Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis

BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is a major health problem associated with myocardial leukocyte infiltration, inflammation, and fibrosis. Monocyte and macrophage subsets play a role in HFPEF but have not been studied. We analyzed peripheral blood monocyte phenotype and plasma markers of monocyte activation in patients with HFPEF, asymptomatic LV diastolic dysfunction (aLVDD), and asymptomatic hypertension (aHTN).

METHODS AND RESULTS: Peripheral blood was collected from 23 aHTN, 30 aLVDD, and 30 HFPEF patients. Peripheral cytokines of classic/pro-inflammatory (tumor necrosis factor alpha, interleukin (IL) 12, IL-6, monocyte chemoattractant protein 1, C-X-C motif chemokine 10) and alternative/anti-inflammatory monocytes (chemokine-C-C motif ligand (CCL) 17, CCL-18, soluble CD163) were increased in aLVDD and HFPEF. Peripheral blood mononuclear cells and monocytes were purified and surface-stained for CD14, CD16, CD163, and CD206. Peripheral monocyte percentage was increased in aLVDD and HFPEF and correlated with echocardiographic LVDD indices. Classic/pro-inflammatory monocyte numbers were increased in aLVDD and HFPEF, and alternative/anti-inflammatory monocyte numbers were increased in HFPEF. CD163 M2-macrophage receptor was reduced in HFPEF. Culture of healthy donor monocytes (n = 3) with HFPEF patient-derived sera (n = 6) promoted M2 macrophage features as evidenced by altered morphology and genes (CD206, IL-10).

CONCLUSIONS: Increased peripheral inflammation, monocytosis, and monocyte differentiation to anti-inflammatory/profibrotic M2 macrophages likely associate with HFPEF and its precedent asymptomatic LVDD phase.

Murine Models of Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction

Left ventricular diastolic dysfunction leads to heart failure with preserved ejection fraction, an increasingly prevalent condition largely driven by modern day lifestyle risk factors. As heart failure with preserved ejection fraction accounts for almost one-half of all patients with heart failure, appropriate nonhuman animal models are required to improve our understanding of the pathophysiology of this syndrome and to provide a platform for preclinical investigation of potential therapies. Hypertension, obesity, and diabetes are major risk factors for diastolic dysfunction and heart failure with preserved ejection fraction. This review focuses on murine models reflecting this disease continuum driven by the aforementioned common risk factors. We describe various models of diastolic dysfunction and highlight models of heart failure with preserved ejection fraction reported in the literature. Strengths and weaknesses of the different models are discussed to provide an aid to translational scientists when selecting an appropriate model. We also bring attention to the fact that heart failure with preserved ejection fraction is difficult to diagnose in animal models and that, therefore, there is a paucity of well described animal models of this increasingly important condition.

Space density distribution of galaxies in the absolute magnitude - rotation velocity plane: a volume-complete Tully-Fisher relation from CALIFA stellar kinematics

We measured the distribution in absolute magnitude - circular velocity space for a well-defined sample of 199 rotating galaxies of the Calar Alto Legacy Integral Field Area Survey (CALIFA) using their stellar kinematics. Our aim in this analysis is to avoid subjective selection criteria and to take volume and large-scale structure factors into account. Using stellar velocity fields instead of gas emission line kinematics allows including rapidly rotating early-type galaxies. Our initial sample contains 277 galaxies with available stellar velocity fields and growth curve r-band photometry. After rejecting 51 velocity fields that could not be modelled because of the low number of bins, foreground contamination, or significant interaction, we performed Markov chain Monte Carlo modelling of the velocity fields, from which we obtained the rotation curve and kinematic parameters and their realistic uncertainties. We performed an extinction correction and calculated the circular velocity v_circ accounting for the pressure support of a given galaxy. The resulting galaxy distribution on the M-r - v(circ) plane was then modelled as a mixture of two distinct populations, allowing robust and reproducible rejection of outliers, a significant fraction of which are slow rotators. The selection effects are understood well enough that we were able to correct for the incompleteness of the sample. The 199 galaxies were weighted by volume and large-scale structure factors, which enabled us to fit a volume-corrected Tully-Fisher relation (TFR). More importantly, we also provide the volume-corrected distribution of galaxies in the M_r - v_circ plane, which can be compared with cosmological simulations. The joint distribution of the luminosity and circular velocity space densities, representative over the range of -20 > M_r > -22 mag, can place more stringent constraints on the galaxy formation and evolution scenarios than linear TFR fit parameters or the luminosity function alone.

A second order control-volume finite-element least-squares strategy for simulating diffusion in strongly anisotropic media

An unstructured mesh �nite volume discretisation method for simulating di�usion in anisotropic media in two-dimensional space is discussed. This technique is considered as an extension of the fully implicit hybrid control-volume �nite-element method and it retains the local continuity of the ux at the control volume faces. A least squares function recon- struction technique together with a new ux decomposition strategy is used to obtain an accurate ux approximation at the control volume face, ensuring that the overall accuracy of the spatial discretisation maintains second order. This paper highlights that the new technique coincides with the traditional shape function technique when the correction term is neglected and that it signi�cantly increases the accuracy of the previous linear scheme on coarse meshes when applied to media that exhibit very strong to extreme anisotropy ratios. It is concluded that the method can be used on both regular and irregular meshes, and appears independent of the mesh quality.

Radiobiological model comparison of 3D conformal radiotherapy and IMRT plans for the treatment of prostate cancer

The main aim of radiotherapy is to deliver a dose of radiation that is high enough to destroy the tumour cells while at the same time minimising the damage to normal healthy tissues. Clinically, this has been achieved by assigning a prescription dose to the tumour volume and a set of dose constraints on critical structures. Once an optimal treatment plan has been achieved the dosimetry is assessed using the physical parameters of dose and volume. There has been an interest in using radiobiological parameters to evaluate and predict the outcome of a treatment plan in terms of both a tumour control probability (TCP) and a normal tissue complication probability (NTCP). In this study, simple radiobiological models that are available in a commercial treatment planning system were used to compare three dimensional conformal radiotherapy treatments (3D-CRT) and intensity modulated radiotherapy (IMRT) treatments of the prostate. Initially both 3D-CRT and IMRT were planned for 2 Gy/fraction to a total dose of 60 Gy to the prostate. The sensitivity of the TCP and the NTCP to both conventional dose escalation and hypo-fractionation was investigated. The biological responses were calculated using the Källman S-model. The complication free tumour control probability (P+) is generated from the combined NTCP and TCP response values. It has been suggested that the alpha/beta ratio for prostate carcinoma cells may be lower than for most other tumour cell types. The effect of this on the modelled biological response for the different fractionation schedules was also investigated.

AITPM Email Newsletter Volume 0902, February 2009: Presidents Message

President’s Report Hello fellow AITPM members, Welcome to the first edition of the AITPM National Newsletter for 2009! I trust we all had a relaxing break and managed to lose track of all things transport for just a little while. I know I had trouble doing so when hunting for a car space at the shopping centre, and experiencing new projects such as the Tugun Bypass – the new gateway between New South Wales and Queensland. Byron Bay is now as close as Noosa for those high profile beach goers of Brisbane. There was also my experience of the reduced posted speed of 90km/h on the Bruce Highway around the troublesome Gympie stretch, when returning from a short Fraser Coast holiday. I expect that this relatively inexpensive safety improvement will pay substantial dividends in terms of crash reduction. The Newsletter took its annual leave last month and is refreshed and ready for a new year to keep us all informed of the latest in traffic and transport engineering, planning and management. I would like to take this opportunity to acknowledge the ongoing significant contributions of many volunteers in the Newsletter’s production. Mr Andrew Hulse, AITPM’s Immediate Past National President, serves as the Editorial Coordinator on behalf of the Institute. Each Branch Committee also includes a Newsletter Coordinator and committee members frequently contribute as well. And the ongoing contributions of readers enable us to offer the Newsletter as a vehicle for dialogue and debate around our sector. If you would like to contribute please email AITPM’s administration officer Josephine Mitton at aitpm@aitpm.com or through your local Branch Committee. I would also like to welcome back on deck our Editor, Mr David Brown of Driven Media, who creates a fantastic package for us each month. Lastly, members would have received the Call for Papers for the AITPM 2009 National Conference, Traffic Beyond Tomorrow, to be held at the Adelaide Convention Centre between 5 – 7 August. Abstracts will be accepted up to 20 February 2009. We look forward to seeing everyone at this, our flagship event for the year. To all a good year ahead, Jon Bunker Post Script: We all will have seen through the media the enormous scale and nature of the two natural disasters Australia is experiencing at present. AITPM’s thoughts are with all of those members, family and friends who may be experiencing hardship as a result of the Victorian bushfires and North Queensland floods. AITPM is a not for profit organisation however the National Executive has taken the decision to donate in measure to the Red Cross Victorian Bushfire Disaster Relief fund and the Queensland Premier’s Disaster Relief fund as a gesture to support our fellow Australians in their time of need. Details about these funds can be found via the Victorian and Queensland Governments’ websites.

AITPM Email Newsletter Volume 0903, March 2009: Presidents Message

President’s Report Hello fellow AITPM members, First I would like on behalf of all AITPM members to send our condolences to all who have been affected by February’s tragic bushfires in regional Victoria, and deliver our best wishes to all of those involved in the rebuilding efforts. Over time I expect that the Victorian Government’s Royal Commission will analyse the circumstances and put forward a range of measures which will improve fire safety in vulnerable areas. As transport professionals it will be important for us to consider the findings and look to undertaking any recommendations that relate to the work we do. Not only in Victoria, but nationwide. In particular, the importance of logistics was highlighted following the fire events. Donors across Australia were this time requested to donate money rather than goods, presumably due in part to problems associated with the transport system coping with additional uncoordinated freight load, whilst being needed to support emergency management vehicle and managed freight movements. Notwithstanding, it was wonderful to see otherwise difficult to obtain goods, such as animal feed, being donated from far afield and transported in kind by trucking operators. As stated in last month’s Newsletter, AITPM made a direct cash donation to the Red Cross Bushfire Appeal immediately following the events, and a further donation to the Queensland Premier’s Disaster Relief Fund to support recovery after the North Queensland floods, which claimed seven lives. Again, we will need to monitor how the rebuilding effort unfolds particularly in regional Victoria and centres including Ingham in North Queensland, but I would urge all AITPM members who are in a position to support the restoration of the affected communities to play a part, particularly over time once the initial shock subsides and the steady job of rebuilding is underway. Onto lighter matters, AITPM’s flagship event, the 2009 AITPM National Conference, Traffic Beyond Tomorrow, being held in Adelaide from 5 to 7 August, is fast approaching. www.aitpm.com has all of the details about how to register, sponsor a booth, and so forth. We are looking forward to catching up with our conference “regulars” and meeting with new folks to AITPM, and Australian traffic and transport planning and management. Adelaide is one of my favourite places to visit and I’m looking forward to riding the light rail line extension through town and checking out progress on the road system development. Best regards all, Jon Bunker