Reconciling Assumptions in Bottom-Up and Top-Down Approaches for Estimating Aerosol Emission Rates From Wildland Fires Using Observations From FIREX-AQ.

Accurate fire emissions inventories are crucial to predict the impacts of wildland fires on air quality and atmospheric composition. Two traditional approaches are widely used to calculate fire emissions: a satellite-based top-down approach and a fuels-based bottom-up approach. However, these methods often considerably disagree on the amount of particulate mass emitted from fires. Previously available observational datasets tended to be sparse, and lacked the statistics needed to resolve these methodological discrepancies. Here, we leverage the extensive and comprehensive airborne in situ and remote sensing measurements of smoke plumes from the recent Fire Influence on Regional to Global Environments and Air Quality (FIREX-AQ) campaign to statistically assess the skill of the two traditional approaches. We use detailed campaign observations to calculate and compare emission rates at an exceptionally high-resolution using three separate approaches: top-down, bottom-up, and a novel approach based entirely on integrated airborne in situ measurements. We then compute the daily average of these high-resolution estimates and compare with estimates from lower resolution, global top-down and bottom-up inventories. We uncover strong, linear relationships between all of the high-resolution emission rate estimates in aggregate, however no single approach is capable of capturing the emission characteristics of every fire. Global inventory emission rate estimates exhibited weaker correlations with the high-resolution approaches and displayed evidence of systematic bias. The disparity between the low-resolution global inventories and the high-resolution approaches is likely caused by high levels of uncertainty in essential variables used in bottom-up inventories and imperfect assumptions in top-down inventories.

Image processing can cause some malignant soft-tissue lesions to be missed in digital mammography images.

AIM: To investigate the effect of image processing on cancer detection in mammography. METHODS AND MATERIALS: An observer study was performed using 349 digital mammography images of women with normal breasts, calcification clusters, or soft-tissue lesions including 191 subtle cancers. Images underwent two types of processing: FlavourA (standard) and FlavourB (added enhancement). Six observers located features in the breast they suspected to be cancerous (4,188 observations). Data were analysed using jackknife alternative free-response receiver operating characteristic (JAFROC) analysis. Characteristics of the cancers detected with each image processing type were investigated. RESULTS: For calcifications, the JAFROC figure of merit (FOM) was equal to 0.86 for both types of image processing. For soft-tissue lesions, the JAFROC FOM were better for FlavourA (0.81) than FlavourB (0.78); this difference was significant (p=0.001). Using FlavourA a greater number of cancers of all grades and sizes were detected than with FlavourB. FlavourA improved soft-tissue lesion detection in denser breasts (p=0.04 when volumetric density was over 7.5%) CONCLUSIONS: The detection of malignant soft-tissue lesions (which were primarily invasive) was significantly better with FlavourA than FlavourB image processing. This is despite FlavourB having a higher contrast appearance often preferred by radiologists. It is important that clinical choice of image processing is based on objective measures.

Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study.

BACKGROUND: Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease. METHODS: We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa. RESULTS: We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an 'interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6. CONCLUSIONS: Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.

MEDXVIEWER: PROVIDING A WEB-ENABLED WORKSTATION ENVIRONMENT FOR COLLABORATIVE AND REMOTE MEDICAL IMAGING VIEWING, PERCEPTION STUDIES AND READER TRAINING.

MedXViewer (Medical eXtensible Viewer) has been developed to address the need for workstation-independent, picture archiving and communication system (PACS)-less viewing and interaction with anonymised medical images. The aim of this paper is to describe the design and features of MedXViewer as well as to introduce the new features available in the latest release (version 1.2). MedXViewer currently supports digital mammography and tomosynthesis. The flexible software design used to develop MedXViewer allows it to be easily extended to support other imaging modalities. Regions of interest can be drawn by a user, and any associated information about a mark, an image or a study can be added. The questions and settings can be easily configured depending on the need of the research allowing both ROC and FROC studies to be performed. Complex tree-like questions can be asked where a given answer presents the user to new questions. The hanging protocol can be specified for each study. Panning, windowing, zooming and moving through slices are all available while modality-specific features can be easily enabled, e.g. quadrant zooming in digital mammography and tomosynthesis studies. MedXViewer can integrate with a web-based image database OPTIMAM Medical Image Database allowing results and images to be stored centrally. The software can, alternatively, run without a network connection where the images and results can be encrypted and stored locally on a machine or external drive. MedXViewer has been used for running remote paper-less observer studies and is capable of providing a training infrastructure and coordinating remote collaborative viewing sessions.

Characterising cytotoxic agent action as a function of the cell cycle using Fourier transform infrared microspectroscopy.

Fourier Transform Infrared (FTIR) micro-spectroscopy measurements were acquired to study infrared signatures of chemotherapeutic response as a function of the cell cycle. Renal carcinoma Caki-2 cells were exposed to IC50 doses of 5-fluorouracil and Paclitaxel for a period of 24 hours. The inherent cell cycle infrared signatures from untreated and drug-treated cells were successfully retrieved by the construction of a robust SVM able to discriminate the cell cycle phases of this cell line with an average accuracy of 83.7%. The overriding infrared signature observed relates to an apoptotic biochemical response that does not appear to be correlated with the events affected by the drugs' mode of action or the cell cycle. Since apoptosis is a well conserved mechanism among living species, these results suggest that both the stages of proliferation as well as the absence/presence of apoptosis need to be taken into account in order to elucidate the fine biochemical details revealing the immediate cellular response to the drug in order to assign reliable spectral patterns of drug action.

Enhanced FTIR bench-top imaging of single biological cells.

A new optical system has recently been developed that enables infrared images to be obtained with a pixel resolution of 1 micron on a bench-top instrument using a thermal source. We present here imaging data from two contrasting cellular systems that represent different challenges. Renal carcinoma cells cytospun onto CaF2 have a largely rounded morphology and thus suffer from strong resonant Mie scattering. Skin fibroblast cells, cultured onto CaF2 on the other hand are very spread out so scatter less strongly but are so thin they deliver extremely weak signals. Using suitable pre-processing methods, including PCA noise reduction and RMieS correction, we demonstrate that useful high resolution images can be obtained from either sample.

A Pilot Study on the Development of Remote Quality Control of Digital Mammography Systems in the NHS Breast Screening Programme.

In the UK, physicists and radiographers perform routine quality control (QC) of digital mammography equipment at daily, weekly and monthly intervals. The tests performed and tolerances are specified by standard protocols. The manual nature of many of the tests introduces variability due to the positioning of regions of interest (ROIs) and can be time consuming. The tools on workstations provided by manufacturers limit the range of analysis that radiographers can perform and do not allow for a standard set of tools and analysis because they are specific to a given manufacturer. Automated software provides a means of reducing the variability in the analysis and also provides the possibility of additional, more complex analysis than is currently performed on the daily, weekly and monthly checks by radiographers. To this end, a set of tools has been developed to analyse the routine images taken by radiographers. As well as automatically reproducing the usual measurements by radiographers more complex analysis is provided. A QC image collection system has been developed which automatically routes QC data from a clinical site to a centralised server for analysis. A Web-based interface has been created that allows the users to view the performance of the mammographic equipment. The pilot system obtained over 3000 QC images from seven X-ray units at a single screening centre over 2 years. The results show that these tools and methods of analysis can highlight changes in a detector over time that may otherwise go unnoticed with the conventional analysis.

In Memoriam: Olga Hudlická (11.07.26-03.05.14).

Dr Olga Hudlická, Professor Emeritus in the Department of Physiology, University of Birmingham Medical School, died suddenly on 3rd May not long after a fall. She was one of the best-known vascular physiologists of the last century, investigating control of blood flow and regulation of angiogenesis in skeletal and cardiac muscle. This article is protected by copyright. All rights reserved.

Exploring the spectroscopic differences of Caki-2 cells progressing through the cell cycle while proliferating in vitro.

FTIR micro-spectral images of Caki-2 cells cytospun onto calcium fluoride (CaF2) slides were used to build a computational model in order to discriminate between the biochemical events of the continuous cell cycle during proliferation. Multivariate analysis and machine learning techniques such as PCA, PLSR and SVMs were used to highlight the chemical differences among the cell cycle phases and also to point out the need for removing the distortion of the spectra due to the morphology of the cells. Results showed cell cycle dependant scattering profiles that enabled the training of a SVM in order to recognise, with a relative high accuracy, each cell cycle phase purely with the scattering curve removed from the FTIR data after being subject to the RMieS-EMSC algorithm.

Visit-to-visit and 24-h blood pressure variability: association with endothelial and smooth muscle function in African Americans.

The purpose of this study was to investigate the association of visit-to-visit and 24-h blood pressure (BP) variability with markers of endothelial injury and vascular function. We recruited 72 African Americans who were non-diabetic, non-smoking and free of cardiovascular (CV) and renal disease. Office BP was measured at three visits and 24-h ambulatory BP monitoring was conducted to measure visit-to-visit and 24-h BP variability, respectively. The 5-min time-course of brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were assessed as measures of endothelial and smooth muscle function. Fasted blood samples were analyzed for circulating endothelial microparticles (EMPs). Significantly lower CD31+CD42- EMPs were found in participants with high visit-to-visit systolic blood pressure (SBP) variability or high 24-h diastolic blood pressure (DBP) variability. Participants with high visit-to-visit DBP variability had significantly lower flow-mediated dilation and higher nitroglycerin-mediated dilation at multiple time-points. When analyzed as continuous variables, 24-h mean arterial pressure variability was inversely associated with CD62+ EMPs; visit-to-visit DBP variability was inversely associated with flow-mediated dilation normalized by smooth muscle function and was positively associated with nitroglycerin-mediated dilation; and 24-h DBP variability was positively associated with nitroglycerin-mediated dilation. All associations were independent of age, gender, body mass index and mean BP. In conclusion, in this cohort of African Americans visit-to-visit and 24-h BP variability were associated with measures of endothelial injury, endothelial function and smooth muscle function. These results suggest that BP variability may influence the pathogenesis of CV disease, in part, through influences on vascular health.

Field evaluations of disposable sticky lures for surveillance of Aedes aegypti (Stegomyia aegypti) and Culex quinquefasciatus in Jakarta.

From December 1997 to April 1998, disposable sticky lures (1608 lure days) were trialled in homes in north Jakarta, Indonesia as surveillance tools for Aedes aegypti (Stegomyia aegypti) (Diptera: Culicidae) and Culex quinquefasciatus (Diptera: Culicidae), referenced to indoor resting adult collections (92 × 10 min). The lures collected 89.4% of the total of 1339 Ae. aegypti and 92.1% of the total of 1272 Cx. quinquefasciatus collected by all methods. Because there were no significant differences with respect to numbers collected in bedrooms, living rooms and kitchens, bedrooms were selected for subsequent trials for reasons of convenience. The main trials involved a replicated complete block design with L-lysine and sodium carbonate. Lures without attractant or with four different dilutions of L-lysine collected 3.4-8.5 times more Ae. aegypti and 4.2-8.1 times more Cx. quinquefasciatus than were collected by mouth aspirator. Lures with or without dilutions of sodium carbonate collected 2.7-5.0 times more Ae. aegypti and 1.8-4.2 times more Cx. quinquefasciatus than aspirator collections. The precision associated with catches of sticky lures was better than that for aspirator collections. Although olfactants generally improved the numbers of mosquitoes collected, the differences in catch between lures with and without attractants were usually non-significant. Any deficit in catch may be offset by increasing the surveillance period to ≥30 days to detect all four dengue serotypes from infected mosquitoes.

Highlighting a need to distinguish cell cycle signatures from cellular responses to chemotherapeutics in SR-FTIR spectroscopy.

Previous research has seen difficulties in establishing clear discrimination by principal component analysis (PCA) between drug-treated cells analysed by single point SR-FTIR spectroscopy, relative to multisampling cell monolayers by conventional FTIR. It is suggested that the issue arises due to signal mixing between cellular-response signatures and cell cycle phase contributions in individual cells. Consequently, chemometric distinction of cell spectra treated with multiple drugs is difficult even with supervised methods. In an effort to separate cell cycle chemistry from cellular response chemistry in the spectra, renal carcinoma cells were stained with propidium iodide and fluorescent-activated cell sorted (FACS) after exposure to a number of chemotherapeutic compounds; 5-fluorouracil (5FU) and a set of novel gold-based experimental compounds. The cell spectra were analysed separately by PCA in G(1), S or G(2)/M phase. The mode of action of established drug 5FU, known to disrupt S phase, was confirmed by FACS analysis. The chemical signature of 5FU-treated cells discriminated against both the control and gold-compound (KF0101)-treated cell spectra, suggesting a different mode of action due to a difference in cellular response.

Ligand-independent activation of EphA2 by arachidonic acid induces metastasis-like behaviour in prostate cancer cells.

BACKGROUND: High intake of omega-6 polyunsaturated fatty acids (PUFA) has been associated with clinical progression in prostate cancer (CaP). This study investigates the signalling mechanism by which the omega-6 PUFA arachidonic acid (AA) induces prostatic cellular migration to bone marrow stroma. METHODS: Western blot analysis of the PC-3, PC3-GFP, DU 145 and LNCaP cells or their lipid raft (LR) components post AA stimulation was conducted in association with assays for adhesion and invasion through the bone marrow endothelial monolayers. RESULTS: Arachidonic acid increased transendothelial migration of PC3-GFP cells (adhesion 37%±0.08, P=0.0124; transmigration 270%±0.145, P=0.0008). Akt, Src and focal adhesion kinase (FAK) pathways were induced by AA and integrally involved in transendothelial migration. LR were critical in AA uptake and induced Akt activity. Ephrin receptor A2 (EphA2), localised in LR, is expressed in DU 145 and PC-3 cells. Arachidonic acid induced a rapid increase of EphA2 Akt-dependent/ligand-independent activation, while knockdown of the EphrinA1 ligand decreased AA induced transendothelial migration, with an associated decrease in Src and FAK activity. Arachidonic acid activated Akt in EphA2(-) LNCaP cells but failed to induce BMEC transendothelial invasion. CONCLUSION: Arachidonic acid induced stimulation of EphA2 in vitro is associated fundamentally with CaP epithelial migration across the endothelial barrier.

Investigating cellular responses to novel chemotherapeutics in renal cell carcinoma using SR-FTIR spectroscopy.

SR-FTIR spectroscopy was evaluated as a technique to discriminate spectral signals of cellular response at the single cell level, when cancer cells are exposed to chemotherapeutics. 5-Fluorouracil, an established drug of known mode of action, was tested against a renal carcinoma cell line (Caki-2), along with two experimental analogues of gold-based compounds. The use of unsupervised principal component analysis (PCA) failed to clearly define any distinction between control and drug treated cell spectra. Supervised principal component linear discriminant analysis (PC-LDA) did have some potential to reveal signatures of cell response and repair but again failed to distinctly discriminate groups of spectra with different drug treatments. Alternatively, clear PCA discrimination was observed in spectra from average cell populations via single point benchtop spectroscopy, probing several cells simultaneously with an increased aperture. The Caki-2 cell line initially appeared to be sensitive to the novel compounds, inducing a cellular response prior to subsequential cell recovery which was assessed by both PCA and cell viability assays.

Inferring coancestry in population samples in the presence of linkage disequilibrium.

In both pedigree linkage studies and in population-based association studies there has been much interest in the use of modern dense genetic marker data to infer segments of gene identity by descent (ibd) among individuals not known to be related, to increase power and resolution in localizing genes affecting complex traits. In this article, we present a hidden Markov model (HMM) for ibd among a set of chromosomes and describe methods and software for inference of ibd among the four chromosomes of pairs of individuals, using either phased (haplotypic) or unphased (genotypic) data. The model allows for missing data and typing error, but does not model linkage disequilibrium (LD), because fitting an accurate LD model requires large samples from well-studied populations. However, LD remains a major confounding factor, since LD is itself a reflection of coancestry at the population level. To study the impact of LD, we have developed a novel simulation approach to generate realistic dense marker data for the same set of markers but at varying levels of LD. Using this approach, we present results of a study of the impact of LD on the sensitivity and specificity of our HMM model in estimating segments of ibd among sets of four chromosomes and between genotype pairs. We show that, despite not incorporating LD, our model has been quite successful in detecting segments as small as 10(6) bp (1 Mpb); we present also comparisons with fastIBD which uses an LD model in estimating ibd.

OXIDATIVE STRESS RESPONSE TO SHORT DURATION BOUT OF SUBMAXIMAL AEROBIC EXERCISE IN HEALTHY YOUNG ADULTS.

PURPOSE: The purpose of this study was to investigate the oxidative stress response to a short duration bout of submaximal exercise in a cohort of healthy young adults. METHODS: 15 apparently healthy college age males and females completed a modified Bruce-protocol treadmill test to 75-80% of their heart rate reserve. Blood samples collected immediately before (pre-exercise), immediately after, 30, 60 and 120 minutes post-exercise were assayed for total antioxidant capacity (TAC), superoxide disumutase (SOD), thiobarbituric acid-reactive substances (TBARS), and protein carbonyls (PC). RESULTS: SOD activity was significantly increased from pre-exercise levels at 30 minutes (77%), 60 minutes (33%), and 120 minutes (37%) post-exercise. TAC levels were also significantly increased from pre-exercise levels at 60 minutes (30%) and 120 minutes (33%) post-exercise. There were no significant changes in biomarkers for reactive oxygen/nitrogen species (RONS) mediated damage (TBARS and PC) across all post-exercise time points. CONCLUSIONS: In a cohort of healthy young adults, a short duration bout of submaximal aerobic exercise elicited increases in antioxidant activity/concentration, but did not evoke changes in oxidative stress-induced damage. These results may suggest that: (1) short duration bouts of submaximal aerobic exercise are sufficient to induce RONS generation; and (2) the antioxidant defense system is capable of protecting against enhanced RONS production induced by a short duration, submaximal exercise bout in healthy young adults.

An investigation of the RWPE prostate derived family of cell lines using FTIR spectroscopy.

Interest in developing robust, quicker and easier diagnostic tests for cancer has lead to an increased use of Fourier transform infrared (FTIR) spectroscopy to meet that need. In this study we present the use of different experimental modes of infrared spectroscopy to investigate the RWPE human prostate epithelial cell line family which are derived from the same source but differ in their mode of transformation and their mode of invasive phenotype. Importantly, analysis of the infrared spectra obtained using different experimental modes of infrared spectroscopy produces similar results. The RWPE family of cell lines can be separated into groups based upon the method of cell transformation rather than the resulting invasiveness/aggressiveness of the cell line. The study also demonstrates the possibility of using a genetic algorithm as a possible standardised pre-processing step and raises the important question of the usefulness of cell lines to create a biochemical model of prostate cancer progression.

Melanoma in solid organ transplant recipients.

This manuscript outlines estimated risk and clinical course of pretransplant MM, donor-transmitted MM and de novo MM posttransplantation and includes an analysis of risk factors for metastasis, data from clinical studies and current and proposed management. MM in situ and thin melanoma (<1 mm) in the transplant population has similar recurrence and survival estimates to those in the general population. A minimum wait time of 2 years prior to transplantation is suggested for MM with a Breslow depth <1 mm and no clinical evidence of metastasis. More advanced MM may adopt a more aggressive course in transplant recipients. Sentinel lymph node biopsy may be of additional prognostic benefit. Revision of immunosuppression in the management of de novo melanoma in collaboration with the transplant team should be considered. Larger studies utilizing uniform staging criteria or at minimum Breslow depth, are required to assess true risk and outcome of MM in the immunosuppressed transplant population. Emphasis remains on patient education and regular screening to provide early detection of MM.

Use of durometry in assessment of venous disease.

OBJECTIVES: Ulceration of the lower limbs is a common debilitating complication of chronic venous hypertension. Detection of preulcerative skin changes would allow for identification of high-risk patients; early active treatment may prevent ulcer formation. METHODS: Patients with isolated venous disease and volunteers attending outpatient clinics underwent assessment of their clinical, aetiological, anatomical and pathological (CEAP) classification. We employed an industrial durometer, an instrument that measures the hardness of metals and plastic, to assess skin induration. The durometer probe was rested perpendicular on their skin 15 cm above the medial malleolus in non-ulcerated tissue, with the patient and limb in recumbency. The average of four measurements was derived. RESULTS: In 107 people, 203 lower limbs (mean age 55.6 years) were assessed. A significant difference in durometry readings was demonstrated between patients with CEAP classes 0, 1 and 2, and those with classes 4, 5 and 6 (P < 0.0005). There was statistically significant evidence that age and CEAP classification correlated with durometry (P < 0.0001). CONCLUSION: Durometry is of potential value in the assessment and monitoring of preulcerative venous disease, and could help to identify high-risk patients. This would assist in the institution of timely and appropriate treatment.

Influence of omega-6 PUFA arachidonic acid and bone marrow adipocytes on metastatic spread from prostate cancer.

BACKGROUND: Prostate cancer (CaP) preferentially metastasises to the bone, and we have previously shown that the poly-unsaturated fatty acid (PUFA) arachidonic acid (AA) is a potent stimulator of CaP invasion. Here we present that AA promotes CaP invasion by inducing bone marrow adipocyte formation. METHODS: Boyden invasion-chamber assays assessed the ability of dietary oils, their PUFA components, and specific PUFA-loaded adipocytes to induce PC-3 invasion. Lipid transfer and metabolism was followed using deuterated AA and Fourier Transform Infrared spectroscopy (FTIR). RESULTS: Poly-unsaturated fatty acid constituents, but not their corresponding dietary oils, induced PC-3 invasion. PUFAs induce bone marrow adipocyte (BM-Ad) differentiation with AA inducing higher levels of BM-Ad differentiation, as compared with other PUFAs (3998+/-514.4 vs 932+/-265.8; P=0.00002), which stimulated greater PC-3 invasion than free AA (22 408.5+/-607.4 vs 16 236+/-313.9; P=0.01111) or adipocytes generated in the presence of other PUFAs. In bone marrow co-culture PC-3 and BM-Ad interactions result in direct uptake and metabolism of AA by PC-3 cells, destruction of the adipocyte and subsequent formation of a bone metastasis. CONCLUSION: The data supports the hypothesis that AA not only promotes CaP invasion, it also prepares the 'soil', making it more supportive for implantation and propagation of the migrating metastatic cell.