Voltage-gated sodium channel expression in mouse DRG after SNI leads to re-evaluation of projections of injured fibers.

BACKGROUND: Dysregulation of voltage-gated sodium channels (Na(v)s) is believed to play a major role in nerve fiber hyperexcitability associated with neuropathic pain. A complete transcriptional characterization of the different isoforms of Na(v)s under normal and pathological conditions had never been performed on mice, despite their widespread use in pain research. Na(v)s mRNA levels in mouse dorsal root ganglia (DRG) were studied in the spared nerve injury (SNI) and spinal nerve ligation (SNL) models of neuropathic pain. In the SNI model, injured and non-injured neurons were intermingled in lumbar DRG, which were pooled to increase the tissue available for experiments. RESULTS: A strong downregulation was observed for every Na(v)s isoform expressed except for Na(v)1.2; even Na(v)1.3, known to be upregulated in rat neuropathic pain models, was lower in the SNI mouse model. This suggests differences between these two species. In the SNL model, where the cell bodies of injured and non-injured fibers are anatomically separated between different DRG, most Na(v)s were observed to be downregulated in the L5 DRG receiving axotomized fibers. Transcription was then investigated independently in the L3, L4 and L5 DRG in the SNI model, and an important downregulation of many Na(v)s isoforms was observed in the L3 DRG, suggesting the presence of numerous injured neurons there after SNI. Consequently, the proportion of axotomized neurons in the L3, L4 and L5 DRG after SNI was characterized by studying the expression of activating transcription factor 3 (ATF3). Using this marker of nerve injury confirmed that most injured fibers find their cell bodies in the L3 and L4 DRG after SNI in C57BL/6 J mice; this contrasts with their L4 and L5 DRG localization in rats. The spared sural nerve, through which pain hypersensitivity is measured in behavioral studies, mostly projects into the L4 and L5 DRG. CONCLUSIONS: The complex regulation of Na(v)s, together with the anatomical rostral shift of the DRG harboring injured fibers in C57BL/6 J mice, emphasize that caution is necessary and preliminary anatomical experiments should be carried out for gene and protein expression studies after SNI in mouse strains

Pain Intensity in the First 96 Hours After Abdominal Surgery: A Prospective Cohort Study.

Multimodal pain management strategies aim to improve postoperative pain control. The purpose of this study was to analyze pain scores and risk factors for acute postoperative pain after various abdominal surgery procedures. Data on 11 different abdominal surgery procedures were prospectively recorded. Pain intensity (rest, mobilization) and patient satisfaction at discharge were assessed using a visual analog scale (VAS; 0-10), and analgesic consumption was recorded until 96 hours postoperation. Demographic, surgery-related, and pain management-related univariate risk factors for insufficient pain control (VAS ≥ 4) were entered in a multivariate logistic regression model. A total of 1,278 patients were included. Overall, mean VAS scores were <3 at all time points, and scores at mobilization were consistently higher than at rest (P < 0.05). Thirty percent of patients presented a prolonged VAS score ≥4 at mobilization at 24 hours, significantly higher than at rest (14%, P < 0.05). High pain scores correlated with high opioid consumption, whereas a variability of pain scores was observed in patients with low opioid consumption. The only independent risk factor for moderate and severe pain (VAS ≥ 4) was younger age (<70 years, P = 0.001). The mean satisfaction score was 8.18 ± 1.29. Among 1,278 patients, pain was controlled adequately during the first four postoperative days, resulting in high levels of patient satisfaction. Pain levels were higher at mobilization. Younger age was the only independent risk factor for insufficient pain control. Preventive treatment in patients <70 years old and before mobilization could be evaluated for potential improvement

Spinal Cord T-Cell Infiltration in the Rat Spared Nerve Injury Model: A Time Course Study.

The immune system is involved in the development of neuropathic pain. In particular, the infiltration of T-lymphocytes into the spinal cord following peripheral nerve injury has been described as a contributor to sensory hypersensitivity. We used the spared nerve injury (SNI) model of neuropathic pain in Sprague Dawley adult male rats to assess proliferation, and/or protein/gene expression levels for microglia (Iba1), T-lymphocytes (CD2) and cytotoxic T-lymphocytes (CD8). In the dorsal horn ipsilateral to SNI, Iba1 and BrdU stainings revealed microglial reactivity and proliferation, respectively, with different durations. Iba1 expression peaked at D4 and D7 at the mRNA and protein level, respectively, and was long-lasting. Proliferation occurred almost exclusively in Iba1 positive cells and peaked at D2. Gene expression observation by RT-qPCR array suggested that T-lymphocytes attracting chemokines were upregulated after SNI in rat spinal cord but only a few CD2/CD8 positive cells were found. A pronounced infiltration of CD2/CD8 positive T-cells was seen in the spinal cord injury (SCI) model used as a positive control for lymphocyte infiltration. Under these experimental conditions, we show early and long-lasting microglia reactivity in the spinal cord after SNI, but no lymphocyte infiltration was found

Somatosensory profiling of patients undergoing alcohol withdrawal: Do neuropathic pain and sensory loss represent a problem?

Chronic heavy alcohol use is known to cause neurological complications such as peripheral neuropathy. Concerning the pathophysiology, few sural nerve and skin biopsy studies showed that small fibers might be selectively vulnerable to degeneration in alcohol-related peripheral neuropathy. Pain has rarely been properly evaluated in this pathology. The present study aims at assessing pain intensity, potential neuropathic characteristics as well as the functionality of both small and large nerve sensitive fibers. In this observational study, 27 consecutive adult patients, hospitalized for alcohol withdrawal and 13 healthy controls were recruited. All the participants underwent a quantitative sensory testing (QST) according to the standardized protocol of the German Research Network Neuropathic Pain, a neurological examination and filled standardized questionnaires assessing alcohol consumption and dependence as well as pain characteristics and psychological comorbidities. Nearly half of the patients (13/27) reported pain. Yet, pain intensity was weak, leading to a low interference with daily life, and its characteristics did not support a neuropathic component. A functional impairment of small nerve fibers was frequently described, with thermal hypoesthesia observed in 52% of patients. Patients with a higher alcohol consumption over the last 2 years showed a greater impairment of small fiber function. Patients report pain but it is however unlikely to be caused by peripheral neuropathy given the non-length-dependent distribution and the absence of neuropathic pain features. Chronic pain in AUD deserves to be better evaluated and managed as it represents an opportunity to improve long-term clinical outcomes, potentially participating to relapse prevention

Axon reflex-mediated vasodilation is reduced in proportion to disease severity in TTR-FAP.

To evaluate the area of the vascular flare in familial amyloid polyneuropathy (FAP). Healthy controls and patients with genetically confirmed FAP were prospectively examined, on the upper and lower limbs, for thermal sensitivity (Medoc TSA-II thermal analyzer) and for axon reflex-mediated flare. The latter was induced by iontophoresis of histamine on the forearm and leg on 2 different visits. We used laser Doppler imaging (LDI) to measure the flare area (LDIflare). Six patients had FAP of variable severity; 1 had generalized analgesia secondary to leprosy (used as a positive control). The median Neurological Impairment Score-Lower Limbs (NIS-LLs) was 6 (0-27). The warmth detection thresholds in the feet were higher in patients (median 43°, interquartile range 39.0°-47.6°) compared with controls (37.4°, 35.3°-39.2°), indicating small fiber impairment. On the leg, LDIflare was smaller in the patients on 2 consecutive visits (controls: median 13.0 and 13.3 cm <sup>2</sup> , IQR 9.7-22.8 and 8.3-16.9; patients 6.9 and 8.0 cm <sup>2</sup> , 2.6-10.8 and 6.4-12.1; <i>p</i> = 0.011). LDIflare on the leg was correlated with NIS-LL (Spearman rank correlation 0.73, <i>p</i> = 0.09 on the first visit; Spearman rank correlation 0.85, <i>p</i> = 0.03 on the second visit). Our study underscores that histamine-induced axon reflex-mediated vascular flare on the leg is reduced in proportion to disease severity in patients with FAP

Nature of antiferromagnetic order in epitaxially strained multiferroic SrMnO3 thin films

Epitaxial films of SrMnO3 and bilayers of SrMnO3/La0.67Sr0.33MnO3 have been deposited by pulsed laser deposition on different substrates, namely, LaAlO3 (001), (LaAlO3)0.3(Sr2AlTaO6)0.7 (001), and SrTiO3 (001), allowing us to perform an exhaustive study of the dependence of antiferromagnetic order and exchange bias field on epitaxial strain. The Néel temperatures (TN) of the SrMnO3 films have been determined by low-energy muon spin spectroscopy. In agreement with theoretical predictions, TN is reduced as the epitaxial strain increases. From the comparison with first-principles calculations, a crossover from G-type to C-type antiferromagnetic orders is proposed at a critical tensile strain of around 1.6±0.1%. The exchange bias (coercive) field, obtained for the bilayers, increases (decreases) by increasing the epitaxial strain in the SrMnO3 layer, following an exponential dependence with temperature. Our experimental results can be explained by the existence of a spin-glass (SG) state at the interface between the SrMnO3 and La0.67Sr0.33MnO3 films. This SG state is due to the competition between the different exchange interactions present in the bilayer and favored by increasing the strain in the SrMnO3 layer

A test of positive suggestions about side effects as a way of enhancing the analgesic response to NSAIDs.

Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been absorbed, might favor analgesia in a clinical interaction model. Sixty-six healthy males participated in a study "to validate pupillometry as an objective measure of analgesia". Participants were unknowingly randomized double-blind to positive vs control information about side effects embedded in a video regarding the study drugs. Sequences of moderately painful heat stimuli applied before and after treatment with diclofenac and atropine served to evaluate analgesia. Atropine was deceptively presented as a co-analgesic, but used to induce side effects. Adverse events (AE) were collected with the General Assessment of Side Effects (GASE) questionnaire prior to the second induced pain sequence. Debriefing fully informed participants regarding the purpose of the study and showed them the two videos.The combination of medication led to significant analgesia, without a between-group difference. Positive information about side effects increased the attribution of AE to the treatment compared to the control information. The total GASE score was correlated with analgesia, i.e., the more AEs reported, the stronger the analgesia. Interestingly, there was a significant between-groups difference on this correlation: the GASE score and analgesia correlated only in the positive information group. This provides evidence for a selective link between AEs and pain relief in the group who received the suggestion that AEs could be taken as a sign "that help was on the way". During debriefing, 65% of participants said they would prefer to receive the positive message in a clinical context. Although the present results cannot be translated immediately to clinical pain conditions, they do indicate the importance of testing this type of modulation in a clinical context

Influence of incommensurate dynamic charge-density wave scattering on the line shape of high-Tc_c cuprates

We show that the spectral lineshape of superconducting La$_{2-x}$Sr$_x$CuO$_4$ (LSCO) and Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$ (Bi2212) can be well described by the coupling of the charge carriers to collective incommensurate charge-density wave (CDW) excitations. Our results imply that besides antiferromagnetic (AF) fluctuations also low-energy CDW modes can contribute to the observed dip-hump structure in the Bi2212 photoemission spectra. In case of underdoped LSCO we propose a possible interpretation of ARPES data in terms of a grid pattern of fluctuating stripes where the charge and spin scattering directions deviate by $\alpha=\pi/4$. Within this scenario we find that the spectral intensity along $(0,0) \to (\pi,\pi)$ is strongly suppressed consistent with recent photoemission experiments. In addition the incommensurate charge-density wave scattering leads to a significant broadening of the quasiparticle-peak around $(\pi,0)$.Comment: 5 pages, 4 figure

Volume I. Introduction to DUNE

The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay—these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. The Deep Underground Neutrino Experiment (DUNE) is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. This TDR is intended to justify the technical choices for the far detector that flow down from the high-level physics goals through requirements at all levels of the Project. Volume I contains an executive summary that introduces the DUNE science program, the far detector and the strategy for its modular designs, and the organization and management of the Project. The remainder of Volume I provides more detail on the science program that drives the choice of detector technologies and on the technologies themselves. It also introduces the designs for the DUNE near detector and the DUNE computing model, for which DUNE is planning design reports. Volume II of this TDR describes DUNE\u27s physics program in detail. Volume III describes the technical coordination required for the far detector design, construction, installation, and integration, and its organizational structure. Volume IV describes the single-phase far detector technology. A planned Volume V will describe the dual-phase technology