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Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

To describe clinical, oculographic and vestibular test profiles in patients with vestibular migraine (VM) who presented with acute peripheral vestibulopathy. VM was diagnosed according to Bárány Society or Neuhauser criteria. Neuro-otological examination, video-head impulse tests (v-HIT), cervical and ocular vestibular-evoked myogenic potentials (cVEMP/oVEMP), subjective visual horizontal (SVH) and audiometry were undertaken. Ten patients presented with prolonged vertigo. All had primary position unidirectional horizontal spontaneous nystagmus (mean slow-phase velocity 9.6 ± 7.0°). Horizontal canal vestibulo-ocular reflex was reduced in all (mean gain 0.54 ± 0.2) with refixation saccades (cumulative amplitude 6.4 ± 3.2°). Abnormality rates for cVEMP, oVEMP and SVH were 30%, 80%, 78%, respectively. Magnetic resonance imaging brain was normal in all patients. Patients were followed up over 6 months to 8 years with no change in the final diagnosis. VM can rarely present as an acute peripheral vestibulopathy with findings that mimic vestibular neuritis and should be considered in the differential diagnosis of acute prolonged vertigo.

The chemistry of transition metal carbynes, LnM≡CR, has historically been dominated by species bearing hydrocarbyl or amino ‘R’ substituents, with other elements appearing only sporadically. In recent years, carbynes and related ‘C1’ species bearing other main‐group substituents, particularly heavier elements of the p‐block, have begun to emerge. This review details the chemistry of heavier pnictogen‐functionalised C1 ligands, MCARn (A=P, As, Sb, Bi; n=0–3), including their syntheses, properties and reactivities, and how these are distinguished from more traditional carbyne complexes. Recent developments in the closely related phospha‐isonitrile LnM(CPR), cya‐phosphide and cya‐arside ligands, LnM(C≡A) (A=P, As), are also discussed.

Toxic metals have been implicated in the pathogenesis of pancreatic cancer. Human exposure to mercury is widespread, but it is not known how often mercury is present in the human pancreas and which cells might contain mercury. We therefore aimed to determine, in people with and without pancreatic cancer, the distribution and prevalence of mercury in pancreatic cells. Paraffin-embedded sections of normal pancreatic tissue were obtained from pancreatectomy samples of 45 people who had pancreatic adenocarcinoma, and from autopsy samples of 38 people without pancreatic cancer. Mercury was identified using two methods of elemental bio-imaging: (1) With autometallography, inorganic mercury was seen in islet cells in 14 of 30 males (47%) with pancreatic cancer compared to two of 17 males (12%) without pancreatic cancer (p = 0.024), and in 10 of 15 females (67%) with pancreatic cancer compared to four of 22 females (19%) without pancreatic cancer (p = 0.006). Autometallographic mercury was present in acinar cells in 24% and in periductal cells in 11% of people with pancreatic cancer, but not in those without pancreatic cancer. (2) Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in islets that stained with autometallography and detected cadmium, lead, chromium, iron, nickel and aluminium in some samples. In conclusion, the genotoxic metal mercury is found in normal pancreatic cells in more people with, than without, pancreatic cancer. These findings support the hypothesis that toxic metals such as mercury contribute to the pathogenesis of pancreatic cancer.

There is strong, and growing, evidence documenting health inequities across the world. However, most governments do not prioritize policies to encourage action on the social determinants of health and health equity. Furthermore, despite evidence concerning the benefits of joined-up, intersectoral policy to promote health and health equity, it is rare for such policy approaches to be applied systematically. To examine the usefulness of political and social science theory in understanding the reasons for this disjuncture between evidence and practice, researchers and public servants gathered in Adelaide for an Academy of the Social Sciences in Australia (ASSA) Workshop. This paper draws together the learnings that emerged from the Workshop, including key messages about the usefulness of various theories as well as insights drawn from policy practice. Discussions during the Workshop highlighted that applying multiple theories is particularly helpful in directing attention to, and understanding, the influence of all stages of the policy process; from the construction and framing of policy problems, to the implementation of policy and evaluation of outcomes, including those outcomes that may be unintended. In addition, the Workshop emphasized the value of collaborations among public health researchers, political and social scientists and public servants to open up critical discussion about the intersections between theory, research evidence and practice. Such critique is vital to render visible the processes through which particular sources of knowledge may be privileged over others and to examine how political and bureaucratic environments shape policy proposals and implementation action.

Vestibular evoked myogenic potentials (VEMPs) are a useful and increasingly popular component of the neuro-otology test battery. These otolith-dependent reflexes are produced by stimulating the ears with air-conducted sound or skull vibration and recorded from surface electrodes placed over the neck (cervical VEMPs) and eye muscles (ocular VEMPs). VEMP abnormalities have been reported in various diseases of the ear and vestibular system, and VEMPs have a clear role in the diagnosis of superior semicircular canal dehiscence. However there is significant variability in the methods used to stimulate the otoliths and record the reflexes. This review discusses VEMP methodology and provides a detailed theoretical background for the techniques that are typically used. The review also outlines the common pitfalls in VEMP recording and the clinical applications of VEMPs.

There is strong, and growing, evidence documenting health inequities across the world. However, most governments do not prioritize policies to encourage action on the social determinants of health and health equity. Furthermore, despite evidence concerning the benefits of joined-up, intersectoral policy to promote health and health equity, it is rare for such policy approaches to be applied systematically. To examine the usefulness of political and social science theory in understanding the reasons for this disjuncture between evidence and practice, researchers and public servants gathered in Adelaide for an Academy of the Social Sciences in Australia (ASSA) Workshop. This paper draws together the learnings that emerged from the Workshop, including key messages about the usefulness of various theories as well as insights drawn from policy practice. Discussions during the Workshop highlighted that applying multiple theories is particularly helpful in directing attention to, and understanding, the influence of all stages of the policy process; from the construction and framing of policy problems, to the implementation of policy and evaluation of outcomes, including those outcomes that may be unintended. In addition, the Workshop emphasized the value of collaborations among public health researchers, political and social scientists and public servants to open up critical discussion about the intersections between theory, research evidence and practice. Such critique is vital to render visible the processes through which particular sources of knowledge may be privileged over others and to examine how political and bureaucratic environments shape policy proposals and implementation action.

We studied the short-latency (SL) effects of postural perturbations produced by impulses applied over the spine of the C7 vertebra or the sternum (“axial impulses”) in 12 healthy subjects. EMG recordings were made bilaterally from the triceps brachii, biceps brachii, soleus, and tibialis anterior muscles, and unilaterally from the deltoid, forearm flexors, forearm extensors, and first dorsal interosseous (FDI) muscles. Sternal impulses evoked short-latency responses in the biceps when subjects leaned posteriorly to support approximately 12% of their body weight with the arms, but these responses were only modestly larger than for isometric contraction of the arms (26.3 vs. 14.7%). In contrast, clear excitatory responses could be evoked in the deltoid, triceps, forearm muscles, and FDI when leaning anteriorly to support similar amounts of body weight. These responses were significantly larger than during isometric contraction. The deltoid (42.5%) and triceps (44.7%) had the largest responses in supported anterior lean and onset latencies increased distally in this condition (mean 31.8 ms in deltoid to 53.7 ms in FDI). There was a disproportionate delay between the forearm muscles and FDI. For both directions of lean, postural reflex responses normally present in the legs were severely attenuated. SL upper limb excitatory responses were bigger in proximal muscles as well as larger and more widespread for anterior axial perturbations compared to posterior axial perturbations when using the arms to support body weight. Our findings also provide further evidence of a role for reticulospinal pathways in mediating these rapid postural responses to accelerations of the trunk.

We studied the response to axial taps (mini-perturbations) of a group of 13 healthy older subjects (mean age 63 ± 12 years, 7 females, 6 males), 12 of whom were also studied using larger applied (macro-) perturbations requiring active postural responses. The mini-perturbation consisted of a brief impulsive force produced by a mini-shaker applied to the trunk at the level of the shoulders and anteriorly at the upper sternum which was perceived as a tap. Acceleration, force platform, and EMG measurements were made. The average peak accelerations for the mini-perturbations were 108 mG (anterior) and − 78.9 mG (posterior). Responses overall were very similar to those previously reported for younger subjects: the perturbation evoked short latency responses in leg muscles, modulated by degree and direction of lean, and were largest for the muscle most relevant for the postural correction. The increases in the amplitude for the main agonist were greater than the increase in tonic activity. With both anterior and posterior lean, co-contraction responses were present. The size of the EMG response to the mini-perturbations correlated with the corresponding earliest EMG responses (0–100, 100–200 ms intervals) to the larger postural perturbations, timing which corresponds to balance responses. The balance responses evoked by the larger imposed postural perturbations may, therefore, receive a contribution through the reflex pathway mediating the axial tap responses, whose efferent limb appears to be the reticulospinal tract.

Vestibular-evoked myogenic potentials (VEMPs) are short-latency muscle reflexes typically recorded from the neck or eye muscles with surface electrodes. They are used clinically to assess otolith function, but are also interesting as they can provide information about the vestibular system and its activation by sound and vibration. Since the introduction of VEMPs more than 25 years ago, VEMPs have inspired animal and human research on the effects of acoustic vestibular stimulation on the vestibular organs, their projections and the postural muscles involved in vestibular reflexes. Using a combination of recording techniques, including single motor unit recordings, VEMP studies have enhanced our understanding of the excitability changes underlying the sound-evoked vestibulo-collic and vestibulo-ocular reflexes. Studies in patients with diseases of the vestibular system, such as superior canal dehiscence and Meniere's disease, have shown how acoustic vestibular stimulation is affected by physical changes in the vestibule, and how sound-evoked reflexes can detect these changes and their resolution in clinical contexts. This review outlines the advances in our understanding of the vestibular system that have occurred following the renewed interest in sound and vibration as a result of the VEMP.

There is strong, and growing, evidence documenting health inequities across the world. However, most governments do not prioritize policies to encourage action on the social determinants of health and health equity. Furthermore, despite evidence concerning the benefits of joined-up, intersectoral policy to promote health and health equity, it is rare for such policy approaches to be applied systematically. To examine the usefulness of political and social science theory in understanding the reasons for this disjuncture between evidence and practice, researchers and public servants gathered in Adelaide for an Academy of the Social Sciences in Australia (ASSA) Workshop. This paper draws together the learnings that emerged from the Workshop, including key messages about the usefulness of various theories as well as insights drawn from policy practice. Discussions during the Workshop highlighted that applying multiple theories is particularly helpful in directing attention to, and understanding, the influence of all stages of the policy process; from the construction and framing of policy problems, to the implementation of policy and evaluation of outcomes, including those outcomes that may be unintended. In addition, the Workshop emphasized the value of collaborations among public health researchers, political and social scientists and public servants to open up critical discussion about the intersections between theory, research evidence and practice. Such critique is vital to render visible the processes through which particular sources of knowledge may be privileged over others and to examine how political and bureaucratic environments shape policy proposals and implementation action.

Objective The provision of written information is a low-cost and readily available intervention that has been found to reduce pain and anxiety in a variety of clinical settings. The current study was undertaken to determine if information provision may improve patients’ experience during conventional electrodiagnostic studies. Methods 128 participants were recruited from a tertiary teaching hospital who were referred for electrodiagnostic studies. They were randomized into 2 groups where the intervention group was provided with written information about the electrodiagnostic testing. Patients were invited to complete a questionnaire that included pain and anxiety using a visual analogue scale (VAS) following the testing. All participants underwent nerve conduction studies (NCS) whilst a subset also underwent subsequent needle electromyography (EMG). Results Those who received information had a statistically significant lower perception of anxiety during NCS, whilst only females who received information had a statistically significant lower perception of pain to both NCS and EMG. Conclusions The provision of written information can reduce the degree of pain and anxiety experienced during electrodiagnostic testing. Significance Improving patient comfort and tolerability during electrodiagnostic testing may have practical implications towards more reliable and accurate results obtained from such investigations that may in turn improve patient diagnosis and management.

In this chapter we explore Kingdon’s multiple streams heuristic, and examine how it has been taken up and used in policy studies. The critical question for policy analysis in Kingdon’s heuristic is not how given problems are selected and addressed through authoritative decision making, but rather the nature of the linkages between three continually flowing and largely independent streams: problems, policies and politics. We observe with interest the extent to which the multiple streams approach has stood the test of time, with its broad applicability across place and topic. Unlike other theories of the policy process, the heuristic put forward by Kingdon provides the tools for analysing a process which is complex, ambiguous and somewhat serendipitous. It includes both structural (windows) and interpersonal (policy entrepreneurs) considerations in the policy process overlaid on the three streams. Kingdon’s heuristic has been applied by scholars coming from various ontological and epistemological standpoints, but we argue that it is perhaps best understood as a constructionist approach.

A prospective study explored the heterogeneous nature of metastatic melanoma using Multiplex immunohistochemistry (IHC) and flow cytometry (FACS). Multiplex IHC data quantitated immune subset number present intra-tumoral (IT) vs the tumor stroma, plus distance of immune subsets from the tumor margin (TM). In addition, mIHC showed a close association between the presence of IT CD8+ T cells and PDL1 expression in melanoma, which was more prevalent on macrophages than on melanoma cells. In contrast, FACS provided more detailed information regarding the T cell subset differentiation, their activation status and expression of immune checkpoint molecules. Interestingly, mIHC detected significantly higher Treg numbers than FACS and showed preferential CD4+ T cell distribution in the tumor stroma. Based on the mIHC and FACS data, we provide a model which defines metastatic melanoma immune context into four categories using the presence or absence of PDL1+ melanoma cells and/or macrophages, and their location within the tumor or on the periphery, combined with the presence or absence of IT CD8+ T cells. This model interprets melanoma immune context as a spectrum of tumor escape from immune control, and provides a snapshot upon which interpretation of checkpoint blockade inhibitor (CBI) therapy responses can be built.

Mohamad Zeina, Annabel Elizabeth Jones, Roxanna Colebatch  GKT School of Medical Education, King’s College London, London, UK We thank Safabakhsh et al1 for their thought-provoking article on interprofessional education (IPE), a topic that we do not believe receives enough attention in medical literature. As medical students who have recently undertaken an IPE module at King’s College London, we believe we are well placed to comment on this paper and how it relates to our experiences at medical school. We wholeheartedly agree with Safabakhsh et al’s1 idea that good IPE is essential for patient care and that a clear framework, such as that set out in the paper, can help achieve this. View the original paper by Safabakhsh and colleagues.&nbsp

We have investigated the effectiveness of two bone-conducted (BC) stimuli in producing vestibular evoked myogenic potentials (VEMPs) following stimulation along midsagittal skull sites. Twenty subjects (mean age 24 yr, range: 18-34 yr; 6 men; 14 women) were studied using a smoothed impulse and a 500-Hz tone burst applied to Nz, Fpz, AFz, Fz, FCz, and Cz with both compressive and rarefactive onset phases. Cervical (cVEMPs) and ocular VEMPs (oVEMPs) were recorded as well as linear acceleration in three axes. cVEMPs evoked by 500 Hz showed no change in response polarity to either stimulus location or phase. cVEMPs evoked by the impulsive stimulus showed larger initial peak amplitudes at AFz and Fz using compressive stimuli and differences in initial peak latency between the two phases. In contrast, amplitude, latency, and response polarity for oVEMPs were markedly affected by stimulus location and phase, which were similar for both BC stimuli, with little correlation with induced acceleration of the head. Latencies were earliest at AFz and Fz where compressive onset stimuli evoked an initial negativity (average latency 8.6-11.0 ms). At other sites compressive onset stimuli usually evoked oVEMPs with an initial positivity. We conclude that both 500 Hz and impulsive stimuli are effective means of evoking cVEMPs and oVEMPs from mid sagittal skull sites. The effects depend upon both location and phase and differ for oVEMPs and cVEMPs. Initial negativities for oVEMPs following compressive stimuli were most consistently obtained using the AFz and Fz sites.

Vestibular evoked myogenic potentials (VEMPs) are short-latency reflexes recorded from the cervical (cVEMPs) and ocular (oVEMPs) muscles. Both reflexes are commonly elicited using air-conducted (AC) and bone-conducted (BC) stimulus modalities. Despite their growing clinical prevalence, the properties they exhibit remain less well studied. Mapping of the oVEMP was carried out for AC and BC modalities. A stable latency and larger more linear response to gaze angle were found for a slightly lateral recording electrode compared to the conventional one. Gaze angle can potentially differentiate between extraocular sources depending on the electrode montage used. AC frequency tuning of cVEMPs and oVEMPs were found to be broadly similar even when middle ear attenuation effects were accounted for. Stimulus phase did not modulate the observed frequency effects. AC stimuli tuning patterns and phase effects differ from those of BC stimuli which suggest differences in their mechanism of activating vestibular receptors. Both BC 500 Hz and BC impulses are effective means of evoking cVEMPs and oVEMPs from mid sagittal skull sites. The effects depend upon both location and phase and differ for cVEMPs and oVEMPs with the most consistent effects occurring for AFz and Fz stimulation. Dissociation between stimulus modalities was found for stimulus phase. Phase did not alter the properties of AC reflexes whereas BC reflexes were affected, more strongly for oVEMPs than for cVEMPs. Differences in phase effects between modalities may relate to their differing mechanisms of transduction. In vestibular neuritis, sparing of cVEMPs and abnormal oVEMPs were observed for AC and BC 500 Hz stimuli while BC impulses were generally affected for both reflexes. Modelling of the findings to AC and BC 500 Hz demonstrated strong utricular dependence for oVEMPs and strong saccular dependence for cVEMPs. Utricular contributions were demonstrated for both reflexes using BC impulses. Properties of cVEMPs and

Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common cooperative changes required for tumourigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET, and MAX. Using whole exome sequencing and high-density single-nucleotide polymorphism arrays, we analysed two to four primary tumours from each patient. We also applied multi-region sampling, to assess intratumoural heterogeneity and clonal evolution, in two cases involving paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour.

Cutaneous melanoma is a malignant neoplasm that arises from melanocytes in the skin, and is a significant cause of morbidity and mortality, especially in Australia. Next generation sequencing studies of cutaneous melanoma have confirmed the role of UV mutagenesis in its aetiology and demonstrated the high somatic mutation burden in this disease. To date, the majority of genomic analyses of cutaneous melanoma have limited their evaluation of somatic mutations to protein coding regions in order to detect cancer driver mutations. The recent discovery of driver mutations within the TERT promoter however has shown that biologically significant somatic events occur within non-coding regions of the melanoma genome. This thesis set out to further explore the presence, timing and biology of promoter-based somatic mutations in cutaneous melanoma. In this thesis, a systematic analysis of mutations in cutaneous melanoma demonstrated enrichment of somatic mutations within active promoters. Furthermore, somatic mutations were located within sequence motifs matching binding sites for ETS and Sp1 transcription factors. The number of promoter mutations within a tumour correlated with clinicopathological markers of chronic UV exposure and overall somatic mutation load. Strikingly, the same promoter mutations were detected in other cutaneous malignancies. In order to evaluate the potential of promoter mutations as biomarkers, a highly sensitive assay was developed to detect TERT promoter mutations, the most prevalent and biologically plausible promoter mutation. Using this assay on a series of benign melanocytic naevi identified TERT promoter mutations in 2/17 samples, providing evidence that these driver mutations occur in benign neoplasms with implications for the interpretation of TERT mutations in borderline clinical samples. Microdissection of melanomas with coexistent radial and vertical growth phases demonstrated that a majority of promoter mutations are early events in melanom

Todd et al. (2014ab) have recently demonstrated the presence of vestibular-dependent contributions to auditory evoked potentials (AEPs) when passing through the vestibular threshold as determined by vestibular evoked myogenic potentials (VEMPs), including a particular deflection labeled as an N42/P52 prior to the long-latency AEPs N1 and P2. In this paper we report the results of an experiment to determine the effect of inter-stimulus interval (ISI) and regularity on potentials recorded above and below VEMP threshold. Five healthy, right-handed subjects were recruited and evoked potentials were recorded to binaurally presented sound stimulation, above and below vestibular threshold, at seven stimulus rates with ISIs of 212, 300, 424, 600, 848, 1200 and 1696 ms. The inner five intervals, i.e. 300, 424, 600, 848, 1200 ms, were presented twice in both regular and irregular conditions. ANOVA on the global field power (GFP) were conducted for each of four waves, N42, P52, N1 and P2 with factors of intensity, ISI and regularity. Both N42 and P52 waves showed significant ANOVA effects of intensity but no other main effects or interactions. In contrast both N1 and P2 showed additional effects of ISI, as well as intensity, and evidence of non-linear interactions between ISI and intensity. A source analysis was carried out consistent with prior work suggesting that when above vestibular threshold, in addition to bilateral superior temporal cortex, ocular, cerebellar and cingulate sources are recruited. Further statistical analysis of the source currents indicated that the origin of the interactions with intensity may be the ISI sensitivity of the vestibular-dependent sources. This in turn may reflect a specific vestibular preference for stimulus rates associated with locomotion, i.e. rates close to 2 Hz, or ISIs close to 500 ms, where saccular afferents show increased gain and the corresponding reflexes are most sensitive.

BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors.

There is currently a paucity of preclinical models available to study the metastatic process in esophageal cancer. Here we report FLO-1, and its isogenic derivative FLO-1LM, as two spontaneously metastatic cell line models of human esophageal adenocarcinoma. We show that FLO-1 has undergone epithelial-mesenchymal transition and metastasizes following subcutaneous injection in mice. FLO-1LM, derived from a FLO-1 liver metastasis, has markedly enhanced proliferative, clonogenic, anti-apoptotic, invasive, immune-tolerant and metastatic potential. Genome-wide RNAseq profiling revealed a significant enrichment of metastasis-related pathways in FLO-1LM cells. Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1. Consistent with this, repression of E-cadherin expression in FLO-1 cells resulted in increased metastatic activity. Importantly, reduced E-cadherin expression is commonly reported in esophageal adenocarcinoma and independently predicts poor patient survival. Collectively, these findings highlight the biological importance of E-cadherin activity in the pathogenesis of metastatic esophageal adenocarcinoma and validate the utility of FLO-1 parental and FLO-1LM cells as preclinical models of metastasis in this disease.

Most cancer DNA sequencing studies have prioritized recurrent non-synonymous coding mutations in order to identify novel cancer-related mutations. Although attention is increasingly being paid to mutations in non-coding regions, standard approaches to identifying significant mutations may not be appropriate and there has been limited analysis of mutational clusters in functionally annotated non-coding regions. We sought to identify clustered somatic mutations (hotspot regions across samples) in functionally annotated regions in melanoma and other cutaneous malignancies (cutaneous squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma). Sliding window analyses revealed numerous recurrent clustered hotspot mutations in proximal promoters, with some specific clusters present in up to 25% of cases. Mutations in melanoma were clustered within ETS and Sp1 transcription factor binding motifs, had a UV signature and were identified in other cutaneous malignancies. Clinicopathologic correlation and mutation analysis support a causal role for chronic UV irradiation generating somatic mutations in transcription factor binding motifs of proximal promoters.

Most cancer DNA sequencing studies have prioritized recurrent non-synonymous coding mutations in order to identify novel cancer-related mutations. Although attention is increasingly being paid to mutations in non-coding regions, standard approaches to identifying significant mutations may not be appropriate and there has been limited analysis of mutational clusters in functionally annotated non-coding regions. We sought to identify clustered somatic mutations (hotspot regions across samples) in functionally annotated regions in melanoma and other cutaneous malignancies (cutaneous squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma). Sliding window analyses revealed numerous recurrent clustered hotspot mutations in proximal promoters, with some specific clusters present in up to 25% of cases. Mutations in melanoma were clustered within ETS and Sp1 transcription factor binding motifs, had a UV signature and were identified in other cutaneous malignancies. Clinicopathologic correlation and mutation analysis support a causal role for chronic UV irradiation generating somatic mutations in transcription factor binding motifs of proximal promoters.

We quantified intraneural blood flow (INBF) using a perfusion measurement software (PixelFlux), and compared it to the qualitative method of counting blood vessels (vessel score) in a cohort of carpal tunnel syndrome (CTS) patients. METHODS: 47 patients (67 wrists) with clinical and electrophysiological diagnosis of CTS, and 20 healthy controls (40 wrists) were enrolled. Median nerve ultrasound (US) was performed at the carpal tunnel inlet to measure the cross-sectional area (CSA) and vessel score. Power Doppler sonograms from nerves with detectable INBF were processed with PixelFlux, to obtain the maximum perfusion intensity (MPI). RESULTS: Forty-nine percent of CTS patients had detectable INBF compared to none in the control group (P<0.0001). MPI correlated significantly with vessel score (r=0.945, P<0.0001), CSA (r=0.613, P<0.0001), and electrophysiological severity (r=0.440, P<0.0001). MPI had higher intra/inter-observer reliability compared to vessel score (0.95 vs 0.47). CONCLUSION: MPI is a better method for quantification of INBF.

Cervical vestibular evoked myogenic potentials (cVEMPs) recorded over the lower quarter of the sternocleidomastoid (SCM) muscle in normal subjects may have opposite polarity to those recorded over the midpoint. It has thus been suggested that vestibular projections to the lower part of SCM might be excitatory rather than inhibitory. We tested the hypothesis that the SCM muscle receives both inhibitory and excitatory vestibular inputs. We recorded cVEMPs in 10 normal subjects with surface electrodes placed at multiple sites along the anterior (sternal) component of the SCM muscle. We compared several reference sites: sternum, ipsilateral and contralateral earlobes, and contralateral wrist. In five subjects, single motor unit responses were recorded at the upper, middle, and lower parts of the SCM muscle using concentric needle electrodes. The surface cVEMP had the typical positive-negative polarity at the midpoint of the SCM muscle. In all subjects, as the recording electrode was moved toward each insertion point, p13 amplitude became smaller and p13 latency increased, then the polarity inverted to a negative-positive waveform (n1-p1). Changing the reference site did not affect reflex polarity. There was a significant short-latency change in activity in 61/63 single motor units, and in each case this was a decrease or gap in firing, indicating an inhibitory reflex. Single motor unit recordings showed that the reflex was inhibitory along the entire SCM muscle. The cVEMP surface waveform inversion near the mastoid and sternal insertion points likely reflects volume conduction of the potential occurring with increasing distance from the motor point.

This study concerned the effects of brisk perturbations applied to the shoulders of standing subjects to displace them either forwards or backwards our aim being to characterise the responses to these disturbances. Subjects stood on a force platform and acceleration was measured at the level of C7, the sacrum and both tibial tuberosities. Surface EMG was measured from soleus (SOL), tibialis anterior (TA), the hamstrings (HS), quadriceps (QUAD), rectus abdominis (RA) and lumbar paraspinal (PS) muscles. Trials were recorded for each of four conditions: subjects’ eyes open (reference) or closed and on a firm (reference) or compliant surface. Observations were also made of voluntary postural reactions to a tap over the deltoid. Anterior perturbations (mean C7 acceleration 251.7 mg) evoked activity within the dorsal muscles (SOL, HS, PS) with a similar latency to voluntary responses to shoulder tapping. Responses to posterior perturbations (mean C7 acceleration -240.4 mg) were more complex beginning, on average, at shorter latency than voluntary activity (median TA 78.0 ms). There was activation of TA, QUAD and SOL associated with initial forward acceleration of the lower legs. The EMG responses consisted of an initial phasic discharge followed by a more prolonged one. These responses differ from the pattern of automatic postural responses that follow displacements at the level of the ankles and it is unlikely that proprioceptive afferents excited by ankle movement had a role in the initial responses. Vision and surface properties had only minor effects. Perturbations of the upper trunk evoke stereotyped compensatory postural responses for each direction of perturbation. For posterior perturbations EMG onset occurs earlier than for voluntary responses.

Objective: To define and compare the input–output properties of 500 Hz and 100 Hz bone-conducted (BC) transmastoid stimulation when evoking cVEMPs and oVEMPs. The findings for 500 Hz were compared with those previously reported for air-conducted (AC) 500 Hz stimulation.Methods: Twelve healthy subjects (18–57 years old) participated in this study, with simultaneous recordings of cVEMPs and oVEMPs bilaterally. Initial intensities of 138 dB (FL) were used and then reduced in 3 or 6 dB increments to 105 dB.Results: For BC 500 Hz, like AC 500 Hz, the relationship between the stimulus and reflex output fitted a power law for most peaks, but not the initial peak of the oVEMP. Some of the subjects did not have early crossed oVEMP responses for BC 500 Hz but all did for 100 Hz. For BC 100 Hz, while the initial waveforms were similar, many of the peaks showed a tendency to saturate at the higher intensities. For both BC 500 Hz and 100 Hz, the initial (contralateral) oVEMP peaks had a higher threshold than for the (ipsilateral) cVEMP responses although this difference was more marked for 500 Hz.Conclusions: BC 500 Hz shows similar properties to AC 500 Hz, consistent with an overlapping spectrum of afferents being excited by both, with bilateral effects for the BC stimulus. BC 100 Hz evokes more non-vestibular peaks, presumably from muscle afferents, for the SCM recordings but is a more reliable method of evoking the early crossed potentials of the oVEMP.Significance: BC 500 Hz is a useful adjunct to the AC 500 Hz stimulus and has similar properties. The BC 100 Hz stimulus may be a more reliable method of evoking the early crossed oVEMP responses.

Postural reflexes were recorded in healthy subjects (n = 17) using brief axial accelerations and tap stimuli applied at the vertebra prominens (C7) and manubrium sterni. Short latency (SL) responses were recorded from the soleus, hamstrings and tibialis anterior muscles and expressed as a percentage of the background EMG prior to stimulus onset. In the majority of postural conditions tested, subjects were recorded standing erect and leaning forward with their feet together. The SL response was larger for soleus than for the hamstrings during standing (soleus vs hamstrings; 70.4 vs 28.1 %), whereas the opposite occurred during kneeling (25.3 vs 127.3 %). Concordant head and trunk accelerations produced larger SL responses than discordant accelerations for soleus and hamstrings, but the evoked excitatory response was independent of head direction and as expected for the direction of truncal acceleration. Postural reflexes for soleus and tibialis anterior were strongly affected by conditions that posed a significant threat to postural stability; stimulation at C7 was associated with significant SL enhancement for soleus during anterior lean while sternal stimulation showed SL enhancement for tibialis anterior during posterior lean. Cutaneous anaesthesia applied over the C7 stimulation site had no significant effect on EMG responses, nor did vision or surface type (rigid or compliant). This study provides further evidence that postural reflexes produced by brief axial accelerations are independent of cutaneous receptors, vestibular afferents and ankle proprioceptors, and demonstrates that postural tasks and truncal orientation significantly affect the evoked response, consistent with a role in stabilising posture.

Objective: To compare and characterise abnormalities for short latency vestibular evoked myogenic potentials (VEMPs) elicited by air- (AC) and two differing types of bone-conducted (BC) stimuli during vestibular neuritis (VN). Methods: AC (500. Hz short tone bursts) and two BC stimuli (500. Hz at the forehead and impulses at the mastoids) were used to evoke cervical and ocular potentials (cVEMPs and oVEMPs) in VN patients (n= 22) and healthy subjects. Results: More abnormalities were observed for the oVEMP than the cVEMP when using either AC 500. Hz or BC 500. Hz. The AC stimulus showed slightly more abnormalities than the BC 500. Hz stimulus. In contrast, BC impulses produced frequent abnormalities for both oVEMPs and cVEMPs. The findings were modelled, based upon presumed selective lesions of the superior nerve. Conclusions: AC 500. Hz stimulation was slightly better than BC 500. Hz in demonstrating abnormalities in patients with VN. BC impulses behave as expected for a predominantly utricular stimulus. The relative contributions of saccular and utricular fibres differ for stimulus type and target reflex. Significance: AC 500 Hz is as effective as BC 500. Hz for investigating VN. BC impulses act most strongly on utricular afferents.

The successive treatment of [W(≡CBr)(CO)2(Tp∗)] (Tp∗ = hydrotris(3,5-dimethylpyrazol-1-yl)borate) with nBuLi and ClPPh2 affords the phosphinocarbyne complex [W(≡CPPh2)(CO)2(Tp∗)] (1), DFT interrogation

To develop evidence based points to consider the use of imaging in the diagnosis and management of juvenile idiopathic arthritis (JIA) in clinical practice. The task force comprised a group of paediatric rheumatologists, rheumatologists experienced in imaging, radiologists, methodologists and patients from nine countries. Eleven questions on imaging in JIA were generated using a process of discussion and consensus. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, scintigraphy and positron emission tomography. The experts used the evidence obtained from the relevant studies to develop a set of points to consider. The level of agreement with each point to consider was assessed using a numerical rating scale. A total of 13 277 references were identified from the search process, from which 204 studies were included in the systematic review. Nine points to consider were produced, taking into account the heterogeneity of JIA, the lack of normative data and consequent difficulty identifying pathology. These encompassed the role of imaging in making a diagnosis of JIA, detecting and monitoring inflammation and damage, predicting outcome and response to treatment, use of guided therapies, progression and remission. Level of agreement for each proposition varied according to the research evidence and expert opinion. Nine points to consider and a related research agenda for the role of imaging in the management of JIA were developed using published evidence and expert opinion.

To develop evidence based points to consider the use of imaging in the diagnosis and management of juvenile idiopathic arthritis (JIA) in clinical practice. The task force comprised a group of paediatric rheumatologists, rheumatologists experienced in imaging, radiologists, methodologists and patients from nine countries. Eleven questions on imaging in JIA were generated using a process of discussion and consensus. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, scintigraphy and positron emission tomography. The experts used the evidence obtained from the relevant studies to develop a set of points to consider. The level of agreement with each point to consider was assessed using a numerical rating scale. A total of 13 277 references were identified from the search process, from which 204 studies were included in the systematic review. Nine points to consider were produced, taking into account the heterogeneity of JIA, the lack of normative data and consequent difficulty identifying pathology. These encompassed the role of imaging in making a diagnosis of JIA, detecting and monitoring inflammation and damage, predicting outcome and response to treatment, use of guided therapies, progression and remission. Level of agreement for each proposition varied according to the research evidence and expert opinion. Nine points to consider and a related research agenda for the role of imaging in the management of JIA were developed using published evidence and expert opinion.

We report the results of a study to record vestibular evoked potentials (VsEPs) of cortical origin produced by impulsive acceleration (IA). In a sample of 12 healthy participants, evoked potentials recorded by 70 channel electroencephalography were obtained by IA stimulation at the nasion and compared with evoked potentials from the same stimulus applied to the forefingers. The nasion stimulation gave rise to a series of positive and negative deflections in the latency range of 26–72 ms, which were dependent on the polarity of the applied IA. In contrast, evoked potentials from the fingers were characterised by a single N50/P50 deflection at about 50 ms and were polarity invariant. Source analysis confirmed that the finger evoked potentials were somatosensory in origin, i.e. were somatosensory evoked potentials, and suggested that the nasion evoked potentials plausibly included vestibular midline and frontal sources, as well as contributions from the eyes, and thus were likely VsEPs. These results show considerable promise as a new method for assessment of the central vestibular system by means of VsEPs produced by IA applied to the head.

We compared the brain areas that showed significant flow changes induced by selective stimulation of muscle and cutaneous afferents using fMRI BOLD imaging. Afferents arising from the right hand were studied in eight volunteers with electrical stimulation of the digital nerve of the index finger and over the motor point of the FDI muscle. Both methods evoked areas of significant activation cortically, subcortically, and in the cerebellum. Selective muscle afferent stimulation caused significant activation in motor-related areas. It also caused significantly greater activation within the contralateral precentral gyrus, insula, and within the ipsilateral cerebellum as well as greater areas of reduced blood flow when compared to the cutaneous stimuli. We demonstrated separate precentral and postcentral foci of excitation with muscle afferent stimulation. We conclude, contrary to the findings with evoked potentials, that muscle afferents evoke more widespread cortical, subcortical, and cerebellar activation than do cutaneous afferents. This emphasizes the importance, for studies of movement, of matching the kinematic aspects in order to avoid the results being confounded by alterations in muscle afferent activation. The findings are consistent with clinical observations of the movement consequences of sensory loss and may also be the basis for the contribution of disturbed sensorimotor processing to disorders of movement.

We report the results of a study to record vestibular evoked potentials (VsEPs) of cortical origin produced by impulsive acceleration (IA). In a sample of 12 healthy participants, evoked potentials recorded by 70 channel electroencephalography were obtained by IA stimulation at the nasion and compared with evoked potentials from the same stimulus applied to the forefingers. The nasion stimulation gave rise to a series of positive and negative deflections in the latency range of 26–72 ms, which were dependent on the polarity of the applied IA. In contrast, evoked potentials from the fingers were characterised by a single N50/P50 deflection at about 50 ms and were polarity invariant. Source analysis confirmed that the finger evoked potentials were somatosensory in origin, i.e. were somatosensory evoked potentials, and suggested that the nasion evoked potentials plausibly included vestibular midline and frontal sources, as well as contributions from the eyes, and thus were likely VsEPs. These results show considerable promise as a new method for assessment of the central vestibular system by means of VsEPs produced by IA applied to the head.

Objective: To determine the amplitude changes of vestibular evoked myogenic potentials (VEMPs) recorded simultaneously from the neck (cVEMPs) and eyes (oVEMPs) in response to 500. Hz, 2. ms air-conducted sound pips over a 30. dB range. Methods: Fifteen healthy volunteers (mean age 29, range 18-57. years old) and one patient with unilateral superior canal dehiscence (SCD) were studied. The stimulus was reduced in increments to 105. dB pSPL for the normals (81. dB pSPL for the SCD patient). A statistical criterion was used to detect responses. Results: Ipsilateral (i-p13/n23) and contralateral (c-n12/p24/n30) peaks for the cVEMP montage and contralateral (c-n10/p16/n21) and ipsilateral (i-n13) peaks for the oVEMP montage were present for the baseline intensity. For the lowest intensity, 6/15 subjects had responses for the i-p13 cVEMP potential and 4/15 had c-n10 oVEMP responses. The SCD patient showed larger responses for nearly all intensities. The cVEMP potentials were generally well fitted by a power law relationship, but the oVEMP c-n10, p16 and n21 potentials showed a significant increase in gradient for the higher intensities. Conclusion: Most oVEMP and cVEMP responses follow a power law relationship but crossed oVEMP responses showed a change in gradient above a threshold. Significance: The pattern of response to AC stimulation may be a property of the pathways underlying the potentials. © 2013 International Federation of Clinical Neurophysiology.

Short lateral head accelerations were applied to investigate the recruitment properties of the reflexes underlying the earliest ocular and cervical electromyographic reflex responses to these disturbances. Components of both reflexes are vestibular dependent and have been termed "ocular vestibular evoked myogenic potentials" and "cervical vestibular evoked myogenic potentials", respectively. Previous investigations using a unilateral vestibular stimulus have indicated that some but not all these vestibular-dependent reflexes show a simple power law relationship to stimulus intensity. In particular, crossed otolith-ocular reflexes showed evidence of an inflection separating two types of behaviour. The present stimulus acts bilaterally, and only the earliest crossed otolith-ocular reflex, previously shown to have a strictly unilateral origin, showed evidence of an inflection. Reflex changes in ocular torsion could, in principle, correct for the changes associated with translation for an elevated eye, but our findings indicated that the responses were consistent with previous reports of tilt-type reflexes. For the neck, both vestibular and segmental (muscle spindle) reflexes were evoked and followed power law relationships, without any clear separation in sensitivity. Our findings are consistent with previous evidence of "tilt-like" reflexes evoked by lateral acceleration and suggest that the departure from a power law occurs as a consequence of a unilateral crossed pathway. For the neck, responses to transients are likely to always consist of both vestibular and non-vestibular (segmental) components. Most of the translation-evoked ocular and cervical reflexes appear to follow power law relationship to stimulus amplitude over a physiological range. © 2014 Springer-Verlag.

The palladium-mediated reaction of [W(≡CBr)(CO)2(Tp∗)] (Tp∗ = hydrotris(3,5-dimethylpyrazol-1-yl)borate) with primary phosphines PH2R (R = Ph, Cy) affords the secondary phosphinocarbyne complexes [W(≡CPHR)(CO)2(Tp∗)], deprotonation of which prov

Todd et al. (2014) have recently demonstrated the presence of vestibular dependent changes both in the morphology and in the intensity dependence of auditory evoked potentials (AEPs) when passing through the vestibular threshold as determined by vestibular evoked myogenic potentials (VEMPs). In this paper we extend this work by comparing left vs. right ear stimulation and by conducting a source analysis of the resulting evoked potentials of short and long latency. Ten healthy, right-handed subjects were recruited and evoked potentials were recorded to both left- and right-ear sound stimulation, above and below vestibular threshold. Below VEMP threshold, typical AEPs were recorded, consisting of mid-latency (MLR) waves Na and Pa followed by long latency AEPs (LAEPs) N1 and P2. In the supra-threshold condition, the expected changes in morphology were observed, consisting of: (1) short-latency vestibular evoked potentials (VsEPs) which have no auditory correlate, i.e. the ocular VEMP (OVEMP) and inion response related potentials; (2) a later deflection, labelled N42/P52, followed by the LAEPs N1 and P2. Statistical analysis of the vestibular dependent responses indicated a contralateral effect for inion related short-latency responses and a left-ear/right-hemisphere advantage for the long-latency responses. Source analysis indicated that the short-latency effects may be mediated by a contralateral projection to left cerebellum, while the long-latency effects were mediated by a contralateral projection to right cingulate cortex. In addition we found evidence of a possible vestibular contribution to the auditory T-complex in radial temporal lobe sources. These last results raise the possibility that acoustic activation of the otolith organs could potentially contribute to auditory processing.

Acoustic sensitivity of the vestibular apparatus is well-established, but the contribution of vestibular receptors to the late auditory evoked potentials of cortical origin is unknown. Evoked potentials from 500 Hz tone pips were recorded using 70 channel EEG at several intensities below and above the vestibular acoustic threshold, as determined by vestibular evoked myogenic potentials (VEMPs). In healthy subjects both auditory mid- and long-latency auditory evoked potentials (AEPs), consisting of Na, Pa, N1 and P2 waves, were observed in the sub-threshold conditions. However, in passing through the vestibular threshold, systematic changes were observed in the morphology of the potentials and in the intensity dependence of their amplitude and latency. These changes were absent in a patient without functioning vestibular receptors. In particular, for the healthy subjects there was a fronto-central negativity, which appeared at about 42 ms, referred to as an N42, prior to the AEP N1. Source analysis of both the N42 and N1 indicated involvement of cingulate cortex, as well as bilateral superior temporal cortex. Our findings are best explained by vestibular receptors contributing to what were hitherto considered as purely auditory evoked potentials and in addition tentatively identify a new component that appears to be primarily of vestibular origin.

The emergence of ‘policy analysis’ as a skilled occupation in the governmental process raised questions about the significance of this work for democratic control in government, and the relationship between the discourses of elected leadership, expert policy analysis, and public norms and understandings, in the construction of policy. The questions are even more acute in the ‘transitional polities’ of Eastern Europe, where the norms of democratic accountability are less well established, but the rules of the game are ‘under reconstruction’. This paper reviews the way the themes of professionalism and participation relate to policy work in transitional polities, the tensions that policy workers face, and the way that the diverse discourses available are mobilized in the discursive construction of policy and policy work., Pojava analize javnih politika kao kvalificiranog zanimanja u procesu vladanja otvorila je pitanja o važnosti te vrste posla za demokratsku kontrolu vlasti, te o odnosu između diskursa izabranih vođa, profesionalnih analitičara politika i javnih normi i razumijevanja u konstrukciji javnih politika. Ta su pitanja još istaknutija u ‘tranzicijskim političkim sustavima’ Istočne Europe, gdje su norme demokratske odgovornosti manje uspostavljene, a pravila igre su u izgradnji. Ovaj rad razmatra u kojem su odnosu teme profesionalizma i participacije s radom na javnim politikama u zemljama u tranziciji, zatim napetosti s kojima se suočavaju oni koji rade na javnih politikama, te na koji se način različiti dostupni diskursi mobiliziraju u diskurzivnoj konstrukciji javnih politika i rada na javnim politikama.