S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation.

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.published_or_final_versio

IgE-Mediated Hypersensitivity Reactions to Cannabis in Laboratory Personnel

Background: There have been sporadic reports of hypersensitivity reactions to plants of the Cannabinaceae family (hemp and hops), but it has remained unclear whether these reactions are immunologic or nonimmunologic in nature. Objective: We examined the IgE-binding and histamine-releasing properties of hashish and marijuana extracts by CAP-FEIA and a basophil histamine release test. Methods: Two workers at a forensic laboratory suffered from nasal congestion, rbinitis, sneezing and asthmatic symptoms upon occupational contact with hashish or marijuana, which they had handled frequently for 25 and 16 years, respectively. Neither patient had a history of atopic disease. Serum was analyzed for specific IgE antibodies to hashish or marijuana extract by research prototype ImmunoCAP, and histamine release from basophils upon exposure to hashish or marijuana extracts was assessed. Results were matched to those of 4 nonatopic and 10 atopic control subjects with no known history of recreational or occupational exposure to marijuana or hashish. Results: Patient 1 had specific IgE to both hashish and marijuana (CAP class 2), and patient 2 to marijuana only (CAP class 2). Controls proved negative for specific IgE except for 2 atopic individuals with CAP class 1 to marijuana and 1 other atopic individual with CAP class 1 to hashish. Stimulation of basophils with hashish or marijuana extracts elicited histamine release from basophils of both patients and 4 atopic control subjects. Conclusions: Our results suggest an IgE-related pathomechanism for hypersensitivity reactions to marijuana or hashish. Copyright (C) 2011 S. Karger AG, Base

Jahn-Teller versus quantum effects in the spin-orbital material LuVO3

We report on combined neutron and resonant x-ray scattering results, identifying the nature of the spin-orbital ground state and magnetic excitations in LuVO3 as driven by the orbital parameter. In particular, we distinguish between models based on orbital Peierls dimerization, taken as a signature of quantum effects in orbitals, and Jahn-Teller distortions, in favor of the latter. In order to solve this long-standing puzzle, polarized neutron beams were employed as a prerequisite in order to solve details of the magnetic structure, which allowed quantitative intensity-analysis of extended magnetic excitation data sets. The results of this detailed study enabled us to draw definite conclusions about classical vs quantum behavior of orbitals in this system and to discard the previous claims about quantum effects dominating the orbital physics of LuVO3 and similar systems.Comment: Phys. Rev. B 91, 161104(R) (2015

Association of Fidaxomicin with C. difficile spores: Effects of Persistence on Subsequent Spore Recovery, Outgrowth and Toxin Production.

Background: We have previously shown that fidaxomicin instillation prevents spore recovery in an in-vitro gut model, whereas vancomycin does not. The reasons for this are unclear. Here, we have investigated persistence of fidaxomicin and vancomycin on C. difficile spores, and examined post-antibiotic exposure spore recovery, outgrowth and toxin production. Methods: Prevalent UK C. difficile ribotypes (n=10) were incubated with 200mg/L fidaxomicin, vancomycin or a non-antimicrobial containing control for 1 h in faecal filtrate or Phosphate Buffered Saline. Spores were washed three times with faecal filtrate or phosphate buffered saline, and residual spore-associated antimicrobial activity was determined by bioassay. For three ribotypes (027, 078, 015), antimicrobial-exposed, faecal filtrate-washed spores and controls were inoculated into broth. Viable vegetative and spore counts were enumerated on CCEYL agar. Percentage phase bright spores, phase dark spores and vegetative cells were enumerated by phase contrast microscopy at 0, 3, 6, 24 and 48 h post-inoculation. Toxin levels (24 and 48h) were determined by cell cytotoxicity assay. Results: Fidaxomicin, but not vancomycin persisted on spores of all ribotypes following washing in saline (mean=10.1mg/L; range= 4.0-14mg/L) and faecal filtrate (mean =17.4mg/L; 8.4-22.1mg/L). Outgrowth and proliferation rates of vancomycin-exposed spores were similar to controls, whereas fidaxomicin-exposed spores showed no vegetative cell growth after 24 and 48 h. At 48h, toxin levels averaged 3.7 and 3.3 relative units (RU) in control and vancomycin-exposed samples, respectively, but were undetectable in fidaxomicin-exposed samples. Conclusion: Fidaxomicin persists on C. difficile spores, whereas vancomycin does not. This persistence prevents subsequent growth and toxin production in vitro. This may have implications on spore viability, thereby impacting CDI recurrence and transmission rates

Shape and orientation of stellar velocity ellipsoids in spiral galaxies

We present a numerical study of the properties of the stellar velocity distribution in stellar discs which have developed a saturated, two-armed spiral structure. We follow the growth of the spiral structure deeply into the non-linear regime by solving the Boltzmann moment equations up to second order. By adopting the thin-disc approximation, we restrict our study of the stellar velocity distribution to the plane of the stellar disc. We find that the outer (convex) edges of stellar spiral arms are characterized by peculiar properties of the stellar velocity ellipsoids, which make them distinct from most other galactic regions. In particular, the ratio \sigma_1:\sigma_2 of the smallest versus largest principal axes of the stellar velocity ellipsoid can become abnormally small (as compared to the rest of the disc) near the outer edges of spiral arms. Moreover, the epicycle approximation fails to reproduce the ratio of the tangential versus radial velocity dispersions in these regions. These peculiar properties of the stellar velocity distribution are caused by large-scale non-circular motions of stars, which in turn are triggered by the non-axisymmetric gravitational field of stellar spiral arms. The magnitude of the vertex deviation appears to correlate globally with the amplitude of the spiral stellar density perturbations. However, locally there is no simple correlation between the vertex deviation and the density perturbations. (Abstract abridged).Comment: 16 pages, 18 figures, Accepted for publication in MNRA

Resolving the complex structure of the dust torus in the active nucleus of the Circinus galaxy

To test the dust torus model for active galactic nuclei directly, we study the extent and morphology of the nuclear dust distribution in the Circinus galaxy using high resolution interferometric observations in the mid-infrared with the MIDI instrument at the Very Large Telescope Interferometer. We find that the dust distribution in the nucleus of Circinus can be explained by two components, a dense and warm disk-like component of 0.4 pc size and a slightly cooler, geometrically thick torus component with a size of 2.0 pc. The disk component is oriented perpendicular to the ionisation cone and outflow and seems to show the silicate feature at 10 micron in emission. It coincides with a nuclear maser disk in orientation and size. From the energy needed to heat the dust, we infer a luminosity of the accretion disk corresponding to 20% of the Eddington luminosity of the nuclear black hole. We find that the interferometric data are inconsistent with a simple, smooth and axisymmetric dust emission. The irregular behaviour of the visibilities and the shallow decrease of the dust temperature with radius provide strong evidence for a clumpy or filamentary dust structure. We see no evidence for dust reprocessing, as the silicate absorption profile is consistent with that of standard galactic dust. We argue that the collimation of the ionising radiation must originate in the geometrically thick torus component. Our findings confirm the presence of a geometrically thick, torus-like dust distribution in the nucleus of Circinus, as required in unified schemes of Seyfert galaxies. Several aspects of our data require that this torus is irregular, or "clumpy".Comment: 20 pages, 16 figures, accepted for publication by A&

Encoded Recoupling and Decoupling: An Alternative to Quantum Error Correcting Codes, Applied to Trapped Ion Quantum Computation

A recently developed theory for eliminating decoherence and design constraints in quantum computers, ``encoded recoupling and decoupling'', is shown to be fully compatible with a promising proposal for an architecture enabling scalable ion-trap quantum computation [D. Kielpinski et al., Nature 417, 709 (2002)]. Logical qubits are encoded into pairs of ions. Logic gates are implemented using the Sorensen-Molmer (SM) scheme applied to pairs of ions at a time. The encoding offers continuous protection against collective dephasing. Decoupling pulses, that are also implemented using the SM scheme directly to the encoded qubits, are capable of further reducing various other sources of qubit decoherence, such as due to differential dephasing and due to decohered vibrational modes. The feasibility of using the relatively slow SM pulses in a decoupling scheme quenching the latter source of decoherence follows from the observed 1/f spectrum of the vibrational bath.Comment: 12 pages, no figure

Boron-Based Inhibitors of the NLRP3 Inflammasome.

NLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics

Elimination of Schistosomiasis Transmission in Zanzibar: Baseline Findings before the Onset of a Randomized Intervention Trial.

Gaining and sustaining control of schistosomiasis and, whenever feasible, achieving local elimination are the year 2020 targets set by the World Health Organization. In Zanzibar, various institutions and stakeholders have joined forces to eliminate urogenital schistosomiasis within 5 years. We report baseline findings before the onset of a randomized intervention trial designed to assess the differential impact of community-based praziquantel administration, snail control, and behavior change interventions. In early 2012, a baseline parasitological survey was conducted in ∼20,000 people from 90 communities in Unguja and Pemba. Risk factors for schistosomiasis were assessed by administering a questionnaire to adults. In selected communities, local knowledge about schistosomiasis transmission and prevention was determined in focus group discussions and in-depths interviews. Intermediate host snails were collected and examined for shedding of cercariae. The baseline Schistosoma haematobium prevalence in school children and adults was 4.3% (range: 0-19.7%) and 2.7% (range: 0-26.5%) in Unguja, and 8.9% (range: 0-31.8%) and 5.5% (range: 0-23.4%) in Pemba, respectively. Heavy infections were detected in 15.1% and 35.6% of the positive school children in Unguja and Pemba, respectively. Males were at higher risk than females (odds ratio (OR): 1.45; 95% confidence interval (CI): 1.03-2.03). Decreasing adult age (OR: 1.04; CI: 1.02-1.06), being born in Pemba (OR: 1.48; CI: 1.02-2.13) or Tanzania (OR: 2.36; CI: 1.16-4.78), and use of freshwater (OR: 2.15; CI: 1.53-3.03) showed higher odds of infection. Community knowledge about schistosomiasis was low. Only few infected Bulinus snails were found. The relatively low S. haematobium prevalence in Zanzibar is a promising starting point for elimination. However, there is a need to improve community knowledge about disease transmission and prevention. Control measures tailored to the local context, placing particular attention to hot-spot areas, high-risk groups, and individuals, will be necessary if elimination is to be achieved

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747