Within You / Without You: Biotechnology, Ontology, and Ethics

As Implantable Cardioverter Defibrillators (ICDs) have become more common, ethical issues have arisen regarding the deactivation of these devices. Goldstein et al., have shown that both patients and cardiologists consider ICD deactivation to be different from the discontinuation of other life-sustaining treatments. It cannot be argued ethically that ICDs raise new questions about the distinction between withholding and withdrawing treatment, and neither the fact that they are used intermittently, nor the duration of therapy, nor the mere fact that they are located inside the body can be considered unique to these devices and morally decisive. However, frequent allusions to the fact that they are located inside the body might provide a clue about what bothers patients and physicians. As technology progresses, some interventions seem to become a part of the patient as a unified whole person, completely replacing body parts and lost physiological functions rather than merely substituting for impaired structure and function. If a life-sustaining intervention can be considered a “replacement”—a part of the patient as a unified whole person—then it seems that deactivation is better classified as a case of killing rather than a case of forgoing a life-sustaining treatment. ICDs are not a “replacement” therapy in this sense. The deactivation of an ICD is best classified, under the proper conditions, as the forgoing of an extraordinary means of care. As technology becomes more sophisticated, however, and new interventions come to be best classified as “replacements” (a heart transplant would be a good example), “discontinuing” these interventions should be much more morally troubling for those clinicians who oppose euthanasia and assisted suicide

Comparison of different dosing regimens (once weekly vs. twice weekly, and once weekly vs. once every two weeks) with epoetin delta in patients with chronic kidney disease: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Anaemia is a common complication of chronic kidney disease and prevalence increases with declining renal function. Renal anaemia has significant implications for the well-being and quality of life of patients and impacts on morbidity and mortality. Anaemia can be well managed by therapy with erythropoiesis-stimulating agents (ESAs). Previous clinical trials have shown that the only human cell-line-derived ESA, epoetin delta, is well tolerated and effective in maintaining haemoglobin levels in anaemic patients with chronic kidney disease. The half-life of epoetin delta suggests that administration of this agent is feasible once weekly and once every two weeks. We report on the design and rationale of a trial to compare once weekly <it>vs</it>. twice weekly, and once weekly <it>vs</it>. once every two weeks dosing of epoetin delta.</p> <p>Design and methods</p> <p>This is a randomized, open-label, multicentre trial. Patients aged 18 years or above with chronic kidney disease (Stages 3–5) are eligible to enter this trial. Two groups of patients form the trial population, those naïve to ESA therapy and those previously stable on ESA therapy. There are two primary objectives of this trial: 1) to demonstrate non-inferiority between twice weekly and once weekly dosing of epoetin delta in previously naïve patients (assessed by haemoglobin at Week 24); 2) to demonstrate non-inferiority between once weekly and once every two weeks dosing in previously stable patients (assessed by average haemoglobin over Weeks 16–24). Among the secondary analyses will be assessments of haematocrit, number(%) of patients meeting predefined targets for haemoglobin and haematocrit levels, and comparisons of average dose. All patients will receive study medication for 24 weeks and dose will be adjusted according to a predefined algorithm to achieve and maintain haemoglobin ≥ 11 g/dL. All patients completing this trial are eligible to enter a 2-year follow-up study to enable monitoring of emergent adverse events, anti-erythropoietin antibody responses, maintenance of efficacy and changes in diabetic retinopathy status.</p> <p>Discussion</p> <p>To our knowledge, this trial is the first to randomize ESA-naïve patients to different dosing regimens of the same ESA. Data generated will help in guiding the most appropriate dosing frequency for epoetin delta, particularly in those patients new to epoetin delta therapy.</p> <p>Trial registration</p> <p><b>ClinicalTrials.gov: </b>NCT00450333</p

Controversies concerning the diagnosis and treatment of bipolar disorder in children

This commentary grows out of an interdisciplinary workshop focused on controversies surrounding the diagnosis and treatment of bipolar disorder (BP) in children. Although debate about the occurrence and frequency of BP in children is more than 50 years old, it increased in the mid 1990s when researchers adapted the DSM account of bipolar symptoms to diagnose children. We offer a brief history of the debate from the mid 90s through the present, ending with current efforts to distinguish between a small number of children whose behaviors closely fit DSM criteria for BP, and a significantly larger number of children who have been receiving a BP diagnosis but whose behaviors do not closely fit those criteria. We agree with one emerging approach, which gives part or all of that larger number of children a new diagnosis called Severe Mood Dysregulation or Temper Dysregulation Disorder with Dysphoria

Evidence for positive selection in the gene fruitless in Anastrepha fruit flies

<p>Abstract</p> <p>Background</p> <p>Many genes involved in the sex determining cascade have indicated signals of positive selection and rapid evolution across different species. Even though <it>fruitless </it>is an important gene involved mostly in several aspects of male courtship behavior, the few studies so far have explained its high rates of evolution by relaxed selective constraints. This would indicate that a large portion of this gene has evolved neutrally, contrary to what has been observed for other genes in the sex cascade.</p> <p>Results</p> <p>Here we test whether the <it>fruitless </it>gene has evolved neutrally or under positive selection in species of <it>Anastrepha </it>(Tephritidae: Diptera) using two different approaches, a long-term evolutionary analysis and a populational genetic data analysis. The first analysis was performed by using sequences of three species of <it>Anastrepha </it>and sequences from several species of <it>Drosophila </it>using the ratio of nonsynonymous to synonymous rates of evolution in PAML, which revealed that the <it>fru </it>region here studied has evolved by positive selection. Using Bayes Empirical Bayes we estimated that 16 sites located in the connecting region of the <it>fruitless </it>gene were evolving under positive selection. We also investigated for signs of this positive selection using populational data from 50 specimens from three species of <it>Anastrepha </it>from different localities in Brazil. The use of standard tests of selection and a new test that compares patterns of differential survival between synonymous and nonsynonymous in evolutionary time also provide evidence of positive selection across species and of a selective sweep for one of the species investigated.</p> <p>Conclusions</p> <p>Our data indicate that the high diversification of <it>fru </it>connecting region in <it>Anastrepha </it>flies is due at least in part to positive selection, not merely as a consequence of relaxed selective constraint. These conclusions are based not only on the comparison of distantly related taxa that show long-term divergence time, but also on recently diverged lineages and suggest that episodes of adaptive evolution in <it>fru </it>may be related to sexual selection and/or conflict related to its involvement in male courtship behavior.</p

Pseudomonas aeruginosa Eliminates Natural Killer Cells via Phagocytosis-Induced Apoptosis

Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes the relapse of illness in immunocompromised patients, leading to prolonged hospitalization, increased medical expense, and death. In this report, we show that PA invades natural killer (NK) cells and induces phagocytosis-induced cell death (PICD) of lymphocytes. In vivo tumor metastasis was augmented by PA infection, with a significant reduction in NK cell number. Adoptive transfer of NK cells mitigated PA-induced metastasis. Internalization of PA into NK cells was observed by transmission electron microscopy. In addition, PA invaded NK cells via phosphoinositide 3-kinase (PI3K) activation, and the phagocytic event led to caspase 9-dependent apoptosis of NK cells. PA-mediated NK cell apoptosis was dependent on activation of mitogen-activated protein (MAP) kinase and the generation of reactive oxygen species (ROS). These data suggest that the phagocytosis of PA by NK cells is a critical event that affects the relapse of diseases in immunocompromised patients, such as those with cancer, and provides important insights into the interactions between PA and NK cells

Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements

Background: Recent assays for individual-specific genome-wide DNA methylation profiles have enabled epigenome-wide association studies to identify specific CpG sites associated with a phenotype. Computational prediction of CpG site-specific methylation levels is important, but current approaches tackle average methylation within a genomic locus and are often limited to specific genomic regions. Results: We characterize genome-wide DNA methylation patterns, and show that correlation among CpG sites decays rapidly, making predictions solely based on neighboring sites challenging. We built a random forest classifier to predict CpG site methylation levels using as features neighboring CpG site methylation levels and genomic distance, and co-localization with coding regions, CGIs, and regulatory elements from the ENCODE project, among others. Our approach achieves 91% -- 94% prediction accuracy of genome-wide methylation levels at single CpG site precision. The accuracy increases to 98% when restricted to CpG sites within CGIs. Our classifier outperforms state-of-the-art methylation classifiers and identifies features that contribute to prediction accuracy: neighboring CpG site methylation status, CpG island status, co-localized DNase I hypersensitive sites, and specific transcription factor binding sites were found to be most predictive of methylation levels. Conclusions: Our observations of DNA methylation patterns led us to develop a classifier to predict site-specific methylation levels that achieves the best DNA methylation predictive accuracy to date. Furthermore, our method identified genomic features that interact with DNA methylation, elucidating mechanisms involved in DNA methylation modification and regulation, and linking different epigenetic processes

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

Social Relationships and Mortality Risk: A Meta-analytic Review

In a meta-analysis, Julianne Holt-Lunstad and colleagues find that individuals' social relationships have as much influence on mortality risk as other well-established risk factors for mortality, such as smoking