Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity

Preceding rule induction with instance reduction methods

A new prepruning technique for rule induction is presented which applies instance reduction before rule induction. An empirical evaluation records the predictive accuracy and size of rule-sets generated from 24 datasets from the UCI Machine Learning Repository. Three instance reduction algorithms (Edited Nearest Neighbour, AllKnn and DROP5) are compared. Each one is used to reduce the size of the training set, prior to inducing a set of rules using Clark and Boswell's modification of CN2. A hybrid instance reduction algorithm (comprised of AllKnn and DROP5) is also tested. For most of the datasets, pruning the training set using ENN, AllKnn or the hybrid significantly reduces the number of rules generated by CN2, without adversely affecting the predictive performance. The hybrid achieves the highest average predictive accuracy

A new metric for quantifying the relative impact of risk factors on loss of working life illustrated in a population of working dogs

In a resource-limited world, organisations attempting to reduce the impact of health or behaviour issues need to choose carefully how to allocate resources for the highest overall impact. However, such choices may not always be obvious. Which has the biggest impact? A large change to a small number of individuals, or a small change to a large number of individuals? The challenge is identifying the issues that have the greatest impact on the population so potential interventions can be prioritised. We addressed this by developing a score to quantify the impact of health conditions and behaviour problems in a population of working guide dogs using data from Guide Dogs, UK. The cumulative incidence of different issues was combined with information about their impact, in terms of reduction in working life, to create a work score. The work score was created at population-level to illustrate issues with the greatest impact on the population and to understand contributions of breeds or crossbreeds to the workforce. An individual work deficit score was also created and means of this score used to illustrate the impact on working life within a subgroup of the population such as a breed, or crossbreed generation. The work deficit scores showed that those removed for behavioural issues had a greater impact on the overall workforce than those removed for health reasons. Additionally trends over time illustrated the positive influence of interventions Guide Dogs have made to improve their workforce. Information highlighted by these scores is pertinent to the effort of Guide Dogs to ensure partnerships are lasting. Recognising that the scores developed here could be transferable to a wide variety of contexts and species, most notably human work force decisions; we discuss possible uses and adaptations such as reduction in lifespan, quality of life and yield in production animals

Reduced CSF turnover and decreased ventricular Aβ42 levels are related

International audienceBACKGROUND: The appearance of Aβ42 peptide deposits is admitted to be a key event in the pathogenesis of Alzheimer's disease, although amyloid deposits also occur in aged non-demented subjects. Aβ42 is a degradation product of the amyloid protein precursor (APP). It can be catabolized by several enzymes, reabsorbed by capillaries or cleared into cerebrospinal fluid (CSF). The possible involvement of a decrease in CSF turnover in A4β2 deposit formation is up to now poorly known. We therefore investigated a possible relationship between a reduced CSF turnover and the CSF levels of the A4β2 peptide.To this aim, CSF of 31 patients with decreased CSF turnover were studied. These patients presented chronic hydrocephalus communicating or obstructive, which required surgery (ventriculostomy or ventriculo-peritoneal shunt). Nine subjects had idiopathic normal pressure hydrocephalus (iNPH), and the other 22 chronic hydrocephalus from other origins (oCH).The Aβ42 peptide concentration was measured by an ELISA test in 31 ventricular CSF samples and in 5 lumbar CSF samples from patients with communicating hydrocephalus. RESULTS: The 5 patients with lumbar CSF analysis had similar levels of lumbar and ventricular Aβ42. A significant reduction in Aβ42 ventricular levels was observed in 24 / 31 patients with hydrocephalus. The values were lower than 300 pg/ml in 5 out of 9 subjects with iNPH, and in 15 out of 22 subjects with oCH. CONCLUSION: The decrease of CSF Aβ42 seems to occur independently of the surgical hydrocephalus aetiology. This suggests that a CSF reduced turnover may play an important role in the decrease of CSF Aβ42 concentration

Pulsatility in CSF dynamics : pathophysiology of idiopathic normal pressure hydrocephalus

Background: It is suggested that disturbed CSF dynamics are involved in the pathophysiology of idiopathic normal pressure hydrocephalus (INPH). The pulsatility curve describes the relationship between intracranial pressure (ICP) and the amplitude of cardiac related ICP pulsations. The position of baseline ICP on the curve provides information about the physiological state of the CSF dynamic system. The objective of the study was to investigate if shunt surgery modifies the pulsatility curve and the baseline position on the curve, and how this relates to gait improvement in INPH. Methods: 51 INPH patients were investigated with lumbar CSF dynamic investigations preoperatively and 5 months after shunt surgery. During the investigation, ICP was measured at baseline, and then a CSF sample was removed, resulting in pressure reduction. After this, ICP was regulated with an automated infusion protocol, with a maximum increase of 24 mm Hg above baseline. The pulsatility curve was thus determined in a wide range of ICP values. Gait improvement was defined as a gait speed increase &gt;= 0.1 m/s. Results: The pulsatility curve was unaltered by shunting. Baseline ICP and amplitude were reduced (-3.0 +/- 2.9 mm Hg; -1.1 +/- 1.5 mm Hg; p &lt; 0.05, n = 51). Amplitude reduction was larger for gait improvers (-1.2 +/- 1.6 mm Hg, n = 42) than non-improvers (-0.2 +/- 0.5 mm Hg, n = 9) (p &lt; 0.05) although mean ICP reduction did not differ. Conclusions: The pulsatility curve was not modified by shunt surgery, while the baseline position was shifted along the curve. Observed differences between gait improvers and non-improvers support cardiac related ICP pulsations as a component of INPH pathophysiology.This project was supported by the Swedish Research Council, VINNOVA, and the Swedish Foundation for Strategic Research through their common initiative: 'Biomedical engineering for improved health' grant No VR3011-2006-7551; and by the European Union through ERDF: Objective 2, Northern Sweden grant No 158715-CMTF.</p

Simulated winter browsing may lead to induced susceptibility of willows to beavers in spring

Browsing may lead to an induced resistance or susceptibility of the plant to the herbivore. We tested the effect of winter browsing by Eurasian beavers (Castor fiber L., 1758) on food quality of holme willows (Salix dasyclados Wimm.) in and after the following growth season. Shrubs were pruned in February, and new shoots from these (cut) shrubs were compared with those of untreated (uncut) ones in May and November. The shoots were analysed for dry matter, nitrogen, acid detergent fibre, and total phenolics. In May, the leaves from the cut treatment had a better food quality (more water, more nitrogen, and less phenolics) than those from the uncut one. There was in part also a systemic response, with lower total phenolics in both the cut and untreated parts of pruned shrubs (uncut–cut) than in the uncut shrubs. In November, we did not find significant differences in biochemistry of bark among cut, uncut, or uncut–cut treatments. These results are in accordance with a cafeteria experiment in the field: in May the beavers preferred shoots from the cut treatment, but in November they showed no preference. The results suggest that willows invest in compensatory growth rather than a defence response early in the regrowing phase.