Biased interpretation in perfectionism and its modification

Perfectionism is a transdiagnostic construct associated with a range of diagnoses, including depression, eating disorders and obsessive compulsive disorder. Treatments that directly target perfectionist cognitions have been shown to successfully reduce associated pathologies. However, the way in which they do this is not clear. We set out to assess the role of one candidate mechanism of action, namely the cognitive process of interpretation of ambiguity. In one experiment we looked for associations between biased interpretation and perfectionism. In a second, we manipulated interpretations, thereby providing a strong test of their aetiological significance. Results from the first experiment confirmed the presence of biased interpretation in perfectionism and demonstrated that these are highly specific to perfection relevant information, rather than reflecting general negativity. The second experiment succeeded in manipulating these perfection relevant interpretations and demonstrated that one consequence of doing so is a change in perfectionist behaviour. Together, these data experimentally demonstrate that biased interpretation of perfection relevant ambiguity contributes to the maintenance of perfectionism, but that it is also possible to reverse this. Clinical implications include the identification of one likely mechanism of therapeutic change within existing treatments, as well as identification of an appropriate evidence based focus for future treatment development. Targeting underlying functional mechanisms, such as biased interpretation, has the potential to offer transdiagnostic benefits.

The role of nonhydrostatic dynamics in controlling development of a surface ocean front

Numerical studies of surface ocean fronts forced by inhomogeneous buoyancy loss show nonhydrostatic convective plumes coexisting with baroclinic eddies. The character of the vertical overturning depends sensitively on the treatment of the vertical momentum equation in the model. It is less well known how the frontal evolution over scales of O(10 km) is affected by these dynamics. Here, we compare highly resolved numerical experiments using nonhydrostatic and hydrostatic models and the convective-adjustment parametrization. The impact of nonhydrostatic processes on average cross-frontal transfer is weak compared to the effect of the O(1 km) scale baroclinic motions. For water-mass distribution and formation rate nonhydrostatic dynamics have similar influence to the baroclinic eddies although adequate resolution of the gradients in forcing fluxes is more important. The overall implication is that including nonhydrostatic surface frontal dynamics in ocean general circulation models will have only a minor effect on scales of O(1 km) and greater.

The 'direct costs' of livestock disease: The development of a system of models for the analysis of 30 endemic livestock diseases in Great Britain

The 'direct costs' attributable to 30 different endemic diseases of farm animals in Great Britain are estimated using a standardised method to construct a simple model for each disease that includes consideration of disease prevention and treatment costs. The models so far developed provide a basis for further analyses including cost-benefit analyses for the economic assessment of disease control options. The approach used reflects the inherent livestock disease information constraints, which limit the application of other economic analytical methods. It is a practical and transparent approach that is relatively easily communicated to veterinary scientists and policy makers. The next step is to develop the approach by incorporating wider economic considerations into the analyses in a way that will demonstrate to policy makers and others the importance of an economic perspective to livestock disease issues.

Drying method influences the development of germinability, dessication tolerance and subsequent longevity of immature seeds of sumauma (Ceiba pentandra (L.) Gaertn. [Bombacaceae])

The ability to germinate, tolerate desiccation and survive in air-dry storage was investigated during early seed development in planta and subsequent ex planta maturation of sumauma (Ceiba pentandra). Immature fruits were collected on three different dates (i.e. from about 5 days before until 7 days after mass maturity). Immature fresh seeds were not able to germinate. Fruits or seeds were subjected immediately after each collection to three different drying treatments with progressively slower rates of dessication: (i) seeds were extracted from the fruits and dried immediately; (ii) fruits were dried in a thin layer; (iii) fruits were dried in a tied polyethylene bag (with 10 holes of 1cm diameter). Drying was in a room maintained at 25 degrees C +/- 3 degrees C and 65%+/- 5% r.h. For treatment (i) the seeds were dried for 6 days in order to reduce moisture content to around 13% ( +/- 2%) moisture content. For treatments (ii) and (iii) the fruits were subjected to different periods of drying depending upon collection date. The results of these post-collection treatments showed generally that the more immature the seeds the slower the rate of drying that is required to improve ability to germinate, ability to tolerate desiccation and potential longevity, but at the third harvest, 7 days after mass maturity, the intermediate drying rate treatment was the most beneficial. Thus post fruit collection treatments can be modified depending upon the stage of seed development in order to provide good to high quality seeds of sumauma when collection has to be made at a site with difficult access at less than ideal times. The results are relevant to seed collection practices for both forestry and ex situ plant biodiversity conservation.

Transcriptome analysis of grain development in hexaploid wheat

Background: Hexaploid wheat is one of the most important cereal crops for human nutrition. Molecular understanding of the biology of the developing grain will assist the improvement of yield and quality traits for different environments. High quality transcriptomics is a powerful method to increase this understanding. Results: The transcriptome of developing caryopses from hexaploid wheat ( Triticum aestivum, cv. Hereward) was determined using Affymetrix wheat GeneChip (R) oligonucleotide arrays which have probes for 55,052 transcripts. Of these, 14,550 showed significant differential regulation in the period between 6 and 42 days after anthesis ( daa). Large changes in transcript abundance were observed which were categorised into distinct phases of differentiation ( 6 - 10 daa), grain fill ( 12 - 21 daa) and desiccation/maturation ( 28 - 42 daa) and were associated with specific tissues and processes. A similar experiment on developing caryopses grown with dry and/or hot environmental treatments was also analysed, using the profiles established in the first experiment to show that most environmental treatment effects on transcription were due to acceleration of development, but that a few transcripts were specifically affected. Transcript abundance profiles in both experiments for nine selected known and putative wheat transcription factors were independently confirmed by real time RT-PCR. These expression profiles confirm or extend our knowledge of the roles of the known transcription factors and suggest roles for the unknown ones. Conclusion: This transcriptome data will provide a valuable resource for molecular studies on wheat grain. It has been demonstrated how it can be used to distinguish general developmental shifts from specific effects of treatments on gene expression and to diagnose the probable tissue specificity and role of transcription factors.

Sequential designs for phase III clinical trials incorporating treatment selection

Most statistical methodology for phase III clinical trials focuses on the comparison of a single experimental treatment with a control. An increasing desire to reduce the time before regulatory approval of a new drug is sought has led to development of two-stage or sequential designs for trials that combine the definitive analysis associated with phase III with the treatment selection element of a phase II study. In this paper we consider a trial in which the most promising of a number of experimental treatments is selected at the first interim analysis. This considerably reduces the computational load associated with the construction of stopping boundaries compared to the approach proposed by Follman, Proschan and Geller (Biometrics 1994; 50: 325-336). The computational requirement does not exceed that for the sequential comparison of a single experimental treatment with a control. Existing methods are extended in two ways. First, the use of the efficient score as a test statistic makes the analysis of binary, normal or failure-time data, as well as adjustment for covariates or stratification straightforward. Second, the question of trial power is also considered, enabling the determination of sample size required to give specified power. Copyright © 2003 John Wiley & Sons, Ltd.

An adaptive group sequential design for phase II/III clinical trials that select a single treatment from several

There is increasing interest in combining Phases II and III of clinical development into a single trial in which one of a small number of competing experimental treatments is ultimately selected and where a valid comparison is made between this treatment and the control treatment. Such a trial usually proceeds in stages, with the least promising experimental treatments dropped as soon as possible. In this paper we present a highly flexible design that uses adaptive group sequential methodology to monitor an order statistic. By using this approach, it is possible to design a trial which can have any number of stages, begins with any number of experimental treatments, and permits any number of these to continue at any stage. The test statistic used is based upon efficient scores, so the method can be easily applied to binary, ordinal, failure time, or normally distributed outcomes. The method is illustrated with an example, and simulations are conducted to investigate its type I error rate and power under a range of scenarios.

Statistical modeling suggests that antiandrogens in effluents from wastewater treatment works contribute to widespread sexual disruption in fish living in English rivers.

BACKGROUND: The widespread occurrence of feminized male fish downstream of some wastewater treatment works has led to substantial interest from ecologists and public health professionals. This concern stems from the view that the effects observed have a parallel in humans, and that both phenomena are caused by exposure to mixtures of contaminants that interfere with reproductive development. The evidence for a "wildlife-human connection" is, however, weak: Testicular dysgenesis syndrome, seen in human males, is most easily reproduced in rodent models by exposure to mixtures of antiandrogenic chemicals. In contrast, the accepted explanation for feminization of wild male fish is that it results mainly from exposure to steroidal estrogens originating primarily from human excretion. OBJECTIVES: We sought to further explore the hypothesis that endocrine disruption in fish is multi-causal, resulting from exposure to mixtures of chemicals with both estrogenic and antiandrogenic properties. METHODS: We used hierarchical generalized linear and generalized additive statistical modeling to explore the associations between modeled concentrations and activities of estrogenic and antiandrogenic chemicals in 30 U.K. rivers and feminized responses seen in wild fish living in these rivers. RESULTS: In addition to the estrogenic substances, antiandrogenic activity was prevalent in almost all treated sewage effluents tested. Further, the results of the modeling demonstrated that feminizing effects in wild fish could be best modeled as a function of their predicted exposure to both anti-androgens and estrogens or to antiandrogens alone. CONCLUSION: The results provide a strong argument for a multicausal etiology of widespread feminization of wild fish in U.K. rivers involving contributions from both steroidal estrogens and xeno-estrogens and from other (as yet unknown) contaminants with antiandrogenic properties. These results may add farther credence to the hypothesis that endocrine-disrupting effects seen in wild fish and in humans are caused by similar combinations of endocrine-disrupting chemical cocktails.

Water deficits promote flowering in Rhododendron via regulation of pre and post initiation development

Flowering is generally considered to be advanced by water deficits in many woody perennial species. A long-standing paradigm being that as a plant senses severe environmental conditions resources are diverted away from vegetative growth and towards reproduction before death. It is demonstrated that in Rhododendron flowering is promoted under water deficit treatments. However, the promotion of flowering is not achieved via all increase in floral initiation, but through separate developmental responses. If regulated deficit irrigation (RDI) is imposed prior to the time of initiation, fewer vegetative nodes are formed before the apical meristems switch to floral initiation, and chronologically, floral initiation occurs earlier. Both RDI and partial rootzone drying (PRD) treatments stimulate the development of more flowers Oil each inflorescence if the treatments are continued after the plant has undergone floral initiation. However, floral initiation is inhibited by soil water deficits. If the soil water deficit continues beyond the stages of floral development then anthesis call occur prematurely oil the fully formed floral buds without a need for a winter chilling treatment. It is hypothesised that inhibition of floral initiation in plants experiencing severe soil water deficits results from the inhibitory action Of ABA transportation to the apical meristem from stressed roots. It is demonstrated that ABA applications to well-watered Rhododendron inhibit floral initiation. (c) 2008 Elsevier B.V. All rights reserved.

Bovine follicle development is associated with divergent changes in activin-A, inhibin-A and follistatin and the relative abundance of different follistatin isoforms in follicular fluid

The aim was to determine whether follicle growth in cattle is accompanied by changes in levels of inhibin-A (inh-A), activin-A (act-A) and different Mr isofomus of follistatin (FS) in bovine follicular fluid (bFF), reflecting differential roles of these proteins during folliculogenesis. Follcles (n= 146) from 2-20 min diameter were dissected from ovaries of similar to 40 cattle. Immunoassays were used to measure total FS, act-A, inh-A, oestradiol (E) and progesterone (P) levels; immunoblotting was used to quanti, the relative abundance of different FS isoforms. Follicle growth from 2-6 mm was associated with a 6-fold increase in inh-A and 30-fold increase in act-A; FS remained uniformly high from 2-10 turn. From 6-2 min, inh-A remained high while act-A and FS fell 3-fold and 2-fold, respectively. Act-A/FS ratio increased 20-fold from 2-6 mm before falling slightly through to 20 mm. Act-A/inh-A ratio increased 6-fold from 2-6 nun before falling 2-fold from 6 to 17-20 mm. These findings imply a marked increase in relative activin 'tone' around the stage at which dominant follicle,;election occurs. When larger follicles (13-20 mm) were subdivided according to E/P ratio, those with high (> 5) E/P ratio had lower (2-fold; P < 0(.)001) levels of inh-A and act-A in comparison to follicles with low (< 5) E/P ratio, but there were no significant diffierences in FS, act-A/inh-A ratio or act-A/FS ratio. Thus follicle size, but not oestrogenic status, has a major influence on the intrafollicular balance between act-A and its opposing factors, inh-A and FS. Six FS isoforms were detected in bFF (apparent Mr: 65, 41, 37, 35, 33 and 31 kDa) averaging 6, 13, 24, 26 13 and 17% respectively of total FS. During growth from 2-20 mm the proportion of total FS represented by 605, 41 and 37 kDa isoforms increased similar to 2-fold while the proportion represented by the 33 and 31 kDa isoforms decreased by 3-fold and 1(.)6-fold, respectively. Treatment of bovine granulosa cells in vitro with FSH and IGF alone or in combination increased total FS secretion up to 12-fold but did not affect the relative abundance of the five different FS isoforms detected. While the functional significance of the intriguing shift in FS isoform abundance in bFF during follicle development remains to be established, we have shown that a marked increase in intrafollicular activin 'tone' accompanies bovine follicle growth from 3-6 min, corresponding to the stage at which the FSH-dependent follicle selection mechanism operates in this species.

Targeting the cell cycle machinery for the treatment of cardiovascular disease

Cardiovascular disease represents a major clinical problem affecting a significant proportion of the world's population and remains the main cause of death in the UK. The majority of therapies currently available for the treatment of cardiovascular disease do not cure the problem but merely treat the symptoms. Furthermore, many cardioactive drugs have serious side effects and have narrow therapeutic windows that can limit their usefulness in the clinic. Thus, the development of more selective and highly effective therapeutic strategies that could cure specific cardiovascular diseases would be of enormous benefit both to the patient and to those countries where healthcare systems are responsible for an increasing number of patients. In this review, we discuss the evidence that suggests that targeting the cell cycle machinery in cardiovascular cells provides a novel strategy for the treatment of certain cardiovascular diseases. Those cell cycle molecules that are important for regulating terminal differentiation of cardiac myocytes and whether they can be targeted to reinitiate cell division and myocardial repair will be discussed as will the molecules that control vascular smooth muscle cell (VSMC) and endothelial cell proliferation in disorders such as atherosclerosis and restenosis. The main approaches currently used to target the cell cycle machinery in cardiovascular disease have employed gene therapy techniques. We will overview the different methods and routes of gene delivery to the cardiovascular system and describe possible future drug therapies for these disorders. Although the majority of the published data comes from animal studies, there are several instances where potential therapies have moved into the clinical setting with promising results.

A novel technique for differentiation of proteins in the development of acid gel structure from control and heat treated milk using confocal scanning laser microscopy

The incorporation of caseins and whey proteins into acid gels produced from unheated and heat treated skimmed milk was studied by confocal scanning laser microscopy (CSLM) using fluorescent labelled proteins. Bovine casein micelles were labelled using Alexa Fluor 594, while whey proteins were labelled using Alexa Fluor 488. Samples of the labelled protein solutions were introduced into aliquots of pasteurised skim milk, and skim milk heated to 90 degrees C for 2 min and 95 degrees C for 8 min. The milk was acidified at 40 degrees C to a final pH of 4.4 using 20 g gluconodelta-lactone/l (GDL). The formation of gels was observed with CSLM at two wavelengths (488 nm and 594 nm), and also by visual and rheological methods. In the control milk, as pH decreased distinct casein aggregates appeared, and as further pH reduction occurred, the whey proteins could be seen to coat the casein aggregates. With the heated milks, the gel structure was formed of continuous strands consisting of both casein and whey protein. The formation of the gel network was correlated with an increase in the elastic modulus for all three treatments, in relation to the severity of heat treatment. This model system allows the separate observation of the caseins and whey proteins, and the study of the interactions between the two protein fractions during the formation of the acid gel structure, on a real-time basis. The system could therefore be a valuable tool in the study of structure formation in yoghurt and other dairy protein systems.

Development of new methodologies for entry to targets of therapeutic interest

This Account provides an overview of strategies that have been reported from our laboratories for the synthesis of targets of therapeutic interest, namely carbohydrates, and prodrugs for the treatment of melanoma. These programmes have involved the development of new synthetic methodologies including the regio- and stereoselective synthesis of specific carbohydrate isomers, and new protecting group methodologies. This review provides an insight into the progress of these research themes, and suggests some applications for the targets that are currently being explored.

The use of proteomics to identify novel therapeutic targets for the treatment of disease

The completion of the Human Genome Project has revealed a multitude of potential avenues for the identification of therapeutic targets. Extensive sequence information enables the identification of novel genes but does not facilitate a thorough understanding of how changes in gene expression control the molecular mechanisms underlying the development and regulation of a cell or the progression of disease. Proteomics encompasses the study of proteins expressed by a population of cells, and evaluates changes in protein expression, post-translational modifications, protein interactions, protein structure and splice variants, all of which are imperative for a complete understanding of protein function within the cell. From the outset, proteomics has been used to compare the protein profiles of cells in healthy and diseased states and as such can be used to identify proteins associated with disease development and progression. These candidate proteins might provide novel targets for new therapeutic agents or aid the development of assays for disease biomarkers. This review provides an overview of the current proteomic techniques available and focuses on their application in the search for novel therapeutic targets for the treatment of disease.