 50 years at the time of diagnosis (in 2013 and 2011 respectively), who are alive at 53 and 75 months since diagnosis. They are still under follow-up, maintaining a good performance status with no radiological evidence of tumour recurrence till date. Both patients had a biopsy, CSF diversion procedure, radical radiotherapy with concomitant temozolomide chemotherapy and 6 cycles of adjuvant temozolomide.

CONCLUSION

Although the overall survival for GBM following only a biopsy and chemoradiotherapy is considered poor, our experience of these tumours in the pineal region show a longer survival with similar treatment, when compared to GBM in cortical location. A larger study including detailed molecular genetic analysis may help in better understanding of the tumour behaviour and whether the location in the pineal region may be of prognostic value. Due to the rarity of GBM in the pineal region, this may only be possible if multiple centres collaborate in such studies.

MANAGEMENT AND OUTCOMES OF INCIDENTAL MENINGIOMAS: IS ROUTINE FOLLOW-UP REQUIRED?

Abstract

BACKGROUND

30% of newly-diagnosed meningiomas are incidental findings. There is no consensus on the optimal management of these patients.

OBJECTIVE

To determine the clinical outcomes of patients diagnosed with incidental meningioma.

METHODS

Single centre retrospective cohort study of patients diagnosed with an incidental meningioma between 2007 and 2015.

RESULTS

441 patients were included (459 meningiomas). Mean age at diagnosis was 63.3 years (range: 19–97); 348 female and 93 male. The main indication for MRI/CT was headache (25.9%). Median meningioma volume at diagnosis was 1.58 cm³ range: 0.06–51.8). Commonest location was convexity (39.9%). At initial presentation, 6 patients underwent surgical resection, 50 were discharged and the remaining 385 entered surveillance imaging (1303 scans in total, 3.4 on average over a median of 36 months [range: 3–120]). Overall outcomes by the end of the study period were: 219 discharged, 12 lost to follow-up, 4 deaths (unrelated to their meningiomas) and 206 under continued observation. Of those 206, 38 (18.4%) (mean age: 52.9 years) had intervention (34 surgery, 2 stereotactic radiosurgery, 2 fractionated radiotherapy) after a median follow-up period of 24 months (range: 3–78). Indications for treatment were radiological progression (n=26), development of symptoms (n=6), and patient preference (n=6). Pathology revealed WHO grade I (benign) in 36 patients and WHO grade II (atypical) in 4 patients, of which one had recurrence 5 months after surgery and required salvage radiotherapy. For 231 patients discharged/lost to follow-up (mean age: 68.1 years), median follow-up duration was 18 months (range: 0–120). Nine patients (3.9%) had further MRI/CT for unrelated symptoms after a median of 37 months.

CONCLUSION

The majority of incidental meningiomas do not require long-term follow-up and our data suggests that a 5-year period is sufficient. Further analyses of clinical and radiological predictors of growth and subsequent intervention are planned.

SHARED DECISION MAKING, THE BRIDGE BETWEEN PATERNALISM AND AUTONOMY.

Abstract

INTRODUCTION

Shared Decision Making (SDM) has been shown to be an effective tool in allowing patients to determine the treatment options best suited to their individual needs and is becoming the new standard of care in modern healthcare. It is invaluable in situations where reasonable options exist for a patient's management, such as Neuro-Oncology.

METHODS

A clinical decision grid was developed for three conditions, low and high grade gliomas and metastases. Three options were given to patients: best medical management or biopsy or resection (+/- adjuvant treatment) for gliomas and stereotactic radiosurgery or resection for metastases. The suitability, advantages and disadvantages were explained for each option and patients encouraged to choose the option that they felt suited them best. We analysed health care professional's attitude towards SDM before and after training using the Advanced Quality Alliance (AQuA) questionnaire. We assessed patient's response to consultations before and after the implementation of SDM using CollaboRATE questionnaire in the first cycle of a Plan Do Study Act (PDSA) process.

RESULTS

Five members of staff were trained in SDM and in response to the 19 point questionnaire (AQuA) there was an overall 28% improvement from 65% to 93% (in their attitude to SDM following training). The breakdown will be presented. 3 decision grids were used in 44 patients by 2 neurosurgeons and CollaboRATE scores remained high and did not change after full implementation with mean scores of 26/27 (range 15–27).

CONCLUSION

SSDM is a useful process that allows patients to make informed decisions regarding their treatment options. Although a significant improvement was seen amongst staff following the introduction of SDM, no difference was seen in the patient response analysis. This may relate to the department already using this methodology prior to its full implementation and the lack of sensitivity of the collaboRATE test.

NOVEL DRUG TARGETS TO AUGMENT TEMOZOLOMIDE SENSITIVITY IN HIGH-GRADE BRAIN TUMOURS

Abstract

Brain tumours kill more children and adults under 40 than any other cancer. Approximately half of primary brain tumours are high-grade malignancies known as glioblastoma multiforme (GBM). Current treatment regimes for GBM combine de-bulking surgery with radiotherapy and the chemotherapeutic DNA alkylating agent temozolomide (TMZ). However, the mean survival for GBM patients is ~15 months, with less than 10% of GBM patients surviving 5 years. This devastating prognosis highlights the urgent need for the development of novel agents to improve GBM treatment. A kinome-wide RNAi screen was carried out in a TMZ resistant GBM cell line. Cells were incubated with a low dose of TMZ and a non-toxic kinase-targeting RNAi. Cell viability was calculated by high-content microscopy and algorithm-based scoring of Hoechst-positive cells. Target validation studies of hits were carried out using additional RNAi libraries and small-molecule compound dose-escalation studies in additional GBM cell lines. We identify Extracellular Regulated Kinase 5 (ERK5) as a novel drug target to augment TMZ sensitivity. ERK5 is part of the MAPK signalling cascade, involved in cell survival and proliferation pathways, as well as cell differentiation and motility. ERK5 is dysregulated in many cancers and over-expression often results in a worse prognosis. At the mRNA level, ERK5 expression in GBM has been shown to be upregulated compared to normal tissue (REMBRANT Database). Using a range of siRNA and small molecule inhibitors in a panel of GBM cells, we have shown ERK5 inhibition sensitises GBM cell lines to TMZ. This will finding will be validated further using primary patient derived cultures and may potentially provide a novel target to improve GBM patient prognosis.

Evaluation of response to stereotactic radiosurgery in brain metastases using multiparametric MRI

Abstract

BACKGROUND

Following stereotactic radiosurgery (SRS), brain metastases initially increase in size in up to a third of cases, suggesting treatment failure. Current imaging using structural MRI cannot differentiate between tumour recurrence and SRS-induced changes, creating difficulties with patient management. Combining multiparametric MRI techniques, which assess tissue physiological and metabolic information has shown promise for answering this clinical question.

MATERIALS AND METHODS

Multiparametric MRI techniques including spectroscopy, diffusion and perfusion imaging were used for differentiation of radiation-induced necrosis and tumour recurrence after SRS for intracranial metastases in six cases. All patients presented with enlargement of the treated lesion, an increase in perilesional brain oedema, and aggravation or appearance of neurological signs and symptoms from 7–29 weeks after primary treatment.

RESULTS

Multiparametric imaging helped to differentiate features of tumour progression (n=4) from radiation-induced necrosis (n=2). A low apparent diffusion coefficient (ADC) <1000 x 10^–6 mm²/s, high relative cerebral blood volume (rCBV) ratio >2.1, high choline:creatine (Cho:Cr) ratio >1.8 suggested tumour recurrence. A high ADC >1000 x 10^–6 mm²/s, low rCBV ratio <2.1, Cho:Cr ratio <1.8 suggested SRS-induced radiation changes. Multiparametric MRI diagnosis was confirmed by histology or radiological and clinical follow up.

CONCLUSION

Multiparametric MRI is helpful in the early identification of radiation-induced necrosis and tumour recurrence, which can be used for monitoring treatment changes in intracranial neoplasms after SRS treatment.

RAPID GENETIC CLASSIFICATION OF GLIOMAS USING RAMAN SPECTROSCOPY

Abstract

BACKGROUND

Raman spectroscopy probes the unique molecular vibrations of a sample to accurately characterise its molecular composition. No sample processing is required allowing for rapid analysis of fresh tissue. The genetic classification of gliomas, particularly isocitrate dehydrogenase (IDH) mutations, is critical for clinical decision-making. With the development of new drugs targeting specific glioma genetic subtypes it will become increasingly important for surgeons to be aware of the genetics of the tumour at the time of operation to inform their surgical strategy. The aim of this study was to use Raman spectroscopy on fresh samples taken straight from the operating theatre and to classify gliomas according to their genetic subtypes. Similar classification models were built using cryosections and formalin-fix paraffin embedded (FFPE) sections.

METHODS

Raman spectra were collected using a Renishaw benchtop RA800 series spectrometer. Parallel sections underwent immunohistochemistry with targeted genetic sequencing when required to confirm the following five glioma subtypes: glioblastoma, IDH-mutated; glioblastoma, IDH-wildtype; astrocytoma, IDH-mutated; astrocytoma, IDH-wildtype; oligodendroglioma.

RESULTS

Fresh tissue samples from 62 patients were collected (9 glioblastoma, IDH-mutated; 35 glioblastoma, IDH-wildtype; 10 astrocytoma, IDH-mutated; 2 astrocytoma, IDH-wildtype; 5 oligodendroglioma, 1 excluded). A principal component-linear discriminant analysis (PCA-LDA) model demonstrated 80%-95% sensitivity and specificity for predicting the five glioma genetic subtypes. For prediction of IDH mutation alone the model gave a 92% sensitivity and 91% specificity. 86 cryosection and 117 FFPE samples underwent Raman with models demonstrating 87–94% sensitivity and 77–80% specificity for predicting IDH mutations. In the fresh tissue samples, the mean time for spectra collection was 9.5 minutes with the whole process from tumour biopsy to genetic classification taking under 30 minutes.

CONCLUSION

These results demonstrate proof of concept that Raman spectroscopy can be used for rapid, intraoperative glioma genetic classification. Further work is being done to refine model building to increase classification performance.

Developments in molecular pathology testing for glioma

Abstract

Genetic analysis is now an integral part of glioma diagnosis and an essential aid to stratification of patient care (Louis et al., 2016). University Hospital Southampton is expanding its test repertoire to reflect these needs. The sensitive and specific technology of droplet digital PCR (ddPCR) can move Isocitrate Dehydrogenase (IDH) mutation testing away from current subjective immunohistochemistry (IHC) methodology. In a small study, 26 cases were tested by IHC, ddPCR and Sanger sequencing. Twenty cases were concordant for IDH R132H by IHC and ddPCR analysis, whilst three cases harboured the rarer IDH R132 or IDH2 variants, not evaluated by these two tests. However, three remaining IHC-IDH1 R132H negative cases were positive for IDH1 R132H by ddPCR, illustrating an improved sensitivity for IDH mutation testing using the digital PCR platform. Generic testing workflow for ddPCR, that meets ISO 15189 accreditation standards, facilitates a quick test work up for Single Nucleotide variant (SNV) mutation analysis. This can support clinical decision making vis-à-vis targeted therapy options and potential clinical trials entry. The use of microsatellite markers analysis provides an alternative method for the evaluation of 1p19q deletion characteristics. Investigation of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation status using high resolution melt (HRM) brings this test in to our standard molecular laboratory workflow. Molecular testing for MGMT methylation status delivers results with fast turnaround time, supporting timely, evidence-based decisions for Temozolomide treatment. The PCR-based nature of these analyses have minimal tissue requirements and this suite of tests can be run on a single sample. Participation in the 100,000 genomes project is providing whole genome data with which to explore a 'one stop shop' approach to glioma molecular testing. In combination with DNA methylome analysis, we wish to evaluate the clinical utility of a pan-genome analysis for our glioma diagnostic and prognostic support service.

FUNCTIONALLY GUIDED SUPRAMAXIMAL RESECTION OF IDH-WILDTYPE GLIOBLASTOMAS AND THE EFFECT ON PROGRESSION FREE SURVIVAL

Abstract

INTRODUCTION

Gross total resection (GTR), defined as complete resection of enhancing tumour on post-operative MRI, increases progression free survival (PFS) in patients with glioblastoma. We have extended the concept of functionally guided supramaximal resection (SMR) where the aim of surgery is to resect up to 2 cm beyond the enhancing tumour in all directions, limited only by functional boundaries. Boundaries are identified by pre-operative diffusion tensor imaging (DTI) scans, to estimate white matter fibre tract location, and awake craniotomy with cortical and subcortical stimulation.

METHODS

Prospective non-randomised functionally guided surgical resection was undertaken in all IDH-wildtype glioblastomas undergoing primary surgical resection by the senior author between 2012–2017. Based on post-operative MRI scans, data on extent of tumour resection were analysed calculating tumour, brain and post resection volumes. Patients were then categorised into three different extent of resection groups: subtotal resection (STR), GTR, and SMR. All patients underwent post-operative radiotherapy and chemotherapy as per the Stupp protocol and were followed up with 3-monthly MRI scans.

RESULTS

69 cases of IDH-wildtype glioblastoma underwent resection within the timeframe. Survival data are currently available for 45 cases. The outcome measure is PFS, where progression is defined as recurrence of tumour. For actual treatment received, median PFS was 43.9 months (95% CI, 22.8–89.8 months) in the SMR group, 29.3 months (95% CI, 7.4–72.3 months) in GTR group and 13.3 months (95% CI, 10.3–27.6 months) in the STR group. The Kaplan-Meier survival curves of the three groups are clearly separated with no crossing. The logrank test indicates there is a significant difference (P value = 0.0003) between the survival curves of the three groups. There was no difference in the incidence of post-operative neurological deficit between the three groups.

CONCLUSION

Supramaximal resection provides a significant increase in PFS compared to the current accepted standard of GTR.

Is it time to radically change the two week wait (2WW) referral pathway for suspected brain and CNS cancer?

Abstract

BACKGROUND

In June 2015, the National Institute for Health and Care Excellence (NICE) published revised 2WW referral guidelines for general practitioners (GP) for patients with suspected brain and CNS cancer. The guidelines are comprehensive and include recommendations for using brain imaging and provision of relevant clinical information at referral.

METHODOLOGY

Retrospective audit of patients referred on 2WW pathway for suspected brain cancer to South Tees Trust between 1/7/2015 and 31/12/2017. Cases were identified from the Trust's 2WW referral database. Data were collected from referral letters and patient records. Quality of referral information was assessed in 10 domains.

RESULTS

122 patients identified. 98 cases audited (50F:48M, median age 61 years, range 16–92 years). 24 cases excluded: non-brain/CNS 2WW referrals (n=12), spinal cases (n=9), records unavailable (n=3). 54 referrals were rejected as non-compliant under 2WW criteria: 30 with chronic symptoms, 20 with benign lesion/normal brain imaging. Compliance with referral information achieved 100% in 1 domain (patient contact details). Details of past medical history, medications, examination and allergies achieved 56–77% compliance. Details of performance status, social history and patient awareness of referral criteria achieved 2–8% compliance.

CONCLUSION

Compliance with the NICE 2WW referral guidelines for brain & CNS cancer is poor. The referral process involves considerable workload for clinical teams especially as 55% of referrals were found to be inappropriate. Compliance may be improved through educational programmes in primary care. Alternatively, by increasing GP access to early cranial imaging, the 2WW pathway could be decommissioned and replaced with a pathway whereby suspected malignancy reported on imaging is linked directly to the neuroscience MDT.

CLINICALLY DELIVERABLE OPTUNE AND DEEP BRAIN STIMULATOR GENERATED ELECTRICAL FIELDS HAVE VARIABLE EFFICACY ON DIFFERENT TYPES OF BRAIN TUMOUR

Abstract

INTRODUCTION

Phase III trials of Tumour Treating Fields (TTFields) (Optune) have shown potentially positive results in both primary and recurrent adult Glioblastoma multiforme (GBM) patients. These results have given credence to electromagnetic fields, presenting a new treatment paradigm for brain tumour patients. Here we present investigations into repurposing deep brain stimulation (DBS) electrodes as a novel delivery method of therapeutic electric fields to high grade brain tumours and compare to TTFields treated cell lines.

METHODS

Medtronic DBS electrodes were inserted into cell culture flasks and delivered electric fields over a range of frequencies and intensities to a panel of GBM, Medulloblastoma and Ependymoma cell lines. Inovitro is the laboratory based TTFields delivery system. Inovitro was used to deliver TTFields over a range of clinically relevant frequencies (100-400kHz) to a panel of paediatric GBM, Medulloblastoma and Ependymoma cell lines. Differences in the effects of both treatments on cell viability, cell cycling, long-term effects of treatment, as well as genome-wide expression were analysed. RESULTS Both DBS electric fields and TTFields negatively affect cell proliferation and viability of brain tumour cell lines. The magnitude of these effects were dependent upon frequency and intensity. Cells treated with either modality were re-seeded and growth rates were compared to non-treated cells. The treated cells experienced significantly slower growth rates following treatment. Cell cycle analysis revealed that DBS treated cells have significant levels of G₀ phase accumulation relative to control flasks, while TTFields treated cells demonstrated greater levels of G₂M phase accumulation across all panels of cell lines tested. The effects of electrotreatment on gene expression will be discussed.

CONCLUSIONS

Both treatment modalities have demonstrated efficacy against our array of brain tumour cell lines. The treatments likely have differing mechanisms of action at the cellular level and this is reflected in the differences that have been observed.

The challenges of treating a high grade glioma in a pregnant patient

Abstract

Glioblastoma diagnosis carries a poor prognosis. A combination of surgical resection and chemo-radiotherapy is the current standard of care with median survival rates of 15 months. A 33 year old lady, pregnant at 26 + 3 weeks gestation presented with a left parietal tumour. Complete resection confirmed a grade IV glioblastoma. Foetal health remained stable and termination was not considered. The patient attended for discussion on adjuvant treatments and was informed of the time critical nature of radiotherapy; temozolomide was not advised during pregnancy. With the patient understanding the increased risks to the foetus, the radiotherapy process for delivering 60Gy/30 fractions was initiated. Standard radiotherapy plans were created using both VMAT and 3D-CRT technique. At the planning CT fiducials were placed at the xiphersternum to represent the maximum superior foetal extent and measurements taken. Using a phantom and TLDs, an estimated dose to the foetus was 30mGy from a VMAT plan and 20mGy from 3-field 3DCRT, assuming a 0.5mm equivalent lead apron. The effects to the foetus were calculated using the Health Protection Agency document RCE-9. Radiotherapy increased the incidence of childhood cancer from 1/500 to 1/250. Additional risk of inheritable effects was (1/6700) and deterministic effects was below the threshold. The increased dose of 10mGy from 3DCRT to VMAT plan meant the additional risk of childhood cancer increased from 1/625 to 1/400. Although considered safe, the patient decided against radiotherapy until after delivery at 32 weeks. We will also present a case of a patient diagnosed with a frontal anaplastic astrocytoma at 19 weeks gestation. The patient consented to go ahead with radiotherapy with similar foetal radiation doses. Considering the health of the foetus and mother brings a unique challenge when planning the management of high grade gliomas.

FIRST UK EXPERIENCE WITH NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION IN PRE-SURGICAL MAPPING

Abstract

OBJECTIVES

Surgery for lesions in eloquent brain areas is challenging due to the underlying risk of causing permanent neurological deficits. To date, Direct Cortical Stimulation (DCS) and intra-operative neuro-monitoring (IOM) represent the gold standard in minimising such risk. Recently, Transcranial Magnetic Stimulation (TMS) has emerged as a mapping tool that assists in optimising surgical planning. The aim of this study is to validate our TMS findings against DCS.

METHODS

Retrospective single-centre analysis of 35 adult patients with TMS, DCS and IOM for space occupying lesion (SOL) at King's College Hospital from February 2017 to February 2018. Patients with arteriovenous malformation were excluded from analysis. We collected data on patient demographics, tumour entity/location, extent of resection (EoR), change of surgical strategy, neurological outcome, and correlated TMS with DCS/IOM.

RESULTS

24/35 patients (68.6%) had pre-operative motor mapping and 11/35 (31.4%) were mapped for language. Histopathology demonstrated a glioma in 85.7% of patients (high grade n=24; low grade n=6) and metastasis (n=2), cavernoma (n=1) and other cases (n=2). TMS resulted in a change of surgical strategy in 34.3% (craniotomy size n=7; surgical pathway n=3; EoR n=1; surgical indication n=1). Sensitivity of TMS for language was 70.6% with a positive predictive value of 60.0% (n=9). TMS motor mapping correlated with DCS/IOM in all cases with snapshot hotspot conformity of 100% (n=5). A total of 12 patients had a new transient neurological deficit which resolved/significantly improved except for one case (expressive dysphasia).

CONCLUSIONS

TMS is a non-invasive, safe and effective adjunct in surgery planning in eloquent brain areas. It is reliable in predicting M1/motor mapping and shows promising results for language mapping. Larger randomised controlled trials are needed to validate these findings.

Skin cancer and welding

Clinical and Experimental Dermatology, EarlyView.

A rare case of finger ischemia following bypass procedure with autologous vein graft for thumb revascularization: a case report and brief review of the literature

Abstract

This case report aims to point out the importance of having in mind anatomical variation in the blood supply to the hand even in emergency settings. A 39-year-old patient presented at our emergency department with a wound on the distal anterolateral third of the left forearm with skin loss, degloving injury of the thumb starting from the 1st metacarpal, exposure of the proximal two thirds of the 1st metacarpal bone, and both radial and ulnar digital arteries of the thumb damaged. A 10-cm-long vein graft was anastomosed in termino-later fashion between the dorsal branch of the radial artery and the uninjured distal part of the ulnar collateral digital artery of the thumb, successfully re-establishing its blood supply. Starting from the 1st postoperative day, the thumb was warm and pink while the other fingers were pale and capillary filling was absent. An urgent arteriography of the left upper extremity demonstrated the presence of normal radial artery, hypoplastic ulnar artery, dominant median artery, and absence of vascularization of the 2nd, 3rd, 4th, and 5th fingers. By the end of 2nd week, the patient underwent amputation of the four fingers at the distal metacarpal level. Anatomical anomalies of hand arterial blood supply are not uncommon, even though rarely reported in literature. Therefore, an instrumental study should be performed before attempting any arterial intervention even in emergency settings. Nevertheless, further studies should be performed to identify ready-to-use tools to make surgeons aware of any anatomic variations in order to avoid such complications.

Level of Evidence: Level V, therapeutic study.

Biochar amendment immobilizes arsenic in farmland and reduces its bioavailability

Abstract

This study aimed to determine effects of biochar derived from wheat straw at 500 °C on arsenic immobilization in a soil-Brassica campestris L system. When the soils amended with 4% modified biochar (MBC), 0.5% Fe grit as zero-valent iron (ZVI), 0.5% Fe grit + 4% MBC (ZMBC), 0.5% ZVI + 4% biochar (ZBC), 4% biochar (BC), and control (without amendments), it confirmed that available arsenic concentration in soils occurred in the following order: ZMBC < MBC < ZVI < ZBC < Control < BC. Water-soluble As (WSAs) was reduced by 89.74% and 92.30% in MBC- and ZMBC-amended soils, respectively, compared to the control. When MBC applied into soil, As uptake of shoot and root decreased by 44.55% and 45.40%, respectively, and ZMBC resulted in 74.92% and 71.80% reduction in shoot and root As of Brassica campestris L. Immobilization effect of As in ZBC was also observed though BC elevated plant As uptake significantly. The immobilization effect of MBC was mainly attributed to Fe₂O₃ impregnation illustrated by x-ray diffraction (XRD) and scanning electron microscopy (SEM) images through sorption, precipitation, and coprecipitation. Such Fe containing complexes might impede As translocation from root to shoot and subsequently reduce As accumulation in the plant with modified biochar amendment.