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

The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation

Proteolysis mediated by matrix metalloproteinases (MMPs) and serine proteinases is associated with cancer invasion and metastasis. Activation of latent proMMPs, and especially the proforms of the type IV collagen degrading gelatinases A and B (proMMP-2 and proMMP-9), is thought to be a critical step in this process. We have recently found that human tumour-associated trypsin-2 is a potent activator of proMMP-9 and it also activates proMMP-2 in vitro. Trypsinogen, MMP-2, and MMP-9 are expressed in ovarian cancer. To elucidate the function of trypsin in vivo, we studied whether high concentrations of trypsinogen-1, trypsinogen-2, their α1-proteinase inhibitor (API) complexes, and tumour-associated trypsin inhibitor (TATI) are associated with proMMP-2 and proMMP-9 activation in ovarian tumour cyst fluids. Zymography and immunofluorometric analysis of 61 cyst fluids showed a significant association between high trypsin concentrations and the activation of MMP-9 (P= 0.003–0.05). In contrast, the trypsin concentrations were inversely associated with the activation of MMP-2 (P= 0.01–0.02). Immunohistochemical analysis of ovarian tumour tissue demonstrated expression of trypsinogen-2 and TATI in the secretory epithelium. MMP-2 was detected both in stromal and epithelial cells whereas MMP-9 was detected in neutrophils and macrophage-like cells in stromal and epithelial areas. These results suggest that trypsin may play a role in the regulation of the MMP-dependent proteolysis associated with invasion and metastasis of ovarian cancer. © 2001 Cancer Research Campaign www.bjcancer.co

Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular conduction delay

AbstractObjectivesWe characterized the relationship between systolic ventricular function and left ventricular (LV) end-diastolic pressure (LVEDP) in patients with heart failure (HF) and baseline asynchrony during ventricular stimulation.BackgroundThe role of preload in the systolic performance improvement that can be obtained in HF patients with LV stimulation is uncertain.MethodsWe measured the maximum rate of increase of LV pressure, LVEDP, aortic pulse pressure (PP) and the atrioventricular mechanical latency (AVL) between left atrial systole and LV pressure onset in 39 patients with HF. Two subgroups were identified: “responder” if PP improved, or “nonresponder.”ResultsMaximum hemodynamic improvement occurred at an atrioventricular (AV) delay that did not decrease LVEDP. Left ventricular and biventricular (BV) stimulation increased systolic hemodynamics significantly, despite no significant increase in LVEDP. All parameters decreased when the LVEDP was decreased by shorter AV delay. Left ventricular and BV stimulation provided better hemodynamics than right ventricular (RV) stimulation. For the nonresponder subgroup, systolic hemodynamics only worsened during AV delay shortening. For the responder subgroup, optimum PP was achieved when AVL was near zero.ConclusionsRestoration of optimal left atrial-ventricular mechanical timing partly contributes to the hemodynamic improvements observed in this patient subgroup. However, preload alone cannot explain the differences seen between RV and BV stimulation and the contradictory PP decreases even at maximal preload in the nonresponder subgroup. These results may be explained by a site-dependent mechanism such as the degree of ventricular synchrony. Caution should be taken in these patients when optimizing AV delays using echocardiography techniques that focus on LV inflow

Traumatic brain injury patients' family members' evaluations of the social support provided by healthcare professionals in acute care hospitals

Aims and objectives The study aimed to examine traumatic brain injury (TBI) patient family members' (FMs) experiences of the support they received from healthcare professionals in acute care hospitals. Background The length of hospitalisation following TBI is constantly decreasing, and patients may return home with several problems. FMs care for the patients at home although they may not be prepared for the patient's medical needs or financial burden of the illness. The burden which some FMs experience can impair patient care and rehabilitation outcomes. Therefore, FMs require support during acute phases of TBI treatment. Design A structured questionnaire was sent to 216 TBI patients FMs. The response rate was 47% (n = 102). Methods A structured questionnaire-based on a systematic literature review and a previous questionnaire on TBI patient FMs' perceptions of support-was developed and used in the data collection. The questionnaire included 46 statements and 11 background questions. Data were collected via an electronic questionnaire. The STROBE checklist was followed in reporting the study. Results A factor analysis identified five factors that describe the guidance of TBI patient FMs: guidance of TBI patients' symptoms and survival; benefits of guidance; needs-based guidance; guidance for use of services; and guidance methods. Most of the FMs (51%-88%) felt that they had not received enough guidance from healthcare professionals in acute care hospitals across all five aspects of support. Conclusions The content of guidance should be developed, and healthcare staff should be trained to consider a FM's starting point when providing guidance. A calm environment, proper timing, sufficient information in different forms and professional healthcare staff were found to be key factors to comprehensive guidance. Involving FMs in the discharge process and rehabilitation of their loved ones both supports the abilities of caregivers and promotes the outcome of the patient's rehabilitation. Relevance to clinical practice This study provides varied information on the need for social support of TBI patients FMs in the early stages of treatment from the FMs' perspective. This research adopted the FM's perspective to identify various areas of social support that need to be developed so that the FMs of TBI patients receive enough support during the early stages of TBI treatment.Peer reviewe

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

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

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

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