PBDE-47 and PBDE mixture (DE-71) toxicities and liver transcriptomic changes at PND 22 after in utero/postnatal exposure in the rat.

Pentabromodiphenyl ethers (PBDE) are found in human tissue, in household dust, and in the environment, and a particular concern is the potential for the induction of cancer pathways from these fat-soluble persistent organic pollutants. Only one PBDE cancer study has been conducted and that was for a PBDE mixture (DE-71). Because it is not feasible to test all PBDE congeners in the environment for cancer potential, it is important to develop a set of biological endpoints that can be used in short-term toxicity studies to predict disease outcome after long-term exposures. In this study, PBDE-47 was selected as the test PBDE congener to evaluate and compare toxicity to that of the carcinogenic PBDE mixture. The toxicities of PBDE-47 and the PBDE mixture were evaluated at PND 22 in Wistar Han rat (Crl: WI (Han)) pups after in utero/postnatal exposure (0, 0.1, 15, or 50 mg/kg; dams, GD6-21; pups, PND 12-PND 21; oral gavage daily dosing). By PND 22, PBDE-47 caused centrilobular hypertrophy and fatty change in liver, and reduced serum thyroxin (T4) levels; similar effects were also observed after PBDE mixture exposure. Transcriptomic changes in the liver included induction of cytochrome p450 transcripts and up-regulation of Nrf2 antioxidant pathway transcripts and ABC membrane transport transcripts. Decreases in other transport transcripts (ABCG5 & 8) provided a plausible mechanism for lipid accumulation, characterized by a treatment-related liver fatty change after PBDE-47 and PBDE mixture exposure. The benchmark dose calculation based on liver transcriptomic data was generally lower for PBDE-47 than for the PBDE mixture. The up-regulation of the Nrf2 antioxidant pathway and changes in metabolic transcripts after PBDE-47 and PBDE mixture exposure suggest that PBDE-47, like the PBDE mixture (NTP 2016, TR 589), could be a liver toxin/carcinogen after long-term exposure.

Blood gene expression profiling of an early acetaminophen response.

Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4 g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing, and 12 genes were detected with expression profiles significantly altered within 24 h. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure, and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.

Genomic indicators in the blood predict drug-induced liver injury.

Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic indicators to a form of chemically induced liver injury. We then use the genomic indicators from the blood as biomarkers for prediction of acetaminophen-induced liver injury and show that the cross-tissue predictability of a response to the pharmaceutical agent (accuracy as high as 92.1%) is better than, or at least comparable to, that of non-therapeutic compounds. We provide a database of gene expression for the highly informative predictors, which brings biological context to the possible mechanisms involved in DILI. Pathway-based predictors were associated with inflammation, angiogenesis, Toll-like receptor signaling, apoptosis, and mitochondrial damage. The results show for the first time and support the hypothesis that genomic indicators in the blood can serve as potential diagnostic biomarkers predictive of DILI.

Tetrabromobisphenol A activates the hepatic interferon pathway in rats.

Tetrabromobisphenol A (TBBPA) is a widely used flame retardant in printed circuit boards, paper, and textiles. In a two-year study, TBBPA showed evidence of uterine tumors in female Wistar-Han rats and liver and colon tumors in B6C3F1 mice. In order to gain further insight into early gene and pathway changes leading to cancer, we exposed female Wistar Han rats to TBBPA at 0, 25, 250, or 1000mg/kg (oral gavage in corn oil, 5×/week) for 13 weeks. Because at the end of the TBBPA exposure period, there were no treatment-related effects on body weights, liver or uterus lesions, and liver and uterine organ weights were within 10% of controls, only the high dose animals were analyzed. Analysis of the hepatic and uterine transcriptomes showed TBBPA-induced changes primarily in the liver (1000mg/kg), with 159 transcripts corresponding to 132 genes differentially expressed compared to controls (FDR=0.05). Pathway analysis showed activation of interferon (IFN) and metabolic networks. TBBPA induced few molecular changes in the uterus. Activation of the interferon pathway in the liver occurred after 13-weeks of TBBPA exposure, and with longer term TBBPA exposure this may lead to immunomodulatory changes that contribute to carcinogenic processes.

Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen.

The diagnosis of drug-induced liver injury is hindered by the limited utility of clinical chemistries. We have shown that hepatotoxicants can produce peripheral blood transcriptome "signatures" (PBTS) in rodents and humans. In this study, 42 adults were treated with acetaminophen (APAP; 1 g every 6 hours) for seven days, followed by three days of placebo. Eleven subjects received only placebo. After five days, 12 subjects (30%) had increases in serum alanine aminotransferase (ALT) levels ("responders"). PBTS of 707 and 760 genes, respectively, could distinguish responders and nonresponders from placebos. Functional analysis of the responder PBTS revealed increased expression of genes involved in TH2-mediated and innate immune responses, whereas the nonresponders demonstrated increased gene expression consistent with a tolerogenic immune response. Taken together, these observations suggest that the clinical subjects with transient increases in serum ALT failed to maintain or intensify a hepatic tolerogenic immune response.

Comparison of a new ovine antigen binding fragment (Fab) antivenin for United States Crotalidae with the commercial antivenin for protection against venom-induced lethality in mice.

Snake venom poisoning is a medical emergency requiring immediate attention and the exercise of considerable judgment. Of the estimated 8,000 bites inflicted by venomous snakes in the United States each year, approximately 6,000 are treated with commercial antivenin. The only commercially available antivenin for North American Crotalidae envenomation is Antivenin (Crotalidae) Polyvalent (equine origin) (ACP; Wyeth Laboratories, Philadelphia, PA). A common complication is the high incidence of hypersensitivity reactions, occurring in more than 75% of patients treated with ACP. To minimize these side effects, a novel, affinity-purified, antigen binding fragment (Fab) antivenom (FabAV) for Crotalidae venom poisoning has been produced from the sera of sheep. The new product is Antivenin Polyvalent Crotalid (Ovine) Fab (Crotab; Therapeutic Antibodies, Inc., Nashville, TN). The current report compares the potencies in mice of FabAV and ACP against venom-induced lethality. The results indicate that FabAV is 3.1-9.6 times more potent than ACP for the prevention of lethality of the nine United States venoms tested. For one of the venoms, Crotalus viridis helleri, FabAV was efficacious while ACP was not.

Peripheral benzodiazepine binding sites in Nb 2 node lymphoma cells: effects on prolactin-stimulated proliferation and ornithine decarboxylase activity.

[3H]Ro 5-4864 binds to Nb 2 node lymphoma cells in a specific saturable and reversible fashion. Scatchard analysis of specific binding data reveals a single, homogeneous class of whole cell binding sites with a Kd of 3.94 +/- 0.22 nM and a Bmax value of 155 +/- 11 fmol (Ro 5-4864 bound)/2 x 10(6) cells. Ro 5-4864, a reported peripheral benzodiazepine receptor agonist both inhibits (10(-6) M) and potentiates (10(-9) M) the mitogenic action of prolactin on the Nb 2 node lymphoma cells. Interestingly, PK 11195, an antagonist, potentiates (10(-9) M) the mitogenic activity of prolactin in these cells. The actions of both Ro 5-4864 and PK 11195 seem to be mediated through a common receptor type since a 10(-6) M concentration of either agent will block the others potentiating action. Furthermore, the simultaneous addition of a 10(-9) M concentration of Ro 5-4864 and PK 11195 does not further increase the effect on prolactin stimulated mitogenesis. Clonazepam, a central benzodiazepine receptor agonist has no effect on prolactin-stimulated mitogenesis in this system. These data suggest that the Nb 2 node lymphoma cells possess a peripheral-type benzodiazepine receptor. In these cells, this receptor seems to serve the function of modulating the ability of the growth factor, prolactin to initiate the mitogenic process. These studies also suggest that Ro 5-4864 is functioning as a partial agonist rather than a 'pure' agonist for the peripheral benzodiazepine receptor in this system.

Reduction of interferon-gamma as a critical mechanism by which ultraviolet radiation prevents tumor rejection.

Mice irradiated with UVB, unlike nonirradiated mice, are highly susceptible to syngeneic, immunogenic tumors induced by UVB irradiation or by chemicals. We postulated that UV induced susceptibility to immunogenic tumors results from a reduction in host capacity to generate an interferon (IFN)-gamma immune response to tumor antigens. Shaved BALB/c mice were exposed to 6 x 10(5) J m-2 of UVB radiation delivered intermittently over 12 weeks. The UVB-irradiated and nonirradiated mice received intradermal injections of UVM12 or BP2 tumor cells. After 0, 1.5, 3, 7 or 21 days, draining lymph nodes were excised. Lymph node cells were incubated with UVM12 or BP2 cells that had received 2.5 Gy of gamma-radiation. After 48 h in culture, supernatants were analyzed for IFN-gamma content by enzyme-linked immunosorbent assay and cellular RNA was extracted for mRNA detection by reverse transcriptase-polymerase chain reaction analysis. At 7 days after tumor injection, draining lymph node cells from nonirradiated control mice secreted significant levels of IFN-gamma and contained at least 0.0729 amol of IFN-gamma mRNA/microgram cDNA upon in vitro exposure to gamma-irradiated tumor cells. Draining lymph node cells removed from UV-irradiated mice contained only 18% as much IFN-gamma mRNA and secreted little or no IFN-gamma when exposed to gamma-irradiated tumor cells. A single injection of antibody directed against murine IFN-gamma rendered normal mice as susceptible as UV-irradiated mice to BP2 tumor cells. Thus, chronic UV irradiation leads to an inability of host tumor draining lymph node cells to mount an IFN-gamma response to tumor antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolactin-stimulated mitogenesis in the Nb2 rat lymphoma cell: lack of protoporphyrin IX effects.

Pharmacological characterization of the Nb2 cell peripheral-type benzodiazepine receptor (PBR) was determined using selected 1,4-benzodiazepines, PK 11195, and protoporphyrin IX (PPIX) to compete for specific [3H] Ro5-4864 binding. These data suggest that PPIX possesses an affinity for the Nb2 cell PBR (Ki = 142 nM). We have previously reported that the peripheral benzodiazepine ligands, Ro5-4864 and PK 11195, modulate prolactin-stimulated mitogenesis in the Nb2 cell(1). In contrast, PPIX, a putative endogenous ligand for the PBR had no effect on prolactin-stimulated mitogenesis in the Nb2 cell over the concentration range from 10(-15) M to 10(-6) M. Taken together these data show that PPIX has an affinity for the Nb2 cell PBR but does not modulate prolactin-stimulated mitogenesis at concentrations which should bind to the Nb2 cell PBR.

Inhibition of DFMO-induced audiogenic seizures by chlordiazepoxide.

Mice given 1% alpha-difluoromethylornithine (DFMO) in the drinking water for 5 weeks developed a hyperactive behavior characterized by uncontrolled running upon stimulation with noise. The running was followed by seizures and sometimes death. These behaviors are characteristic of audiogenic seizures. Strain differences in susceptibility to DFMO-induced audiogenic seizures were observed. The order of sensitivity to this DFMO effect was: C3HeB/FEJ = C3H/HeN > CBA/J = BALB/c. Chronic DFMO treatment was found to deplete whole brain putrescine and spermidine, but not spermine nor gamma-aminobutyric acid (GABA), in the 2 strains of mice analyzed, C3H/HeN and BALB/c. The audiogenic seizures were eliminated by pretreatment with the benzodiazepine, chlordiazepoxide (Librium) (40 mg/kg, ip) 105 minutes prior to testing for seizures.

The nurse teacher's role in the practice setting.

In the light of the education reforms brought about by the implementation of Project 2000 it is essential that nurse teachers critically appraise their role and function. In particular, they need to give careful consideration to their role in relation to the practice setting. Whilst the English National Board (1989) indicate that nurse teachers should retain their clinical competence and be able to teach in both classroom and practice settings, little has been written in respect of the implications of this directive. This paper considers the issue of clinical competence and explore some of the different dimensions of the nurse teacher's role in the practice setting, in respect of teaching, providing educational support and facilitating good practice. Finally, some of the issues relating to the successful fulfilment of this role are identified for consideration.

Preparation of nurses to meet the needs of an ethnically diverse society: educational implications.

In recognizing the multiethnic composition of contemporary society in the UK, this paper considers the implications for nurse education in respect of preparing practitioners who are capable of meeting the needs of an ethnically diverse population. It begins by considering briefly some contextual issues relating to the health needs of ethnic minorities and how they impact upon nursing practice. The literature clearly indicates some of the complexities that nurses face in attempting to deliver care which is responsive to the individual needs of patients in a multicultural context. The question then arises as to how nurse education can most effectively prepare future practitioners. Consideration is given to the curriculum content, methods and approaches that may be utilized together with different teaching and learning strategies. The case is made for the need for nurse educators to also consider the recruitment and support of students from ethnic minority groups, if nursing is to make progress in responding more appropriately to the needs of ethnic minority groups in the UK.

An evaluation of a portfolio as an assessment tool for teaching practice placements.

The experience gained on teaching practice placement forms an important and integral part of nurse teacher preparation courses. The importance of assessing student teacher performance in such practice settings is readily acknowledged (English National Board (ENB) 1988) and successful student teacher performance during teaching practice experience is considered a pre-requisite to granting a licence to practice as a nurse teacher. This article discusses the development and subsequent evaluation of an assessment strategy, incorporating the development of a portfolio, employed on a 2 year degree programme concerned with the preparation of nurse teachers.

Researching in collaboration: a guide to successful partnership.

Having been invited to present a conference paper on the experiences of working in a collaborative research team ( 1 ), we discovered that there was very little in the way of published advice for would-be researchers on developing a research partnership. Confronted with this lack of authoritative guidance we were forced into a reflexive exploration of our own collective experiences of engaging in research. This in itself became a process of self examination and disclosure, through which a number of principles evolved that we could identify as inherent in our working relationship. This paper examines those principles within the context of our current research, opening up for discussion the possibility that such principles could be applied to other research situations in relation to the dynamics of the research team and the process of project management.

Nursing development units: factors influencing their progress.

Nursing development units (NDUs) have long been advocated as 'test-beds' for pioneering leading-edge practice development. This article reports on the findings of a study examining factors influencing the development of NDUs, and, more recently, established multidisciplinary practice development units (PDUs). Individual and focus group interviews were undertaken with key stakeholders involved in six NDUs/PDUs accredited by the University of Leeds. The findings from the study highlight a number of internal and external factors that have impacted upon the progress made by these units. Importantly, the role of the clinical leader, the staffing establishment, organizational infrastructures to facilitate dissemination and the nature of the support from managers and medical staff have all influenced the success of the NDUs/PDUs. In order to ensure the long-term viability of an NDU/PDU it is essential that practice development is planned and managed in a systematic and coordinated way with a full appraisal undertaken of the human, physical and financial resources necessary to implement and disseminate change and that the work of the NDU/PDU is incorporated in the trust's strategic plans in order to ensure organizational support.

Transcultural competence: the challenge for nurse education.

Several recent health policy directives highlight the need to overcome the health disadvantage and discrimination experienced by many members of minority ethnic communities. However, there is ample evidence to indicate that nurses frequently fall short of providing sensitive and appropriate care to minority ethnic patients. If these policy objectives are to be met, it is essential that nurse education provides students with the opportunity to develop transcultural competence. This article examines the current policy context before considering the principles underpinning the development of transcultural competence. It concludes by discussing how nurse education might more effectively prepare nurses to meet the needs of minority ethnic communities.

Cardiac rehabilitation: the needs of South Asian cardiac patients.

There is an indication that South Asian people in the UK experience greater delays than white British populations in obtaining appropriate treatment and intervention despite experiencing higher levels of coronary heart disease (Chaturvedi et al, 1997). Evidence suggests that access to and uptake of UK cardiac rehabilitation services is disproportionately low in South Asian populations (NHS Centre for Reviews and Dissemination, 1998). This article examines the results of an audit of cardiac rehabilitation among cardiac patients of South Asian origin who were admitted to a large city teaching hospital in Sheffield. The results are discussed in the light of current concerns about the adequacy of communication with non-English speaking NHS patients. The implications for access to services and clinical practice are considered.

Evidence-based care: can we overcome the barriers?

Evidence-based care has become the new mantra within the NHS, despite the fact that the concept of applying research to practice has been promoted for several decades. However, literature on the subject suggests that formidable obstacles remain to the integration of research into care delivery. This article describes a study which used Funk et al's (1991a,b) Barriers Scale with a population of nurses in a large teaching hospital in the UK. This scale was specifically developed to identify barriers to the introduction of research into practice, and modified for a UK context. The results suggest that a complex array of barriers exist but that foremost among these is the nature of the organizations within which nurses work. Comparisons are made with data from the USA, and the need to create time for nurses to implement change, and to empower them to do so, is stressed.

Sharing best practice: developing a Web-based database.

This article reports on the development of a web-based interactive database that was designed to facilitate the dissemination of practice development, research and audit projects across a large NHS trust. A multidisciplinary team worked collaboratively to design the database in order to ensure that it incorporated features which made it easy for the end user. Concise structured information on each project was recorded and search facilities incorporated to facilitate access to information. Hyperlinks to other web pages on the Internet and the Trust intranet were created and full reports/publications of projects were included for those who wanted more information. The subsequent implementation across the organization involved promoting the database, helping practitioners develop skills to access information, setting up quality review procedures for projects and evaluating its use. The development of the database has highlighted that time, the availability of computers in clinical areas and skills development are important considerations when taking forward information technology (IT) initiatives.

Pressure damage prevention: basing practice on evidence.

As part of an initiative to develop evidence-based practice at the Northern General Hospital, Sheffield, a three-part project was undertaken. The aims were to identify barriers to using research in nursing, establish a baseline of nurses' knowledge and its influence on their practice in one essential area of nursing care--pressure damage prevention--and develop a strategy for change which took account of the findings from the first two parts of the project. In this article, the authors describe the second part of the project which examined nursing knowledge and practice with reference to the management of pressure damage prevention. The findings are discussed and the authors recommend that nurses integrate into their practice evidence from sources such as systematic reviews.