The first report of macrocyclic lactone resistant cyathostomins in the UK.

In recent years, resistance to the benzimidazole (BZ) and tetrahydropyrimidine (PYR) anthelmintics in global cyathostomin populations, has led to reliance on the macrocyclic lactone drugs (ML-of which ivermectin and moxidectin are licensed in horses) to control these parasites. Recently, the first confirmed case of resistance to both ivermectin (IVM) and moxidectin (MOX) was reported in the USA in yearlings imported from Ireland. This suggests that ML resistance in cyathostomins has emerged, and raises the possibility that regular movement of horses may result in rapid spread of ML resistant cyathostomins. Resistance may go undetected due to a lack of surveillance for ML efficacy. Here, we report anthelmintic efficacies in cyathostomins infecting UK Thoroughbreds on four studs. Faecal egg count reduction tests (FECRT) were performed to define resistance (resistance = FECR <95% lower credible interval (LCI) < 90%). Stud A yearlings had FECRs of 36.4-78.6% (CI:15.7-86.3) after three IVM treatments, 72.6% (CI: 50.8-85.2) after MOX, and 80.8% (CI: 61.9-90.0) after PYR. Mares on stud A had a FECR of 97.8% (CI: 93.3-99.9) and 98% (95.1-99.4) after IVM and MOX treatment, respectively. Resistance to MLs was not found in yearlings or mares on studs B, C or D with FECR after MOX OR IVM treatment ranging from 99.8 to 99.9% (95.4-100); although yearlings on studs B, C and D all had an egg reappearance period (ERP) of six weeks for MOX and stud C had a four-week ERP for IVM. This study describes the first confirmed case of resistance to both licensed ML drugs on a UK Thoroughbred stud and highlights the urgent need for a) increased awareness of the threat of ML resistant parasites infecting horses, and b) extensive surveillance of ML efficacy against cyathostomin populations in the UK, to gauge the extent of the problem.

Quality of survival assessment in European childhood brain tumour trials, for children below the age of 5 years.

The highest incidence rate of childhood brain tumours is in children below the age of five years, who are particularly vulnerable to the effects of treatments. The assessment of quality of survival (QoS) in multiple domains is essential to compare the outcomes for different tumour types and treatment regimens. The aim of this position statement is to present the domains of health and functioning to be assessed in children from birth to five years, to advance the collection of a common QoS data set in European brain tumour trials. The QoS group of the European Society of Paediatric Oncology (SIOP-E) Brain Tumour group conducted consensus discussions over a period of six years to establish domains of QoS that should be prioritised in clinical trials involving children under 5 years. The domains of health and functioning that were agreed to affect QoS included: medical outcomes (e.g. vision, hearing, mobility, endocrine), emotion, behaviour, adaptive behaviour, and cognitive functioning. As for children aged five years and older, a 'core plus' approach is suggested in which core assessments are recommended for all clinical trials. The core component for children from birth to three years includes indirect assessment which, in this age-group, requires proxy assessment by a parent, of cognitive, emotional and behaviour variables and both direct and indirect endocrine measures. For children from four years of age direct cognitive assessment is also recommended as 'core'. The 'plus' components enable the addition of assessments which can be selected by individual countries and/or by, age-, treatment-, tumour type- and tumour location-specific trials.

Attitudes towards worm egg counts and targeted selective treatment against equine cyathostomins.

Gastrointestinal nematodes present a major threat to the health and welfare of equids worldwide. Anthelmintic resistance (AR) is increasingly reported and challenges effective control in horses and ponies in many regions. The use of faecal worm egg counts (FECs) to support targeted treatment (FEC-TT) and targeted selective treatment (FEC-TST) has been promoted as an effective deworming strategy that may prolong the useful life of anthelmintics and reduce the costs associated with parasite control. However, treatment applied at set intervals or on pre-determined dates remains common. A structural equation model was developed to identify factors influencing the uptake of FEC-directed treatment strategies, based on well-established socio-psychological theories of intentional health-related behaviours: the Theory of Planned Behaviour and the Health Belief Model. More than 850 valid responses were received from horse owners in the UK via an online survey. The intention to use FECs prior to deworming was not influenced by the perceived risk of anthelmintic resistance or that of gastrointestinal nematode infection but was positively influenced by a negative attitude towards anthelmintics, a positive attitude towards FECs, an increase in social pressure (e.g. significant others think the respondent should use FECs) and an increase in perceived control over their deworming programme. The results were consistent with a similar study conducted on FEC-TT in cattle in Belgium. An increase in respondents' self-perceived level of knowledge significantly increased the intention to use FECs via mediating factors. These results suggest that knowledge transfer activities aimed at increasing awareness and understanding of sustainable nematode control practices may be more effective at encouraging behaviour change than emphasising the dangers of nematodes and AR, which had limited influence on behaviour intention in this study population.

Implications of between-isolate variation for climate change impact modelling of Haemonchus contortus populations.

The impact of climate change on parasites and parasitic diseases is a growing concern and numerous empirical and mechanistic models have been developed to predict climate-driven spatial and temporal changes in the distribution of parasites and disease risk. Variation in parasite phenotype and life-history traits between isolates could undermine the application of such models at broad spatial scales. Seasonal variation in the transmission of the haematophagous gastrointestinal nematode Haemonchus contortus, one of the most pathogenic helminth species infecting sheep and goats worldwide, is primarily determined by the impact of environmental conditions on the free-living stages. To evaluate variability in the development success and mortality of the free-living stages of H. contortus and the impact of this variability on future climate impact modelling, three isolates of diverse origin were cultured at a range of temperatures between 15°C and 37°C to determine their development success compared with simulations using the GLOWORM-FL H. contortus model. No significant difference was observed in the developmental success of the three isolates of H. contortus tested, nor between isolates and model simulations. However, development success of all isolates at 37°C was lower than predicted by the model, suggesting the potential for overestimation of transmission risk at higher temperatures, such as those predicted under some scenarios of climate change. Recommendations are made for future climate impact modelling of gastrointestinal nematodes.

Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient.

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.

Neurocognitive effects of CNS tumors.

There is ample evidence that many children treated for brain tumors experience long-term neurocognitive deficits. The severity of those deficits is determined by a complex interaction of the child's genetic make-up and age, neuroanatomical damage caused by tumor and surgery, radiotherapy and chemotherapy, the psychosocial environment, and the intensity of targeted rehabilitation. The consequences of neurocognitive deficits are moderated by the number and severity of other deficits, including neurological and endocrine impairments, and this wider context must be considered. The impact of intellectual decline on academic functioning is evident, and underlies, for example, poor reading, writing, and mathematical skills. The effects of early brain damage on development are cumulative as more functions are expected to mature. Many survivors of CNS tumors can be expected to grow into deficits that have far-reaching consequences not only for academic achievement but also for their psychological and social development and their ability to be self-sufficient. Because the problems typically only become apparent over time, surveillance for their detection is an essential prerequisite for early educational and other interventions to support learning and successful transition to independent adult life.

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour.

The effects of ethanol on the brain are concentration dependent. Low concentrations (mM) intoxicate, while greater than 100 mM anaesthetize. Of most relevance to human alcohol addiction are mechanisms of intoxication. Previously, Caenorhabditis elegans has been employed in genetic screens to define effectors of intoxication. Here, we inform interpretation of these studies by providing evidence that ethanol rapidly equilibriates across C. elegans cuticle. Importantly, the effect of ethanol on muscle activity rapidly reaches steady-state, and the concentration-dependence of the effect is very similar in intact animals and exposed muscle. Thus the cuticle does not present an absorption barrier for ethanol, and furthermore the internal concentration is likely to approach that applied externally. Thus, modelling intoxication in C. elegans requires exposure to external ethanol less than 100 mM. Furthermore, the permeability of the cuticle to ethanol enables analysis of precisely controlled concentration-dependent effects of acute, chronic, and episodic ethanol exposure on behaviour.

Development of a new photocatalytic oxidation air filter for aircraft cabin.

UNLABELLED: A new photocatalytic oxidation air filter (PCO unit) has been designed for aircraft cabin applications. The PCO unit is designed as a regenerable VOC removal system in order to improve the quality of the recirculated air entering the aircraft cabin. The PCO was designed to be a modular unit, with four UV lamps sandwiched between two interchangeable titanium dioxide coated panels. Performances of the PCO unit has been measured in a single pass mode test rig in order to show the ability of the unit to decrease the amount of VOCs (toluene, ethanol, and acetone) entering it (VOCs are fed separately), and in a multipass mode test rig in order to measure the ability of the unit to clean the air of an experimental room polluted with the same VOCs (fed separately). Triangular cell panels have been chosen instead of the wire mesh panels because they have higher efficiency. The efficiency of the PCO unit depends on the type of VOCs that challenges it, toluene being the most difficult one to oxidise. The efficiency of the PCO unit decreases when the air flow rate increases. The multipass mode test results show that the VOCs are oxidized but additional testing time would be necessary in order to show if they can be fully oxidized. The intermediate reaction products are mainly acetaldehyde and formaldehyde whose amount depends on the challenge VOC. The intermediate reaction products are also oxidized and additional testing time would be necessary in order to show if they can be fully oxidized. The development of this new photocatalytic air filter is still going on. PRACTICAL IMPLICATIONS: The VOC/odor removing adsorbers are available for only a small proportion of aircraft currently in service. The photocatalytic oxidation (PCO) technique has appeared to be a promising solution to odors problems met in aircraft. This article reports the test results of a new photocatalytic oxidation air filter (PCO unit) designed for aircraft cabin applications. The overall efficiency of the PCO unit is function of the compound (toluene, ethanol, and acetone) that challenges the unit and toluene appears to be the most difficult compound to oxidize. Test results have shown the influence of the design of the PCO unit, the air flow rate and the type of UV on the efficiency of the PCO unit. The results obtained in this study represent a first attempt on the way to design a filter for VOC removal in cabin aircraft applications. The PCO technique used by the tested prototype unit is able to partially oxidized the challenge VOCs but one has to be aware that some harmful intermediate reaction products (mainly formaldehyde and acetaldehyde) are produced during the oxidation process before being partially oxidized too.

Complete androgen insensitivity caused by a splice donor site mutation in intron 2 of the human androgen receptor gene resulting in an exon 2-lacking transcript with premature stop-codon and reduced expression.

Various mutations within the human androgen receptor gene have been documented to cause defective sexual differentiation in karyotypic male individuals. In this study, we report a previously undescribed point mutation at the donor splice-site of the second intron of the androgen receptor gene in a patient with a completely female phenotype. The sequence alteration was detected by single-strand-conformation-analysis-PCR and genomic sequencing. Applying competitive reverse transcribed PCR, cDNA sequencing and Western blotting, we could demonstrate considerable aberrations of structure and concentration of the transcript and its translation product in the patient's fibroblasts from the genital region. (1) In the transcript, exon 1 and 3 are directly linked to each other, the complete second exon is skipped. The mRNA predictively suffers a codon frame-shift in exon 3 associated with a premature termination between codons 598 and 599, leading to a truncated androgen receptor protein lacking any in vivo function. (2) Steady-state concentration levels of transcript and protein are abnormally low. Our observations highlight the influence of exon-flanking intron sequences on proper expression and function of gene products.

Regulation of CD97 protein in thyroid carcinoma.

CD97 is a dimeric glycoprotein belonging to the secretin receptor superfamily and is abundantly expressed in cells of hematopoietic origin. The aim of this study was to analyze the expression of the CD97 protein in thyroid carcinomas and the role of all-trans-retinoic acid (RA) in the regulation of CD97 protein in monolayer culture of the human follicular thyroid carcinoma cell line FTC-133. In normal thyroid tissue, no immunoreactivity of CD97 could be found, whereas in differentiated thyroid carcinomas, CD97 expression was either lacking or low. Undifferentiated anaplastic thyroid carcinomas revealed high CD97 expression. The expression of CD97 protein seems to be correlated to the postoperative histopathological classification staging. Approximately 50% of FTC-133 cells expressed the CD97 protein under basal culture conditions. No differences were found in the number of CD97-positive cells after TSH, forskolin, and insulin treatment compared to control values. Epidermal growth factor treatment led to an increase in CD97 immunostaining (up to 90%), whereas phorbol 12-myristate 13-acetate slightly decreased the immunoreactivity of CD97 (from 50% to 30%). Under basal conditions, RA treatment for 72 h led to a decrease in total cell number by 33% and in CD97-positive cells from 50% to 30%. TSH, forskolin, phorbol 12-myristate 13-acetate, and insulin showed no effect after 72-h pretreatment with RA, whereas epidermal growth factor treatment led to a slight increase in the number of the CD97-positive cells (from 30% to 40%) compared to the control value. These data suggest that CD97 expression may play an important role in the dedifferentiation of thyroid tumors, and RA might interfere with this process in thyroid carcinoma by suppressing the dedifferentiation marker CD97.

Controlling persistent organic pollutants-what next?

Within the context of current international initiatives on the control of persistent organic pollutants (POPs), an overview is given of the scientific knowledge relating to POP sources, emissions, transport, fate and effects. At the regional scale, improvements in mass balance models for well-characterised POPs are resulting in an ability to estimate their environmental concentrations with sufficient accuracy to be of help for some regulatory purposes. The relevance of the parameters used to define POPs within these international initiatives is considered with an emphasis on mechanisms for adding new substances to the initial lists. A tiered approach is proposed for screening the large number of untested chemical substances according to their long-range transport potential, persistence and bioaccumulative potential prior to more detailed risk assessments. The importance of testing candidate POPs for chronic toxicity (i.e. for immunotoxicity, endocrine disruption and carcinogenicity) is emphasised as is a need for the further development of relevant SAR (structure activity relationship) models and in vitro and in vivo tests for these effects. Where there is a high level of uncertainty at the risk assessment stage, decision-makers may have to rely on expert judgement and weight-of-evidence, taking into account the precautionary principle and the views of relevant stake-holders. Close co-operation between the various international initiatives on POPs will be required to ensure that assessment criteria and procedures are as compatible as possible.

Survival analysis in observational studies.

Multi-centre databases are making an increasing contribution to medical understanding. While the statistical handling of randomized experimental studies is well documented in the medical literature, the analysis of observational studies requires the addressing of additional important issues relating to the timing of entry to the study and the effect of potential explanatory variables not introduced until after that time. A series of analyses is illustrated on a small data set. The influence of single and multiple explanatory variables on the outcome after a fixed time interval and on survival time until a specific event are examined. The analysis of the effect on survival of factors that only come into play during follow-up is then considered. The aim of each analysis, the choice of data used, the essentials of the methodology, the interpretation of the results and the limitations and underlying assumptions are discussed. It is emphasized that, in contrast to randomized studies, the basis for selection and timing of interventions in observational studies is not precisely specified so that attribution of a survival effect to an intervention must be tentative. A glossary of terms is provided.

An empirical comparison of expert-derived and data-derived classification trees.

Classification trees provide an attractively transparent discrimination technique, and may be derived from both expert opinion and from data analysis. We consider a real and complex problem concerning the diagnosis of babies with suspected critical congenital heart disease into one of 27 classes. A full loss matrix for all possible misclassifications was obtained from clinical assessments. A tree derived from expert opinion was compared with those derived from analysis of 571 past cases, both for the full problem and for a subset of 6 diseases. Automatic methods for tree creation and pruning were found to have problems for rare diseases, and hand-pruning was carried out. Inclusion of costs led to much improved clinical performance, even for trees that had originally been constructed to minimize classification errors. The expert tree showed a specific building strategy that could not be reproduced automatically. The expert tree generally outperformed those derived from data, particularly in the ability to identify important composite features.

Empathy as related to creativity, dogmatism, and expressiveness.

Empathy (affective sensitivity) was hypothesized to be positively related to creativity and expressiveness and inversely related to dogmatism, when gender and age were controlled. Participants were 56 graduate students enrolled in counseling and educational psychology courses at a large southwestern (U.S.) university. Participants were administered the Affective Sensitivity Scale (Kagan & Schneider, 1977) to measure empathy, the Statement of Past Creative Activities (Bull & Davis, 1980) to measure creativity, the Opinion Scale (Kleiber, Veldman, & Menaker, 1973) to measure dogmatism, and the Extended Personal Attributes Questionnaire (Spence, Helmreich, & Holahan, 1979) to measure expressiveness. The results of multiple regressions provide support for the hypotheses that empathy is positively related to creativity and inversely related to dogmatism, but the results do not support the hypothesized positive relationship between empathy and expressiveness. Implications of these findings for persons serving as counselors and counselor educators are discussed.

Presentation and attrition in complex pulmonary atresia.

OBJECTIVES: This study summarized patterns of presentation and attrition in complex pulmonary atresia. BACKGROUND: Assessment of the potential impact of surgical strategies for managing complex pulmonary atresia requires information about variability in age and physiology at presentation of the condition. METHODS: We performed a retrospective review of age at presentation, referral source, pulmonary artery and collateral anatomy and surgical history of 218 patients from two institutions dealing with congenital heart disease throughout life. RESULTS: Approximately 65% of pulmonary atresia appears in infancy, with 50% of patients severely symptomatic from cyanosis and 25% from heart failure. Compared with those presenting undiagnosed, patients referred secondarily for specialist management tend to be older when first seen, and care must be taken when generalizing about the natural history of the condition from their survival experience. Overall actuarial survival, including the effects of operation, suggests that 60% (95% confidence limits [CL] 43 to 73) of patients presenting in infancy survive to their first birthday, 65% (95% CL 51 to 74) of those alive at 1 year old survive to the age of 10, and 16% (95% CL 5 to 31) of those alive at 10 years old survive to age 35. CONCLUSIONS: Novel surgical approaches have generally been applied beyond infancy in patients selected by their survival through the period of greatest attrition for this disease. Unless successful application in symptomatic infants is demonstrated, we cannot assume that these serial and complicated operations will have a major impact on the outlook of most patients with complex pulmonary atresia.

An empirical map of critical loads of acidity for soils in Great Britain.

The method used to produce a critical load map of acidity for soils in Great Britain is described. Critical loads were assigned to the dominant soil in each 1 km grid square of the UK national grid. Mineral soils were assigned a critical load based on mineralogy and chemistry, using approaches appropriate to UK conditions. Critical loads for peat soils are based primarily on a maximum acceptable reduction of peat pH, and results from laboratory equilibration studies. The map shows that soils with small critical loads (<0.5 kmol(c) ha(-1) year(-1)) i.e. highly sensitive to acidic deposition, dominate in the north and west of Britain; the south and east are dominated by soils with large critical loads, with small areas of more sensitive soils associated with sandy soil-forming materials. A modified critical load map illustrates the potential impact of agricultural liming on soil critical loads.

The sensitivity of surface waters of Great Britain to acidification predicted from catchment characteristics.

Using a combination of soil, land use and geological information, a map of Great Britain has been derived which indicates the sensitivity of surface waters to acidification. For the geological information, a slightly modified version of an available map was used which indicated the sensitivity of groundwaters to acidification. For soils, 1-km databases of soil information for England and Wales and for Scotland were employed to map the soil sensitivity as determined by buffering capacity. The derived soils map was modified to take account of agricultural liming in arable and managed grassland areas using the ITE Land Classification. The final map of surface water sensitivity was obtained by using a geographic information system overlay procedure which enabled each combination of soil and geology sensitivity to be uniquely defined. The final sensitivity classification was based upon expert knowledge and the experience of a similar sensitivity mapping exercise for Wales.

An introduction to critical loads.

The critical loads approach to emission controls of gaseous pollutants is a concept with a short but eventful history. Despite difficulties with definitions and agreed values, its acceptance within the UN-ECE Convention on Long Range Transboundary Air Pollution has provided the impetus for developing methods to put critical loads to a practical use-the revision of the UNECE emission protocols for sulphur and nitrogen. Methodologies first focus upon quantifying a pollutant threshold at which harmful effects occur on particular sensitive receptors (usually biological species). This threshold is known as the critical load for deposited pollutants, and as the critical level for gaseous pollutants acting on receptors. To calculate a critical load, biological effects are usually 'translated' to critical chemical values, e.g. harmful effects on fish 'translate' to alkalinity or aluminium concentrations in water; thus, critical load calculations may be based upon the chemistry of a system. Such calculations may be performed using simple, steady-state models, whilst the use of more complex, dynamic models provides an insight into the past and future trends. Maps of critical loads can be drawn using calculated values, and maps of pollutant deposition data will then show geographical areas where critical loads are exceeded. Spatial emission-deposition models can identify sources contributing to areas of excess loads and quantify necessary emission reductions. Optimization procedures applied to such models can derive abatement strategies related to economic costs and critical load effects. The critical load calculations may also be used to underpin the setting of target loads; these are pollutant loads, determined by political agreement, which take account of social, economic and political considerations.