Ineffective off-label use of recombinant activated factor VII in a case of bone-marrow transplantation-related gastrointestinal bleeding

BACKGROUND: For patients with a normal coagulation system, who experience serious bleeding, sound evidence for recombinant activated factor VII (rFVIIa) as an effective haemostatic agent is only scarcely available so far from controlled clinical trials. In systematic reviews on the clinical use of rFVIIa, treatment failures were only rarely reported. CASE PRESENTATION: We present a 45-year old, Caucasian male with persistent intestinal bleeding due to enterocolitis associated with cytomegalovirus infection and acute graft-versus-host-disease. He had received allogeneic peripheral blood stem cell transplantation from an unrelated HLA-identical donor because of chronic myelogenous leukaemia diagnosed two years earlier. Bleeding started at day 18 after transplantation with bloody diarrhea, which was treated with multiple transfusions of fresh frozen plasma, platelet, and red blood cell concentrates, and continued relentlessly, despite all efforts, including continued transfusions, high-dose prednisolone, broad antibiotic and antiviral coverage, and tranexamic acid. Recombinant FVIIa was started at boluses of 90–120 μg/kg every 4–8 hours. Despite more than 10 doses, recurrent severe bleeding progressed to refractory shock, multiorgan failure and death. CONCLUSIONS: Little can be concluded from single case reports of clinical improvement, because publication bias in favour of positive effects is likely. Our case suggests that rFVIIa is not a panacea, in particular for severe bleeding after bone-marrow transplantation. As long as rigorous, controlled studies or comprehensive registries are lacking, conventional interventions remain the standard of care in non-haemophilic patients with severe bleeding

Extended Gravity Theories and the Einstein-Hilbert Action

I discuss the relation between arbitrarily high-order theories of gravity and scalar-tensor gravity at the level of the field equations and the action. I show that $(2n+4)$-order gravity is dynamically equivalent to Brans-Dicke gravity with an interaction potential for the Brans-Dicke field and $n$ further scalar fields. This scalar-tensor action is then conformally equivalent to the Einstein-Hilbert action with $n+1$ scalar fields. This clarifies the nature and extent of the conformal equivalence between extended gravity theories and general relativity with many scalar fields.Comment: 12 pages, Plain Latex, SUSSEX-AST-93/7-

75 years of Tourism Review: survival by transformation: a perspective article

Purpose: The purpose of this paper is to reconstruct and analyze the long history of Tourism Review and try to outline the future of this journal. Design/methodology/approach: The authors show that Tourism Review has been a good example of multiple life cycles over time and of survival by adaption. Findings: The authors illustrate also how this journal has seen decline, as well as revival, and stagnation, as well as innovation. Originality/value: It is also a proxy of the state and issues of tourism research and publication over 75 years

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia

Apolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart Disease

BACKGROUND: Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls). METHODS: The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a). RESULTS: Triglyceride-carrying ApoC1, ApoC3, and ApoE (apolipoproteins) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM. CONCLUSIONS: Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction

Hospitality entrepreneurs managing quality of life and business growth

The hospitality industry is dominated by small- and medium-sized enterprises (SMEs).They are often led by entrepreneurs who face the challenge of simultaneously managing business decisions and their own wellbeing. The competitiveness of tourism destinations often depends on these entrepreneurs and therefore understanding their motivations and work patterns is critical. Research on individual wellbeing increasingly builds on the concept of quality of life (QoL). Hospitality and tourism literature so far predominantly focused on investigating QoL for tourists and residents, rather than for entrepreneurs’ QoL, even though being key stakeholders in the hospitality industry. Therefore, this study explores the factors influencing hospitality entrepreneurs’ quality of life (“HE-QoL”) and how these relate to business growth. Results of a 380 hospitality entrepreneurs’ survey identify six distinct factors of HE-QoL. Two groups of HE-QoL are identified with significant differences in fitness level activity, entrepreneurial competencies and business growth. Findings lead to recommendations to reduce stress to improve HE-QoL, and to develop entrepreneurial competencies, which help to cope with entrepreneurial challenges. Tourism destinations and politics can support hospitality entrepreneurs in these actions by creating conditions that foster social exchange in regional communities and trust in political and economic stability

Inhibition of profibrotic microRNA-21 affects platelets and their releasate.

Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors

A model of collaborative innovation between local government and tourism operators

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‘Kamikaze’ heritage tourism in Japan: A pathway to peace and understanding?

Reflecting the wider belief that international tourism offers the opportunity to encourage peace and understanding amongst peoples and nations, one objective of Japan’s recent tourism development policy is the enhancement of mutual understanding and the promotion of international peace. The purpose of this paper is to consider the extent to which this objective is achievable, particularly in the context of continuing controversy surrounding the country’s confrontation of its twentieth century military heritage in general and its role in the Pacific War in particular. Based on research at two ‘difficult’ heritage sites, Chiran Peace Museum in Kagoshima Prefecture and Yūshūkan War Museum in Tokyo, it explores specifically how the kamikaze phenomenon is commemorated and interpreted for international visitors, in so doing revealing a significant degree of dissonance at both sites. Not only is a selective narrative of heroic sacrifice presented within a wider revisionist history of the Pacific War but also no attempt is made to acknowledge the prevailing cultural context that might underpin a more nuanced understanding of the kamikaze. Hence, the paper concludes that a meaningful opportunity to enhance international understanding has been missed