Determining the haemodynamic significance of arterial stenosis: the relationship between CT angiography, computational fluid dynamics, and non-invasive fractional flow reserve.

Coronary artery disease causes significant morbidity and mortality worldwide. Invasive coronary angiography (ICA) is currently the reference standard investigation. Fractional flow reserve (FFR) complements traditional ICA by providing extra information on blood flow, which has convincingly led to better patient management and improved cost-effectiveness. Computed tomography coronary angiography (CTCA) is suitable for the investigation of chest pain, especially in the low- and intermediate-risk groups. FFR generated using CT data (producing FFRCT) may improve the positive predictive value of CTCA. The basic science of FFRCT is like a "black box" to most imaging professionals. A fundamental principle is that good quality CTCA is likely to make any post-processing easier and more reliable. Both diagnostic and observational studies have suggested that the accuracy and the short-term outcome of using FFRCT are both comparable with FFR in ICA. More multidisciplinary research with further refined diagnostic and longer-term observational studies will hopefully pinpoint the role of FFRCT in existing clinical pathways.

Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are known to have poorer short-term prognosis compared to stable coronary artery (CAD) patients undergoing elective PCI. Few studies have made direct comparison of long-term mortality between ACS and stable CAD patients undergoing PCI. The aim of our study was to compare the long-term mortality following PCI between patients with ACS and those with stable CAD. METHODS: We examined consecutive patients undergoing PCI with stenting at a tertiary referral hospital. Clinical, angiographic and biochemical data were collected and analysed. The primary outcome was all-cause mortality retrieved from the Statewide Death Registry database. RESULTS: Included were 1923 consecutive PCI patients (970 stable CAD and 953 ACS). The mean follow-up time was 4.1 years ± 1.8 years. In-hospital mortality was 1.4% overall, seen exclusively in patients with ACS (n=28, 2.9%). Post-discharge mortality was 6.7% among patients with stable CAD and 10.5% for ACS (P<0.01). Multivariate predictors of post-discharge deaths for both groups included age (HR 1.08 per year, P<0.001) and impaired renal function (HR 2.49, P<0.001). Following adjustment for these factors, an ACS indication for PCI was not associated with greater post-discharge mortality (adjusted HR 1.18: 0.85-1.64, P=0.32). CONCLUSIONS: Patients undergoing PCI following an ACS have higher long-term mortality to those with stable CAD, which is potentially explained by a greater prevalence of comorbidities. This suggests that for the ACS population, contemporary interventional and medical management strategies may effectively and specifically counter the adverse prognostic impact of coronary instability and myocardial damage.

Antiphospholipid syndrome and rheumatic fever: a case spanning three decades of changing concepts and common immunological mechanisms.

We present a case of primary antiphospholipid syndrome (APS), initially diagnosed as acute rheumatic fever, resulting in severe mitral valve incompetence. This case raises questions of the specificity of the Jones diagnostic criteria for rheumatic fever in a population where it is infrequently encountered. There are similarities in clinical, pathological and echocardiographic presentations between rheumatic fever and APS, in addition to common immunological mechanisms. Our case highlights the possibility that rather than rheumatic fever being primarily responsible for her recurrent attacks of chorea and arthritis, the streptococcal infections in our patient occurred either in the setting of underlying antiphospholipid antibodies ('second hit' phenomenon), or may have triggered the development of pathogenic antibodies (molecular mimicry), subsequently leading to the clinical evolution of APS. During the three decades of our patient and her recurrent problems, there has been an evolving knowledge of the mechanisms of APS and rheumatic fever, allowing us to extend our understanding beyond symptoms and syndromes, to a better realization of the underlying immunological relationship between the two.

Administration of an insulin powder to the lungs of cynomolgus monkeys using a Penn Century insufflator.

A powder formulation of live-attenuated measles vaccine is being developed for administration to the lungs. The safety and efficacy of the powder will be assessed by insufflation into cynomolgus monkeys. A Penn Century insufflator has been evaluated for powder dosing to the monkeys using an insulin formulation having similar physicochemical characteristics to the vaccine powder. Insulin pharmacokinetics were compared following dosing by powder insufflation, solution instillation into the trachea and subcutaneous injection. The insulin dosed to the lungs and trachea was more rapidly absorbed than that administered subcutaneously. Insulin bioavailability was greater from the inhaled powder than from the instilled solution. The findings confirm that the Penn Century device is suitable for vaccine powder dosing to the deep lung.

Butter as an indicator of regional persistent organic pollutant contamination: further development of the approach using polychlorinated dioxins and furans (PCDD/Fs), and dioxin-like polychlorinated biphenyls (PCBs).

The potential for use of butter as a widely available, relatively uniform lipid-rich matrix for the determination of spatial distributions of persistent organic pollutants has already been demonstrated. The present study determines the contributions to toxicity equivalence (TEQ) from polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) using butter samples from 24 countries world wide. Concentrations of PCDD/Fs and dioxin-like PCBs ranged from 0.07 to 5.69 pg SigmaWHO-TEQ g(-1) lipid. For most samples, PCDD/F TEQ fell within ranges reported for European dairy products over the last decade (0.3-2 pg x g(-1) lipid I-TEQ), though a single sample from Spain was a notable exception. Other than this sample, the highest values were recorded for samples from the Netherlands and Italy, with those from India, China and Tunisia also being relatively high. The contribution from non-ortho-PCBs was particularly significant in samples from Germany, Austria, Italy, the Czech Republic, Tunisia, India and Argentina. Although overall TEQs were generally highest in European and Mediterranean butters, elevated levels were also apparent in industrializing regions of Asia (India, China) and Latin America (Argentina). More detailed regional studies would be necessary to identify likely dioxin and PCB sources in each case. Nevertheless, this study supports the utility of butter as a monitoring matrix that may be especially applicable in regions for which monitoring programmes are currently lacking.

Modifying the release of leuprolide from spray dried OED microparticles.

A range of oligosaccharide ester derivatives (OEDs) have been designed as drug delivery matrices for controlled release. The synthetic hormone analogue, leuprolide, was encapsulated within these matrices using hydrophobic ion pairing and solvent spray drying. The particles produced modified the release of leuprolide in vitro (dissolution in phosphate buffered saline) and in vivo (subcutaneous and pulmonary delivery in the rat). Release rate was dependent on drug loading and could be manipulated by choice of OED and by combining different OEDs in different ratios. Leuprolide encapsulated in the OEDs retained biological activity as evidenced by elevation in plasma luteinising hormone levels following subcutaneous injection of leuprolide recovered from OED particles in vitro prior to in vivo administration.

The global distribution of PCBs and organochlorine pesticides in butter.

In this study we explored the use of butter as a sampling matrix to reflect the regional and global scale distribution of PCBs and selected organochlorine pesticides/metabolites in air. This was because persistent organic pollutants (POPs) concentrate in dairy fats, where concentrations are controlled by feed intake (primarily from pasture/silage), which is in turn primarily controlled by atmospheric deposition. Butter sigmaPCB concentrations varied by a factor of approximately 60 in 63 samples from 23 countries. They were highest in European and North American butter and lowest in southern hemisphere (Australian, New Zealand) samples, consistent with known patterns of historical global usage and estimated emissions. Concentrations in butter reflected differences in the propensity of PCB congeners to undergo long range atmospheric transport from global source regions to remote areas and the relatively even distribution of HCB in the global atmosphere. Concentrations of p,p'-DDT, p,p'-DDE, and HCH isomers all varied over many orders of magnitude in the butter samples, with highest levels in areas of current use (e.g. India and south/central America for DDT; India, China, and Spain for HCH). We conclude that butter is sensitive to local, regional, and global scale spatial and temporal atmospheric trends of many POPs and may therefore provide a useful sampling medium for monitoring purposes. However, to improve the quantitative information derived on air concentrations requires an awareness of climatic and livestock management factors which influence air-milk fat transfer processes.

A congener-specific PCDD/F emissions inventory for the UK: do current estimates account for the measured atmospheric burden?

Considerable effort has been expended in the UK and elsewhere to quantify and rank PCDD/F primary sources and emissions to the environment, principally the atmosphere, so that cost-effective source reduction measures can be taken. Here, we predict a congener-specific emissions inventory for primary and secondary nondioxin-regulated sources to the UK atmosphere, estimated to have ranged from 3 to 22 kg in 1996. The inventory profile is dominated by OCDD (approximately 30-40%), 1,2,3,4,6,7,8-HpCDD (approximately 15-19%) and 1,2,3,4,6,7,8-HpCDF (approximately 14-19%). Congeners 2,3,4,7,8-PeCDF and 1,2,3,7,8-PeCDD dominate the sigmaTEQ composition. Mass balance modelling suggests that the predicted congener pattern in UK air (based on the emission inventory) is similar to observed measurements, with absolute concentrations being estimated within a factor of 2 for most congeners. Calculations taking into account atmospheric weathering processes and long range (advective) transport suggest that PCDD/F sources to ambient air are primarily ongoing and that atmospheric mixing will mask individual emission source profiles/identities. This supports measured evidence for the consistency of PCDD/F air profiles observed around the UK throughout the year.

Low dose fractionated radiation enhances the radiosensitization effect of paclitaxel in colorectal tumor cells with mutant p53.

BACKGROUND: The current study was undertaken to investigate the influence of wild-type or mutant p53 status on the radiosensitizing effect of paclitaxel in colorectal tumor cell lines. METHODS: HCT-116 (contains wild-type p53) and HT-29 (contains mutant p53) established from moderately differentiated colorectal carcinomas were used in this study. Colony-forming assay was performed after exposure to either different radiation doses (0.5-6 gray [Gy]) or paclitaxel (1-10 nM) or in combination. Induction of p53 and p21(waf1/cip1) by these treatments were determined by immunocytochemistry and Western blot analysis. RESULTS: Radiation caused an increase in nuclear p53 and p21(waf1/cip1) proteins in HCT-116 cells, indicating that p53 functionally induced p21(waf1/cip1). However, induction of nuclear p53 and p21(waf1/cip1) protein was not evident in HT-29 cells, suggesting that p53 was not functional in these cells. Survival data showed that the HCT-116 cells (survival fraction of exponentially growing cells that were irradiated at the clinically relevant dose of 2 Gy [SF(2)] = 0.383; dose required to reduce the fraction of cells to 37% [D(0)] = 223 centigray [cGy]) were significantly sensitive to ionizing radiation (P < 0.008) when compared with the HT-29 cells (SF(2) = 0.614; D(0) = 351 cGy). Paclitaxel caused a higher degree of clonogenic inhibition in HCT-116 (D(0) = 0.7 nM) than HT-29 (D(0) = 1.11 nM) cells (P < 0.06). When paclitaxel and radiation were combined, an enhanced radiosensitizing effect (P < 0.05) was observed in HCT-116 cells (SF(2) = 0.138; D(0) = 103 cGy), whereas in HT-29 cells no significant radiosensitization of paclitaxel was observed (SF(2) = 0.608; D(0) = 306 cGy). However, pretreatment with paclitaxel followed by multifractionated low dose radiation (0.5- or 1-Gy fractions for a total dose of 2 Gy) significantly enhanced the radiosensitizing effect in both HCT-116 and HT-29 cells. CONCLUSIONS: The results of the current study suggested that multifractionated radiation given at very low doses after exposure of cells to paclitaxel conferred a potent radiation sensitizing effect irrespective of p53 status.

A generic model of human lifetime exposure to persistent organic contaminants: development and application to PCB-101.

We have developed a model which successfully reconstructs the lifetime polychlorinated biphenyl (PCB)-101 burden of the UK population for individuals born between 1920 and 1980. It not only follows burdens and clearance of persistent organic contaminants throughout a human lifetime--taking changes in age and body composition into account--but also, importantly, incorporates changing environmental concentrations of the compound of interest. Predicted results agree well with available measured lipid concentrations in human tissues. Its unique construction takes into account both changing environmental concentrations of PCBs in principal food groups and changing dietary habits during the time period. Because environmental burdens of persistent organic contaminants have changed over the last 60 years, residues in food will also have mirrored this change. Critically in this respect, the year in which an individual was born determines the shape and magnitude of their exposure profile for a given compound. Observed trends with age represent an historical legacy of exposure and are not simply a function of equal yearly cumulative inputs. We can demonstrate that the release profile of PCB-101 controls levels in the food supply and ultimately the burden of individuals throughout their life. This effect is expected to be similar for other PCB congeners and persistent organic compounds such as polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs). Models of this type have important applications as predictive tools to estimate the likely impact of source-reduction strategies on human tissue concentrations.

Human exposure to PCDD/Fs in the UK: the development of a modelling approach to give historical and future perspectives.

In order to assess the long-term impact of persistent organic contaminants such as polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) it is important to be able to quantify historical exposure. An understanding of past exposure is not only important to place our current body burdens in perspective, but is useful in assessing our potential future exposure. Unfortunately, very few direct measurements of our main source of exposure (i.e., food) over the past decades are available. This study attempts to reconstruct the historical exposure of the UK population to PCDD/Fs using a combination of emission estimates, information on environmental temporal trends derived from sediment cores and archived materials, and environmental/human fate modelling. Predicted adipose and blood lipid concentrations for a typical cross section of the population are derived over time (1920-2000), which is compared with measured data. The approach has been tested with two PCDDs and two PCDFs and showed encouraging agreement with measured data. Certain parts of the modelling methodology have been highlighted where there is still poor understanding of the processes governing fate and behaviour. These areas are discussed and recommendations for future improvements are made. The paper thus represents an initial modelling approach which defines both the historical (1920-present) and future (present-2020) fate of PCDD/Fs in the UK population.

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres.

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.

Assessment of organic contaminant fate in waste water treatment plants. I: Selected compounds and physicochemical properties.

An extensive and comprehensive literature review has been conducted for compounds which we hypothesise could be present in sludge and maintain their integrity following application to agricultural land. The following compounds have been selected for review; chlorinated paraffins, quintozene, brominated diphenyl ethers, polychlorinated naphthalenes, polydimethylsiloxanes, chloronitrobenzenes, and a range of biologically active and pharmaceutical compounds. All have received interest as a result of their persistence and/or toxicity in environmental media. Physicochemical property information has also been compiled and/or calculated. In this way, an accompanying paper will attempt to predict compound fate in waste water treatment plants (WWTPs) and assess likely transfers from soil/plants to grazing livestock. These papers describe a first attempt to predict the fate of these classes of compounds in the environment and prioritise those of greatest concern.

Dioxin-like PCBs in the environment-human exposure and the significance of sources.

Dioxin-like PCBs represent an important component of the Sigma-TEQ in many environmental media. Specifically, in animal produce and in fish PCBs dominate the Sigma-TEQ ingested by humans. This in turn leads to high background body burdens in humans with PCB-TEQ greater than that associated with PCDD/Fs. High fish consumers are apparently subject to elevated TEQ exposure from dioxin-like PCBs. This has important implications for exposure assessment studies which have previously only been concerned with PCDDs and PCDFs. Unlike PCDD/Fs, dioxin-like PCBs are not controlled within the food chain. Sources and pathways of exposure are poorly defined. Aroclor formulations and their subsequent usage are considered to be the most important sources in terms of human exposure to some TEF-rated congeners, notably PCB-118, PCB-156 and part of PCB-126. Emissions from combustion sources contribute additional PCB-126. More research is needed to place these compounds in an integrated risk evaluation framework.

Congener specific transfer of PCDD/Fs from air to cows' milk: an evaluation of current modelling approaches.

Three different approaches have been used to model the transfer of individual PCDD/F congeners from the air to cows' milk. These are: (1) an 'Equilibrium Partitioning' approach, (2) a 'Deposition Velocity' approach and (3) a 'Scavenging' approach. Air-leaf transfers and livestock feed-milk transfers, the two most critical components of the food chain exposure model, are discussed. A representative database for measured PCDD/Fs in UK air, herbage and milk is presented and the performance of each predicted model concentration against this measured dataset is assessed. Weaknesses and uncertainties associated with modelling the complex transfer processes involved are highlighted.

Persistence and fate of polychlorinated biphenyls (PCBs) in sewage sludge-amended agricultural soils.

Four metal enriched sewage sludges containing different concentrations of polychlorinated biphenyls (PCBs) were applied to two field soils in the UK in 1968. Samples of the sludges, sludge-amended soils and soils from untreated control plots were stored and analysed retrospectively. Sludge concentrations ranged from 1 to 7 mg SigmaPCB kg(-1). The pattern of PCBs was similar in three of the four sludges, with congeners 14, 18, 28 and 52 present at the highest concentrations. The fourth sludge contained higher amounts of congeners 149, 153, 138 and 180. SigmaPCB concentrations in control plot soil have declined over the last 20 years, indicating a reduction in atmospheric deposition inputs of PCBs to the soil. SigmaPCB concentrations also declined on the sludge-amended plots, reaching control plot concentrations (30-60 microg SigmaPCB kg(-1)) in the late-1980s. Half-lives ranged from < 1 to 8.5 years for congeners 18, 28 and SigmaPCB. Biodegradation and/or the formation of reversibly sorbed soil PCB residues could not account for the losses observed. Volatilisation is implicated as the most important loss process on both the control and sludge-amended plots. Using the fugacity approach, congener concentrations in soils at Luddington were predicted still to have not reached equilibrium with the air. Further losses to the atmosphere are likely.

Conjunctival oxygen tension monitoring during liver transplantation.

Conjunctival oxygen tension has been noted in animal studies to correlate with oxygen delivery. In order to assess this relationship in man, we compared the proportional changes in conjunctival oxygen tension with those in oxygen delivery that occur on the placement and release of the inferior vena caval clamps in 10 patients during orthotopic liver transplantation without veno-venous bypass. We also examined the changes in mixed venous oxygen saturation at these times. We found a statistically significant correlation between both parameters and oxygen delivery (p < 0.001). However, analysing the data on a Bland and Altman plot of difference versus mean, it is our conclusion that the variation in the data is such that neither conjunctival oxygen tension nor mixed venous oxygen saturation can be used clinically to predict the changes in oxygen delivery that occur during liver transplantation.