On Hemangioblasts in Chicken

Hemangioblasts are bi-potential precursors for blood and endothelial cells (BCs and ECs). Existence of the hemangioblast in vivo by its strict definition, i.e. a clonal precursor giving rise to these two cell types after division, is still debated. Using a combination of mitotic figure analysis, cell labeling and long-term cell tracing, we show that, in chicken, cell division does not play a major role during the entire ventral mesoderm differentiation process after gastrulation. One eighth of cells do undergo at least one round of division, but mainly give rise to daughter cells contributing to the same lineage. Approximately 7% of the dividing cells that contribute to either the BC or EC lineage meet the criteria of true hemangioblasts, with one daughter cell becoming a BC and the other an EC. Our data suggest that hemangioblast-type generation of BC/EC occurs, but is not used as a major mechanism during early chicken development. It remains unclear, however, whether hemangioblast-like progenitor cells play a more prominent role in later development

NIH Disease Funding Levels and Burden of Disease

BACKGROUND: An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time. METHODS: We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization's Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method. RESULTS: In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods. CONCLUSIONS: Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade

Metabolomics to unveil and understand phenotypic diversity between pathogen populations

Visceral leishmaniasis is caused by a parasite called Leishmania donovani, which every year infects about half a million people and claims several thousand lives. Existing treatments are now becoming less effective due to the emergence of drug resistance. Improving our understanding of the mechanisms used by the parasite to adapt to drugs and achieve resistance is crucial for developing future treatment strategies. Unfortunately, the biological mechanism whereby Leishmania acquires drug resistance is poorly understood. Recent years have brought new technologies with the potential to increase greatly our understanding of drug resistance mechanisms. The latest mass spectrometry techniques allow the metabolome of parasites to be studied rapidly and in great detail. We have applied this approach to determine the metabolome of drug-sensitive and drug-resistant parasites isolated from patients with leishmaniasis. The data show that there are wholesale differences between the isolates and that the membrane composition has been drastically modified in drug-resistant parasites compared with drug-sensitive parasites. Our findings demonstrate that untargeted metabolomics has great potential to identify major metabolic differences between closely related parasite strains and thus should find many applications in distinguishing parasite phenotypes of clinical relevance

Estimating the returns to UK publicly funded cancer-related research in terms of the net value of improved health outcomes

© 2014 Glover et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background - Building on an approach developed to assess the economic returns to cardiovascular research, we estimated the economic returns from UK public and charitable funded cancer-related research that arise from the net value of the improved health outcomes. Methods - To assess these economic returns from cancer-related research in the UK we estimated: 1) public and charitable expenditure on cancer-related research in the UK from 1970 to 2009; 2) net monetary benefit (NMB), that is, the health benefit measured in quality adjusted life years (QALYs) valued in monetary terms (using a base-case value of a QALY of GB£25,000) minus the cost of delivering that benefit, for a prioritised list of interventions from 1991 to 2010; 3) the proportion of NMB attributable to UK research; 4) the elapsed time between research funding and health gain; and 5) the internal rate of return (IRR) from cancer-related research investments on health benefits. We analysed the uncertainties in the IRR estimate using sensitivity analyses to illustrate the effect of some key parameters. Results - In 2011/12 prices, total expenditure on cancer-related research from 1970 to 2009 was £15 billion. The NMB of the 5.9 million QALYs gained from the prioritised interventions from 1991 to 2010 was £124 billion. Calculation of the IRR incorporated an estimated elapsed time of 15 years. We related 17% of the annual NMB estimated to be attributable to UK research (for each of the 20 years 1991 to 2010) to 20 years of research investment 15 years earlier (that is, for 1976 to 1995). This produced a best-estimate IRR of 10%, compared with 9% previously estimated for cardiovascular disease research. The sensitivity analysis demonstrated the importance of smoking reduction as a major source of improved cancer-related health outcomes. Conclusions - We have demonstrated a substantive IRR from net health gain to public and charitable funding of cancer-related research in the UK, and further validated the approach that we originally used in assessing the returns from cardiovascular research. In doing so, we have highlighted a number of weaknesses and key assumptions that need strengthening in further investigations. Nevertheless, these cautious estimates demonstrate that the returns from past cancer research have been substantial, and justify the investments made during the period 1976 to 1995.Wellcome Trust, Cancer Research UK, the National Institute of Health Research, and the Academy of Medical Sciences

Arthroscopic observation was useful to detect loosening of the femoral component of unicompartmental knee arthroplasty in a recurrent hemoarthrosis

A case of recurrent hemarthrosis of the knee after a mobile-bearing unicompartmental knee arthroplasty (UKA; Oxford UKA) is described. A 58-year-old man met with a road traffic accident 10 months after UKA. He developed anteromedial pain and hemarthrosis of the knee joint 1 month after the accident, which required multiple aspirations. Physical examination showed no instability. Plain radiograph revealed no signs of loosening. All laboratory data, including bleeding and coagulation times, were within normal limits. Diagnostic arthroscopy demonstrated loosening of the femoral component. Any intraarticular pathology other than nonspecific synovitis was ruled out. The loose femoral component and polyethylene meniscal bearing were revised. Since then, hemarthrosis has not recurred

Understanding fear of opportunism in global prize-based science contests: Evidence for gender and age differences

Global prize-based science contests have great potential for tapping into diverse knowledge on a global scale and overcoming important scientific challenges. A necessary step for knowledge to be utilized in these contests is for that knowledge to be disclosed. Knowledge disclosure, however, is paradoxical in nature: in order for the value of knowledge to be assessed, inventors must disclose their knowledge, but then the person who receives that knowledge does so at no cost and may use it opportunistically. This risk of potential opportunistic behavior in turn makes the inventor fearful of disclosing knowledge, and this is a major psychological barrier to knowledge disclosure. In this project, we investigated this fear of opportunism in global prize-based science contests by surveying 630 contest participants in the InnoCentive online platform for science contests. We found that participants in these science contests experience fear of opportunism to varying degrees, and that women and older participants have significantly less fear of disclosing their scientific knowledge. Our findings highlight the importance of taking differences in such fears into account when designing global prize-based contests so that the potential of the contests for reaching solutions to important and challenging problems can be used more effectively

Chromogranin A, a significant prognostic factor in small cell lung cancer

Chromogranin A (CgA) is a protein present in neuroendocrine vesicles. Small cell lung cancer (SCLC) is considered a neuroendocrine tumour. It is possible to demonstrate CgA expression in SCLC by immunohistochemical methods. Since CgA is released to the circulation it might also work as a clinical tumour marker. We used a newly developed two-site enzyme-linked immunosorbent assay for CgA in plasma from 150 newly diagnosed patients with SCLC. Follow-up was for a minimum of 5 years. Thirty-seven per cent of the patients had elevated pretreatment values and the values were significantly related to stage of disease. Multivariable analysis by Cox's proportional hazard model including nine known prognostic factors disclosed performance status as the most influential prognostic factor followed by stage of disease, CgA and LDH. A simple prognostic index (PI) could be established based on these four pretreatment features. In this way the patients could be separated into three groups with significant different prognosis. The median survival and 95% confidence intervals for the three groups were as follows: 424 days (311–537), 360 days (261–459) and 174 days (105–243). © 1999 Cancer Research Campaig

An embedded longitudinal multi-faceted qualitative evaluation of a complex cluster randomized controlled trial aiming to reduce clinically important errors in medicines management in general practice

<p>Abstract</p> <p>Background</p> <p>There is a need to shed light on the pathways through which complex interventions mediate their effects in order to enable critical reflection on their transferability. We sought to explore and understand key stakeholder accounts of the acceptability, likely impact and strategies for optimizing and rolling-out a successful pharmacist-led information technology-enabled (PINCER) intervention, which substantially reduced the risk of clinically important errors in medicines management in primary care.</p> <p>Methods</p> <p>Data were collected at two geographical locations in central England through a combination of one-to-one longitudinal semi-structured telephone interviews (one at the beginning of the trial and another when the trial was well underway), relevant documents, and focus group discussions following delivery of the PINCER intervention. Participants included PINCER pharmacists, general practice staff, researchers involved in the running of the trial, and primary care trust staff. PINCER pharmacists were interviewed at three different time-points during the delivery of the PINCER intervention. Analysis was thematic with diffusion of innovation theory providing a theoretical framework.</p> <p>Results</p> <p>We conducted 52 semi-structured telephone interviews and six focus group discussions with 30 additional participants. In addition, documentary data were collected from six pharmacist diaries, along with notes from four meetings of the PINCER pharmacists and feedback meetings from 34 practices. Key findings that helped to explain the success of the PINCER intervention included the perceived importance of focusing on prescribing errors to all stakeholders, and the credibility and appropriateness of a pharmacist-led intervention to address these shortcomings. Central to this was the face-to-face contact and relationship building between pharmacists and a range of practice staff, and pharmacists’ explicitly designated role as a change agent. However, important concerns were identified about the likely sustainability of this new model of delivering care, in the absence of an appropriate support network for pharmacists and career development pathways.</p> <p>Conclusions</p> <p>This embedded qualitative inquiry has helped to understand the complex organizational and social environment in which the trial was undertaken and the PINCER intervention was delivered. The longitudinal element has given insight into the dynamic changes and developments over time. Medication errors and ways to address these are high on stakeholders’ agendas. Our results further indicate that pharmacists were, because of their professional standing and skill-set, able to engage with the complex general practice environment and able to identify and manage many clinically important errors in medicines management. The transferability of the PINCER intervention approach, both in relation to other prescribing errors and to other practices, is likely to be high.</p

Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression

Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification. © 1999 Cancer Research Campaig