Different distribution of adriamycin in normal and leukaemic rats.

Adriamycin (ADR) accumulates in well-perfused organs in the rat. This effect is especially evident for long periods in marrow and spleen of healthy animals. In rats bearing the Brown Norway Acute Myeloid Leukaemia (BNML) the in vivo distribution is significantly different. Maximum ADR levels in those organs which are morphologically infiltrated by leukaemic cells are significantly lower than in normal rats, while the persistence of measurable ADR concentrations does not change. On the contrary, ADR concentrations in organs not infiltrated by leukaemic cells are the same or slightly higher than in normal rats. Possible causes for these differences are either the differential properties of normal and leukaemic cells in their uptake and excretion of ADR, or anatomical and vascular changes. It is evident that, significantly different from normal. This observation may help in the prevention of toxicity by drug monitoring in serum

Retrieval Contexts and the Concreteness Effect: Dissociations in Memory of Concrete and Abstract Words

Decades of research on the concreteness effect, namely better memory for concrete as compared with abstract words, suggest it is a fairly robust phenomenon. Nevertheless, little attention has been given to limiting retrieval contexts. Two experiments evaluated intentional memory for concrete and abstract word lists in three retrieval contexts: free recall, explicit word-stem completion, and implicit word-stem completion. Concreteness effects were observed in free recall and in explicit word-stem completion, but not in implicit word-stem completion. These findings are consistent with both a bidirectional version of the relational-distinctiveness processing framework (Ruiz-Vargas, Cuevas, & Marschark, 1996) and a second framework combining insights from dual coding theory (Paivio, 1971, 1986) and the transfer appropriate processing framework (Roediger, Weldon, & Challis, 1989). Also, consistent with the relational-distinctiveness framework, the second experiment suggested that concreteness effects might depend on relational processing at encoding: Concreteness effects were observed in explicit memory for related word lists but not for unrelated word lists. © 2005 Psychology Press Ltd

Immunomagnetic t-lymphocyte depletion (ITLD) of rat bone marrow using OX-19 monoclonal antibody

Graft versus host disease (GVHD) may be abrogated and host survival prolonged by in vitro depletion of T lymphocytes from bone marrow (BM) prior to allotransplantation. Using a mouse anti-rat pan T-lymphocyte monoclonal antibody (0×19) bound to monosized, magnetic, polymer beads, T lymphocytes were removed in vitro from normal bone marrow. The removal of the T lymphocytes was confirmed by flow cytometry. Injection of the T-lymphocyte-depleted bone marrow into fully allogeneic rats prevents the induction of GVHD and prolongs host survival. A highly efficient technique of T-lymphocyte depletion using rat bone marrow is described. It involves the binding of OX-19, a MoAb directed against all rat thy-mocytes and mature peripheral T lymphocytes, to monosized, magnetic polymer spheres. Magnetic separation of T lymphocytes after mixing the allogeneic bone marrow with the bead/OX-19 complex provides for a simple, rapid depletion of T lymphocytes from the bone marrow. In vitro studies using flow cytometry and the prevention of GVHD in a fully allogeneic rat bone marrow model have been used to demonstrate the effectiveness of the depletion procedure. © 1989 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

An ex-ante analysis of transport impacts of a distance-based heavy goods vehicle charge in the Netherlands

In 2017, the newly installed Dutch government announced in its coalition agreement to introduce a distance-based heavy goods vehicle charge, similar to the charges levied in other European countries. To study the possible transport impacts, we applied available models and methods in preparation for the introduction of this truck charge in the Netherlands in 2023, in order to present decision information to the government on different aspects of the charge. In this paper we present the analysis of different implementation scenarios for a distance-based truck charge. Different behavioural responses can be expected in terms of freight transport demand, mode choice, logistic efficiency, and route choice. Many studies however lack sufficient detail to properly describe the impact of road charges for HGV on OD flows and freight traffic. In our contribution we explore the bandwidth of impacts of different pricing schemes, using strategic transport models for freight demand and traffic assignment, with detailed modal split and route choice models, ensuring a proper representation of generalsed transport costs. We explain how we use available transport models in an overarching analytical framework to make a comprehensive impact assessment of the different responses, and to decompose the impacts on the different responses. Final impacts are quantified in terms of freight demand (spatial pattern of transport flows), modal split and traffic flows (route choice, and congestion). Depending on the pricing scenario the tonne kilometres decrease by 0.4%–4.8% on average. The modal shift impacts are stronger on longer transport distances: this is explained both by the larger impact of a distance-based charge on these routes, and by higher substitution possibilities to barge or rail. The results indicate that the overall impacts of the introduction of the different charging alternatives are moderate. However, the network impacts at local level can be substantial due to the impact of re-routing of truck trips to avoid charge

Climate change challenges for central banks and financial regulators

The academic and policy debate regarding the role of central banks and financial regulators in addressing climate-related financial risks has rapidly expanded in recent years. This Perspective presents the key controversies and discusses potential research and policy avenues for the future. Developing a comprehensive analytical framework to assess the potential impact of climate change and the low-carbon transition on financial stability seems to be the first crucial challenge. These enhanced risk measures could then be incorporated in setting financial regulations and implementing the policies of central banks

Debating the Desirability of New Biomedical Technologies: Lessons from the Introduction of Breast Cancer Screening in the Netherlands

Health technology assessment (HTA) was developed in the 1970s and 1980s to facilitate decision making on the desirability of new biomedical technologies. Since then, many of the standard tools and methods of HTA have been criticized for their implicit normativity. At the same time research into the character of technology in practice has motivated philosophers, sociologists and anthropologists to criticize the traditional view of technology as a neutral instrument designed to perform a specific function. Such research suggests that the tools and methods of more traditional forms of HTA are often inspired by an ‘instrumentalist’ conception of technology that does not fit the way technology actually works. This paper explores this hypothesis for a specific case: the assessments and deliberations leading to the introduction of breast cancer screening in the Netherlands. After reconstructing this history of HTA ‘in the making’ the stepwise model of HTA that emerged during the process is discussed. This model was rooted indeed in an instrumentalist conception of technology. However, a more detailed reconstruction of several episodes from this history reveals how the actors already experienced the inadequacy of some of the instrumentalist presuppositions. The historical case thus shows how an instrumentalist conception of technology may result in implicit normative effects. The paper concludes that an instrumentalist view of technology is not a good starting point for HTA and briefly suggests how the fit between HTA methods and the actual character of technology in practice might be improved

Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumour growth

BACKGROUND: The outgrowth of new vessels – angiogenesis – in the tumour mass is considered to be a limiting factor of tumour growth. To inhibit the matrix lysis that is part of the tumour angiogenesis, we employed the chimeric protein mhATF-BPTI, composed of the receptor binding part of the urokinase (ATF) linked to an inhibitor of plasmin (BPTI). METHODS: For delivery, recombinant adenovirus encoding the transgene of interest was injected intravenously or locally into the tumour. The anti tumour effect of this compound was compared to that of human endostatin and of mhATF alone in two different rat bronchial carcinomas growing either as subcutaneous implants or as metastases. RESULTS: Significant inhibition of the tumour growth and decrease of the number of lung metastasis was achieved when the concentration of mhATF-BPTI at the tumour site was above 400 of ng / g tissue. This concentration could be achieved via production by the liver, only if permissive to the recombinant adenovirus. When the tumour cells could be transduced, local delivery of the vector was enough to obtain a response. In the case of metastasis, the capacity of the lung tissue to concentrate the encoded protein was essential to reach the required therapeutic levels. Further, endostatin or mhATF could not reproduce the effects of mhATF-BPTI, at similar concentrations (mhATF) and even at 10-fold higher concentration (endostatin). CONCLUSION: The ATF-BPTI was shown to inhibit tumour growth of different rat lung tumours when critical concentration was reached. In these tumour models, endostatin or ATF induce almost no tumour response

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs) are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected. METHODOLOGY/PRINCIPAL FINDINGS: We aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC) class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID) mice could be attained provided that recipients' natural killer (NK) cells were depleted prior to cell transplantation. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable

Primary care nurses' experiences of how the mass media influence frontline healthcare in the UK

Background: Mass media plays an important role in communicating about health research and services to patients, and in shaping public perceptions and decisions about health. Healthcare professionals also play an important role in providing patients with credible, evidence-based and up-to-date information on a wide range of health issues. This study aims to explore primary care nurses' experiences of how mass media influences frontline healthcare.<p></p> Methods: In-depth telephone interviews were carried out with 18 primary care nurses (nine health visitors and nine practice nurses) working in the United Kingdom (UK). Interviews were recorded and transcribed. The data was analysed using thematic analysis, with a focus on constant comparative analysis.<p></p> Results: Three themes emerged from the data. First, participants reported that their patients were frequently influenced by controversial health stories reported in the media, which affected their perceptions of, and decisions about, care. This, in turn, impinged upon participants' workloads as they had to spend additional time discussing information and reassuring patients. Second, participants also recalled times in their own careers when media reports had contributed to a decline in their confidence in current healthcare practices and treatments. Third, the participants in this study suggested a real need for additional resources to support and expand their own media literacy skills, which could be shared with patients.<p></p> Conclusion: In an ever expanding media landscape with greater reporting on health, nurses working in the primary care setting face increasing pressure to effectively manage media stories that dispute current health policies and practices. These primary care nurses were keen to expand their media literacy skills to develop critical autonomy in relation to all media, and to facilitate more meaningful conversations with their patients about their health concerns and choices.<p></p&gt