The Last Chapter in the Story: A Place for Aristotle\u27s Eudaemonia in the Lives of the Terminally Ill

The \u27deficiency model\u27 of aging has often been criticized for its lack of attention to the individual patient\u27s narrative understanding of his own life. However, such narrative conceptions tend to focus on a generic adult person, situated in specific on-going projects and relationships, moving toward a more or less clear conception of the future. What interest me, on the other hand, are those individuals who have become aware of their own death as imminent, and who therefore strive to compose the \u27last chapter\u27 of their life story. Imminence is not to be taken in chronological or clinical terms, but as revealing an attitude to oneself and one\u27s own life. The composition of the last chapter requires recollecting and reappraising the events of one\u27s life in an effort to make sense of the life as a whole. I propose revising the ancient Greek word eudaemonia to capture this sense of achieving an integrated meaning to one\u27s life

Synthesis, characterization and biological studies of S- benzyl-b-N-(benzoyl)dithiocarbazate and its metal complexes

S-Benzyl-b-N-(benzoyl) dithiocarbazate (SBNBODTC) a new disubstituted dithio-carbazate oxygen–sulfur (OS) donor ligand derived from reaction of S-benzyl dithiocarbazate with benzoyl chloride, formed bischelated complexes of general formula [M(OS)2] where M is Cu2+, Ni2+, Cd2+, Co2+ or Pb2+ and OS is a uninegative bidentate ligand. The ligand and its metal complexes have been characterized by a variety of physico-chemical techniques. S-benzyl-b-N-(benzoyl) dithiocarbazate crystallized with Z0 = 2 in its thione form in cis–cis conformation, with the N–N bond adopting a cis geometry with respect to C@S, while the S-benzyl group adopts a cis geometry with respect to the thione sulfur atom across the C–S bond.SBNBODTC, Cu(OS)2, Ni(OS)2 and Pb(OS)2 display marked cytotoxicity against HL-60 (human myeloid leukemia)while Cd(OS)2 and Co(OS)2 are moderately cytotoxic. The compounds showed moderate but selective activity towards targeted pathogens

The influence of perfusion solution on renal graft viability assessment

BACKGROUND: Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall’s hypertonic citrate (HOC) and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion. METHODS: Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation. RESULTS: When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used. CONCLUSIONS: We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard

Solar wind dynamic pressure and electric field as the main factors controlling Saturn's aurorae

The interaction of the solar wind with Earth's magnetosphere gives rise to the bright polar aurorae and to geomagnetic storms(1), but the relation between the solar wind and the dynamics of the outer planets' magnetospheres is poorly understood. Jupiter's magnetospheric dynamics and aurorae are dominated by processes internal to the jovian system(2), whereas Saturn's magnetosphere has generally been considered to have both internal and solar-wind-driven processes. This hypothesis, however, is tentative because of limited simultaneous solar wind and magnetospheric measurements. Here we report solar wind measurements, immediately upstream of Saturn, over a one-month period. When combined with simultaneous ultraviolet imaging(3) we find that, unlike Jupiter, Saturn's aurorae respond strongly to solar wind conditions. But in contrast to Earth, the main controlling factor appears to be solar wind dynamic pressure and electric field, with the orientation of the interplanetary magnetic field playing a much more limited role. Saturn's magnetosphere is, therefore, strongly driven by the solar wind, but the solar wind conditions that drive it differ from those that drive the Earth's magnetosphere.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62975/1/nature03333.pd

The Involvement of IL-17A in the Murine Response to Sub-Lethal Inhalational Infection with Francisella tularensis

Background: Francisella tularensis is an intercellular bacterium often causing fatal disease when inhaled. Previous reports have underlined the role of cell-mediated immunity and IFNc in the host response to Francisella tularensis infection. Methodology/Principal Findings: Here we provide evidence for the involvement of IL-17A in host defense to inhalational tularemia, using a mouse model of intranasal infection with the Live Vaccine Strain (LVS). We demonstrate the kinetics of IL-17A production in lavage fluids of infected lungs and identify the IL-17A-producing lymphocytes as pulmonary cd and Th17 cells. The peak of IL-17A production appears early during sub-lethal infection, it precedes the peak of immune activation and the nadir of the disease, and then subsides subsequently. Exogenous airway administration of IL-17A or of IL-23 had a limited yet consistent effect of delaying the onset of death from a lethal dose of LVS, implying that IL-17A may be involved in restraining the infection. The protective role for IL-17A was directly demonstrated by in vivo neutralization of IL-17A. Administration of anti IL-17A antibodies concomitantly to a sub-lethal airway infection with 0.16LD50 resulted in a fatal disease. Conclusion: In summary, these data characterize the involvement and underline the protective key role of the IL-17A axis in the lungs from inhalational tularemia

Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD

Application of the Phenomenex EZ:faast™ amino acid analysis kit for rapid gas-chromatographic determination of concentrations of plasma tryptophan and its brain uptake competitors

The Phenomenex EZ:faast™ amino acid analysis kit is available for gas (GC) or liquid (LC) chromatographic analysis of amino acids (AA) using mass spectrometry (MS) and other GC detectors. We used it for rapid GC determination of plasma tryptophan, its brain uptake competitors (Val, Leu, Ile, Phe and Tyr) and many other amino acids. Based on solid-phase extraction, this fast method enables one person to process two plasma samples in 8–10 min and six samples in ∼15 min up to GC injection and a 7-min GC run per plasma sample. Using a Perkin-Elmer Clarus 500 GC, a Total Chrome software, a flame-ionisation detector (FID) and norvaline as internal standard, we used this method to analyse ∼1,000 plasma samples from normal subjects undergoing acute tryptophan depletion and loading tests. The limit of detection for most amino acids is 1 nmol/ml (1 μM) and in many cases less. With manual injection, coefficients of variation for the above six amino acids were 1.5–6.2% (intra-assay) and 3.8–9.7% (inter-assay). This simple, rapid and elegant method will be valuable to the amino acid analyst and researcher, as it can save much manpower time and meet urgent emergency requests and the demands of a high-throughput laboratory

Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions

Background: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. Methods: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. Results: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). Conclusions: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL

An interplanetary shock traced by planetary auroral storms from the Sun to Saturn

A relationship between solar activity and aurorae on Earth was postulated(1,2) long before space probes directly detected plasma propagating outwards from the Sun(3). Violent solar eruption events trigger interplanetary shocks(4) that compress Earth's magnetosphere, leading to increased energetic particle precipitation into the ionosphere and subsequent auroral storms(5,6). Monitoring shocks is now part of the 'Space Weather' forecast programme aimed at predicting solar-activity-related environmental hazards. The outer planets also experience aurorae, and here we report the discovery of a strong transient polar emission on Saturn, tentatively attributed to the passage of an interplanetary shock - and ultimately to a series of solar coronal mass ejection (CME) events. We could trace the shock-triggered events from Earth, where auroral storms were recorded, to Jupiter, where the auroral activity was strongly enhanced, and to Saturn, where it activated the unusual polar source. This establishes that shocks retain their properties and their ability to trigger planetary auroral activity thoughout the Solar System. Our results also reveal differences in the planetary auroral responses on the passing shock, especially in their latitudinal and local time dependences.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62930/1/nature02986.pd