© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the (...) frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

Claims about ‘the meaning of life’ have tended to be made and discussed in conjunction with bold metaphysical and theological affirmations. For life to have meaning, there must be a comprehensive divine plan to give it meaning, or there must be an intelligible cosmic process with a ‘telos’ that a man needs to know if his life is to be meaningfully orientated. Or, it is thought to be a condition of the meaningfulness of life, that values should be ultimately ‘conserved’ (...) in some way, that no evil should be unredeemable and irrational. And it may be claimed that if death were to end our experience, meaninglessness would triumph. (shrink)

Uteroferrin, a purple‐colored, iron‐containing acid phosphatase, with many of the properties of a lysosomal hydrolase, transports iron from the mother to the conceptus in pregnant pigs. Uteroferrin, however, is but one member of what may be a broad class of iron‐containing phosphatases with unusual spectral properties which result from a novel type of di‐iron active site. The biological function of uteroferrin is unknown. We argue here that the in vivo function of uteroferrin, despite its undoubted ability to act as a (...) potent acid phosphatase, is that of a transplacental iron transporter. (shrink)

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of this for autoimmunity. BioEssays 22:627–636, (...) 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Patient safety has only recently been subjected to wide-spread systematic study. Healthcare differs from other high risk industries in being more diverse and multi-contextual, and less certain and regulated. Also many patient safety problems are low-frequency events associated with many, varied contributing factors. The subject of this paper is the epistemology of patient safety (the science of the method of finding out about patient safety). Patient safety research is considered here on the background of a risk management framework which requires (...) researchers to: • Understand the context - as a subset of healthcare quality, services and systems research, with technical and human behavioural (cultural) components and a range of external and internal organisational influences, a wide range of research disciplines is necessary • Identify the risks - identify the things that go wrong and the frequency and nature of different types of incidents from sources such as medical record review, observational studies, audit, incident and medico-legal reports • Analyse the risks - deconstruct the things that go wrong, identifying contributing factors and trying to detect trends and patterns in contributing factors, detection, mitigation factors, ameliorating factors and actions taken to reduce risk • Evaluate the risks - decide on priorities, identifying preventive and corrective strategies and judging the risk- and cost-benefit of potential corrective strategies such as standardisation or simplification of a process or device • Manage the risk - evaluate and scope preventive and/or corrective strategies and then implement these, or place the problem on a risk register pending solution, or accept that what is needed is unaffordable • Communicate and consult - use interactive sessions, audit, on-going feedback, reminders and patient mediated prompts • Monitor and review the state of the problem - get baseline trends and patterns so that changes can be tracked and properly attributed to an intervention A hierarchy of levels of evidence has been proposed for clinical research and we argue that insufficient weighting has been given to lower ranked levels of research and to qualitative research, although critical interpretive synthesis is now gaining acceptance in mainstream thinking (e.g. by the Cochrane Collaboration). Fundamental challenges remain including how to grasp the elusive concept of patient safety, how to quantify, characterise and cost the problems, how to judge the extent to which harm can be attributed to errors, violations or system failures, how to identify contributing factors and the extent to which they can be implicated, how to judge whether incidents or their precursors are preventable, how to generate strong evidence to make healthcare safer and how to translate research into practice. Future directions include addressing the mundane as well as rare, dramatic events, and developing further research in non-hospital settings and in developing countries. In summary, a mixture of qualitative and quantitative methods, using information from all available data sources and combining retrospective, real time and prospective study designs, is necessary to address some of the more difficult patient safety problems. (shrink)