Ethics review: 'Living wills' and intensive care – an overview of the American experience

Withdrawal and limitation of life support in the intensive care unit is common, although how this decision is reached can be varied and arbitrary. Inevitably, the patient is unable to participate in this discussion because their capacity is limited by the nature of the illness and the effects of its treatment. Physicians often discuss these decisions with relatives in an attempt to respect the patient's wishes despite evidence suggesting that the relatives may not correctly reflect the patient's desires. Advance decisions, commonly known as 'living wills', have been proposed as a way of facilitating the maintenance of an individual's autonomy when they become incapacitated. Others have argued that legalising advance decisions is euthanasia by the back door. In October 2007 in England and Wales, advance decisions will become legally binding as part of the 2005 Mental Capacity Act. This has been the case in the USA for many years. The purpose of the present review is to examine the published literature regarding the effect of advance decisions in relation to the provision of adult critical care

The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design

Large entropy production inside black holes: a simple model

Particles dropped into a rotating black hole can collide near the inner horizon with enormous energies. The entropy produced by these collisions can be several times larger than the increase in the horizon entropy due to the addition of the particles. In this paper entropy is produced by releasing large numbers of neutrons near the outer horizon of a rotating black hole such that they collide near the inner horizon at energies similar to those achieved at the Relativistic Heavy Ion Collider. The increase in horizon entropy is approximately 80 per dropped neutron pair, while the entropy produced in the collisions is 160 per neutron pair. The collision entropy is produced inside the horizon, so this excess entropy production does not violate Bousso's bound limiting the entropy that can go through the black hole's horizon. The generalized laws of black hole thermodynamics are obeyed. No individual observer inside the black hole sees a violation of the second law of thermodynamicsComment: 10 page

Echocardiographic assessment and percutaneous closure of multiple atrial septal defects

Atrial septal defect closure is now routinely performed using a percutaneous approach under echocardiographic guidance. Centrally located, secundum defects are ideal for device closure but there is considerable morphological variation in size and location of the defects. A small proportion of atrial septal defects may have multiple fenestrations and these are often considered unsuitable for device closure. We report three cases of multiple atrial septal defects successfully closed with two Amplatzer septal occluders

An Improved Algorithm For Unmixing First‐Order Reversal Curve Diagrams Using Principal Component Analysis

First‐order reversal curve (FORC) diagrams of synthetic binary mixtures with single‐domain, vortex state, and multi‐domain end members (EMs) were analyzed using principal component analysis (FORC‐PCA). Mixing proportions derived from FORC‐PCA are shown to deviate systematically from the known weight percent of EMs, which is caused by the lack of reversible magnetization contributions to the FORC distribution. The error in the mixing proportions can be corrected by applying PCA to the raw FORCs, rather than to the processed FORC diagram, thereby capturing both reversible and irreversible contributions to the signal. Here we develop a new practical implementation of the FORC‐PCA method that enables quantitative unmixing to be performed routinely on suites of FORC diagrams with up to four distinct EMs. The method provides access not only to the processed FORC diagram of each EM, but also to reconstructed FORCs, which enables objective criteria to be defined that aid identification of physically realistic EMs. We illustrate FORC‐PCA with examples of quantitative unmixing of magnetic components that will have widespread applicability in paleomagnetism and environmental magnetism

Bypass or Angioplasty for Severe Limb Ischaemia? A Delphi Consensus Study

AbstractObjectives: to examine the level of agreement among vascular surgeons and interventional radiologists regarding their preference for the surgical or endovascular management of severe limb ischaemia.Design: Delphi consensus study using 596 different hypothetical patient scenarios.Participants: Delphi consensus group for the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.Methods: twenty consultant vascular surgeons and 17 interventional radiologists completed both rounds of the study. The scenarios detailed the anatomical extent of disease, whether the patients had rest pain only or had tissue loss, and whether or not a suitable vein for bypass was available. Panellists were asked to score their treatment preference for either surgery or angioplasty on an eight-point scale. Outliers (top 10% and bottom 10% responses) were removed. If the remaining 80% of responses fell within a 3-point range, this was defined as “agreement”. If they did not, this was considered “disagreement”.Results: there was substantial disagreement in 484 (81%) of scenarios in round 1 and 401 (67%) in round 2. This disagreement was greater among surgeon than radiologists in both round 1 (83 vs 65%) and round 2 (69 vs 42%). Surgeons also demonstrated less convergence between rounds.Conclusions: there is substantial disagreement between and among surgeons and radiologists with regard to the appropriateness of surgery or angioplasty for severe limb ischaemia. This lack of consensus stems from the absence of an evidence base and means that the same patient may receive entirely different treatment depending on which hospital and consultant they attend. Not only may this unexplained variation be clinically unsatisfactory, it has major implications for the planning and use of health service resources

Metabolic flexibility as a major predictor of spatial distribution in microbial communities

A better understand the ecology of microbes and their role in the global ecosystem could be achieved if traditional ecological theories can be applied to microbes. In ecology organisms are defined as specialists or generalists according to the breadth of their niche. Spatial distribution is often used as a proxy measure of niche breadth; generalists have broad niches and a wide spatial distribution and specialists a narrow niche and spatial distribution. Previous studies suggest that microbial distribution patterns are contrary to this idea; a microbial generalist genus (Desulfobulbus) has a limited spatial distribution while a specialist genus (Methanosaeta) has a cosmopolitan distribution. Therefore, we hypothesise that this counter-intuitive distribution within generalist and specialist microbial genera is a common microbial characteristic. Using molecular fingerprinting the distribution of four microbial genera, two generalists, Desulfobulbus and the methanogenic archaea Methanosarcina, and two specialists, Methanosaeta and the sulfate-reducing bacteria Desulfobacter were analysed in sediment samples from along a UK estuary. Detected genotypes of both generalist genera showed a distinct spatial distribution, significantly correlated with geographic distance between sites. Genotypes of both specialist genera showed no significant differential spatial distribution. These data support the hypothesis that the spatial distribution of specialist and generalist microbes does not match that seen with specialist and generalist large organisms. It may be that generalist microbes, while having a wider potential niche, are constrained, possibly by intrageneric competition, to exploit only a small part of that potential niche while specialists, with far fewer constraints to their niche, are more capable of filling their potential niche more effectively, perhaps by avoiding intrageneric competition. We suggest that these counter-intuitive distribution patterns may be a common feature of microbes in general and represent a distinct microbial principle in ecology, which is a real challenge if we are to develop a truly inclusive ecology

Use of a dual reporter plasmid to demonstrate bactofection with an attenuated aroa- derivative of Pasteurella multocida b:2

A reporter plasmid pSRG has been developed which expresses red fluorescent protein (RFP) from a constitutive prokaryotic promoter within Pasteurella multocida B:2 and green fluorescent protein (GFP) from a constitutive eukaryotic promoter within mammalian cells. This construct has been used to determine the location and viability of the bacteria when moving from the extracellular environment into the intracellular compartment of mammalian cells. Invasion assays with embryonic bovine lung (EBL) cells and an attenuated AroA- derivative of Pasteurella multocida B:2 (strain JRMT12), harbouring the plasmid pSRG, showed that RFP-expressing bacteria could be detected intracellularly at 3 h post-invasion. At this stage, some EBL cells harbouring RFP-expressing bacteria were observed to express GFP simultaneously, indicating release of the plasmid into the intracellular environment. At 5 h post-invasion, more EBL cells were expressing GFP, while still harbouring RFP-expressing bacteria. Concurrently, some EBL cells were shown to express only GFP, indicating loss of viable bacteria within these cells. These experiments proved the functionality of the pSRG dual reporter system and the potential of P. multocida B:2 JRMT12 for bactofection and delivery of a DNA vaccine