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The lens is formed in utero with new secondary lens fibres added as outer layers throughout life in a growth pattern characteristic of the species. This study examined the time course of beagle lens growth to better understand the optimal starting age of dogs for safety studies to support adult versus paediatric indications, and to assess the feasibility of non-invasively monitoring lens growth with high frequency ultrasound. Ultrasound scanning was performed in six female beagle dogs using the Vevo770. All dogs were imaged in B-mode using local anaesthetic but without sedation. Imaging was carried out every 2 weeks from 8 to 22 weeks of age and then monthly until 62 weeks of age. The dogs tolerated the procedure well. The lens was visible in all dogs and measuring the lens thickness with high frequency ultrasound demonstrated good analytical reproducibility [Root Mean Square (RMS) = 3.13%]. No differences between the left and right eye existed and lens thickness correlated with body weight. The highest weekly growth rate was before 12 weeks of age. A statistically significant difference between monthly thickness was detected until 42 weeks of age at which point growth reached a plateau. During the experiment, lenses grew by 29.7% reaching an average thickness of 6.4 mm ± 0.03. By 10 months of age (the typical age used for routine toxicological evaluation), beagles have reached a plateau in lens growth that is analogous to human adults. Where lens is a target organ of concern it is suggested that beagles under 6 months old may be a better model for determining paediatric safety. Copyright © 2014 John Wiley & Sons, Ltd.

Summary The health impact resulting from a few days of elevated air pollution concentrations has been the focus of much recent research, most of which assesses the effects of single pollutants rather than composite air quality indicators. The average concentrations of these pollutants across the study region are typically estimated by averaging the measurements from the available network of monitors, and this simplistic approach has several deficiencies. Firstly, it is unlikely to be the average concentration across the region under study, owing to the likely non-random placement of the monitoring network. Secondly, the true spatial average is an unknown quantity, and hence the uncertainty in any estimate should be allowed for when estimating its health effects. This paper proposes a novel Bayesian hierarchical framework for addressing these problems, which consists of statistical models for estimating spatially representative measures of single pollutants and composite air quality indicators, and the health effects of these pollution measures while correctly allowing for their uncertainty. This methodological development is motivated by an epidemiological study of the effects of air pollution on respiratory mortality in Greater London, England, between 2003 and 2005. The key findings from this study are that traditional approaches are likely to underestimate the uncertainty in the health effects of air pollution compared with the approach proposed here and increased risks of between 1.4% and 3.1% are associated with 1-standard-deviation increases in the concentrations of ozone, particulate matter (PM10) and the composite air quality indicator that is adopted here.

Big data in healthcare can bring significant clinical and cost benefits. Of equal but often overlooked importance is the role of patient satisfaction data in improving the quality of healthcare service and treatment, where satisfaction is measured through feedback by patients on their meetings with medical specialists and experts. One of the major problems in analyzing patient feedback data is the nonstandard research designs often used for gathering such data: the designs can be uncrossed, unbalanced, and fully nested. Traditional measures of data reliability are more difficult to calculate for such data. Also, patient data can contain significant proportions of missing values that further complicate the calculation of reliability. This paper describes a reliability approach that is robust in the face of nonstandard research designs and missing values for use with large-scale patient survey data. The dataset contains nearly 85,000 patient responses to over 2,000 healthcare practitioners in five different subtypes over a 15-year period in the United Kingdom. Reliability measures are calculated to provide benchmarks involving minimum numbers of patients and practitioners for deeper drill-down analysis. The paper concludes with a demonstration of how regression models generated from big patient feedback data can be assessed in terms of reliability at the total data level as well as drill-down levels.

Epigenetics describes the study of heritable changes in gene expression that occur in the absence of a change to the DNA sequence. Specific patterns of epigenetic signatures can be stably transmitted through mitosis and cell division and form the molecular basis for developmental stage- and cell type-specific gene expression. Associations have been observed that endogenous and exogenous stimuli can change the epigenetic control of both somatic and stem cell differentiation and thus influence phenotypic behaviours and/or disease progression. In relation to drug safety, DNA methylation changes have been identified in many stages of tumour development following exposure to non-genotoxic carcinogens. However, it is not clear whether DNA methylation changes cause cancer, or arise as a consequence of the transformed state. Toxic agents could act at different levels, by directly modifying the epigenome or indirectly by altering signalling pathways. These alterations in chromatin structure may or may not be heritable but are probably reversible. That said, there is currently insufficient data to support inclusion of epigenetic profiling into pre-clinical evaluation studies. Several international collaborations aim to generate data to determine whether epigenetic modifications are causal links in disease and/or tumour progression. It will only be when an understanding of chemical mode-of-action is required that evaluation of epigenetic changes might be considered. The current toxicological testing battery is expected to identify any potential adverse effects regardless of the mechanism, epigenetic or otherwise. It is recommended that toxicologists keep a close watch of new developments in this field, in particular identification of early epigenetic markers for non-genotoxic carcinogenicity. Scientific collaborations between academia and industry will help to understand inter-individual variations in response to drug and toxin exposure to be able to distinguish between adverse and non-adverse epigenetic changes.

Adverse drug reactions represent a major stumbling block to drug development and those with an immune etiology are the most difficult to predict. We have developed an in vitro T-cell priming culture method using peripheral blood from healthy volunteers to assess the allergenic potential of drugs. The drug metabolite nitroso sulfamethoxazole (SMX-NO) was used as a model drug allergen to establish optimum assay conditions. Naive T cells were cocultured with monocyte-derived dendritic cells at a ratio of 25:1 in the presence of the drug for a period of 8 days, to expand the number of drug-responsive T cells. The T cells were then incubated with fresh dendritic cells, and drug and their antigen responsiveness analyzed using readouts for proliferation, cytokine secretion, and cell phenotype. All five volunteers showed dose-dependent proliferation as measured by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester content and by (3)H-thymidine uptake. CD4 T cells that had divided in the presence of SMX-NO had changed from a naive phenotype (CD45RA+) to a memory phenotype (CD45RO+). These memory T cells expressed the chemokine receptors CCR2, CCR4, and CXCR3 suggesting a mixture of T(H)1 and T(H)2 cells in the responding population, with a propensity for homing to the skin. Drug stimulation was also associated with the secretion of a mixture of T(H)1 cytokines (interferon γ) and T(H)2 cytokines (interleukin [IL]-5 and IL-13) as detected by ELISpot. We are currently developing this approach to investigate the allergenic potential of other drugs, including those where an association between specific human leucocyte antigen alleles and susceptibility to an immunological reaction has been established.

The health risks associated with short-term exposure to air pollution have been the focus of much recent research, most of which has considered linear concentration–response functions (CRFs) between ambient concentrations of pollution and a health response. A much smaller number of studies have relaxed this assumption of linearity and allowed the shape of the function to be estimated from the data. However, this increased flexibility has resulted in CRFs being estimated that appear unfeasible, often showing decreases in the risk to health with increasing concentrations. Therefore, this paper proposes a Bayesian hierarchical model for estimating constrained CRFs in this context, which is based on monotonic integrated splines. These splines produce non-decreasing CRFs, owing to the associated regression parameters being constrained to be non-negative, which we ensure by modelling the latter with a ‘slab and spike’ prior. The efficacy of our approach is assessed via simulation before being applied to a study of ozone concentrations and respiratory disease in Greater London between 2000 and 2005. Copyright © 2012 John Wiley & Sons, Ltd.

The requirement for doctors and other medical professionals to undertake periodic performance evaluation is growing. Tools and techniques for such performance evaluation are at an early stage of development, but it is likely that feedback from colleagues and patients will play an important role. The aim of this paper is to evaluate two feedback tools (CFET for colleague feedback and DISQ for patient feedback) for the purpose of periodic performance evaluation of doctors. The data used in this study came from over 200 doctors currently working in hospital settings within the UK. The results indicate that there is close correspondence between the outcomes of manual screening procedures used by the UK General Medical Council (GMC) and the output from the two feedback tools Also, the paper shows that it is possible to combine colleague and patient feedback for a doctor, thereby extending our knowledge of how screening techniques based on questionnaires can produce a multisource view currently not available to...

The transcription factor Nrf2 regulates expression of multiple cellular defence proteins through the antioxidant response element (ARE). Nrf2-deficient mice (Nrf2−/−) are highly susceptible to xenobiotic-mediated toxicity, but the precise molecular basis of enhanced toxicity is unknown. Oligonucleotide array studies suggest that a wide range of gene products is altered constitutively, however no equivalent proteomics analyses have been conducted. To define the range of Nrf2-regulated proteins at the constitutive level, protein expression profiling of livers from Nrf2−/− and wild type mice was conducted using both stable isotope labelling (iTRAQ) and gel electrophoresis methods. To establish a robust reproducible list of Nrf2-dependent proteins, three independent groups of mice were analysed. Correlative network analysis (MetaCore) identified two predominant groups of Nrf2-regulated proteins. As expected, one group comprised proteins involved in phase II drug metabolism, which were down-regulated in the absence of Nrf2. Surprisingly, the most profound changes were observed amongst proteins involved in the synthesis and metabolism of fatty acids and other lipids. Importantly, we show here for the first time, that the enzyme ATP-citrate lyase, responsible for acetyl-CoA production, is negatively regulated by Nrf2. This latter finding suggests that Nrf2 is a major regulator of cellular lipid disposition in the liver., Graphical abstract

David Chaney (2001) argues that access to lifestyle templates are available primarily through multiple media channels, where lifestyle is an example of a new “social form” based on specific patterns of consumer choice. This article examines a very particular kind of “celebrity.” It is concerned with how television, print, and advertising contribute to the construction of media stars whose function is to transfer knowledge of particular lifestyles to the lived experience of ordinary people. It looks at systems that direct the flow of such information and why the proliferation of this new breed of expert arises out of a particular set of historic conditions, namely the rise of and recent challenges to neo-liberalism. Specifically, it explores the role of the celebrity expert as cultural intermediary at a time when objective and subjective class positions do not necessarily coincide. The social anxieties that arise as a con sequence sees the domination of the market as an economic and cultural space in which such anxieties are increasingly played out. This allows questions to be posed that consider the proliferation of the celebrity expert, their role as tastemakers in contemporary culture and how viewers appropriate, or not, the particular lifestyles that are communicated across popular media forms.

The Patient Partnership in Care (PPiC) questionnaire was designed to measure the ability of health professionals to work in partnership with patients with long-term conditions (LTCs) to support and motivate self-management. It is a generic, 16-item questionnaire, contained on two sides of A4, incorporating space for two written comments. In a baseline survey, 97 clinicians gathered responses from 1,660 patients with LTCs in eight centres across the UK. The questionnaire was found to have face validity, construct validity, good internal consistency and sensitivity to change. It consists of two, unidimensional subscales covering patient–clinician partnership and the patient's confidence to manage their LTC (Cronbach's alpha 0.977 and 0.877 respectively). Health professionals who participated in three four-hour training sessions focusing on skills that support patients with self-management showed a significantly improved score in both subscales (with moderate effect sizes: –0.56 for both subscales). ...

Whilst it can be argued that home improvements are cyclical and largely informed by the “wealth effect” as a function of the state of the housing market, this article turns its attention to homeowners and their participation in such activities. In particular it provides evidence of a progressive decline across the last decade in do-it-yourself (DIY) activity independent of fluctuations in house prices. Through an examination of the concept of “time compression” the choice and selection of leisure activities, of which DIY was once a considered option, is identified as subject to heightened competition, with preference given to those that supply an immediate sense of gratification. As a consequence of this, the “cash-rich time-poor” increasingly turn to tradesmen to realize their visions of domestic transformation, more interested in outcome than process; acceptability over authenticity. Furthermore, such changes in the temporal register also inform the search for and production of innovative televi...

In two successive years, 2,012 practices surveyed over 400,000 patients per year in the UK using the Improving Practice Questionnaire (IPQ). In the second survey, of the 27 questionnaire items, a statistically significant improvement was seen in scores for 12 items, while scores were maintained for 13 items and significantly decreased for only two items, namely satisfaction with opening hours and contacting the practice by telephone. Scores for perceived practitioner capability were maintained regardless of practice size, showing a continued high level of satisfaction of over 80 per cent in this area. These scores could still be improved, particularly for considering the patient as a person and taking into account their personal situation in deciding possible treatments. Scores for the capacity of the practice to deliver a high-quality service with regard to supporting services and access were inversely correlated with practice size. Improvement in these scores indicated that listening to patients...

U.S. and Australian media vehicles are not required to publish or broadcast every commercial advertising message submitted. To the contrary, owners and managers are free to designate anyone's messa...

GST pi (GSTP) is a member of the glutathione S-transferase (EC 2.5.1.18; GST) family of enzymes that catalyse the conjugation of electrophilic species with reduced glutathione and thus play an important role in the detoxification of electrophilic metabolites. Deletion of GSTP in mice has previously been shown to lead to enhanced susceptibility to chemical-induced skin carcinoma, consistent with its known metabolic functions. A decreased susceptibility to paracetamol hepatotoxicity has also been observed, which has not been fully explained. One possibility is that deletion of the GSTP gene locus results in compensatory changes in other proteins involved in defence against chemical stress. We have therefore used complementary protein expression profiling techniques to perform a systematic comparison of the protein expression profiles of livers from GSTP null and wild-type mice. Analysis of liver proteins by two-dimensional electrophoresis confirmed the absence of GSTP in null mice whereas GSTP represented 3-5% of soluble protein in livers from wild-type animals. There was a high degree of quantitative and qualitative similarity in other liver proteins between GSTP null and wild-type mice. There was no evidence that the absence of GSTP in null animals resulted in enhanced expression of other GST isoforms in the null mice (GST alpha, 1.48%, GST mu, 1.68% of resolved proteins) compared with the wild-type animals (GST alpha, 1.50%, GST mu, 1.40%). In contrast, some members of the thiol specific antioxidant family of proteins, notably antioxidant protein 2 and thioredoxin peroxidases, were expressed at a higher level in the GSTP null mouse livers. These changes presumably reflect the recently described role of GSTP in cell signalling and may underlie the protection against paracetamol toxicity seen in these animals.

1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N -acetyl- p -benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S -transferases (GST), such as GST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP ( GstP1/P2 (−/−) ). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type ( GstP1/P2 (+/+) ) mice and GstP1/P2 (−/−) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2 (+/+) and GstP1/P2 (−/−) mice, GSH levels only recovered in the GstP1/P2 (−/−) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of GST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity.

Exposure of cells to toxic chemical species can result in reduced glutathione (GSH) depletion, generation of free radicals, and/or binding to critical cell determinants. Chemical stress is usually followed by a concerted cellular response aimed at restoring homeostasis, although the precise initial stimulus for the response is unclear. We have focused on one component of this stress response, the up-regulation of gamma-glutamylcysteine synthetase (gamma-GCS) and the preceding molecular events involved in its regulation in an in vivo mouse model. Male CD-1 mice received buthionine sulphoximine (BSO; 7.2 mmol/kg), diethyl maleate (DEM; 4.2 mmol/kg), paracetamol (APAP; 3.5 and 1.0 mmol/kg), or carbon tetrachloride (CCl(4); 1.0 and 0.2 mmol/kg). Biochemical (serum transaminase and hepatic GSH levels) and molecular (c-jun and c-fos messenger RNA [mRNA] levels and activator protein 1 [AP-1] DNA binding activity) parameters were measured, as well as the consequent effects on gamma-GCS levels and activity. All compounds produced GSH depletion, but only the higher doses of APAP and CCl(4) caused liver damage. DEM, APAP, and CCl(4) increased c-jun and c-fos mRNA levels, together with an increase in AP-1 binding; BSO failed to induce AP-1 despite an increase in c-fos. Interestingly, the effects on gamma-GCS varied markedly according to the compound: BSO and DEM increased gamma-GCS enzyme activity, although only DEM, but not BSO, resulted in an increase in gamma-GCS(h) mRNA and protein. In contrast, APAP and CCl(4) both increased gamma-GCS(h) mRNA and protein; however, there was a marked dose-dependent decrease in gamma-GCS activity. These data indicate that the effect of chemical stress on the liver is compound specific and is not merely dependent on depletion of GSH.

Background: Collagen cross-link molecules such as pyridinoline (PYD), deoxypyridinoline (DPD), and N-terminal cross-linked peptides (NTX) have been measured in urine as indices of bone resorption. However, very little is known regarding the excretion of pyridinolines into other biological fluids. We report a collection device, normalizing analyte, and high-sensitivity immunoassay for quantitative analysis of free pyridinoline cross-links in sweat. Methods: Flame atomic emission and ion-selective electrode techniques were used to measure potassium as a sweat volume marker. The Pyrilinks immunoassay for urine free pyridinolines was optimized to increase sensitivity for measurements in sweat. The precision, accuracy, and detection limit of this assay were characterized. To assess values and variability of sweat pyridinolines in human subjects, a nonocclusive skin patch was used to collect sweat samples from a reference group and from a mixed group experiencing accelerated bone resorption, postmenopausal women and men receiving gonadotropin-releasing hormone for prostate cancer. Results: The immunoassay intra- and interassay variations were ≤10% and Conclusion: We conclude that this new platform sweat collection technology and PYD immunoassay show potential as an indicator of bone resorption.

The lens is formed in utero with new secondary lens fibres added as outer layers throughout life in a growth pattern characteristic of the species. This study examined the time course of beagle lens growth to better understand the optimal starting age of dogs for safety studies to support adult versus paediatric indications, and to assess the feasibility of non-invasively monitoring lens growth with high frequency ultrasound. Ultrasound scanning was performed in six female beagle dogs using the Vevo770. All dogs were imaged in B-mode using local anaesthetic but without sedation. Imaging was carried out every 2 weeks from 8 to 22 weeks of age and then monthly until 62 weeks of age. The dogs tolerated the procedure well. The lens was visible in all dogs and measuring the lens thickness with high frequency ultrasound demonstrated good analytical reproducibility [Root Mean Square (RMS) = 3.13%]. No differences between the left and right eye existed and lens thickness correlated with body weight. The highest weekly growth rate was before 12 weeks of age. A statistically significant difference between monthly thickness was detected until 42 weeks of age at which point growth reached a plateau. During the experiment, lenses grew by 29.7% reaching an average thickness of 6.4 mm ± 0.03. By 10 months of age (the typical age used for routine toxicological evaluation), beagles have reached a plateau in lens growth that is analogous to human adults. Where lens is a target organ of concern it is suggested that beagles under 6 months old may be a better model for determining paediatric safety.

The contemporary consumer is fundamentally Janus-headed. On the one hand, the amount of choice now available and the means to access it points towards a highly individualistic, authentic consumer who sees themselves as the architect of their own consumption patterns. And yet, as Simmel observed back in 1904, we continue to use fashion and trends as a mechanism by which we may secure group belonging. The majority of e-commerce sites, for example, allow us to rank search results by the ‘most popular’ in terms of other consumers’ previous choices or the ‘like’ facility on Facebook, which allows users to independently display their allegiance to a brand and which functions as a purchasing security blanket in terms of managing adherence to the taste cultures of those closest to us. A second paradox that this chapter will address is that of the issue of consumerempowerment. Jenkins (2008: 3) addresses how technological changes inform consumption, specifically the ways in which ‘consumers are encouraged to seek out new information and make connections among dispersed media content’. And yet, one could argue that while we may be more informed in terms of making choices, those choices are always framed within the context of a capitalist system, with the pursuit of profit remaining that system’s raison d’etre. Today consumers are no longer simply seen as ‘a market’ to sell into (Jenkins and Deuze 2008: 9), but rather as the principal drivers of what is supplied and, ultimately, consumed. Furthermore, they are also active in shaping the marketplaces, physical and virtual, in which such transactions take place. However, while evidencing such activity, this chapter also considers whether consumer participation is engendering a sense of belonging as information is shared online, thus enhancing the decision-making process; or is itturning the consumer into a market researcher, working for free in the cultivation of a more transparent marketplace with businesses then drawing upon this information to provide themselves with a more competitive edge based on consumers’ comments and findings? In this context, the chapter asks, is the rise of online ‘prosumer’ activity a positive outcome of convergence culture in that the fusion of participatory culture and collective intelligence now allows the marketplace to be shaped for the benefit of all, or only for the enhancement of a minority?

Toxicity accounts for approximately 30% of compound failures during clinical trials. There is therefore a need for novel approaches to assess the safety of new drugs more reliably. In vivo imaging is widely used in the pharmaceutical industry to assess efficacy in both animal models and during clinical trials; however, its impact on the safety evaluation of new chemical entities has not yet been fully explored. This chapter provides an overview of the benefits that magnetic resonance imaging and spectroscopy (MRI/S) can bring to the safety evaluation of pharmaceuticals in particular in providing reproducible, non‐invasive biomarkers of either harm or lack of harm, which have both animal welfare and translational impact. Particular focus is placed on the assessment of hepatic and cardiac toxicity, which are major contributors to drug attrition due to safety issues.

Older consumers have long been the ‘invisible majority’ in advertising despite the rapid increase in an ageing population. A significant proportion of this population have high levels of disposable income, even in times of recession, but advertisers are not encouraging them to part with it. This paper intends to find out why advertisers have been slow or struggle to target older consumers effectively. The aims of this study are two-fold. First, it explores the portrayal and representation of older consumers in Tesco's ‘Dotty’ campaign and Marks & Spencer's (M&S) ‘Twiggy’ campaign, with special reference to the use of celebrities. The second aim is to demonstrate how the focus has shifted from the more traditional, negative stereotyping (Tesco campaign) to a more progressive approach, presenting aspirational images that older consumers can identify with (M&S campaign). Although both campaigns were effective in terms of increasing profits, this paper suggests that the ongoing M&S example of using older celebrities in advertising campaigns demonstrates a more effective creative strategy that is in tune not only with a growing population of older consumers but is also especially applicable in times of economic uncertainty.

Introduction: While immunosuppression for solid organ transplant is associated with an increased risk of lymphoproliferative disease (LPD), this has been more difficult to establish in autoimmune disorders, even though patients are often treated with similar agents. One reason is that autoimmune disease may elevate baseline LPD risk. However, associations have been shown with certain rare types of LPD; most strikingly hepatosplenic lymphoma, now known to occur as a consequence of anti-TNF-alpha therapy in young men with inflammatory bowel disease (IBD) (J Ped Gast Nutr. 2007; 44:265-7). We have noticed a rise in the incidence of another rare lymphoma in autoimmune disease patients: primary central nervous system (PCNS) LPD. Six cases have been diagnosed at our institution since 2010, with none before that dating back to onset of electronic records in 1986. All of these patients were taking mycophenolate mofetil (MMF) and/or thiopurines. A similar rise in reported cases has been seen in the literature (Fig 1) with suggestion of but no direct association with drug treatment shown. We systematically investigated this trend. Methods: We searched our pathology database to identify all LPD cases diagnosed over a 28-year period in patients treated for autoimmune disease as well as all similar cases involving the CNS reported in the literature over the past 40 years. Statistical analyses were performed using the Fisher's exact test. Results: We identified 44 cases of LPD arising in patients treated for autoimmune disease, including 6 with PCNS disease (Table 1). Of LPDs in patients on anti-TNF-alpha agents, 4/5 had a T-cell phenotype, and 3 had IBD. By contrast, in patients who developed LPD while taking methotrexate, the majority for rheumatoid arthritis, only 1/18 had a T-cell phenotype. Instead they were categorized as polymorphous, Hodgkin or large B-cell morphologies, which were frequently EBV-positive (67%), but never involved the brain (0/18). The LPDs arising in patients on MMF and/or thiopurines showed a similar morphologic profile but were more likely to involve the CNS. In particular, MMF was significantly associated with PCNS compared to non-CNS disease (p We reviewed all cases of CNS LPD in patients treated for autoimmune disease reported in the literature (34 reports, 40 patients), including 32 with PCNS LPD and 8 with secondary CNS involvement. The vast majority of PCNS cases arose in patients taking MMF and/or thiopurines (29/32), but only MMF was significantly associated with primary compared to secondary CNS involvement (p Conclusions: While the overall risk of LPD in the context of autoimmune disease treatment has been controversial, the interaction between drug type and individual patient characteristics may dramatically increase risk for certain lymphomas. We now demonstrate a significant association between use of MMF and PCNS LPD, which appears to cluster in patients with a history of SLE, MG or IBD. Of interest, all 3 autoimmune patients in the JHH database who developed PCNS LPD following solid organ transplant (not shown) also had SLE. While methotrexate never produced a PCNS LPD in our series, it has been infrequently found in the literature. There is no evidence of an increased baseline risk of PCNS LPD in autoimmune patients; indeed, only one reported case in an untreated patient could be identified in the literature (J Rheum 1978; 5:75-78). In addition, EBV-associated PCNS lymphoma is virtually always seen in the context of immunosuppression. Further investigation into the increased risk of specific types of LPD with immunosuppressive treatment is warranted with significant implications for tailoring treatment options. Table 1. Demographics of JHH and Reported CNS Cases ('*' p Disclosures Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding.

The Arnold Centre for young children and their families is the first of its kind in Rotherham, housing a large nursery school and much more. Helen Powell explains.

The rise of the service sector in post-industrial Britain has brought with it a new requisite skill, namely, ‘emotional labour’ defined as ‘the management of feeling to create a publicly observable facial and bodily display; emotional labour is sold for a wage and therefore has an exchange value’ (Hochschild, 2003, p. 7). In this context, the financial service industries deal with our insecurities and anxieties; the travel industry our fantasies and dreams; the entertainment industries our routes of escapism. Service provision becomes foregrounded in advertising campaigns, store interactions and after-sales customer care, all of which concentrate on the management of the consumer’s emotions. This approach relies initially upon finding a point of access to the consumer’s heart and then building upon this connection through the increased personalisation of service provision. Managed successfully, it has an important value within the marketplace, namely, the generation of loyalty and trust. However, with every market sector proliferated by choice and intense competition, more brands are seeking to harness consumer constancy through access to and mobilisation of our emotions. That is to say, exploiting the capacity of the brand to make a particular emotional impact on the consumer through various points of interaction.

The features of interest that make Poole Harbour internationally important are explained and the significance of Poole Harbour in its context as part of a network of special sites across Europe is discussed. The Habitats Regulations make special provisions for European Marine Sites and the requirements of Regulations 33 and 34 in particular are explained.

This correlational study was designed to determine if successful completion of the associate degree nursing program and success on the NCLEX-RN were correlated to scores on the Educational Resources, Inc. NET and Pre-RN Examinations. Data were collected from the educational records of the sixty-eight successful graduates from the fall 2001 class. This study found composite scores on the NET and Pre-RN were statistically significant, and were useful in predicting success on the NCLEX-RN. Consistent with the literature, this study found standardized measures and educational records may be useful screening tools for admission to nursing school, to predict success in the nursing program, and the NCLEX-RN. Faculty may utilize these findings in advising students, for developing support services and to assist students in developing an action plan to prepare for the NCLEX-RN. As suggested by sample size and correlations, a replication study was designed.

Convenient techniques for measuring rates of bone turnover have been developed in recent years with the advent of biochemical markers of bone metabolism. One recent of these techniques is a collection method and quantitative enzyme immunoassay for free pyridinoline crosslinks in human sweat. The concentrations of pyridinoline crosslinks in 5-day sweat collections and first morning void and 24-hour urine collections from healthy subjects and subjects with established metabolic bone disorders were determined. T-scores were higher in the sweat system than in the urine system by up to 10-fold in postmenopausal subjects, women with hyperparathyroidism, and subjects with postmenopausal osteoporosis. For subjects with postmenopausal osteoporosis, receiver-operating characteristic curve analysis yielded areas under the curve of 0.699, 0.629, and 0.520 for sweat pyridinoline, first morning void urine pyridinoline, and 24 hour urine pyridinoline respectively. The areas under the curve of the sweat and first morning void urine measurements were significantly greater (p

Idiosyncratic drug toxicity is a major complication of drug therapy and drug development. Such adverse drug reactions (ADRs) include anaphylaxis, blood dyscrasias, hepatotoxicity and severe cutaneous reactions. They are usually serious and can be fatal. At present, prediction of idiosyncratic ADRs at the preclinical stage of drug development is not possible because there are no suitable animal models and we do not understand the basic mechanisms involved in the toxicity when it does occur in man. Many idiosyncratic reactions appear to have an immunological aetiology. For example, there is increasing evidence for the role of T lymphocytes in severe skin reactions. Nevertheless, the sequence of events by which a simple chemical can elicit severe tissue damage remains poorly understood and alternative novel mechanisms of toxicity must also be explored. The purpose of this article will be to review the currently accepted mechanisms of idiosyncratic drug toxicity at the chemical and the molecular levels. In particular, we will consider how recent advances in cellular immunology and molecular biology can improve our understanding of both the chemical and clinical aspects of drug hypersensitivity. Recent advances in the role of both inter- and intra-cellular signalling in the regulation of the immune response to drugs and their metabolites will be discussed. The long-term aim of such research is to provide test systems for the evaluation of drug safety and patient susceptibility to idiosyncratic drug toxicity.

Cytochrome P4502E1 (CYP2E1) is constitutively expressed in human liver and is responsible for the metabolic bioactivation of a wide variety of xenobiotics, including a number of protoxins and procarcinogens. CYP2E1 expression is regulated at several levels including pre-transcriptional, transcriptional and post-transcriptional levels, and any variation in enzyme concentration and hence activity may represent increased risk of toxicity or carcinogenicity. We have investigated variability in the levels of CYP2E1 mRNA, protein and functional activity in a human liver bank, and attempted to relate these parameters to the RsaI restriction fragment length polymorphism in the 5'-flanking region. Variation in CYP2E1 mRNA (18-fold) was greater than the variation seen in CYP2E1 protein (twofold) and functional activity (fourfold) determined using two probe substrates, chlorzoxazone and p-nitrophenol. Although protein and functional activity showed a significant correlation (r = 0.93 and r = 0.83 for chlorzoxazone and p-nitrophenol, respectively), there was no correlation between any of these parameters and mRNA levels. Also, the variation in CYP2E1 activity could not be directly accounted for by the RsaI polymorphism in our samples. In conclusion, our results are consistent with a complex regulation of CYP2E1 and the fact that it is highly conserved in the human population. The absence of a relationship between the RsaI polymorphism and CYP2E1 activity is consistent with other studies performed in Caucasians, but does not exclude an effect of this polymorphism on inducibility of CYP2E1.