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Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macro-Bound Enhancers’, that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.

The versatility of somatosensation arises from heterogenous human dorsal root ganglion (DRG) neurons. The critical information to decipher their functions, i.e., the soma transcriptome, is lacking due to technical difficulties. Here we developed a novel approach to isolate individual human DRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed that touch-, cold-, and itch-sensing neuronal types were relatively conserved, while the pain-sensing neurons displayed marked divergence. Soma transcriptomes of human DRG neurons predicted novel functional features, which were confirmed using single-cellin vivoelectrophysiological recordings. These results support a close relationship the between physiological properties of human sensory afferents and molecular profiles uncovered by the single-soma RNA-seq dataset. In summary, by conducting single-soma RNA-seq of human DRG neurons, we generated an unprecedented neural atlas for human somatosensation.

IntroductionThe role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Aδ-fiber range consistent with the canonical view that “fast pain” is signaled by Aδ nociceptors. We recently demonstrated that human skin is equipped with ultrafast (Aβ range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception.MethodsWe revisited our earlier work on NWR measurements in which, following convention, only reflex responses in the presumed Aδ range were considered. In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings.ResultsIn both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings based on reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range.ConclusionWe found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. Whether these are signaled by the ultrafast nociceptors remains to be determined.

Background One of the main limitations of radiation therapy is the resistance of tumor cells. This study aimed at evaluating the relationship between the expression of epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and tumor radiosensitivity in patients with non-small cell lung cancer. Methods Medical case files, pathological results for EGFR and EML4-ALK, and computerized tomography scans of patients with NSCLC treated with thoracic radiation therapy were analyzed. Results The sample size was 101 patients with mean age 58.43 ± 9.89 years. Statistically significant differences were observed in the mean reduction of long tumor diameter during the early treatment phase in EGFR-positive versus EGFR-negative patients (p value = 0.04) and in short tumor diameter during the late treatment phase in EGFR-positive versus EGFR-negative patients (p value = 0.04). Conclusion Patients with overexpression of EGFR mutations are more radiosensitive during the early treatment phase, and EML4-ALK mutations were less radiosensitive regardless of phases.

Background Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested. Methods An initial cohort (n = 10) received repeated injections (5 mu g: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2). Results The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (similar to 43%) hyperalgesia at day 7 compared with the other groups. Conclusions The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration. Significance In a double-blind placebo-controlled drug-crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre-emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia. Funding Agencies|Western Sydney University School of Medicine under the Research Training Program (RTP)

Resume Le corps calleux est la commissure inter-hemispherique la plus importante du systeme nerveux central. Il constitue un element de morphologie complexe ayant plusieurs rapports intimes avec les differentes structures avoisinantes. Les progres techniques, notamment de l’imagerie par resonance magnetique (IRM) a totalement change l’approche diagnostique de la pathologie du corps calleux et a permis d’en modifier la prise en charge et le suivi. Les causes d’anomalie de signal du corps calleux sont dominees par les pathologies demyelinisantes et vasculaires. Les autres causes d’atteinte du corps calleux peuvent etre de nature metabolique, traumatique, tumorale, toxique et des causes micellaires ont ete individualisees.

Brushed stimuli are perceived as pleasant when stroked lightly on the skin surface of a touch receiver at certain velocities. While the relationship between brush velocity and pleasantness has been widely replicated, we do not understand how resultant skin movements - e.g., lateral stretch, stick-slip, normal indentation - drive us to form such judgments. In a series of psychophysical experiments, this work modulates skin movements by varying stimulus stiffness and employing various treatments. The stimuli include brushes of three levels of stiffness and an ungloved human finger. The skin's friction is modulated via non-hazardous chemicals and washing protocols, and the skin's thickness and lateral movement are modulated by thin sheets of adhesive film. The stimuli are hand-brushed at controlled forces and velocities. Human participants report perceived pleasantness per trial using ratio scaling. The results indicate that a brush's stiffness influenced pleasantness more than any skin treatment. Surprisingly, varying the skin's friction did not affect pleasantness. However, the application of a thin elastic film modulated pleasantness. Such barriers, though elastic and only 40 microns thick, inhibit the skin's tangential movement and disperse normal force. The finding that thin films modulate affective interactions has implications for wearable sensors and actuation devices.

C-tactile (CT) fibers, a population of unmyelinated (C) fibers that respond particularly well to gentle stroking, are widely believed to subserve affective touch. However, these fibers (termed C low-threshold mechanoreceptors (C-LTMRs) in non-human mammals) have also been proposed to be involved in the modulation of pain. Intriguingly, functional evidence from both human and animal studies indicates that CT/C-LTMR fibers can both contribute to allodynia as well as mediate pain inhibition. In the spinal cord, C-LTMR fibers form glomerular synaptic arrangements, providing input to several populations of interneurons within the nociceptive circuitry. Thus, the CT/C-LTMR system conveys signals that are subject to intricate processing in the spinal cord and is well-situated within spinal sensory pathways to enable the modulation of pain.

One of the main limitations of radiation therapy is the resistance of tumor cells. This study aimed at evaluating the relationship between the expression of epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and tumor radiosensitivity in patients with non-small cell lung cancer.Medical case files, pathological results for EGFR and EML4-ALK, and computerized tomography scans of patients with NSCLC treated with thoracic radiation therapy were analyzed.The sample size was 101 patients with mean age 58.43 ± 9.89 years. Statistically significant differences were observed in the mean reduction of long tumor diameter during the early treatment phase in EGFR-positive versus EGFR-negative patients (p value = 0.04) and in short tumor diameter during the late treatment phase in EGFR-positive versus EGFR-negative patients (p value = 0.04).Patients with overexpression of EGFR mutations are more radiosensitive during the early treatment phase, and EML4-ALK mutations were less radiosensitive regardless of phases.

Aim Patellofemoral instability is where various stabilising factors of the patellofemoral joint undergo pathomorphological changes. It has an incidence rate of 5.8 per 100,000 in UK and has been associated with osteoarthritis[1]. Variations in the factors that stabilise the patellofemoral joint can be observed on MRI including measurements of the trochlea in relation to the patella, the femur and soft tissue changes. This study aims to compare different measures used to detect and quantify patellofemoral instability on MRIs and to look for any significant difference in their use both in isolation and together. Method 109 MRI reports of 78 patients diagnosed with patellofemoral instability were reviewed and all quantitative and qualitative parameters reported were inputted in a data table. Quantitative elements known as the Dejour protocol included the trochlear sulcus angle, patellar tilt angle, tibial tuberosity-trochlear groove distance and the Insall-Salvati ratio. Qualitative factors involved facet changes, patellar position, and any damage to soft tissue. Results It was found that the Insall-Salvati ratio greater than 1.2 and the patellar tilt angle of greater than 11 degrees irregular ranges had the greatest incidence in the MRI reports found 77.1% and 87.6% respectively in MRIs that reported them. Conclusions There is a discrepancy between quantitative parameters in their correlation with patellofemoral instability for the MRI reports observed. [1]: Ye Q, Yu T, Wu Y, Ding X, Gong X. Patellar instability: the reliability of magnetic resonance imaging measurement parameters. BMC Musculoskeletal Disorders. 2019;20(1).

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Detection of scattering and absorption properties in both visible and near-infrared regions are crucial to quantify multiple functional responses in tissue. We developed a compact, clinical spatial frequency domain imaging (SFDI) system around a custom, nine wavelength, compound-eye camera, spanning ~450-1000nm. In addition to the characterization and validation of this device, we performed a preliminary in-vivo investigation to evaluate the imager’s ability to characterize dermal response under a noxious heating protocol. Increases in hemoglobin and water concentration are detected as well as slight alterations in the reduced scattering spectrum that maybe correlated with cellular and extra-cellular reactivity.

Ageing is accompanied by a steady decline in touch sensitivity and acuity. Conversely, pleasant touch, such as experienced during a caress, is even more pleasant in old age. There are many physiological changes that might explain these perceptual changes, but researchers have not yet identified any specific mechanisms. Here, we review both the perceptual and structural changes to the touch system that are associated with ageing. The structural changes include reduced elasticity of the skin in older people, as well as reduced numbers and altered morphology of skin tactile receptors. Effects of ageing on the peripheral and central nervous systems include demyelination, which affects the timing of neural signals, as well as reduced numbers of peripheral nerve fibres. The ageing brain also undergoes complex changes in blood flow, metabolism, plasticity, neurotransmitter function, and, for touch, the body map in primary somatosensory cortex. Although several studies have attempted to find a direct link between perceptual and structural changes, this has proved surprisingly elusive. We also highlight the need for more evidence regarding age-related changes in peripheral nerve function in the hairy skin, as well as the social and emotional aspects of touch.

This study describes a novel and versatile method of incorporating graphene nano-platelets (GNP) into composite laminates to investigate its effect on mode I and mode II interlaminar fracture toughness (ILFT). Non-woven thermoplastic veil interleaves have been modified by spray deposition with a GNP dispersion to give either a continuous or strip-patterned distribution. The coated interleaves were used to modify the interlaminar region of carbon fibre reinforced polymer (CFRP) laminates. The fracture surfaces were characterised by scanning electron and optical microscopy.The continuous GNP distribution in mode I prevented the formation of carbon fibre bridging, resulting in similar initiation and propagation values. In mode II, the increased thickness of the interlaminar region, coupled with the uneven fracture surface showed the highest increase in the mode II ILFT for the continuous GNP distribution. The strip-patterned GNP distribution showed reduced carbon fibre bridging compared to the baseline CFRP and thermoplastic interleave laminates. This may be due to small scale fibre bridging between the deposited GNP-strips which also lead to peaks and troughs in the load-displacement response. In mode II, it is suggested that the deposited GNP-strips were sufficiently tough to re-direct the propagating crack from the modified interlaminar region to the adjacent ply.

The temporal pattern of action potentials can convey rich information in a variety of sensory systems. We describe a new non-invasive technique that enables precise, reliable generation of action potential patterns in tactile peripheral afferent neurons by brief taps on the skin. Using this technique, we demonstrate sophisticated coding of temporal information in the somatosensory system, that shows that perceived vibration frequency is not encoded in peripheral afferents as was expected by either their firing rate or the underlying periodicity of the stimulus. Instead, a burst gap or silent gap between trains of action potentials conveys frequency information. This opens the possibility of new encoding strategies that could be deployed to convey sensory information using mechanical or electrical stimulation in neural prostheses and brain-machine interfaces, and may extend to senses beyond artificial encoding of aspects of touch. We argue that a focus on appropriate use of effective temporal coding offers more prospects for rapid improvement in the function of these interfaces than attempts to scale-up existing devices. Funding Agencies|NHMRCNational Health and Medical Research Council of Australia [APP1028284]; ARCAustralian Research Council [DP200100630]; Australian Government Research Training Program ScholarshipAustralian GovernmentDepartment of Industry, Innovation and Science

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)—ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)—50 μl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.

Introduction Les tumeurs cerebrales peuvent etre responsables de diabete insipide central mais la potomanie est rare. Observation Nous rapportons le cas d’un patient de 15 ans, sans antecedents pathologiques notables, qui consultait pour un syndrome polyuropolydipsique de 4 a 5 litres par jour. L’examen physique etait normal. La glycemie, la calcemie, l’ionogramme ainsi que le bilan antehypophysaire etaient normaux. Le test de restriction hydrique montrait une concentration des urines en faveur d’une potomanie. Devant la persistance de la symptomatologie et la nycturie perturbant le sommeil, avec vomissements, une IRM hypophysaire etait demandee. Elle montrait une tumeur pineale de 13 mm avec absence d’individualisation de la posthypophyse. Le diagnostic de germinome non secretant metastatique a ete retenu devant l’apparition, trois mois apres, de nouvelles localisations cerebrales a l’imagerie de controle. Le patient a beneficie de radiotherapie en IMRT delivrant 36 Gy a raison de 1,8 Gy, 5 fractions par semaine, sur l’ensemble de l’encephale et du nevraxe, avec amelioration progressive des signes fonctionnels mais apparition d’un panhypopituitarisme. L’IRM hypophysaire de controle un mois apres radiotherapie ne trouve aucune image lesionnelle intracrânienne. Le controle radiologique annuel pendant 3 ans note une stabilite des sequelles post-radiques avec absence de recidive. Conclusion Les tumeurs intracrâniennes posent souvent un probleme de retard diagnostique. En cas de SPUPD genant non explique par une anomalie metabolique ou endocrinienne, une imagerie cerebrale trouve son indication meme si l’epreuve de restriction hydrique montre une potomanie.

Background C-tactile (CT) afferents are unmyelinated low-threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation. Methods In total, 44 healthy volunteers experienced heat pain and CT optimal (slow brushing) and CT sub-optimal (fast brushing or vibration) stimuli. Three different experimental paradigms were used: Concurrent application of heat pain and tactile (slow brushing or vibration) stimulation; Slow brushing, applied for variable duration and intervals, preceding heat pain; Slow versus fast brushing preceding heat pain. Results Slow brushing was effective in reducing pain, whereas fast brushing or vibration was not. The reduction in pain was significant not only when the CT optimal touch was applied simultaneously with the painful stimulus but also when the two stimuli were separated in time. For subsequent stimulation, the pain reduction was more pronounced for a shorter time interval between brushing and pain. Likewise, the effect was more robust when pain was preceded by a longer duration of brush stimulation. Strong CT-related pain reduction was associated with low anxiety and high calmness scores obtained by a state anxiety questionnaire. Conclusions Slow brushing – optimal for CT activation – is effective in reducing pain from cutaneous heating. The precise mechanisms for the pain relief are as yet unknown but possible mechanisms include inhibition of nociceptive projection neurons at the level of the dorsal horn as well as analgesia through cortical mechanisms. Significance Slow brushing stimuli – optimal for activation of C-tactile fibres – can reduce pain from cutaneous heating. No such effect was seen with fast brushing or vibration. These observations indicate the role of C-tactile fibres in pain modulation.

PURPOSE OF THE STUDY The purpose of the study was to evaluate neurodegeneration along brain visual pathways in primary open angle glaucoma (POAG) using improved analysis methods of volumetric and diffusion tensor magnetic resonance imaging (MRI) data. METHODS Eleven POAG patients (60.0±9.2 y) with primarily mild to moderate POAG and 11 age-matched controls (55.9±7.5 y) were studied using structural and diffusion tensor MRI. Surface-based segmentation was applied to structural MRI to obtain visual cortical area and volume. Fiber tracking was applied to diffusion tensor data to obtain diffusion parameters along the optic tract and optic radiation. MRI parameters in glaucoma patients were compared with the corresponding left and right visual fields and retinal nerve fiber layer thicknesses, instead of with the left and right eye. RESULTS Area and volume of the primary visual cortex were significantly reduced in POAG patients compared with controls (P

Human-to-human touch conveys rich, meaningful social and emotional sentiment. At present, however, we understand neither the physical attributes that underlie such touch, nor how the attributes evoke responses in unique types of peripheral afferents. Indeed, nearly all electrophysiological studies use well-controlled but non-ecological stimuli. Here, we develop motion tracking and algorithms to quantify physical attributes – indentation depth, shear velocity, contact area, and distance to the cutaneous sensory space (receptive field) of the afferent – underlying human-to-human touch. In particular, 2-D video of the scene is combined with 3-D stereo infrared video of the toucher’s hand to measure contact interactions local to the receptive field of the receiver’s afferent. The combined and algorithmically corrected measurements improve accuracy, especially of occluded and misidentified fingers. Human subjects experiments track a toucher performing four gestures – single finger tapping, multi-finger tapping, multi-finger stroking and whole hand holding – while action potentials are recorded from a first-order afferent of the receiver. A case study with one rapidly-adapting (Pacinian) and one C-tactile afferent examines temporal ties between gestures and elicited action potentials. The results indicate this method holds promise in determining the roles of unique afferent types in encoding social and emotional touch attributes in their naturalistic delivery.

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies amp;lt; 60 Hz) and vibratory hum (frequencies amp;gt; 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types. Funding Agencies|National Health and Medical Research Council [APP1028284, DP170100064]

BackgroundWe have previously shown that an intramuscular infusion of 5% hypertonic saline (HS) produces a painful response to normally innocuous stimuli applied to overlying and adjacent skin regions. In the current study, we explored whether a similar interaction could be observed between adjacent, contralateral and remote muscles. Indeed, widespread muscle pain-hypersensitivity is a hallmark of chronic pain conditions such as fibromyalgia.Methods5% HS was infused into the flexor carpi ulnaris (FCU) muscle to develop a stable baseline pain (n=30). In separate experiments, each of the three test locations (n=10 per site), the adjacent abductor digiti minimi (ADM), contralateral FCU and contralateral tibialis anterior (TA) (part 1-3, respectively), 50μL of 0.9% normal saline (NS) was infused (in triplicate) prior to, during and following HS-induced muscle pain.ResultsUnder control conditions (no background pain), the infusion of NS was imperceptible by all subjects. In the presence of HS-induced background pain (FCU), in part 1 the NS co-infusion into ADM increased overall pain by 17%. This was replicated in the contralateral FCU (part 2) with a 12% pain increase, and in the TA (part 3) with a 15% pain increase in response to the NS co-infusions. Notably, over 80% of subjects perceived the NS-induced increase in pain at the HS-infusion location (FCU) rather than the NS-infusion location (adjacent, contralateral and remote).ConclusionsIntramuscular infusion of HS results in pain-hypersensitivity to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.SignificanceThis work provides evidence for a regionally diffuse type of pain hypersensitivity, manifesting as a painful response to normally sub-perceptual stimulation in the context of acute experimentally induced muscle pain. This phenomenon may provide parallels to clinically relevant painful conditions and neuropathies.

Pain can be signaled as fast as touch in human peripheral nerves., The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated (“fast” pain) or unmyelinated (“slow” pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.

Pituitary apoplexy is an uncommon but potentially life-threatening emergency due to abrupt ischemic infarction or hemorrhage of the pituitary tumor. In many instances, pituitary apoplexy is the initial presentation in patients who were not previously diagnosed to have pituitary adenomas. Variety of precipitating factors have been linked to the occurrence of pituitary apoplexy, which include pregnancy. However, pituitary apoplexy related to pregnancy is limited to isolated case reports and very small case series. The main symptom is headache of sudden onset associated with visual disturbances, signs of meningeal irritation, and/or endocrine dysfunction. In the context of pregnancy the diagnosis of pituitary apoplexy can be challenging and confused with other complex conditions such as pre-eclampsia. Magnetic resonance imaging is the most sensitive sequence to confirm the diagnosis by revealing a pituitary tumor with hemorrhagic and/or necrotic components. Corticotropic deficiency with adrenal insufficiency is a potentially life-threatening disorder for both mother and the fetus if left untreated. The choice between conservative management with dopamine agonists and glucocorticoid, this "wait and see approach" and trans-sphenoidal resection depend on the severity of neuro-ophtalmic signs and the gestational week. In this article, we present three cases of pituitary apoplexy related to pregnancy. Pituitary apoplexy occurred in the third trimester in the three cases. It was the first presentation of an unknown pituitary adenoma in two cases, and complicated a preexisting macroprolactinoma in the other case. All three cases of our patients had sudden onset of severe headache and deterioration of the visual field in two cases. The pituitary MRI performed in our patients was the essential tool confirming the diagnosis of pituitary apoplexy. In all the patients was prompt replacement of deficient hormones especially glucocorticoids with close surveillance. The trans-sphenoidal resection was indicated in two pregnant women; as the first choice treatment in one case presenting with papillary edema, and as the second line after the deterioration of the visual field in one case. In the lack of guidelines of management pituitary apoplexy in case of pregnancy, we review the existing literature with pertinent clinical presentation, radiological findings, management and maternal/fetal outcomes of this rare pathology. The aim is to provide a rational framework for therapeutic management of pituitary apoplexy during pregnancy.

Objectifs Confirmer le diagnostic d’une fistule carotido-caverneuse (FCC) en se basant sur la clinique et les donnees de l’imagerie (angio-TDM et angio-IRM) : – rappeler la classification de Barrow des FCC ; – illustrer les differents aspects en imagerie et en angiographie des FCC ; – preciser l’apport de la radiologie interventionnelle dans le traitement des FCC. Materiels et Methodes Etude retrospective des patients ayant beneficie d’un traitement endovasculaire d’une FCC entre 2012 et 2018. Tous nos patients ont eu une angio-TDM et une angio-IRM. Une angiographie cerebrale diagnostique a ete realisee chez tous nos patients. La technique d’embolisation de la FCC a ete choisie en fonction des donnees angiographiques. Une angiographie de controle a ete realisee entre 3et 6 mois post-embolisation. Resultats Nous avons collige 16 patients âges entre 11et 59 ans. Un contexte traumatique a ete retrouve chez 14 patients. La symptomatologie revelatrice a ete une exophtalmie pulsatile avec chemosis chez tous les patients. En imagerie, une exophtalmie unilaterale, une dilatation de la veine ophtalmique et une opacification precoce du sinus caverneux des le temps arteriel ont ete les elements cles du diagnostic ( Fig. 1 ). La FCC a ete secondaire a une rupture d’un anevrisme arteriel de la carotide intra-caverneuse dans 2 cas. La voie arterielle avec embolisation par des Coils selon la technique de remodelage au ballon a ete utilisee dans l’ensemble des cas, la voie veineuse a ete utilisee chez une patiente. Une exclusion complete et immediate a ete obtenue chez 12 patients ( Fig. 2 ). L’exclusion etait partielle dans 4 cas. Le controle angiographique realise 3 mois apres l’embolisation a revele l’exclusion spontanee chez 3 de ces patients. Un seul patient a necessite une reprise. Un patient a eu une recanalisation de sa FCC apres exclusion complete necessitant une 2eme embolisation apres 3 mois. Conclusion Les FCC sont rares avec predilection du contexte post traumatique. L’angiographie constitue une pierre angulaire dans le diagnostic, l’etablissement de la strategie therapeutique endovasculaire et le suivi post embolisation.

It is generally agreed that cold allodynia is a consequence of impaired (Aδ-fibre-mediated) central inhibition of C-nociceptive inputs. However, it is also known that C polymodal nociceptors are not activated at innocuous low temperatures. Recently, we demonstrated the contribution of C-tactile fibres to tactile allodynia. In this study, we investigated whether this, or a related, C-fibre class contributes to cold allodynia. In 30 healthy and 3 chronic pain subjects, a series of normally innocuous localised thermal stimuli were applied to the skin overlying a painful tibialis anterior muscle (induced by infusion of hypertonic saline). The effects of thermal stimulation on muscle pain were observed before and after compression blockade of myelinated fibres. Furthermore, intradermal capsaicin, menthol and TTA-A2 were used for desensitisation of TRPV1, TRPM8, and T-type calcium (Cav3.2) channels, respectively. Before muscle pain, all thermal stimuli were reported as nonpainful regardless of whether myelinated fibres were conducting or not. During muscle pain, dynamic skin cooling (32°C → 20°C) evoked significant and reproducible increases in the overall pain intensity (allodynia). This increase was short lived and locked to the dynamic phase of cooling with pain levels returning to baseline during sustained cooling. Dynamic warming (32°C → 39°C) had no effect on pain levels. Cold allodynia persisted after nerve compression and TRPV1 and TRPM8 desensitisation but was abolished by localised Cav3.2 blockade. In clinical subjects, C-fibre-mediated allodynia was observed without the need for experimental pain-producing manipulations. In conclusion, cold allodynia represents a non-TRPV1- and non-TRPM8-dependent phenomenon, which is mediated by low-threshold Cav3.2-expressing C fibres.

Radiotherapy is the ionizing radiation used for treatment of cancer and other diseases. Although radiotherapy is the major treatment for cancer, a lot of patients do not undergo radiation due to associated risks such as radiation pneumonitis, cardiovascular complications, development of secondary tumor, and lymphedema. However, the advantages of nanotechnology provide a unique potential to enhance radiotherapeutic performance, in particular by utilizing gold nanoparticles (Au NPs). In this review, we briefly describe the current direction of research towards the use of Au NPs for radiotherapeutic enhancement, combination, monitoring and in side effect reductions.

PURPOSE To investigate retinotopic functional representation in the visual cortex of mild to moderate primary open-angle glaucoma (POAG) participants and age-matched normal volunteers using high-resolution retinotopic blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS fMRI was performed on 9 POAG participants (61±11 y old) and 9 age-matched controls (58±5 y old) were studied. A wide-view visual presentation (±55 degrees) was used to evaluate central and peripheral vision. Cortical magnification factors and BOLD% changes as a function of eccentricity. Correlation analysis between BOLD% changes and visual field scores, and between BOLD% changes and retinal nerve fiber layer thicknesses was performed. Comparison of BOLD% changes for individual visual field quadrants between POAG subgroups and normal group was performed. RESULTS BOLD% changes of POAG participants in peripheral visual regions were reduced compared to normals but similar in central visual regions, consistent with the notion of peripheral vision being affected first and more compared to central vision. fMRI retinotopic mapping revealed enlarged representation of the parafovea in the visual cortex of POAG participants compared to normals. Cortical magnification of the central, but not peripheral, visual representation in the visual cortex was larger in POAG participants, suggesting functional remapping. BOLD% changes of individual visual field quadrants were significantly correlated with visual field scores and with retinal nerve fiber layer thickness in the corresponding quadrants. CONCLUSIONS These results support the hypothesis that there are functional alteration and remapping in the topographic representation of the visual cortex in POAG participants, and these changes are correlated with disease severity.

Background: It has long been known that a concomitantly cooled stimulus is perceived as heavier than the same object at a neutral temperature-termed Webers Phenomenon (WP). In the current study, we re-examined this phenomenon using well-controlled force and temperature stimuli to explore the complex interplay between thermal and tactile systems, and the peripheral substrates contributing to these interactions. A feedback-controlled apparatus was constructed using a mechanical stimulator attached to a 5- x 5-mm thermode. Force combinations of 0.5 and 1 N (superimposed on 1-N step) were applied to the ulnar territory of dorsal hand. One of the forces had a thermal component, being cooled from 32 to 28 degrees C at a rate of 2 degrees C/s with a 3-s static phase. The other stimulus was thermally neutral (32 degrees C). Participants were asked to report whether the first or the second stimulus was perceived heavier. These observations were obtained in the all-fibre-intact condition and following the preferential block of myelinated fibres by compression of ulnar nerve. Results: In normal condition, when the same forces were applied, all subjects displayed a clear preference for the cooled tactile stimulus as being heavier than the tactile-only stimulus. The frequency of this effect was augmented by an additional similar to 17% when cooling was applied concurrently with the second stimulus. Following compression block, the mean incidence of WP was significantly reduced regardless of whether cooling was applied concurrently with the first or the second stimulus. However, while the effect was abolished in case of former (elicited in amp;lt; 50% of trials), the compression block had little effect in four out of nine participants in case of latter who reported WP in at least 80% of trials (despite abolition of vibration and cold sensations). Conclusions: WP was found to be a robust tactile-thermal interaction in the all-fibre-intact condition. The emergence of inter-individual differences during myelinated block suggests that subjects may adopt strategies, unbeknownst to them, that focus on the dominant input (myelinated fibres, hence WP abolished by block) or the sum of convergent inputs (myelinated and C fibres, hence WP preserved during block) in order to determine differences in perceived heaviness. Funding Agencies|Western Sydney University Early Career Research Grant [P00021752]; School of Medicine, Western Sydney University