Expression of multidrug resistance markers ABCB1 (MDR-1/P-gp) and ABCC1 (MRP-1) in renal cell carcinoma.

Background Renal cell carcinoma patients respond poorly to conventional chemotherapy, this unresponsiveness may be attributable to multidrug resistance (MDR). The mechanisms of MDR in renal cancer are not fully understood and the specific contribution of ABC transporter proteins which have been implicated in the chemoresistance of various cancers has not been fully defined in this disease. Methods In this retrospective study the expression of two of these transporter efflux pumps, namely MDR-1 P-gp (ABCB1) and MRP-1 (ABCC1) were studied by immunohistochemistry in archival material from 95 renal cell carcinoma patients. Results In the first study investigating MDR-1 P-gp and MRP-1 protein expression patterns in renal cell carcinoma patients, high levels of expression of both efflux pumps are observed with 100% of tumours studied showing MDR-1 P-gp and MRP-1 positivity. Conclusion Although these findings do not prove a causal role, the high frequency of tumours expressing these efflux pumps suggests that they may be important contributors to the chemoresistance of this tumour type.

Detection of glucocorticoid bioactivity in bovine urine samples using a reporter gene assay.

The illegal use of anabolic substances in the meat producing industry is an ongoing problem due to the continual production of new synthetic compounds and/or the practice of low-level cocktail administration to avoid detection by the surveillance schemes of EU member states National Plan surveillance systems.

We present a highly sensitive reporter gene assay and sample extraction procedure based on a two step solid phase extraction and high performance liquid chromatography, developed for the detection of glucocorticoid abuse in bovine urine. The assay is capable of detecting compounds with glucocorticoid bioactivity and is extremely sensitive with an EC50 of 0.79 ng mL-1 for dexamethasone. New or unknown compounds with glucocorticoid bioactivity and low-level cocktail mixtures are detectable by this assay.

Cross-reactivity data for a range of 11ß-hydroxyglucocorticoids has been provided. This assay shows low interference from the 11-keto prohormones and other steroidal hormones. The assay may be suitable for application in other matrices such as hair. In conclusion this screening assay offers advantages over existing analytical techniques.

Inquiring into Non-Accidental Child Deaths: Reviewing the Review Process

There is significant public and professional interest in the non-accidental death of children where abuse and neglect are suspected of being contributory factors. Systems for reviewing these deaths have been developed in each of the four jurisdictions within the UK. The main aims are to ensure that individuals and professionals are held to account if practice falls below the expected standard, whilst also seeking to strengthen the systems for protecting children through reflecting on what lessons, if any, can be learnt from the death of a child through abuse or neglect. Recently, the benefit of such inquiries and the quality of serious case reviews have come under scrutiny. In this paper, the authors report the findings of a Delphi study that sought to explore how the process of conducting reviews following the death of a child could be improved through seeking the views of experienced professionals responsible for child protection in Northern Ireland. The authors conclude that the system does command professional support, but could be improved through greater attention to process issues and a stronger emphasis on translating learning into action. In common with research looking at other recent practice developments, there is a need to focus on process indicators as a means to ensuring that well intentioned policies are translated into workable and functioning practices.

‘Making Older People Equal: Reforming the Law on Access to Education and Other Services’

Age-based discrimination in the supply of goods and services (including educational services) has only very recently been outlawed in the United Kingdom by the Equality Act 2010, the relevant sections of which have not yet been brought into force. This paper critically considers the Act and its implications, as well as the current proposal for an EU Directive on Goods and Services.The greatest immediate potential of the Equality Act lies in the general prohibition against age discrimination and the scope of the exceptions to it. The paper argues that exceptions permitting service providers to discriminate against older people (i.e. negative exceptions) should be very specifically set out in the reforming legislation.There should be no general defence to a claim of age discrimination based around the concept of ‘reasonableness’, which would not be consistently interpreted by courts and tribunals in a way that steers clear of traditional ageist assumptions and stereotyping.The paper argues that service providers should be permitted to discriminate in favour of older people (i.e. make positive exceptions) if the reason for doing do so satisfi es legislative criteria which are designed, amongst other things, to meet the particular needs of older persons or to promote social inclusion. Under this proposal, preferential treatment such as age-related concessionary fees for adult education courses and programmes would be lawful.

Fasciola hepatica: Histological changes in the reproductive structures of triclabendazole (TCBZ)-sensitive and TCBZ-resistant flukes after treatment in vivo with TCBZ and the related benzimidazole derivative, Compound Alpha

Twenty-four shed-reared lambs were each infected orally with 250 metacercariae of Fasciola hepatica, using either the triclabendazole (TCBZ)-sensitive Cullompton isolate or the TCBZ-resistant Sligo isolate. Twelve weeks after infection the lambs were treated with TCBZ (10 mg/kg) or with the experimental fasciolicide, Compound Alpha (Cpd alpha), a benzimidazole derivative of TCBZ (15 mg/kg). The lambs were euthanised 48,72 and 96 h after TCBZ treatment, or 24, 48 and 72 h after Cpd a treatment, and flukes were collected from the liver and/or gall bladder of each animal. Untreated animals harbouring 12-week infections were euthanised 24 h after administration of anthelmintic to the treatment groups, and the untreated flukes provided control material. A semi-quantitative assessment of the degree of histological change induced by the two drugs after different times of exposure was achieved by scoring the intensity of three well-defined lesions that developed in the testes and uteri of a representative sample of flukes from each lamb. In general, it was found that in those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles), there was progressive loss of cell content due to apparent failure of cell division to keep pace with expulsion of the mature or effete products. Further, actively dividing cell types tended to become individualised, rounded and condensed, characteristic of apoptotic cell death. Protein synthetic activity was apparently inhibited in the Mehlis' secretory cells. In the uterus, where successful formation of shelled eggs represents the culmination of a complex sequence of cytokinetic, cytological and synthetic activity involving the vitelline follicles, the ovary and the Mehlis' gland, histological evidence indicating failure of ovigenesis was evident from 24 h post-treatment onwards. The development of these lesions may be related to the known antitubulin activity of the benzimidazole class of anthelmintics, to the induction of apoptosis in cells where mitosis or meiosis has aborted due to failure of spindle formation, and to drug-induced inhibition of protein synthesis. The semi-quantitative findings indicated that Cpd a is slightly less efficacious than TCBZ itself in causing histological damage to the reproductive structures of TCBZ-sensitive flukes, and that, like TCBZ, it caused no histological damage in flukes of the TCBZ-resistant isolate. This study illustrates the potential utility of histological techniques for conveniently screening representative samples of flukes in field trials designed to validate instances of drug resistance or to test the efficacy of new products against known drug-resistant and drug-susceptible fluke isolates. It also provides reference criteria for drug-induced histopathological changes in fluke reproductive structures which may aid interpretation of TEM findings. (C) 2009 Elsevier B.V. All rights reserved.

Welfare epidemiology as a tool to assess the welfare impact of inherited defects on the pedigree dog population

The effect that breed standards and selective breeding practices have on the welfare of pedigree dogs has recently come under scrutiny from both the general public and scientific community. Recent research has suggested that breeding for particular aesthetic traits, such as tightly curled tails, highly domed skulls and short muzzles predisposes dogs with these traits to certain inherited defects, such as spina bifida, syringomyelia and brachycephalic airway obstruction syndrome, respectively. Further to this, there is a very large number of inherited diseases that are not related to breed standards, which are thought to be prevalent, partly as a consequence of inbreeding and restricted breeding pools. Inherited diseases, whether linked to conformation or not, have varying impact on the individuals affected by them, and affect varying proportions of the pedigree dog population. Some diseases affect few breeds but are highly prevalent in predisposed breeds. Other diseases affect many breeds, but have low prevalence within each breed. In this paper, we discuss the use of risk analysis and severity diagrams as means of mapping the overall problem of inherited disorders in pedigree dogs and, more specifically, the welfare impact of specific diseases in particular breeds.

Inherited defects in pedigree dogs. Part 2: Disorders that are not related to breed standards

Recent debate concerning health problems in pedigree animals has highlighted gaps in current knowledge of the prevalence, severity and welfare implications of deleterious inherited traits within the pedigree dog population. In this second part of a two-part review, inherited disorders in the top 50 UK Kennel Club registered breeds were researched using systematic searches of existing databases. A set of inclusion and exclusion criteria, including an evidence strength scale (SEHB), were applied to search results. A total of 312 non-conformation linked inherited disorders was identified, with German shepherd dogs and Golden retrievers associated with the greatest number of disorders. The most commonly reported mode of inheritance was autosomal recessive (71%; 57 breed-disorder combinations), and the most common primarily affected body system was the nervous sensory system. To provide a true assessment of the scale of inherited disorders in the pedigree dogs studied more effort is required to collect accurate prevalence data.