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Objectives To assess interlaboratory variability of total serum bilirubin (TSB) results in newborns. Initiated following a clinical incident in which a neonate was transferred to a tertiary hospital for treatment of severe hyperbilirubinemia but on arrival was reclassified into a lower risk category due to a 20% difference in TSB between laboratories. Methods Fresh residual plasma samples from hospital-born infants were pooled to obtain 11 samples across a range of total bilirubin concentrations. Aliquots were light-protected and measured on 7 commercial platforms at 4 accredited medical laboratories. Data from The Royal College of Pathologists of Australasia Quality Assurance Programs’ (RCPAQAP) Neonatal Bilirubin program was analysed. Results Twenty-four to 30% difference in results for individual samples, largely due to calibration differences between assays. When interpreted according to guidelines, results from different platforms would have led to different clinical interventions in some cases. RCPAQAP results showed significant within-method bias but were not shown to be commutable with patient samples. Conclusions There are clinically significant method-dependent differences in TSB results from neonatal samples, consistent with our clinical incident. The differences are largely due to lack of standardisation of calibrator values. This has implications for healthcare resource use and possibly for the neurodevelopment of infants. Intervention is needed at a number of levels, including clinical reporting of incidents arising from discordant results, commitment by manufacturers to ensure metrological traceability of methods with sufficiently low uncertainty in the final measurements, and availability of commutable quality assurance material to monitor assay performance, especially at the clinical decision points for neonatal jaundice.

The role of an External Quality Assurance (EQA) program is generally seen as providing a service to routine laboratories that their analytical performance is satisfactory and stimulating corrective action in the event of poor results. It is recognised that an ideal EQA program uses materials that are commutable with patient samples and have values assigned by higher-order reference methods. Despite this, most routine EQA programs use materials without verified commutability and use consensus means (based on either peer group or all laboratories) as target values. We propose an ongoing role for EQA programs using non-commutable materials and consensus targets to support the measurement services of routine laboratories. This is provided the relevant comparators supplied by the laboratory, e.g. reference intervals and clinical decision points, are based on the same or equivalent measurement system as is used by the laboratory. Materials without verified commutability often have certain practical advantages, which may include the range of analyte concentrations, verified stability, replicate samples and, significantly, lower costs. Laboratories using such programs need to be aware of the limitations, especially comparing results from different measurement systems. However, we also recognise that as well as individual laboratories, data from EQA programs informs manufacturers, professional organisations, clinical guideline writers and other medical bodies For consideration beyond an individual laboratory, proper assessment of differences between measurement systems (results harmonization) and demonstration of correct implementation of metrological traceability (methods trueness) become vital, and for that purpose, commutability of EQA materials and traceability of target values are required.

In spite of a strong commercial interest in hot dipped aluminised steel strip, research over the past 60 years has been somewhat piecemeal. A relatively smaller body of work exists on this material compared with the equivalent galvanised product but the lack of systematic study and development means that it is difficult to rationalise and appraise the existing literature. This review is intended to provide an overall view of the salient results of previous work, providing key entry points to available literature.IMR/269© 1994 The Institute of Materials and ASM International. At the time the work was carried out Dr Richards and Mr Clarke were in the Division of Materials and Minerals Engineering, School of Engineering, University of Wales, Cardiff, UK. Dr Jones is in the Faculty of Technology, North East Wales Institute, Wrexham, Clwyd, UK and Dr Clements is with British Steel pic, Llanwern Works, Newport, Gwent, UK.

Following the accident at the Chernobyl Nuclear Power Plant in 1986, the United Kingdom Government imposed restrictions on the consumption of sheep meat that became contaminated by nuclear fallout to ensure it was extremely unlikely that any consumers would receive an unacceptable dose. The international context for the restrictions is summarized and a brief review of the strategies employed by the UK is presented. An analysis using the J-value framework, including the de minimis quantum of life expectancy, is made of the cost effectiveness of the sheep meat restrictions in force until 2012, in terms of 4 categories of consumer ranging from the average to the extreme. The paper shows that the risk to the general population was very low indeed at the time the restrictions were removed in 2012. Retaining the restrictions for an extra year, would have averted the dose to the average consumer by a fraction of a microSievert, corresponding to a gain in life expectancy of 8 seconds. Meanwhile for the ICRP Representative Person, the gain in life expectancy from retaining the restrictions for an extra year ranged between 17 and 25 seconds. These gains were adjudged nugatory, as they were a factor of between 8 and 23 below the de minimis quantum of life expectancy. This new measure provides a meaningful quantitative criterion for judging when the radiation exposure of a large population is trivial in the sense used by the ICRP. The gains in life expectancy for the Field Representative Person and the Extreme Consumer were above the trivial level, but the associated J-values were 10 and 40, an order of magnitude or more above the value of unity where a case could be made for retaining the restrictions for another year. The high J-values and/or de minimis life expectancy ratios suggest that the food restrictions could almost certainly have been ended earlier. Also discussed are: the choice of the Representative Person, the role of intervention levels, the extent to which conservatisms in analysis are warranted and how socio-political factors in decision making can be taken into account in a transparent way.

After heat shock or other metabolic stress, heat shock proteins (Hsps) are expressed at high levels in all tissues and cells. The highly inducible 70 kDa heat shock protein (Hsp70) is associated with improved post-ischemic myocardial contractile recovery. Similarly, the small 27 kDa heat shock protein (Hsp27), that is abundant in muscle, is also linked with improved myocardial function after ischemic injury. Various Hsps have pro-survival functions that include chaperone, anti-apoptotic and/or anti-inflammatory activity. In this review we will summarize our understanding of myocardial protection and present evidence for protection having time dependent aspects that appear to be stimulus dependent.

The paper uses utility theory to investigate how much should be spent to avert all costs from an industrial accident apart from direct human harm. These “environmental costs” will include those of evacuation, clean-up and business disruption. Assuming the organisation responsible will need to pay such costs, the difference between its expected utility with and without an environmental protection system constitutes a rational decision variable for whether or not the scheme should be installed. The value of utility is dependent on the coefficient of relative risk aversion, “risk-aversion” for short. A model of an organisation's decision-making process has been developed using the ABCD model, linking the organisation's assets, A , the cost of the protection scheme, B , the cost of consequences, C , and the expected utility difference with and without the scheme, D . Increasing the organisation's risk-aversion parameter will tend to make it less reluctant to invest in a protection system, but can bring about such investment only when the scheme is relatively close to financial break-even. For such borderline schemes, the amount the organisation is prepared to spend on the protection system will rise as the risk-aversion increases. The ratio of this sum to the break-even cost is named the “Limiting Risk Multiplier”, the maximum value of which is governed by the maximum feasible value of risk-aversion. However, the mathematical model shows that increasing the risk-aversion will reduce the clarity of decision making generally. Although the reluctance to invest in a protection scheme may change sign and turn into a positive desire to invest as the risk-aversion increases, the absolute value of this parameter is a continuously decreasing function of risk-aversion, tending asymptotically to zero. As a result, discrimination will gradually diminish, being lost altogether at the “point of indiscriminate decision”. Here the decision maker will be able to distinguish neither advantage in installing the scheme nor disadvantage in installing its inverse. There is a close correspondence between this mathematically predicted state and that of panic, where an individual has become so fearful that his actions become random. The point of indiscriminate decision provides a natural upper bound for the value of risk-aversion. This bounds the Limiting Risk Multiplier in turn, and so sets an objective upper limit on the amount that it is rational to spend on an environmental protection system.

Part 2 extends the analysis to show that it is possible to find the “permission point”, the value of (the coefficient of relative) risk-aversion, at which decisions to sanction environmental protection are most likely to be made. The mathematical model describes the process by which the decision maker varies his risk-aversion over a range of feasible values to find the risk-aversion that will give him the greatest desire to invest in the protection system under consideration. If he can find such a risk-aversion before losing discrimination (because the system is too expensive, given its performance), he will adopt it as his “permission point” and decide in favour of the expenditure. The permission point is, of course, bounded above by the point of indiscriminate decision. A maximum Risk Multiplier calculated at the point of indiscriminate decision may be applied to the protection expenditure at monetary break-even to give the maximum, rational outlay on protection. Moreover, it is possible to model how the average UK adult should take decisions on protection to maximise his utility. Different situations will call for different values of risk-aversion, which may explain why economists have come up with differing estimates of this parameter in the past. However, a central, average risk-aversion may be calculated for the average UK adult as 0.85, which is within 4% of the value, 0.82, found from the newly reported method based on a trade-off between income and future free time, and is consistent with several recent economic estimates. Worked examples assess how much an organisation should spend on a protection scheme to prevent accidents with very large environmental consequences.

A severe accident on an industrial plant has the potential to cause, in addition to human harm, general damage and hence expense, associated with ground contamination, evacuation of people and business disruption, for example. The total cost of damages, given the name “environmental costs” in this paper, may be comparable with or larger than the cost of direct health consequences, as assessed objectively by the J -value approach. While the low probability of the accident may mean that the expectation of monetary loss is small, the paper develops a utility-based approach to determine how much should be spent on protection systems to protect against both environmental costs and human harm. The behaviour of the fair decision maker in an organisation facing possible environmental costs is represented by an Atkinson Utility function, which is dependent on the organisation's assets and on the elasticity of marginal utility or, equivalently, the coefficient of relative risk aversion, “risk-aversion” for short. A Second Judgment Value, J 2 , may be derived from the spend on the protection system after subtracting the amount sanctioned to prevent direct human harm. This net, environmental expenditure is divided by the most that it is reasonable to spend to avert environmental costs at the highest, rational risk-aversion. The denominator in this ratio is found by first calculating the maximum, sensible spend at a risk-aversion of zero, and then multiplying this figure by a Risk Multiplier to give the maximum, fair amount to avert environmental costs. The Risk Multiplier incorporates a risk-aversion that is as large as it can be without rendering the organisation's safety decisions indiscriminate and hence random. An overall, Total Judgment Value, the J T -value, may also be calculated, which takes into account the reduction in both human harm and environmental cost brought about by the protection system. The new J T -value will show similar behaviour to the original J -value, in that J T -values up to unity will indicate reasonable value for money, while J T -values greater than unity will indicate a prima facie overspend on protection that will need to be justified by further argument. While the analysis is phrased in terms of environmental costs, the treatment is sufficiently general for all costs, including onsite damages, loss of capability etc. to be included. The new, J T -value method provides for a full and objective evaluation of the worth of any industrial protection system. A worked example is given.

The paper presents a new derivation of the J-value method for assessing health and safety expenditure that highlights the fact that two trade-offs are involved. The trade-off between safety spend and the resulting improvement in life expectancy rests on a prior trade between free-time fraction and income, made at a societal level. It is suggested that each trade is a specific instance of a more general exchange between expected free-time and income, and that the terms of the trade-off are similar, so that the percentage increase in life expectancy has the same value as a similar percentage increase in total expected free-time. The theoretical framework suggests that the average person values all his time equally, but perceives that he has sold his expected working time to an employer, so that, while he will still place a value on it, he does not see that value as coming to him, but rather going to his employer in exchange for the compensation he is being paid. Thus he values the extra years of life expectancy he obtains from a health and safety measure solely in terms of the extra years of free-time he expects to gain. The value of the exponent in the life-quality index has been shown to be equal to both the modulus of the elasticity of expected future free-time with respect to income and the modulus of the elasticity of life expectancy with respect to income. The indifference curves on the planes of income versus life expectancy and income versus discounted life expectancy have been shown to be the loci of J = 1. The actuarial basis for the calculation of working time fraction to the end of life has been explained, and data on the share of wages in Gross Domestic Product have been discussed. Based on recent statistics from the UK economy, the average person would be prepared to forego about 5½% of his income to the end of life in order to increase his life expectancy or discounted life expectancy by 1%, and would require his lifetime income to be increased by 5½% to compensate him for a loss of 1% in his life expectancy, discounted or otherwise. A small degree of asymmetry will, however, occur for larger percentage changes in life expectancy, with the average person requiring somewhat more compensation for a loss of life expectancy than he is prepared to pay for a gain.

The newly released findings by the International Commission on Radiation Protection (ICRP) led to a review of the lifetime risk coefficients for fatal cancer used in J-value analysis of nuclear safety systems. The change in life expectancy a safety system brings about by averting a radiation exposure needs to be estimated in order to calculate the safety system's J-value, and this is done following the ICRP's practice of using risk coefficients that are uniform across both genders and all ages in the defined population group (either workers or the general population). The ICRP predicted uniformly lower radiation risks in 2007 than in 1990 on a like-for-like basis, but it was found that the ICRP's new risk coefficients needed to be multiplied by a compensating factor specific to each population when used in calculating the radiation-induced change in life expectancy. Incorporating the new compensating factor leads to a decrease in the J-value calculated of about 5% for workers and 15% for the general population compared with earlier, reported results. These adjustments are not large compared with the uncertainties associated with radiation harm and the economics of installing a safety system, but will strengthen slightly the case for spending on a nuclear safety measure.

The basis of the manSievert as a unit for collective radiation dose is discussed and previous recommendations are considered for how much should be spent to avert a collective dose of 1 manSv. New calculations are given using the J-value method. It is shown that the value to be assigned to averting a manSievert depends on the duration of averted exposure as well as on the net discount rate and the loan rate thought to be appropriate. Different figures will result depending on whether the exposed group consists of workers or the general public. The variation with dose duration is so large that it is not possible to recommend a single figure for the value of a manSievert. Instead, tables are given at two conservative, loan and net discount rates for the value of a manSievert as a function of exposure time. The base data for the J-value method need to be updated annually, and this means that the values given in the tables will increase over time as people live longer and become richer.

The J-value method enables health and safety schemes aimed at preserving or extending life to be assessed on a common, objective basis for the first time, irrespective of industrial sector. For this it requires an estimate of the improvement in life expectancy that the health and safety scheme will bring about. This paper extends the range of nuclear-safety-system lifetimes for which it is possible to calculate the increased life expectancy amongst nuclear-plant workers whose radiation exposure the safety system has reduced. Whereas the previous mathematical technique was able to cater for a nuclear-safety-system lifetime up to the working lifetime of the nuclear-plant workers (typically between 45 and 50 years), the new method extends without limit the range of tractable, safety-system lifetimes. This is important now that the design lifetime of nuclear power stations can be up to 60 years. The development will also facilitate the assessment of safety systems and procedures to protect workers on long-term nuclear decommissioning and waste sites; in the latter case, the service life-time could be hundreds of years. The case when the safety-system lifetime is greater than the working lifetime is addressed by splitting the workforce into a set of three cohorts, one for existing workers and two for new recruits. The discounted life expectancy is found for each cohort, and then a weighted average is used to give the overall value. An additional mathematical device is then used to reduce the number of cohorts required from three to two, namely existing workers and new recruits. A similar mathematical device is applied (in Appendix A) to reduce from three to two the number of workforce cohorts needed when the length of the safety system's service lifetime is less than the working lifetime. Finally, a further mathematical instrument is incorporated in the model equations, which allows a unified treatment to be applied to each of the cohorts, existing workers and new recruits, across all possible service lifetimes of a nuclear safety system. Since new results on gain in life expectancy may be fed into a J-value analysis, this development extends significantly the range of nuclear-safety systems for which the J-value technique may be used to measure cost-effectiveness.

The life extension achieved by a safety scheme that reduces or eliminates a prolonged radiation exposure is a necessary parameter for calculating the Judgment-or J-value, which enables the scheme's worth to be measured on a common, objective scale against which health and safety spend across all economic sectors can be assessed. The life-expectancy calculation for radiation exposure is necessarily complex because of the long and stochastic incubation periods associated with radiation-induced cancers. Analytical methods are presented to reduce the size of this calculation approximately a hundredfold. This renders the J-value assessment much quicker and easier for new safety systems that may be considered for nuclear plant.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity. © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Brucellosis is a widespread, economically devastating and highly infectious zoonosis. In cattle, infection predominantly is caused by Brucella abortus, and is usually detected in pregnant females through abortions. Great Britain (GB) has been declared free from brucellosis (officially brucellosis free (OBF)) since 1993 and as such is required by European Union (EU) regulations to testor =20% of both beef and dairy cattle24 months old routinely. Currently, however, GB serologically tests more cattle than required and the issue of reducing the level of testing has come under consideration. We developed a simulation model to determine the rate of spread of brucellosis under a variety of testing regimes. For dairy herds, we found that reducing the level of testing would have a major effect on the rate of spread of infection, should it be imported. For beef herds, reducing the level of testing would have much less effect. We also found that abortion notification is a very-important additional means of surveillance. As a result of our predictions, policy-makers decided not to reduce the level of testing and actively to promote abortion notification.

Our study evaluated the effectiveness of the Beef Empire Days carcass index in ranking beef carcasses compared to rankings based on carcass prices. Two price sets were used: the average prices between January 1998 and June 2001, and a short-range price determined from the average prices between April and September of 2001. Additionally, carcass data from the top live-placing cattle were compared to the data of the highest indexing carcasses. The live show judges were very accurate in selecting for ribeye size. However, they selected cattle that were fatter, but did not marble as well as the high indexing carcasses. Changes that might improve the index are identified. However, the Beef Empire Days index ranked carcasses moderately well compared to the pricing system.

Hypoxic pulmonary vasoconstriction (HPV) is a regulatory feature of the pulmonary circulation that ensures consistent matching of perfusion to ventilation in the normal lung. However, under pathophysiological conditions, HPV contributes to the elevated pulmonary arterial pressure inherent to numerous disease states. Consequently, control of HPV is an avenue of potential therapy for such conditions. This review discusses the role of hydrogen peroxide (H(2)O(2)) as an intracellular signal in the pulmonary circulation, concentrating on the potential involvement of H(2)O(2) in HPV and in the control of pulmonary arterial tone. Sites of hypoxic pulmonary arterial H(2)O(2) production include the mitochondrial electron transport chain, a microsomal electron transport chain containing an NADH oxidoreductase and alternatively, a membrane-bound NADPH oxidase. Each of these sources of H(2)O(2) and the effect of hypoxia on the production of reactive oxygen species are considered. The review also discusses the variance in vascular reactivity of H(2)O(2), which is described to elicit both pulmonary arterial vasoconstriction and dilatation at varying concentrations. The redox capabilities of H(2)O(2) are also considered. The relevance of all of these actions of H(2)O(2) are also assessed as potential pharmacological targets for the future development of therapy for lung diseases that are characterised by some degree of HPV and in the pathogenesis of pulmonary diseases in which reactive oxygen species are implicated.

The purpose of this subacute 22-day study was to evaluate methods for canine circulating immunoglobulins (IgM, IgG, and IgE) and select B- and T-lymphocyte populations (CD4-helpers, CD8-suppressors, pan-T and pan-B) for immunotoxicity testing using an organ system (concordance) approach. The challenge substance for immunoglobulin testing was repeated immunization with six-way distemper vaccination (DHLAPP), while the challenge substance for leukocyte subpopulations was treatment with cyclophosphamide. Immunoglobulin measurements were made by capture enzyme-linked immunosorbent assay (ELISA), and leukocyte immunophenotyping by fluorescein isothiocyanate/phycoerythrin conjugation (flow cytometry). A battery of parameters that would be used in a typical regulatory study were taken to aid interpretation of the data generated by these methods. Body weights, food consumption, clinical observations, complete clinical chemistry and urinalysis measurements were taken. Gross pathology and micropathology of sternal bone marrow, spleen, mesenteric and retropharyngeal lymph nodes, thymus, liver and kidney were completed. The ELISA method demonstrated acceptable intra-assay reproducibility for IgM, IgG and IgE, with values in good agreement as reported for radial immunodiffusion. The immunologic challenge demonstrated a biological trend of an increase in IgM that preceded an increase in IgG with no discernible trend in IgE response, and no abnormalities in lymphocyte subpopulations. Principle flow cytometry findings related to cyclophosphamide were that the relative percent of B cells decreased dramatically and progressively after compound administration; being statistically decreased in males on day 22 compared with day −5. The relative percent CD4 and CD8 contribution increased, but the CD4/CD8 ratio remained relatively unchanged as total white blood cells decreased progressively. The increase in relative percent CD4 (males only) was statistically significant according to a two-sample t -test on days 17, 20 and 22 when compared with the pre-treatment day −5. There was a relative percent increase in CD5-panT, but absolute numbers were dramatically decreased. We conclude that an organ system approach to assessment of the immune system which incorporates humoral antibody, enumeration of lymphocyte populations and pathologic evaluation of the lymphoreticular organs assists in the interpretation of an adverse toxicological response. The ELISA method for measurement of Igs detected the expected levels of IgG, IgM and IgE due to repeated vaccinations and to cyclophosphamide treatment. The flow cytometry method was acceptable for measuring select canine lymphocyte populations and detecting the expected decrease in B cells due to cyclophosphamide treatment. Both methods may be added to a testing battery for assessing immunotoxicity in canine regulatory studies.

The possibility of predicting kilograms of lean pork, the percentage of lean, and lean gain per day using measurements taken during the early finishing phase was studied using real-time ultrasound measurements on 164 barrows. Initial live weight (IWT), ultrasound backfat (IUBF), and ultrasound loin muscle area (IULA) were determined at 16 to 19 wk of age (70 kg). Final measures were obtained as the average pen weight reached 110 kg (22 to 24 wk of age). Initial kilograms of lean pork (IKOL) and the percentage of lean (ILEAN) were estimated with IWT and IUBF as the independent variables. Average daily gain, backfat accretion (BFACR), and lean gain per day (LGPD) were calculated from the initial and final measures. Pearson correlation coefficients were determined among the variables at the initial and final measures. The IULA and IKOL were correlated with the amount of lean tissue at slaughter (FKOL) (r=0.305 and 0.315, respectively; P

Intensive production of swine has brought an increase in the volume of manure produced on farms with limited land area. Exceeding the capacity of soil and crops to handle this volume of manure results in nutrient accumulation in and on the soil that can produce leakage of nutrients to the environment and pollution could result. Environmental nutrition is defined as the concept of formulating cost-effective diets and feeding animals to meet their minimum mineral needs for acceptable performance, reproduction, and carcass quality with minimal excretion of minerals. Pigs normally excrete 45 to 60% of N, 50 to 80% of Ca and P, and 70 to 95% of K, Na, Mg, Cu, Zn, Mn, and Fe when fed diets containing commonly used feedstuffs. Although it is not possible to make pigs 100% efficient in utilization of nutrients, it is possible to reduce the amount of nutrients excreted through careful nutrient management. Several strategies are possible for reducing nutrients excreted: 1) improvements in feed efficiency, 2) more accurate nutrient requirement information for animals and compositional data for feed ingredients, 3) reduced feeding of excess nutrients through overformulation, 4) feeding for optimal rather than maximum performance, 5) use of crystalline amino acids and high quality protein, 6) improving the availability of P and some other minerals, 7) use of phase feeding and separate-sex feeding, and 8) reduced feed waste. Some strategies have a much greater potential for reducing nutrients excreted than other strategies. In the future, diet formulation and feeding must be integrated into total production systems so that swine production systems are environmentally safe as well as economically viable.

The anti-inflammatory and restorative effects of the flavonoid-enriched fraction AF4 were examined in a mouse model of experimental autoimmune encephalomyelitis (EAE). Relative to EAE mice that received vehicle (water, 10 ml/kg/day), oral administration of AF4 (25 mg/kg/day) beginning 24 h after the onset of clinical signs reduced disease severity from days 19–31 post-immunization. AF4-mediated recovery from EAE was preceded by reduced plasma concentrations of TNFα and IL-1β on day 18 followed by decreased cytokine production and neuropathology in the cerebellum and spinal cord on day 31. Clinical improvement for EAE-AF4 mice from days 18 to 31 was accompanied by the elevated expression of genes that mediate remyelination. These findings suggest that AF4 decreased EAE severity by promoting the resolution of inflammation and improving functional recovery in the CNS.

The British Standard Code of Practice for noise control on construction and demolition sites has been in existence for 21 years. In that time, it has evolved and been expanded to cover both other open site activities and also to include vibration. This paper considers the evolution and some of the thought processes and driving forces to implement the changes which have occurred. It also reviews experience of the use of the Code and perceived shortfalls, and whether these have any material impact on the Code's validity. Experience has shown that the Code has stood the test of time and served the construction industry well, particularly where it has been more widely used on major development and infrastructure projects.

The deformation behavior of commercially produced hot-dipped zinc and zinc-alloy coatings on steel under simple uniaxial tension has been studied. The strong basal plane texture of the hot-dipped galvanized coatings was found to be unfavorable for plastic flow and accounted for the extensive cracking observed during deformation. The eutectic structure in Galfan coatings was found to be beneficial in suppressing the formation of microcracks at low strain levels, although when grain boundary dents were present, cracks formed easily at these locations. Microcracks were observed in Galvalume coatings at all levels of strain. A technique to measure the coating plasticity has been developed to quantify the level of cracking in coatings at varying degrees of deformation.

Radiologists, blinded to the final diagnosis, reviewed mammograms which had been reported as normal at the prevalent screen, in a group of 133 patients with cancer detected 3 years later at the first incident screen. The aim of this study was to assess whether the mammograms at the prevalent screen demonstrated the cancers picked up at the incident screen, using a similar method to that described by the Northern Regional Audit Group for classification of interval cancers. Of the total number of cancers detected at the incident round there were 30 (22.6%) which could be classified as false negative or missed at the prevalent round. Of these, 25 (83.3%) had been either diagnosed as benign or not noticed on screening, the remainder (5) had been misdiagnosed on assessment. The most common histological type was invasive ductal; 22 (88%) were either Grade 1 or 2. Of the 27 false negative cancers with documented histological lymph node assessment 25% had associated axillary node metastases. By combining the above false negative rate for incident cancers with a similarly calculated one for interval cancers, it was possible to calculate the prevalent round sensitivity for cancer detection at 79.0% for single reading and 85.5% for double reading.

The Backgrounds Data Center (BDC), located in the Space Sciences Division (SSD) of the Naval Research Laboratory (NRL), is the designated archive for celestial and earth backgrounds data collected by Ballistic Missile Defense Organization (BMDO) science research programs, including the upcoming Midcourse Space Experiment (MSX) data set. We extract and populate relational database catalogs with metadata and these catalogs to locate archived data products which our users request. The advent of Jason Ng's (NCSA) GSQL protocols have allowed us to construct World-Wide Wed interfaces to our catalogs, greatly improving their utility to users. We have modified these scripts to work with our INGRES RDBMS. We have enhanced the standard GSQL interface by incorporating the use of ‘on the fly’ form and graphical image construction. With dynamic forms, users generate their own forms by pre-selecting those query parameters they wish to use to search on databases. Users can also select query complexity ranging from rank novice to direct interaction with Standard Query Language (SQL). Dynamic image mapping adds a graphical layer to the WWW forms interface, and permits users to select data by interacting with images only. These techniques allow for an uncluttered and intuitive representation of the catalog databases to users.

Habitual consumption of dietary flavonoids known to improve mitochondrial bioenergetics and inhibit various secondary sources of reactive oxygen species (ROS) reduces the risk for neurodegenerative disorders such as Parkinson's disease (PD), stroke, and Alzheimer's disease (AD). Combining specific dietary flavonoids selected on the basis of oral bioavailability, brain penetration, and the inhibition of multiple processes responsible for excessive ROS production may be a viable approach for the prevention and treatment of neurodegenerative disorders. Inclusion of flavonoids that raise cAMP levels in the brain may be of additional benefit by reducing the production of proinflammatory mediators and stimulating the transcriptional machinery necessary for mitochondrial biosynthesis. Preclinical models suggest that flavonoids reduce hearing loss resulting from treatment with the chemotherapeutic drug cisplatin by opposing the excessive production of ROS and proinflammatory mediators implicated in PD, stroke, and AD. Flavonoid combinations optimized for efficacy in models of cisplatin-induced hearing loss (CIHL) may therefore have therapeutic utility for neurodegenerative disorders.

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10 -8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10 -4, Bonferroni corrected), of which six reached P < 5 × 10 -8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. © 2012 Nature America, Inc. All rights reserved.

We describe a new financial diagnostic method, related to the entropy generated when a limit trader satisfies market demand by filling orders, thereby playing the role of a Maxwell Demon. By comparing the real cumulative trading volume to some measure of historically “normal” demand, one may determine whether the market shows excess order or disorder, and accordingly adjust one’s trading strategy.

The design of an EVA (extravehicular activity) antenna sampling and switching system is presented. The system utilizes four separate antennas for full spherical coverage with a space station. The antennas are placed at optimal locations on the back-pack of the EVA astronaut for best coverage performance. Continuous power-level monitoring of the four antennas results in the selection of the best antenna (the one receiving the highest signal level) for communication purposes. The system consists of four log conical spiral antennas, two single-pole-four-throw PIN diode switches, and a double conversion sampling channel that feeds a peak-level detector. A microcontroller algorithm cycles the sampling and switching of antennas based on the level detector output. Attention is given to the block diagram of the system, the development of in-house components, the control algorithm, and the results of composite antenna pattern testing. Measured composite patterns are compared to a computer-synthesized composite pattern derived from individual antenna patterns. >

The author discusses changes in the requirements and specifications of military hybrids, some of the changes occurring in their design, and some of the newer materials and techniques used in their manufacture. Particular attention is given to the computer-aided design of hybrids, substrate materials, thick-film materials and processes, thin-film materials and processes, the tape-transfer process, and assembly processes. >

A circuit model has been developed for a family of composite-based, low-voltage field-emitter-array cathodes. The arrays were fabricated by thin-film technology from directionally solidified oxide-metal composite materials. The typical field-emission-array contained 10/sup 7/ individual electron guns per cm2 of area. The dimensions of each electron gun is such that it operates with a cathode-extractor (cathode-gate) potential of less than 200 volts. A circuit model that predicts the performance of these emitter arrays is needed if they are to be used as electron sources in vacuum electronic devices. This work develops the requisite circuit model from the physical properties of the array, and characterizes the parameters of the circuit model using theoretical and experimental techniques.

The relationships between the inhaled dose of foot and mouth disease virus and the outcomes of infection and disease were examined by fitting dose-response models to experimental data. The parameters for both the exponential and beta-poisson models were estimated using maximum likelihood and Bayesian methods. The median probability of infection given a single inhaled TCID50 was estimated to be 0·031 with 95% Bayesian credibility intervals (CI) of 0·018–0·052 for cattle, and 0·045 (CI = 0·024–0·080) for sheep. These estimates were used to construct dose-response curves and uncertainty distributions for use in quantitative risk assessments.

Coiled Tubing was introduced to the Karachaganak Field in 1997 as part of a package of technical enhancements designed to improve field productivity. Initially planned only for acid stimulation work during the summer, the service has been extended into an all year round support to the Workover, Stimulation and Well Service programs. Examples of the type of operations performed are described. These include tubing cutting, cleaning and acid washing as required to remove tailpipes during workovers. Fishing to clean up old wells prior to the workover. Inflatable packer isolations for acid stimulation and wellhead repairs. Introducing a new service, such as coiled tubing, to any location, presents an interesting challenge. Developing and applying the techniques within the service, particularly on an established, corrosive, gas/condensate production field with old, high rate, well stock, located in a remote area with extreme weather conditions, challenges the technical application of Engineers, operators and support services.

Technical grade disulfoton (DiSyston) was fed to Beagle dogs (four animals per sex and treatment level) at nominal concentrations of 0, 0.5, 4 and 12 ppm for 1 year. The purpose of this study was to characterize the potential general and neurovisual toxicity according to routine Environmental Protection Agency (EPA) guideline requirements, and by use of ancillary ocular and neurologic tests established in this Laboratory. Ophthalmological tests included: ocular tissue cholinesterase and histopathology, electroretinography (ERG), tracking, refractivity, intraocular pressure and pachymetry (corneal thickness) measurements. Neurological examinations included; peripheral and cranial reflex tests, task performance tests, gait and behavioral observations, and rectal temperature measurements. Plasma, erythrocyte and corneal cholinesterase were significantly depressed at 4 and 12 ppm in both sexes. Brain cholinesterase was depressed at 4 and 12 ppm in females. Retinal cholinesterase was depressed at 4 ppm in females and at 12 ppm in males. Ciliary body cholinesterase was depressed at 12 ppm in both sexes. Despite these cholinergic effects, there were no ophthalmologic findings in measurements of ERG, tracking, refractivity, intraocular pressure or pachymetry. There were no clinical neurology findings related to compound administration. We conclude that 0.5 ppm was a no-observable effect level (NOEL), and effects were limited to cholinesterase changes that had no detectable physiologic impact. This study demonstrates that special mechanistic investigations incorporated within guideline studies, enhances scientific integrity and can minimize the need for dedicated organ system studies.

Hypoxic pulmonary vasoconstriction (HPV) of rat pulmonary arteries in vitro occurs in four phases. Initial vasodilation (phase 1), is followed by transient contraction (phase 2), further vasodilation (phase 3) and finally a second sustained contraction (phase 4). We have investigated the role of ET-1 in HPV using the ETA receptor antagonist CI-1020. Small rat pulmonary arteries (SPA, n=32, diameter=454+/-22 microM) were mounted in a wire myograph. Two contractions to 80 microM KCl ensured response reproducibility and relaxation to 10 microM acetyl choline following constriction with 100 microM prostaglandin F2alpha (PGF2alpha) to indicate endothelial integrity. A control hypoxic response was produced following priming with 5 microM PGF2alpha. Vessels (n=8) were then exposed to either vehicle or CI-1020 (1, 10 or 100 microM) for 30 min in the dark before re-exposure to PGF2alpha and hypoxia. Responses were standardized as a percentage of contraction to 80 mM KCl. Vehicle caused an increase in phase 2 of HPV of +2.51+/-4.20% (expressed as difference between pre- and post-drug values). CI-1020 (1, 10 and 100 microM) caused a significant reduction in phase 2 of HPV of -9. 76+/-1.40%, -9.23+/-2.30% and -7.96+/-1.70%, respectively (P

Abstract This paper describes the experience and learning gained whilst, designing, planning and installing a Multi-Lateral Well on the Forties field operated by BP Exploration in the UKCS. This project was initiated by the Research and Development groups of BP Exploration and Halliburton Energy Services, and sponsored by the European Union's Joule-THERMIE Program which supports the implementation of technology in Europe. The objectives of the project were to drill and complete a dual lateral well with commingled production, at minimum risk and cost, and to monitor and report the production performance. The difference between this project and the majority of multi-lateral wells drilled to date will be the installation of a cemented junction with connectivity, isolation and re-entry capability. The successful execution of this project will provide the industry with data on the long term performance of a cased hole, cemented, junction design. It will also provide production performance from a dual lateral well and give details of the challenges facing the management of such a well in a mature field environment. It is anticipated that this will lead to increases in the application of this technology, improve the economical recoverable reserves from mature fields and reduce the cost of new fields. Introduction Multi-lateral wells offer innovative and economical ways to produce hydrocarbons. Economic analysis on Forties shows that for in-fill drilling, the cost to drill and complete a dual lateral well is less than the cost to re-drill two wells and becomes particularly attractive on platforms where the number of available well slots is limited. However, until recently, the application of multi-lateral wells was limited to wells that did not require through tubing reservoir access for stimulation or water, scale and sand management. Junction construction advances through system development and testing by Longbottom demonstrated the possibility existed of cost effectively constructing and installing a design which provided isolation, access and connectivity. The experience and learning gained by the implementation of this project, enhances the ability to construct a cased and cemented dual lateral, operate each lateral as a separate well and perform those remedial operations presently available to the industry. The risk and uncertainty surrounding a project of this nature means that without the support of programmes like THERMIE, initial economics are sensitive when it comes to applying new technology in a mature field environment such as Forties. Remaining well targets are relatively small and production is complicated by demands for sand, scale and water management. In-fill and sidetrack drilling is expected to continue at least until 1999. If the recent success of the in-fill program continues, some platforms will become slot constrained. The application of new technologies, like multilateral wells, are expected to enable more targets to be reached from fewer surface locations. This well is the first step in this new direction. Forties Field Information The Forties field (Fig. 1) was the first major oil field discovered in the British sector of the North Sea. The field is located predominantly in block 21/10 and lies some 180 km (112 miles) ENE of Aberdeen. The discovery well drilled in 1970 encountered oil in good quality Paleocene sands. Further appraisal drilling confirmed a Stock Tank Oil Initially in Place of approximately 4.2 billion barrels. The field was developed as described by Brand et al using 5 platforms (Alpha, Bravo, Charlie, Delta and Echo) with first oil being produced in 1975. To date, 2.2 billion barrels have been produced. It is estimated that a further 280 million barrels of oil will be recovered from the field. P. 227

Abstract As part of its objectives to increase recoverable reserves and reduce development costs in Norway's Oseberg field, Norsk Hydro has aggressively employed extended reach horizontal drilling over the past four years. Critical to the success realized in the Oseberg development program has been the use of an integrated steerable drilling assembly that features a near-bit sensor providing real-time measurements of the well path, thus enabling drilling in a corridor of one to two meters. Problems with orienting fixed cutter bits in the highly demanding sliding mode necessitated the use of tungsten carbide insert (TCI) roller cone bits to follow the required trajectory. This paper describes the development of new IADC 437 and 447 Class TCI bits, which culminated in a unique gauge cutting structure with diamond-enhanced, chisel-shaped cutting elements. The authors will review the bearing, seal and cutting structure limitations of conventional roller cone bits used in earlier Oseberg wells, emphasizing the negative impact of excessive gauge wear and short bearing life to overall well costs. Laboratory and field data will be presented, with emphasis on the lessons learned during extensive cutting structure and bearing/seal examinations. The successful application of the new design in the Oseberg development drilling program will be discussed in detail. Introduction Norway's Oseberg field, located approximately 130 km north-west of Bergen, was discovered in 1979 and is presently being developed via two platforms - the Oseberg B and C - which are situated 15 km apart. The Oseberg reservoir section is located in the Middle Jurassic comprising several sand units: the Tarbert Upper and Lower Ness, Etive and Oseberg formations (Fig. 1). The Tarbert shows subangular and subrounded sandstones moderately sorted with a thickness of up to 60 m TVD. Firm and blocky coal and silty claystones sequences interbed the sandstones in the Ness formation. The Etive shows angular to subrounded sandstones with silicate cementation and siltstones at the base. The Oseberg formation is the main reservoir, consisting of medium to coarse-grained fan delta sandstones of excellent reservoir quality. The vertical thickness is 20 to 60 m TVD. The Rannoch claystone sequence separates the Etive and Oseberg formations. The first horizontal well was drilled on the field in 1992, and since then 20 wells have been successfully drilled and completed. Over that time, the lengths of both the horizontal section and the Total Measured Depth (TMD) have increased progressively. In 1995, Well C-26A established a then-world record with its 7,853 m horizontal displacement. In that well, the horizontal section was 2,100 m and the total depth 9,325 m. In early 1996, the first multi-lateral wells - C12A, B and C - were successfully drilled from the Oseberg C platform. To maximize the recoverable hydrocarbons in the horizontal reservoir sections, the deviations from the trajectory have to be kept within a tight tolerance on vertical and tangential variations (often 1m). The tight tolerances force the operator to drill the reservoirs with a reservoir navigation tool (RNT). Both fixed cutter (PDC) and roller cone tungsten carbide insert drill bits (TCI) are used, depending on the lithology and operating demands. Historically, dulled TCI bits exhibited severe abrasive wear in the gauge area, frequently resulting in under-gauge hole and early seal failures. Thus, to avoid the risk of losing cones, the operator was forced to pull bits after short times on bottom. Lost cones generally cause difficult and expensive fishing jobs. P. 541^