Interference of the T cell and antigen-presenting cell costimulatory pathway using CTLA4-Ig (abatacept) prevents Staphylococcal enterotoxin B pathology

Abstract Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p &amp;lt; 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p &amp;lt; 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.</jats:p

Surface composition and properties of Ganymede: Updates from ground-based observations with the near-infrared imaging spectrometer SINFONI/VLT/ESO

Ganymede's surface exhibits great geological diversity, with old dark terrains, expressed through the surface composition, which is known to be dominated by two constituents: H2O-ice and an unidentified darkening agent. In this paper, new investigations of the composition of Ganymede's surface at global scale are presented. The analyses are derived from the linear spectral modeling of a high spectral resolution dataset, acquired with the near-infrared (1.40–2.50 μm) ground-based integral field spectrometer SINFONI (SINgle Faint Object Near-IR Investigation) of the Very Large Telescope (VLT hereafter) located in Chile. We show that, unlike the neighboring moon Europa, photometric corrections cannot be performed using a simple Lambertian model. However, we find that the Oren-Nayar (1994) model, generalizing the Lambert's law for rough surfaces, produces excellent results. Spectral modeling confirms that Ganymede's surface composition is dominated by H2O-ice, which is predominantly crystalline, as well as a darkening agent, but it also clearly highlights the necessity of secondary species to better fit the measurements: sulfuric acid hydrate and salts, likely sulfates and chlorinated. A latitudinal gradient and a hemispherical dichotomy are the strongest spatial patterns observed for the darkening agent, the H2O-ice, and the sulfuric acid: the darkening agent is by far the major compound at the equator and mid-latitudes (≤ ± 35°N), especially on the trailing hemisphere, while the H2O-ice and the sulfuric acid are mostly located at high latitudes and on the leading hemisphere. This anti-correlation is likely a consequence of the bombardment of the constituents in the Jovian magnetosphere which are much more intense at latitudes higher than ±35°N. Furthermore, the modeling confirms that polar caps are enriched in small, fresh, H2O-ice grains (i.e. ≤50 μm) while equatorial regions are mostly composed of larger grains (i.e. ≥200 μm, up to 1 mm). Finally, the spatial distribution of the salts is neither related to the Jovian magnetospheric bombardment nor the craters. These species are mostly detected on bright grooved terrains surrounding darker areas. Endogenous processes, such as freezing of upwelling fluids going through the ice shell, may explain this distribution. In addition, a small spectral residue that might be related to brines and/or hydrated silica-bearing minerals are located in the same areas

Individual differences underlying susceptibility to addiction: Role for the endogenous oxytocin system

AbstractRecent research shows that the effects of oxytocin are more diverse than initially thought and that in some cases oxytocin can directly influence the response to drugs and alcohol. Large individual differences in basal oxytocin levels and reactivity of the oxytocin system exist. This paper will review the literature to explore how individual differences in the oxytocin system arise and examine the hypothesis that this may mediate some of the individual differences in susceptibility to addiction and relapse.Differences in the oxytocin system can be based on individual factors, e.g. genetic variation especially in the oxytocin receptor, age or gender, or be the result of early environmental influences such as social experiences, stress or trauma. The paper addresses the factors that cause individual differences in the oxytocin system and the environmental factors that have been identified to induce long-term changes in the developing oxytocin system during different life phases.Individual differences in the oxytocin system can influence effects of drugs and alcohol directly or indirectly. The oxytocin system has bidirectional interactions with the stress-axis, autonomic nervous system, neurotransmitter systems (e.g. dopamine, serotonin and GABA/glutamate) and the immune system. These systems are all important, even vital, in different phases of addiction.It is suggested that early life adversity can change the development of the oxytocin system and the way it modulates other systems. This in turn could minimise the negative feedback loops that would normally exist. Individuals may show only minor differences in behaviour and function unless subsequent stressors or drug use challenges the system. It is postulated that at that time individual differences in oxytocin levels, reactivity of the system or interactions with other systems can influence general resilience, drug effects and the susceptibility to develop problematic drug and alcohol use

Measurement of Lower-hybrid Drift Turbulence in a Reconnecting Current Sheet

We present a detailed study of fluctuations in a laboratory current sheet undergoing magnetic reconnection. The measurements reveal the presence of lower-hybrid-frequency range fluctuations on the edge of current sheets produced in the Magnetic Reconnection Experiment (MRX). The measured fluctuation characteristics are consistent with theoretical predictions for the lower-hybrid drift instability (LHDI). Our observations suggest that the LHDI does not provide any significant turbulent resistivity in MRX current sheets

Management of oromandibular dystonia with botulinum A toxin: a series of cases.

Oromandibular dystonia is a disorder of movement that is often misdiagnosed. We present our experience of six patients treated with botulinum A toxin, for whom we recorded the symptoms, the group of muscles targeted, and the quantity of botulinum toxin used. We used the Glasgow Benefit Inventory (GBI) questionnaire to record and analyse outcomes after treatment. Five of the six patients had a good outcome as recorded by the GBI, the mean (SD) score of which was +40 (28), which reflected that the patients were well satisfied. The overall improvement in the categories of general health, social health, and physical health were 82%, 37%, and 31%, respectively. Botulinum type A toxin is an effective treatment of oromandibular dystonia. It is important for clinicians to recognise the condition, as treatment is well-tolerated and can improve quality of life

Understanding infection prevention and control in nursing homes: A qualitative study.

Infections have been identified as a priority issue in nursing homes (NHs). We conducted a qualitative study purposively sampling 10 NHs across the country where 6-8 employees were recruited (N = 73). Semi-structured, open-ended guides were used to conduct in-depth interviews. Data were audiotaped, transcribed and a content analysis was performed. Five themes emerged: \u27Residents\u27 Needs\u27, \u27Roles and Training\u27 \u27Using Infection Data,\u27 \u27External Resources\u27 and \u27Focus on Hand Hygiene.\u27 Infection prevention was a priority in the NHs visited. While all sites had hand hygiene programs, other recommended areas were not a focus and many sites were not aware of available resources. Developing ways to ensure effective, efficient and standardized infection prevention and control in NHs continues to be a national priority

The orbit structure of Dynkin curves

Let G be a simple algebraic group over an algebraically closed field k; assume that Char k is zero or good for G. Let \cB be the variety of Borel subgroups of G and let e in Lie G be nilpotent. There is a natural action of the centralizer C_G(e) of e in G on the Springer fibre \cB_e = {B' in \cB | e in Lie B'} associated to e. In this paper we consider the case, where e lies in the subregular nilpotent orbit; in this case \cB_e is a Dynkin curve. We give a complete description of the C_G(e)-orbits in \cB_e. In particular, we classify the irreducible components of \cB_e on which C_G(e) acts with finitely many orbits. In an application we obtain a classification of all subregular orbital varieties admitting a finite number of B-orbits for B a fixed Borel subgroup of G.Comment: 12 pages, to appear in Math

Periodic Orbits and Escapes in Dynamical Systems

We study the periodic orbits and the escapes in two different dynamical systems, namely (1) a classical system of two coupled oscillators, and (2) the Manko-Novikov metric (1992) which is a perturbation of the Kerr metric (a general relativistic system). We find their simple periodic orbits, their characteristics and their stability. Then we find their ordered and chaotic domains. As the energy goes beyond the escape energy, most chaotic orbits escape. In the first case we consider escapes to infinity, while in the second case we emphasize escapes to the central "bumpy" black hole. When the energy reaches its escape value a particular family of periodic orbits reaches an infinite period and then the family disappears (the orbit escapes). As this family approaches termination it undergoes an infinity of equal period and double period bifurcations at transitions from stability to instability and vice versa. The bifurcating families continue to exist beyond the escape energy. We study the forms of the phase space for various energies, and the statistics of the chaotic and escaping orbits. The proportion of these orbits increases abruptly as the energy goes beyond the escape energy.Comment: 28 pages, 23 figures, accepted in "Celestial Mechanics and Dynamical Astronomy

Specific Heat Study of the Magnetic Superconductor HoNi2B2C

The complex magnetic transitions and superconductivity of HoNi2B2C were studied via the dependence of the heat capacity on temperature and in-plane field angle. We provide an extended, comprehensive magnetic phase diagram for B // [100] and B // [110] based on the thermodynamic measurements. Three magnetic transitions and the superconducting transition were clearly observed. The 5.2 K transition (T_{N}) shows a hysteresis with temperature, indicating the first order nature of the transition at B=0 T. The 6 K transition (T_{M}), namely the onset of the long-range ordering, displays a dramatic in-plane anisotropy: T_{M} increases with increasing magnetic field for B // [100] while it decreases with increasing field for B // [110]. The anomalous anisotropy in T_{M} indicates that the transition is related to the a-axis spiral structure. The 5.5 K transition (T^{*}) shows similar behavior to the 5.2 K transition, i.e., a small in-plane anisotropy and scaling with Ising model. This last transition is ascribed to the change from a^{*} dominant phase to c^{*} dominant phase.Comment: 9 pages, 11 figure