The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the ...Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.
The composition of asteroids and their connection to meteorites provide insight into geologic processes that occurred in the early Solar System. We present spectra of the Nightingale crater region on ...near-Earth asteroid Bennu with a distinct infrared absorption around 3.4 micrometers. Corresponding images of boulders show centimeters-thick, roughly meter-long bright veins. We interpret the veins as being composed of carbonates, similar to those found in aqueously altered carbonaceous chondrite meteorites. If the veins on Bennu are carbonates, fluid flow and hydrothermal deposition on Bennu's parent body would have occurred on kilometer scales for thousands to millions of years. This suggests large-scale, open-system hydrothermal alteration of carbonaceous asteroids in the early Solar System.
Inflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with ...excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach.
Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive ...agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.
Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific ...immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy.
The exploration of near‐Earth asteroids has revealed dynamic surfaces characterized by mobile, unconsolidated material that responds to local geophysical gradients, resulting in distinct morphologies ...and boulder distributions. The OSIRIS‐REx (Origins, Spectral Interpretation, Resource Identification, and Security‐Regolith Explorer) mission confirmed that asteroid (101955) Bennu is a rubble pile with an unconsolidated surface dominated by boulders. In this work, we documented morphologies indicative of mass movement on Bennu and assessed the relationship to slope and other geologic features on the surface. We found globally distributed morphologic evidence of mass movement on Bennu up to ~70° latitude and on spatial scales ranging from individual boulders (meter scale) to a single debris flow ~100 m long and several meters thick. The apparent direction of mass movement is consistent with the local downslope direction and dominantly moves from the midlatitudes toward the equator. Mass movement appears to have altered the surface expression of large (≥30m diameter) boulders, excavating them in the midlatitudes and burying them in the equatorial region. Up to a 10 ± 1 m depth of material may have been transported away from the midlatitudes, which would have deposited a layer ~5 ± 1 m thick in the equatorial region assuming a stagnated flow model. This mass movement could explain the observed paucity of small (<50‐m diameter) craters and may have contributed material to Bennu's equatorial ridge. Models of changes in slope suggest that the midlatitude mass movement occurred in the past several hundred thousand years in regions that became steeper by several degrees.
Plain Language Summary
Mass movement is the flow of loose material such as rock fragments across the surface of a planetary body (for instance, a landslide). We searched images of the surface of asteroid (101955) Bennu for evidence of mass movement. We found that rocks of various sizes have moved downslope, and evidence of this movement is apparent at most locations on the asteroid. By measuring the distribution of, and surface elevation around, the largest boulders on the surface of Bennu, we also found that the downslope movement of material appears to have excavated large boulders from the subsurface in the midlatitudes and buried large boulders near the equator. Our observation that material on Bennu has moved in what is currently the local downslope direction is not necessarily expected, because the downslope direction can change based on how quickly the asteroid is rotating, which varies over time. Thus, we can infer that this movement happened in the geologically recent past—probably within the past several hundred thousand years. These results can help us understand how geologic features like craters are erased, how the equatorial ridge formed, and how Bennu (and potentially other asteroids) change shape over time.
Key Points
Signatures of mass movement on Bennu are globally distributed at multiple spatial scales
Mass movement may have removed a ~10‐m‐thick layer of material from the midlatitudes and deposited a ~5‐m‐thick layer near the equator
Mass movement that left visible evidence on Bennu occurred within the past several hundred thousand years
Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools ...for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The "irritable nociceptor" subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials.
Here, absolute cross sections for the addition of s- and d-wave neutrons to 14C and 14N have been determined simultaneously via the (d,p) reaction at 10 MeV/u. The difference between the neutron and ...proton separation energies, ΔS, is around -20 MeV for the 14C+n system and +8 MeV for 14N+n. The population of the 1s1/2 and 0d5/2 orbitals for both systems is reduced by a factor of approximately 0.5 compared with the independent single-particle model, or about 0.6 when compared with the shell model. This finding strongly contrasts with results deduced from intermediate-energy knockout reactions between similar nuclei on targets of 9Be and 12C. The simultaneous technique used removes many systematic uncertainties.
From 1998 to 2008, 1229 foodborne outbreaks caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus were reported in the United States; 39% were reported with a confirmed ...etiology. Vomiting was commonly reported in B. cereus (median, 75% of cases) and S. aureus outbreaks (median, 87%), but rarely in C. perfringens outbreaks (median, 9%). Meat or poultry dishes were commonly implicated in C. perfringens (63%) and S. aureus (55%) outbreaks, and rice dishes were commonly implicated in B. cereus outbreaks (50%). Errors in food processing and preparation were commonly reported (93%), regardless of etiology; contamination by a food worker was only common in S. aureus outbreaks (55%). Public health interventions should focus on these commonly reported errors to reduce the occurrence of outbreaks caused by B. cereus, C. perfringens, and S. aureus in the United States.
In May of 2011, NASA selected the
O
rigins,
S
pectral
I
nterpretation,
R
esource
I
dentification, and
S
ecurity–
R
egolith
Ex
plorer (OSIRIS-REx) asteroid sample return mission as the third mission ...in the New Frontiers program. The other two New Frontiers missions are
New Horizons
, which explored Pluto during a flyby in July 2015 and is on its way for a flyby of Kuiper Belt object 2014 MU69 on January 1, 2019, and
Juno
, an orbiting mission that is studying the origin, evolution, and internal structure of Jupiter. The spacecraft departed for near-Earth asteroid (101955) Bennu aboard an United Launch Alliance Atlas V 411 evolved expendable launch vehicle at 7:05 p.m. EDT on September 8, 2016, on a seven-year journey to return samples from Bennu. The spacecraft is on an outbound-cruise trajectory that will result in a rendezvous with Bennu in November 2018. The science instruments on the spacecraft will survey Bennu to measure its physical, geological, and chemical properties, and the team will use these data to select a site on the surface to collect at least 60 g of asteroid regolith. The team will also analyze the remote-sensing data to perform a detailed study of the sample site for context, assess Bennu’s resource potential, refine estimates of its impact probability with Earth, and provide ground-truth data for the extensive astronomical data set collected on this asteroid. The spacecraft will leave Bennu in 2021 and return the sample to the Utah Test and Training Range (UTTR) on September 24, 2023.
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