Histone deacetylase inhibitors induce apoptosis in human eosinophils and neutrophils

BACKGROUND: Granulocytes are important in the pathogenesis of several inflammatory diseases. Apoptosis is pivotal in the resolution of inflammation. Apoptosis in malignant cells is induced by histone deacetylase (HDAC) inhibitors, whereas HDAC inhibitors do not usually induce apoptosis in non-malignant cells. The aim of the present study was to explore the effects of HDAC inhibitors on apoptosis in human eosinophils and neutrophils. METHODS: Apoptosis was assessed by relative DNA fragmentation assay, annexin-V binding, and morphologic analysis. HDAC activity in nuclear extracts was measured with a nonisotopic assay. HDAC expression was measured by real-time PCR. RESULTS: A HDAC inhibitor Trichostatin A (TSA) induced apoptosis in the presence of survival-prolonging cytokines interleukin-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in eosinophils and neutrophils. TSA enhanced constitutive eosinophil and neutrophil apoptosis. Similar effects were seen with a structurally dissimilar HDAC inhibitor apicidin. TSA showed additive effect on the glucocorticoid-induced eosinophil apoptosis, but antagonized glucocorticoid-induced neutrophil survival. Eosinophils and neutrophils expressed all HDACs at the mRNA level except that HDAC5 and HDAC11 mRNA expression was very low in both cell types, HDAC8 mRNA was very low in neutrophils and HDAC9 mRNA low in eosinophils. TSA reduced eosinophil and neutrophil nuclear HDAC activities by ~50-60%, suggesting a non-histone target. However, TSA did not increase the acetylation of a non-histone target NF-κB p65. c-jun-N-terminal kinase and caspases 3 and 6 may be involved in the mechanism of TSA-induced apoptosis, whereas PI3-kinase and caspase 8 are not. CONCLUSIONS: HDAC inhibitors enhance apoptosis in human eosinophils and neutrophils in the absence and presence of survival-prolonging cytokines and glucocorticoids

Detecting Current Noise with a Josephson Junction in the Macroscopic Quantum Tunneling Regime

We discuss the use of a hysteretic Josephson junction to detect current fluctuations with frequencies below the plasma frequency of the junction. These adiabatic fluctuations are probed by switching measurements observing the noise-affected average rate of macroscopic quantum tunneling of the detector junction out of its zero-voltage state. In a proposed experimental scheme, frequencies of the noise are limited by an on-chip filtering circuit. The third cumulant of current fluctuations at the detector is related to an asymmetry of the switching rates.Comment: 26 pages, 10 figures. To appear in Journal of Low Temperature Physics in the proceedings of the ULTI conference organized in Lammi, Finland (2006

User needs elicitation via analytic hierarchy process (AHP). A case study on a Computed Tomography (CT) scanner

Background: The rigorous elicitation of user needs is a crucial step for both medical device design and purchasing. However, user needs elicitation is often based on qualitative methods whose findings can be difficult to integrate into medical decision-making. This paper describes the application of AHP to elicit user needs for a new CT scanner for use in a public hospital. Methods: AHP was used to design a hierarchy of 12 needs for a new CT scanner, grouped into 4 homogenous categories, and to prepare a paper questionnaire to investigate the relative priorities of these. The questionnaire was completed by 5 senior clinicians working in a variety of clinical specialisations and departments in the same Italian public hospital. Results: Although safety and performance were considered the most important issues, user needs changed according to clinical scenario. For elective surgery, the five most important needs were: spatial resolution, processing software, radiation dose, patient monitoring, and contrast medium. For emergency, the top five most important needs were: patient monitoring, radiation dose, contrast medium control, speed run, spatial resolution. Conclusions: AHP effectively supported user need elicitation, helping to develop an analytic and intelligible framework of decision-making. User needs varied according to working scenario (elective versus emergency medicine) more than clinical specialization. This method should be considered by practitioners involved in decisions about new medical technology, whether that be during device design or before deciding whether to allocate budgets for new medical devices according to clinical functions or according to hospital department

Atomic Hydrogen Properties of AGN Host Galaxies: HI in 16 NUclei of GAlaxies (NUGA) Sources

We present a comprehensive spectroscopic imaging survey of the distribution and kinematics of atomic hydrogen (HI) in 16 nearby spiral galaxies hosting low luminosity AGN, observed with high spectral and spatial resolution (resolution: ~20 arcsec, 5 km/s) using the NRAO Very Large Array (VLA). The sample contains a range of nuclear types, ranging from Seyfert to star-forming nuclei and was originally selected for the NUclei of GAlaxies project (NUGA) - a spectrally and spatially resolved interferometric survey of gas dynamics in nearby galaxies designed to identify the fueling mechanisms of AGN and the relation to host galaxy evolution. Here we investigate the relationship between the HI properties of these galaxies, their environment, their stellar distribution and their AGN type. The large-scale HI morphology of each galaxy is classified as ringed, spiral, or centrally concentrated; comparison of the resulting morphological classification with AGN type reveals that ring structures are significantly more common in LINER than in Seyfert host galaxies, suggesting a time evolution of the AGN activity together with the redistribution of the neutral gas. Dynamically disturbed HI disks are also more prevalent in LINER host galaxies than in Seyfert host galaxies. While several galaxies are surrounded by companions (some with associated HI emission), there is no correlation between the presence of companions and the AGN type (Seyfert/LINER).Comment: 54 pages, 7 figures, accepted for publication in AJ. The full-resolution version is available at http://www.mpia.de/homes/haan/research.htm

Understanding economic evidence for the prevention and treatment of atopic eczema

Background Atopic eczema is an inflammatory skin condition, with a similar impact on health-related quality-of-life as other chronic diseases. Increasing pressures on resources within the NHS increase the importance of having good economic evidence to inform their allocation. This paper aims to educate dermatologists about economic methods with illustration to currently available economic evidence on eczema. Methods/design The type and role of different types of economic evidence is illustrated by evidence found in a systematic literature search conducted across 12 online databases published until 22nd May 2017. Primary empirical studies either reporting the results of a cost of illness study or evaluating the cost, utility or full economic evaluation of interventions for preventing or treating eczema were included. Two reviewers independently assessed studies for eligibility and performed data abstraction, with disagreements resolved by a third reviewer. Evidence tables of results were produced for narrative discussion. The reporting quality of economic evaluations was assessed. Results 78 studies (described in 80 papers) were deemed eligible. 33 (42%) were judged to be economic evaluations, 12 (15%) cost analyses, 6 (8%) utility analyses, 26 (34%) cost-of-illness studies and 1 feasibility study (1%). The calcineurin inhibitors: tacrolimus and pimecrolimus, as well as barrier creams had most economic evidence available. Partially hydrolysed infant formula was the most commonly evaluated prevention. Conclusions The current level of economic evidence for interventions aimed at preventing and treating eczema is limited compared to that available for clinical outcomes suggesting that greater collaboration between clinicians and economists might be beneficial

The properties of the local spiral arms from RAVE data: two-dimensional density wave approach

Using the RAVE survey, we recently brought to light a gradient in the mean galactocentric radial velocity of stars in the extended solar neighbourhood. This gradient likely originates from non-axisymmetric perturbations of the potential, among which a perturbation by spiral arms is a possible explanation. Here, we apply the traditional density wave theory and analytically model the radial component of the two-dimensional velocity field. Provided that the radial velocity gradient is caused by relatively long-lived spiral arms that can affect stars substantially above the plane, this analytic model provides new independent estimates for the parameters of the Milky Way spiral structure. Our analysis favours a two-armed perturbation with the Sun close to the inner ultra-harmonic 4:1 resonance, with a pattern speed \Omega_p=18.6^{+0.3}_{-0.2} km/s/kpc and a small amplitude A=0.55 \pm 0.02% of the background potential (14% of the background density). This model can serve as a basis for numerical simulations in three dimensions, additionally including a possible influence of the galactic bar and/or other non-axisymmetric modes.Comment: 9 pages, 4 figures, accepted for publication in MNRA

Controversial role of plant sterol esters in the management of hypercholesterolaemia

Hypercholesterolaemia is a risk factor of cardiovascular diseases and is therefore a major target for primary and secondary prevention. Maintaining a healthy diet and lifestyle reduces cardiovascular risk. 'Functional foods'; supplemented with phytosterols are advertised for the management of hypercholesterolaemia and have become a widely used non-prescription approach to lower plasma cholesterol levels. It is estimated that in 2005 worldwide 3 billion US-dollars were spent on various functional foods that have regulator-approved health claims for the management of elevated cholesterol levels. In September 2000, the US Food and Drug Administration (FDA) issued an interim final rule allowing a health claim for reducing the risk of coronary heart disease for foods that contain phytosterols and are low in saturated fat and cholesterol. In fact, this was only the 12th time the FDA has authorized a health claim. The National Cholesterol Education Program Expert Panel (NCEP ATP III) recommends since 2001 phytosterol enriched functional foods as part of an optimal dietetic prevention strategy in primary and secondary prevention of cardiovascular diseases. The American Heart Association (AHA) has followed and sees phytosterols 'as a therapeutic option ... for individuals with elevated cholesterol levels';. Since then other well-esteemed societies such as the Spanish Cardiology Society, the Association of Clinical and Public Health Nutritionists in Finland, and the National Heart Foundation in Australia, to name only a few, have identified phytosterols as an important additional dietary option in the management of hypercholesterolaemia. However, recently released guidelines are more critical of food supplementation with phytosterols and draw attention to significant safety issues

Asymmetric effects of false positive and false negative indications on the verification of alerts in different risk conditions

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Indications from alerts or alarm systems can be the trigger for decisions, or they can elicit further information search. We report an experiment on the tendency to collect additional information after receiving system indications. We varied the proclivity of the alarm system towards false positive or false negative indications and the perceived risk of the situation. Results showed that false alarm-prone systems led to more frequent re-checking following both alarms and non-alarms in the high risk condition, whereas miss-prone systems led to high re-checking rates only for non-alarms, representing an asymmetry effect. Increasing the risk led to more re-checks with all alarm systems, but it had a stronger impact in the false alarm-prone condition. Results regarding the relation of risk and the asymmetry effect of false negative and false positive indications are discussed