Lung Circulation Modeling: Status and Prospect

Mathematical modeling has been used to interpret anatomical and physiological data obtained from metabolic and hemodynamic studies aimed at investigating structure-function relationships in the vasculature of the lung, and how these relationships are affected by lung injury and disease. The indicator dilution method was used to study the activity of redox processes within the lung. A steady-state model of the data was constructed and used to show that pulmonary endothelial cells may play an important role in reducing redox active compounds and that those reduction rates can be altered with oxidative stress induced by exposure to high oxygen environments. In addition, a morphometric model of the pulmonary vasculature was described and used to detect, describe,and predict changes in vascular morphology that occur in response to chronic exposure to low-oxygen environments, a common model of pulmonary hypertension. Finally, the model was used to construct simulated circulatory networks designed to aid in evaluation of competing hypotheses regarding the relative contribution of various morphological and biomechanical changes observed with hypoxia. These examples illustrate the role of mathematical modeling in the integration of the emerging metabolic, hemodynamic, and morphometric databases

SPECT Imaging of Pulmonary Blood Flow in a Rat

Small animal imaging is experiencing rapid development due to its importance in providing high-throughput phenotypic data for functional genomics studies. We have developed a single photon emission computed tomography (SPECT) system to image the pulmonary perfusion distribution in the rat. A standard gamma camera, equipped with a pinhole collimator, was used to acquire SPECT projection images at 40 sec/view of the rat thorax following injection of Tc99m labeled albumin that accumulated in the rat\u27s lungs. A voxel-driven, ordered-subset expectation maximization reconstruction was implemented. Following SPECT imaging, the rat was imaged using micro-CT with Feldkamp conebeam reconstruction. The two reconstructed image volumes were fused to provide a structure/function image of the rat thorax. Reconstruction accuracy and performance were evaluated using numerical simulations and actual imaging of an experimental phantom consisting of Tc99m filled chambers with known diameters and count rates. Full-width half-maximum diameter measurement errors decreased with increasing chamber diameter, ranging from \u3c 6% down to 0.1%. Errors in the ratio of count rate estimates between tubes were also diameter dependent but still relatively small. This preliminary study suggests that SPECT will be useful for imaging and quantifying the pulmonary blood flow distribution and the distribution of Tc99m labeled ligands in the lungs of small laboratory animals

Distribution of Capillary Transit Times in Isolated Lungs of Oxygen-Tolerant Rats

Rats pre-exposed to 85% O2 for 5–7 days tolerate the otherwise lethal effects of 100% O2. The objective was to evaluate the effect of rat exposure to 85% O2 for 7 days on lung capillary mean transit time (t¯c) and distribution of capillary transit times (h c(t)). This information is important for subsequent evaluation of the effect of this hyperoxia model on the redox metabolic functions of the pulmonary capillary endothelium. The venous concentration vs. time outflow curves of fluorescein isothiocyanate labeled dextran (FITC-dex), an intravascular indicator, and coenzyme Q1 hydroquinone (CoQ1H2), a compound which rapidly equilibrates between blood and tissue on passage through the pulmonary circulation, were measured following their bolus injection into the pulmonary artery of isolated perfused lungs from rats exposed to room air (normoxic) or 85% O2 for 7 days (hyperoxic). The moments (mean transit time and variance) of the measured FITC-dex and CoQ1H2 outflow curves were determined for each lung, and were then used in a mathematical model [Audi et al. J. Appl. Physiol. 77: 332–351, 1994] to estimate t¯c and the relative dispersion (RDc) of h c(t). Data analysis reveals that exposure to hyperoxia decreases lung t¯c by 42% and increases RDc, a measure h c(t) heterogeneity, by 40%

Challenging the orthodoxy: union learning representatives as organic intellectuals

Teacher education and continuing professional development have become a key areas of controversy in England since the period of school sector restructuring following the 1988 Education Reform Act. More recently teacher training and professional development have often been used to promote and reinforce a narrow focus on the government’s ‘standards agenda’. However, the emerging discourse of ‘new professionalism’ has raised the profile of professional development in schools, and together with union learning representatives, there are opportunities to secure real improvements in teachers’ access to continuing professional development. This paper argues however that union learning representatives must go beyond advocating for better access to professional development and should raise more fundamental questions about the nature of professional development and the education system it serves. Drawing on Gramsci’s notion of the ‘organic intellectual’, the paper argues that union learning representatives have a key role as organisers of ideas – creating spaces in which the ideological dominance of current policy orthodoxy might be challenged

Dairy heifers naturally exposed to Fasciola hepatica develop a type-2 immune response and concomitant suppression of leukocyte proliferation

Fasciola hepatica is a parasitic trematode of global importance in livestock. Control strategies reliant on anthelmintics are unsustainable due to the emergence of drug resistance. Vaccines are under development, but efficacy is variable. Evidence from experimental infection suggest vaccine efficacy may be affected by parasite-induced immunomodulation. Little is known about the immune response to F. hepatica following natural exposure. Hence we analysed the immune responses over time in calves naturally exposed to F. hepatica infection.Cohorts of replacement dairy heifer calves (n=42) with no prior exposure to F. hepatica, on three commercial dairy farms, were sampled over the course of a grazing season. Exposure was determined through F. hepatica-specific serum antibody ELISA and fluke egg counts. Concurrent changes in peripheral blood leukocyte sub-populations, lymphocyte proliferation and cytokine responses were measured. Relationships between fluke infection and immune responses were analysed using multivariable linear mixed effect models.All calves from one farm showed evidence of exposure, whilst cohorts from the remaining two farms remained negative over the grazing season. A type-2 immune response was associated with exposure, with increased interleukin (IL)-4 production, IL-5 transcription and eosinophilia. Suppression of parasite-specific PBMC proliferation was evident; while decreased mitogen stimulated IFN-γ production suggested immunomodulation, which was not restricted to parasite-specific responses. Our findings show that the global immune response is modulated towards a non-proliferative type-2 state following natural challenge with F. hepatica This has implications for vaccination programmes in terms of the timing of administration of vaccination programmes, and for host susceptibility to co-infecting pathogens

Characterisation of the Medipix3 detector for 60 and 80 keV electrons

In this paper we report quantitative measurements of the imaging performance for the current generation of hybrid pixel detector, Medipix3, used as a direct electron detector. We have measured the modulation transfer function and detective quantum efficiency at beam energies of 60 and 80 keV. In single pixel mode, energy threshold values can be chosen to maximize either the modulation transfer function or the detective quantum efficiency, obtaining values near to, or exceeding those for a theoretical detector with square pixels. The Medipix3 charge summing mode delivers simultaneous, high values of both modulation transfer function and detective quantum efficiency. We have also characterized the detector response to single electron events and describe an empirical model that predicts the detector modulation transfer function and detective quantum efficiency based on energy threshold. Exemplifying our findings we demonstrate the Medipix3 imaging performance recording a fully exposed electron diffraction pattern at 24-bit depth together with images in single pixel and charge summing modes. Our findings highlight that for transmission electron microscopy performed at low energies (energies <100 keV) thick hybrid pixel detectors provide an advantageous architecture for direct electron imaging

Medipix3 Demonstration and understanding of near ideal detector performance for 60 & 80 keV electrons

In our article we report first quantitative measurements of imaging performance for the current generation of hybrid pixel detector, Medipix3, as direct electron detector. Utilising beam energies of 60 & 80 keV, measurements of modulation transfer function (MTF) and detective quantum efficiency (DQE) have revealed that, in single pixel mode (SPM), energy threshold values can be chosen to maximize either the MTF or DQE, obtaining values near to, or even exceeding, those for an ideal detector. We have demonstrated that the Medipix3 charge summing mode (CSM) can deliver simultaneous, near ideal values of both MTF and DQE. To understand direct detection performance further we have characterized the detector response to single electron events, building an empirical model which can predict detector MTF and DQE performance based on energy threshold. Exemplifying our findings we demonstrate the Medipix3 imaging performance, recording a fully exposed electron diffraction pattern at 24-bit depth and images in SPM and CSM modes. Taken together our findings highlight that for transmission electron microscopy performed at low energies (energies <100 keV) thick hybrid pixel detectors provide an advantageous and alternative architecture for direct electron imagin

99MTc-Hexamethylpropyleneamine Oxime Imaging for Early Detection of Acute Lung Injury in Rats Exposed to Hyperoxia or Lipopolysaccharide Treatment

99mTc-Hexamethylpropyleneamine oxime (HMPAO) is a clinical single-photon emission computed tomography biomarker of tissue oxidoreductive state. Our objective was to investigate whether HMPAO lung uptake can serve as a preclinical marker of lung injury in two well-established rat models of human acute lung injury (ALI). Rats were exposed to \u3e95% O2 (hyperoxia) or treated with intratracheal lipopolysaccharide (LPS), with first endpoints obtained 24 h later. HMPAO was administered intravenously before and after treatment with the glutathione-depleting agent diethyl maleate (DEM), scintigraphy images were acquired, and HMPAO lung uptake was quantified from the images. We also measured breathing rates, heart rates, oxygen saturation, bronchoalveolar lavage (BAL) cell counts and protein, lung homogenate glutathione (GSH) content, and pulmonary vascular endothelial filtration coefficient (Kf). For hyperoxia rats, HMPAO lung uptake increased after 24 h (134%) and 48 h (172%) of exposure. For LPS-treated rats, HMPAO lung uptake increased (188%) 24 h after injury and fell with resolution of injury. DEM reduced HMPAO uptake in hyperoxia and LPS rats by a greater fraction than in normoxia rats. Both hyperoxia exposure (18%) and LPS treatment (26%) increased lung homogenate GSH content, which correlated strongly with HMPAO uptake. Neither of the treatments had an effect on Kf at 24 h. LPS-treated rats appeared healthy but exhibited mild tachypnea, BAL, and histological evidence of inflammation, and increased wet and dry lung weights. These results suggest the potential utility of HMPAO as a tool for detecting ALI at a phase likely to exhibit minimal clinical evidence of injury

An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity

It is widely accepted that canonical Wnt (cWnt) signaling is required for the differentiation of osteoprogenitors into osteoblasts. Furthermore, tumor-derived secretion of the cWnt-antagonist Dickkopf-1 (Dkk-1) is known to cause bone destruction, inhibition of repair and metastasis in many bone malignancies, but its role in osteosarcoma (OS) is still under debate. In this study, we examined the role of Dkk-1in OS by engineering its overexpression in the osteochondral sarcoma line MOS-J. Consistent with the known role of Dkk-1 in osteoblast differentiation, Dkk-1 inhibited osteogenesis by the MOSJ cells themselves and also in surrounding tissue when implanted in vivo. Surprisingly, Dkk-1 also had unexpected effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro and caused the formation of larger and more destructive tumors than controls upon orthotopic implantation. These effects were attributed in part to upregulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1). Direct inhibition of ALDH1 reduced viability under stressful culture conditions, whereas pharmacological inhibition of cWnt or overexpression of ALDH1 had a protective effect. Furthermore, we observed that ALDH1 was transcriptionally activated in a c-Jun-dependent manner through a pathway consisting of RhoA, MAP-kinase-kinase-4 and Jun N-terminal Kinase (JNK), indicating that noncanonical planar cell polarity-like Wnt signaling was the mechanism responsible. Together, our results therefore demonstrate that Dkk-1 enhances resistance of OS cells to stress by tipping the balance of Wnt signaling in favor of the non-canonical Jun-mediated Wnt pathways. In turn, this results in transcriptional activation of ALDH1 through Jun-responsive promoter elements. This is the first report linking Dkk-1 to tumor stress resistance, further supporting the targeting of Dkk-1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells

Easy on that trigger dad: a study of long term family photo retrieval

We examine the effects of new technologies for digital photography on people's longer term storage and access to collections of personal photos. We report an empirical study of parents' ability to retrieve photos related to salient family events from more than a year ago. Performance was relatively poor with people failing to find almost 40% of pictures. We analyze participants' organizational and access strategies to identify reasons for this poor performance. Possible reasons for retrieval failure include: storing too many pictures, rudimentary organization, use of multiple storage systems, failure to maintain collections and participants' false beliefs about their ability to access photos. We conclude by exploring the technical and theoretical implications of these findings